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Acrylamide, a water-soluble α,β-unsaturated amide, is a contaminant in baked and fried starchy foods, including french fries, potato chips, and bread, as a result of Maillard reactions involving asparagine and reducing sugars. Additional sources of acrylamide exposure include cigarettes, laboratory procedures involving polyacrylamide gels, and various occupations (e.g, monomer production and polymerization processes). Acrylamide is carcinogenic in experimental animals. To obtain data for developing quantitative risk assessments for dietary exposures to acrylamide, the Food and Drug Administration nominated acrylamide for an in-depth toxicological evaluation by the National Toxicology Program. As part of this evaluation, male and female B6C3F1/Nctr (C57BL/6N x C3H/HeN MTV-) mice and male and female F344/N Nctr rats were exposed to acrylamide (at least 99.4% pure) in drinking water for 2 years. 2-WEEK STUDY IN RATS: Groups of four male and four female F344/N rats were administered 0, 0.14, 0.35, 0.70, 1.41, 3.52, or 7.03 mM acrylamide in the drinking water (0, 10, 25, 50, 100, 250, or 500 ppm acrylamide) or 0.0, 7.4, 18.5, 37, 74, 185, or 370 mg acrylamide per kg diet for 14 days. One male rat administered 7.03 mM acrylamide in the drinking water died on day 14. Male and female rats receiving 7.03 mM acrylamide weighed 56% and 64% of controls, respectively. Male and female rats fed 370 mg acrylamide per kg diet weighed 74% and 83% of controls, respectively. Female rats receiving 3.52 mM acrylamide in drinking water and male rats fed 185 mg acrylamide per kg diet weighed 85% and 89% of controls, respectively. Rats receiving 7.03 mM acrylamide in drinking water or 370 mg acrylamide per kg diet exhibited hind-leg paralysis on day 14. Mild to moderate dilatation of the urinary bladder was observed in all rats given 370 mg acrylamide per kg diet, and in three of four male rats and all four female rats given 7.03 mM acrylamide in drinking water, and in one of four male rats given 3.52 mM acrylamide in drinking water. Mild to moderate degeneration of the germinal epithelium in the seminiferous tubules of the testes was noted microscopically in all male rats given 7.03 mM acrylamide in drinking water and in two of four male rats fed 370 mg acrylamide per kg diet. 2-WEEK STUDY IN MICE: Groups of four male and four female B6C3F1 mice were administered 0, 0.14, 0.35, 0.70, 1.41, 3.52, or 7.03 mM acrylamide in the drinking water (0, 10, 25, 50, 100, 250, or 500 ppm acrylamide) or 0.0, 7.4, 18.5, 37, 74, 185, or 370 mg acrylamide per kg diet for 14 days. None of the mice administered 7.03 mM acrylamide in the drinking water survived the 14-day study. Mice administered 7.03 mM acrylamide in the drinking water showed marked decreases in body weight (greater than 25% compared to control mice) after seven days of treatment, and two of the mice displayed hind leg paralysis. No significant adverse effects were observed in mice administered 3.52 mM acrylamide in the drinking water for 14 days. Female B6C3F1 mice given 370 mg acrylamide per kg diet for 14 days showed a modest decrease (11%) in body weight. No other significant adverse effects were observed in mice administered any dose of acrylamide in the diet. 3-MONTH STUDY IN RATS: Groups of eight male and eight female F344/N rats were administered 0.0, 0.14, 0.35, 0.70, 1.41, or 3.52 mM acrylamide in the drinking water (0, 10, 25, 50, 100, or 250 ppm acrylamide) or 0.0, 7.4, 18.5, 37, 74, or 185 mg acrylamide per kg diet for 13 weeks. After 13 weeks, male and female rats administered 3.52 mM acrylamide weighed 73% and 71% of the control rats, respectively. Male and female rats fed 185 mg acrylamide per kg diet for 13 weeks weighed 86% and 82% of the control rats, respectively. Hind-leg paralysis was observed in all rats administered 3.52 mM acrylamide in the drinking water or 185 mg acrylamide per kg diet. Four of eight female rats administered 1.41 mM acrylamide also displayed hind-leg paralysis. Radiculoneuropathy (a degenerative lesion) involving the sciatic nerve and lumbar spinal cord was observed in all male and female rats administered 3.52 mM acrylamide or 185 mg acrylamide per kg diet. A low incidence of radiculoneuropathy was also noted in female rats fed 74 mg acrylamide per kg diet. The neuronal degenerative changes were accompanied, at times, by atrophy in skeletal muscle of the hind-limb and luminal dilation of the urinary bladder. All rats treated with 3.52 mM acrylamide displayed increased hemosiderin pigment in their spleens and hyperplasia of red blood cell precursors in their bone marrow. Two of eight male rats fed 185 mg acrylamide per kg diet also had increased hemosiderin pigment in their spleens. Degeneration of the germ cells in the testes was observed in all male rats given 1.41 or 3.52 mM acrylamide, or 185 mg acrylamide per kg diet. A lower incidence of this lesion was also detected in all other doses of acrylamide in the diet. 3-MONTH STUDY IN MICE: Groups of eight male and eight female B6C3F1 mice were administered 0, 0.14, 0.35, 0.70, 1.41, or 3.52 mM acrylamide in the drinking water (0, 10, 25, 50, 100, or 250 ppm acrylamide) or 0.0, 18.5, 37, 74, 185, or 370 mg acrylamide per kg diet. After 13 weeks, the male and female mice given 3.52 mM acrylamide weighed 86% and 94% of their respective control mice; male mice administered 1.41 mM acrylamide weighed 91% of the control male mice; and male and female mice fed 370 mg acrylamide per kg diet weighed 87% and 81% of their respective control groups. Hind-limb paralysis was observed in all mice administered 3.52 mM acrylamide or 370 mg acrylamide per kg diet. Radiculoneuropathy involving the sciatic nerve, lumbar spinal cord, or both was observed in all male and female mice administered 3.52 mM acrylamide. Radiculoneuropathy, involving primarily the sciatic nerve, was also noted in one of eight female mice fed 185 mg acrylamide per kg diet and in mice fed 370 mg acrylamide per kg diet. The neuronal degenerative changes were accompanied, at times, by atrophy in skeletal muscle of the hind-limb and luminal dilation of the urinary bladder. Degeneration of the germ cells in the testes was observed in six of eight male mice given 3.52 mM acrylamide and seven of seven mice fed 370 mg acrylamide per kg diet. 2 YEAR STUDY IN RATS: Groups of 48 male and 48 female F344/N rats were administered acrylamide in the drinking water ad libitum for 2 years. Concentrations of 0.0875, 0.175, 0.35, and 0.70 mM acrylamide (6.25, 12.5, 25, and 50 ppm acrylamide) resulted in an average daily consumption of approximately 0.33, 0.66, 1.32, and 2.71 mg acrylamide per kg body weight in male F344/N rats and 0.44, 0.88, 1.84, and 4.02 mg acrylamide per kg body weight in female F344/N rats. Acrylamide had no effect upon the survival of male F344/N rats. Female F344/N rats administered 0.175, 0.35, or 0.70 mM acrylamide had decreased survival compared to control female F344/N rats. Acrylamide caused significant dose-related decreasing trends in body weight in F344/N rats. At the end of the 2 year period, male and female F344/N rats administered 0.70 mM acrylamide weighed 86% and 85% of their respective control groups. Feed consumption was generally not affected by acrylamide; water consumption in female F344/N rats was increased at later time points. In male F344/N rats, the incidence of epididymis malignant mesothelioma, combined epididymis or testicular tunica malignant mesothelioma, heart malignant incidences of schwannoma, pancreatic islets adenoma, thyroid gland follicular cell carcinoma, and combined thyroid gland follicular cell adenoma or carcinoma was increased significantly in the 0.70 mM acrylamide group. In female F344/N rats, the incidence of clitoral gland carcinoma was increased significantly in the 0.0875, 0.175, and 0.70 mM acrylamide groups. The incidence of mammary gland fibroadenoma was increased significantly at 0.175, 0.35, and 0.70 mM acrylamide. Significant increases in neoplasm incidences were also observed in oral mucosa squamous cell papilloma, combined oral mucosa or tongue squamous cell papilloma or carcinoma, combined skin fibroma, fibrosarcoma, or sarcoma, and combined thyroid gland follicular cell adenoma or carcinoma at 0.70 mM acrylamide. 2-YEAR STUDY IN MICE: Groups of 48 male and 48 female B6C3F1 mice were administered acrylamide in the drinking water ad libitum for 2 years. Concentrations of 0.0875, 0.175, 0.35, and 0.70 mM acrylamide (6.25, 12.5, 25, and 50 ppm acrylamide) resulted in average daily consumption of approximately 1.04, 2.20, 4.11, and 8.93 mg acrylamide per kg body weight in male B6C3F1 mice and 1.10, 2.23, 4.65, and 9.96 mg acrylamide per kg body weight in female B6C3F1 mice. Acrylamide caused dose-related decreasing trends in survival in B6C3F1 mice, with the survival being significantly decreased in male B6C3F1 mice administered 0.70 mM acrylamide and female B6C3F1 mice given 0.35 and 0.70 mM acrylamide. Acrylamide caused only sporadic changes in body weight in B6C3F1 mice, with the magnitude of the change never exceeding 6% of the respective control body weight. Food and water consumption was generally not affected by acrylamide, except for an increased consumption by female B6C3F1 mice in the 0.70 mM acrylamide group toward the end of the study. In male B6C3F1 mice, the incidence of harderian gland adenoma and combined harderian gland adenoma or adenocarcinoma was increased significantly in all acrylamide dose groups. The incidence of lung alveolar/bronchiolar adenoma and combined lung alveolar/bronchiolar adenoma or carcinoma was increased significantly at 0.175 and 0.70 mM acrylamide, and the incidence of stomach (forestomach) squamous cell papilloma and combined stomach (forestomach) squamous cell papilloma or carcinoma was increased significantly at 0.35 and 0.70 mM acrylamide. (ABSTRACT TRUNCATED)

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The objective of this review is to synthesise the best available evidence on the effectiveness of web-based programs on the reduction of childhood obesity in school age children. Childhood obesity is one of the most serious public health challenges of the 21st century. The problem is global and is steadily affecting many low- and middle-income countries, particularly in urban settings.[1] The prevalence has increased at an alarming rate globally.[2] The International Association for the Study of Obesity; estimates that up to 200 million school aged children are either overweight or obese, of those 40-50 million are classified as obese. Obesity has negative health impact in childhood, as well as in the long term.Overweight and obesity are defined as abnormal or excessive fat accumulation that may impair health. Body mass index (BMI) is a simple index of weight-for-height that is commonly used to classify overweight and obesity. It is defined as a person's weight in kilograms divided by the square of his/her height in meters (kg/m). The World Health Organization defines overweight as BMI greater than or equal to 25 and BMI greater than or equal to 30 as obesity. Children two years of age or older with a BMI between the 85 and 94 percentile on age-growth charts are considered overweight; children with a BMI greater than the 95 percentile are considered obese. BMI provides the most useful population-level measure of overweight and obesity as it is the same for both sexes and for all ages worldwide. Measures of central obesity such as the waist:hip ratio and waist circumference can provide more robust indices of overall obesity-related health risk than BMI alone. A BMI z-score is a quantitative measure of the deviation of a specific BMI percentile from the mean of that population. A positive z-score indicates a child is heavier than the mean and a negative z-score indicates a child is lighter than the mean. Thus, a z-score compares the BMI of a given child to the BMI distribution for a population of children of the same age and sex.The incidence of obesity has more than doubled since 1980. Overweight and obesity now ranks as the fifth leading global risk for mortality. Sixty-five percent of the world's population lives in countries where childhood overweight and obesity kills more people than being underweight. In addition, 44% of the diabetes burden, 23% of the ischemic heart disease burden, and between 7% and 41% of certain cancer burdens are attributable to overweight and obesity.Childhood obesity continues to be a significant health problem in the United States. There has been a rapid rise in obesity among the school-age population despite efforts made by Healthy People 2010 in promoting weight management and physical activity. These on-going efforts have been extended to be part of the goals for Healthy People 2020. The United States Centers for Disease Control and Prevention calculated that approximately 17% children between the ages of two to nineteen years of age were at or above the 97 percentile for being obese. These figures are more than three times the anticipated 5% set in the Healthy People 2010 report.Overweight and obese children are likely to stay obese into adulthood and are more likely to develop non-communicable diseases like diabetes and cardiovascular diseases at a younger age. In addition to a higher risk of obesity and non-communicable diseases later in life, affected children experience adverse outcomes such as breathing difficulties, increased risk of fractures, hypertension, and early markers of cardiovascular disease, different forms of cancers, insulin resistance, and psychological effects. Childhood obesity is associated with a higher chance of obesity, premature death, and disability in adulthood. If a child is overweight before eight years of age, obesity in adulthood is likely to be more severe.Child and adolescent obesity is also associated with increased risk of emotional problems. Teens with weight problems tend to have much lower self-esteem and are less popular with their peers. Depression, anxiety, and obsessive compulsive disorder can also occur as a result of childhood obesity.In addition to the diseases associated with obesity, the economic consequences of obesity are enormous for families, health care systems, and the global economy. Direct medical costs include preventative, diagnostic, and treatment services related to overweight and associated co-morbidities. European nations spend 2-8% of their health care budgets on obesity, equating to 0.6% of their gross domestic product. In the United States, estimates based on 2008 data indicated that overweight and obesity account for $147 billion in total medical expenditure. This shows an increase from the $117 billion spent in the year 2000.While indirect costs of overweight and obesity on society can be significantly higher, they are often overlooked. These costs stem from childhood obesity continuing on to obesity in adulthood, which can then results in income lost from decreased productivity, reduced opportunities and restricted activity, illness, absenteeism, and premature death. In addition, there are high costs associated with the numerous infrastructure changes that societies must make to cope with obese people such as reinforced beds, operating tables and wheel chairs; enlarged turnstiles and seats in in public gathering spaces; and modifications to transportation safety standards.Obesity is reaching pandemic proportions across much of the world, and its consequences are set to impose unparalleled health, financial and social burdens on global society unless effective actions are taken to reverse the trend. Reducing the incidence of obesity in childhood can help children grow into adults with normal body weights and the tools necessary to sustain a health weight.Haerens, et al. explains the importance of school-based programs in dealing with the serious problem of childhood obesity and overweight. The school setting is known as having a powerful influence on student's eating and physical activities. Programs that may have a more positive impact are those that help increase physical activity and promote healthy foods in youth. Previous studies looking at the implementation of diet and exercise programs in schools were effective in changing food habits and increasing physical activity; however, few of these studies showed a reduction in body weight. The Planet Health study, conducted over a period of two years, focused on healthy life style and showed a reduction in obesity in girls but not in boys. The M-span study, a two-year study involving proper diet, exercise, and parental support showed a reduction of BMI only in boys. Haerens, et al. further explains that the above mentioned studies needed to be done in a more personalised manner in order to achieve more positive result; however, they are limited by the time consumption and financial demands necessary to carry out the proposed intervention.Haerens, et al. conducted a two year study of the effect of a program including physical activity, healthy eating, and parental support with a computer-tailored component on BMI and BMI z-score in boys and girls. This intervention resulted in significant reduction in BMI in girls only. Carlson, et al. conducted a 12-month web-based weight loss intervention program which included physical activity and dietary behaviour. The program was found to be a potential low cost method to positively impact public health and health behaviours. Furthermore, 55% of the participants in the intervention group compared with 35% in the control group made an improvement in moderate-to-vigorous physical activity and diet. Doyle, et al. conducted an randomised controlled trial evaluating the effects of an Internet delivered program targeting weight loss on 80 overweight ethnically diverse 12-17 year olds. BMI z-scores were reduced in the intervention group compared with the usual care group post intervention and the intervention group maintained their reduction in BMI z-score at the four month follow up; however, statistical significance was not achieved at the four month follow up due to improvements in weight loss in the usual care group over time.The United States Department of Health and Human Services report of 2009 indicates that school aged children spend an average of 7 hours and 11 minutes per day watching television, using a computer, and playing video games. Using these technology devices as educational tools could have significant impact by increasing knowledge about healthy choices.Web-based technology has become part of our children's life in the last decade providing the foundation to a large number of daily activities. The use of web-based technology may be one method to provide a more personalised intervention to reduce obesity in school-aged children.The search for previously conducted systematic reviews on the effectiveness of web based programs on obesity in children identified a systematic review conducted by An, et al., which included studies published between 1995 and April 2009. A critical appraisal of this systematic review determined it to be of reduced quality due to lack of transparency in reporting the details of the search strategy, inclusion and exclusion criteria, and assessment of the primary studies' methodological quality. The proposed systematic review will expand on the prior systematic review using the rigorous search strategy and assessment for methodological quality outlined below to identify the best available research to determine the effectiveness of web-based programs on childhood obesity. The current review will also seek to identify any more current research on the topic while expanding the inclusion criteria from the internet-based interventions included in An, et al. to other forms for web-based technologies, such as smart phones, that have become increasingly popular with this population.The use of the web for communication purposes came into existence in 1991, but it was not really until the mid to late 1990's that information professionals understood its usefulness and the magnitude of a medium that would have far-reaching positive consequences. This systematic review will include studies published from 1991 to the present date to identify all relevant studies on this topic.

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Polybrominated biphenyls are synthetic chemicals used as flame retardants. The technical product used in these studies, Firemaster FF-1(R)), is a mixture of brominated biphenyls. Firemaster FF-1(R)) is a known liver carcinogen in rats and mice and is one of three compounds chosen by the National Toxicology Program to investigate the potential value of perinatal exposures in assessing chemical carcinogenicity. Chronic toxicity and carcinogenicity studies of polybrominated biphenyls (Firemaster FF-1(R)) were conducted in F344/N rats and B6C3F1 mice of each sex. The studies were designed to determine: a) the effects of polybrominated biphenyls in rats and mice receiving adult ( F1) exposure only (a typical carcinogenicity study), b) the toxic and carcinogenic effects of polybrominated biphenyls in rats and mice receiving perinatal (F0) exposure only (dietary exposure of dams prior to breeding and throughout gestation and lactation), and c) the effects of combined perinatal and adult exposure to polybrominated biphenyls. STUDIES IN F344/N RATS: The exposure levels selected for F1 exposure, based on studies of polybrominated biphenyls in the literature, were 3, 10, and 30 ppm. In a preliminary study to determine the perinatal dietary concentrations for the 2-year study, female rats were administered 1 to 30 ppm polybrominated biphenyls in the feed beginning 60 days prior to breeding and continuing throughout gestation, lactation, and up to 4 weeks postweaning. The mean preweaning litter weight of the 30 ppm group was less than 80% of the mean litter weight of the control group at days 0, 4, and 12. At weaning, the mean weight of litters in this group was 80% of the control group mean. The final mean body weights (28 days after weaning) of males and females receiving 30 ppm were 13% to 19% lower than the final mean body weights of the controls. Therefore, dietary concentrations of 0, 1, 3, and 10 ppm were selected for the F0 exposure levels in the 2-year study. The eight F0 F1 exposure combinations selected for the 2-year study are shown in the following table (see page 6 of full technical report). Adult-Only Exposure The major organ affected by toxicity of polybrominated biphenyls was the liver. Rats evaluated at 9 months had decreased body weights, hepatomegaly, nonneoplastic histopathologic changes in the liver, mild anemia, increases in serum cholesterol concentrations, and decreases in serum triglyceride concentrations (males only). In rats receiving adult only exposure (F0 F1 concentrations of 0:10 or 0:30 ppm), there were no significant effects on survival. Mean body weights were significantly reduced in 0:10 and 0:30 ppm male rats and in 0:30 ppm female rats. Males and females exposed to 0:10 or 0:30 ppm had increased incidences of hepatocellular neoplasms (males: 0:0 ppm, 1/50; 0:10 ppm, 12/49; 0:30 ppm, 41/50; females: 0/50,12/50, 39/50). Increased incidences of the following nonneoplastic lesions were associated with the administration of polybrominated biphenyls: eosinophilic foci, cytoplasmic vacuolization, oval cell hyperplasia, and hypertrophy in the liver of males and females; acanthosis, inflammation, and ulceration of the forestomach in exposed males; and cystic endometrial hyperplasia of the uterus in 0:30 ppm females. Perinatal-Only Exposure For rats receiving only perinatal exposure (10:0 ppm), there were no changes in survival or body weights compared to the 0:0 ppm control groups. In female rats, there were no effects on neoplasm incidences, but perinatal exposure was associated with a marginally increased incidence of hepatocellular adenoma in male rats (0:0 ppm, 1/50; 10:0 ppm, 5/50). The incidences of nonneoplastic lesions in the liver were increased in exposed males (eosinophilic foci and cytoplasmic vacuolization) and females (eosinophilic foci). Combined Perinatal and Adult Exposure Combined perinatal and adult exposure resulted in marginally reduced survival compared to the 0:0 ppm control group for male rats in the 3:10, 10:10, and 10:30 ppm groups. No significant survival differences were obseant survival differences were observed in female rats. The final mean body weights of male and female rats receiving 3:10,10:10, or 10:30 ppm were lower than those of the 0:0 ppm controls. In male rats, there were no enhancing effects of combined perinatal and adult exposure on the incidence of hepatocellular neoplasms. However, perinatal exposure enhanced the development of liver neoplasms in female rats receiving 10 or 30 ppm adult exposure. A combined analysis of all male and female exposure groups also revealed increased incidences of mononuclear cell leukemia that were considered related to polybrominated biphenyls exposure. STUDIES IN B6C3F1 MICE: The exposure levels selected for the F1 exposure, based on studies of polybrominated biphenyls in the literature, were 3,10, and 30 ppm. In a preliminary study to determine the perinatal dietary concentrations for the 2-year study, female C57BL/6N mice were exposed to 1 to 30 ppm polybrominated biphenyls in the feed beginning 60 days before breeding to C3H/HeN males, continuing throughout gestation and lactation and up to 4 weeks postweaning. There were no clear chemical-related effects on survival or growth at any phase of the study; therefore, 0, 3,10, and 30 ppm dietary concentrations were selected for the F0 exposure levels in the 2-year study. The eight F0 F1 exposure combinations selected for the 2-year study are shown in the table below (see page 7 of full technical report). Adult-Only Exposure The major organ affected by toxicity of polybrominated biphenyls was the liver. Animals evaluated at 9 months had lower body weights than the controls, hepatomegaly, and histopathologic changes in the liver. In mice receiving adult-only exposure, no males or females in the 0:30 ppm group survived to the end of the study. Neither survival nor body weights were affected in the 0:10 ppm groups. Males and females receiving 0:10 or 0:30 ppm had markedly increased incidences of hepatocellular neoplasms (males: 0:0 ppm, 16/50; 0:10 ppm, 48/49; 0:30 ppm, 48/50; females: 5/50, 42/50, 47/48). Increased incidences of nonneoplastic liver lesions including cytomegaly (hypertrophy), fatty change (cytoplasmic vacuolization), bile duct hyperplasia, eosinophilic and clear cell foci, and necrosis of individual hepatocytes were related to treatment with polybrominated biphenyls. Increased incidences and severity of chronic nephropathy in the kidney and excessive hematopoiesis in the spleen of 0:30 ppm males and females were also considered to be related to exposure to polybrominated biphenyls. Perinatal-Only Exposure There were no survival or body weight differences in mice receiving only perinatal exposure (30:0 ppm). Perinatal exposure resulted in significantly increased incidences of hepatocellular neoplasms in males and females. The incidences of nonneoplastic lesions (cytomegaly, eosinophilic foci, clear cell foci) were increased in males and females. Combined Perinatal and Adult Exposure Combined perinatal and adult exposure resulted in markedly reduced survival for females in the 30:10 ppm group; no mice receiving 30:30 ppm survived to the end of the study. In those groups receiving adult exposure of 30 ppm, mean body weights were not affected. The incidence of hepatocellular neoplasms in male and female mice was significantly increased. At the 9-month interim evaluation the incidence of hepatocellular adenomas was significantly increased in males (0:30 ppm, 1/10; 30:30 ppm, 7/10). The incidence of hepatocellular adenomas in 30:30 ppm females was similar to that of 0:30 ppm females (0:30 ppm, 0/10; 30:30 ppm, 3/10). At the end of the study the incidence of hepatocellular adenomas in males was statistically increased (0:30 ppm, 42/50; 30:30 ppm, 48/50). The incidence of hepatocellular adenomas in 30:30 ppm females was statistically decreased compared to that of 0:30 ppm females (0:30 ppm, 46/48; 30:30 ppm, 41/47). It was not possible to assess the potential enhancing effect of combined perinatal and adult exposure on hepatocellular neoplasms because adult-only exposure resulted in such high (84% to 98%) liver neoplasm incidences. CONCLUSIONS: Adult-Only Exposure Under the conditions of these 2-year, adult-only, dietary exposure studies, there was clear evidence of carcinogenic activity for polybrominated biphenyls in male and female F344/N rats and male and female B6C3F1 mice based on increased incidences of hepatocellular neoplasms. Perinatal-Only Exposure Perinatal exposure alone (through dietary administration of 10:0 ppm polybrominated biphenyls to the dams) had no effect on the incidences of neoplasms in female F344/N rats, but in male F344/N rats, perinatal exposure was associated with a marginally increased incidence of hepatocellular adenomas that may have been related to chemical administration. In male and female B6C3F1 mice, perinatal exposure to 30:0 ppm polybrominated biphenyls resulted in significantly increased incidences of hepatocellular neoplasms. The incidences of a number of nonneoplastic lesions in the liver (cytomegaly, eosinophilic focus, and clear cell focus) were increased in male and female B6C3F1 mice. Combined Perinatal and Adult Exposure Combined perinatal and adult dietary exposure to polybrominated biphenyls confirmed findings of the adult-only exposures for the increased incidences of hepatocellular neoplasms in F344/N rats and B6C3F1 mice. In male F344/N rats, there were no enhancing effects of combined perinatal and adult exposure. However, perinatal exposure enhanced the susceptibility of female F344/N rats receiving adult exposure of 10 or 30 ppm to the induction of liver neoplasms. For male and female F344/N rats, a combined analysis of the incidences of leukemia in the adult-only, perinatal-only, and combined perinatal and adult exposure groups revealed an apparent association between increasing incidences of mononuclear cell leukemia and exposure to polybrominated biphenyls. In male and female B6C3F1 mice, it was not possible to adequately assess the enhancing effects of combined perinatal and adult exposure on hepatocellular neoplasms, because adult-only exposure to 10 or 30 ppm polybrominated biphenyls resulted in high incidences (84% to 98%) of liver neoplasms. However, with increased perinatal exposure, there were increases in the numbers of B6C3F1 mice with hepatocellular carcinomas and in the numbers of B6C3F1 mice with multiple hepatocellular adenomas, which suggests an enhancement of polybrominated biphenyls-related hepatocellular carcinogenicity associated with perinatal exposure. Synonyms: PBBs; polybrominated biphenyl mixture; hexabromobiphenyl (technical grade); brominated biphenyls; polybromobiphenyls

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About 70% to 80% of adults with cancer experience chemotherapy-induced nausea and vomiting (CINV). CINV remains one of the most distressing symptoms associated with cancer therapy and is associated with decreased adherence to chemotherapy. Combining 5-hydroxytryptamine-3 (5-HT₃) receptor antagonists with corticosteroids or additionally with neurokinin-1 (NK₁) receptor antagonists is effective in preventing CINV among adults receiving highly emetogenic chemotherapy (HEC) or moderately emetogenic chemotherapy (MEC). Various treatment options are available, but direct head-to-head comparisons do not allow comparison of all treatments versus another.  OBJECTIVES: • In adults with solid cancer or haematological malignancy receiving HEC - To compare the effects of antiemetic treatment combinations including NK₁ receptor antagonists, 5-HT₃ receptor antagonists, and corticosteroids on prevention of acute phase (Day 1), delayed phase (Days 2 to 5), and overall (Days 1 to 5) chemotherapy-induced nausea and vomiting in network meta-analysis (NMA) - To generate a clinically meaningful treatment ranking according to treatment safety and efficacy • In adults with solid cancer or haematological malignancy receiving MEC - To compare whether antiemetic treatment combinations including NK₁ receptor antagonists, 5-HT₃ receptor antagonists, and corticosteroids are superior for prevention of acute phase (Day 1), delayed phase (Days 2 to 5), and overall (Days 1 to 5) chemotherapy-induced nausea and vomiting to treatment combinations including 5-HT₃ receptor antagonists and corticosteroids solely, in network meta-analysis - To generate a clinically meaningful treatment ranking according to treatment safety and efficacy SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, conference proceedings, and study registries from 1988 to February 2021 for randomised controlled trials (RCTs). We included RCTs including adults with any cancer receiving HEC or MEC (according to the latest definition) and comparing combination therapies of NK₁ and 5-HT₃ inhibitors and corticosteroids for prevention of CINV. We used standard methodological procedures expected by Cochrane. We expressed treatment effects as risk ratios (RRs). Prioritised outcomes were complete control of vomiting during delayed and overall phases, complete control of nausea during the overall phase, quality of life, serious adverse events (SAEs), and on-study mortality. We assessed GRADE and developed 12 'Summary of findings' tables. We report results of most crucial outcomes in the abstract, that is, complete control of vomiting during the overall phase and SAEs. For a comprehensive illustration of results, we randomly chose aprepitant plus granisetron as exemplary reference treatment for HEC, and granisetron as exemplary reference treatment for MEC. Highly emetogenic chemotherapy (HEC) We included 73 studies reporting on 25,275 participants and comparing 14 treatment combinations with NK₁ and 5-HT₃ inhibitors. All treatment combinations included corticosteroids. Complete control of vomiting during the overall phase We estimated that 704 of 1000 participants achieve complete control of vomiting in the overall treatment phase (one to five days) when treated with aprepitant + granisetron. Evidence from NMA (39 RCTs, 21,642 participants; 12 treatment combinations with NK₁ and 5-HT₃ inhibitors) suggests that the following drug combinations are more efficacious than aprepitant + granisetron for completely controlling vomiting during the overall treatment phase (one to five days): fosnetupitant + palonosetron (810 of 1000; RR 1.15, 95% confidence interval (CI) 0.97 to 1.37; moderate certainty), aprepitant + palonosetron (753 of 1000; RR 1.07, 95% CI 1.98  to 1.18; low-certainty), aprepitant + ramosetron (753 of 1000; RR 1.07, 95% CI 0.95 to 1.21; low certainty), and fosaprepitant + palonosetron (746 of 1000; RR 1.06, 95% CI 0.96 to 1.19; low certainty).  Netupitant + palonosetron (704 of 1000; RR 1.00, 95% CI 0.93 to 1.08; high-certainty) and fosaprepitant + granisetron (697 of 1000; RR 0.99, 95% CI 0.93 to 1.06; high-certainty) have little to no impact on complete control of vomiting during the overall treatment phase (one to five days) when compared to aprepitant + granisetron, respectively.  Evidence further suggests that the following drug combinations are less efficacious than aprepitant + granisetron in completely controlling vomiting during the overall treatment phase (one to five days) (ordered by decreasing efficacy): aprepitant + ondansetron (676 of 1000; RR 0.96, 95% CI 0.88 to 1.05; low certainty), fosaprepitant + ondansetron (662 of 1000; RR 0.94, 95% CI 0.85 to 1.04; low certainty), casopitant + ondansetron (634 of 1000; RR 0.90, 95% CI 0.79 to 1.03; low certainty), rolapitant + granisetron (627 of 1000; RR 0.89, 95% CI 0.78 to 1.01; moderate certainty), and rolapitant + ondansetron (598 of 1000; RR 0.85, 95% CI 0.65 to 1.12; low certainty). We could not include two treatment combinations (ezlopitant + granisetron, aprepitant + tropisetron) in NMA for this outcome because of missing direct comparisons.  Serious adverse events We estimated that 35 of 1000 participants experience any SAEs when treated with aprepitant + granisetron. Evidence from NMA (23 RCTs, 16,065 participants; 11 treatment combinations) suggests that fewer participants may experience SAEs when treated with the following drug combinations than with aprepitant + granisetron: fosaprepitant + ondansetron (8 of 1000; RR 0.23, 95% CI 0.05 to 1.07; low certainty), casopitant + ondansetron (8 of 1000; RR 0.24, 95% CI 0.04 to 1.39; low certainty), netupitant + palonosetron (9 of 1000; RR 0.27, 95% CI 0.05 to 1.58; low certainty), fosaprepitant + granisetron (13 of 1000; RR 0.37, 95% CI 0.09 to 1.50; low certainty), and rolapitant + granisetron (20 of 1000; RR 0.57, 95% CI 0.19 to 1.70; low certainty). Evidence is very uncertain about the effects of aprepitant + ondansetron (8 of 1000; RR 0.22, 95% CI 0.04 to 1.14; very low certainty), aprepitant + ramosetron (11 of 1000; RR 0.31, 95% CI 0.05 to 1.90; very low certainty), fosaprepitant + palonosetron (12 of 1000; RR 0.35, 95% CI 0.04 to 2.95; very low certainty), fosnetupitant + palonosetron (13 of 1000; RR 0.36, 95% CI 0.06 to 2.16; very low certainty), and aprepitant + palonosetron (17 of 1000; RR 0.48, 95% CI 0.05 to 4.78; very low certainty) on the risk of SAEs when compared to aprepitant + granisetron, respectively.  We could not include three treatment combinations (ezlopitant + granisetron, aprepitant + tropisetron, rolapitant + ondansetron) in NMA for this outcome because of missing direct comparisons.  Moderately emetogenic chemotherapy (MEC) We included 38 studies reporting on 12,038 participants and comparing 15 treatment combinations with NK₁ and 5-HT₃ inhibitors, or 5-HT₃ inhibitors solely. All treatment combinations included corticosteroids. Complete control of vomiting during the overall phase We estimated that 555 of 1000 participants achieve complete control of vomiting in the overall treatment phase (one to five days) when treated with granisetron. Evidence from NMA (22 RCTs, 7800 participants; 11 treatment combinations) suggests that the following drug combinations are more efficacious than granisetron in completely controlling vomiting during the overall treatment phase (one to five days): aprepitant + palonosetron (716 of 1000; RR 1.29, 95% CI 1.00 to 1.66; low certainty), netupitant + palonosetron (694 of 1000; RR 1.25, 95% CI 0.92 to 1.70; low certainty), and rolapitant + granisetron (660 of 1000; RR 1.19, 95% CI 1.06 to 1.33; high certainty).  Palonosetron (588 of 1000; RR 1.06, 95% CI 0.85 to 1.32; low certainty) and aprepitant + granisetron (577 of 1000; RR 1.06, 95% CI 0.85 to 1.32; low certainty) may or may not increase complete response in the overall treatment phase (one to five days) when compared to granisetron, respectively. Azasetron (560 of 1000; RR 1.01, 95% CI 0.76 to 1.34; low certainty) may result in little to no difference in complete response in the overall treatment phase (one to five days) when compared to granisetron. Evidence further suggests that the following drug combinations are less efficacious than granisetron in completely controlling vomiting during the overall treatment phase (one to five days) (ordered by decreasing efficacy): fosaprepitant + ondansetron (500 of 100; RR 0.90, 95% CI 0.66 to 1.22; low certainty), aprepitant + ondansetron (477 of 1000; RR 0.86, 95% CI 0.64 to 1.17; low certainty), casopitant + ondansetron (461 of 1000; RR 0.83, 95% CI 0.62 to 1.12; low certainty), and ondansetron (433 of 1000; RR 0.78, 95% CI 0.59 to 1.04; low certainty). We could not include five treatment combinations (fosaprepitant + granisetron, azasetron, dolasetron, ramosetron, tropisetron) in NMA for this outcome because of missing direct comparisons.  Serious adverse events We estimated that 153 of 1000 participants experience any SAEs when treated with granisetron. Evidence from pair-wise comparison (1 RCT, 1344 participants) suggests that more participants may experience SAEs when treated with rolapitant + granisetron (176 of 1000; RR 1.15, 95% CI 0.88 to 1.50; low certainty). NMA was not feasible for this outcome because of missing direct comparisons.  Certainty of evidence Our main reason for downgrading was serious or very serious imprecision (e.g. due to wide 95% CIs crossing or including unity, few events leading to wide 95% CIs, or small information size). Additional reasons for downgrading some comparisons or whole networks were serious study limitations due to high risk of bias or moderate inconsistency within networks. This field of supportive cancer care is very well researched. However, new drugs or drug combinations are continuously emerging and need to be systematically researched and assessed. For people receiving HEC, synthesised evidence does not suggest one superior treatment for prevention and control of chemotherapy-induced nausea and vomiting.  For people receiving MEC, synthesised evidence does not suggest superiority for treatments including both NK₁ and 5-HT₃ inhibitors when compared to treatments including 5-HT₃ inhibitors only. Rather, the results of our NMA suggest that the choice of 5-HT₃ inhibitor may have an impact on treatment efficacy in preventing CINV.  When interpreting the results of this systematic review, it is important for the reader to understand that NMAs are no substitute for direct head-to-head comparisons, and that results of our NMA do not necessarily rule out differences that could be clinically relevant for some individuals.

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Sertindole is an atypical antipsychotic, which is thought to give a lower incidence of extrapyramidal side effects at clinically effective doses than typical antipsychotic drugs. In December 1998, Lundbeck Ltd., the manufacturers of sertindole, voluntarily suspended the availability of the drug due to concerns about cardiac arrhythmia and sudden cardiac death associated with its use. However, based on the advice of an appointed expert group, the Committee for Proprietary Medicinal Products (CPMP) lifted the suspension of sertindole in October 2001, a decision that was ratified by the European Commission on the 26th of June 2002. Lundbeck have committed to the CPMP to carry out two post-marketing surveillance (PMS) studies (which were initiated in July 2002) to provide additional epidemiological data under conditions of normal drug usage. Initial marketing of the product will be restricted and Lundbeck is currently in discussions with the US health authorities (FDA) to investigate whether, and if so when, it would be possible to launch Serdolect in the US market. To determine the effects of sertindole compared with placebo, typical and other atypical antipsychotic drugs for schizophrenia and related psychoses. Our Initial searches included electronic searches of Biological Abstracts (1980-1999), The Cochrane Library (Issue 1, 1999), The Cochrane Schizophrenia Group's Register (August 2000), EMBASE (1980-1999), LILACS (1982-1996), MEDLINE (1966-1999), PSYNDEX (1977-1995) and PsycLIT (1974-1999). In addition, we searched pharmaceutical databases on the Dialog Corporation Datastar and Dialog services. We searched references of all identified studies for further trials. We contacted the manufacturer of sertindole and authors of trials. We updated the literature search by searching the Cochrane Schizophrenia Group's Trials Register in April 2003. All randomised controlled trials that compared sertindole to placebo or other antipsychotic (atypical or typical) drug treatments for patients with schizophrenia or related psychosis . We independently inspected citations and, where possible abstracts; ordered papers for re-inspection and quality assessment and independently extracted data. For homogeneous dichotomous data, we calculated the risk ratio (RR), 95% confidence interval (CI) and, where appropriate, the number needed to treat (NNT) or number needed to harm (NNH) on an intention-to-treat basis. For continuous data, we calculated weighted mean differences (WMD). We inspected all data for heterogeneity. Currently the review includes three studies with a total of 1,104 participants. One was a medium term (eight weeks) placebo controlled study that examined three different doses of sertindole (8, 12 and 20mg/day). The remaining two studies compared the use of sertindole with haloperidol (10mg/day). One was a short term study (six weeks) that looked at four different doses of sertindole (8, 16, 20, 24mg/day) and the other was a long term study (one year) that evaluated the use of sertindole 24mg/day in participants attending outpatients. We excluded two large important studies because they did not report any usable data. (Both had greater than 50% loss to follow-up and data on 'leaving the study early' was inadequately reported). SERTINDOLE VERSUS PLACEBO: Sertindole at 20mg/day was found to be more effective than placebo in terms of BPRS total scores (1 study, n=78, MD 6.2, CI -11.8 to -0.6) and CGI total end point scores (1 study, n=78, MD -0.9, CI -1.6 to -0.2). A marginally statistically significantly greater number of participants that were treated with 20 mg of sertindole were reported to have been 'very much improved' as compared to those taking placebo (1 study, n=102, RR 7.6, CI 1.0 to 57.9, NNT 7.9, CI 4.3 to 41.1). There was no statistically significant difference between sertindole at 8 or 12 mg/day and placebo for these three outcome measures. There were no statistically significant differences between sertindole (8, 12 or 20 mg) and placebo for the incidence of extrapyramidal symptoms, extrapyramidal related events or use of medication to avoid extrapyramidal symptoms. There were no statistically significant differences found between sertindole and placebo for the movement disorders akathisia, cogwheel rigidity, hypertonia and tremor or somnolence. At eight weeks a statistically significant difference between placebo and all sertindole groups (8, 12 and 20 mg) for mean change from baseline in the QT and QTc intervals were observed (p values and SD were not reported). There was a statistically significant greater mean weight gain among participants taking sertindole (20 mg, mean weight gain of 3.3 kg) as compared to placebo (mean weight gain of 0.8 kg; p<0.05). SERTINDOLE VERSUS HALOPERIDOL: At one year, a greater number of participants who were treated with haloperidol as compared to sertindole (24mg/day) were leaving the study early due to any reason (1 study, n=282, RR 0.6, CI 0.4 to 1.0, NNH 8.8, CI 4.7 to 74.0) or non-compliance (1 study, n=282, RR 0.2, CI 0.0 to 0.7, NNH 12.8, CI 7.7 to 37.8). However, at six weeks, there was no statistically significant difference between sertindole (at 8, 16, 20, or 24mg) and haloperidol for this latter outcome. The incidence of EPS was higher among those treated with haloperidol than sertindole at 8, 16, 20 or 24mg/day (8mg: 1 study, n=245, RR 0.1, CI 0.0 to 0.7, NNH 11.4, CI 7.1 to 29.8; 16mg: 1 study, n=252, RR 0.3, CI 0.1 to 1.0, NNH 15.5, CI 8.0 to 217.9; and 20mg: 1 study, n=253, RR 0.2, CI 0.1 to 0.8, NNH 13.7, CI 7.7 to 68.3; 24mg: 2 studies, n=524, RR 0.6, CI 0.4 to 0.8, NNH 8.7, CI 5.4 to 23.0). More participants treated with haloperidol experienced akathisia, tremor and hypertonia than those treated with sertindole (Akathisia - 8mg: 1 study, n=245, RR 0.2, CI 0.1 to 0.5, NNH 6.0, CI 4.1 to 11.2; 16mg: 1 study, n=252, RR 0.1, CI 0.0 to 0.3, NNH 5.4, CI 3.9 9.0; 20mg: 1 study, n=253, RR 0.3, CI 0.2 to 0.7, NNH 7.3, CI 4.6 to 17.9; 24mg: 2 studies, n=524, RR 0.5, CI 0.3 to 0.7, NNH 8.6, CI 5.6 to 18.3. Tremor - 8mg: 1 study, n=245, RR 0.3, CI 0.1 to 0.7, NNH 8.5, CI 5.2 to 24.0; 16mg: 1 study, n=252, RR 0.2, CI 0.1 to 0.5, NNH 7.3, 4.8 to 15.6; 20mg: 1 study, n=253, RR 0.2, CI 0.1 to 0.6, NNH 7.8, CI 4.9 to 18.1; 24mg: 2 studies, n=524, RR 0.4, CI 0.2 to 0.6, NNH 8.2, CI 5.6 to 15.3. For Hypertonic - 24mg: 2 studies, n=524, RR 0.5, CI 0.3 to 0.8, NNH 12.4, CI 7.5 to 35.0; for sertindole 8, 16 and 20mg there was no statistically significant differences between the treatment groups). One study reported that at six weeks, there was a statistically significant greater increase from baseline to final value in mean QTc interval in the sertindole 16, 20 and 24mg groups (20, 26, and 24msec, respectively) than in the haloperidol group (0msec; p value was not reported), but no SD or any other measure of variance for the effect sizes were reported. For one long term study only one participant from the sertindole group (24mg) had a QT interval that exceeded 500msec (1 study, n=282, RR 3.0 CI 0.1 to 73.0), but 11participants treated with Sertindole had QTc intervals of at least 500msec, compared to none in the haloperidol treated group (1 study, n=282, RR 23.0, CI 1.4 to 386.6, NNH 12.8, CI 8.2 to 29.6). At six weeks, fewer participants treated with sertindole at 8mg or 24mg were affected by somnolence than those treated with haloperidol (sertindole 8mg: 1 study, n=245, RR 0.1, CI 0.0 to 0.7, NNH 11.4, CI 7.1 to 29.8; 24mg: 2 studies, n=524, RR 0.6, CI 0.4 to 1.0, NNH 14.8, CI 7.7 to 205.2). The incidence of rhinitis was found to be statistically significantly higher among those taking sertindole at 16 or 24mg as compared to haloperidol (16mg: 1 study, n=252, RR 10.8, CI 1.4 to 82.6, NNH 12.7, CI 7.7 to 36.7; 24mg: 2 studies, n= 524, RR 2.1, CI 1.4 to 3.1, NNH 8.7, CI 5.6 to 18.6). At one year, 33 participants treated with sertindole (24mg) had experienced the sexual adverse event of decreased ejaculatory volume, compared with six participants treated with haloperidol. However the number of included male participants was not reported and therefore the RR could not be calculated. At one year, more participants taking sertindole (24mg/day) had put on weight compared to those taking haloperidol (1 study, n=282, RR 6.3, CI 1.9 to 20.9, NNH 8.8, CI 5.7 to 19.1). At six weeks, all of the sertindole groups showed an increase in body weight from baseline to final evaluation ranging from 1.3kg to 1.9kg, all of which represented a statistically significantly different weight change than that recorded for the haloperidol treatment group (-0.1Kg). However, the actual weight gain for each sertindole dosage group was not reported and no SD or any other measure of variance was given. Sertindole at a dose of 20mg/day was found to be more antipsychotic than placebo. When used at 8, 12 or 20mg/day it appears to be as acceptable as placebo (in terms of various adverse events including movement disorders and somnolence), but seems to be associated with more cardiac problems (8, 12 or 20mg/day) and an increase in weight gain (20mg/day) than placebo. Sertindole at a dose of 24mg/day was better tolerated than haloperidol (in terms of participants leaving the study early). It was also found to be was associated with fewer movement disorders (at 8, 16, 20 or 24mg/day) and sedation (8 or 24mg/day) than haloperidol. However, it was shown to cause more cardiac anomalies (16, 20 or 24mg/day), weight gain (all doses combined), rhinitis (16 or 24mg/day), and problems with sexual functioning (24mg/day) than haloperidol. One short term study reported that sertindole 16mg/day was the most optimal dose.

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Antiretroviral drugs (ARV) reduce viral replication and can reduce mother-to-child transmission of HIV either by lowing plasma viral load in pregnant women or through post-exposure prophylaxis in their newborns. In rich countries, highly active antiretroviral therapy (HAART) has reduced the vertical transmission rates to around 1-2%, but HAART is not yet widely available in low and middle income countries. In these countries, various simpler and less costly antiretroviral regimens have been offered to pregnant women or to their newborn babies, or to both. To determine whether, and to what extent, antiretroviral regimens aimed at decreasing the risk of mother-to-child transmission of HIV infection achieve a clinically useful decrease in transmission risk, and what effect these interventions have on maternal and infant mortality and morbidity. We sought to identify all relevant studies regardless of language or publication status by searching the Cochrane HIV/AIDS Review Group Trials Register, The Cochrane Library, Medline, EMBASE and AIDSearch and relevant conference abstracts. We also contacted research organizations and experts in the field for unpublished and ongoing studies. The original review search strategy was updated in 2006. Randomised controlled trials of any antiretroviral regimen aimed at decreasing the risk of mother-to-child transmission of HIV infection compared with placebo or no treatment. Two authors independently selected relevant studies, extracted data and assessed trial quality. For the primary outcomes, we used survival analysis to estimate the probability of infants being infected with HIV (the observed proportion) at various specific time-points and calculated efficacy at a specific time as the relative reduction in the proportion infected. Efficacy, at a specific time, is defined as the preventive fraction in the exposed group compared to the reference group, which is the relative reduction in the proportion infected: 1-(Re/Rf). For those studies where efficacy and hence confidence intervals were not calculated, we calculated the approximate confidence intervals for the efficacy using recommended methods. For analysis of results that are not based on survival analyses we present the relative risk for each trial outcome based on the number randomised. No meta-analysis was conducted as no trial assessed the identical drug regimens. Eighteen trials including 14,398 participants conducted in 16 countries were eligible for inclusion in the review. The first trial began in April 1991 and assessed zidovudine (ZDV) versus placebo and since then, the type, dosage and duration of drugs to be compared has been modified in each subsequent trial. Antiretrovirals versus placebo In breastfeeding populations, three trials found that:ZDV given to mothers from 36 to 38 weeks gestation, during labour and for 7 days after delivery significantly reduced HIV infection at 4-8 weeks (Efficacy 32.00%; 95% CI 0.64 to 63.36), 3 to 4 months (Efficacy 34.00%; 95% CI 6.56 to 61.44), 6 months (Efficacy 35.00%; 95% CI 9.52 to 60.48), 12 months (Efficacy 34.00%; 95% CI 8.52 to 59.48) and 18 months (Efficacy 30.00%; 95% CI 2.56 to 57.44).ZDV given to mothers from 36 weeks gestation and during labour significantly reduced HIV infection at 4 to 8 weeks (Efficacy 44.00%; 95% CI 8.72 to 79.28) and 3 to 4 months (Efficacy 37.00%; 95% CI 3.68 to 70.32) but not at birth.ZDV plus lamivudine (3TC) given to mothers from 36 weeks gestation, during labour and for 7 days after delivery and to babies for the first 7 days of life (PETRA 'regimen A') significantly reduced HIV infection (Efficacy 63.00%; 95% CI 41.44 to 84.56) and a combined endpoint of HIV infection or death (Efficacy 61.00%; 95% CI 41.40 to 80.60) at 4 to 8 weeks but these effects were not sustained at 18 months.ZDV plus 3TC given to mothers from the start of labour until 7 days after delivery and to babies for the first 7 days of life (PETRA 'regimen B') significantly reduced HIV infection (Efficacy 42.00%; 95% CI 12.60 to 71.40) and HIV infection or death at 4 to 8 weeks (Efficacy 36.00%; 95% CI 8.56 to 63.44) but the effects were not sustained at 18 months.ZDV plus 3TC given to mothers during labour only (PETRA 'regimen C') with no treatment to babies did not reduce the risk of HIV infection at either 4 to 8 weeks or 18 months. In non-breastfeeding populations, three trials found that:ZDV given to mothers from 14 to 34 weeks gestation and during labour and to babies for the first 6 weeks of life significantly reduced HIV infection in babies at 18 months (Efficacy 66.00%; 95% CI 34.64 to 97.36).ZDV given to mothers from 36 weeks gestation and during labour with no treatment to babies ('Thai-CDC regimen') significantly reduced HIV infection at 4 to 8 weeks (Efficacy 50.00%; 95% CI 12.76 to 87.24) but not at birthZDV given to mothers from 38 weeks gestation and during labour with no treatment to babies did not influence HIV transmission at 6 months. Longer versus shorter regimens using the same antiretrovirals One trial in a breastfeeding population found that:ZDV given to mothers during labour and to their babies for the first 3 days of life compared with ZDV given to mothers from 36 weeks and during labour (similar to 'Thai-CDC') resulted in HIV infection rates that were not significantly different at birth, 4-8 weeks, 3 to 4 months, 6 months and 12 months. Three trials in non-breastfeeding populations found that:ZDV given to mothers from 28 weeks gestation during labour and to infants for the first 3 days after birth compared with ZDV given to mothers from 35 weeks gestation through labour and to infants from birth to 6 weeks significantly reduced HIV infection rate at 6 months (Efficacy 45.00%; 95% CI 1.88 to 88.12) but compared with the same regimen ZDV given to mothers from 28 weeks gestation through labour and to infants from birth to 6 weeks did not result in a statistically significant difference in HIV infection at 6 months. ZDV given to mothers from 35 weeks gestation during labour and to infants for the first 3 days after birth was considered ineffective for reducing transmission rates and this regimen was discontinued.An antenatal/intrapartum course of ZDV used for a median of 76 days compared with an antenatal/intrapartum ZDV regimen used for a median 28 days with no treatment to babies in either group did not result in HIV infection rates that were significantly different at birth and at 3 to 4 months. In a programme where mothers were routinely receiving ZDV in the third trimester of pregnancy and babies were receiving one week of ZDV therapy, a single dose of nevirapine (NVP) given to mothers in labour and to their babies soon after birth compared with a single dose of NVP given to mothers only resulted in HIV infection rates that were not significantly different at birth and 6 months. However the reduction in risk of HIV infection or death at 6 months was marginally significant (Efficacy 45.00%; 95% CI -4.00 to 94.00). Antiretroviral regimens using different drugs and durations of treatment In breastfeeding populations, three trials found that:A single dose of NVP given to mothers at the onset of labour plus a single dose of NVP given to their babies immediately after birth ('HIVNET 012 regimen') compared with ZDV given to mothers during labour and to their babies for a week after birth resulted in lower HIV infection rates at 4-8 weeks (Efficacy 41.00%; 95% CI 11.60 to 70.40), 3-4 months (Efficacy 39.00%; 95% CI 11.56 to 66.44), 12 months (Efficacy 36.00%; 95% CI 8.56 to 63.44) and 18 months (Efficacy 39.00%; 95% CI 13.52 to 64.48). In addition, the NVP regimen significantly reduced the risk of HIV infection or death at 4-8 weeks (Efficacy 42.00%; 95% CI 14.56 to 69.44), 3 to 4 months (Efficacy 40.00%; 95% CI 14.52 to 65.48), 12 months (Efficacy 32.00%; 95% CI 8.48 to 55.52) and 18 months (Efficacy 33.00%; 95% CI 9.48 to 56.52). The 'HIVNET 012 regimen' plus ZDV given to babies for 1 week after birth compared with the 'HIVNET 012 regimen' alone did not result in a statistically significant difference in HIV infection at 4 to 8 weeks.A single dose of NVP given to babies immediately after birth plus ZDV given to babies for 1 week after birth compared with a single dose of NVP given to babies only significantly reduced the HIV infection rate at 4 to 8 weeks (Efficacy 37.00%; 95% CI 3.68 to 70.32). Five trials in non-breastfeeding populations found that:In a population in which mothers were receiving 'standard' ARV for HIV infection a single dose of NVP given to mothers in labour plus a single dose of NVP given to babies immediately after birth ('HIVNET 012 regimen') compared with placebo did not result in a statistically significant difference in HIV infection rates at birth and at 4 to 8 weeks. The 'Thai CDC regimen' compared with the 'HIVNET 012 regimen' did not result in a significant difference in HIV infection at 4 to 8 weeks.A single dose of NVP given to babies immediately after birth compared to ZDV given to babies for the first 6 weeks of life did not result in a significant difference in HIV infection rates at 4-8 weeks and 3 to 4 months.ZDV plus 3TC given to mothers in labour and for a week after delivery and to their infants for a week after birth (similar to 'PETRA regimen B') compared with NVP given to mothers in labour and immediately after delivery plus a single dose of NVP to their babies immediately after birth (similar to 'HIVNET 012 regimen') did not result in a significant difference in the HIV infection rate at 4 to 8 weeks. (ABSTRACT TRUNCATED)

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DIOXIN TOXIC EQUIVALENCY FACTOR EVALUATION OVERVIEW: Polyhalogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) have the ability to bind to and activate the ligand-activated transcription factor, the aryl hydrocarbon receptor (AhR). Structurally related compounds that bind to the AhR and exhibit biological actions similar to TCDD are commonly referred to as "dioxin-like compounds" (DLCs). Ambient human exposure to DLCs occurs through the ingestion of foods containing residues of DLCs that bioconcentrate through the food chain. Due to their lipophilicity and persistence, once internalized they accumulate in body tissue, mainly adipose, resulting in chronic lifetime human exposure. Since human exposure to DLCs always occurs as a complex mixture, the toxic equivalency factor (TEF) methodology has been developed as a mathematical tool to assess the health risk posed by complex mixtures of these compounds. The TEF methodology is a relative potency scheme that ranks the dioxin-like activity of a compound relative to TCDD, which is the most potent congener. This allows for the estimation of the potential dioxin-like activity of a mixture of chemicals, based on a common mechanism of action involving an initial binding of DLCs to the AhR. The toxic equivalency of DLCs was nominated for evaluation because of the widespread human exposure to DLCs and the lack of data on the adequacy of the TEF methodology for predicting relative potency for cancer risk. To address this, the National Toxicology Program conducted a series of 2-year bioassays in female Harlan Sprague-Dawley rats to evaluate the chronic toxicity and carcinogenicity of DLCs and structurally related polychlorinated biphenyls (PCBs) and mixtures of these compounds. Mixtures of polychlorinated biphenyls (PCBs) including 3,3',4,4',5-pentachlorobiphenyl (PCB 126) and 2,3',4,4',5-pentachlorobiphenyl (PCB 118) were produced commercially before 1977 for the electric industry as dielectric insulating fluids for transformers and capacitors. Manufacture and use of these chemicals were stopped because of increased PCB residues in the environment, but they continue to be released into the environment through the use and disposal of products containing PCBs, as by-products during the manufacture of certain organic chemicals, during combustion of some waste materials, and during atmospheric recycling. This PCB mixture study was conducted as part of the dioxin TEF evaluation that includes conducting multiple 2-year rat bioassays to evaluate the relative chronic toxicity and carcinogenicity of DLCs, structurally related PCBs, and mixtures of these compounds. This study was originally a study of PCB 118 alone. However, midway through the study PCB 126 was identified as one of the minor contaminants (0.622%) of the bulk PCB 118 (98.5% pure). Given the 1,000-fold higher potency of PCB 126 for inducing dioxin-like effects (based on the TEFs for PCB 126 and PCB 118 of 0.1 and 0.0001, respectively), it was expected that the effects of administration of this compound would be due to the combined dioxin-like effects of both PCB 126 and PCB 118. Therefore, this study was reclassified as a mixture study of PCB 126 and PCB 118. 2-YEAR STUDY: Groups of female Harlan Sprague-Dawley rats were administered the PCB mixture containing PCB 126 and PCB 118 by gavage in corn oil:acetone (99:1) or vehicle alone, 5 days per week for up to 104 weeks. Dose groups are referred to by the total levels of TCDD toxic equivalents (TEQ) provided by the PCBs in the mixture in each dose group. Groups of 81 female rats were administered 7, 22, 72, or 216 ng TEQ/kg; a group of 86 female rats was administered 360 ng TEQ/kg; and a group of 81 female rats was administered the corn oil:acetone vehicle alone. Up to 10 rats per group were evaluated at 14, 31, or 53 weeks. No animals in the 360 ng TEQ/kg group were examined at 53 weeks. A group of 50 female rats was administered 360 ng TEQ/kg for 30 weeks and then the vehicle alone for the remainder of the study. Nominal doses of PCB 118 and levels of PCB 126 in each dose group used were: 7 ng TEQ/kg dose group: 62 ng/kg PCB 126 and 10 microg/kg PCB 118 7 ng TEQ/kg dose group: 62 ng/kg PCB 126 and 10 microg/kg PCB 118 22 ng TEQ/kg dose group: 187 ng/kg PCB 126 and 30 microg/kg PCB 118 72 ng TEQ/kg dose group: 622 ng/kg PCB 126 and 100 microg/kg PCB 118 216 ng TEQ/kg dose group: 1,866 ng/kg PCB 126 and 300 microg/kg PCB 118 360 ng TEQ/kg dose group: 3,110 ng/kg PCB 126 and 500 microg/kg PCB 118 No animals in the 216 or 360 ng TEQ/kg core study groups survived to the end of the study, and survival in the 360 ng TEQ/kg stop-exposure group was significantly less than in the vehicle control group. Mean body weights of 72 ng TEQ/kg rats were less than those of the vehicle controls after week 33 of the study, and mean body weights of the 216 and 360 ng TEQ/kg core study rats and the 360 ng TEQ/kg stop-exposure group rats were less than those of the vehicle controls throughout most of the study. Clinical findings related to the administration of the binary mixture of PCB 126 and PCB 118 included abnormal breathing, thinness, and ruffled hair. Thyroid Hormone Concentrations: Alterations in serum thyroid hormone levels were evaluated at the 14-, 31-, and 53-week interim evaluations. Total thyroxine (T4) and free T4 were significantly lower in most dose groups than in vehicle controls at the 14- and 31-week interim evaluations. Serum T3 was significantly lower in the 360 ng TEQ/kg group compared to vehicle controls at 31 weeks only. TSH levels were higher in the 216 and 360 ng TEQ/kg groups than in vehicle controls at 31 weeks only. Hepatic Cell Proliferation Data To evaluate hepatocyte replication, analysis of labeling of replicating hepatocytes with 5-bromo-2'-deoxyuridine was conducted at the 14-, 31-, and 53-week interim evaluations. Labeling indices were elevated at doses above 216 ng TEQ/kg at 31 weeks and at doses above 72 ng TEQ/kg at 53 weeks. Cytochrome P450 Enzyme Activities: CYP1A1-associated 7-ethoxyresorufin-O-deethylase (EROD) and CYP1A2-associated acetanilide-4-hydroxylase (A4H) activities were evaluated at the 14-, 31-, and 53-week interim evaluations to evaluate the expression of known dioxin-responsive genes. In addition, CYP2B-associated pentoxyresorufin-O-deethylase (PROD) activity was also analyzed. Hepatic and pulmonary EROD (CYP1A1) activity, hepatic A4H (CYP1A2) activity, and hepatic PROD (CYP2B1) activity were significantly greater in all dosed groups compared to the vehicle controls at weeks 14, 31, and 53. Determinations of PCB 126 and PCB 118 Concentrations in Tissues: The tissue disposition of PCB 126 and PCB 118 was analyzed in the liver, lung, fat, and blood of up to 10 rats in each group at the 14-, 31-, and 53-week interim evaluations, except for the 360 ng TEQ/kg group at 53 weeks. The tissue disposition of PCB 126 and PCB 118 was also analyzed in 10 rats per group at the end of the 2-year study in the vehicle control, 7, 22, and 72 ng TEQ/kg core study groups and the 360 ng TEQ/kg stop-exposure group. Detectable concentrations of PCB 126 and PCB 118 were observed in the liver, fat, lung, and blood. The highest levels of PCB 126 were seen in the liver whereas the highest levels of PCB 118 were seen in the fat. In general, tissue concentrations increased with increasing doses of the mixture and increasing duration of exposure. Hepatic levels of PCB 126 and PCB 118 in the 72 ng TEQ/kg group at the end of the 2-year study were 284 ng/g and 3,769 ng/g, respectively. On a TCDD equivalents basis this corresponds to 28 ng TEQ/g and 0.4 ng TEQ/g for PCB 126 and PCB 118, respectively. Cessation of administration of the mixture in the stop-exposure group led to declines in the tissue concentrations of both PCB 126 and PCB 118 to levels comparable to those observed in the 7 ng TEQ/kg group at the end of the 2-year study. Pathology and Statistical Analyses: At 14, 31, and 53 weeks, liver weights were significantly increased in treated groups with more pronounced effects occurring in the higher dose groups. At 14 weeks, hepatocyte hypertrophy and pigmentation were seen at doses less than 72 ng TEQ/kg. Exposure to the PCB mixture led to significant toxicity in the liver. At higher doses, the incidences of toxic hepatopathy were increased as indicated by increased incidences of multinucleated hepatocytes and diffuse fatty change. At 31 weeks, most rats in the 216 and 360 ng TEQ/kg groups had multiple hepatic nonneoplastic lesions. At 53 weeks all animals administered 216 ng TEQ/kg had multiple nonneoplastic lesions. The spectrum of effects and the severity of effects at the interim and 2-year time points increased with dose and duration of exposure. At the end of the 2-year study in all dosed groups, there were significantly increased incidences and severity of toxic hepatopathy characterized by hepatocyte hypertrophy, multinucleated hepatocytes, pigmentation, toxic hepatopathy, diffuse fatty change, nodular hyperplasia, centrilobular fibrosis, cholangiofibrosis, oval cell hyperplasia, bile duct cyst, bile duct hyperplasia, and portal fibrosis. There were also increased incidences of hepatocyte glandular structures, necrosis, centrilobular degeneration, eosinophilic focus, and metaplasia. The incidences of cholangiocarcinoma (multiple and/or single) were significantly increased in groups administered 22 ng TEQ/kg or greater at 2 years. The incidences of hepatocellular adenoma were also significantly increased in the 216 and 360 ng TEQ/kg core study groups. In addition, single occurrences of hepatocholangioma, cholangioma, or hepatocellular carcinoma were observed in some dosed groups administered 72 ng TEQ/kg or greater. In the lung at 53 weeks, the incidences of cystic keratinizing epithelioma and bronchiolar metaplasia were significantly increased in the 216 ng TEQ/kg group. (ABSTRACT TRUNCATED).

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Before proceeding to a discussion of the experiments upon cold-blooded animals, it is necessary to review briefly some of the work recently done with the bacillus of leprosy. The appearance of the bacillus in man and its behavior under artificial cultivation, and in the tissues of lower animals, should be considered in order that comparisons may be drawn. In their studies with the organism under cultivation, Duval and Gurd pointed out that the long, slender, and beaded appearance of the leprosy bacillus described by Hansen, in 1872, is lost when removed for several generations from the parent stem, and under artificial cultivation the organism becomes unbeaded, short, and coccoid. Duval also noted that these changes in morphology were always followed by rapid multiplication of the organism. Duval argues, a priori, that the bacillus is not in a favorable environment in the human tissues. If these deductions are correct, the morphology of the leprosy bacillus should vary according to the resistance offered by the tissues of different animals. The resistance of the human host to the leprosy bacillus becomes more evident in the light of the clinical aspect of the disease. The long period of incubation, the duration of the disease, and the disappearance of the bacilli preceding the healing of the infected foci show that the resistance offered to the bacillus by the human tissues is not to be overestimated. This opinion is confirmed when the behavior of the leprosy bacillus under cultivation and in the tissues of various mammals is compared. When cats, rabbits, bats, guinea pigs, and rats are inoculated either below the skin or into the peritoneal cavity with large quantities of Bacillus leprae, a slight local reaction follows within twenty-four to forty-eight hours, but no definite lesions are produced and the bacilli soon disappear. The resistance of some animals to Bacillus leprae is well illustrated by two cats which were inoculated subcutaneously and intraperitoneally with a heavy suspension of Bacillus leprae. These animals were killed and examined three days later, but the bacilli were not demonstrable from the regions about the sites of inoculation. Pigeons are likewise refractory. It is impossible to cause a local reaction in these birds, and the injected bacilli disappear rapidly. Hence, probably no multiplication takes place in them. Goats, young pigs, and white and dancing mice are in a degree susceptible to injections, and though undoubted lesions are produced, and multiplication of the bacilli occurs, the lesions and bacilli disappear after a limited time. Acid-fast bacilli which are recovered from the lesions are long, slim, and beaded, though the organisms used in the inoculations were short, unbeaded, and coccoid. Monkeys inoculated with cultures of the short unbeaded forms react promptly. The lesions resulting, though confined in most instances to the site of inoculation, occasionally appear at distant points. The number of bacilli present in the nodules and their arrangement within typical lepra cells show that multiplication has taken place. The organism has, however, changed from the short coccoid form to the long, slender, beaded form. Though the lesions induced and the bacilli present are in every way similar to those found in man, their tendency to disappear gradually after a quiescent stage clearly denotes that the tissues of the monkey, although less refractory than the tissues of the animals previously mentioned, still offer resistance to invasion. While mammals react but poorly to inoculations of the leprosy bacillus, this reaction manifests itself in various ways in different species. For example, while multiplication of the organism with the production of lesions occurs in some species, in others that are more refractory, the injected bacilli assume the involuted or beaded forms and do not multiply or produce lesions; in others, still more resistant to the action of the leprosy bacillus, the organisms quickly undergo granular metamorphosis and disappear. Furthermore, in some species the lesions are, in most instances, limited to the site of inoculation, and though presenting all the characteristics of the lesion in man, the nodules and the bacilli disappear after a variable time. This behavior of the leprosy bacillus can be accounted for only by the degree of resistance offered by the tissues of the individual host. Since the morphology of the organism invariably changes from the short coccoid to the large beaded form when placed in insusceptible animals, and conversely, from the long beaded forms to the short coccoid forms when placed in susceptible animals, the deduction can be drawn that the organism varies in morphology and rapidity of growth according to the susceptibility of the host. Examples of similar behavior of Bacillus leprae in the human subject are known to all investigators of leprosy. Ulcers and nodular areas often heal, and the bacilli disappear with little or no treatment. It is true that while older lesions are healing, new ones are constantly appearing, yet the duration of the disease and its undoubted tendency towards healing shows that conditions in the human subject are variable, and suggests that the organism has its natural habitat in some other host. The experiments presented here serve to show that the bacillus of leprosy meets but little or no resistance in the tissues of cold-blooded animals, multiplies in their tissues, and may be harbored by them without apparent discomfort or external evidence of the disease. That no appreciable resistance is offered to the multiplication of the leprosy bacillus by many species of cold-blooded animals is shown by the fact that aside from the trauma produced by the inoculation and the slight initial reaction of the tissues, the organism continues to grow profusely, and to invade the tissues without further reaction. Quite the opposite condition occurs in mammals: in some of these the leprosy bacillus degenerates into a granular mass shortly after inoculation; in others that are less refractory, typical lesions appear, but they seldom extend from the point of inoculation; and while the bacilli multiply slowly, they do not infiltrate the tissues, but disappear after a short time, the lesions healing. That multiplication of Bacillus leprae occurs in the tissues of cold-blooded animals is shown by the fact that while animals examined a few days after inoculation show but a few scattered organisms, those killed at longer intervals show a proportional increase in the number of bacilli. Furthermore, the few bacilli found at the early-period are extracellular and scattered, while after longer periods they tend to be massed and enclosed in large lepra cells. The supposition that these lepra cells are phagocytes has naturally arisen. Duval holds that they are not phagocytes in the true sense of the term, that the bacilli penetrate the cells rather than that the cells engulf them, after which, finding conditions for growth favorable, they multiply without causing serious injury to the cell. The size of the cell depends upon the size of the colony within. The experimental work bears out this view since the decrease in number of the organisms observed in animals killed shortly after inoculation depends not upon phagocytic action nor upon cells which appear later when active lesions are established. In early lesions, the lepra cells are smaller, barely measuring twenty to thirty microns in diameter, and contain but few bacilli; whereas in older ones, they attain a diameter of 100 microns or even more, and contain enormous numbers of bacilli. Were this increase in size due to phagocytic action, some cells would be found in which the limit of their capacity had been reached; and they would either contain a mass of dead and disintegrated bacteria or would themselves show evidence of disintegration. On the contrary, the bacilli, though they occupy most of the cell, show no signs of disintegration, and the nucleus and the cytoplasm of the cell retain normal staining properties. That the invasion and multiplication of the bacilli cause an irritation is evident by the amitotic divisions of the nucleus which occur in the larger cells. The absence of external evidence of invasion by Bacillus leprae in cold-blooded animals, and the apparent lack of discomfort caused by the presence of the organism within their tissues, are points which should be remembered in considering the sources from which leprosy may be transmitted. In not a single instance in the numerous experiments presented here would it have been possible, from any external sign, to suspect that the animals were harboring multitudes of leprosy bacilli. While the evidence in support of the opinion that leprosy may be transmitted from man to man appears sufficiently strong to warrant this belief, the number of cases in which infection can be actually traced to this source is small. Since leprosy is known to be prevalent where fish and sea-food are plentiful, and since the experiments here recorded prove that fish can be infected by being fed cultures of Bacillus leprae, or nodules from human lepers, or bits of fish previously infected with the leprosy organism, account should be taken of the possibility that leprosy, in certain localities, may arise from this source of infection. The question as to how and from what source leprosy bacilli enter the human body may be still regarded as an open one. Isolated examples of direct infection of healthy human beings from lepers have been reported by Arning and Nonne, by Manson, and others. The notion that the agency of infection is already infected human beings, that is lepers, is at the foundation of the modern practice of the isolation and segregation of lepers, which would seem to have brought about a definite decrease in the prevalence of the disease. (ABSTRACT TRUNCATED)

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Molybdenum is an essential element for the function of nitrogenase in plants and as a cofactor for enzymes including xanthine oxidoreductase, aldehyde oxidase, and sulfide oxidase in animals. Molybdenum trioxide is used primarily as an additive to steel and corrosion-resistant alloys. It is also used as a chemical intermediate for molybdenum products; an industrial catalyst; a pigment; a crop nutrient; components of glass, ceramics, and enamels; a flame retardant for polyester and polyvinyl chloride resins; and a reagent in chemical analyses. Molybdenum trioxide was nominated by the NCI for toxicity and carcinogenicity studies as a representative inorganic molybdenum compound. The production of molybdenum trioxide is the largest of all the molybdenum compounds examined. Male and female F344/N rats and B6C3F1 mice were exposed to molybdenum trioxide (approximately 99% pure) by inhalation for 14 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and cultured Chinese hamster ovary cells. 14-DAY STUDY IN RATS: Groups of five male and five female F344/N rats were exposed to 0, 3, 10, 30, 100, or 300 mg molybdenum trioxide/m(3). Rats were exposed for 6 hours per day, 5 days per week, for a total of 10 exposure days during a 14-day period. All rats survived to the end of the study. The final mean body weights of male rats exposed to 100 mg/m(3) and male and female rats exposed to 300 mg/m(3) were significantly lower than those of the control groups. Male rats exposed to 300 mg/m(3) lost weight during the study. There were no clinical findings related to exposure to molybdenum trioxide. No chemical-related lesions were observed. 14-DAY STUDY IN MICE: Groups of five male and five female B6C3F1 mice were exposed to 0, 3, 10, 30, 100, or 300 mg molybdenum trioxide/m(3). Mice were exposed 6 hours per day, 5 days per week, for a total of 10 exposure days during a 14-day period. All mice survived to the end of the study. Final mean body weights of male and female mice exposed to 300 mg/m(3) were significantly lower than those of the control groups. Male mice exposed to 300 mg/m(3) lost weight during the study. There were no clinical findings related to exposure to molybdenum trioxide. No chemical-related lesions were observed. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were exposed to molybdenum trioxide by inhalation at concentrations of 0, 1, 3, 10, 30, or 100 mg/m(3) for 6.5 hours per day, 5 days per week, for 13 weeks. All rats survived to the end of the study. The final mean body weights of exposed rats were similar to those of the control groups. No clinical findings related to molybdenum trioxide exposure were observed. There were no significant chemical-related differences in absolute or relative organ weights, hematology or clinical chemistry parameters, sperm counts or motility, or liver copper concentrations between control and exposed rats. No chemical-related lesions were observed. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were exposed to molybdenum trioxide by inhalation at concentrations of 0, 1, 3, 10, 30, or 100 mg/m(3) for 6.5 hours per day, 5 days per week, for 13 weeks. All mice survived to the end of the study. The final mean body weights of exposed mice were similar to those of the control groups. There were no chemical-related clinical findings. There were no significant differences in absolute or relative organ weights or sperm counts or motility between control and exposed mice. There were significant increases in liver copper concentrations in female mice exposed to 30 mg/m(3) and in male and female mice exposed to 100 mg/m(3) compared to those of the control groups. No chemical-related lesions were observed. 2-YEAR STUDIES IN RATS: Groups of 50 male and 50 female F344/N rats were exposed to molybdenum trioxide by inhalation at concentrations of 0, 10, 30, or 100 mg/m(3). Rats were exposed for 6 hours per day, 5 days per week, for 106 weeks. Survival, Body Weights, and Special Studies: Survival rates of exposed maleed male and female rats were similar to those of the control groups. Mean body weights of exposed groups of male and female rats were similar to those of the control groups throughout the study. There was a significant exposure-dependent increase in blood molybdenum concentration in exposed rats. Blood concentrations of molybdenum in exposed male rats were greater than those in exposed female rats. There were no toxicologically significant differences in bone density or curvature between control and exposed rats. Pathology Findings: The incidences of alveolar/bronchiolar adenoma or carcinoma (combined) were increased in male rats with a marginally significant positive trend. No increase in the incidences of lung neoplasms occurred in female rats. Incidences of chronic alveolar inflammation in male and female rats exposed to 30 or 100 mg/m(3) were significantly greater than those in the control groups. No nasal or laryngeal neoplasms were attributed to exposure to molybdenum trioxide. Incidences of hyaline degeneration in the nasal respiratory epithelium in 30 and 100 mg/m(3) males and in all exposed groups of females were significantly greater than those in the control groups. The incidences of hyaline degeneration in the nasal olfactory epithelium of all exposed groups of females were significantly greater than that in the control group. In the larynx, incidences of squamous metaplasia of the epithelium lining the base of the epiglottis in all exposed groups of male and female rats were significantly greater than those in the control groups and increased with increasing exposure concentration. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female B6C3F1 mice were exposed to molybdenum trioxide by inhalation at concentrations of 0, 10, 30, or 100 mg/m(3). Mice were exposed for 6 hours per day, 5 days per week, for 105 weeks. Survival, Body Weights, and Special Studies: The survival rate of male mice exposed to 30 mg/m(3) was marginally lower than that of the control group; survival rates of 10 and 100 mg/m(3) males and of all exposed groups of females were similar to those of the control groups. Mean body weights of exposed male mice were generally similar to those of the control group throughout the study. Mean body weights of exposed female mice were generally greater than those of the control group from week 11 until the end of the study. There was a significant exposure-dependent increase in blood molybdenum concentration in exposed mice. There were no toxicologically significant differences in bone density or curvature between control and exposed mice. Pathology Findings: The incidences of alveolar/bronchiolar carcinoma in all exposed groups of males were significantly greater than that in the control group. Incidences of alveolar/bronchiolar adenoma in females in the 30 and 100 mg/m(3) groups were significantly greater than that in the control group. Incidences of alveolar/bronchiolar adenoma or carcinoma (combined) in 10 and 30 mg/m(3) males and in 100 mg/m(3) females were significantly greater than those in the control groups and exceeded the historical control ranges for 2-year NTP inhalation studies. Incidences of metaplasia of the alveolar epithelium of minimal severity in the centriacinar region of the lung were significantly increased in all exposed groups of mice. The incidences of histiocyte cellular infiltration in all exposed groups of males were significantly greater than that in the control group. Incidences of hyaline degeneration of the respiratory epithelium of the nasal cavity in 100 mg/m(3) males and females and hyaline degeneration of the olfactory epithelium of the nasal cavity in 100 mg/m(3) females were significantly greater than those in the control groups. The incidences of squamous metaplasia of the epithelium lining the base of the epiglottis were significantly increased in all exposed groups of males and females. In both male and female mice, the incidences of hyperplasia of the laryngeal epithelium in level II of the larynx increased with increasing exposure concentration. The increase was statistically significant only in mice exposed to 100 mg/m(3) with 82% of male and 70% of female mice affected. GENETIC TOXICOLOGY: Molybdenum trioxide was not mutagenic in any of five strains of Salmonella typhimurium, and it did not induce sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells in vitro. All tests were conducted with and without S9 metabolic activation enzymes. CONCLUSIONS: Under the conditions of these 2-year inhalation studies, there was equivocal evidence of carcinogenic activity of molybdenum trioxide in male F344/N rats based on a marginally significant positive trend of alveolar/bronchiolar adenoma or carcinoma (combined). There was no evidence of carcinogenic activity of molybdenum trioxide in female F344/N rats exposed to 10, 30, or 100 mg/m(3). There was some evidence of carcinogenic activity of molybdenum trioxide in male B6C3F1 mice based on increased incidences of alveolar/bronchiolar carcinoma and adenoma or carcinoma (combined). There was some evidence of carcinogenic activity of molybdenum trioxide in female B6C3F1 mice based on increased incidences of alveolar/bronchiolar adenoma and adenoma or carcinoma (combined). Exposure of male and female rats to molybdenum trioxide by inhalation resulted in increased incidences of chronic alveolar inflammation, hyaline degeneration of the respiratory epithelium, hyaline degeneration of the olfactory epithelium (females), and squamous metaplasia of the epiglottis. Exposure of male and female mice to molybdenum trioxide by inhalation resulted in increased incidences of metaplasia of the alveolar epithelium, histiocyte cellular infiltration (males), hyaline degeneration of the respiratory epithelium, hyaline degeneration of the olfactory epithelium (females), squamous metaplasia of the epiglottis, and hyperplasia of the larynx. Synonyms: Molybdic oxide; molybdic trioxide; molybdic anhydride; molybdenum (VI) oxide; molybdenum peroxide; molybdic acid anhydride; molybdenum anhydride; natural molybdite; molybdena

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Furan serves as an intermediate in the synthesis and preparation of numerous linear polymers used to prepare temperature-resistant structural laminates and to prepare copolymers used in machine dishwashing products as alternatives to phosphorus- and nitrogen-containing detergents. Toxicology and carcinogenesis studies were conducted by administering furan (purity > 99%) in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 16 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Drosophila melanogaster, mouse bone marrow cells, mouse L5178Y lymphoma cells, and Chinese hamster ovary cells. 16-Day Studies: Groups of five male rats received doses of 0, 5, 10, 20, 40, or 80 mg of furan per kg of body weight and groups of five female rats and five mice of each sex received doses of 0, 10, 20, 40, 80, and 160 mg/kg in corn oil by gavage. All male and female mice and female rats that received 160 mg/kg, all male and female rats and all male and four female mice that received 80 mg/kg, and three male mice that received 40 mg/kg died by day 8. Final mean body weights of male rats that received 20 mg/kg and of male and female rats that received 40 mg/kg were significantly lower than controls. Final mean body weights of male mice that received 10 or 20 mg/kg were significantly greater than controls. Mottled and enlarged livers were observed at necropsy in male rats that received 20, 40, or 80 mg/kg and in females that received 40, 80, or 160 mg/kg. No lesions were observed at necropsy that were considered related to furan administration in mice. 13-Week Studies: Groups of 10 rats of each sex and groups of 10 female mice received doses of 0, 4, 8, 15, 30, or 60 mg of furan per kg of body weight, and groups of 10 male mice received doses of 0, 2, 4, 8, 15, or 30 mg/kg in corn oil by gavage. Nine male and four female rats that received 60 mg/kg died before the end of the studies. There were no chemical-related deaths in mice. Final mean body weights of male rats that received 15 or 30 mg/kg and female rats that received 60 mg/kg were significantly lower than controls. Final mean body weights of male mice that received 60 mg/kg were significantly lower than controls. Relative and absolute liver weights in both sexes of rats and mice were increased in groups that received furan, as were relative and absolute kidney weights in female rats that received furan. Thymus weights were decreased in all groups of rats that received furan. Toxic lesions of the liver (bile duct hyperplasia, cholangiofibrosis, cytomegaly and degeneration of hepatocytes, and nodular hyperplasia of hepatocytes) were associated with furan administration in all dose groups of rats; the severity of the lesions increased with dose. Kidney lesions (tubule dilatation and necrosis of tubule epithelium) were present in rats that received 30 or 60 mg/kg. Thymic atrophy and testicular or ovarian atrophy were also observed in rats exposed to 60 mg/kg furan. Toxic liver lesions (cytomegaly, degeneration, and necrosis of hepatocytes) were also present in all groups of furan-exposed mice. Bile duct hyperplasia and cholangiofibrosis were observed in groups of mice receiving 30 or 60 mg/kg. Doses selected for the 2-year studies of rats and mice were based on the hepatotoxicity associated with exposure to furan. 2-Year Studies: Groups of 70 rats of each sex were administered 2, 4, or 8 mg furan per kg body weight in corn oil by gavage 5 days per week for 2 years. After 9 and 15 months of chemical exposure, 10 rats per group were evaluated for the presence of treatment-associated lesions. Groups of 50 mice of each sex received doses of 8 or 15 mg/kg furan 5 days per week for 2 years. Body Weight and Survival: Mean body weights of male rats that received 8 mg/kg furan were lower than controls from approximately week 73 to the end of the study. Survival of male and female rats that received 8 mg/kg was lower than controls from approximately week 85 to the end of the studies as a result of moribund condition associatedassociated with liver and biliary tract neoplasms and mononuclear cell leukemia. Mean body weights of male and female mice that received 15 mg/kg furan were lower than controls during the studies. Survival of low- and high-dose male and high-dose female mice was lower than controls from approximately week 80 to the end of the studies as a result of moribund condition associated with liver neoplasms. Neoplastic and Nonneoplastic Lesions: Cholangiocarcinoma of the liver occurred in all groups of dosed rats (males: control, 0/50; low dose, 43/50; mid dose, 48/50; high dose, 49/50; females: 0/50; 49/50; 50/50; 48/50) and was present in many rats of each sex at the 9- and 15-month interim evaluations (9-month: males - 0/10, 5/10, 7/10, 10/10; females - 0/10, 4/10, 9/10, 10/10; 15-month: males - 0/10, 7/10, 9/10, 6/10; females - 0/10, 9/10, 9/10, 7/10). Hepatocellular adenomas or carcinomas (combined) were significantly increased in male rats after 2 years of chemical administration (1/50, 5/50, 22/50, 35/50) and hepatocellular adenomas were significantly increased in female rats (0/50, 2/50, 4/50, 7/50); hepatocellular neoplasms were not observed at the 9- or 15-month interim evaluations. Increased incidences of numerous nonneoplastic liver lesions were present in rats administered furan. These lesions included biliary tract fibrosis, hyperplasia, chronic inflammation, and proliferation and hepatocyte cytomegaly, cytoplasmic vacuolization, degeneration, nodular hyperplasia, and necrosis. The incidence of mononuclear cell leukemia was increased in male and female rats that received 4 or 8 mg/kg furan (males: 8/50, 11/50, 17/50, 25/50; females: 8/50, 9/50, 17/50, 21/50); the incidence in the 8 mg/kg groups of each sex exceeded the historical control ranges for corn oil gavage studies. The severity of nephropathy increased with dose and the incidence was significantly increased in all groups of dosed rats; this increased severity was accompanied by an associated increased incidence of parathyroid hyperplasia (renal secondary hyperparathyroidism). The incidence of forestomach hyperplasia was increased in male and female rats (males: 1/50, 4/49, 7/50, 6/50; females: 0/50, 2/50, 5/50, 5/50) and the incidence of subacute inflammation of the forestomach was increased in female rats (0/50, 1/50, 5/50, 6/50). No forestomach neoplasms were observed in males; a squamous papilloma was present in one low-dose female. The incidences of hepatocellular adenomas and carcinomas were significantly increased in mice receiving furan (males: adenoma - 20/50, 33/50, 42/50; carcinoma - 7/50, 32/50, 34/50; females: adenoma - 5/50, 31/50, 48/50; carcinoma - 2/50, 7/50, 27/50). The incidences of numerous nonneoplastic hepatocellular lesions were increased in dosed mice. These lesions included hepatocyte cytomegaly, degeneration, necrosis, multifocal hyperplasia, and cytoplasmic vacuolization and biliary tract dilatation, fibrosis, hyperplasia, and inflammation. The incidences of benign pheochromocytoma and focal hyperplasia of the adrenal medulla were increased in low- and high-dose male and in high-dose female mice (benign pheochromocytoma: males - 1/49, 6/50, 10/50; females - 2/50, 1/50, 6/50). The incidences of squamous papilloma, focal inflammation, and papillary hyperplasia of the forestomach were increased in male mice (squamous papilloma: 0/49, 1/50, 3/50; focal inflammation: 9/49, 13/50, 21/50; papillary hyperplasia: 7/49, 14/50, 22/50). Stop-Exposure Study: A separate 2-year study was conducted in which 50 male rats were administered 30 mg/kg furan in corn oil by gavage 5 days per week for 13 weeks and then maintained for the remainder of the 2 years without additional furan administration. Groups of 10 animals were evaluated for the presence of treatment-related lesions at the end of the 13-week period of furan administration and at 9 and 15 months. Neoplastic and Nonneoplastic Lesions: Cholangiocarcinoma of the liver occurred with an overall incidence of 100% (40/40) and hepatocellular carcinoma occurred with an overall incidence of 15% (6/40) in stop-exposure male rats that survived at least 9 months. Cholangiocarcinoma was observed in all 10 males at both the 9-month and 15-month interim evaluations. Hepatocellular carcinoma was first observed in 2 males at the 15-month interim evaluation. Genetic Toxicology: Furan was negative for induction of gene mutations in Salmonella typhimurium strains TA100, TA1535, TA1537, and TA98 in the presence and the absence of exogenous metabolic activation (S9). Furan was negative for the induction of sex-linked recessive lethal mutations in germ cells of male Drosophila melanogaster when administered either by feeding or by injection. In vitro tests for genotoxicity in mammalian cells, however, were positive. Furan induced trifluorothymidine resistance in mouse L5178Y lymphoma cells in the absence of S9, and sister chromatid exchanges and chromosomal aberrations in Chinese hamster ovary cells, with and without S9. Furan administered to male B6C3F1 mice by intraperitoneal injection induced chromosomal aberrations but not sister chromatid exchanges in bone marrow cells. Conclusions: Under the conditions of these 2-year gavage studies there was clear evidence of carcinogenic activity of furan in male and female F344/N rats based on increased incidences of cholangiocarcinoma and hepatocellular neoplasms of the liver and on increased incidences of mononuclear cell leukemia. There was clear evidence of carcinogenic activity of furan in male and female B6C3F1 mice based on increased incidences of hepatocellular neoplasms of the liver and benign pheochromocytomas of the adrenal gland. Nonneoplastic liver lesions associated with furan administration in rats and mice included biliary tract fibrosis, hyperplasia, inflammation, and proliferation, as well as hepatocellular cytomegaly, degeneration, hyperplasia, necrosis, and vacuolization. In rats, increased severity of nephropathy with an associated increased incidence of parathyroid hyperplasia was associated with exposure to furan. Synonyms: Divinylene oxide, tetrole, furfuran, oxole, 1,4-epoxy-1,3-butadiene, axole, oxacyclopentadiene

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Vanadium pentoxide, commercially the most important compound of vanadium, presents a potential occupational hazard during the cleaning of oil-fired boilers and furnaces, the handling of catalysts, and during the refining, processing, or burning of vanadium-rich mineral ores or fossil fuels. Vanadium pentoxide was nominated for study by the National Cancer Institute as a representative of the metals class study. Male and female F344/N rats and B6C3F1 mice were exposed to vanadium pentoxide (99% pure) by inhalation for 16 days, 14 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and mouse peripheral blood. 16-DAY STUDY IN RATS: Groups of five male and five female rats were exposed to particulate aerosols of vanadium pentoxide at concentrations of 0, 2, 4, 8, 16, or 32 mg/m(3) by inhalation, 6 hours per day, 5 days per week for 16 days. Three males in the 32 mg/m(3) group died before the end of the study. Mean body weights of males and females exposed to 8 mg/m(3) or greater were less than those of the chamber controls. Clinical findings included rapid respiration and hypoactivity in rats exposed to 16 or 32 mg/m(3). Relative lung weights of 4 mg/m(3) or greater males and 2 mg/m(3) or greater females were significantly greater than those of the chamber controls. Lavage fluid analysis indicated an inflammatory response in the lung that was either directly mediated by vanadium pentoxide or was secondary to lung damage induced by vanadium pentoxide exposure. 16-DAY STUDY IN MICE: Groups of five male and five female mice were exposed to particulate aerosols of vanadium pentoxide at concentrations of 0, 2, 4, 8, 16, or 32 mg/m(3) by inhalation, 6 hours per day, 5 days per week for 16 days. All males exposed to 32 mg/m(3) and one 8 mg/m(3) male died or were killed moribund before the end of the study. Mean body weights of 16 mg/m(3) males and 8 mg/m(3) or greater females were significantly less than those of the chamber controls, and the 32 mg/m(3) females lost weight during the study. Absolute and relative lung weights of 4 mg/m(3) or greater males and all exposed groups of females and liver weights of 16 mg/m(3) males were significantly greater than those of the chamber controls. The mediastinal lymph nodes were enlarged in 4, 8, and 16 mg/m(3) males and females, and lymphoid hyperplasia was confirmed histologically. Lavage fluid analysis indicated an inflammatory response in the lung that was either directly mediated by vanadium pentoxide or was secondary to lung damage induced by vanadium pentoxide exposure. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were exposed to particulate aerosols of vanadium pentoxide at concentrations of 0, 1, 2, 4, 8, or 16 mg/m(3) by inhalation, 6 hours per day, 5 days per week for 3 months. Seven males and three females exposed to 16 mg/m(3) died during the study. Mean body weights were significantly less in males exposed to 4 mg/m(3) or greater and in females exposed to 16 mg/m(3). Abnormal breathing, thinness, lethargy, abnormal posture, and ruffled fur were observed in rats exposed to 16 mg/m(3). Hematology results indicated that exposure of rats to vanadium pentoxide induced a microcytic erythrocytosis in males and females. Absolute and relative lung weights were significantly greater for 4 mg/m(3) or greater males and females than for the chamber controls as were the relative lung weights of 2 mg/m(3) males. The estrous cycle of females exposed to 8 mg/m(3) was significantly longer than that of the chamber control group, and the number of cycling females in the 16 mg/m(3) group was reduced. The incidences of several nonneoplastic lesions of the lung and nose were significantly increased in males and females exposed to 2 mg/m(3) or greater. Data from pulmonary function analyses indicated that a restrictive lung disease was present in male and female rats exposed to 4 mg/m(3) or greater, while an obstructive lung disease was present only in the 16 mg/m(3) groups. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female mice were exposed to particulate aerosols of vanadium pentoxide at concentrations of 0, 1, 2, 4, 8, or 16 mg/m(3) by inhalation, 6 hours per day, 5 days per week for 3 months. One male exposed to 16 mg/m(3) died before the end of the study. Mean body weights of 8 and 16 mg/m(3) males and 4 mg/m(3) or greater females were significantly less than those of the chamber controls. Absolute and relative lung weights of males and females exposed to 4 mg/m(3) or greater were significantly greater than those of the chamber controls. The epididymal spermatozoal motility of males exposed to 8 or 16 mg/m(3) was significantly decreased. Some mice exposed to 2 or 4 mg/m(3) had inflammation of the lung, and all mice exposed to 8 or 16 mg/m(3) had inflammation and epithelial hyperplasia of the lung. 16-DAY SPECIAL STUDY IN RATS: Groups of 60 female rats were exposed to particulate aerosols of vanadium pentoxide at concentrations of 0, 1, or 2 mg/m(3) and groups of 40 female rats were exposed to 4 mg/m(3) by inhalation, 6 hours per day, 5 days per week for 16 days. Alveolar and bronchiolar epithelial hyperplasia was observed in most rats exposed to 2 or 4 mg/m(3) on days 6 and 13. Histiocytic infiltration and inflammation occurred in a time- and concentration-related manner. Cell turnover rates were increased in the terminal bronchioles on days 6 and 13 and in the alveoli in the 4 mg/m(3) group on day 6 and in all exposed groups on day 13. Assessment of lung vanadium concentrations suggested deposition and clearance exhibited linear kinetics over the exposure range studied. Lung clearance half-times ranged from 4.42 to 4.96 days. 16-DAY SPECIAL STUDY IN MICE: Groups of 60 female mice were exposed to particulate aerosols of vanadium pentoxide at concentrations of 0, 2, or 4 mg/m(3) and groups of 40 female mice were exposed to 8 mg/m(3) by inhalation, 6 hours per day, 5 days per week for 16 days. Alveolar and bronchiolar epithelial hyperplasia occurred with similar incidences and severities among the exposed groups on days 6 and 13, and time- and concentration-related increases in the incidences of interstitial inflammation and histiocytic infiltration also occurred in these groups. Cell turnover rates were increased in the terminal bronchioles on day 6 and remained greater than those of the chamber controls on day 13. In the alveoli, cell turnover rates were increased in an exposure concentration-related manner on day 13; cell turnover rates were increased only in the 8 mg/m(3) group on day 6. Assessment of lung vanadium concentrations suggested deposition and clearance exhibited linear kinetics over the exposure range studied. Lung clearance half-times ranged from 2.40 to 2.55 days. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were exposed to particulate aerosols of vanadium pentoxide at concentrations of 0, 0.5, 1, or 2 mg/m(3) by inhalation, 6 hours per day, 5 days per week for 104 weeks. Survival and body weights of males and females were generally similar to those of the chamber controls. Mean body weights of females exposed to 2 mg/m(3) were less than those of the chamber controls throughout the study. Alveolar/bronchiolar neoplasms were present in exposed groups of male rats, and the incidences often exceeded the historical control ranges. Alveolar/bronchiolar adenomas were present in 0.5 and 1 mg/m(3) females; one 2 mg/m(3) female also had an alveolar/bronchiolar carcinoma. The incidence of alveolar/bronchiolar adenoma in the 0.5 mg/m(3) group was at the upper end of the historical control ranges. Nonneoplastic lesions related to vanadium pentoxide exposure occurred in the respiratory system (lung, larynx, and nose) of male and female rats, and the severities of these lesions generally increased with increasing exposure concentration. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were exposed to particulate aerosols of vanadium pentoxide at concentrations of 0, 1, 2, or 4 mg/m(3) by inhalation, 6 hours per day, 5 days per week for 104 weeks. Survival of 4 mg/m(3) males was significantly less than that of the chamber controls. Mean body weights of 4 mg/m(3) males and all exposed groups of females were generally less than those of the chamber controls throughout the study, and those of males exposed to 2 mg/m(3) were less from week 85 to the end of the study. Many mice exposed to vanadium pentoxide were thin, and abnormal breathing was observed in some mice, particularly those exposed to 2 or 4 mg/m(3). The incidences of alveolar/bronchiolar neoplasms were significantly increased in all groups of exposed males and females. Nonneoplastic lesions related to vanadium pentoxide exposure occurred in the respiratory system (lung, larynx, and nose) of male and female mice, and the severities of these lesions generally increased with increasing exposure concentration. Bronchial lymph node hyperplasia was present in many exposed females. K-ras codon 12 mutation and loss of heterozygosity on chromosome 6 were detected in vanadium pentoxide-induced alveolar/bronchiolar carcinomas from mice. Vanadium pentoxide was not mutagenic in Salmonella typhimurium strain TA97, TA98, TA100, TA102, or TA1535, with or without induced rat or hamster liver S9 enzymes. Under the conditions of this 2-year inhalation study, there was some evidence of carcinogenic activity of vanadium pentoxide in male F344/N rats and equivocal evidence of carcinogenic activity of vanadium pentoxide in female F344/Nrats based on the occurrence of alveolar/bronchiolar neoplasms. There was clear evidence of carcinogenic activity of vanadium pentoxide in male and female B6C3F1 mice based on increased incidences of alveolar/bronchiolar neoplasms. (ABSTRACT TRUNCATED)

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Overview Psychosocial occupational epidemiology has mainly focused on the demand-control and, to a much lesser extent, the effort-reward-imbalance (ERI) models. These models and the strong focus on them raise some conceptual and methodological issues we will address in the following letter. The conceptual issues include the empirical confirmation of the assumptions of these models, the extent to which the focus on the demand-control and ERI models is warranted, and whether the sub-dimensions of the scales in these models have common health effects. We argue that there is a lack of empirical approval of (i) the assumptions behind both models and (ii) the focus on these models. The methodological issues include how exposure to job strain is categorized, how ERI previously has been measured, and the validity of self-reports of job strain. We argue that (i) a population independent definition of job strain is lacking, (ii) the older measurements of ERI mix exposure and effect, and (iii) we know little regarding the validity of the measurement of the psychosocial working environment. Finally, we suggest that analyses of monitoring data with a broader focus on the psychosocial working environment can be used to shed light to some of the issues raised above. Introduction In the last three decades (1, 2), psychosocial occupational epidemiology related to coronary heart disease (CHD) has mainly focused on the job-strain model, also referred to as the demand-control model (3, 4). In this model, two aspects of work are deemed relevant: demands and control. Negative consequences to health are to be expected when high demands are simultaneously present with low control. This combination has been termed job strain (3, 4). Recently, there has also been increased interest in the ERI model (5, 6) which considers the level of effort relative to rewards at work: an imbalance is present when the efforts outweigh the rewards (5, 6). In longitudinal studies of CHD, there has been only a limited focus on investigating occupational psychosocial factors outside of these two models (1, 2). In this letter, we would like to raise some conceptual and methodological issues which are inherent to these two stress models but also which arise from the heavy emphasis placed on them. Conceptual issues The conceptual issues we discuss below are empirical confirmation of the assumptions of these models and to what extent the focus on the demand-control and ERI models is warranted. Investigating the assumptions of the models Both the demand-control and the ERI models are based on assumptions which have only been tested empirically to a limited extent (1, 2). We pose three specific questions: (i) Does the interaction of demands and control constitute a risk factor for CHD? (ii) Does the imbalance between effort and reward explain more variance in CHD risk than high effort and low reward alone? (iii) Do the sub-dimensions of the scales in these models have common health effects? Regarding the interaction of demands and control. The concept of the demand-control model is useful when the health risk of being exposed to job strain (simultaneous high demands and low control) differs greatly from the sum of individual health risks of being exposed solely to high demands and low control. If this interaction were not present, it would be warranted to look separately at high demands and low control. This would for instance counteract overlooking those persons exposed to low control but not high demands (known as "passive work"; 3, 4). It should be emphasized that the interaction of demands and control has only been tested in very few - underpowered - cases (1, 2). Initial support for an interaction within the demand-control model can be tentatively derived from the work of the IPD-Work Consortium (7): In a reanalysis of an earlier study (8), it was shown that while neither demands nor job control alone (appendix to 8) predicted CHD, job strain did when controlling for sex, age and socioeconomic status (SES) (9). This indicates that an interaction takes place. Controlling for SES is of high relevance - otherwise, the results point in a different direction (10). However, a formal test of interaction was not performed on the IPD-Work Consortium data. Even the IPD study itself might not have sufficient statistical power to analyze a possible interaction directly: this requires many more observations than simply looking at the main effects (2). If one is interested in investigating an interaction, more incident outcomes are often required (11). Regarding effort-reward imbalance. Similarly to the combined effect of demands and control described above, focusing on the ERI model makes sense only if the imbalance of effort and reward explains the risk of CHD over and above the effect of high efforts and low rewards. To our knowledge, this has not been verified in any longitudinal study of CHD (1, 2). Regarding the effect of sub-dimensions. Finally, using the scales of the two models (demands and control or efforts and rewards) is meaningful only if the sub-dimensions of the scales all have about equal effect sizes and signs. For example, the scale psychological demands covers the sub-dimensions work pace, role conflict and work amount while control covers both influence (decision authority) and opportunities for development (skill discretion). Do these dimensions predict the risk of CHD to equal amounts within their respective scales? For now, this has not been tested elaborately to our knowledge (1, 2, 12). Consequently, it is possible that certain risk factors in the psychosocial work environment may be overlooked due to different risk factors being merged into one scale. Is the focus on the demand-control and ERI models warranted? In the past, longitudinal epidemiological research on psychosocial work characteristics and their association with the risk of CHD has mainly focused on the demand-control and - to a much lesser extent - ERI models (1). For example, in a recent review (2) covering 44 papers and including 170 analyses, 70% percent of those dealt with these models or sub-dimensions thereof. Interestingly, the demand-control model alone accounted for 66% of the analyses and ERI only 4%. A further 11% of the analyses dealt with working hours, 9% with social support, 5% with job insecurity, 3% with leadership and the remaining 3% covered conflicts, justice or predictability. Maintaining the currently high degree of focus on the DC and ERI models requires evidence that job strain and ERI are by far the most important risk factors for CHD. The review by Pejtersen et al (2) has additionally pointed out that of the 44 studies mentioned above, only two - an IPD-Work Consortium study (8) and a Swedish case-control study (13) - contained analyses with sufficient statistical power to detect an elevated CHD risk of 20%. These two sufficiently powered studies available as of April 2013 have led to the following conclusions: (i) job strain was found to be predictive of CHD in the IPD-Work Consortium study (8); and (ii) both low control and low social support predicted CHD in the Swedish study (13). Recently, a well-powered study on working hours (14) indicated that long working hours constitute a risk factor for CHD. Additionally, a recently published large study on job insecurity (15) is worth mentioning. While there was not sufficient power to detect a 20% increased risk due the relatively low prevalence of job insecurity, the study did have sufficient power to find a risk of 1.32 - which is the value actually found empirically (15). Summarizing the small number of well-powered studies available at this time indicates that both model dimensions (job strain) as well as non-model dimensions (social support and working hours) predict CHD (8, 13-15). In this context, one should bear in mind that the variety of possible dimensions that can be considered as constituting "psychosocial work environment" is large. The latter is exemplified by a recent analysis of the psychosocial content of seven European work environment monitoring questionnaires which showed that there are 34 distinct dimensions of the psychosocial work environment (16). Around half of these dimensions are not found in either the demand-control or ERI models (16). These include for instance emotional demands, demands on hiding emotions, sensorial demands, meaning of work, commitment to the workplace, organizational influence, trust, social community at work, quality of leadership, predictability, role clarity, restructuring, safety culture, work life balance, and negative acts (eg, violence, bullying). Little is currently known on the health effects of these "non-model" dimensions. Research on their possible effects might show that they are small - and that the DC and ERI dimensions are indeed the main psychosocial risk factors for CHD. However, results may also point to the importance of the non-model dimensions. To date, this remains to be investigated. Methodological issues In addition to the conceptual issues discussed above, we would like to highlight some methodological issues related to one or both of these models. The three main points address: (i) how exposure to job strain is categorized; (ii) how ERI has been measured up to now; and (iii) the validity of self-reports of job strain. Practical definition of job strain Job strain is usually operationalized as a median split of the two dimensions demands and control in the population investigated (3, 17). Hence, whether a certain worker experiences job strain or not depends on which other workers are part of the sample (18). This poses a problem when the distributions of demands and control differ between populations. Comparisons between Denmark and Spain and across Europe suggest that such differences exist (19, 20), rendering it at the least a challenge to combine populations in meta-analyses. (ABSTRACT TRUNCATED)

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IT WILL BE SEEN FROM THE ABOVE THAT WE HAVE STUDIED THE CONDITIONS ASSOCIATED WITH THE DEPOSIT OF CALCAREOUS SALTS: (I) in connection with normal and pathological ossification, and (2) in pathological calcification as exhibited in (a) atheroma of the vessels; (b) calcification of caseating tubercular lesions; (c) calcification of inflammatory new growth, and (d) degenerating tumors; and we have induced experimentally deposits of calcareous salts in the lower animals: (a) within celloidin capsules containing fats and soaps; (b) in the kidney, and (c) in connection with fat necrosis. I. We have found that bone formation and pathological calcareous infiltration are wholly distinct processes. In the former there is no evidence of associated fatty change, and the cells associated with the process of deposition of calcium are functionally active. In the latter there is an antecedent fatty change in the affected areas, and the cells involved present constant evidences of degeneration. The view that would seem to account best for the changes observed in the latter case is that with lowered vitality the cells are unable to utilize the products brought to them by the blood, or which they continue to absorb, so that the normal series of decompositions associated with their metabolism fails to take place and hence they interact among themselves in the cytoplasm with the result that insoluble compounds replace soluble ones. II. Besides the fact that calcification is always preceded by fatty change within the cells, another fact should be emphasized. namely: that combination of the fats present with calcium salts to form calcium soaps tends to occur. The stages immediately preceding these are difficult to follow with anything approaching certainty, perhaps because the earlier stages vary under different conditions. In fat necrosis, for instance, the cells affected are normally storehouses for neutral fats, and as long as they remain healthy neutral fats alone are present in them. When they are subjected to the action of the pancreatic juice with its fat-splitting ferment the cells are killed and coincidently the neutral fats are decomposed, fatty acids being deposited. The fatty acids now slowly combine with the calcium salts. In degenerating lipomata the process would seem to be similar. But in other cases the cells are not obviously fat-containing in the normal state; nevertheless prior to calcification they undergo so-called fatty degeneration, which is really a form of cell degeneration accompanied by fat infiltration. As regards the source of the cell fats in general we may safely accept: 1. That fats are transported in the blood as diffusible soaps. 2. That taken up by the cells these soaps may either- (a) Be reconverted into neutral fats and become stored in the cytoplasm as such, or (b) undergo assimilation proper, becoming part and parcel of the cell substance, in which case they are not recognizable by the ordinary microchemical tests. 3. If these two possibilities be accepted it follows that the appearance of fats and soaps in the degenerating cell may be due to either- (a) Absorption or infiltration of soaps from the surrounding medium, the degenerating cell retaining the power of splitting off the fat but being unable to utilize this in metabolism. (b) Cytoplasmic disintegration with dissociation of the soap-albumen combination or, more broadly, liberation of the fats from their combination with the cytoplasm. The appearances seen in the cells of atheromatous areas indicate that the first of these does occur. III. In areas undergoing calcareous infiltration we have demonstrated. the presence of soaps, and this often in such quantities that they can be isolated and estimated by gross chemical methods. By microchemical methods also we have been able to show that after removing all the neutral fats and fatty acids by petroleum ether there remains behind a substance giving with Sudan III the reaction we associate with the presence of soap. And experimentally we have produced these soaps within the organism, more particularly by placing capsules containing fats and fatty acids within the tissues and after several days finding that the capsules contain calcium soaps and possess a calcium content far in excess of that of the normal blood and lymph. IV. While these are the facts, certain of the details of this reaction demand elucidation. The existence of sodium and it may be potassium soaps in the degenerated cells is comprehensible if we accept that these are present in the circulating lymph and simply undergoing absorption. But even then, as these are diffusible substances how is it to be explained that they become stored up in these particular areas? We have found that, as a matter of fact, in regions which give the reaction for soaps, but which give no reaction for calcium (which therefore presumably contain at most amounts of the insoluble calcium soap too small to need consideration, the ordinary solvents for potassium and sodium soaps do not forthwith remove the stainable material; they are relatively insoluble. The reason for this insolubility is suggested by the observations made in the test tube, that soap solutions mixed with solutions of white of egg or blood serum form a precipitate of combined soap and albumen, which likewise is insoluble in water and alcohol. The indications are therefore that in cells undergoing degeneration, with degeneration of the cytoplasm, certain albuminous molecules unite with the soaps present to form relatively insoluble soap-albuminate. V. With regard to calcium soaps, these are also present and in certain stages appear to be the dominating form in the affected tissues. Two questions suggest themselves, viz.: what is the source of calcium, and what is the process by which they become formed? As to the source, the amount present in well-marked calcification is far in excess of the normal calcium contents of the affected tissue. If in the kidneys of experimental calcification three hundred times as much calcium may be present as in the normal kidney (von Kossa), the calcium must be conveyed to the part by the blood and lymph, and that this is so is demonstrated, as we have pointed out, by the distribution of the infiltration in solid organs, that like ovarian fibroids have undergone necrosis, in which the earliest deposits are superficial. As to the process, there are three possibilities: 1. That sodium and potassium soaps and soap albuminates are first formed and that interaction occurs between them and the diffused calcium salts from the lymph, the less soluble-calcium replacing the sodium and potassium. 2. That under certain conditions the calcium salts act directly on the neutral fats present in the degenerating cells. 3. That the neutral fats are first broken down into fatty acids and that these react with the calcium salts to form the soaps. We are assured that the first process occurs and that because in the boundary zone of areas of calcification we can detect soapy particles devoid of calcium, identical in position and arrangement with the particles more deeply placed which give the calcium reactions. But this is not the only reaction. In case of fat necrosis we see clearly that the third process is in evidence. And we are far from being convinced that the second does not also obtain. We have been impressed by the large accumulation of neutral fats in the cells in cases of early atheroma and the absence at any stage of the process of recognizable fatty acid. While soaps, it is true, are compounds of fatty acids with alkalies, it is recognized in ordinary domestic life that they can be formed by the direct action of strong lye upon ordinary fats, and this even in the cold. It is quite possible therefore that there occurs a similar direct process in the organism. The point is worth noting, however, that this does not occur in healthy cells the seat of fatty infiltration. We therefore leave this an open question, only laying down that, as indicated by the hyalin albuminous matrix left when calcium salts are dissolved out of an area of calcification, there must exist a calcium soap- or fat-albuminate similar to the potassium and sodium soap-albuminates already mentioned-such an albuminate as we can form with calcium soaps in the test tube. VI. In old areas of calcification soaps are largely if not entirely wanting, although these are to be detected at the periphery, when the process is still advancing. The reactions given by these older areas are almost entirely those of calcium phosphate, though some calcium carbonate is at times to be made out. This seems surely to indicate that the final stage in calcification is an interaction between the calcium soap-albuminates and substances containing phosphoric and carbonic acids. Such substances, it is needless to say, are present in considerable amounts in the lymph and blood. We must conclude that the acid sodium phosphates of the lymph act on the calcium soap, the highly insoluble calcium phosphates being formed (plus the albuminous moiety of the original compound) and diffusible sodium soap being liberated, while similarly alkaline carbonates form calcium carbonate and liberate sodium and potassium soaps. Calcium phosphate and calcium carbonate thus become the insoluble earthy salts of old crystalline areas of calcification. VII. As already stated very little soap is to be found in these old areas. It is possibly worth suggestion that the soaps liberated in this last reaction, as they diffuse out, again react with diffusible calcium salts and form calcium soaps which once more react with the alkaline salts to produce the phosphates and carbonates; that, in short, they have a katalytic action. (ABSTRACT TRUNCATED)

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Indium phosphide is used to make semiconductors,injection lasers, solar cells, photodiodes, and light-emittingdiodes. Indium phosphide was nominated for study because of its widespread use in the microelectronics industry, the potential for worker exposure,and the absence of chronic toxicity data. Male and female F344/N rats and B6C3F1 mice were exposed to indium phosphide (greater than 99% pure) by inhalation for 14 weeks or 2 years. The frequency of micronuclei was determined in the peripheral blood of mice exposed to indium phosphide for 14 weeks. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were exposed to particulate aerosols of indium phosphide with amass median aerodynamic diameter of approximately 1.2 microm at concentrations of 0, 1, 3, 10, 30, or 100 mg/m3 by inhalation, 6 hours per day, 5 days per week (weeks 1 through 4 and weeks 10 through 14) or 7 days per week (weeks 5 through 9) to accommodate a concurrent teratology study. One male in the 100 mg/m3 group died before the end of the study. Body weight gains of all males and females exposed to 100 mg/m3 were less than those of the chamber controls. As a result of indium phosphide exposure, the lungs of all exposed rats had a gray to black discoloration and were significantly enlarged, weighing 2.7- to 4.4-fold more than those of the chamber controls. Indium phosphide particles were observed throughout the respiratory tract and in the lung-associated lymph nodes. A spectrum of inflammatory and proliferative lesions generally occurred in the lungs of all exposed groups of rats and consisted of alveolar proteinosis, chronic inflammation, interstitial fibrosis, and alveolar epithelial hyperplasia. Pulmonary inflammation was attended by increased leukocyte and neutrophil counts in the blood. The alveolar proteinosis was the principal apparent reason for the increase in lung weights. Indium phosphide caused inflammation at the base of the epiglottis of the larynx and hyperplasia of the bronchial and mediastinal lymph nodes. Exposure to indium phosphide affected the circulating erythroid mass. It induced a microcytic erythrocytosis consistent with bone marrow hyperplasia and hematopoietic cell proliferation of the spleen. Hepatocellular necrosis was suggested by increased serum activities of alanine aminotransferase and sorbitol dehydrogenase in all exposed groups of males and in 10 mg/m3 or greater females and was confirmed microscopically in 100 mg/m3 males and females. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were exposed to particulate aerosols of indium phosphide with a mass median aerodynamic diameter of approximately 1.2 microm at concentrations of 0, 1, 3, 10, 30, or 100 mg/m3 by inhalation, 6 hours per day, 5 days per week (weeks 1 through 4 and weeks 10 through 14)or 7 days per week (weeks 5 through 9). Although the effects of indium phosphide exposure were similar in rats and mice, mice were more severely affected in that all males and females in the 100 mg/m3 groups either died or were removed moribund during the study. One male and three females in the 30 mg/m3 group were also removed before the end of the study. In general, body weight gains were significantly less in males and females exposed to 3 mg/m3 or greater compared to those of the chamber controls. Mice exposed to 30 or 100 mg/m3 were lethargic and experienced rapid, shallow breathing. As in rats, lungs were discolored and enlarged 2.6- to 4.1-fold greater than those of chamber controls due to the exposure-induced alveolar proteinosis. Indium phosphide particles were observed in the nose, trachea,larynx, and lymph nodes of some exposed males and females. Alveolar proteinosis, chronic active inflammation,interstitial fibrosis, and alveolar epithelial hyperplasia were observed; these effects were more severe than in rats. Hyperplasia in the bronchial lymph nodes and squamous metaplasia, necrosis, and suppurative inflammation of the larynx were observed in some exposed males and females. Exposure to indium phosphide induced a microcytic erythrocytosis which was consistent with the observed hematopoietic cell proliferation of the spleen.2-YEAR STUDY IN RATS Groups of 60 male and 60 female rats were exposed to particulate aerosols of indium phosphide at concentrations of 0, 0.03, 0.1, or 0.3 mg/m3, 6 hours per day,5 days per week, for 22 weeks (0.1 and 0.3 mg/m3 groups) or 105 weeks (0 and 0.03 mg/m3 groups). Animals in the 0.1 and 0.3 mg/m3 group were maintained on filtered air from exposure termination at week 22 until the end of the studies. Ten males and 10 females per group were evaluated at 3 months. 3-Month Interim Evaluation: Exposure to indium phosphide for 3 months caused a microcytic erythrocytosis and also caused enlarged lungs and lesions in the respiratory tract and lung associated lymph nodes. Although qualitatively similar to those observed in the 14-week studies, these effects were considerably less severe. However, the lesions in the lungs of rats exposed to 0.1 or 0.3 mg/m3 were considered sufficiently severe that exposure was discontinued in these groups, and the groups were allowed to continue unexposed for the remainder of the study. Survival, Body Weights, and Clinical Findings: Exposure to indium phosphide had no effect on survival or body weight gain. During the last 6 months of the study, rats in the 0.03 and 0.3 mg/m3 groups became lethargic and males breathed abnormally. Pathology Findings: At 2 years, exposure to indium phosphide caused increased incidences of alveolar/bronchiolar adenomas and carcinomas in rats. Squamous cell carcinoma of the lung occurred in four male rats exposed to 0.3 mg/m3. As observed in the 14-week study and at the 3-month interim evaluation, a spectrum of inflammatory and proliferative lesions of the lung were observed in all exposed groups of males and females;however, the extent and severity of the lesions were generally greater and included atypical hyperplasia,chronic inflammation, alveolar epithelial hyperplasia and metaplasia, alveolar proteinosis, and interstitial fibrosis. Exposure to indium phosphide also caused increased incidences of benign and malignant pheochromocytomas of the adrenal gland in males and females. Marginal increases in the incidences of mononuclear cell leukemia in males and females, fibroma of the skin in males, and carcinoma of the mammary gland in females may have been related to exposure to indium phosphide. 2-YEAR STUDY IN MICE: Groups of 60 male and 60 female mice were exposed to particulate aerosols of indium phosphide at concentrations of 0, 0.03, 0.1, or 0.3 mg/m3, 6 hours per day,5 days per week, for 21 weeks (0.1 and 0.3 mg/m3 groups) or 105 weeks (0 and 0.03 mg/m3 groups). Animals in the 0.1 and 0.3 mg/m3 groups were maintained on filtered air from exposure termination at week 21 until the end of the studies. Ten males and 10 females per group were evaluated at 3 months. 3-Month Interim Evaluation:Exposure to indium phosphide for 3 months affected the circulating erythroid mass and caused enlarged lungs and lesions in the respiratory tract and lung associated lymph nodes. These effects, although qualitatively similar to those observed in the 14-week studies, were considerably less severe. However, the lesions in the lungs of mice exposed to 0.1 mg/m3 and greater were considered sufficiently severe that exposure was discontinued in these groups and the groups were allowed to continue unexposed for the remainder of the study. Survival and Body Weights: In general, exposure to indium phosphide for 2 years reduced survival and body weight gain in exposed males and females. Pathology Findings:At 2 years, exposure to indium phosphide caused increased incidences of alveolar/bronchiolar carcinomas in males and alveolar/bronchiolar adenomas and carcinomas in females. In addition to the alveolar proteinosis and chronic active inflammation seen at earlier time points, serosa fibrosis and pleural mesothelial hyperplasia were also present. The incidences of hepatocellular neoplasms were also significantly increased in exposed males and females. Exposed groups of males and females had increased incidences of eosinophilic foci of the liver at 2 years. Marginal increases in the incidences of neoplasms of the small intestines in male mice may have been related to exposure to indium phosphide. Exposure to indium phosphide also caused inflammation of the arteries of the heart, primarily the coronary arteries and the proximal aorta, and to a lesser extent the lung-associated lymph nodes in males and in females. TISSUE BURDEN ANALYSES: Deposition and clearance studies of indium following long term exposure of rats and mice to indium phosphide by inhalation were performed. Although there were quantitative differences in lung burden and kinetic parameters for rats and mice, qualitatively they were similar. Deposition of indium in the lungs appeared to follow a zero-order (constant rate) process. Retained lung burdens throughout the studies were proportional to exposure concentration and duration. No differences in elimination rates of indium from the lungs were observed as a function of exposure concentration in either rats or mice. These studies indicated that elimination of indium was quite slow. Mice exhibited clearance half-times of 144 and 163 days for the 0.1 and 0.3 mg/m3 groups, respectively, as compared to 262 and 291 days for rats exposed to the same concentrations. The lung deposition and clearance model was used to estimate the total amount of indium deposited in the lungs of rats and mice after exposure to 0.03 mg/m3 for 2 years or to 0.1 or 0.3 mg/m3 for 21 or 22 weeks, the lung burdens at the end of the 2-year study, and the area under lung burden curves (AUC). For both species, estimates at the end of 2 years indicated that the lung burdens in the continuously exposed 0.03 mg/m3 groups were greater than those in the 0.1 or 0.3 mg/m3 groups. (ABSTRACT TRUNCATED)

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[formula: see text] Fumonisin B1 is a mycotoxin produced by the fungus Fusarium moniliforme, one of the major species found in corn. There are no known commercial or medical uses of fumonisin B1. Fumonisin B1 was nominated by the FDA Center for Food Safety and Applied Nutrition for study because of its occurrence in corn and corn-based products in the United States and its toxicity in field exposure of horses and pigs. Male and female F344/N Nctr BR rats and B6C3F1/Nctr BR (C57BL/6N x C3H/HeN MTV-) mice were exposed to fumonisin B1 (92% pure) in feed for 28 days or (greater than 96% pure) for 2 years. 28-DAY STUDY IN RATS: Groups of 10 male and 10 female rats were fed diets containing 0, 99, 163, 234, or 484 ppm fumonisin B1 for 28 days. There were no exposure-related deaths in rats. The mean body weights of the 484 ppm groups were significantly less (-16%) than those of the controls. Dietary concentrations of 99, 163, 234, and 484 ppm fumonisin B1 resulted in average daily doses of 12, 20, 28, and 56 mg fumonisin B1/kg body weight for males and females. Additional groups of male and female rats were exposed to the same concentrations of fumonisin B1 for 28 days for clinical pathology studies. The concentrations of creatinine, cholesterol, triglycerides, and total bile acids, as well as activities of the enzymes alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, and gamma-glutamyltransferase, were generally significantly greater in the 484 ppm groups than in the control groups at all time points, indicating hyperlipidemia and a hepatic effect. Fumonisin B1 is an inhibitor of ceramide synthase, resulting in an interruption of de novo sphingolipid synthesis. This enzyme inhibition results in increased levels of sphinganine (or increased sphinganine:sphingosine ratio) in tissues and urine. Urinary sphinganine was increased in groups of males exposed to 163 ppm or greater, while urinary sphinganine was increased in all exposed groups of females. The kidney weights, relative to body weight, of all exposed groups of rats were less than those of the control groups, decreasing by approximately 11% in the females and 20% in the males. Apoptosis and degeneration of the kidney were observed in all exposed males and in most females exposed to 163 ppm or greater. The incidences of minimal to mild apoptosis, degeneration, and mitotic alteration of the liver were significantly increased in 234 and 484 ppm males and in females exposed to 163 ppm or greater. The incidences of bile duct hyperplasia were significantly increased in males and females in the 484 ppm groups. In the core study, male rats in all exposed groups and females exposed to 163 ppm or greater had significantly increased percentages of hepatocytes in one or more proliferative (non-G0) states. 28-DAY STUDY IN MICE: Groups of 12 male and 12 female mice were fed diets containing 0, 99, 163, 234, or 484 ppm fumonisin B1 for 28 days. There were no exposure-related deaths in mice. The mean body weights of the 484 ppm groups of males were significantly less than those of the controls. Feed consumption by males exposed to 484 ppm was less than that by the controls; dietary concentrations of 99, 163, 234, and 484 ppm fumonisin B1 resulted in average daily doses of approximately 19, 31, 44, and 93 mg/kg for males and 24, 41, 62, and 105 mg/kg for females. Additional groups of male and female mice were exposed to the same concentrations of fumonisin B1 for 28 days for clinical pathology studies. Cholesterol and total bile acid concentrations and alanine aminotransferase and alkaline phosphatase activities were increased at 484 ppm, indicating hyperlipidemia and a hepatic effect. Urinary sphinganine concentrations and sphinganine/sphingosine ratios were increased in 484 ppm male mice. In 484 ppm males and all exposed groups of females, the incidences of hepatocellular necrosis, diffuse periportal hypertrophy, and diffuse centrilobular hyperplasia, as well as hyperplasia of the bile canaliculi and Kupffer cells, were generally significantly greater than those in the controls. Core study males exposed to 99, 163, or 234 ppm had significantly increased incidences of hepatocellular cytoplasmic alteration. Hepatocytes of 484 ppm male mice and all exposed groups of female mice were induced into proliferative (non-G0) states. 2-YEAR STUDY IN RATS: Groups of 48 male and 48 female rats (40 for 5 ppm groups) were fed diets containing 0, 5, 15, 50, or 150 ppm fumonisin B1 (males) or 0, 5, 15, 50, or 100 ppm fumonisin B1 (females) (equivalent to average daily doses of approximately 0.25, 0.76, 2.5, or 7.5 mg/kg to males and 0.31, 0.91, 3.0, or 6.1 mg/kg to females) for 105 weeks. Additional groups of four male and four female rats were exposed to the same concentrations as the core study animals and were evaluated at 6, 10, 14 or 26 weeks. Survival, Body Weights, and Feed Consumption Survival, mean body weights, and feed consumption of exposed male and female rats were generally similar to the controls throughout the study. Clinical Pathology Findings Sphinganine/sphingosine ratios were increased in the urine of 15, 50 and 150 ppm males and 50 and 100 ppm females exposed to fumonisin B1 for up to 26 weeks. The sphinganine/sphingosine ratios were also increased in kidney tissue of 50 and 150 ppm males (85- and 119-fold) and 50 and 100 ppm females (7.8- and 22-fold) at 2 years. Cell Proliferation Analyses Renal tubule epithelial cell proliferation was increased in 50 and 150 ppm male rats exposed to fumonisin B1 for up to 26 weeks. Renal tubule epithelial cell proliferation was marginally increased in 100 ppm females. Organ Weights and Pathology Findings Kidney weights of 50 and 150 ppm males were less than those of the controls at 6, 10, 14, and 26 weeks and at 2 years. Kidney weights of 100 ppm females were less than those of the controls at 26 weeks, and kidney weights of 15, 50, and 100 ppm females were less than those of the controls at 2 years. At 2 years, there was a significant increase in the incidences of renal tubule adenoma from none in the groups receiving 15 ppm or less to five of 48 in 150 ppm males. Renal tubule carcinomas were not present in male rats receiving 15 ppm or less and occurred in seven of 48 and 10 of 48 male rats in the 50 and 150 ppm groups, respectively. Incidences of apoptosis of the renal tubule epithelium were generally significantly increased in males exposed to 15 ppm or greater for up to 26 weeks. The incidences of focal renal tubule epithelial hyperplasia were significantly increased in 50 and 150 ppm males at 2 years. 2-YEAR STUDY IN MICE: Groups of 48 male and 48 female mice were fed diets containing 0, 5, 15, 80, or 150 ppm (males) or 0, 5, 15, 50, or 80 ppm (females) fumonisin B1 (equivalent to average daily doses of approximately 0.6, 1.7, 9.7, or 17.1 mg/kg to males or 0.7, 2.1, 7.1, or 12.4 mg/kg to females) for 105 weeks. Additional groups of four male and four female mice were exposed to the same concentrations as the core study animals and were evaluated at 3, 7, 9, or 24 weeks. Survival, Body Weights, and Feed Consumption Survival of males and females in the 15 ppm groups and of 5 ppm females was significantly greater and survival of 80 ppm males and females was significantly less than that of the control groups. Mean body weights and feed consumption of exposed mice were generally similar to the controls. Organ Weights and Pathology Findings Liver weights, relative to body weight, were increased 1.3- and 2.9-fold in 50 and 80 ppm females at 2 years. At 2 years, the incidences of hepatocellular adenoma in 50 and 80 ppm females were significantly greater than those in the controls and occurred with a positive trend. Similarly, the incidences of hepatocellular carcinoma increased from none in the groups receiving 0, 5, or 15 ppm fumonisin B1 to 10 of 47 females at 50 ppm and nine of 45 females at 80 ppm. The incidences of hepatocellular hypertrophy were significantly increased in 15, 80, and 150 ppm males and in 50 and 80 ppm females at 2 years. The incidences of hepatocellular apoptosis were significantly increased in 50 and 80 ppm females at 2 years. Under the conditions of these 2-year feed studies, there was clear evidence of carcinogenic activity of fumonisin B1 in male F344/N rats based on the increased incidences of renal tubule neoplasms. There was no evidence of carcinogenic activity of fumonisin B1 in female F344/N rats exposed to 5, 15, 50, or 100 ppm. There was no evidence of carcinogenic activity of fumonisin B1 in male B6C3F1 mice exposed to 5, 15, 80, or 150 ppm. There was clear evidence of carcinogenic activity of fumonisin B1 in female B6C3F1 mice based on the increased incidences of hepatocellular neoplasms. The sphinganine/sphingosine ratios were increased in the urine and the kidney tissue of rats receiving diets containing fumonisin B1. There was evidence of apoptosis and increased cell proliferation of the renal tubule epithelium in exposed rats, particularly in those groups of males that developed renal tubule neoplasms. Increased incidences of hyperplasia of the renal tubule epithelium also occurred in these groups of male rats. In mice exposed to the higher concentrations of fumonisin B1, males and females had increased incidences of hepatocellular hypertrophy and females had increased incidences of hepatocellular apoptosis.

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It has been found that although there is some parallelism between the quantity of tubercle bacilli demonstrable histologically and the number of colonies that can be isolated from a given tissue, the culture method is far the more efficient in indicating quantitative relations. Tubercle bacilli were not perceived in the organs of rabbits 1 day after infection with the modified BCG although as many as 1,500 colonies were isolated from one of them. This may be solely because it is difficult to see widely dispersed single minute acid-fast rods in the diffuse infiltrations of mononuclears with their hyperchromatic nuclei and sparse cytoplasm. Later, with the formation of tubercle, the parallelism is much closer. The culture method gives evidence concerning the number of living tubercle bacilli in the tissue. The significance of the accumulation of acid-fast particles in the tissues has been discussed. It has been seen that from the beginning this accumulation is greater in the Kupffer cells of the liver, in the macrophages of the spleen and in the reticular cells of the bone marrow than within the mononuclears of the lung, the organ where the bacilli grow with the greatest rapidity and are destroyed with the greatest difficulty. Acid-fast particles are more prominent with the bovine than with the human bacillus or the BCG, the microorganism that is destroyed with the greatest difficulty thus leaving more incompletely digested bacillary debris at a given time within the cells. Thus it seems permissible to conclude from the presence of acid-fast material that some tubercle bacilli are undergoing destruction even 24 hours after infection. The initial accumulation of polynuclear leucocytes corresponds with the subsequent severity of the infection. Despite the greater primary localization of bacilli in the liver, this initial inflammatory reaction with all three infections is much greater in the lung than in the liver. In each organ it is more intense with the bovine than with the less virulent strains. The multiplication of the bacillus and its accumulation within large mononuclear and young epithelioid cells is accompanied by an intense formation of new mononuclears by mitosis. The more rapid the growth of the bacillus, the more conspicuous the regeneration of these cells. Thus with all strains mitosis is more intense in the more susceptible organ, as in the lung compared with the liver; with the most virulent strain the most extensive and diffuse accumulation of these new cells corresponds with the greater rise in the numbers of bovine bacilli after the lag of the 1st week. With the maturation of the epithelioid cells and the formation of tubercles the bacilli have already been greatly reduced numerically and the speed of this process diminishes with the virulence of the three strains used. The faster the development of tubercle the faster the destruction of the bacillus and the earlier the resorption of the tubercle. Tubercle bacilli never accumulate in such large numbers in the mononuclears of the liver as they do in the lung. Though at first the tubercles in the liver may be more numerous than those in the lung they never attain the same size. The formation of new mononuclears by mitosis is restricted and Langhans' giant cells appear very early (1st and 2nd weeks). In the lung, giant cells are not found until much later with the BCG and the human bacillus (4th week); they were not noted in the interstitial tubercles with the bovine type, but the extension of these tubercles was accompanied by an unabated mitosis of mononuclears until the death of the animal. The liver tubercles are resorbed early even with the bovine infection. Associated with these histological differences are the slow initial growth and the early and complete destruction of the tubercle bacilli even of bovine type in the liver, and the more rapid initial growth in the lung, with the later destruction of the BCG and the human bacillus and the unabated growth of the bovine bacillus. Similar differences were observed between the splenic pulp and corpuscle. In the former the accumulation of acid-fast particles was much greater and the tubercles developed earlier. Mitosis of mononuclears was less frequent and giant cells appeared earlier. Tubercle bacilli, always intracellular, disappeared from the tubercles in the pulp sooner than from those in the corpuscle, and the tubercles themselves first disappeared from the pulp. Consequently with the persistence of bacilli mitosis continued in the tubercles of the corpuscle and these attained a much larger size. Moreover individual resistance is linked with the ability to form mature tubercles early. In two animals simultaneously infected with the same strain and killed at the same time, the destruction or retardation of the bacillus is greater in that rabbit in which maturation of the tubercle and of epithelioid cells has proceeded further (Figs. 15 and 16). These observations indicate that the mononuclears of different organs or even of the same organ, as in the different parts of the spleen, have a different capacity to destroy the tubercle bacillus, and that the transformation of the mononuclear into the mature epithelioid cell follows its destruction of the tubercle bacilli. In the lung the more virulent types of bacillus are destroyed within the epithelioid cells of interstitial tubercles but persist in foci of tuberculous pneumonia. In this organ in rabbits infected with the human strain and to a lesser degree in rabbits infected with the bovine strain, the parasite largely disappears from the epithelioid cells of interstitial tubercles. But with both strains tubercle bacilli in large numbers may accumulate within epithelioid cells lying free in the alveoli. With the human type they are numerous within the cells and free in caseous material in the localized foci of caseous pneumonia. With the bovine infection, this caseous pneumonia is more often widespread and in the areas of caseous pneumonia the greater part of the vast accumulation of bovine bacilli in the lungs is found; as many as 200,000 colonies have been isolated from 10 mg. of tissue (Fig. 11). Flooding of the respiratory passages by the caseation of tuberculous lesions into the bronchi plays an important rôle in dissemination of tubercle bacilli through the lung. The process on the contrary is predominantly interstitial when the bovine bacillus is held in check (Fig. 12). Thus there is apparently some factor acting in the alveoli that favors the growth of the parasite. The accumulation of tubercle bacilli is seen especially in the peripheral epithelioid cells in immediate contact with the alveolar space. In the same lung the bacilli are much fewer in the interstitial tubercles. The accumulation in human tuberculosis of large numbers of tubercle bacilli in the tissues lining cavities is well known. Novy and Soule (20) have shown that within certain limits the growth of the bacillus in vitro is proportional to the oxygen tension of its environment. Corper, Lurie and Uyei (21) have confirmed these observations and have noted further that a difference in the gaseous environment of the bacilli equal to the difference between the conditions existing in the alveolar air and the venous blood is sufficient to cause a considerable increase in the growth of the microorganism in vitro. Loebel, Shorr and Richardson (22) by the use of Warburg's manometer have found that the oxygen consumption of tuberculous tissue is such that a tubercle 0.5 mm. thick would completely exhaust the oxygen of the air before it reached the center. These observations suggest that a factor responsible for the greater multiplication of the bacillus in the cells of the alveoli may be the greater oxygen tension of the alveolar air. In the liver, spleen and bone marrow even with the bovine infection many instances were found of the effective destruction of the parasite synchronously with the maturation of epithelioid cells and the formation of tubercle. On the other hand, in the spleen and bone marrow of some rabbits, living bacilli persisted within the epithelioid cells of isolated tubercles even 2 months after infection, a condition never found with the human type or BCG infection. Thus the epithelioid cell is the means of defense for the rabbit against the bovine type bacillus, and as such it is usually adequate in the liver, spleen and bone marrow though ineffective in the lung and kidney. In the latter, descending infection, and the occasional colony-like multiplication of bacilli in unorganized material, tubular casts, determine the long persistence of large numbers of bacilli in this organ. In differentiating the mononuclear phagocyte of the connective tissues into the monocyte and clasmatocyte Sabin and her coworkers (23) have maintained that the clasmatocyte can efficiently destroy the tubercle bacillus but that the monocyte and its derivatives, the epithelioid and Langhans' giant cells, cannot. With the progress of the disease they have noted that the monocytes accumulate in great numbers in the foci of infection and overflow into general circulation (4). White (24) and Sabin and her coworkers have concluded that tuberculosis is specifically a disease of the monocyte, and that this cell and its derivatives act as incubators for the tubercle bacillus. Doan and Sabin (25) have therefore sought, with indecisive results, to protect the body against tuberculosis by an antimonocytic serum. However it has been shown here that although an intense multiplication of mononuclears is associated with the growth of the tubercle bacillus, their transformation into mature epithelioid cells is constantly associated with its destruction, and the rapidity of the destruction varies with the rapidity of the maturation of tubercle. (ABSTRACT TRUNCATED)

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Promethazine hydrochloride is a drug used for the management of allergic conditions, motion sickness and nausea, and as a sedative to (treat psychiatric disorders. This drug was nominated for testing by the Food and Drug Administration because of its widespread use in human medicine and because of lack of data on its potential carcinogenicity. Oral administration is the most common route of human exposure. Toxicology and carcinogenicity studies were conducted by administering promethazine hydrochloride (>99% pure) in distilled water by gavage to groups of male and female F344/N rats and B6C3F1 mice for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, in cultured Chinese hamster ovary cells, and in Drosophila melanogaster. 16-DAY STUDY IN RATS: Groups of five male and five female rats received 0, 18.5, 55.5, 166.5, 500, or 1,500 mg promethazine hydrochloride/kg body weight once daily, 5 days per week for a total of 12 doses in a 16-day period. All rats receiving 1,500 mg/kg, four males and four females receiving 500 mg/kg, and one male and one female receiving 166.5 mg/kg died during the study. No deaths occurred in the remaining dose groups. Final mean body weights of rats receiving 166.5 mg/kg were significantly lower (12% to 25%) than those of the controls. Clinical findings included decreased activity, ocular discharge, and labored breathing in males and females receiving 166.5, 500, and 1,500 mg/kg as well as tremors in females receiving 166.5 and 500 mg/kg. There were dose-related increases in the absolute and relative liver weights of rats. Focal suppurative inflammation occurred in the nose of some male and female rats receiving 55 or 166.5 mg/kg and in the trachea of some male and female rats receiving 166.5 mg/kg. 16-DAY STUDY IN MICE: Groups of five male and five female mice received 0, 18.8, 37.5, 75, 150, or 300 mg promethazine hydrochloride/kg body weight once daily, 5 days per week for a total of 12 doses in a 16-day period. Two females receiving 75 mg/kg, one male and one female receiving 150 mg/kg, and four females receiving 300 mg/kg died during the study. No deaths occurred in the remaining dose groups. Final mean body weights of mice receiving promethazine hydrochloride were similar to those of the controls. However, in male and female controls, the final mean body weights were 11% to 12% lower than the initial mean body weights. Clinical findings occurred as early as the first day of the study and included decreased activity in male and female mice receiving 150 and 300 mg/kg. Tremors occurred in one male and five females in the 300 mg/kg group on day 1 and in one male in the 150 mg/kg group and five males and one female in the 300 mg/kg group on day 2. Absolute and relative liver weights of male mice receiving 75, 150, or 300 mg/kg were significantly greater than those of the controls. No chemical related lesions were present in male or female mice. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats received 0, 3.7, 11.1, 33.3, 100, or 300 mg promethazine hydrochloride/kg body weight once daily, 5 days per week for 13 weeks. One female receiving 100 mg/kg and six males and nine females receiving 300 mg/kg died during the study. No deaths occurred in the remaining dose groups. Final mean body weights of male rats receiving 100 or 300 mg/kg were significantly lower (19% to 22%) than those of the controls. Mean body weight gain of females receiving 100 mg/kg was significantly lower (14%) than that of the controls. Clinical findings in rats included hunched posture and labored breathing. Absolute and relative liver weights of males receiving 11.1, 33.3, 100, or 300 mg/kg and females receiving 33.3 or 100 mg/kg were significantly greater than those of the controls. Focal suppurative inflammation of the nose and trachea occurred with an increased incidence in rats receiving 100 and 300 mg/kg. A dose-related increased incidence of vacuolar degeneration of the nasal olfactory epithelium occurred in male and female rats that received 11.1, 33.3, or urred in male and female rats that received 11.1, 33.3, or 100 mg/kg. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice received 0, 5, 15, 45, 135, or 405 mg promethazine hydrochloride/kg body weight once daily, 5 days per week for 13 weeks. One control female, one female receiving 5 mg/kg, two females receiving 45 mg/kg, four females receiving 135 mg/kg, and all mice receiving 405 mg/kg died during the study. No deaths occurred in the remaining dose group. Final mean body weights of mice receiving 135 mg/kg were significantly lower (8% to 9%) than those of the controls. Clinical findings of toxicity included labored breathing and decreased activity in one 135 mg/kg female. Absolute and relative liver weights increased in a dose-related trend in both sexes. No chemical-related lesions were observed in mice. 2-YEAR STUDY IN RATS: Based on mortality and body weight differences observed at higher levels, doses of promethazine hydrochloride selected for the 2-year study in rats were 0, 8.3, 16.6, and 33.3 mg/kg. Groups of 60 male or 60 female rats were administered promethazine hydrochloride in deionized water by gavage once daily, 5 days per week for up to 103 weeks. Up to ten male and ten female rats per dose group were evaluated at 15 months. Survival, Body Weights, and Clinical Findings: There was a significant dose-related decrease in survival of rats. The survival rates in the 16.6 and 33.3 mg/kg male groups and in the 33.3 mg/kg female group were significantly lower than those of the controls. The final mean body weight of male rats receiving 33.3 mg/kg promethazine hydrochloride was 10% lower than that of the controls. Final mean body weights of female rats in the 16.6 and 33.3 mg/kg groups were 9% and 11% lower than that of the controls, respectively. No chemical-related clinical findings were noted in any dose group. Significant increases in the absolute and relative liver weights of mid- and high-dose female rats and the relative liver weights of mid- and high-dose male rats were observed at the 15-month interim evaluation. There were no biologically significant differences in the hematology or clinical chemistry parameters measured at 15 months. Pathology Findings: No neoplasms that could be attributed to promethazine hydrochloride administration were found in male or female rats. Several neoplasms occurred with a significantly decreased incidence in rats receiving promethazine hydrochloride. These included adrenal medullary pheochromocytoma (benign or malignant) and pituitary gland adenoma in the 33.3 mg/kg males and uterine stromal polyp in the 33.3 mg/kg females. The decreased incidences of adrenal medullary pheochromocytoma were chemical related. The decreased incidences of pituitary gland adenoma and uterine stromal polyp may have been related to chemical administration. Diffuse fatty change of the liver of male rats increased with dose and was attributed to chemical administration. 2-YEAR STUDY IN MICE: Based on mortality and body weight differences observed at higher levels, the doses of promethazine hydrochloride selected for the 2-year study were 0, 11.25, 22.5, and 45 mg/kg for male mice and 0, 3.75, 7.5, and 15 mg/kg for female mice. Groups of 60 male or 60 female mice were administered promethazine hydrochloride in deionized water by gavage once daily, 5 days per week for up to 103 weeks. Up to 10 male and 10 female mice per dose group were evaluated at 15 months. Survival, Body Weights, and Clinical Findings: Survival of mice receiving promethazine hydrochloride was similar to that of the controls. Mean body weights of mice were within 7% of those of the controls throughout the study. There were no chemical-related clinical findings in male or female mice. There were no differences in hematology or clinical chemistry parameters measured at 15 months that were attributed to the administration of promethazine hydrochloride. Pathology Findings: There were no neoplasms or nonneoplastic lesions that were attributed to the administration of promethazine hydrochloride. GENETIC TOXICOLOGY: Promethazine hydrochloride did not induce gene mutations in Salmonella typhimurium strains TA97, TA98, TA100, TA1535, or TA1537, or a significant increase in chromosomal aberrations in cultured Chinese hamster ovary cells; both of these tests were conducted with and without exogenous metabolic activation (S9). A small dose-related increase in sister chromatid exchanges was observed in cultured Chinese hamster ovary cells in the presence of S9; this response was considered to be equivocal. No increase in sister chromatid exchanges was observed in the absence of S9. Promethazine hydrochloride did not induce sex-linked recessive lethal mutations in germ cells of male Drosophila melanogaster administered the chemical by feeding or injection. CONCLUSIONS: Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity of promethazine hydrochloride in male or female F344/N rats receiving 8.3, 16.6, or 33.3 mg/kg. There was no evidence of carcinogenic activity of promethazine hydrochloride in male B6C3F1 mice receiving 11.25, 22.5, or 45 mg/kg. There was no evidence of carcinogenic activity of promethazine hydrochloride in female B6C3F1 mice receiving 3.75, 7.5, or 15 mg/kg. The decrease in the incidences of adrenal medullary pheochromocytoma in male rats was considered to be related to promethazine hydrochloride administration. The decrease in the incidences of pituitary gland adenoma in male rats and uterine stromal polyp in female rats may have been related to promethazine administration. Synonyms: Phenothiazine,10-(2-(dimethylamino)propyl)-,monochlorohydrate; 10H-phenothiazine-10-ethanamine;10-(2-dimethylamino-2-methylethyl)phenothiazine hydrochloride; N-(2 -dimethylamino-2 -methyl)ethylphenothiazine hydrochloride Trade names: Diprazi; Kinetosin; Phenergan; Phenergan hydrochloride; Promine; Pipolfen; Plletia; Prorex; Promantine; Pyrethia; Romergan hydrochlonde

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Current risk assessments of 1,3-butadiene (BD*) are complicated by limited evidence of its carcinogenicity in humans. Hence, there is a critical need to identify early events and factors that account for the heightened sensitivity of mice to BD-induced carcinogenesis and to deter-mine which animal model, mouse or rat, is the more useful surrogate of potency for predicting health effects in BD-exposed humans. HEI sponsored an earlier investigation of mutagenic responses in mice and rats exposed to BD, or to the racemic mixture of 1,2-epoxy-3-butene (BDO) or of 1,2,3,4-diepoxybutane (BDO2; Walker and Meng 2000). In that study, our research team demonstrated (1) that the frequency of mutations in the hypoxanthine-guanine phosphoribosyl transferase (Hprt) gene of splenic T cells from BD-exposed mice and rats could be correlated with the species-related differences in cancer susceptibility; (2) that mutagenic-potency and mutagenic-specificity data from mice and rats exposed to BD or its individual epoxy intermediates could provide useful information about the BD metabolites responsible for mutations in each species; and (3) that our novel approach to measuring the mutagenic potency of a given chemical exposure as the change in Hprt mutant frequencies (Mfs) over time was valuable for estimating species-specific differences in mutagenic responses to BD exposure and for predicting the effect of BD metabolites in each species. To gain additional mode-of-action information that can be used to inform studies of human responses to BD exposure, experiments in the current investigation tested a new set of five hypotheses about species-specific patterns in the mutagenic effects in rodents of exposure to BD and BD metabolites: 1. Repeated BD exposures at low levels that approach the occupational exposure limit for BD workers (set by the U.S. Occupational Safety and Health Administration) are mutagenic in female mice. 2. The differences in mutagenic responses of the Hprt gene to BD in similarly exposed rodents of a given species (reported in various earlier studies) are primarily associated with age-related thymus activity and trafficking of T cells and with sex-related differences in BD metabolism. 3. The mutagenic potency of the stereochemical forms of BD's epoxy intermediates plays a significant role in the species-related mutagenicity of BD. 4. The hydrolysis-detoxification pathway of BD through 1,2-dihydroxy-3-butene (BD-diol) is a major contributor to mutagenicity at high-level BD exposures in mice and rats. 5. Significant and informative species-specific differences in mutation spectra can be identified by examining both large- and small-scale genetic alterations in the Hprt gene of BD-exposed mice and rats. The first four hypotheses were tested by exposing mice and rats to BD, meso-BDO2, or BD-diol and measuring Hprt Mfs as the primary biomarker. For this, we used the T-cell-cloning assay of lymphocytes isolated from the spleens of exposed and control (sham-exposed) mice and rats. The first hypothesis was tested by exposing female B6C3F1 mice (4 to 5 weeks of age) by inhalation for 2 weeks (6 hours/day, 5 days/week) to 0 or 3 ppm BD. Hprt Mfs were measured at the time of peak mutagenic response after exposure for this age of mice. We then compared the resulting data to those from mutagenicity studies with mice of the same age that had been exposed in a similar protocol to higher levels of BD (Walker and Meng 2000). In mice exposed to 3 ppm BD (n = 27), there was a significant 1.6-fold increase over the mean background Hprt Mf in control animals (n = 24, P = 0.004). Calculating the efficiency of Hprt mutant induction, by dividing induced Hprt Mfs by the respective BD exposure levels, demonstrated that the mutagenic potency of 3 ppm BD was twice that of 20 ppm BD and almost 20 times that of 625 or 1250 ppm BD in exposed female mice. Sample-size calculations based on the Hprt Mf data from this experiment demonstrated the feasibility of conducting a future experiment to find out whether induced Mfs at even lower exposure levels (between 0.1 and 1.0 ppm BD) fit the supralinear exposure-response curve found with exposures between 3.0 and 62.5 ppm BD, or whether they deviate from the curve as Mf values approach the background levels found in control animals. The second hypothesis was tested by estimating mutagenic potency for female mice exposed by inhalation for 2 weeks to 0 or 1250 ppm BD at 8 weeks of age and comparing this estimate to that reported for female mice exposed to BD in a similar protocol at 4 to 5 weeks of age (Walker and Meng 2000). For these two age groups, the shapes of the mutant splenic T-cell manifestation curves were different, but the mutagenic burden was statistically the same. These results support our contention that the disparity in responses reported in earlier Hprt-mutation studies of BD-exposed rodents is related more to age-related T-cell kinetics than to age-specific differences in the metabolism of BD. The third hypothesis was tested by estimating mutagenic potency for female mice and rats (4 to 5 weeks of age) exposed by inhalation to 2 or 4 ppm meso-BDO2 and comparing these estimates to those previously obtained for female mice and rats of the same age and exposed in a similar protocol to (+/-)-BDO2 (Meng et al. 1999b; Walker and Meng 2000). These exposures to stereospecific forms of BDO2 caused equivalent mutagenic effects in each species. This suggests that the small differences in the mutagenic potency of the individual stereoisomers of BDO2 appear to be of less consequence in characterizing the sources of BD-induced mutagenicity than the much larger differences between the mutagenic potencies of BDO2 and the other two BD epoxides (BDO and 1,2-dihydroxy-3,4-epoxybutane [BDO-diol]). The fourth hypothesis was tested in several experiments. First, female and male mice and rats (4 to 5 weeks of age) were exposed by nose only for 6 hours to 0, 62.5, 200, 625, or 1250 ppm BD or to 0, 6, 18, 24, or 36 ppm BD-diol primarily to establish BD and BD-diol exposure levels that would yield similar plasma concentrations of BD-diol. Second, animals were exposed in inhalation chambers for 4 weeks to 0, 6, 18, or 36 ppm BD-diol to determine the mutagenic potency estimates for these exposure levels and to compare these estimates with those reported for BD-exposed female mice and rats (Walker and Meng 2000) in which similar blood levels of BD-diol had been achieved. Measurements of plasma concentrations of BD-diol (via a gas chromatography and mass spectrometry [GC/MS] method developed for this purpose) showed these results: First, BD-diol accumulated in a sublinear manner during a single 6-hour exposure to more than 200 ppm BD. Second, BD-diol accumulated in a linear manner during single (6-hour) or repeated (4-week) exposure to 6 or 18 ppm BD and in a sublinear manner with increasing levels of BD-diol exposure. Third, exposure of female mice and rats to 18 ppm BD-diol produced plasma concentrations equivalent to those produced by exposure to 200 ppm BD (exposure to 36 ppm BD-diol produced plasma concentrations of about 25% of those produced by exposure to 625 ppm BD). In general, 4-week exposure to 18 or 36 ppm BD-diol was significantly mutagenic in female and male mice and rats. The differences in mutagenic responses between the species and sexes were not remarkable, except that the mutagenic effects were greatest in female mice. The substantial differences in the exposure-related accumulation of BD-diol in plasma after rodents were exposed to more than 200 ppm BD compared with the relatively small differences in the mutagenic responses to direct exposures to 6, 18, or 36 ppm BD-diol in female mice provided evidence that the contribution of BD-diol-derived metabolites to the overall mutagenicity of BD has a narrow range of effect that is confined to relatively high-level BD exposures in mice and rats. This conclusion was supported by the results of parallel analyses of adducts in mice and rats concurrently exposed to BD-diol (Powley et al. 2005b), which showed that the exposure-response curves for the formation of N-(2,3,4-trihydroxybutyl)valine (THB-Val) in hemoglobin, formation of N7-(2,3,4-trihydroxybutyl)guanine (THB-Gua) in DNA, and induction of Hprt mutations in exposed rodents were remarkably similar in shape (i.e., supralinear). Combined, these data suggest that trihydroxybutyl (THB) adducts are good quantitative indicators of BD-induced mutagenicity and that BD-diol-derived BDO-diol (the major source of the adducts) might be largely responsible for mutagenicity in rodents exposed to BD-diol or to hight levels of BD. The mutagenic-potency studies of meso-BDO2 and BD-diol reported here, combined with our earlier studies of BD, (+/-) BDO, and(+/-)-BDO2 (Walker and Meng 2000), revealed important trends in species-specific mutagenic responses that distinguish the relative degree to which the epoxy intermediates contribute to mutation induction in rodents at selected levels of BD exposures. These data as a whole suggest that , in mice, BDO2 largely causes mutations at exposures less than 62.5 ppm BD and that BD-diol-derived metabolites add to these mutagenic effects at higher BD exposures. In rats, it appears that the BD-diol pathway might account for nearly all the mutagenicity at the hight-level BD exposures where significant increases in Hprt Mfs are found and cancers are induced. Additional exposure-response studies of hemoglobin and DNA adducts specifics to BDO2, BDO-diol, and other reactive intermediates are needed to determine more definitively the relative contribution of each metabolite to the DNA alkylation and mutation patterns induced by BD exposure in mice and rats. For the fifth hypothesis, a multiplex polymerase chain reaction (PCR) procedure for the analysis of genomic DNA mutations in the Hprt gene of mice was developed. (ABSTRACT TRUNCATED)

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Antiretroviral drugs reduce viral replication and can reduce mother-to-child transmission of HIV either by lowering plasma viral load in pregnant women or through post-exposure prophylaxis in their newborns. In rich countries, highly active antiretroviral therapy (HAART) which usually comprises three drugs, has reduced the mother-to-child transmission rates to around 1-2%, but HAART is not always available in low- and middle-income countries. In these countries, various simpler and less costly antiretroviral regimens have been offered to pregnant women or to their newborn babies, or to both. To determine whether, and to what extent, antiretroviral regimens aimed at decreasing the risk of mother-to-child transmission of HIV infection achieve a clinically useful decrease in transmission risk, and what effect these interventions have on maternal and infant mortality and morbidity. We sought to identify all relevant studies regardless of language or publication status by searching the Cochrane HIV/AIDS Review Group Trials Register, The Cochrane Library, MEDLINE, EMBASE and AIDSearch and relevant conference abstracts. We also contacted research organizations and experts in the field for unpublished and ongoing studies. The original review search strategy was conducted in 2002 and updated in 2006 and again in 2009. Randomised controlled trials of any antiretroviral regimen aimed at decreasing the risk of mother-to-child transmission of HIV infection compared with placebo or no treatment, or compared with another antiretroviral regimen. Two authors independently selected relevant studies, extracted data and assessed trial quality. For the primary outcomes, we used survival analysis to estimate the probability of infants being infected with HIV (the observed proportion) at various specific time-points and calculated efficacy at a specific time as the relative reduction in the proportion infected. Efficacy, at a specific time, is defined as the preventive fraction in the exposed group compared to the reference group, which is the relative reduction in the proportion infected: 1-(Re/Rf). For those studies where efficacy and hence confidence intervals were not calculated, we calculated the approximate confidence intervals for the efficacy using recommended methods. For analysis of results that are not based on survival analyses we present the relative risk for each trial outcome based on the number randomised. No meta-analysis was conducted as no trial assessed identical drug regimens. Twenty-five trials including 18,901 participants with a median trial sample size of 627 ranging from 50 to 1,844 participants were included in this update. Twenty-two trials randomised mothers (18 pre-natally and four in labour) and followed up their infants, and three trials randomised infants. The first trial began in April 1991 and assessed zidovudine (ZDV) versus placebo and since then, the type, dosage and duration of drugs to be compared has been modified in each subsequent trial. We present the results stratified by regimen and type of feeding.Antiretrovirals versus placebo In breastfeeding populations, three trials found that:ZDV given to mothers from 36 to 38 weeks gestation, during labour and for 7 days after delivery significantly reduced HIV infection at 4-8 weeks (Efficacy 32.00%; 95% CI 1.50 to 62.50), 3 to 4 months (Efficacy 33.07%; 95% CI 5.57 to 60.57), 6 months (Efficacy 34.55%; 95% CI 9.05 to 60.05), 12 months (Efficacy 34.31%; 95% CI 9.30 to 59.32) and 18 months (Efficacy 29.74%; 95% CI 2.73 to 56.75).ZDV given to mothers from 36 weeks gestation and during labour significantly reduced HIV infection at 4 to 8 weeks (Efficacy 43.78%; 95% CI 8.78 to 78.78) and 3 to 4 months (Efficacy 36.95%; 95% CI 2.94 to 70.96) but not at birth.ZDV plus lamivudine (3TC) given to mothers from 36 weeks gestation, during labour and for 7 days after delivery and to babies for the first 7 days after birth (PETRA 'regimen A') significantly reduced HIV infection (Efficacy 62.75%; 95% CI 40.76 to 84.74) and a combined endpoint of HIV infection or death (Efficacy 62.75 [, ]61.00%; 95% CI 40.76 to 84.74) at 4 to 8 weeks but these effects were not sustained at 18 months.ZDV plus 3TC given to mothers from the start of labour until 7 days after delivery and to babies for the first 7 days after birth (PETRA 'regimen B') significantly reduced HIV infection (Efficacy 41.83%; 95% CI 12.82 to 70.84) and HIV infection or death at 4 to 8 weeks (Efficacy 35.91%; 95% CI 8.41 to 63.41) but the effects were not sustained at 18 months.ZDV plus 3TC given to mothers during labour only (PETRA 'regimen C') with no treatment to babies did not reduce the risk of HIV infection at either 4 to 8 weeks or 18 months.In non-breastfeeding populations, three trials found that:ZDV given to mothers from 14 to 34 weeks gestation and during labour and to babies for the first 6 weeks after birth significantly reduced HIV infection in babies at 18 months (Efficacy 66.22%; 95% CI 33.94 to 98.50).ZDV given to mothers from 36 weeks gestation and during labour with no treatment to babies ('Thai-CDC regimen') significantly reduced HIV infection at 4 to 8 weeks (Efficacy 50.26%; 95% CI 13.80 to 86.72) but not at birthZDV given to mothers from 38 weeks gestation and during labour with no treatment to babies did not influence HIV transmission at 6 months.Longer versus shorter regimens using the same antiretrovirals One trial in a breastfeeding population found that:ZDV given to mothers during labour and to their babies for the first 3 days after birth compared with ZDV given to mothers from 36 weeks and during labour (similar to 'Thai-CDC') resulted in HIV infection rates that were not significantly different at birth, 4-8 weeks, 3 to 4 months, 6 months and 12 months.Three trials in non-breastfeeding populations found that:ZDV given to mothers from 28 weeks gestation during labour and to infants for the first 3 days after birth compared with ZDV given to mothers from 35 weeks gestation through labour and to infants from birth to 6 weeks significantly reduced HIV infection rate at 6 months (Efficacy 45.35 %; 95% CI 1.39 to 89.31) but compared with the same regimen ZDV given to mothers from 28 weeks gestation through labour and to infants from birth to 6 weeks did not result in a statistically significant difference in HIV infection at 6 months. ZDV given to mothers from 35 weeks gestation during labour and to infants for the first 3 days after birth was considered ineffective for reducing transmission rates and this regimen was discontinued.An antenatal/intrapartum course of ZDV used for a median of 76 days compared with an antenatal/intrapartum ZDV regimen used for a median 28 days with no treatment to babies in either group did not result in HIV infection rates that were significantly different at birth and at 3 to 4 months.In a programme where mothers were routinely receiving ZDV in the third trimester of pregnancy and babies were receiving one week of ZDV therapy, a single dose of nevirapine (NVP) given to mothers in labour and to their babies soon after birth compared with a single dose of NVP given to mothers only resulted in HIV infection rates that were not significantly different at birth and 6 months. However the reduction in risk of HIV infection or death at 6 months was marginally significant (Efficacy 45.00%; 95% CI -4.00 to 94.00).Antiretroviral regimens using different drugs and durations of treatmentIn breastfeeding populations, three trials found that:A single dose of NVP given to mothers at the onset of labour plus a single dose of NVP given to their babies immediately after birth ('HIVNET 012 regimen') compared with ZDV given to mothers during labour and to their babies for a week after birth resulted in lower HIV infection rates at 4-8 weeks (Efficacy 41.00%; 95% CI 11.84 to 70.16), 3-4 months (Efficacy 38.91%; 95% CI 11.24 to 66.58), 12 months (Efficacy 35.98 [9.25, 62.71]36.00%; 95% CI 8.56 to 63.44) and 18 months (Efficacy 39.15%; 95% CI 13.81 to 64.49). In addition, the NVP regimen significantly reduced the risk of HIV infection or death at 4-8 weeks (Efficacy 41.74%; 95% CI 14.30 to 69.18), 3 to 4 months (Efficacy 40.00%; 95% CI 14.34 to 65.66), 12 months (Efficacy 32.17%; 95% CI 8.51 to 55.83) and 18 months (Efficacy 32.57 [9.93, 55.21]33.00%; 95% CI 9.93 to 55.21).The 'HIVNET 012 regimen' plus ZDV given to babies for 1 week after birth compared with the 'HIVNET 012 regimen' alone did not result in a statistically significant difference in HIV infection at 4 to 8 weeks.A single dose of NVP given to babies immediately after birth plus ZDV given to babies for 1 week after birth compared with a single dose of NVP given to babies only significantly reduced the HIV infection rate at 4 to 8 weeks (Efficacy 36.79%; 95% CI 3.57 to 70.01).Five trials in non-breastfeeding populations found that:In a population in which mothers were receiving 'standard' antiretroviral for HIV infection a single dose of NVP given to mothers in labour plus a single dose of NVP given to babies immediately after birth ('HIVNET 012 regimen') compared with placebo did not result in a statistically significant difference in HIV infection rates at birth and at 4 to 8 weeks.The 'Thai CDC regimen' compared with the 'HIVNET 012 regimen' did not result in a significant difference in HIV infection at 4 to 8 weeks.A single dose of NVP given to babies immediately after birth compared to ZDV given to babies for the first 6 weeks after birth did not result in a significant difference in HIV infection rates at 4-8 weeks and 3 to 4 months. (ABSTRACT TRUNCATED)

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In the early to mid 1990s, 1-bromopropane was used primarily as an intermediate in the production of pesticides, quaternary ammonium compounds, flavors and fragrances, pharmaceuticals, and other chemicals in well-controlled, closed processes. In the mid to late 1990s, it was introduced as a less toxic replacement for methylene chloride in emissive applications such as vapor and immersion degreasing operations and critical cleaning of electronics and metals. 1-Bromopropane was also introduced as a nonflammable, nontoxic, fast-drying, and inexpensive solvent for adhesive resins, and has been marketed as a replacement for ozone depleting refrigerants. 1-Bromopropane was nominated for study by the Occupational Safety and Health Administration based on the potential for widespread occupational and environmental exposure and a lack of toxicity and carcinogenicity data. Male and female F344/N rats and B6C3F1 mice were exposed to 1-bromopropane (99% or greater pure) by inhalation for 2 weeks, 3 months, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and Escherichia coli and mouse peripheral blood. 2-WEEK STUDY IN RATS: Groups of five male and five female rats were exposed to 1-bromopropane vapor at concentrations of 0, 125, 250, 500, 1,000, or 2,000 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 16 days. All rats survived to the end of the study except one 500 ppm male. Mean body weights of 2,000 ppm rats were significantly less than those of the chamber controls. The absolute kidney weight of 1,000 ppm males, relative kidney weights of all exposed groups of males, and absolute and relative kidney weights of all exposed groups of females were significantly increased. The absolute and relative liver weights of 1,000 ppm males, relative liver weights of 500 and 2,000 ppm males, and absolute and relative liver weights of 500 ppm or greater females were significantly increased. Nasal lesions included suppurative inflammation in males exposed to 500 ppm or greater, respiratory epithelial necrosis in 1,000 and 2,000 ppm males, and respiratory epithelial regeneration in 1,000 and 2,000 ppm females. 2-WEEK STUDY IN MICE: Groups of five male and five female mice were exposed to 1-bromopropane vapor at concentrations of 0, 125, 250, 500, 1,000, or 2,000 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 17 days. All 2,000 ppm males, two 2,000 ppm females, four 500 ppm males, one 1,000 ppm male, and one 1,000 ppm female died early. The mean body weight gain of 1,000 ppm males was significantly less than that of the chamber controls. Abnormal breathing, lethargy, and eye discharge were observed primarily during week 1 in groups exposed to 500 ppm or greater. Liver weights of 1,000 ppm males and of females exposed to 500 ppm or greater were significantly increased. Kidney weights of 1,000 and 2,000 ppm females were significantly increased. Microscopic lesions related to 1-bromopropane exposure occurred in the lung, liver, and nose of males and females and were primarily seen in mice exposed to 500 ppm or greater. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were exposed to 1-bromopropane vapor at concentrations of 0, 62.5, 125, 250, 500, or 1,000 ppm, 6 hours plus T90 (10 minutes) per day, 5 days per week for 14 weeks. Additional clinical pathology groups of 10 male and 10 female rats were exposed to the same concentrations for 23 days. All rats survived to the end of the study. Mean body weights of 1,000 ppm males were significantly less than those of the chamber controls. The increases in sorbitol dehydrogenase activities in 500 ppm males and 1,000 ppm males and females were consistent with the histopathologic evidence of mild hepatotoxicity caused by 1-bromopropane. Liver weights of males exposed to 250 ppm or greater and of females exposed to 125 ppm or greater were significantly increased. Spleen and kidney weights of 1,000 ppm females were significantly increased. Exposure concentration-related decreases of 28% in sperm motility and 37% in sperm counts were seen in the 1,000 ppm group of male rats. Female rats in all three exposure groups evaluated exhibited altered estrous cycles, spending significantly more time in extended estrus and less time in extended diestrus. The incidences of cytoplasmic vacuolization of the liver were significantly increased in males exposed to 250 ppm or greater and in females exposed to 500 ppm or greater. Hepatocyte degeneration was also observed in 1,000 ppm females. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female mice were exposed to 1-bromopropane vapor at concentrations of 0, 62.5, 125, 250, or 500 ppm, 6 hours plus T90 (10 minutes) per day, 5 days per week for 14 weeks. One 250 ppm male and four males and five females in the 500 ppm groups died early. Mean body weights of exposed groups were similar to those of the chamber controls. Lethargy was observed in males and females exposed to 500 ppm, and abnormal breathing was observed in moribund mice. The kidney, liver, and lung weights of 500 ppm females were significantly greater than those of the chamber controls. The kidney weights of 500 ppm males were significantly decreased. Sperm counts in the 500 ppm group of male mice were 28% less than that in the chamber controls. Female mice exhibited altered estrous cycles, with females in the 500 ppm group spending significantly more time in extended diestrus and those in the 250 ppm group spending significantly more time in extended estrus compared to the chamber controls. Nonneoplastic lesions were observed in the nose, larynx, trachea, lung, and liver of 500 ppm males and females and in the adrenal cortex of 500 ppm females. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were exposed to 1-bromopropane vapor at concentrations of 0, 125, 250, or 500 ppm, 6 hours plus T90 (10 minutes) per day, 5 days per week for 105 weeks. Survival of 500 ppm males was significantly less than that of the chamber control group. Mean body weights of exposed groups were similar to those of the chamber controls. Increased incidences of macroscopic, soft, pale-yellow to green, variably sized nodules were seen predominantly in the nose and skin of exposed rats. The number of animals with multiple masses was increased in the 500 ppm groups. In most cases, these lesions were microscopically shown to be suppurative inflammation, many with Splendore-Hoeppli material. The incidence of adenoma of the large intestine (colon or rectum) was significantly greater in 500 ppm females than in the chamber control group. The incidence of adenoma of the large intestine in 250 ppm males exceeded the historical control ranges for inhalation studies and all routes. The incidences of keratoacanthoma, basal cell adenoma, basal cell carcinoma, or squamous cell carcinoma (combined) were significantly greater in all exposed groups of males than in the chamber control group and exceeded the historical control range for inhalation studies. The incidences of keratoacanthoma and of keratoacanthoma or squamous cell carcinoma (combined) in 250 and 500 ppm males were also significantly increased and exceeded the historical control ranges for inhalation studies. In 500 ppm females, the incidence of squamous cell papilloma, keratoacanthoma, basal cell adenoma, or basal cell carcinoma (combined) exceeded the historical control range for inhalation studies. The incidence of malignant mesothelioma was significantly greater in 500 ppm males than in the chamber control group. The incidences of pancreatic islet adenoma in all exposed groups of males and of pancreatic islet adenoma or carcinoma (combined) in 125 and 250 ppm males were significantly increased. Treatment-related nonneoplastic lesions were observed in the respiratory system of exposed male and female rats. In the nose, the incidences of suppurative chronic inflammation, chronic active inflammation, glandular hyperplasia, respiratory epithelial hyperplasia (females), and respiratory metaplasia of the olfactory epithelium (females) were increased in all exposed groups. In the larynx, the incidences of chronic active inflammation and squamous metaplasia (except 125 ppm females) were increased in all exposed groups, and the incidences of suppurative chronic inflammation were increased in the 500 ppm groups. Also, chronic inflammation of the lung was observed in the 500 ppm females. In the trachea, there were increased incidences of chronic active inflammation in all exposed groups of females and 500 ppm males, and the incidence of epithelial hyperplasia was increased in 500 ppm females. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were exposed to 1-bromopropane vapor at concentrations of 0, 62.5, 125, or 250 ppm, 6 hours plus T90 (10 minutes) per day, 5 days per week for 105 weeks. Survival of exposed groups was similar to that of the chamber controls. Mean body weights of all exposed groups were similar to those of the chamber controls throughout the study. In the females, there were increased incidences of alveolar/bronchiolar adenoma, alveolar/bronchiolar carcinoma, and alveolar/bronchiolar adenoma or carcinoma (combined); the incidences of alveolar/bronchiolar adenoma or carcinoma (combined) were significantly increased in all exposed groups of females. There were significantly increased incidences of cytoplasmic vacuolization of the bronchiolar epithelium in all exposed male groups and regeneration of the bronchiolar epithelium in all exposed groups of males and females. In the nose, there were significantly increased incidences of cytoplasmic vacuolization of the respiratory epithelium in all exposed groups of males and in 125 and 250 ppm females. There were significantly increased incidences of respiratory epithelial hyperplasia in all exposed female groups and in 62.5 and 250 ppm males. (ABSTRACT TRUNCATED)

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Physicians in Egypt and other Arab and developing countries still have to deal on a daily basis with large numbers of patients with advanced stages of breast cancer at presentation. Efforts at measuring the magnitude of the breast cancer issues, epidemiology, and awareness, are now moving further in the right direction. We are now starting to face the challenges of early detection of breast cancer as well as the implementation of proper modern management. Dorria S. Salem et al. publish in this issue of the Journal of Egyptian NCI an outline and initial results of a very ambitious Women Health Outreach Program (WHOP) designed to be completed in 5 phases 1. She and her co-authors state that those 5 phases include a prior training and demonstration phase that was completed in the Imaging Unit of Kasr El Aini Hospital in Cairo, as well as a one-year pilot phase completed between October 2007 and October 2008. Authors present us with results of screening of 20.098 women over the age of 45 years, between October 30, 2007 and February 9, 2009 in Cairo, Alexandria and Suez Governorates in Egypt. In addition to breast cancer, WHOP included screening for diabetes, hypertension and obesity. WHOP investigators are to be congratulated for this extraordinary ambitious project and all the efforts put into it. They were well prepared in regards to having a multi-disciplinary working team and they included in their project programs for training of clerks, data managers, radiographers, nurses, radiologists and other physicians who deal with diagnosis and management of breast cancer. They also included engineers and arranged for mobile units to reach women who could not otherwise reach them. WHOP investigators are to be commended also for performing a field plan demonstration project and testing it and for measuring citizens' response before finalizing their plans and starting the project1. They set a great example for other people working in the field. Breast cancer is the most common female malignancy in women in almost all Arab countries [2-5]. Randomized trials of mammographic screening of average-risk women above 50 years reduced breast cancer mortality by more than 36%. Analysis of the eight randomized trials, including the Canadian trials on women, ages 40-49 years old, showed a relative reduction of breast cancer deaths by 18% [6]. There is an obvious overlap as women with ages ranging from 40-49 years old reach the age of 50 and above, and enjoy the more clear benefits of mammographic screening beyond the age of 50 years. Many societies, including the American Cancer Society, recommend mammographic screening starting at age 40 years [7,8]. As it would be very difficult in this day and age to do more studies on breast cancer screening, and in view of the observations that almost 50% of cases are below the age of 50 years with a median age of 48-52 years at presentation, we recommend screening be done starting age 40, where resources are available and where setup for breast cancer care is appropriate [4,9]. Salem et al. report an initial very significant and alarming number of 10.215 women out of 20.098 women to be overweight and 2692 women to be obese [1]. Their observation that there is no significant correlation with breast cancer is only a one point in time observation and it cannot be used to confirm or refute any potential relationship between overweight, obesity and breast cancer. Future results, follow-up, and multivariate analysis will be awaited. Correlation of mammographic abnormalities with diabetes and hypertension in WHOP participants are very preliminary and will also need further multivariate analysis. WHOP investigators report that they invited women aged 45 years and up for screening. Eligibility criteria listed include only two points, women should have no personal history of breast cancer and no recent mammography [1], authors neither describe clinical history nor physical breast examination of selected and invited women. In future reports, authors will be asked about the assessement of those invited women, and what were the results and outcome if referred women were found to have abnormalities in their breasts. In another study from Cairo, Egypt, women were taught how to examine themselves, and authors reported that many were found to have clinical breast cancers for which they were effectively downstaged, and therefore treated for cancers that would have otherwise presented later as more advanced cases [10]. This issue brings me back to re-emphasize the importance of awareness, teaching women self-breast exam, and clinical breast examination once-a-year by a physician, particularly in countries with limited resources. Breast cancer awareness campaigns emphasize the benefits of early detection by promoting breaking of taboos, and teaching scientific facts that early breast cancer can be cured, and that cure can be achieved without the need of mastectomy. Advanced breast cancer is devastating to women and to their husbands and children, and therefore campaigns should be directed towards women as well as husbands who should be asked to encourage their wives to enroll in screening campaigns. Campaigns have begun to reduce the effects of taboos and people started to talk more freely about cancer, in fact, we and many centers in Arab countries have started to see more cases of early breast cancer and even a significant number of cases with microcalcifications [4]. Breast cancer screening in countries with limited resources have been recently reviewed [11,12]. As for the management of abnormal findings, Dorria S. Salem et al. [1] report performing FNAB as first line management in suspicious cases and reserving core biopsies for inconclusive cases. I fully agree with the authors' efforts to ensure accurate diagnosis and the importance of having an experienced cytopathologist. However, FNA is useful and recommended when there is a palpable tumor or a highly suspicious tumor with irregular borders and infiltrative characteristics on mammography and ultrasound. Core biopsy is indicated when FNA is inconclusive as the authors state, and also if mammography shows micro-calcifications where FNA cannot distinguish between in-situ and infiltrative carcinoma. A core biopsy is important for better assessment of pathology and determination of receptors (estrogen, progesterone, and HER2 receptors) especially in patients with large tumors who require preoperative (neoadjuvant) therapy, particularly when targeted anti-HER2 therapy is indicated [13]. In the present report, WHOP investigators [1] report that 31 patients, out of 86 true positive cancers, underwent modified radical mastectomy while 21 had breast-conserving surgery. Eleven patients required only excisional biopsy and had benign tumors, 25 had surgery at private institutions and no data is available on them. Further WHOP reports will be awaited to report to us on the stages and follow-up information on all patients. Availability of experienced surgeons and radiation oncology are also important issues when referring patients for partial or total mastectomy. After screening of over 20000 women, authors report that abnormal mammographies with BiRADS 4 and 5 were found in 433 cases (reported as 2.1%). Additional work-up with ultrasound and FNA/biopsy showed 2 false negatives, 110 false positives, and confirmed 86 true positive cases (0.4% of total 20.098 women screened). In the US, the likelihood of a woman being called back for additional testing after first round of screening is an average of 11% (range 3-57%) [14]. In women for whom a biopsy is then indicated, the likelihood of finding an invasive and/or insitu cancer is 25-47% [15]. This is what we call positive predictive value (PPV) and it varies with expertise and patients own risk factors for breast cancer. What is of concern in this present WHOP article, although not unexpected, is that more than half of the recalled women did not show up or no feedback is available on them. This should generate yet another important experience on how to deal with missing information and how to assure follow-up of patients in Egypt and other Arab countries, as well as in all limited resource countries. WHOP investigators will be asked to report in the future on screening intervals and data collection. Screening started at age 45 years, and data were analyzed by 10-year age groups starting age 50, which makes comparisons somehow difficult. In view of the high incidence of women with breast cancer with young age at presentation, it would be more helpful if WHOP investigators revise the starting age for screening mammography and make it 40 years and analyze data according to 10-year age groups starting age 40 years. On the other hand, it is important to note that increasing the time interval of periodic mammography diminished the mortality reduction by allowing undetected growth of interval cancers. Increasing the screening interval of women in their forties from annual to every 2 years or to every 3 years would diminish mortality reduction rates from 36% to 18% and to 4%, respectively [16]. Once a screening strategy is adopted, women aged 40 years and up should be screened at yearly intervals because data from Egypt and other Arab countries indicate that 50% of breast cancers are seen in women below age 50 years, and because young women have more aggressive tumors [17,18] and may be missed by two-year intervals. Finally, WHOP investigators, staff, and their sponsors are to be commended for this excellent, well planned and executed project that sets a great example for devotion for science and public health. In addition to regional and national cancer registries, they provide many new innovative approaches to characterize, diagnose and treat breast cancer in Egypt and other Arab countries. (ABSTRACT TRUNCATED)

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Several essential oils contain pulegone and are used for flavoring foods, drinks, and dental products, as fragrance agents, and in herbal medicines. Pulegone was nominated for study by the National Institute of Environmental Health Sciences based on the potential for human exposure and the absence of carcinogenicity data. Male and female F344/N rats and B6C3F1 mice received pulegone (approximately 96% pure) by gavage for 2 weeks, 3 months, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, and mouse peripheral blood erythrocytes. 2-WEEK STUDY IN RATS: Groups of five male and five female rats were administered 0, 37.5, 75, 150, 300, or 600 mg pulegone/kg body weight in corn oil by gavage, 5 days per week for 16 days. All male rats and nearly all female rats in the 300 and 600 mg/kg groups died prior to the end of the study. All moribund sacrifices and early deaths were attributed to liver toxicity. Mean body weight gains of males administered 37.5 or 150 mg/kg were significantly less than that of the vehicle controls. Clinical findings in 300 and 600 mg/kg rats included nasal/eye discharge, thinness, lethargy, and ruffled fur. Liver and kidney weights of dosed groups of females were generally significantly greater than those of the vehicle control group. The incidences of necrosis and cytoplasmic vacuolization of the liver in 300 and 600 mg/kg males and females were significantly greater than those in the vehicle control groups. 2-WEEK STUDY IN MICE: Groups of five male and five female mice were administered 0, 18.75, 37.5, 75, 150, or 300 mg pulegone/kg body weight in corn oil by gavage, 5 days per week for 16 days. Four females and one male in the 300 mg/kg groups died by study day 5. All early deaths were attributed to liver toxicity. Mean body weights of the dosed groups were similar to those of the vehicle controls. Clinical findings were observed only in 300 mg/kg mice and included thinness, lethargy, and ruffled fur. Liver weights of 300 mg/kg males were significantly greater than those of the vehicle controls. The incidences of cytoplasmic vacuolization and diffuse fatty change in 300 mg/kg females and necrosis in 300 mg/kg males were significantly greater than those in the vehicle controls. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were administered 0, 9.375, 18.75, 37.5, 75, or 150 mg pulegone/kg body weight in corn oil by gavage, 5 days per week for 14 weeks. All rats survived until the end of the study except for one female in the 150 mg/kg group that died on day 9. Mean body weights of 75 and 150 mg/kg males and 150 mg/kg females were significantly less than those of the vehicle controls. At the end of the study, there was a small dose-related decrease in the erythron, evidenced by decreases in the hematocrit and hemoglobin values and the erythrocyte counts. An apparent erythroid response to the decreased erythron was evidenced by increased reticulocyte counts. Reduced and oxidized glutathione levels were generally increased in 75 and 150 mg/kg males and in 37.5 mg/kg or greater females. Absolute and relative liver weights of 75 and 150 mg/kg females and relative liver weights of males administered 18.75 mg/kg or greater were significantly greater than those of the vehicle controls. The absolute kidney weight of 150 mg/kg females and the relative kidney weights of all dosed groups, except 9.375 mg/kg males, were significantly greater than those of the vehicle controls. Absolute and relative thymus weights of 150 mg/kg males and females and the absolute thymus weight of 75 mg/kg males were significantly less than those of the vehicle controls. In the kidney, there was hyaline glomerulopathy in 75 mg/kg males and 150 mg/kg males and females. The incidence of renal tubule protein casts was significantly increased in the 150 mg/kg females. In the liver, incidences of bile duct hyperplasia and hepatocyte hypertrophy in 75 and 150 mg/kg males and 150 mg/kg females, hepatocyte focal necrosis in 150 mg/kg males, and oval cell hyperplasia and periportal fibrosis in 150 mg/kg males and females were increased. Incidences of bone marrow hyperplasia in 37.5 mg/kg males and 75 and 150 mg/kg males and females, heart mineralization in 150 mg/kg males, glandular stomach mineralization in 75 and 150 mg/kg females, and cellular histiocytic infiltration in the lung and ovarian cyst in 150 mg/kg females were significantly increased. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female mice were administered 0, 9.375, 18.75, 37.5, 75, or 150 mg pulegone/kg body weight in corn oil by gavage, 5 days per week for 14 weeks. All mice survived to the end of the study. Mean body weights of dosed mice were similar to those of the vehicle controls. Reduced and oxidized glutathione levels were generally greater than vehicle control levels in 150 mg/kg males and in 75 and 150 mg/kg females. Liver weights of 150 mg/kg males and 75 and 150 mg/kg females were significantly greater than those of the vehicle controls. No histopathologic lesions were observed that could be attributed to the administration of pulegone. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were administered 0, 18.75 (males only), 37.5, 75, or 150 (females only) mg pulegone/kg body weight in corn oil by gavage, 5 days per week for up to 104 weeks. Due to excessive morbidity and mortality, 75 mg/kg males and 150 mg/kg females were not administered pulegone after week 60 (stop-exposure); these groups were administered the corn oil vehicle until the end of the study. Survival of 37.5 mg/kg males was significantly less than that of the vehicle controls; only two 75 mg/kg stop-exposure males survived, and no 150 mg/kg stop-exposure females survived to the end of the study. Compared to those of the vehicle controls, mean body weights were less in 75 mg/kg stop-exposure males after week 13 and in 75 mg/kg and 150 mg/kg stop-exposure females after weeks 21 and 9, respectively. Clinical findings included thinness, lethargy, and ruffled fur in the 75 mg/kg stop-exposure males and 150 mg/kg stop-exposure females. The incidences of urinary bladder papilloma and of papilloma or carcinoma (combined) were significantly increased in 150 mg/kg stop-exposure females. In the kidney, incidences of hyaline glomerulopathy were significantly increased in 37.5 mg/kg and 75 mg/kg stop-exposure males and in all dosed groups of females. The severity of chronic progressive nephropathy was increased in 37.5 mg/kg and 75 mg/kg stop-exposure males and in 75 mg/kg and 150 mg/kg stop-exposure females; the incidences of nephropathy were significantly increased in 75 mg/kg and 150 mg/kg stop-exposure females. The incidence of renal cyst was significantly increased in 75 mg/kg stop-exposure males. In the liver, incidences of diffuse hepatocyte cellular alteration were significantly increased in 37.5 mg/kg and 75 mg/kg stop-exposure males and 75 mg/kg and 150 mg/kg stop-exposure females. There were significant increases in the incidences of other liver lesions including fatty change, bile duct cyst, hepatocyte necrosis, oval cell hyperplasia, bile duct hyperplasia, and portal fibrosis. In the nose, 37.5 mg/kg and 75 mg/kg stop-exposure males and all dosed groups of females had significantly increased incidences of olfactory epithelium degeneration. All dosed groups of females had significantly increased incidences of respiratory metaplasia of the olfactory epithelium and nasal inflammation. In the forestomach, incidences of inflammation and ulcer were significantly increased in 37.5 mg/kg and 75 mg/kg stop-exposure males, and incidences of epithelial hyperplasia and perforation were increased in 75 mg/kg stop-exposure males. In the glandular stomach, the incidence of inflammation was significantly increased in 75 mg/kg stop-exposure males. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were administered 0, 37.5, 75, or 150 mg pulegone/kg body weight in corn oil by gavage, 5 days per week for 105 weeks. Survival of all dosed groups was similar to that of the vehicle controls. Mean body weights of 150 mg/kg males and females were less than those of the vehicle controls after weeks 25 and 33, respectively. The incidences of multiple hepatocellular adenoma were significantly increased in all dosed groups of males, and the incidences of hepatocellular adenoma (includes multiple) and hepatoblastoma (includes multiple) were significantly increased in the 75 mg/kg males. The combined incidences of hepatocellular adenoma, hepatocellular carcinoma, or hepatoblastoma occurred with positive trends and were significantly increased in 75 mg/kg males and 150 mg/kg females. The incidence of hepatocellular adenoma was significantly increased in 150 mg/kg females. The incidences of several nonneoplastic liver lesions were significantly increased, primarily in the 75 and 150 mg/kg groups. These nonneoplastic lesions included clear cell, eosinophilic, and mixed cell foci; focal fatty change; centrilobular hepatocyte hypertrophy; intravascular hepatocyte; necrosis; pigmentation; bile duct cyst and hyperplasia; and oval cell hyperplasia. In the kidney, incidences of hyaline glomerulopathy were significantly increased in all dosed groups of males and 75 and 150 mg/kg females. The incidence of mineralization was significantly increased in 150 mg/kg females, and the incidence of nephropathy in 150 mg/kg females and severity of nephropathy in 150 mg/kg males were increased. Incidences of congestion of the glomerulus were increased in 150 mg/kg males and females. The incidence of osteoma or osteosarcoma (combined) in all organs of 75 mg/kg females exceeded the historical control ranges. One 150 mg/kg male and one 75 mg/kg female had nasal osteoma; no nasal osteomas have been observed in historical control mice. (ABSTRACT TRUNCATED)

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The transfusion efficacy of ATK, which contain fully functional platelets, is beyond all doubt. The equivalence of ATK and PTK has been subject of many studies. Some of those studies show the superiority of ATK's, while others do not, but there have been no studies that demonstrated a superiority of PTK's. The superiority of platelets stored in plasma and in third generation additive solution was demonstrated in clinical studies; therefore, it cannot be said that all the platelet concentrates on the German market are equivalent in efficacy. Of decisive importance, above all, is the risk of transfusion-transmitted infections with known pathogens, or those not yet discovered. This risk is different for ATK compared to PTK. Taking this difference in risk and the difference in donor exposure of transfused patients into account, it can definitely be said that ATK and PTK are not equivalent. In 2012, the Robert-Koch-Institute (RKI) published a mathematical risk model for different platelet concentrates and assessed the risk of transmitting known pathogens such as HIV, HCV, and HBV. The risk was higher for PTK compared to ATK. The relative risks for PTK derived from 4BCs were 2.2 (95%--CI: 2.1-2.4) for HIV, 2.7 (95%--CI: 2.5-3.0) for HCV, and 2.2 (95%--CI: 2.8-3.7) for HBV. At the present time, these are the relative risks of transfusion-transmitted infections with the traditional pathogens for PTK compared to ATK. In addition to the RKI assessed risks, there is the theoretical risk of a new, unknown agent, transmitted through blood exposure. The magnitude of this risk is hardly predictable for PTK. The experience gathered so far, especially in the last three decades, with the emergence of HIV, prions, and West Nil virus, shows that the biological nature of a next transfusion-transmissible infectious agent cannot be predictable. This agent, if we think at a conventional sexually transmissible agent with nucleic acid and long latent period, would spread first in areas with high population density and thereby reduce the theoretical advantage of ATK (but definitely would not nullify it!). It is equally plausible, however, that this agent would behave like a prion, non-sexual transmission, or like a West-Nil virus, a non-contagious vector-transmitted agent. For PTK this would mean a relative risk up to 4 times (PTK from 4 BCs) or 5 times (PTK from 5 BCs) higher than the risk estimated by the Robert-Koch-Institute. If, taking the passive surveillance data and the changing variables (donor frequency, donor population, and donor location) into account, the risk of transmission of an infection via ATK (exposure to 1 donor) with HIV, HCV, and HBV moves closer to the higher risk of PTK (exposure to 4 or 8 donors, in case of double ATK per patient), this result of the risk model calculation by no means indicates any equivalency between PTK and ATK with respect to the risk of transmission of infection. The modifiable variables of donor frequency, donor population, and donor location need to be modified, as scientific deductions, in such a way that the avoidable risk of ATK which is influenced by these variables can be corrected to the minimum risk of a transmission of infection of HIV, HBV, and HCV via ATK in comparison to PTK. The minimum risk of a possible transmission of infection via ATK (exposure to 1 donor) is the basic intrinsic risk of each individual blood donation. The basic intrinsic risk increases relative to the number of blood donations or exposure to donors (PtK has an unalterable, production-dependent exposure to 4 or 8 donors). Let us consider a 1:1.000 prevalence for a new pathogen, which is spread equally in each donor population (apheresis and whole blood) and the present case of approximately 500,000 transfused platelet concentrates in Germany. This means that for the production of 4 PTK about 2 million donations are processed, 2,000 infectious Buffy-Coats are obtained and, thereby, 2,000 infectious PTK. In the case of ATK, considering five (5) donations per year, theoretically, it would mean 100 donors infected and 500 infectious ATK. Considering 15 apheresis donations per donor per year, this would mean that 33 donors are infected, but still 500 infectious ATK would be produced. The prion is an example of a pathogen that, although its existence is well known, cannot be proven or pathogen-reduced. In addition, it has a very long incubation period compared to the donation intervals. Due to the manufacturing process, PTK has a 4-fold higher donor exposure and therefore a 4-fold higher risk for transfusion-transmitted infections compared to ATK. If a patient needs the transfusion of two platelet concentrates, by transfusing a double-ATK from the same donor the risk of transfusion-transmitted infections will remain the same. On the other hand, the risk will increase by 8-fold by transfusing two PTK. The only current possibility to prevent or to minimize the risk of infection with prions is to minimize the donor exposure by transfusing ATK instead of PTK. Hypothetical risk scenarios carry significant weight in law. This can be seen in the constant rulings of the German Federal Supreme Court (Bundesgerichtshofs (BGH)) on the so-called hypothetical risk explanations (BGH, NJW 1996, 776, 777; 2000, 1784, 1787; 2005, 2614, 2616). Therefore, a risk does not need to be confirmed to be subject to compulsory explanation. It is sufficient that serious voices in the medical scientific community point to specific risks, which cannot be set aside as insignificant outside opinions, but must be viewed as serious warnings. According to the rulings, patients must even be informed of rare and often extremely rare risks, which could, should they come true, significantly impact daily life and, despite their rarity, are specific to the treatment and are startling for the ordinary person (BGH, 15.02.2000- VI ZR 48199 -; BGH, 30.11.2004 - VI ZR 209104 -; OLG Hamm, 29.09.2010 - 1-3 V 169109). These conditions have been fulfilled for PTK according to current knowledge, especially since, in the meantime in several rulings, the federal supreme court has required the reference to as yet unknown risks (refer to BGH, 13.06.2006 - VI ZR 323104 - for the use of new medical treatment methods, BGH, 27.06.2007 - VI ZR 55105 for experimental therapy using new, unapproved medication BGH, 06.07.2010 - VI ZR 198109 - for unknown risks cannot be excluded, for example based on anatomical conditions). ATK and PTK are therapeutic alternatives with the same range of indications for treatment using thrombocytes, however, with differing risks of infection, with different exposures to donors, and with different efficacy. ATK and PTK. ATK and PTK are therapeutic alternatives in terms of pharmaceutical law based on the different risks and the different quality. Patients must be informed of therapeutic alternatives such as ATK and PTK according to the patient rights law. Denial of reimbursement for additional fees for ATK by individual insurance companies (or paying authorities) deviates blatantly, as seen in the ruling of the Social Court of of the Saarland in this matter, from the basic requirement of the Transfusion Law (Transfusionsgesetz (TFG)) and is legally incorrect. The legality of the question whether the transfusion of ATK is indicated or if PTK had sufficed, is not allowable within the context of an MDK-Test according to subsection 275 ff. SGB V. The denial is a direct infringment on the treatment authority of the attending hospital physician and is illegal according to subsection 275 Abs. 5 SGBV. It is certainly possible to establish a full ATK supply and can be immediately realized by increasing donation rates from 5 to 8.3 apheresis donations per year in the current scenario of apheresis structure and donor population. The donation interval between two apheresis donations would be 49 days. A complete supply with ATK can also be immediately implemented by enlarging the donor population, keeping the current apheresis donation frequency. The donor pool must be increased by 24,576 donors, which means a 67% increase of the existing donor population. A transition to an ATK supply that can cover the entire demand can certainly be realized in a short period of time, while assuring a complete supply with PTK is not a realistic option. All existing studies advise taking extreme caution with any alternative to the current German gold standard for the treatment of hyporegenerative thrombocytopenia. A prophylactic transfusion of a non-pathogen-inactivated platelet concentrate with on average 3 x 10(11) platelets is recommended when the platelet count drops below the threshold of 10,000/microL. All other alternatives to this strategy show an increase in intracranial bleeding events. The existing studies on platelet dose (PLADO-Trial and StoP-Trial) do not recommend deviating from 3 x 10(11) platelets per unit. On the contrary, these studies demonstrate that the only practicable way is to individually correlate every platelet transfusion to the patient body surface. Considering the current knowledge, it is not justified to lower the standard dose and, for certain patient groups, to switch from prophylaxis to therapeutic platelet transfusion. Applying ATK or PTK with a lower platelet content and only for therapeutic purposes, could considerably increase the bleeding risk, especially for WHO grades III and IV. This will also affect all the patients who receive an induction treatment. Through pathogen reduction, in parallel with platelet loss (Apoptosis), the function of the treated platelets is impaired. Alternatively, the cell destruction caused during this process could result in a release of platelet microRNA directly into the supernatant or in microvesicles. This reduction of microRNA will affect the storage of the platelets. (ABSTRACT TRUNCATED)

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In the present condition of the technique of cultivation of tissues, the only possible way of studying leucocytic secretions was to grow colonies of leucocytes in a medium of known properties and to examine the modifications of these properties under the influence of the living cells. The method was far from perfect, because the secretions were mixed with serum and accumulated for 48 hours in a medium where they probably underwent partial destruction. But an approximate idea of certain of the qualities of the secretions, although not of their quantity, could be derived from the experiments. In the fluids extracted from the cultures, we attempted to detect the presence of the leucocytic secretions through their physiological effects on homologous and foreign cells. Two kinds of substances were sought, those which act on homologous cells, and those which destroy foreign erythrocytes. The secretion by leucocytes of substances necessary to the nutrition of other cells was considered as probable long ago. Renaut thought that the main function of the white blood corpuscles was to bring to the fixed cells of the tissues the food material which they need. While the existence of physiological relations between leucocytes and tissue cells could be considered as almost certain, their nature had remained practically unknown. It was probable, however, that the substances secreted by leucocytes were analogous to the growth-activating and unstable substances which are found in embryonic tissues, leucocytes, and certain adult tissues. When connective tissue was aseptically inflamed, or when an aseptic peritoneal exudate contained many leucocytes, aqueous extracts of both connective tissue and peritoneal exudate were found to have acquired the power of stimulating cell proliferation. These experiments showed that leucocytes could bring to the tissues some activating substances. But it remained to be ascertained whether leucocytes, while they are alive, could secrete similar substances either spontaneously or under the stimulus of a foreign factor. Leucocytes are supposed to be, as is well know, the origin of the substances which protect the organism against infection. Although the problem of the origin of alexin and antibodies has been investigated by many experimenters, it is not yet completely solved. It was of interest, therefore, to ascertain whether leucocytic secretions could increase the natural hemolytic effect of hen serum on sheep or rabbit erythrocytes, and whether these secretions would become more active under the influence of a foreign protein. The substances which destroy foreign cells are not necessarily different from those which act on homologous cells. The word substance is used for simplicity of description and may be taken as meaning only a given property of an unknown substrate. A comparison was made of certain properties of sera extracted after 48 hours incubation from media containing leucocytes and from media containing no leucocytes. The serum from the leucocytic cultures was always found to be more favorable to the growth of homologous fibroblasts than the serum from the culture media incubated without leucocytes. The natural hemolytic power of the serum on sheep erythrocytes was found to be increased in about SO per cent of the experiments. In other experiments, we found that when two culture media free of cells were placed, one in an incubator at +38 degrees C. and the other in a refrigerator at +5 degrees C. for 48 hours, the serum from the incubated medium partly lost its hemolytic action on sheep or rabbit erythrocytes, while that from the refrigerated medium remained normal; at the same time, the inhibiting action of the incubated medium on homologous fibroblasts had increased very much. This effect of incubation indicates that certain unstable constituents of serum are destroyed by heat. Then the changes found in the properties of the serum from cultures of leucocytes are due to the fraction of the activating substances which has not been destroyed by incubation at 38 degrees C. A quantitative study of the secretions is, therefore, impossible with the present technique, which can furnish only qualitative indications about the substances set free by the leucocytes. We have ascertained also whether a medium containing leucocytes and kept in the refrigerator undergoes any change under the influence of the cells while they are in a condition of latent life. Gabritschewski dishes with and without leucocytes were placed in a refrigerator at a temperature of about +5 degrees C. After 48 hours, the hemolytic power on sheep erythrocytes of the serum from the leucocytic cultures had increased slightly and its inhibiting action on the growth of homologous fibroblasts had decreased. Then certain substances favorable to the growth of homologous cells and toxic for heterologous cells were diffused by the leucocytes into their medium. But the action of these substances was weaker than in the case of the cultures kept in the incubator. This experiment showed that leucocytes under certain conditions diffuse alexin or natural hemolysins which originate from them at the same time as the substances which activate homologous cells. In other experiments, although leucocytes were frozen at -10 degrees C., treated with distilled water, or extracted with saline solution, they did not yield any hemolysin. To summarize: Leucocytes, cultivated in plasma, always secreted substances which increased the rate of growth of homologous cells. Less frequently, they set free substances which hemolyzed foreign erythrocytes. The growth-promoting substances are analogous to those contained in embryonic tissues, and probably represent some of the foodstuffs brought to fixed tissue cells by leucocytes. They may possess the function of rejuvenating cells which have ceased to multiply when the cicatrization of a wound or the repair of a fracture requires a resumption of tissue activity. According to this hypothesis, the leucocytes brought to the surface of a wound by the process of inflammation would not only oppose bacterial invasion, but also bring to the tissues the material necessary to cell multiplication. It seems that in some cases regeneration is started by substances brought to the tissues by other cells. Loeb thinks that in Tubularia, when endodermic cells gather at the end where a new polyp is about to be formed, the substances given off by these cells are responsible for polyp formation.(6) There may be an analogy between this phenomenon and the secretion by leucocytes of growth-activating substances at the surface of a wound. If we assume that leucocytes in vivo set free their secretions in the blood stream, certain variations of the growth-inhibiting action of normal serum can be better understood. The rate of proliferation of homologous fibroblasts is much slower in the serum of an old chicken than in that of a young one. When the serum is heated at 56 degrees and 70 degrees C. for (1/2) hour, it becomes still more inhibiting. A substance favorable to cell activity has disappeared. It is therefore permissible to suppose that the growth-inhibiting power of serum and its variations are due to the antagonistic action of two substances, one growth-promoting and thermolabile, and the other growth-inhibiting and thermostable, the activating substance being always weaker in its effect than the inhibiting one. We know that activating substances can be extracted from embryonic tissue, from muscle and gland tissues, and from leucocytes of the adult animal, and that they are thermolabile and very unstable. Leucocytic secretions seem to have some of the properties of leucocytic extracts. It is probable that the activating substances which disappear from the heated serum are secreted by leucocytes and other cells. An increase of these secretions, then, would diminish the inhibiting action of serum on homologous fibroblasts. On the contrary, a decrease of the secretions in the serum would increase its inhibiting effect on homologous cells. The strong inhibiting action of serum in old age would be due partly to a reduction in the amount and activity of the substances secreted by leucocytes and tissue cells in the humors of the organism. Leucocytes also secreted in vitro substances which were toxic for foreign cells. Although the results were not constant, the serum appeared to become slightly more hemolytic for sheep or rabbit erythrocytes, under the influence of the leucocytes. The hemolysis of rabbit corpuscles by hen serum is due, according to Hyde,(9) to a complex sensitizer alexin, and not merely to alexin, as Bordet thought. When a foreign protein was added to the culture medium, the leucocytic secretions increased, as was shown by the action on homologous fibroblasts of sera taken from cultures of leucocytes with and without casein. The presence in the medium of the cultures of leucocytes of only 0.1 per 1,000 casein did not markedly modify the action of their serum on the proliferation of fibroblasts. When the concentration of casein in the leucocyte cultures reached 1 per 1,000, the growth of chicken fibroblasts in the serum extracted from the Gabritschewski dishes became more rapid. But there was no parallel increase of the hemolytic action of the serum upon sheep erythrocytes. We found that chicken serum containing 0.1 per 1,000 casein was barely toxic for homologous fibroblasts, while it became markedly inhibiting when the casein concentration reached 1 per 1,000. Probably, there is a relation between the toxicity of the medium, the increase of leucocytic secretions, and the time of the increase. The change brought about by casein in the equilibrium of the system composed of the cells and their medium determines the secretion by the leucocytes of substances which increase the activity of homologous cells and oppose the inhibiting effect of the foreign proteins. (ABSTRACT TRUNCATED)

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Airborne fine particulate matter (PM<sub2.5</sub; particulate matter ≤ 2.5 μm in aerodynamic diameter) plays a key role in air quality, climate, and public health. Globally, the largest mass fraction of PM<sub2.5</sub is organic, dominated by secondary organic aerosol (SOA) formed from atmospheric oxidation of volatile organic compounds (VOCs). Isoprene from vegetation is the most abundant nonmethane VOC emitted into Earth's atmosphere. Isoprene has been recently recognized as one of the major sources of global SOA production that is enhanced by the presence of anthropogenic pollutants, such as acidic sulfate derived from sulfur dioxide (SO<sub2</sub), through multiphase chemistry of its oxidation products. Considering the abundance of isoprene-derived SOA in the atmosphere, understanding mechanisms of adverse health effects through inhalation exposure is critical to mitigating its potential impact on public health. Although previous studies have examined the toxicological effects of certain isoprene-derived gas-phase oxidation products, to date, no systematic studies have examined the potential toxicological effects of isoprene-derived SOA, its constituents, or its SOA precursors on human lung cells. The overall objective of this study was to investigate the early biological effects of isoprene-derived SOA and its subtypes on BEAS-2B cells (a human bronchial epithelial cell line), with a particular focus on the alteration of oxidative stress- and inflammation-related genes. To achieve this objective, there were two specific aims. 1. Examine toxicity and early biological effects of SOA derived from the photochemical oxidation of isoprene, considering both urban and downwind-urban types of chemistry. 2. Examine toxicity and early biological effects of SOA derived directly from downstream oxidation products of isoprene (i.e., epoxides and hydroperoxides). Isoprene-derived SOA was first generated by photooxidation of isoprene under natural sunlight in the presence of nitric oxide (NO) and acidified sulfate aerosols. Experiments were conducted in a 120-m<sup3</sup outdoor Teflon-film chamber located on the roof of the Gillings School of Global Public Health, University of North Carolina at Chapel Hill (UNC-Chapel Hill). BEAS-2B cells were exposed to chamber- generated isoprene-derived SOA using the Electrostatic Aerosol in Vitro Exposure System (EAVES). This approach allowed us to generate atmospherically relevant compositions of isoprene-derived SOA and to examine its toxicity through in vitro exposures at an air-liquid interface, providing a more biologically relevant exposure model. Isoprene-derived SOA samples were also collected, concurrently with EAVES sampling, onto Teflon membrane filters for in vitro resuspension exposures and for analysis of aerosol chemical composition by gas chromatography/electron ionization-quadrupole mass spectrometry (GC/EI-MS) with prior trimethylsilylation and ultra-performance liquid-chromatography coupled to high-resolution quadrupole time-of-flight mass spectrometry equipped with electrospray ionization (UPLC/ESI-HR-QTOFMS). Isoprene-derived SOA samples were also analyzed by the dithiothreitol (DTT) assay in order to characterize their reactive oxygen species (ROS)-generation potential. Organic synthesis of known isoprene-derived SOA precursors, which included isoprene epoxydiols (IEPOX), methacrylic acid epoxide (MAE), and isoprene-derived hydroxyhydroperoxides (ISOPOOH), was conducted in order to isolate major isoprene-derived SOA formation pathways from each other and to determine which of these pathways (or SOA types) is potentially more toxic. Since IEPOX and MAE produce SOA through multiphase chemistry onto acidic sulfate aerosol, dark reactive uptake experiments of IEPOX and MAE in the presence of acidic sulfate aerosol were performed in a 10-m<sup3</sup flexible Teflon indoor chamber at UNC-Chapel Hill. Since the generation of SOA from ISOPOOH (through a non-IEPOX route) requires a hydroxyl radical (•OH)-initiated oxidation, ozonolysis of tetramethylethylene (TME) was used to form the needed •OH radicals in the indoor chamber. The resultant low-volatility multifunctional hydroperoxides condensed onto nonacidified sulfate aerosol, yielding the ISOPOOH-derived SOA needed for exposures. Similar to the outdoor chamber SOAs, IEPOX, MAE- and ISOPOOH-derived SOAs were collected onto Teflon membrane filters and were subsequently chemically characterized by GC/EI-MS and UPLC/ESI-HR-QTOFMS as well as for ROS-generation potential using the DTT assay. These filters were also used for resuspension in vitro exposures. By conducting gene expression profiling, we provided mechanistic insights into the potential health effects of isoprene-derived SOA. First, gene expression profiling of 84 oxidative stress- and 249 inflammation-associated human genes was performed for cells exposed to isoprene-derived SOA generated in our outdoor chamber experiments in EAVES or by resuspension. Two pathway-focused panels were utilized for this purpose: (1) nCounter GX Human Inflammation Kit comprised of 249 human genes (NanoString), and (2) Human Oxidative Stress Plus RT2 Profiler PCR Array (Qiagen) comprised of 84 oxidative stress-associated genes. We compared the gene expression levels in cells exposed to SOA generated in an outdoor chamber from photochemical oxidation of isoprene in the presence of NO and acidified sulfate seed aerosol to cells exposed to a dark control mixture of isoprene, NO, and acidified sulfate seed aerosol to isolate the effects of the isoprene-derived SOA on the cells using the EAVES and resuspension exposure methods. Pathway-based analysis was performed for significantly altered genes using the ConsensusPathDB database, which is a database system for the integration of human gene functional interactions to provide biological pathway information for a gene set of interest. Pathway annotation was performed to provide biological pathway information for each gene set. The gene-gene interaction networks were constructed and visualized using the GeneMANIA Cytoscape app (version 3.4.1) to predict the putative function of altered genes. Lastly, isoprene-derived SOA collected onto filters was used in resuspension exposures to measure select inflammatory biomarkers, including interleukin 8 (<iIL-8</i) and prostaglandin-endoperoxide synthase 2 (<iPTGS2</i) genes, in BEAS-2B cells to ensure that effects observed from EAVES exposures were attributable to particle-phase organic products. Since EAVES and resuspension exposures compared well, gene expression profiling for IEPOX-, MAE- and ISOPOOH-derived SOA were conducted using only resuspension exposures. Chemical characterization coupled with biological analyses show that atmospherically relevant compositions of isoprene-derived SOA alter the levels of 41 oxidative stress-related genes. Of the different composition types of isoprene-derived SOA, MAE- and ISOPOOH-derived SOA altered the greatest number of genes, suggesting that carbonyl and hydroperoxide functional groups are oxidative stress promoters. Taken together, the different composition types accounted for 34 of the genes altered by the total isoprene-derived SOA mixture, while 7 remained unique to the total mixture exposures, indicating that there is either a synergistic effect of the different isoprene-derived SOA components or an unaccounted component in the mixture. The high-oxides of nitrogen (NO<subx</sub) regime, which yielded MAE- and methacrolein (MACR)-derived SOA, had a higher ROS-generation potential (as measured by the DTT assay) than the low- NO<subx</sub regime, which included IEPOX- and isoprene-derived SOA. However, ISOPOOH-derived SOA, which also formed in the low- NO<subx</sub regime, had the highest ROS-generation potential, similar to 1,4-naphthoquinone (1,4-NQ). This suggests that aerosol-phase organic peroxides contribute significantly to particulate matter (PM) oxidative potential. MAE- and MACR- derived SOA showed equal or greater ROS-generation potential than was reported in prior UNC-Chapel Hill studies on diesel exhaust PM, highlighting the importance of a comprehensive investigation of the toxicity of isoprene-derived SOA. Notably, ISOPOOH-derived SOA was one order of magnitude higher in ROS-generation potential than diesel exhaust particles previously examined at UNC-Chapel Hill. As an acellular assay, the DTT assay may not be predictive of oxidative stress; therefore, we also focused on the gene expression results from the cellular exposures. We have demonstrated that the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and the redox-sensitive activation protein-1 (AP-1) transcription factor networks have been significantly altered upon exposure to isoprene-derived SOA. The identification of Nrf2 pathway in cells exposed to isoprene-derived SOA is in accordance with our findings using the DTT assay, which measures the thiol reactivity of PM samples as a surrogate for their ROS-generation potential. Specifically, our results point to the cysteine-thiol modifications within cells that lead to activation of Nrf2-related gene expression. However, based on our gene expression results showing no clear relationship between DTT activity and the number of altered oxidative stress-related genes, the DTT activity of isoprene-derived SOA may not be directly indicative of toxicity relative to other SOA types. While activation of Nrf2-associated genes has been identified with responses to oxidative stress and linked to traffic related air pollution exposure in both toxicological and epidemiological studies, their implicit involvement in this study suggests that activation of Nrf2-related gene expression may occur with exposures to all sorts of PM types. By controlling the exposure time, method, and dose we demonstrated that among the SOA derived from previously identified individual precursors of isoprene-derived SOA, ISOPOOH-derived SOA alters more oxidative stress related genes than does IEPOX-derived SOA, but fewer than MAE-derived SOA. This suggests that the composition of MAE-derived SOA may be the greatest contributor to alterations of oxidative stress-related gene expression observed due to isoprene-derived SOA exposure. Further study on induced levels of protein expression and specific toxicological endpoints is necessary to determine if the observed gene expression changes lead to adverse health effects. In addition, such studies have implications for pollution-control strategies because NO<subx</sub and SO<sub2</sub are controllable pollutants that can alter the composition of SOA, and in turn alter its effects on gene expression. The mass fraction of different components of atmospheric isoprene derived SOA should be considered, but altering the fraction of high- NO<subx</sub isoprene-derived SOA (e.g., MAE derived SOA) may yield greater changes in gene expression than altering the fraction of low- NO<subx</sub isoprene derived SOA types (ISOPOOH- or IEPOX-derived SOA). Finally, this study confirms that total isoprene-derived SOA alters the expression of a greater number of genes than does SOA derived from the tested precursors. This warrants further work to determine the underlying explanation for this observation, which may be uncharacterized components of isoprene-derived SOA or the potential for synergism between the studied components.

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The objective of this analysis was to determine the strength of association between age, gender, ethnicity, family history of disease and refractive error and the risk of developing glaucoma or ARM? A routine eye exam serves a primary, secondary, and tertiary care role. In a primary care role, it allows contact with a doctor who can provide advice about eye care, which may reduce the incidence of eye disease and injury. In a secondary care role, it can via a case finding approach, diagnose persons with degenerative eye diseases such as glaucoma and or AMD, and lead to earlier treatment to slow the progression of the disease. Finally in a tertiary care role, it provides ongoing monitoring and treatment to those with diseases associated with vision loss. Glaucoma is a progressive degenerative disease of the optic nerve, which causes gradual loss of peripheral (side) vision, and in advanced disease states loss of central vision. Blindness may results if glaucoma is not diagnosed and managed. The prevalence of primary open angle glaucoma (POAG) ranges from 1.1% to 3.0% in Western populations, and from 4.2% to 8.8% in populations of African descent. It is estimated up to 50% of people with glaucoma are aware that they have the disease. In Canada, glaucoma disease is the second leading cause of blindness in people aged 50 years and older. Tonometry, inspection of the optic disc and perimetry are used concurrently by physicians and optometrists to make the diagnosis of glaucoma. In general, the evidence shows that treating people with increased IOP only, increased IOP and clinical signs of early glaucoma or with normal-tension glaucoma can reduce the progression of disease. Age-related maculopathy (ARM) is a degenerative disease of the macula, which is a part of the retina. Damage to the macula causes loss of central vision affecting the ability to read, recognize faces and to move about freely. ARM can be divided into an early- stage (early ARM) and a late-stage (AMD). AMD is the leading cause of blindness in developed countries. The prevalence of AMD increases with increasing age. It is estimated that 1% of people 55 years of age, 5% aged 75 to 84 years and 15% 80 years of age and older have AMD. ARM can be diagnosed during fundoscopy (ophthalmoscopy) which is a visual inspection of the retina by a physician or optometrist, or from a photograph of the retina. There is no cure or prevention for ARM. Likewise, there is currently no treatment to restore vision lost due to AMD. However, there are treatments to delay the progression of the disease and further loss of vision. A periodic oculo-visual assessment is defined "as an examination of the eye and vision system rendered primarily to determine if a patient has a simple refractive error (visual acuity assessment) including myopia, hypermetropia, presbyopia, anisometropia or astigmatism." This service includes a history of the presenting complaint, past medical history, visual acuity examination, ocular mobility examination, slit lamp examination of the anterior segment, ophthalmoscopy, and tonometry (measurement of IOP) and is completed by either a physician or an optometrist. THE MEDICAL ADVISORY SECRETARIAT CONDUCTED A COMPUTERIZED SEARCH OF THE LITERATURE IN THE FOLLOWING DATABASES: OVID MEDLINE, MEDLINE, In-Process &amp; Other Non-Indexed Citations, EMBASE, INAHTA and the Cochrane Library. The search was limited to English-language articles with human subjects, published from January 2000 to March 2006. In addition, a search was conducted for published guidelines, health technology assessments, and policy decisions. Bibliographies of references of relevant papers were searched for additional references that may have been missed in the computerized database search. Studies including participants 20 years and older, population-based prospective cohort studies, population-based cross-sectional studies when prospective cohort studies were unavailable or insufficient and studies determining and reporting the strength of association or risk- specific prevalence or incidence rates of either age, gender, ethnicity, refractive error or family history of disease and the risk of developing glaucoma or AMD were included in the review. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used to summarize the overall quality of the body of evidence. A total of 498 citations for the period January 2000 through February 2006 were retrieved and an additional 313 were identified when the search was expanded to include articles published between 1990 and 1999. An additional 6 articles were obtained from bibliographies of relevant articles. Of these, 36 articles were retrieved for further evaluation. Upon review, 1 meta-analysis and 15 population-based epidemiological studies were accepted for this review PRIMARY OPEN ANGLE GLAUCOMA: Age Six cross-sectional studies and 1 prospective cohort study contributed data on the association between age and PAOG. From the data it can be concluded that the prevalence and 4-year incidence of POAG increases with increasing age. The odds of having POAG are statistically significantly greater for people 50 years of age and older relative to those 40 to 49 years of age. There is an estimated 7% per year incremental odds of having POAG in persons 40 years of age and older, and 10% per year in persons 49 years of age and older. POAG is undiagnosed in up to 50% of the population. The quality of the evidence is moderate. Gender Five cross-sectional studies evaluated the association between gender and POAG. Consistency in estimates is lacking among studies and because of this the association between gender and prevalent POAG is inconclusive. The quality of the evidence is very low. Ethnicity Only 1 cross-sectional study compared the prevalence rates of POAG between black and white participants. These data suggest that prevalent glaucoma is statistically significantly greater in a black population 50 years of age and older compared with a white population of similar age. There is an overall 4-fold increase in prevalent POAG in a black population compared with a white population. This increase may be due to a confounding variable not accounted for in the analysis. The quality of the evidence is low. Refractive Error Four cross-sectional studies assessed the association of myopia and POAG. These data suggest an association between myopia defined as a spherical equivalent of -1.00D or worse and prevalent POAG. However, there is inconsistency in results regarding the statistical significance of the association between myopia when defined as a spherical equivalent of -0.5D. The quality of the evidence is very low. Family History of POAG Three cross-sectional studies investigated the association between family history of glaucoma and prevalent POAG. These data suggest a 2.5 to 3.0 fold increase in the odds having POAG in persons with a family history (any first-degree relative) of POAG. The quality of the evidence is moderate. AGE-RELATED MACULOPATHY: Age Four cohort studies evaluated the association between age and early ARM and AMD. After 55 years of age, the incidence of both early ARM and AMD increases with increasing age. Progression to AMD occurs in up to 12% of persons with early ARM. The quality of the evidence is low Gender Four cohort studies evaluated the association between gender and early ARM and AMD. Gender differences in incident early ARM and incident AMD are not supported from these data. The quality of the evidence is lows. Ethnicity One meta-analysis and 2 cross-sectional studies reported the ethnic-specific prevalence rates of ARM. The data suggests that the prevalence of early ARM is higher in a white population compared with a black population. The data suggest that the ethnic-specific differences in the prevalence of AMD remain inconclusive. Refractive Error Two cohort studies investigated the association between refractive error and the development of incident early ARM and AMD. The quality of the evidence is very low. Family History Two cross-sectional studies evaluated the association of family history and early ARM and AMD. Data from one study supports an association between a positive family history of AMD and having AMD. The results of the study indicate an almost 4-fold increase in the odds of any AMD in a person with a family history of AMD. The quality of the evidence, as based on the GRADE criteria is moderate. The prevalence of glaucoma is estimated at 1 to 3% for a Caucasian population and 4.2 to 8.8% for a black population. The incidence of glaucoma is estimated at 0.5 to 2.5% per year in the literature. The percentage of people who go blind per year as a result of glaucoma is approximately 0.55%. The total population of Ontarians aged 50 to 64 years is estimated at 2.6 million based on the April 2006 Ontario Ministry of Finance population estimates. The range of utilization for a major eye examination in 2006/07 for this age group is estimated at 567,690 to 669,125, were coverage for major eye exams extended to this age group. This would represent a net increase in utilization of approximately 440,116 to 541,551. The percentage of Ontario population categorized as black and/or those with a family history of glaucoma was approximately 20%. Therefore, the estimated range of utilization for a major eye examination in 2006/07 for this sub-population is estimated at 113,538 - 138,727 (20% of the estimated range of utilization in total population of 50-64 year olds in Ontario), were coverage for major eye exams extended to this sub-group. This would represent a net increase in utilization of approximately 88,023 to 108,310 within this sub-group. The total cost of a major eye examination by a physician is $42. (ABSTRACT TRUNCATED)

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The purpose of this evidence-based review was to examine the effectiveness and cost-effectiveness of spectral-domain (SD) optical coherence tomography (OCT) in the diagnosis and monitoring of patients with retinal disease, specifically age-related macular degeneration (AMD) and diabetic macular edema (DME). Specifically, the research question addressed was: What is the sensitivity and specificity of spectral domain OCT relative to the gold standard? TARGET POPULATION AND CONDITION The incidence of blindness has been increasing worldwide. In Canada, vision loss in those 65 years of age and older is primarily due to AMD, while loss of vision in those 18 years of age and older is mainly due to DME. Both of these conditions are diseases of the retina, which is located at the back of the eye. At the center of the retina is the macula, a 5 mm region that is responsible for what we see in front of us, our ability to detect colour, and fine detail. Damage to the macula gives rise to vision loss, but early detection of asymptomatic disease may lead to the prevention or slowing of the vision loss process. There are two main types of AMD, 'dry' and 'wet'. Dry AMD is the more prevalent of the two, accounting for approximately 85% of cases and characterized by small deposits of extracellular material called "drusen" that build up in Bruch's membrane of the eye. Central vision loss is gradual with blurring and eventual colour fading. Wet AMD is a less prevalent condition (15% of all AMD cases) but it accounts for 90% of severe cases. It's characterized by the appearance of retinal fluid with vision loss due to abnormal blood vessels/leakage within weeks to months of diagnosis. In 2003, the Canadian National Institute for the Blind (CNIB) prevalence estimate for AMD was 1 million Canadians, including approximately 400,000 affected Ontarians. The incidence in 2003 was estimated to be 78,000 new cases in Canada, with approximately one-third of these cases arising in Ontario (n=26,000). Over the next 25 years, the number of new cases is expected to triple. DME is caused by complications of diabetes mellitus, both Type 1 and Type 2. It is estimated that 1-in-4 persons with diabetes has this condition, though it occurs more frequently among those with type 2 diabetes. The condition is characterized by a swelling of the retina caused by leakage of blood vessels at the back of the eye. In early stages of the disease, vision may still be normal but it can degrade rapidly in later stages. In 2003, the CNIB prevalence estimate for DME was 0.5 million Canadians, with approximately 200,000 Ontarians affected. The incidence of DME is more difficult to ascertain; however, based on an annual incidence rate of 0.8% (for those 20 years of age or older) and the assumption that 1-in-4 persons with diabetes is affected, the incidence of DME in Ontario is estimated to be 21,000 new cases per year. OPTICAL COHERENCE TOMOGRAPHY: Prior to the availability of OCT, the standard of care in the diagnosis and/or monitoring of retinal disease was serial testing with fluorescein angiography (FA), biomicroscopy (BM), and stereo-fundus photography (SFP). Each of these is a qualitative measure of disease based on subjective evaluations that are largely dependent on physician expertise. OCT is the first quantitative visual test available for the diagnosis of eye disease. As such, it is allows for a more objective evaluation of the presence/absence of retinal disease and it is the only test that provides a measure of retinal thickness. The technology was developed at the Michigan Institute of Technology (MIT) in 1991 as a real-time imaging modality and is considered comparable to histology. It's a light-wave based technology producing cross-sectional images with scan rates and resolution parameters that have greatly improved over the last 10 years. It's also a non-invasive, non-contact visual test that requires just 3 to 5 minutes to assess both eyes. There are two main types of OCT system, both licensed by Health Canada as class II devices. The original patent was based on a time domain (TD) system (available from 1995) that had an image rate of 100 to 400 scans per second and provided information for a limited view of the retina with a resolution in the range of 10 to 20 μm. The newer system, spectral domain (SD) OCT, has been available since 2006. Improvements with this system include (i) a faster scan speed of approximately 27,000 scans per second; (ii) the ability to scan larger areas of the retina by taking six scans radially-oriented 30 degrees from each other; (iii) increased resolution at 5μm; and (iv) 'real-time registration,' which was not previously available with TD. The increased scan speed of SD systems enables the collection of additional real-time information on larger regions of the retina, thus, reducing the reliance on assumptions required for retinal thickness and volume estimates based on software algorithms. The faster scan speed also eliminates image distortion arising from patient movement (not previously possible with TD), while the improvement in resolution allows for clearer and more distinguishable retinal layers with the possibility of detecting earlier signs of disease. Real-time registration is a new feature of SD that enables the identification of specific anatomical locations on the retina, against which subsequent tests can be evaluated. This is of particular importance in the monitoring of patients. In the evaluation of treatment effects, for example, this enables the same anatomic retinal location to be identified at each visit. A literature search was performed on February 13, 2009 using Ovid MEDLINE, MEDLINE In-Process &amp; Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing &amp; Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 2003 to February 2009. The subject headings and keywords searched included AMD, DME, and OCT (the detailed search strategy can be viewed in Appendix 1). Excluded were case reports, comments, editorials, non-systematic reviews, and letters. Abstacts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. In total, 542 articles were included for review. Inclusion CriteriaExclusion CriteriaEnglish-language articles and health technology assessments.RCTs and observational studies of OCT and AMD or DME.Studies focusing on either diagnosis or monitoring of disease.Studies in which outcomes were not specific to those of interest in this report.Studies of pediatric populations.Studies on OCT as a screening tool.Studies that did not assess comparative effectiveness of OCT with a referent, as specified below in "Comparisons of Interest". Studies of sensitivity, specificity. COMPARISONS OF INTEREST: Evidence exists for the following comparisons of interest: OCT compared with the reference "fluorescein angiography" for AMD.OCT compared with the reference "biomicroscopy" or "stereo or fundus photography" for DME. SUMMARY OF EXISTING EVIDENCE: No evidence for the accuracy of SD OCT compared to either FA, BM or SFP was published between January 2006 to February 2009; however, two technology assessments were found, one from Alberta and the other from Germany, both of which contain evidence for TD OCT. Although these HTAs included eight studies each, only one study from each report was specific to this review. Additionally, one systematic review was identified for OCT and DME. It is these three articles, all pertaining to time and not spectral domain OCT, as well as comments from experts in the field of OCT and retinal disease, that comprise the evidence contained in this review. Upon further assessment and consultations with experts in the methodology of clinical test evaluation, it was concluded that these comparators could not be used as references in the evaluation of OCT. The main conclusion was that, without a third test as an arbiter, it is not possible to directly compare the sensitivity and specificity of OCT relative to either FA for AMD and stereo- or fundus - photography for DME. Therefore, in the absence of published evidence, it was deemed appropriate to consult a panel of experts for their views and opinions on the validity of OCT and its utility in clinical settings. This panel consisted of four clinicians with expertise in AMD and/or DME and OCT, as well as a medical biophysicist with scientific expertise in ocular technologies. This is considered level 5 evidence, but in the absence of an appropriate comparator for further evaluation of OCT, this may be the highest level of evidence possible. The conclusions for SD OCT based on Level 5 evidence, or expert consultation, are as follows: OCT is considered an essential part of the diagnosis and follow-up of patients with DME and AMD.OCT is adjunctive to FA for both AMD and DME but should decrease utilization of FA as a monitoring modality.OCT will result in a decline in the use of BM in the monitoring of patients with DME, given its increased accuracy and consistency.OCT is diffusing rapidly and the technology is changing. Since FA is still considered pivotal in the diagnosis and treatment of AMD and DME, and there is no common outcome against which to compare these technologies, it is unlikely that RCT evidence of efficacy for OCT will ever be forthcoming.In addition to the accuracy of OCT in the detection of disease, assessment of the clinical utility of this technology included a rapid review of treatment effects for AMD and DME. The treatment of choice for AMD is Lucentis®, with or without Avastin® and photodynamic therapy. (ABSTRACT TRUNCATED)

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Mortality is associated with long-term exposure to fine particulate matter (particulate matter ≤2.5 μm in aerodynamic diameter; PM<sub2.5</sub), although the magnitude and form of these associations remain poorly understood at lower concentrations. Knowledge gaps include the shape of concentration-response curves and the lowest levels of exposure at which increased risks are evident and the occurrence and extent of associations with specific causes of death. Here, we applied improved estimates of exposure to ambient PM<sub2.5</sub to national population-based cohorts in Canada, including a stacked cohort of 7.1 million people who responded to census year 1991, 1996, or 2001. The characterization of the shape of the concentration-response relationship for nonaccidental mortality and several specific causes of death at low levels of exposure was the focus of the Mortality-Air Pollution Associations in Low Exposure Environments (MAPLE) Phase 1 report. In the Phase 1 report we reported that associations between outdoor PM<sub2.5</sub concentrations and nonaccidental mortality were attenuated with the addition of ozone (O<sub3</sub) or a measure of gaseous pollutant oxidant capacity (O<subx</sub), which was estimated from O<sub3</sub and nitrogen dioxide (NO<sub2</sub) concentrations. This was motivated by our interests in understanding both the effects air pollutant mixtures may have on mortality and also the role of O<sub3</sub as a copollutant that shares common sources and precursor emissions with those of PM<sub2.5</sub. In this Phase 2 report, we further explore the sensitivity of these associations with O<sub3</sub and O<subx</sub, evaluate sensitivity to other factors, such as regional variation, and present ambient PM<sub2.5</sub concentration-response relationships for specific causes of death. PM<sub2.5</sub concentrations were estimated at 1 km<sup2</sup spatial resolution across North America using remote sensing of aerosol optical depth (AOD) combined with chemical transport model (GEOS-Chem) simulations of the AOD:surface PM<sub2.5</sub mass concentration relationship, land use information, and ground monitoring. These estimates were informed and further refined with collocated measurements of PM<sub2.5</sub and AOD, including targeted measurements in areas of low PM<sub2.5</sub concentrations collected at five locations across Canada. Ground measurements of PM<sub2.5</sub and total suspended particulate matter (TSP) mass concentrations from 1981 to 1999 were used to backcast remote-sensing-based estimates over that same time period, resulting in modeled annual surfaces from 1981 to 2016. Annual exposures to PM<sub2.5</sub were then estimated for subjects in several national population-based Canadian cohorts using residential histories derived from annual postal code entries in income tax files. These cohorts included three census-based cohorts: the 1991 Canadian Census Health and Environment Cohort (CanCHEC; 2.5 million respondents), the 1996 CanCHEC (3 million respondents), the 2001 CanCHEC (3 million respondents), and a Stacked CanCHEC where duplicate records of respondents were excluded (Stacked CanCHEC; 7.1 million respondents). The Canadian Community Health Survey (CCHS) mortality cohort (mCCHS), derived from several pooled cycles of the CCHS (540,900 respondents), included additional individual information about health behaviors. Follow-up periods were completed to the end of 2016 for all cohorts. Cox proportional hazard ratios (HRs) were estimated for nonaccidental and other major causes of death using a 10-year moving average exposure and 1-year lag. All models were stratified by age, sex, immigrant status, and where appropriate, census year or survey cycle. Models were further adjusted for income adequacy quintile, visible minority status, Indigenous identity, educational attainment, labor-force status, marital status, occupation, and ecological covariates of community size, airshed, urban form, and four dimensions of the Canadian Marginalization Index (Can-Marg; instability, deprivation, dependency, and ethnic concentration). The mCCHS analyses were also adjusted for individual-level measures of smoking, alcohol consumption, fruit and vegetable consumption, body mass index (BMI), and exercise behavior. In addition to linear models, the shape of the concentration-response function was investigated using restricted cubic splines (RCS). The number of knots were selected by minimizing the Bayesian Information Criterion (BIC). Two additional models were used to examine the association between nonaccidental mortality and PM<sub2.5</sub. The first is the standard threshold model defined by a transformation of concentration equaling zero if the concentration was less than a specific threshold value and concentration minus the threshold value for concentrations above the threshold. The second additional model was an extension of the Shape Constrained Health Impact Function (SCHIF), the eSCHIF, which converts RCS predictions into functions potentially more suitable for use in health impact assessments. Given the RCS parameter estimates and their covariance matrix, 1,000 realizations of the RCS were simulated at concentrations from the minimum to the maximum concentration, by increments of 0.1 μg/m<sup3</sup. An eSCHIF was then fit to each of these RCS realizations. Thus, 1,000 eSCHIF predictions and uncertainty intervals were determined at each concentration within the total range. Sensitivity analyses were conducted to examine associations between PM<sub2.5</sub and mortality when in the presence of, or stratified by tertile of, O<sub3</sub or O<subx</sub. Additionally, associations between PM<sub2.5</sub and mortality were assessed for sensitivity to lower concentration thresholds, where person-years below a threshold value were assigned the mean exposure within that group. We also examined the sensitivity of the shape of the nonaccidental mortality-PM<sub2.5</sub association to removal of person-years at or above 12 μg/m<sup3</sup (the current U.S. National Ambient Air Quality Standard) and 10 μg/m<sup3</sup (the current Canadian and former [2005] World Health Organization [WHO] guideline, and current WHO Interim Target-4). Finally, differences in the shapes of PM<sub2.5</sub-mortality associations were assessed across broad geographic regions (airsheds) within Canada. The refined PM<sub2.5</sub exposure estimates demonstrated improved performance relative to estimates applied previously and in the MAPLE Phase 1 report, with slightly reduced errors, including at lower ranges of concentrations (e.g., for PM<sub2.5</sub &lt;10 μg/m<sup3</sup). Positive associations between outdoor PM<sub2.5</sub concentrations and nonaccidental mortality were consistently observed in all cohorts. In the Stacked CanCHEC analyses (1.3 million deaths), each 10-μg/m<sup3</sup increase in outdoor PM<sub2.5</sub concentration corresponded to an HR of 1.084 (95% confidence interval [CI]: 1.073 to 1.096) for nonaccidental mortality. For an interquartile range (IQR) increase in PM<sub2.5</sub mass concentration of 4.16 μg/m<sup3</sup and for a mean annual nonaccidental death rate of 92.8 per 10,000 persons (over the 1991-2016 period for cohort participants ages 25-90), this HR corresponds to an additional 31.62 deaths per 100,000 people, which is equivalent to an additional 7,848 deaths per year in Canada, based on the 2016 population. In RCS models, mean HR predictions increased from the minimum concentration of 2.5 μg/m<sup3</sup to 4.5 μg/m<sup3</sup, flattened from 4.5 μg/m<sup3</sup to 8.0 μg/m<sup3</sup, then increased for concentrations above 8.0 μg/m<sup3</sup. The threshold model results reflected this pattern with -2 log-likelihood values being equal at 2.5 μg/m<sup3</sup and 8.0 μg/m<sup3</sup. However, mean threshold model predictions monotonically increased over the concentration range with the lower 95% CI equal to one from 2.5 μg/m<sup3</sup to 8.0 μg/m<sup3</sup. The RCS model was a superior predictor compared with any of the threshold models, including the linear model. In the mCCHS cohort analyses inclusion of behavioral covariates did not substantially change the results for both linear and nonlinear models. We examined the sensitivity of the shape of the nonaccidental mortality-PM<sub2.5</sub association to removal of person-years at or above the current U.S. and Canadian standards of 12 μg/m<sup3</sup and 10 μg/m<sup3</sup, respectively. In the full cohort and in both restricted cohorts, a steep increase was observed from the minimum concentration of 2.5 μg/m<sup3</sup to 5 μg/m<sup3</sup. For the full cohort and the &lt;12 μg/m<sup3</sup cohort the relationship flattened over the 5 to 9 μg/m<sup3</sup range and then increased above 9 μg/m<sup3</sup. A similar increase was observed for the &lt;10 μg/m<sup3</sup cohort followed by a clear decline in the magnitude of predictions over the 5 to 9 μg/m<sup3</sup range and an increase above 9 μg/m<sup3</sup. Together these results suggest that a positive association exists for concentrations &gt;9 μg/m<sup3</sup with indications of adverse effects on mortality at concentrations as low as 2.5 μg/m<sup3</sup. Among the other causes of death examined, PM<sub2.5</sub exposures were consistently associated with an increased hazard of mortality due to ischemic heart disease, respiratory disease, cardiovascular disease, and diabetes across all cohorts. Associations were observed in the Stacked CanCHEC but not in all other cohorts for cerebrovascular disease, pneumonia, and chronic obstructive pulmonary disease (COPD) mortality. No significant associations were observed between mortality and exposure to PM<sub2.5</sub for heart failure, lung cancer, and kidney failure. In sensitivity analyses, the addition of O<sub3</sub and O<subx</sub attenuated associations between PM<sub2.5</sub and mortality. When analyses were stratified by tertiles of copollutants, associations between PM<sub2.5</sub and mortality were only observed in the highest tertile of O<sub3</sub or O<subx</sub. Across broad regions of Canada, linear HR estimates and the shape of the eSCHIF varied substantially, possibly reflecting underlying differences in air pollutant mixtures not characterized by PM<sub2.5</sub mass concentrations or the included gaseous pollutants. Sensitivity analyses to assess regional variation in population characteristics and access to healthcare indicated that the observed regional differences in concentration-mortality relationships, specifically the flattening of the concentration-mortality relationship over the 5 to 9 μg/m<sup3</sup range, was not likely related to variation in the makeup of the cohort or its access to healthcare, lending support to the potential role of spatially varying air pollutant mixtures not sufficiently characterized by PM<sub2.5</sub mass concentrations. In several large, national Canadian cohorts, including a cohort of 7.1 million unique census respondents, associations were observed between exposure to PM<sub2.5</sub with nonaccidental mortality and several specific causes of death. Associations with nonaccidental mortality were observed using the eSCHIF methodology at concentrations as low as 2.5 μg/m<sup3</sup, and there was no clear evidence in the observed data of a lower threshold, below which PM<sub2.5</sub was not associated with nonaccidental mortality.

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From the foregoing description of the histological changes in the leptomeninx it is quite evident that we are dealing with a chronic, stationary, healing form of tuberculous inflammation. This statement is substantiated, in the first place, by the clinical history. The only reasonable interpretation of the symptoms would establish the duration of the process as four months. The imaginable contingency that there existed first a meningeal syphilitic lesion that was dispersed by the iodide of potassium only to be followed by a tuberculous infection is so remote and unlikely that it need not be discussed. At all events the tuberculous leptomeningitis, which presented a typical distribution, began insidiously, existed at times in a latent condition, and pursued a very anomalous course, marked by a relative mildness of all the symptoms, and thus it came about that when an apparent or real improvement followed the administration of iodide of potassium able observers were induced to make an erroneous diagnosis. Death occurred as a result of an intercurrent infection. The long duration of the process is also shown, anatomically, by the thick layer of firm, translucent and gelatinous material that matted together the structures at the base, and also by the evident adhesions between the pia and the brain. The histological examination furnishes proof positive of the correctness of the conclusion in regard to the peculiar character of this process because it shows: (1) That the tuberculous proliferation is uniform in development and has reached nearly the same stage of evolution throughout the entire extent of the leptomeninx involved; it is not a process that has advanced by exacerbations and irregular extensions; the lesions are, generally speaking, of nearly the same age everywhere and must have begun at about the same time. (2) That only a very limited degree of caseous degeneration is present, pointing to an early arrest of the activity of the tubercle bacillus or to a very decided diminution or attenuation of its virulence. (3) That the subendothelial intimal proliferations of epithelioid cells, so generally found in acute tuberculous leptomeningitis,* have in this case become more or less completely changed into distinct fibrous tissue in which but very slight, if any, direct evidence of its tuberculous origin can be found. It is only by recognizing that the chronic endarteritis is most marked in correspondence with the most advanced adventitial tuberculous changes, and by finding an imperfect, much altered giant cell in one district of intimal thickening, that we were able to establish the direct kinship of the endovascular changes with those of the pia in general. (4) That acute inflammatory changes, in the form of emigration of polymorphonuclear leucocytes and of fibrinous exudation, are entirely absent in all parts of the district involved. The presence of a turbid serous fluid is of course not at all inconsistent with the view that the anatomical changes are of long duration. (5) That the granulation tissue present is, in general, undergoing fibrillation and contains a rich supply of enabryonal capillary vessels as well as of larger blood-vessels of evidently new formation. The absence of any considerable extent of polymorphonuclear leucocytic infiltration in this tissue has already been referred to. The cells in the granulation tissue correspond to the cells of embryonal or formative connective tissue. Vacuolation is rarely present. (6) That the unusually large number of giant cells present are remarkably free from evidences of necrosis and degeneration of the character ordinarily observed in tuberculous proliferations, that they do not contain in demonstrable form tubercle bacilli, and that the majority of the giant cells seem to be separating into individual cells and smaller masses often with, but sometimes also without, evidences of nuclear disintegration. The possibility that these phenomena may signify fusion instead of the sundering of cells will be discussed below. For these reasons there can be no doubt that the general claim that we are dealing with an instance of chronic, healing tuberculous meningitis must be regarded as established beyond dispute. The growth of tubercle bacilli in the glycerine-agar tubes, inoculated with the fluid from the pial meshes, and the demonstration of tubercle bacilli, though in very small numbers, between the cells of the embryonal tissue, furnish the positive evidence that we are actually dealing with a tuberculous process due to living and not to dead bacilli. The degree of virulence of the cultures of tubercle bacilli was, unfortunately perhaps, not studied. The presence of living tubercle bacilli in a tissue free from active and acute changes characteristic of tuberculosis demonstrates that, whatever the actual degree of virulence of the bacilli may have been, the tissue in which they were found was at this time relatively immune from their action. The manner in which this immunity was produced, and in which the process of healing was initiated, need not be discussed at this time any further than to again direct attention to the fact that the bacilli lost their virulency as regards the cells in this leptomeninx before these cells underwent any marked degree of degeneration. The cells of the tuberculous proliferations survived the further action of the bacilli whose original effect it was to initiate cell accumulation or proliferation; the cells also retained sufficient vitality to develop, in some instances at any rate, into formative cells according as their origin would dictate, e. g. into fibroblasts. That fibroblasts are formed only by embryonal connective tissue cells, and not by wandering cells, such as the large mononuclear leucocytes, we are well aware, is possibly still a disputable assumption, and we do not consider it pertinent to discuss the question any further in connection with this study, but would only emphasize the point that some of the cells of tuberculous proliferations may, under favorable circumstances, become formative cells, and, furthermore, that the amount of formative tissue produced may be far in excess of what is actually needed for purposes of repair only. Surely the appearances here noted indicate that the bacillus of tuberculosis has the power to stimulate fixed cells to multiply, unless one assumes that all, or almost all, the formative cells here seen are derived from wandering cells attracted by the presence of the bacillus and its products. As to the ultimate fate of the formative and other cells in this healing tuberculous tissue no final statements can be made. It must be remembered that it is only one stage in the process of healing that is dealt with. The well marked evidences of fibrillation, the quite extensive formation of new vessels, the absence of evidences of degenerative changes in the uninuclear cells, all point to the production of new fibrous tissue as sure to occur, but it seems quite probable that occasional epithelioid cells may undergo or have undergone dropsical or other forms of degeneration, although it is certainly apparent that so far as the small cells are concerned the involution of the tuberculous tissue is not occurring through disintegration. Perhaps the most interesting feature in this case is the opportunity it affords to study the changes in the giant cells of healing, non-degenerated tuberculous tissue. In the first place, the large number of giant cells is quite remarkable. The general characters of the tissue in which they are found recall the fact that giant cells are regarded as quite constant elements in chronic mild tuberculosis; often the giant cells are the only cells that contain bacilli (Koch). In this instance the giant cells do not contain bacilli that are demonstrable by the usual methods; neither do they contain bodies that can be definitely interpreted as degenerate forms of bacilli such as those found by Metchnikoff, Stchastny, Weicker, and others, in the giant cells of Spermophilus guttatus, in avian and in human tuberculosis. Metchnikoff states, however, that he knows of the occurrence of such degenerate forms only in the Spermophilus guttatus under the circumstances mentioned, and in the rabbit and guinea-pig in mammalian tuberculosis, but not in man; consequently, the manner in which the giant cells rid themselves of the bacilli undoubtedly present in their interior at some time during their existence, must as yet remain without any explanation. In the description of the histological changes the various appearances presented by the giant cells are described somewhat minutely. The essential observations made concern, in my opinion, the further fate of giant cells which are still found to persist in healing nondegenerated tuberculous tissue. It was, I believe, quite conclusively shown that the consecutive changes appear to consist in the breaking up of the nuclei, the removal of the detritus by phagocytes, and the formation of a few apparently viable uninuclear cells in the case of more degenerated, exhausted giant cells, while other, and, as it would seem, better preserved or younger giant cells, separate into a number of individual, uninuclear cells with but little or no nuclear disintegration. Objection might be raised to this interpretation of the appearances in the giant cells. While no one could very well dispute the view that part of the giant cells are undergoing retrogressive and absorptive changes with the production of some viable cells, a question might well be raised concerning the nature of the process taking place in those giant cells that have been spoken of as splitting up or dividing into uninuclear cells and smaller multinucleated masses without much evidence of nuclear disintegration. (ABSTRACT TRUNCATED)

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Ginkgo biloba extract has been used primarily as a medicinal agent in the treatment or prevention of cardiovascular and cerebrovascular dysfunction. Ginkgo biloba extract was nominated for study by the National Cancer Institute because of its widespread use as an herbal supplement to promote mental function and the limited availability of toxicity and carcinogenicity data. Furthermore, one of the major ingredients in Ginkgo biloba extract, quercetin, is a known mutagen. The Ginkgo biloba extract used in the current studies was procured from a supplier known to provide material to United States companies and contained 31.2% flavonol glycosides, 15.4% terpene lactones (6.94% bilo-balide, 3.74% ginkgolide A, 1.62% ginkgolide B, 3.06% ginkgolide C), and 10.45 ppm ginkgolic acid. Male and female F344/N rats and B6C3F1/N mice were administered Ginkgo biloba extract in corn oil by gavage for 3 months or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, and mouse peripheral blood erythrocytes. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were administered 0, 62.5, 125, 250, 500, or 1,000 mg Ginkgo biloba extract/kg body weight in corn oil by gavage, 5 days per week for 14 weeks. Additional groups of 10 male and 10 female rats (clinical pathology study) were administered the same doses, 5 days per week for 23 days. All rats survived to the end of the study. Mean body weights of all dosed groups were similar to those of the vehicle control groups. Liver weights of all dosed groups of males and females were significantly greater than those of the vehicle control groups. The incidences of hepatocyte hypertrophy in all dosed groups of males and in 500 and 1,000 mg/kg females were significantly greater than those in the vehicle control groups; there was a dose-related increase in severity of this lesion in males. Hepatocyte fatty change occurred in all dosed males. The incidences of thyroid gland follicular cell hypertrophy were significantly increased in 500 and 1,000 mg/kg males and in 1,000 mg/kg females. The incidences of pigmentation in the olfactory epithelium of the nose were significantly increased in 500 and 1,000 mg/kg males and in females administered 125 mg/kg or greater. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female mice were administered 0, 125, 250, 500, 1,000, or 2,000 mg Ginkgo biloba extract/kg body weight in corn oil by gavage, 5 days per week for 14 weeks. One female mouse in the 1,000 mg/kg group died of a dosing accident during week 11. Mean body weights of 2,000 mg/kg females were significantly less than those of the vehicle control group. Ruffled fur was observed in two 1,000 mg/kg males between weeks 7 and 8 and all 2,000 mg/kg males between weeks 5 and 9. Liver weights of 250 mg/kg or greater males and all dosed groups of females were significantly greater than those of the vehicle control groups. Kidney weights of 2,000 mg/kg males were significantly less than those of the vehicle control group. The Markov transition matrix analyses indicate female mice in the 2,000 mg/kg group had a significantly higher probability of extended estrus than did the vehicle control females. The incidences of hepatocytic hypertrophy were significantly increased in males and females in the 250 mg/kg or greater groups. Significantly increased incidences of focal hepatocytic necrosis occurred in 1,000 and 2,000 mg/kg males. The incidences of hyaline droplet accumulation in the respiratory epithelium of the nose were significantly increased in 500 mg/kg males and 1,000 and 2,000 mg/kg females. In the olfactory epithelium of the nose, the incidences of hyaline droplet accumulation were significantly increased in the 125 (female only), 500, and 1,000 mg/kg groups. Incidences of atrophy of the olfactory epithelium were significantly increased in the 1,000 mg/kg groups. The incidences of pigment accumulation in macrophages in the olfactory epithelium were significantly increased in males in the 500 mg/kg or greater groups and in 1,000 and 2,000 mg/kg females. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were administered 0, 100, 300, or 1,000 mg Ginkgo biloba extract/kg body weight in corn oil by gavage, 5 days per week for 104 or 105 (females) weeks. Additional groups of 10 male and 10 female rats (special study) were administered the same doses, 5 days per week for 14 weeks. Survival of 1,000 mg/kg males was significantly less than that of the vehicle controls. At week 14, all dosed groups of males and 1,000 mg/kg females had increased levels of thyroid stimulating hormone compared to those of the vehicle control groups. There were no significant decreases in the levels of triiodothyronine or total thyroxine. Mean body weights of 300 mg/kg males and females were less (10% or more) than those of the vehicle controls after week 93, and those of 1,000 mg/kg males and females were less after week 89. Clinical findings included ruffled fur in seven, eight, and 10 males in the 100, 300, and 1,000 mg/kg groups, respectively, beginning at week 89; four vehicle control males also had ruffled fur. Liver weights were significantly increased in all dosed groups of special study rats at 14 weeks. In the liver at 2 years, incidences of hepatocellular adenoma were slightly increased in 100 and 300 mg/kg males. Significantly increased incidences of nonneoplastic lesions at 2 years included hepatocyte hypertrophy and bile duct hyperplasia in all dosed groups of males and females, focal fatty change in all dosed groups of females, cystic degeneration in 100 and 1,000 mg/kg males, and oval cell hyperplasia and necrosis in 1,000 mg/kg males. In the thyroid gland, incidences of follicular cell adenoma were slightly increased in 300 and 1,000 mg/kg males and 300 mg/kg females. Single incidences of follicular cell carcinoma occurred in the 300 and 1,000 mg/kg female groups. There were significantly increased incidences of follicular cell hypertrophy in all dosed groups of males and females and follicle hyperplasia in all dosed groups of males. In the nose, adenoma of the respiratory epithelium occurred in two females receiving 300 mg/kg. Except for respiratory epithelium hyperplasia in 100 mg/kg females, the incidences of transitional epithelium and respiratory epithelium hyperplasia were significantly increased in all dosed groups of males and females. Except for olfactory epithelium respiratory metaplasia in 100 mg/kg females, the incidences of atrophy, respiratory metaplasia, nerve atrophy, and pigmentation were significantly increased in the olfactory epithelium of all dosed groups of males and females. Incidences of goblet cell hyperplasia in the respiratory epithelium were significantly increased in 300 and 1,000 mg/kg males and females, and incidences of chronic active inflammation were significantly increased in 1,000 mg/kg males and females. The incidence of submucosa fibrosis was significantly increased in 1,000 mg/kg males. The incidences of mononuclear cell leukemia in 300 and 1,000 mg/kg males were significantly greater than that in the vehicle controls. Dose-related increased severity of kidney nephropathy was noted in all dosed groups of males. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were administered 0, 200, 600, or 2,000 mg Ginkgo biloba extract/kg body weight in corn oil by gavage, 5 days per week for 104 weeks. Survival of 600 and 2,000 mg/kg males was significantly less than that of the vehicle controls; survival of 600 mg/kg females was significantly greater than that of the vehicle controls. Mean body weights of 600 and 2,000 mg/kg males were less (10% or more) than those of the vehicle controls after weeks 85 and 77, respectively; mean body weights of 2,000 mg/kg females were generally less than those of the vehicle controls between weeks 17 and 69 and after week 93. In the liver, there were significantly increased incidences of hepatocellular adenoma in all dosed groups of females, hepatocellular carcinoma in all dosed groups of males and 2,000 mg/kg females, and hepatoblastoma in all dosed groups of males and 600 and 2,000 mg/kg females. The increased incidences of these neoplasms were primarily due to increased incidences of multiple adenoma, carcinoma, and hepatoblastoma. Except for the incidences of hepatocellular carcinoma or hepatoblastoma (combined) in 200 and 600 mg/kg females, the incidences of hepatocellular adenoma or carcinoma (combined), hepatocellular carcinoma or hepatoblastoma (combined), and hepatocellular adenoma, hepatocellular carcinoma, or hepatoblastoma (combined) were significantly increased in all dosed groups of males and females. Significantly increased incidences of nonneoplastic liver lesions included hypertrophy in all dosed groups of males and females, erythrophagocytosis in all dosed groups of males and in 600 and 2,000 mg/kg females, hematopoietic cell proliferation, inflammation, and necrosis in 600 and 2,000 mg/kg males, and cytoplasmic vacuolization, eosinophilic focus, and mixed cell focus in all dosed groups of females. In the thyroid gland, two incidences each of follicular cell adenoma occurred in the 600 and 2,000 mg/kg male groups. The incidence of follicle hyperplasia was significantly increased in 2,000 mg/kg males, and the incidences of follicular cell hypertrophy were significantly increased in 2,000 mg/kg males and 600 and 2,000 mg/kg females. In the forestomach, the incidences of inflammation, epithelium hyperplasia, and epithelium hyperkeratosis were significantly increased in all dosed groups of males and in 2,000 mg/kg females; the incidences of epithelium ulcer were significantly increased in 2,000 mg/kg males and females. GENETIC TOXICOLOGY Ginkgo biloba extract was mutagenic in S. typhimurium strains TA98 and TA100, and in E. coli strain WP2 uvrA/pKM101, with and without exogenous metabolic activation. (ABSTRACT TRUNCATED)

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Butyl benzyl phthalate is a plasticizer added to polymers to give flexibility and softness. It is used extensively in polyvinyl chloride and in cellulose plastics, polyvinyl acetate, polysulfides, and polyurethane. Butyl benzyl phthalate was nominated as part of a class study of phthalates. Previous studies of butyl benzyl phthalate by the NTP (1982a) resulted in chemical-related mortality in male rats beginning at about 14 weeks of exposure and, thus, were inadequate for evaluating carcinogenicity in male rats. The companion studies revealed a marginal increase in leukemia in female rats and no evidence of carcinogenicity in B6C3F1 mice. Consequently, the present evaluations were conducted only in F344/N rats. Male and female F344/N rats were given butyl benzyl phthalate (at least 97% pure) in feed for 10 weeks, 26 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, L5178Y mouse lymphoma cells, cultured Chinese hamster ovary cells, mouse bone marrow cells, and Drosophila melanogaster. 10-WEEK MODIFIED MATING STUDY IN RATS: Groups of 15 male F344/N rats were given 0, 300, 2,800, or 25,000 ppm butyl benzyl phthalate (equivalent to average daily doses of approximately 20, 200, or 2,200 mg butyl benzyl phthalate/kg body weight) in feed for 10 weeks. All rats survived to the end of the study. The final mean body weight and body weight gain of the 25,000 ppm group were significantly less than those of the controls. Feed consumption by the 25,000 ppm group was less than that by the controls at the end of the study. A few minimal hematology changes occurred in the 25,000 ppm male rats. There was some evidence of a minimal anemia characterized by a decreased erythrocyte count and increases in mean cell hemoglobin and platelet count. The absolute and relative prostate gland weights of the 25,000 ppm males were significantly less than those of the controls. Degeneration of the seminiferous tubule germinal epithelium was observed in all males from the 25,000 ppm group. The absolute right cauda, right epididymis, and right testis weights of the 25,000 ppm males were significantly less than those of the controls. The epididymal spermatozoal concentrations in 2,800 and 25,000 ppm males were significantly less than that in the controls. Although 10 females mated to 25,000 ppm males were initially found to be sperm positive, none of these females were pregnant at necropsy. The fertility indices of males and females in the 25,000 ppm group were significantly lower than those of the controls. The maternal body weights of females mated to 300 and 2,800 ppm males were similar to those of females mated to control males. There were no significant differences in litter data between the controls and the 300 and 2,800 ppm groups. 26-WEEK STUDY IN RATS: Groups of 15 male F344/N rats were given 0, 300, 900, 2,800, 8,300, or 25,000 ppm butyl benzyl phthalate in feed for 26 weeks. Dietary levels of 300, 900, 2,800, and 8,300 ppm delivered average daily doses of approximately 30, 60, 180, and 550 mg butyl benzyl phthalate/kg body weight. The final mean body weight and body weight gain of the 25,000 ppm males were significantly less than those of the controls. Except for the 25,000 ppm males, feed consumption by all exposed groups was similar to that by the controls. An exposure-related macrocytic responsive anemia was present in the 25,000 ppm group at all time points. Additionally, minimal erythrocyte count decreases occurred sporadically in the 2,800 and 8,300 ppm groups at various time points. Reticulocyte counts were increased on days 60 and 90. Increases in mean cell hemoglobin and mean cell hemoglobin concentrations occurred in the 8,300 and 25,000 ppm rats. The absolute right cauda, right epididymis, and right testis weights and the sperm concentration of 25,000 ppm males were significantly less than those of the controls. The incidences of hypospermia and of atrophy of the seminiferous tubule in the testis and of hypospermia in the epididymis in 25,000 ppm males were significantly greater than those in the in the controls. Degenerative changes of the testis and epididymis in the 25,000 ppm males were qualitatively and quantitatively similar to those observed in males in the 10-week modified mating study. 2-YEAR STUDY IN RATS: Groups of 60 male F344/N rats were given 0, 3,000, 6,000, or 12,000 ppm butyl benzyl phthalate (equivalent to average daily doses of approximately 120, 240, or 500 mg butyl benzyl phthalate/kg body weight), and groups of 60 female F344/N rats were given 0, 6,000, 12,000, or 24,000 ppm butyl benzyl phthalate (equivalent to average daily doses of approximately 300, 600, or 1,200 mg/kg) in feed for 2 years. Survival, Body Weights, and Feed Consumption: Survival of all exposed groups of male and female rats was similar to that of the controls. Mean body weights of the 12,000 ppm males and 24,000 ppm females were less than those of the controls throughout most of the study. Feed consumption by the females exposed to 24,000 ppm was less than that by the controls at the beginning of the study, but was similar to that by the controls by week 6. Hematology and Hormone Assays: In general, hematology changes were sporadic and minor. At 6 months, a minimal decrease in erythrocyte count and an increase in mean cell hemoglobin, similar to that which occurred in the 26-week study, occurred in male rats in the 12,000 ppm group. In female rats, a decreased hematocrit value occurred at 15 months in the 24,000 ppm group. There was also a mild decrease in triiodothyronine concentrations in the 24,000 ppm females at 6 and 15 months and at the end of the study. Pathology Findings: of pancreatic acinar cell adenoma and adenoma or carcinoma (combined) in 12,000 ppm males were significantly greater than those in the controls. The incidences of adenoma and of adenoma or carcinoma (combined) in 12,000 ppm males exceeded the ranges of historical controls from NTP 2-year feed studies. One carcinoma was observed in one 12,000 ppm male, and two adenomas were observed in 24,000 ppm females. At 2 years, the incidence of focal hyperplasia of the pancreatic acinar cell in 12,000 ppm males was significantly greater than that in the controls. At 2 years, transitional epithelial papillomas in the urinary bladder were observed in one control female and in two 24,000 ppm females. The incidence of this neoplasm exceeded the range of historical controls from NTP 2-year feed studies. The incidence of transitional epithelial hyperplasia in 24,000 ppm females was significantly greater than that in the controls. The absolute right kidney weight of 12,000 ppm females and the relative right kidney weights of all exposed groups of males and of 24,000 ppm females were significantly greater than those of the controls at the 15-month interim evaluation. The severities of renal tubule pigmentation in 12,000 ppm males and in 24,000 ppm females were greater than those in the controls at 15 months and 2 years. At 2 years, the incidences of kidney mineralization in 6,000 and 24,000 ppm females were significantly less than that in the controls, and the severity was decreased in exposed females. The incidence of preputial gland adenoma or carcinoma (combined) in 12,000 ppm male rats was significantly less than in the controls, and the incidences occurred with a negative trend. GENETIC TOXICOLOGY: Results from in vitro mutagenicity tests with butyl benzyl phthalate were uniformly negative. No mutagenic response was obtained in any of several strains of Salmonella typhimurium treated with up to 11,550 mg/plate butyl benzyl phthalate, with or without S9 metabolic activation enzymes. Negative results were also obtained in in vitro studies of mammalian cell systems with and without S9. No induction of trifluorothymidine resistance in L5178Y mouse lymphoma cells or sister chromatid exchanges and chromosomal aberrations in cultured Chinese hamster ovary cells were observed. These assays also were conducted with and without S9. No significant increase in sex-linked recessive lethal mutations was observed in germ cells of male Drosophila melanogaster after administration of butyl benzyl phthalate either in feed or by injection. In contrast to the negative results obtained in vitro and in Drosophila, butyl benzyl phthalate gave positive responses in two in vivo studies with mice. Results of a mouse bone marrow sister chromatid exchange test were positive at sample times of 23 and 42 hours, but no confirmatory test was conducted. Chromosomal aberrations were induced in bone marrow cells of male mice sampled 17 hours after intraperitoneal injection of 5,000 mg/kg butyl benzyl phthalate. CONCLUSIONS: Under the conditions of this 2-year feed study, there was some evidence of carcinogenic activity of butyl benzyl phthalate in male F344/N rats based on the increased incidences of pancreatic acinar cell adenoma and of acinar cell adenoma or carcinoma (combined). There was equivocal evidence of carcinogenic activity of butyl benzyl phthalate in female 344/N rats based on the marginally increased incidences of pancreatic acinar cell adenoma and of transitional epithelial papilloma of the urinary bladder. Exposure of rats to butyl benzyl phthalate in feed for 2 years resulted in focal hyperplasia in the pancreas in male rats and in transitional epithelial hyperplasia in the urinary bladder of female rats. Synonyms: A13-14777; BBP; 1,2-benzenedicarboxylic acid butyl phenylmethyl ester (9CI); benzyl n-butyl phthalate; n-butyl benzyl phthalate; butyl phenylmethyl 1,2-benzenedicarboxylate; NCI-C54375; phthalic acid benzyl butyl ester (8CI) Trade names: Palatinol BB; Santicizer 160; Sicol 160; Unimoll BB

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2,2-Bis(bromomethyl)-1,3-propanediol is used as a fire retardant in unsaturated polyester resins, in molded products, and in rigid polyurethane foam. 2,2-Bis(bromomethyl)-1,3-propanediol was chosen for study because it is a widely used flame retardant and little toxicity and carcinogenicity data were available. Groups of male and female F344/N rats and B6C3F1 mice were exposed to technical grade 2,2-bis(bromomethyl)-1,3-propanediol (78.6% pure) in feed for 13 weeks or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, mouse bone marrow, and mouse peripheral blood. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were fed diets containing 0, 1,250, 2,500, 5,000, 10,000, or 20,000 ppm 2,2-bis(bromomethyl)- 1,3-propanediol for 13 weeks. These levels corresponded to approximately 100, 200, 400, 800, or 1,700 mg 2,2-bis(bromomethyl)-1,3-propanediol/kg body weight (males) and 100, 200, 400, 800, or 1,600 mg/kg (females). No rats died during the studies. The final mean body weights and weight gains of 5,000, 10,000, and 20,000 ppm males and females were significantly lower than those of the controls. Feed consumption by exposed animals was lower than that by controls at week 1, but was generally similar to or slightly higher than that by controls at week 13. No chemical-related clinical findings were observed. Chemical-related differences in clinical pathology parameters included increased urine volumes accompanied by decreased urine specific gravity and minimally increased protein excretion in 10,000 and 20,000 ppm males. In females, urine parameters were less affected than males. Water deprivation tests demonstrated that male and female rats were able to adequately concentrate their urine in response to decreased water intake. Serum protein and albumin concentrations in female rats exposed to 2,500 ppm and higher were slightly lower than those of the controls. Renal papillary degeneration was present in 5,000 and 10,000 ppm males, and in 20,000 ppm males and females. Hyperplasia of the urinary bladder was present in 20,000 ppm males. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were fed diets containing 0, 625, 1,250, 2,500, 5,000, or 10,000 ppm 2,2-bis(bromomethyl)-1,3-propanediol for 13 weeks. These levels corresponded to approximately 100, 200, 500, 1,300, or 3,000 mg 2,2-bis(bromomethyl)-1,3-propanediol/kg body weight (males) and 140, 300, 600, 1,200, or 2,900 mg/kg (females). One control female, two males and one female receiving 625 ppm, one female receiving 1,250 ppm, one female receiving 2,500 ppm, one female receiving 5,000 ppm, and three males receiving 10,000 ppm died during the study. The final mean body weights and body weight gains of males and females receiving 1,250, 2,500, 5,000, or 10,000 ppm and of females receiving 625 ppm were significantly lower than those of the controls. Feed consumption by exposed mice was generally higher than that by controls throughout the study. Clinical findings included abnormal posture and hypoactivity in 10,000 ppm male and female mice. Blood urea nitrogen concentrations of 5,000 ppm females and 10,000 ppm males and females were greater than those of controls. Also, urine specific gravity was lower in 10,000 ppm females. Differences in organ weights generally followed those in body weights. Papillary necrosis, renal tubule regeneration, and fibrosis were observed in the kidneys of 2,500 and 5,000 ppm males and 10,000 ppm males and females. Urinary bladder hyperplasia was observed in 5,000 and 10,000 ppm males and females. 2-YEAR STUDY IN RATS: Groups of 60 male and 60 female rats received 2,500, 5,000, or 10,000 ppm 2,2-bis(bromomethyl)- 1,3-propanediol in feed for 104 to 105 weeks. Groups of 70 males and 60 females received 0 ppm 2,2-bis(bromomethyl)-1,3-propanediol in feed for 104 to 105 weeks. A stop-exposure group of 70 male rats received 20,000 ppm 2,2-bis(bromomethyl)-1,3-propanediol in feed for 3 months, after which animals received undosed feed for the remainder of the 2-year styear study. Average daily doses of 2,2-bis(bromomethyl)-1,3-propanediol were 100, 200, or 430 mg/kg body weight for males and 115, 230, or 460 mg/kg for females. Stop-exposure males received an average daily dose of 800 mg/kg. Ten animals from the 0 ppm male group and the 20,000 ppm stop-exposure group were evaluated at 3 months; nine or 10 control animals and five to nine animals from each of the continuous-exposure groups were evaluated at 15 months. Survival, Body Weights, Feed Consumption, and Clinical Findings: Survival of 5,000 and 10,000 ppm continuous-exposure study males and females and 20,000 ppm stop-exposure males was significantly lower than that of the controls. Mean body weights of exposed male and female rats receiving 10,000 ppm and stop-exposure males receiving 20,000 ppm were lower than those of the controls throughout most of the study. In the continuous-exposure study, feed consumption by exposed rats was generally similar to that by controls throughout the study. In 20,000 ppm stop-exposure males, the feed consumption was lower than that by controls. Clinical findings included skin and/or subcutaneous masses on the face, tail, and the ventral and dorsal surfaces of exposed rats. Pathology Findings: In the 2-year continuous and stop-exposure studies in male rats, exposure to 2,2-bis(bromomethyl)-1,3-propanediol was associated with neoplastic effects in the skin, mammary gland, Zymbal's gland, oral cavity, esophagus, forestomach, small and large intestines, mesothelium, urinary bladder, lung, thyroid gland, hematopoietic system, and seminal vesicle. Nonneoplastic effects in the kidney, lung, thyroid gland, seminal vesicle, pancreas, urinary bladder, and forestomach were also observed. In females, 2-year exposure to 2,2-bis(bromomethyl)-1,3-propanediol was associated with neoplastic effects in the oral cavity, esophagus, mammary gland, and thyroid gland. Nonneoplastic effects in the kidney were also observed. These findings are outlined in the two summary tables. 2-YEAR STUDY IN MICE: Groups of 60 male and 60 female mice received 0, 312, 625, or 1,250 ppm 2,2-bis(bromomethyl)-1,3-propanediol in feed for 104 to 105 weeks. Average daily doses of 2,2-bis(bromomethyl)-1,3-propanediol were 35, 70, or 140 mg/kg (males) and 40, 80, or 170 mg/kg (females). Eight to 10 animals from each group were evaluated at 15 months. Survival, Body Weights, Feed Consumption, and Clinical Findings: Survival of 1,250 ppm males and females was significantly lower than that of the controls. Mean body weights of exposed male and female mice were similar to controls throughout the study. Final mean body weights were also generally similar to those of controls. Feed consumption by exposed male and female mice was similar to that by controls. Clinical findings included tissue masses involving the eye in exposed mice. Pathology Findings: Exposure of male mice to 2,2-bis(bromomethyl)-1,3-propanediol for 2 years was associated with neoplastic effects in the harderian gland, lung, and kidney. Exposure of female mice to 2,2-bis(bromomethyl)-1,3-propanediol was associated with increased incidences of neoplasms of the harderian gland, lung, and skin. Nonneoplastic effects in the lung were also observed in exposed females. These findings are outlined in the two summary tables. GENETIC TOXICOLOGY: 2,2-Bis(bromomethyl)-1,3-propanediol was mutagenic in Salmonella typhimurium strain TA100 when tested in the presence of induced 30&amp;percnt; hamster liver S9; all other strain/activation combinations gave negative results. In cultured Chinese hamster ovary cells, 2,2-bis(bromomethyl)-1,3-propanediol induced chromosomal aberrations only in the presence of S9; no induction of sister chromatid exchanges was observed in cultured Chinese hamster ovary cells after treatment with 2,2-bis(bromomethyl)-1,3-propanediol, with or without S9. In vivo, 2,2-bis(bromomethyl)-1,3-propanediol induced significant increases in the frequencies of micronucleated erythrocytes in male and female mice. Significant increases in micronuclei were observed in peripheral blood samples from male and female mice exposed to 2,2-bis(bromomethyl)-1,3-propanediol for 13 weeks via dosed feed. Results of a bone marrow micronucleus test in male mice, where 2,2-bis(bromomethyl)-1,3-propanediol was administered by gavage, were considered to be equivocal due to inconsistent results obtained in two trials. An additional bone marrow micronucleus test was performed with male and female mice and 2,2-bis(bromomethyl)-1,3-propanediol was administered as a single intraperitoneal injection; results of this test were positive in females and negative in males. CONCLUSIONS: Under the conditions of these 2-year feed studies, there was clear evidence of carcinogenic activity of 2,2-bis-(bromomethyl)-1,3-propanediol (FR-1138) in male F344/N rats based on increased incidences of neoplasms of the skin, subcutaneous tissue, mammary gland, Zymbal's gland, oral cavity, esophagus, forestomach, small and large intestines, mesothelium, urinary bladder, lung, thyroid gland, and seminal vesicle, and the increased incidence of mononuclear cell leukemia. There was clear evidence of carcinogenic activity of 2,2-bis(bromomethyl)-1,3-propanediol in female F344/N rats based on increased incidences of neoplasms of the oral cavity, esophagus, mammary gland, and thyroid gland. There was clear evidence of carcinogenic activity of 2,2-bis(bromomethyl)-1,3-propanediol in male B6C3F1 mice based on increased incidences of neoplasms of the harderian gland, lung, and kidney. There was clear evidence of carcinogenic activity of 2,2-bis(bromomethyl)-1,3-propanediol in female B6C3F1 mice based on increased incidences of neoplasms of the harderian gland, lung, and subcutaneous tissue. Slight increases in the incidences of neoplasms of the pancreas and kidney in male rats; forestomach in male mice; and forestomach, mammary gland, and circulatory system in female mice may have also been related to treatment. Exposure of male and female rats to 2,2-bis(bromomethyl)-1,3-propanediol was associated with alveolar/bronchiolar hyperplasia in the lung (males only); focal atrophy, papillary degeneration, transitional epithelial hyperplasia (pelvis), and papillary epithelial hyperplasia in the kidney; follicular cell hyperplasia in the thyroid gland (males only); hyperplasia in the seminal vesicle and pancreas (males only); mucosal hyperplasia in the forestomach (males only); and urinary bladder hyperplasia (males only). Exposure of mice to 2,2-bis(bromomethyl)-1,3-propanediol was associated with hyperplasia of the alveolar epithelium in females. Synonyms: 2,2-Bis(2-bromomethyl)-1,3-propanediol; 1,3-dibromo-2,2-dihydroxymethylpropane; 1,3-dibromo-2,2-dimethylolpropane; 2,2-dibromomethyl-1,3-propanediol; dibromopentaerythritol; dibromoneopentyl glycol; pentaerythritol dibromide; pentaerythritol dibromohydrin

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DIOXIN TOXIC EQUIVALENCY FACTOR EVALUATION OVERVIEW: Polyhalogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) have the ability to bind to and activate the ligand-activated transcription factor, the aryl hydrocarbon receptor (AhR). Structurally related compounds that bind to the AhR and exhibit biological actions similar to TCDD are commonly referred to as "dioxin-like compounds" (DLCs). Ambient human exposure to DLCs occurs through the ingestion of foods containing residues of DLCs that bio-concentrate through the food chain. Due to their lipophilicity and persistence, once internalized they accumulate in body tissues, mainly adipose, resulting in chronic lifetime human exposure. Since human exposure to DLCs always occurs as a complex mixture, the toxic equivalency factor (TEF) methodology has been developed as a mathematical tool to assess the health risk posed by complex mixtures of these compounds. The TEF methodology is a relative potency scheme that ranks the dioxin-like activity of a compound relative to TCDD, the most potent congener. This allows for the estimation of the potential dioxin-like activity of a mixture of chemicals, based on a common mechanism of action involving an initial binding of DLCs to the AhR. The toxic equivalency of DLCs was nominated for evaluation because of the widespread human exposure to DLCs and the lack of data on the adequacy of the TEF methodology for predicting relative potency for cancer risk. To address this, the National Toxicology Program conducted a series of 2-year bioassays in female Harlan Sprague-Dawley rats to evaluate the chronic toxicity and carcinogenicity of DLCs and structurally related polychlorinated biphenyls (PCBs) and mixtures of these compounds. 2-YEAR STUDY: The 2-year study of a binary mixture of PCB 126 and PCB 153 was designed to assess the carcinogenicity of a constant ratio mixture of PCB 126 and PCB 153. In addition, varying ratio mixture groups were used to assess the impact of increasing PCB 153 on the carcinogenicity of PCB 126. Dose groups were divided into two study arms (Figure 1). TCDD equivalent (TEQ) doses are based on the PCB 126 doses after adjustment for the PCB 126 TEF of 0.1. Groups of 81 (Groups 2, 3, 5, and 7) or 80 (Groups 4 and 6) female rats received a mixture of PCB 126 and PCB 153 in corn oil:acetone (99:1) by gavage 5 days per week for up to 105 weeks; a group of 81 female rats received the corn oil:acetone (99:1) vehicle only and served as the vehicle control (Group 1). Up to 10 rats per group were evaluated at 14, 31, and 53 weeks. Survival of all dosed groups was similar to that of the vehicle controls. The mean body weights of Groups 4 and 5 were generally less than those of the vehicle controls after week 25. The mean body weights of Group 6 were less after week 12, and those of Group 7 were less after week 8. Thyroid Hormone Concentrations: Alterations in serum thyroid hormone levels were evaluated at the 14-, 31-, and 53-week interim evaluations. In the constant ratio groups, serum total thyroxine (T(4)) and free T(4) generally showed a treatment-related decrease relative to controls. Serum total triiodothyronine (T(3)) exhibited a treatment-related increase at the 14-, 31-, and 53-week interim evaluations, but serum thyroid stimulating hormone (TSH) levels were increased at the 14-week time point only. In the varying ratio groups, the decrease in total and free T(4) was more pronounced in those groups dosed with the increasing proportion of PCB 153 at the 31- and 53-week time points. Hepatic Cell Proliferation Data: To evaluate hepatocyte replication, analysis of labeling of replicating hepatocytes with 5-bromo-2'-deoxyuridine was conducted at the 14-, 31-, and 53-week interim evaluations. At 31 and 53 weeks, a significant increase in the hepatocellular labeling index occurred in Group 7. In the varying ratio groups, the labeling index at the 53-week interim time point was significantly higher in Group 6, which had the highest proportion of PCB 153 compared to the other varying ratio groups. Cytochrome P450 Enzyme Activities: To evaluate the expression of known PCB 126-responsive genes, CYP1A1-associated 7-ethoxyresorufin-O-deethylase (EROD) and CYP1A2-associated acetanilide-4-hydroxylase (A4H) activities were evaluated at the 14-, 31-, and 53-week interim evaluations. In addition, PCB 153-inducible CYP2B-associated 7-pent-oxyresorufin-O-dealkylase (PROD) activity was analyzed. In the constant ratio Groups 2, 3, 5, and 7, hepatic and pulmonary EROD (CYP1A1) activities, hepatic A4H (CYP1A2) activities, and hepatic PROD (CYP2B) activities were significantly greater in all dosed groups compared to the vehicle controls at weeks 14, 31, and 53. In the varying ratio groups, hepatic EROD, A4H, and PROD activities at 14 weeks were higher in groups receiving a greater proportion of PCB 153 in the PCB mixture. At 31 and 53 weeks, hepatic CYP1A1 and CYP1A2 enzyme activities in Group 6 were generally lower than in Groups 4 and 5. Determinations of PCB 126 and PCB 153 Concentrations in Tissues: Concentrations of PCB 126 and PCB 153 were determined in fat, liver, lung, and blood at the 14-, 31-, and 53-week interim evaluations and at the end of the 2-year study (105 weeks). PCB 126 was not detectable in vehicle control animals, but increased with increasing dose of PCB 126 and duration of exposure; the highest concentrations were found in liver and fat, and lower levels were seen in lung and blood. Increasing the proportion of PCB 153 in the mixture relative to PCB 126 led to a general decrease in the amount of PCB 126 in liver and lung at the later time points, whereas in fat and blood, there was generally either no effect of PCB 153 on the disposition of PCB 126, or there was an increase in the amount of PCB 126 in the tissue. In vehicle control animals, PCB 153 was detectable in the fat at all time points, in the lung at all time points except 53 weeks, and in the liver and blood at 2 years. PCB 153 was measurable in all examined tissues of treated animals, with the highest concentrations found in fat at the end of the 2-year study in groups administered the highest doses of PCB 153. Pathology and Statistical Analyses -- Constant Ratio Mixture of PCB 126 and PCB 153: At 14, 31, and 53 weeks, the absolute and relative liver weights of all dosed groups were generally greater than those of the vehicle controls. Exposure to the PCB mixture led to significant toxicity in the liver. At 14 weeks, the incidences of several nonneoplastic liver lesions were increased compared to the vehicle controls including hepatocyte hypertrophy, pigmentation, multinucleated hepatocytes, and diffuse fatty change. The spectrum and severity of effects increased with dose and duration of exposure. At the end of the 2-year study, there were significantly increased incidences and severities of toxic hepatopathy characterized by hepatocyte hypertrophy, multinucleated hepatocytes, pigmentation, diffuse and focal fatty change, eosinophilic focus, nodular hyperplasia, cholangiofibrosis, oval cell hyperplasia, bile duct cysts, bile duct hyperplasia, necrosis, and portal fibrosis. Significantly increased incidences of hepatocellular adenoma, cholangiocarcinoma, and hepatocholangioma were observed in the study. In addition, two animals in the highest dose group had hepatocellular carcinoma. The incidences of these lesions generally exceeded the historical vehicle control ranges. At 2 years, a significantly increased incidence of cystic keratinizing epithelioma of the lung was observed in Group 7. In addition, single occurrences of squamous cell carcinoma were seen in the top two dose groups. Nonneoplastic effects whose incidences were increased in the lung included bronchiolar metaplasia of the alveolar epithelium and squamous metaplasia. Significantly increased incidences of squamous cell carcinoma (gingival) of the oral mucosa were seen at the end of the 2-year study and were accompanied by increased incidences of gingival squamous hyperplasia. In the pancreas at 53 weeks, the incidence of acinar cytoplasmic vacuolization was significantly increased in the highest dose group. At 2 years, increased incidences of acinar atrophy and acinar cytoplasmic vacuolization were seen in addition to pancreatic acinar neoplasms in dosed groups. In Groups 5 and 7, these incidences exceeded the historical vehicle control ranges. In the uterus at 2 years, there was a marginal increase in the incidence of squamous cell carcinoma in Group 5. Numerous nonneoplastic effects were seen in other organs at the interim time points including atrophy of the thymus and follicular cell hypertrophy of the thyroid gland. These responses were also affected by administration of the mixture of PCB 126 and PCB 153 at the end of the 2-year study and were accompanied by additional nonneoplastic responses in numerous organs including atrophy of the adrenal cortex and cortical hyperplasia, severity of nephropathy, and incidences of pigmentation of the kidney. Other nonneoplastic lesions that were treatment related were forestomach hyperplasia, hyperplasia of the nasal respiratory epithelium, metaplasia of the olfactory epithelium, and ectasia of the mandibular lymph node. Varying Ratio Mixture of PCB 126 and PCB 153: An effect of increasing the proportion of PCB 153 in the PCB mixture was seen in several tissues, most notably in the liver. Treatment-related nonneoplastic effects seen across the varying ratio groups were generally the same as those seen in the constant ratio groups. In general there was a positive effect of PCB 153 in the mixture on the incidences and severities of these lesions with higher incidences and higher severities being seen in Group 6, which had the highest proportion of PCB 153. (ABSTRACT TRUNCATED).

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To assess the efficacy of ivermectin in addition to standard treatment compared to standard treatment alone in reducing hospitalizations in the COVID-19 patient population. IVERCOR-COVID19 will be a single-center, prospective, randomized, double-blind, parallel group (1:1 ratio), placebo-controlled study. Patients who meet the following criteria will be invited to participate: Inclusion criteria: (1) Over 18 years of age who reside in the province of Corrientes at the time of diagnosis. (2) Confirmed diagnosis of COVID-19 by polymerase chain reaction (PCR) test for detection of SARS-CoV2 in the last 48 h. (3) In the case of women of childbearing age, they must be using a contraceptive method of proven efficacy and safety (barrier, hormonal, or permanent contraceptives) for at least 3 months prior to inclusion in the present study and for the entire period of time for the duration of the study and until at least 30 days after the end of this study. A woman will be considered to have no reproductive capacity if she is postmenopausal (at least 2 years without her menstrual cycles) or if she has undergone surgical sterilization (at least 1 month before the time of inviting her to participate in this study). (4) Weight at the time of inclusion greater than 48 kg. (5) That they sign the informed consent for participation in the study. (1) pregnant or breastfeeding women; (2) known allergy to ivermectin or some of the components of ivermectin tablets or placebo; (3) current use of home oxygen; (4) require hospitalization due to COVID-19 at the time of diagnosis or history of hospitalization for COVID-19; (5) presence of mal-absorptive syndrome; (6) presence of any other concomitant acute infectious disease; (7) known history of severe liver disease, for example liver cirrhosis; (8) need or use of antiviral drugs at the time of admission for another viral pathology other than COVID-19; (9) need or use of hydroxychloroquine or chloroquine; (10) use of ivermectin up to 7 days prior to randomization; (11) patients on dialysis or who have required it in the last 2 months or who plan to do it in the next 2 months; and (12) current participation or in the last 30 days in a research study that has included the administration of a drug (Table 1). Table 1 Ivermectin/placebo dose according to patient weight Patient weight Ivermectin/placebo dose Total dose (mg) Equal to or greater than 48 kg and less than 80 kg 2 tablets of 6 mg each at the time of inclusion and 2 tablets 24 h after the first intake 24 Equal or greater than 80 kg and less than 110 kg 3 tablets of 6 mg each at the time of inclusion and 3 tablets 24 h after the first intake 36 Equal or greater than 110 kg 4 tablets of 6 mg each at the time of inclusion and 4 tablets 24 h after the first intake 48 The study will be carried out by the Ministry of Public Health of the Province of Corrientes (Argentina) in coordination with the Institute of Cardiology of Corrientes in the Province of Corrientes, Argentina. Intervention group: patients who are randomized to ivermectin will receive the dose according to their weight (patients up to 80 kg will receive 2 tablets of 6 mg ivermectin; patients with more than 80 kg and up to 110 kg will receive 3 tablets of 6 mg of ivermectin; patients weighing more than 110 kg will receive 4 tablets of 6 mg ivermectin) the day they enter the study and the same dose 24 h after the first dose. patients who are randomized to placebo will receive the dose according to their weight (patients up to 80 kg will receive 2 tablets of 6 mg placebo; patients with more than 80 kg and up to 110 kg will receive 3 tablets of 6 mg of placebo; patients weighing more than 110 kg will receive 4 tablets of 6 mg placebo) on the day they enter the study and the same dose 24 h after the first dose (Table 2). Table 2 Inclusion and exclusion criteria Inclusion criteria Exclusion criteria 1. Over 18 years of age who reside in the province of Corrientes at the time of diagnosis 1. Pregnant or breastfeeding women 2.Confirmed diagnosis of COVID-19 by polymerase chain reaction test for detection of SARS-CoV2 in the last 48 h 2. Known allergy to ivermectin or some of the components of ivermectin tablets or placebo 3. In case of being women of childbearing age, they must be using a contraceptive method of proven efficacy and safety (barrier, hormonal, or permanent contraceptives) for at least 3 months prior to inclusion in the present study, during the entire period of time for the duration of the study, and until at least 30 days after the end of this study. A woman will be considered to have no reproductive capacity if she is postmenopausal (at least 2 years without her menstrual cycles) or if she has undergone surgical sterilization (at least 1 month before the time of inviting her to participate in this study) 3. Current use of home oxygen 4. Weight at the time of inclusion equal to or greater than 48 kg 4. That require hospitalization due to COVID-19 at the time of diagnosis or history of hospitalization for COVID-19 5. That they sign the informed consent for participation in the study 5. Presence of mal-absorptive syndrome 6. Presence of any other concomitant acute infectious disease 7. Known history of severe liver disease, for example liver cirrhosis 8. Need or use of antiviral drugs at the time of admission for another viral pathology other than COVID-19 9. Need or use of hydroxychloroquine or chloroquine 10. Use of ivermectin up to 7 days prior to randomization 11. Patients on dialysis or who have required it in the last 2 months or who plan to do it in the next 2 months 12. Current participation or in the last 30 days in a research study that has included the administration of a drug MAIN OUTCOMES: Primary outcome will be the percentage of hospitalizations in patients with COVID-19 in the intervention and control groups. time to hospitalization in each of the arms of the study: number of days elapsed from the inclusion in the study until the hospitalization of the patient; percentage of use of invasive mechanical ventilation in each of the study arms: every patient who is connected to invasive mechanical ventilation after signing the informed consent and before the final study visit; time to invasive mechanical ventilation in each of the arms of the study: number of days elapsed from inclusion in the study to connection to invasive mechanical ventilation of the patient; percentage of patients requiring dialysis in each of the study arms: all patients who require renal replacement therapy of any kind, temporary or permanent, and which begins after signing the informed consent and before the final visit; mortality from all causes in each of the two trial groups: death of the patient, from any cause. Negative PCR swab at 3 ± 1 and 12 ± 2 days after entering the study. Ivermectin safety: it will be analyzed according to the incidence of adverse events that patients present in the intervention and control groups. The end of study (EOS) is recorded as the day the patient is discharged or death. Discharge will be granted according to the current recommendations of the Ministry of Public Health of the Province of Corrientes. A follow-up visit (EOF) will be made by phone 30 days after the EOS when vital status will be verified. Randomization will be done through a web system with randomly permuted blocks. Randomization will be carried out by one of the investigators who will not participate in the inclusion of patients or in the delivery of medication (Table 3). Table 3 EOS end of study, EOF end of follow-up Visit Basal and randomization, day 0 Day 3 ± 1 Day 12 ± 2 V#1 V#2 V#3 EOS EOF Informed consent X - - - - Inclusion/exclusion criteria X - - - - Demographic data and medical history X - - - - Concomitant medication X - - - - Vital signs* X X - - - Anthropometric data<sup^</sup X - - - - Basal laboratory X - - - - PCR swab - X X - - Assessment of adverse events - X X X - Final objective evaluation - X X X X Randomization X - - - - Adherence to treatment X X - - - *Includes heart rate, temperature, and oxygen saturation by a digital saturometer ^Includes weight and height BLINDING (MASKING): The participants, investigators, care providers, and outcome assessors will be blinded. We will include a total of 500 patients (250 patients in each group). This is version 1.0, 17 August 2020. The recruitment started on 19 August 2020, and we anticipate the trial will finish recruitment on 31 December 2020. ClinicalTrials.gov NCT04529525 . Registered on 26 August 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting the dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol.

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To critically review all literature related to pacifier use for full-term healthy infants and young children.The specific review questions addressed are:What is the evidence of adverse and/or positive outcomes of pacifier use in infancy and childhood in relation to each of the following subtopics: INCLUSION CRITERIA: Specific criteria were used to determine which studies would be included in the review: (i) the types of participants; (ii) the types of research design; and (iii) the types of outcome measures. To be included a study has to meet all criteria.The participants included in the review were healthy term infants and healthy children up to the age of 16 years. Studies that focused on preterm infants, and infants and young children with serious illness or congenital malformations were excluded. However, some total population studies did include these children.It became evident early in the review process that very few randomised controlled trials had been conducted. A decision was made to include observational epidemiological designs, specifically prospective cohort studies and, in the case of sudden infant death syndrome research, case-control studies. Purely descriptive and cross-sectional studies were excluded, as were qualitative studies and all other forms of evidence.A number of criteria have been proposed to establish causation in the scientific and medical literature. These key criteria were applied in the review process and are described as follows: (i) consistency and unbiasedness of findings; (ii) strength of association; (iii) temporal sequence; (iv) dose-response relationship; (v) specificity; (vi) coherence with biological background and previous knowledge; (vii) biological plausibility; and (viii) experimental evidence.Studies that did not meet the requirement of appropriate temporal sequencing of events and studies that did not present an estimate of the strength of association were not included in the final review.Our specific interest was pacifier use related to:Studies that examined pacifier use related to procedural pain relief were excluded. Studies that examined the relationship between pacifier use and gastro-oesophageal reflux were also excluded as this information has been recently presented as a systematic review. The review comprised published and unpublished research literature. The search was restricted to reports published in English, Spanish and German. The time period covered research published from January 1960 to October 2003. A protocol developed by New Zealand Health Technology Assessment was used to guide the search process. The search comprised bibliographic databases, citation searching, other evidence-based and guidelines sites, government documents, books and reports, professional websites, national associations, hand search, contacting national/international experts and general internet searching. All studies identified during the database search were assessed for relevance to the review based on the information provided in the title, abstract and descriptor/MeSH terms, and a full report was retrieved for all studies that met the inclusion criteria. Studies identified from reference list searches were assessed for relevance based on the study title. Keywords included: dummy, dummies, pacifier(s), soother(s), comforter(s), non-nutritive sucking, infant, child, infant care.Initially, studies were reviewed for inclusion by pairs of principal investigators. Authorship of articles was not concealed from the reviewers. Next, the methodological quality of included articles was assessed independently by groups of three or more principal investigators and clinicians using a checklist. All 20 studies that were accepted met minimum set criteria, but few passed without some methodological concern. To meet the requirements of the Joanna Briggs Institute, reasons for acceptance and non-acceptance at each phase were clearly documented. An assessment protocol and report form was developed for each of the three phases of review. The first form was created to record investigators' evaluations of studies included in the initial review. Those studies that failed to meet strict inclusion criteria were excluded at this point. A second form was designed to facilitate an in-depth critique of epidemiological study methodology. The checklist was pilot tested and adjustments were made before reviewers were trained in its use. When reviewers could not agree on an assessment, it was passed to additional reviewers and discussed until a consensus was reached. At this stage, studies other than cohort, case-control and randomised controlled trials were excluded. Issues of clarification were also addressed at this point. The final phase was that of integration. This phase, undertaken by the principal investigators, was assisted by the production of data extraction tables. Through a process of trial and error, a framework was formulated that adequately summarised the key elements of the studies. This information was tabulated under the following headings: authors/setting, design, exposure/outcome, confounders controlled, analysis and main findings. With regard to the breast-feeding outcome, 10 studies met the inclusion criteria, comprising two randomised controlled trials and eight cohort studies. The research was conducted between 1995 and 2003 in a wide variety of settings involving research participants from diverse socioeconomic and cultural backgrounds. Information regarding exposure and outcome status, and potential confounding factors was obtained from: antenatal and postnatal records; interviews before discharge from obstetric/midwifery care; post-discharge interviews; and post-discharge postal and telephone surveys. Both the level of contact and the frequency of contact with the informant, the child's mother, differed widely. Pacifier use was defined and measured inconsistently, possibly because few studies were initiated expressly to investigate its relationship with breast-feeding. Completeness of follow-up was addressed, but missing data were not uniformly identified and explained. When comparisons were made between participants and non-participants there was some evidence of differential loss and a bias towards families in higher socioeconomic groups. Multivariate analysis was undertaken in the majority of studies, with some including a large number of sociodemographic, obstetric and infant covariates and others including just maternal age and education.As might be expected given the inconsistency of definition and measurement, the relationship between pacifier use and breast-feeding was expressed in many different ways and a meta-analysis was not appropriate. In summary, only one study did not report a negative association between pacifier use and breast-feeding duration or exclusivity. Results indicate an increase in risk for a reduced overall duration of breast-feeding from 20% to almost threefold. The data suggest that very infrequent use may not have any overall negative impact on breast-feeding outcomes.Six sudden infant death syndrome case-control studies met the criteria for inclusion. The research was conducted with information gathered between 1984 and 1999 in Norway, UK, New Zealand, the Netherlands and USA. Exposure information was obtained from a variety of sources including: hospital and antenatal records, death scene investigation, and interview and questionnaire. Information for cases was sought within 2 days after death, within 2-4 weeks after death and in one study between 3 and 11 years after death. Information for controls was sought from as early as 4 days of a nominated sudden infant death syndrome case, to between 1 and 7 weeks from the case date, and again in one study some 3-11 years later. In the majority of the studies case ascertainment was determined by post-mortem. Pacifier use was again defined and measured somewhat inconsistently. All studies controlled for confounding factors by matching and/or using multivariate analysis. Generally, antenatal and postnatal factors, as well as infant care practices, and maternal, family and socioeconomic issues were considered.All five studies reporting multivariate results found significantly fewer sudden infant death syndrome cases used a pacifier compared with controls. That is, pacifier use was associated with a reduced incidence of sudden infant death syndrome. These results indicate that the risk of sudden infant death syndrome for infants who did not use a pacifier in the last or reference sleep was at least twice, and possibly five times, that of infants who did use a pacifier.Three studies reported a moderately sized positive association between pacifier use and a variety of infections. Conversely, one study found no positive association between pacifier use at 15 months of age and a range of infections experienced between the ages of 6 and 18 months. Given the limited number of studies available and the variability of results, no meaningful conclusions could be drawn.Five cohort studies and one case-control study focused on the relationship between pacifier use and dental malocclusion. Not one of these studies reported a measure of association, such as an estimate of relative risk. It was therefore not possible to include these studies in the final review.Implications for practice It is intended that this review be used as the basis of a 'best practice guideline', to make health professionals aware of the research evidence concerning these health and developmental consequences of pacifier use, because parents need clear information on which they can base child care decisions. With regard to the association between pacifier use and infection and dental malocclusion it was found that, due to the paucity of epidemiological studies, no meaningful conclusion can be drawn. There is clearly a need for more epidemiological research with regard to these two outcomes. The evidence for a relationship between pacifier use and sudden infant death syndrome is consistent, while the exact mechanism of the effect is not well understood. As to breast-feeding, research evidence shows that pacifier use in infancy is associated with a shorter duration and non-exclusivity. It is plausible that pacifier use causes babies to breast-feed less, but a causal relationship has not been irrefutably proven.Because breast-feeding confers an important advantage on all children and the incidence of sudden infant death syndrome is very low, it is recommended that health professionals generally advise parents against pacifier use, while taking into account individual circumstances.

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The principle of informed consent, aimed at the lawfulness of health assistance, tends to reflect the concept of autonomy and of decisional autodetermination of the person requiring and requesting medical and/or surgical interventions. This legal formula, over the last few years, has gained not only considerable space but also importance in the doctrinal elaboration and approaches, as well as juridical interpretations, thereby influencing the everyday activities of the medical profession. Informed consent is still the object of continuous explorations, not only asfar as concerns the already confirmed theoretical profile but, instead, the ambiguous practical and consequential aspect. Analysing how the concept and role of consensus was born and developed with the more adequate and reasonable excursions to make it valid and obtain it, it is impossible not to take into consideration, on the one hand, the very ancient philosophical origins and, on the other, the fact that it was conditioned by religion with the moral aspects and the accelerated deontological evolution with pathways parallel to the needs and the progress offered by new forms of treatment and novel biotechnological applications. The principle of consent is a relatively new condition. In fact, already in the times of not only the Egyptian civilisation, but also the Greek and Roman, documents have been found which show how the doctor's intervention had, in some way, first to be approved by the patient. Plato (law IV) had already foreseen the problems, the procedures and the modes of information which are, in synthesis, at the root of the principles of the present formula of informed consent and correlated the practice of the information and consensus with the quality and social position of the patient. The only guarantee that the patient might have, derived from a fundamental principle of medicine of all times: "in disease, focus on two aims, to improve and not to cause damage". A figure can be recognised, in the Hippocratic physician, that cared about the patient's suffering, but never neglected looking after his own outcome, endeavouring to avoid becoming involved in lack of success and death of a patient. The concept of consensus is inexistent, albeit, there is an awareness of the presence of precautious and preventive information. In the behaviour of doctors, in ancient times, it is not difficult to recognize the true motives and the real reasons that, already in those days, give rise to the necessary "defensive medicine" particularly as far as concerns the social status of the patient. Already from the early origins, continuing the Hippocratic tradition, the relationship between doctor and patient was consolidated, based upon two very definite criteria, represented, on the one hand, by the professional duty of the physician to do what is bestfor the patient and, on the other, the duty of the patient to completely accept the physician's decisions and intervention. The Hippocratic physician respected a principle of professional responsibility which was more religious and of a moral type, but, from a legal point of view, very weak inasmuch as it depended upon regulations elaborated by human beings. The conviction and certainty that the physician acted, in the interest of his patient's well-being, has been passed down over the centuries endowing the physician with moral authority and a kind of legal impunity, conditions which corresponded, in an almost reflection-likefashion, with the duty of obedience and subjection, on the part of the patient. Christianity was grafted into this consolidated vision of the sacral character of medicine and medical practice, which did not substantially change the Hippocratic type of ethical behaviour. Non only the population but also the Christian physician was aware of the religious importance of his intense activity as a mission and compared to a special kind of priesthood in safe-guarding health, considered as a gift of God. Therefore, invested with this authority which derived from his professional role and from his very work, he felt it his duty to guide the patient, deciding and for him. The patient is an ignorant person who does not have the knowledge, the intellectual capacity or moral authority to oppose or disagree with the wishes and decisions of the physician who, instead, on account of his doctrine, knows exactly what is goodfor him. In this regard, if we were to speak of consensus concerning the physician's intervention, he would be considered useless in as much as obvious and understood when seeking help. The attitude of the patient towards the physician has always tended to one of strong faith and characterized by psychological subjection borne out by traditions thousands of years old. A patient who was sick, again, as an attitude of respect and gratitude, followed the treatment but never asked for any explanations regarding the therapeutic effects and the physician refrained from taking any initiative to inform the patient or his/her family. Each phenomenon, therefore, has a precise origin, a well-defined history and when its importance tends to significantly condition the activities concerning Man, a desire emerges to learn the origin and the history. As is well known, a trial commenced in Nuremberg, on December 19, 1946, of Nazi doctors and a code was defined in which the judges, all Americans, clearly emphasized a view of medical research and technology: science should never transform or consider human beings as an instrument to be employed for scientific purposes. In actual fact, documents exist providing evidence that a few decades before the drawing up of the Nuremberg Code, the need had been expressed, in Germany itself to somehow make medical interventions and actions legal by means of the use and practice of consensus. The moral and ethical principles in those documents, even if not available as bibliographic references in the English literature, certainly merit, from a historical viewpoint to be considered as conceptual elements and doctrinal and socio-cultural products, even if at that time, of little practical importance, which belong to the European culture and, in particular, and almost paradoxically, in the light of what happened, to the German culture. The United States of America is held to be the country of origin of informed consent, the initial aim of which was make sure that the correct dignity of the patient's independence be reserved at the time of decision making and choice of medical options. Reports on this topic, in fact, first appeared in the USA, at the beginning of the 18th Century, with problems focusing on and limited to only the simple rights of the patient in giving his/her approval of the health intervention later to be conceptually developed, along the lines of an itinerary with, at intervals, famous legal actions, until in the 20th Century, informed consent was reached, a criterion that, as is well known, foresees and includes not only the important and fundamental autonomy of the patient to decide, which stems ones personal rights, but also the essential objective element, which is, information. The expression informed consent has simply been transposed in Italian and roughly translated in an ambiguous fashion into "consenso informato" when, on the contrary, it should be referred to as "informazione per il consenso" "information for consensus" not only to respect the concept but, surely, for a more correct deciphering and a more precise interpretation related to the numerous concepts it presupposes and implies. Information and consent may be compared to the two sides of the same coin. These are the two important pillars that coincide and are joined giving weight to the medical responsibility, as far as concerns consent to the health intervention: on the one hand, having obtained consent,following correct and sincere information interpreted and deciphered as an important phase and an essential indicator of correct, scrupulous medico-professional procedure and, on the other, the consensus itself conceived as a duty aiming at the maximum respect of the rights to autodetermination, independence and autonomy of the patient, as a person. At the beginning of the Nineties, as we have seen, we were made aware of a series of legal actions regarding medical responsibility which was greatly conditioned by the Anglosaxon influence which initially induced many Italian magistrates and forensic physicians to adopt an extremely rigid attitude with no attempt to comply, in any way, with the culture and traditions of our country and our tradition which has always been inspired by good common sense, both medical and human. The American experience has been very rapidly adopted, by some, without a profound, complete and necessary historical and evolutional analysis aimed at those intertwined principles that have been motifs that have gradually led to the legal references in those emblematic cases referred to, the conclusions of which continue to attract a great deal of attention. In Italy, the legal and doctrinal evolution of informed consent, even if following a little more rapidly the traces, steps, problems and interpretations of the various aspects drawn up, characterized and applied in the United States, has not only occurred at a later time, but, despite reaching the same meaningful objectives, the same considerations, the same importance, and, unfortunately, the same inconveniences, has had quite different aims, approaches and articulations. In this respect, it is enough to focus attention on the different cultural traditions and religious routes, on the different doctrinal background, the particular historical origins and the individual legal aspects, all extremely different one from the other. (ABSTRACT TRUNCATED)

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Continuing with comparative genomic exploration of worldwide butterfly fauna, we use all protein-coding genes as they are retrieved from the whole genome shotgun sequences for phylogeny construction. Analysis of these genome-scale phylogenies projected onto the taxonomic classification and the knowledge about butterfly phenotypes suggests further refinements of butterfly taxonomy that are presented here. As a general rule, we assign most prominent clades of similar genetic differentiation to the same taxonomic rank, and use criteria based on relative population diversification and the extent of gene exchange for species delimitation. As a result, 7 tribes, 4 subtribes, 14 genera, and 9 subgenera are proposed as new, i.e., in subfamily Pierinae Swainson, 1820: Calopierini Grishin, <btrib. n.</b (type genus <iCalopieris</i Aurivillius, 1898); in subfamily Riodininae Grote, 1895: Callistiumini Grishin, <btrib. n.</b (type genus <iCallistium</i Stichel, 1911); in subfamily Nymphalinae Rafinesque, 1815: Pycinini Grishin, <btrib. n.</b (type genus <iPycina</i Doubleday 1849), Rhinopalpini Grishin, <btrib. n.</b (type genus <iRhinopalpa</i C. &amp; R. Felder 1860), Kallimoidini Grishin, <btrib. n.</b (type genus <iKallimoides</i Shirôzu &amp; Nakanishi 1984), Vanessulini Grishin, <btrib. n.</b (type genus <iVanessula</i Dewitz 1887), and Doleschalliaini Grishin, <btrib. n.</b (type genus <iDoleschallia</i C. &amp; R. Felder 1860); in tribe Mesosemiini Bates, 1859: <iEunogyrina</i Grishin, <bsubtrib. n.</b (type genus <iEunogyra</i Westwood, 1851); in tribe Satyrini Boisduval, 1833: Callerebiina Grishin, <bsubtrib. n.</b (type genus <iCallerebia</i Butler, 1867), Gyrocheilina Grishin, <bsubtrib. n.</b (type genus <iGyrocheilus</i Butler, 1867), and Calistina Grishin, <bsubtrib. n.</b (type genus <iCalisto</i Hübner, [1823]); in subfamily Euselasiinae Kirby, 1871: <iPelolasia</i Grishin, <bgen. n.</b (type species <iEurygona pelor</i Hewitson, [1853]), <iMyselasia</i Grishin, <bgen. n.</b (type species <iEurygona mys</i Herrich-Schäffer, [1853]), <iEurylasia</i Grishin, <bgen. n.</b (type species <iEurygona euryone</i Hewitson, 1856), <iMaculasia</i Grishin, <bgen. n.</b (type species <iEuselasia albomaculiga</i Callaghan, 1999), and <iEugelasia</i Grishin, <bgen. n.</b (type species <iEurygona eugeon</i Hewitson, 1856); in subtribe Mesosemiina Bates, 1859: <iEctosemia</i Grishin, <bgen. n.</b (type species <iPapilio eumene</i Cramer, 1776) and <iEndosemia</i Grishin, <bgen. n.</b (type species <iPapilio ulrica</i Cramer, 1777); in tribe Symmachiini Reuter, 1896: <iTigria</i Grishin, <bgen. n.</b (type species <iMesene xypete</i Hewitson, 1870) and <iAsymma</i Grishin, <bgen. n.</b (type species <iSymmachia virgatula</i Stichel, 1910); in tribe Riodinini Grote, 1895: <iPutridivora</i Grishin, <bgen. n.</b (type species <iCharis argyrea</i Bates, 1868), <iChadia</i Grishin, <bgen. n.</b (type species <iCharis cadytis</i Hewitson, 1866), <iInkana</i Grishin, <bgen. n.</b (type species <iCharis incoides</i Schaus, 1902), and <iOco</i Grishin, <bgen. n.</b (type species <iSymmachia ocellata</i Hewitson, 1867); in subtribe Zabuellina Seraphim, Freitas &amp; Kaminski, 2018: <iTeenie</i Grishin, <bgen. n.</b (type species <iCalydna tinea</i Bates, 1868); <iBoreographium</i Grishin, <bsubgen. n.</b (type species <iPapilio marcellus</i Cramer, 1777, parent genus <iEurytides</i Hübner, [1821]), <iEsperourus</i Grishin, <bsubgen. n.</b (type species <iPapilio esperanza</i Beutelspacher, 1975, parent genus <iPterourus</i Scopoli, 1777), <iHyppasonia</i Grishin, <bsubgen. n.</b (type species <iPapilio hyppason</i Cramer, 1775, parent genus <iHeraclides</i Hübner, [1819]), <iSisymbria</i Grishin, <bsubgen. n.</b (type species <iPieris sisymbrii</i Boisduval, 1852, parent genus <iPontia</i [Fabricius], 1807), <iGreenie</i Grishin, <bsubgen. n.</b (type species <iThecla sheridonii</i [sic] Edwards, 1877, parent genus <iCallophrys</i Billberg, 1820), <iMagda</i Grishin, <bsubgen. n.</b (type species <iErebia magdalena</i Strecker, 1880, parent genus <iErebia</i Dalman, 1816), and in genus <iEresia</i Boisduval, 1836: <iNotilia</i Grishin, <bsubgen. n.</b (type species <iEresia orthia</i Hewitson, 1864), <iLevinata</i Grishin, <bsubgen. n.</b (type species <iEresia levina</i Hewitson, 1872), and <iIthra</i Grishin, <bsubgen. n.</b (type species <iPhyciodes ithra</i Kirby, 1900). Furthermore, we resurrect 6 genera, change the rank of 36 currently used genera to subgenus, synonymize 3 subtribes, 42 genera or subgenera, assign 3 genera to tribes and subtribes, and transfer 34 additional species to genera different from those these taxa are presently assigned to, present evidence to support 7 taxa as species instead of subspecies, and 1 taxon as a subspecies instead of species. Namely, the following taxa are valid genera: <iTerias</i Swainson, 1821 (not in <iEurema</i Hübner, [1819]), <iErythia</i Hübner, [1819] and <iMarmessus</i Hübner, [1819] (not in <iEuselasia</i Hübner, [1819]), <iEucorna</i Strand, 1932 (not in <iVoltinia</i Stichel, 1910), <iCremna</i Doubleday, 1847 (not in <iNapaea</i Hübner, [1819]), and <iHallonympha</i Penz &amp; DeVries, 2006 (not in <iZabuella</i Stichel, 1911). The following taxa are best treated as subgenera: <iZegris</i Boisduval, 1836 of <iAnthocharis</i Boisduval, Rambur, [Duménil] &amp; Graslin, [1833]; <iBaltia</i Moore, 1878 and <iPontieuchloia</i Verity, 1929 of <iPontia</i [Fabricius], 1807; <iPhrissura</i Butler, 1870 of <iAppias</i Hübner, [1819]; <iSaletara</i Distant, 1885 of <iCatophaga</i Hübner, 1819; <iLeodonta</i Butler, 1870 of <iPereute</i Herrich-Schäffer, 1867; <iTakashia</i M. Okano &amp; T. Okano, 1985 of <iPolycaena</i Staudinger, 1886; <iCorrachia</i Schaus, 1913 of <iStyx</i Staudinger, 1876; <iIonotus</i Hall, 2005 and <iVoltinia</i Stichel, 1910 of <iCremna</i Doubleday, 1847; <iHermathena</i Hewitson, 1874 of <iIthomiola</i C. &amp; R. Felder, 1865; <iLucillella</i Strand, 1932 of <iEsthemopsis</i C. &amp; R. Felder, 1865; <iMesenopsis</i Godman &amp; Salvin, 1886 and <iXenandra</i C. &amp; R. Felder, 1865 of <iSymmachia</i Hübner, [1819]; <iPirascca</i J. Hall &amp; Willmott, 1996 of <iPterographium</i Stichel, 1910; <iImelda</i Hewitson, 1870 of <iEchenais</i Hübner, [1819]; <iCalicosama</i J. Hall &amp; Harvey, 2001 of <iBehemothia</i Hall, 2000; <iPolygrapha</i Staudinger, 1887 and <iFountainea</i Rydon, 1971 of <iAnaea</i Hübner, [1819]; <iSiderone</i Hübner, [1823] and <iPhantos</i Dias, 2018 of <iZaretis</i Hübner, [1819]; <iHarsiesis</i Fruhstorfer, 1911 of <iPlatypthima</i Rothschild &amp; Jordan, 1905; <iVila</i Kirby, 1871 of <iBiblis</i Fabricius, 1807; <iDiaethria</i Billberg, 1820 and <iPerisama</i Doubleday, 1849 of <iCallicore</i Hübner, [1819]; <iAntigonis</i C. Felder, 1861 of <iHaematera</i Doubleday, 1849; <iAsterope</i Hübner, [1819], <iNica</i Hübner, [1826], <iPeria</i Kirby, 1871, and <iCallicorina</i Smart, 1976 of <iTemenis</i Hübner, [1819]; <iAnthanassa</i Scudder, 1875, <iCastilia</i Higgins, 1981, <iTelenassa</i Higgins, 1981, <iDagon</i Higgins, 1981, and <iJanatella</i Higgins, 1981 of <iEresia</i Boisduval, 1836; and <iWallengrenia</i Berg, 1897 of <iPolites</i Scudder, 1872. The following taxa are junior subjective synonyms: Maniolina Grote, 1897 of Erebiina Tutt, 1896; Melanargiina Wheeler, 1903 of Satyrina Boisduval, 1833; Phyciodina Higgins, 1981 of Melitaeina Herrich-Schäffer, 1843; <iCunizza</i Grote, 1900 of <iHesperocharis</i C. Felder, 1862; <iReliquia</i Ackery, 1975 of <iPontia</i [Fabricius], 1807; <iTatochila</i A. Butler, 1870, <iPiercolias</i Staudinger, 1894, <iHypsochila</i Ureta, 1955, <iTheochila</i W. D. Field, 1958, <iPierphulia</i W. D. Field, 1958, and <iInfraphulia</i W. D. Field, 1958 of <iPhulia</i Herrich-Schäffer, 1867; <iMesapia</i Gray, 1856 of <iAporia</i Hübner, [1819]; <iCatasticta</i Butler, 1870 of <iArchonias</i Hübner, 1827; <iSandia</i Clench &amp; P. Ehrlich, 1960 and<iXamia</i Clench, 1961 of <iIncisalia</i Scudder, 1872; <iHades</i Westwood, 1851 of <iMethone</i Doubleday, 1847; <iSemomesia</i Westwood, 1851, <iMesophthalma</i Westwood, 1851, <iPerophthalma</i Westwood, 1851 and <iLeucochimona</i Stichel, 1909 of <iMesosemia</i Hübner, [1819], <iXynias</i Hewitson, 1874 of <iMesenopsis</i Godman &amp; Salvin, 1886; <iStichelia</i J. Zikán, 1949 of <iSymmachia</i Hübner, [1819]; <iChimastrum</i Godman &amp; Salvin, 1886 of <iMesene</i Doubleday, 1847; <iAlethea</i Nielsen &amp; Salazar, [2018] of <iPirascca</i J. Hall &amp; Willmott, 1996; <iPanaropsis</i J. Hall, 2002 of <iPterographium</i Stichel, 1910; <iComphotis</i Stichel, 1910 of <iPhaenochitonia</i Stichel, 1910; <iColaciticus</i Stichel, 1910 of <iBaeotis</i Hübner, [1819]; <iNahida</i Kirby, 1871 of <iIthomeis</i Bates, 1862; <iMachaya</i Hall &amp; Willmott, 1995 of <iPachythone</i Bates, 1868; <iPercnodaimon</i Butler, 1876 and <iErebiola</i Fereday, 1879 of <iArgyrophenga</i Doubleday, 1845; <iHestinalis</i Bryk, 1938 of <iMimathyma</i Moore, 1896; <iCatacore</i Dillon, 1948 of <iDiaethria</i Billberg, 1820; <iMesotaenia</i Kirby, 1871 and <iOrophila</i Staudinger, 1886 of <iPerisama</i Doubleday, 1849; <iPaulogramma</i Dillon, 1948 of <iCatagramma</i Boisduval, 1836; <iPanacea</i Godman &amp; Salvin, 1883 of <iBatesia</i C. Felder &amp; R. Felder, 1862; <iNapeocles</i Bates, 1864 of <iSiproeta</i Hübner, [1823]; <iTexola</i Higgins, 1959 and <iDymasia</i Higgins, 1960 of <iMicrotia</i H. Bates, 1864; <iTisona</i Higgins, 1981 of <iOrtilia</i Higgins, 1981; <iAbananote</i Potts, 1943 and <iAltinote</i Potts, 1943 of <iActinote</i Hübner, [1819]; <iEpiscada</i Godman &amp; Salvin, 1879 of <iCeratinia</i Hübner, 1816; and <iAppia</i Evans, 1955 of <iPompeius</i Evans, 1955. The following genera are placed in taxonomic hierarchy: <iPrestonia</i Schaus, 1920 belongs to Euremini Grote, 1898; <iPetrocerus</i Callaghan, 1979 belongs to Theopina Clench, 1955; and <iParalasa</i Moore, 1893 belongs to Ypthimina Reuter, 1896. The following taxa are distinct species rather than subspecies (of species shown in parenthesis): <iPyrisitia westwoodii</i (Boisduval, 1836) (not <iPyrisitia dina</i (Poey, 1832)), <iBiblis aganisa</i Boisduval, 1836 (not <iBiblis hyperia</i (Cramer, 1779)), <iPhystis variegata</i (Röber, 1913) and <iPhystis pratti</i (A. Hall, 1935) (not <iPhystis simois</i (Hewitson, 1864)), <iPhocides batabano</i (Lucas, 1857) and <iPhocides bicolora</i (Boddaert, 1783) (not <iPhocides pigmalion</i (Cramer, 1779)), <iLobotractus mysie</i (Dyar, 1904) (not <iLobotractus valeriana</i (Plötz, 1881)). <iNahida coenoides</i (Hewitson, 1870) is conspecific with <iIthomeis aurantiaca</i H. Bates, 1862. Additional new and revised combinations are: <iTeriocolias deva</i (E. Doubleday, 1847), <iTeriocolias reticulata</i (A. Butler, 1871), <iHesperocharis leucothea</i (Molina, 1782), <iMethone euploea</i (Hewitson, [1855]), <iMethone eucerus</i (Hewitson, 1872), <iMethone hypophaea</i (Godman &amp; Salvin, 1878), <iMethone eubule</i (R. Felder, 1869), <iMethone onorata</i (Hewitson, 1869), <iMethone authe</i (Godman, 1903), <iMethone dolichos</i (Staudinger, [1887]), <iMethone baucis</i (Stichel, 1919), <iMethone eucrates</i (Hewitson, 1872), <iNapaea danforthi</i A. Warren &amp; Opler, 1999, <iNapaea dramba</i (J. Hall, Robbins &amp; Harvey, 2004), <iNapaea sanarita</i (Schaus, 1902), <iNapaea agroeca</i Stichel, 1910, <iNapaea tumbesia</i J. Hall &amp; Lamas, 2001, <iNapaea umbra</i (Boisduval, 1870), <iNapaea phryxe</i (C. &amp; R. Felder, 1865), <iNapaea cebrenia</i (Hewitson, [1873]), <iNapaea loxicha</i (R.G. Maza &amp; J. Maza, 2016), <iNapaea maya</i (J. Maza &amp; Lamas, 2016), <iNapaea necaxa</i (R.G. Maza &amp; J. Maza, 2018), <iNapaea totonaca</i (R.G. Maza &amp; J. Maza, 2016), <iMesene aeolia</i (Bates, 1868), <iPterographium hypochloris</i (Bates, 1868), <iPhaenochitonia florus</i (Fabricius, 1793), <iOurocnemis carausius</i (Westwood, 1851), <iOurocnemis principalis</i (Hopffer, 1874), <iOurocnemis renaldus</i (Stoll, 1790), and <iOurocnemis aerosus</i (Stichel, 1924), <iHallonympha maculosa</i (Bates, 1868), <iExoplisia aphanis</i (Stichel, 1910), <iPhystis fontus</i (A. Hall, 1928), <iPhocides batabano okeechobee</i (Worthington, 1881), and <iPhocides batabano batabanoides</i (W. Holland, 1902). Finally, we confirm the combination <iZabuella castanea</i (Prittwitz, 1865) and find <iPyrgus centaureae dzekh</i Gorbunov, 2007 as a new subspecies for North America.

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DIOXIN TOXIC EQUIVALENCY FACTOR EVALUATION OVERVIEW: Polyhalogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) have the ability to bind to and activate the ligand-activated transcription factor, the aryl hydrocarbon receptor (AhR). Structurally related compounds that bind to the AhR and exhibit biological actions similar to TCDD are commonly referred to as "dioxin-like compounds" (DLCs). Ambient human exposure to DLCs occurs through the ingestion of foods containing residues of DLCs that bioconcentrate through the food chain. Due to their lipophilicity and persistence, once internalized they accumulate in adipose tissue resulting in chronic lifetime human exposure. Since human exposure to DLCs always occurs as a complex mixture, the Toxic Equivalency Factor (TEF) methodology has been developed as a mathematical tool to assess the health risk posed by complex mixtures of these compounds. The TEF methodology is a relative potency scheme that ranks the dioxin-like activity of a compound relative to TCDD that is the most potent congener. This allows for the estimation of the potential dioxin-like activity of a mixture of chemicals, based on a common mechanism of action involving an initial binding of DLCs to the AhR. The toxic equivalency of DLCs was nominated for evaluation, because of the widespread human exposure to DLCs and the lack of data on the adequacy of the TEF methodology for predicting relative potency for cancer risk. To address this, the National Toxicology Program conducted a series of 2-year bioassays in female Harlan Sprague-Dawley rats to evaluate the chronic toxicity and carcinogenicity of DLCs and structurally-related polychlorinated biphenyls (PCBs) and mixtures of these compounds. 3,3',4,4',5-Pentachlorobiphenyl (PCB 126) was produced commercially before 1977 for the electric industry as a dielectric insulating fluid for transformers and capacitors. Manufacture and use of the chemical was stopped because of increased PCB residues in the environment, but it continues to be released into the environment through the use and disposal of products containing PCBs, as by-products during the manufacture of certain organic chemicals, and during combustion of some waste materials. Bioaccumulation of PCB 126 results in persistent levels in animal and human tissues and the biological responses to PCB 126 are similar to those of TCDD, a known human carcinogen. PCB 126 was selected for study by the National Toxicology Program as a part of the dioxin TEF evaluation to assess the cancer risk posed by complex mixtures of polychlorinated dibenzodioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and PCBs. The dioxin TEF evaluation includes conducting multiple 2-year rat bioassays to evaluate the relative chronic toxicity and carcinogenicity of DLCs, structurally related PCBs, and mixtures of these compounds. PCB 126 was included since this is the most potent coplanar PCB that has dioxin-like activities. While one of the aims of the dioxin TEF evaluation was a comparative analysis across studies, in this Technical Report only the results of the PCB 126 study are presented and discussed. Female Harlan Sprague-Dawley rats were administered PCB 126 (99% pure) in corn oil with acetone by gavage for 14, 31, or 53 weeks or 2 years. 2-YEAR STUDY: Groups of 81 female rats were administered 30, 100, 175, 300, 550, or 1,000 ng PCB 126/kg body weight in corn oil:acetone (99:1) by gavage, 5 days per week, for up to 104 weeks; a group of 81 vehicle control female rats received the corn oil/acetone vehicle alone. A group of 28 rats received 10 ng/kg for up to 53 weeks only. Up to 10 rats per group were evaluated at 14, 31, or 53 weeks. A stop-exposure group of 50 female rats was administered 1,000 ng/kg PCB 126 in corn oil:acetone (99:1) by gavage for 30 weeks then the vehicle for the remainder of the study. Mean body weights of 30 and 100 ng/kg rats were similar to those of the vehicle controls during most of the study, mean body weights of 175 and 300 ng/kg rats were less than those of the vehicle controls during year 2 of the study, and mean body weights of 550 ng/kg, 1,000 ng/kg core study, and 1,000 ng/kg stop-exposure rats were less than those of the vehicle controls after week 17. THYROID HORMONE CONCENTRATIONS: Alterations in serum thyroid hormone levels were evaluated at the 14-, 31- and 53- week interim evaluations. In the 550 and 1,000 ng/kg rats, total thyroxine (T4) and free T4 were significantly lower than vehicle controls and serum triiodothyronine (T3) and thyroid stimulating hormone (TSH) levels were significantly higher than vehicle controls at the 14-week interim evaluation. Serum T3 was also significantly higher in the 300 ng/kg rats compared to vehicle controls at 14 weeks. At 31 weeks, T3 was significantly higher at doses of 100 ng/kg or greater compared to vehicle controls. TSH levels were higher in 550 and 1,000 ng/kg rats than in vehicle controls. At 53 weeks, significantly lower serum concentrations of total T4 and free T4 were observed compared to vehicle controls in groups administered 175 ng/kg or greater and 30 ng/kg or greater, respectively. Serum T3 levels were significantly higher at doses of 175 ng/kg or greater compared to vehicle controls. No changes in TSH were observed between vehicle controls and dosed rats at 53 weeks. HEPATIC CELL PROLIFERATION DATA: To evaluate hepatocyte replication, analysis of labeling of replicating hepatocytes with 5-bromo-2'-deoxyuridine was conducted at the 14-, 31-, and 53-week interim evaluations. The hepatocellular labeling index was significantly higher at doses of 300 ng/kg or greater at 14 weeks and 175 ng/kg or greater at 31 weeks compared to vehicle controls. No statistically significant differences were observed between vehicle controls and PCB 126 dosed rats at 53 weeks. However at 53 weeks, a 5.8-fold increase above the vehicle controls was observed in the 1,000 ng/kg group. CYTOCHROME P450 ENZYME ACTIVITIES: To evaluate the expression of known dioxin-responsive genes, CYP1A1 associated 7-ethoxyresorufin-O-deethylase (EROD) activity and CYP1A2-associated acetanilide 4-hydroxylase (A-4-H) activity were evaluated at the 14-, 31-, and 53-week interim evaluations. In addition, CYP2B associated pentoxyresorufin-O-deethylase (PROD) activity was also analysed. Hepatic PROD (CYP2B1) and hepatic and pulmonary EROD (CYP1A1) activity were significantly greater in all dosed groups than in vehicle controls at weeks 14, 31, and 53. Hepatic A-4-H (CYP1A2) activity was significantly greater in the 30, 100, 175, 300, 550, and 1,000 ng/kg groups compared to vehicle controls at weeks 14, 31, and 53. DETERMINATIONS of PCB 126 CONCENTRATIONS IN TISSUES: The tissue disposition of PCB 126 was analyzed in the liver, lung, fat, and blood of all rats in vehicle controls and all dosed groups at the 14-, 31-, and 53-week interim evaluations and in 10 rats per group including vehicle controls at the end of the 2-year study (104 weeks). Detectable concentrations of PCB 126 were observed in the liver, fat, lung, and blood. Measurable concentrations of PCB 126 were present in the liver and fat at weeks 31, 53, and 104. Hepatic and fat concentrations increased with increasing doses of PCB 126. Measurable concentrations of PCB 126 were present in vehicle control lung tissue at 53 and 104 weeks. No PCB 126 was observed in the blood from the vehicle control rats. Lung and blood concentrations tended to increase with increasing doses of PCB 126, with a few exceptions. In the stop-exposure group, PCB 126 concentrations in liver and fat were lower than the levels observed in the 30 ng/kg group. In the stop-exposure group, lung tissue PCB 126 concentrations were equivalent to the levels observed in the 30 ng/kg group. In blood from the stop-exposure group, PCB 126 concentrations were equivalent to the levels observed in the 100 ng/kg group. PATHOLOGY AND STATISTICAL ANALYSES: Absolute and relative liver weights were significantly increased at all time points and correlated with increased incidences of hepatocellular hypertrophy. At 2 years, there were significant treatment-related increases in the incidences of cholangiocarcinoma and hepatocellular adenoma. Three hepatocholangiomas were seen in the 1,000 ng/kg core study group and a single incidence of cholangioma each occurred in the 550 and 1,000 ng/kg core study groups. At 2 years, a significant dose-related increase in hepatic toxicity was observed and was characterized by increased incidences of numerous lesions including hepatocyte hypertrophy, multinucleated hepatocytes, diffuse fatty change, bile duct hyperplasia, bile duct cyst, oval cell hyperplasia, necrosis, pigmentation, inflammation, nodular hyperplasia, portal fibrosis, cholangiofibrosis, and toxic hepatopathy. The incidences of these lesions were generally decreased in the 1,000 ng/kg stop-exposure group compared to the 1,000 ng/kg core study group. The lung weights of 1,000 ng/kg rats were generally significantly increased at weeks 14, 31, and 53. At 2 years, treatment related increases in the incidences of cystic keratinizing epithelioma and squamous cell carcinomas were observed. In addition, dose-related increases in the incidences of bronchiolar metaplasia of the alveolar epithelium and squamous metaplasia were also observed. The incidence of gingival squamous cell carcinoma of the oral mucosa was significantly increased in the 1,000 ng/kg core study group at 2 years. Gingival squamous cell carcinoma, although reduced in incidence as compared to the 1,000 ng/kg core study group, was still present in the 1,000 ng/kg stop-exposure group. At 2 years, adenomas and/or carcinomas were present in the adrenal cortex of most core study groups and in the 1,000 ng/kg stop-exposure group. Dose-related effects on the incidences of adrenal cortex atrophy and cytoplasmic vacuolization were also seen. (ABSTRACT TRUNCATED)

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On the basis of available data with regard to the chemical and physical properties of the "substrate" luciferin (LH(2)) and enzyme, luciferase (A), and of kinetic data derived both from the reaction in extracts of Cypridina, and from the luminescence of intact bacteria, the fundamental reactions involved in the phenomenon of bioluminescence have been schematized. These reactions provide a satisfactory basis for interpreting the known characteristics of the system, as well as the theoretical chemistry with regard to the control of its over-all velocity in relation to various factors. These factors, here studied experimentally wholly with bacteria, Photobacterium phosphoreum in particular, include pH, temperature, pressure, and the drugs sulfanilamide, urethane, and alcohol, separately and in relation to each other. Under steady state conditions of bacterial luminescence, with excess of oxidizable substrate and with oxygen not limiting, the data indicate that the chief effects of these agents center around the pace setting reactions, which may be designated by the equation: A + LH(2) --&gt; ALH(2) following which light emission is assumed proportional to the amount of the excited molecule, AL*. The relation between pH and luminescence intensity varies with (a), the buffer mixture and concentration, (b), the temperature, and (c), the hydrostatic pressure. At an optimum temperature for luminescence of about 22 degrees C. in P. phosphoreum, the effects of increasing or decreasing the hydrogen ion concentration are largely reversible over the range between pH 3.6 and pH 8.8. The relation between luminescence intensity and pH, under the experimental conditions employed, is given by the following equation, in which I(1) represents the maximum intensity, occurring about pH 6.5; I(2) the intensity at any other given pH; K(5) the equilibrium constant between hydrogen ions and the AL(-); and K(6) the corresponding constant with respect to hydroxyl ions: See PDF for Equation The value of K(5), as indicated by the data, amounts to 4.84 x 10(4), while that of K(6) amounts to 4.8 x 10(5). Beyond the range between approximately pH 3.8 and 8.8, destructive effects of the hydrogen and hydroxyl ions, respectively, were increasingly apparent. By raising the temperature above the optimum, the destructive effects were apparent at all pH, and the intensity of the luminescence diminished logarithmically with time. With respect to pH, the rate of destruction of the light-emitting system at temperatures above the optimum was slowest between pH 6.5 and 7.0, and increased rapidly with more acid or more alkaline reactions of the medium. The reversible effects of slightly acid pH vary with the temperature in the manner of an inhibitor (Type I) that acts independently of the normal, reversible denaturation equilibrium (K(1)) of the enzyme. The per cent inhibition caused by a given acid pH in relation to the luminescence intensity at optimum pH, is much greater at low temperatures, and decreases as the temperature is raised towards the optimum temperature. The observed maximum intensity of luminescence is thus shifted to slightly higher temperatures by increase in (H(+)). The apparent activation energy of luminescence is increased by a decrease in pH. The value of DeltaHdouble dagger at pH 5.05 was calculated to be 40,900 calories, in comparison with 20,700 at a pH of 6.92. The difference of 20,200 is taken to represent an estimate of the heat of ionization of ALH in the activation process, and compares roughtly with the 14,000 calories estimated for the same process, by analyzing the data from the point of view of hydrogen ions as an inhibitor. The decreasing temperature coefficient for luminescence in proceeding from low temperatures towards the optimum is accounted for in part by the greater degree of ionization of ALH. At the optimum temperature and acid reactions, pressures up to about 500 atmospheres retard the velocity of the luminescent oxidation. At the same temperature, with decrease in hydrogen ion concentration, the pressure effect is much less, indicating a considerable volume increase in the process of ionization and activation. In the extremely alkaline range, beyond pH 9, luminescence is greatly reduced, as compared with the intensity at neutrality, and under these conditions pressure causes a pronounced increase in intensity, presumably by acting upon the reversible denaturation equilibrium of the protein enzyme, A. Sulfanilamide, in neutral solutions, acts on luminescence in a manner very much resembling that of hydrogen ions at acidities between pH 4.0 and pH 6.5. Like the hydrogen ion equilibrium, the sulfanilamide equilibrium involves a ratio of approximately one inhibitor molecule to one enzyme molecule. The heat of reaction amounts to about 11,600 calories or more in a reversible combination that evidently evolves heat. Like the action of H ions, sulfanilamide causes a slight shifting of maximum luminescence intensity in the direction of higher temperatures, and an increase in the energy of activation. The effect of sulfanilamide on the growth of broth cultures of eight species of luminous bacteria indicates that there is no regular relationship among the different organisms between the concentration of the drug that prevents growth, and that which prevents luminescence in the cells which develop in the presence of sulfanilamide. p-Aminobenzoic acid (PAB) antagonizes the sulfanilamide inhibition of growth in luminous bacteria, and the cultures that develop are luminous. When (PAB) is added to cells from fully developed cultures, it has no effect on luminescence, or causes a slight inhibition, depending on the concentration. With luminescence partly inhibited by sulfanilamide, the addition of PAB has no effect, or has an inhibitory effect which adds to that caused by sulfanilamide. Two different, though possibly related, enzyme systems thus appear to limit growth and luminescence, respectively. The possible mechanism through which both the inhibitions and the antagonism take place is discussed. The irreversible destruction of the luminescent system at temperatures above that of the maximum luminescence, in a medium of favorable pH to which no inhibitors have been added, proceeds logarithmically with time at both normal and increased hydrostatic pressures. Pressure retards the rate of the destruction, and the analysis of the data indicates that a volume increase of roughly 71 cc. per gm. molecule at 32 degrees C. takes place in going from the normal to the activated state in this reaction. At normal pressure, the rate of destruction has a temperature coefficient of approximately 90,000 calories, or about 20,000 calories more than the heat of reaction in the reversible denaturation equilibrium. The data indicate that the equilibrium and the rate process are two distinct reactions. The equation for luminescence intensity, taking into account both the reversible and irreversible phases of the reaction is given below. In the equation b is a proportionality constant; k' the rate constant of the luminescent reaction; A(0) the total luciferase; A(0i) the total initial luciferase at time t equals 0; k(n) the rate constant for the destruction of the native, active form of the enzyme; k(d) the rate constant for the destruction of the reversibly denatured, inactive form; t the time; and the other symbols are as indicated above: See PDF for Equation For reasons cited in the text, k(n) evidently equals k(d). Urethane and alcohol, respectively, act in a manner (Type II) that promotes the breaking of the type of bonds broken in both the reversible and irreversible reactions and so promotes the irreversible denaturation. This result is in contrast to the effects of sulfanilamide, which at appropriate concentrations may give rise to the same initial inhibition as that caused by urethane, but remains constant with time. The inhibition caused by urethane and alcohol, respectively, increases as the temperature is raised. As a result, the apparent optimum is shifted to lower temperatures, and the activation energy for the over-all process of luminescence diminishes. An analysis for the approximate heat of reaction in the equilibrium between these drugs and the enzyme, indicates 65,000 calories for urethane, and 37,000 for alcohol. A similar analysis with respect to the effect of hydroxyl ions as the inhibitor gives 60,300 calories. The effects of alcohol and urethane are sensitive to hydrostatic pressure. Moderate inhibitions at optimum temperature and pH, caused by relatively small concentrations of either drug, are completely abolished by pressures of 3,000 to 4,000 pounds per square inch. At optimum temperature and pH, increasing concentrations of alcohol caused the apparent optimum pressure for luminescence to shift markedly in the direction of higher pressures. Analysis of the data with respect to concentration of alcohol at different pressures indicated that the ratio of alcohol to enzyme molecules amounted to approximately 4, at 7,000 pounds, but only about 2.8 at normal pressures. This phenomenon was taken to indicate that more than one equilibrium is established between the alcohol and the protein. A similar interpretation was suggested in connection with the fact that analysis of the relation between concentration of urethane and amount of inhibition at different temperatures also indicated a ratio of urethane to enzyme molecules that increased with temperature in the equilibria involved. Analysis of the data with respect to pressure and the inhibition caused by a given concentration of alcohol at different temperatures indicated that the volume change involved in the combination of alcohol with the enzyme must be very small, while the actual effect of pressure is apparently mediated through the reversible denaturation of the protein enzyme, which is promoted by alcohol, urethane, and drugs of similar type.

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p-Chloroaniline has a large production volume and is used as a dye intermediate. Toxicology and carcinogenesis studies of p-chloroaniline (greater than 99% pure) were conducted by administering p-chloroaniline hydrochloride in water by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 16 days, 13 weeks, or 2 years. Vehicle controls were given deionized water by gavage. All doses were calculated as p-chloroaniline; the chemical was administered as the hydrochloride after dissolution in water containing molar equivalents of hydrochloric acid. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse L5178Y lymphoma cells, and Chinese hamster ovary (CHO) cells. Hematologic parameters were measured at the end of the 13-week studies and at 6, 12, 18, and 24 months in the 2-year studies. Supplemental studies of the distribution and disposition of p-chloroaniline were conducted in male F344 rats. Sixteen-Day and Thirteen-Week Studies: In the 16-day studies, male and female rats and mice received 25, 50, 100, or 400 mg/kg of body weight. The vehicle controls received deionized water. All rats and mice that received 200 or 400 mg/kg died during the first 6 days of the studies. Some deaths occurred in each of the lower dose groups of mice. Splenic enlargement was observed at necropsy in rats administered 25, 50, or 100 mg/kg. Congestion of the spleen and hemosiderin deposition in the renal cortical tubular epithelial cells were observed at 100 mg/kg in male and female rats. Compound-related lesions in mice included hemosiderosis of the liver Kupffer cells and congestion of the spleen. In the 13-week studies, 10 rats of each sex were administered doses of 0, 5, 10, 20, 40, or 80 mg/kg. All male rats lived to the end of the 13-week studies. One of 10 female rats that received 80 mg/kg died from unknown causes. The final mean body weights of rats that received 80 mg/kg were 16% lower than that of vehicle controls for males and 4% lower for females. In the 13-week studies in mice, 10 animals of each sex were administered doses of 0, 7.5, 15, 30, 60, or 120 mg/kg. Deaths in mice were not related to p-chloroaniline hydrochloride administration. The final mean body weights of dosed and vehicle control mice were similar. In both rats and mice, no chemically related effects on organ weights were observed at necropsy, except for the spleen, which was enlarged as a function of increasing dose. Methemoglobin was increased in dosed groups and resulted in a secondary anemia, the severity of which was dose related. Compound-related lesions observed histologically, including pigmentation (hemosiderin) in the kidney, spleen, and liver and hematopoiesis in the liver and spleen, reflected the response to the hemolytic anemia and methemoglobinemia induced by p-chloroaniline hydrochloride. Based on these results, groups of 50 rats of each sex were administered 2, 6, or 18 mg/kg p-chloroaniline hydrochloride in water by gavage, 5 days per week for 103 weeks. Groups of 50 mice of each sex were administered 3, 10, or 30 mg/kg on the same schedule. Metabolism and Disposition Studies in Rats: The metabolism and disposition studies in F344/N rats showed that metabolic and excretory pathways were not saturated by p-chloroaniline administered orally at doses ranging from 0.3 to 30 mg/kg. p-Chloroaniline was rapidly metabolized and excreted primarily in urine with a half-life of approximately 2 hours. Body Weight and Survival in the Two-Year Studies: Mean body weights of dosed rats were generally within 5% of those of vehicle controls throughout the studies. The survival of the low and mid dose groups of male rats and of the low and high dose groups of female rats was significantly greater than that of the vehicle controls (male: vehicle control, 18/49; low dose, 32/50; mid dose, 32/50; high dose, 21/50; female: 27/50; 39/50; 36/50; 37/50). The increased survival was attributed to the decreased incidences of mononuclear cell leukemia. Mean body weights of high dose male and female mice were generally within 5% of those of vehiclwithin 5&amp;percnt; of those of vehicle controls throughout the studies. The survival of the mid dose group of male mice was lower than that of the vehicle controls after week 99 (male: 43/50; 36/50; 29/50; 35/50; female: 39/50; 42/50; 44/50; 41/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Fibrosis of the spleen was increased in dosed male and high dose female rats (male: vehicle control, 3/49; low dose, 11/50; mid dose, 12/50; high dose, 41/50; female: 1/50; 2/50; 3/50; 42/50). Cellular infiltration of lipocytes (fatty metaplasia) was observed in the spleen at increased incidences in high dose rats (male: 0/49; 0/50; 0/50; 24/50; female: 0/50; 0/50; 0/50; 11/50). The incidence of uncommon sarcomas of the spleen in high dose male rats was significantly greater than that in the vehicle controls (fibrosarcomas, osteosarcomas, or hemangiosarcomas, combined: 0/49; 1/50; 3/50; 38/50). Many of these tumors metastasized to one or more sites. In female rats, one fibrosarcoma of the spleen was found in a mid dose animal, and one osteosarcoma of the spleen was found in a high dose animal. The historical incidence of splenic connective tissue sarcomas (all types) in water gavage vehicle controls is 1/298 (0.3&amp;percnt;) for male rats and 0/297 for female rats. The historical incidence of hemangiosarcomas in water gavage controls is 0/300 for male rats and 1/297 (0.3&amp;percnt;) for female rats. Adrenal medullary hyperplasia was observed at an increased incidence in high dose female rats (4/50; 4/50; 7/50; 24/50). Marginally increased incidences of pheochromocytomas were seen in high dose male (13/49; 14/48; 15/48; 26/49) and female (2/50; 3/50; 1/50; 6/50) rats. The historical incidence of pheochromocytomas in water gavage vehicle control male F344/N rats is 121/299 (40&amp;percnt; &amp;plusmn; 16&amp;percnt;); the historical incidence in water gavage vehicle control female F344/N rats is 20/295 (7&amp;percnt; &amp;plusmn; 2&amp;percnt;). The incidences of mononuclear cell leukemia in dosed male and female rats were lower than those in vehicle controls (male: 21/49; 3/50; 2/50; 3/50; female: 10/50; 2/50; 1/50; 1/50). The incidences of malignant lymphomas in dosed male and female mice were lower than those in vehicle controls (male: 10/50; 3/49; 9/50; 3/50; female: 19/50; 12/50; 5/50; 10/50). Hematologic and methemoglobin measurements were made on blood samples collected from 15 randomly selected male and female rats per dose group at 6, 12, 18, and 24 months. In general, the high dose group at various intervals showed mild hemolytic anemia and dose-related increases in methemoglobin. In rats, compound-related nonneoplastic lesions were seen histopathologically in the bone marrow, spleen, and liver. These lesions included bone marrow hyperplasia, hepatic hemosiderosis, and splenic fibrosis and suggest compound-related effects on the hematopoietic system in general, the erythropoietic system specifically, and mesenchymal cells in the spleen. In male mice, the incidence of hemangiosarcomas of the liver or spleen in high dose male mice was greater than that in the vehicle controls (4/50; 4/49; 1/50; 10/50). The historical incidence of hemangiomas or hemangiosarcomas at all sites (combined) in water gavage vehicle control male B6C3F1 mice is 11/350 (3&amp;percnt; &amp;plusmn; 3&amp;percnt;). The incidences of hepatocellular adenomas or carcinomas (combined) were increased in dosed male mice (11/50; 21/49; 20/50; 21/50), primarily due to increased incidences of hepatocellular carcinomas (3/50; 7/49; 11/50; 17/50). Hepatocellular carcinomas metastasized to the lung in 1/50 vehicle control, 1/49 low dose, 2/50 mid dose, and 9/50 high dose male mice. The historical incidence ofhepatocellular neoplasms in water gavage vehicle controls is 106/347 (31 &amp;plusmn; 6&amp;percnt;). Genetic Toxicology: p-Chloroaniline was mutagenic in S. typhimurium strains TA98 and TA100 in the presence of exogenous metabolic activation; no increase in revertant colonies was observed in strains TA97, TA1535, or TA1537. p-Chloroaniline induced trifluorothymidine (Tft) resistance in mouse L5178Y lymphoma cells with and without metabolic activation. In cultured CHO cells, treatment with p-chloroaniline produced significant increases in sister chromatid exchanges (SCEs) both with and without metabolic activation (S9); chromosomal aberrations were significantly increased only in the presence of S9. Audit: The data, documents, and pathology materials from the 2-year studies of p-chloroaniline have been audited. The audit findings show that the conduct of the studies is documented adequately and support the data and results given in this Technical Report. Conclusions: Under the conditions of these 2-year water gavage studies, there was clear evidence of carcinogenic activity of p-chloroaniline hydrochloride for male F344/N rats, as indicated by increased incidences of uncommon sarcomas of the spleen. Pheochromocytomas of the adrenal gland may also have been associated with chemical administration. There was equivocal evidence of carcinogenic activity of p-chloroaniline hydrochloride for female F344/N rats, as indicated by the presence of uncommon sarcomas of the spleen in one mid and one high dose animal and the increased incidence of pheochromocytomas of the adrenal gland. There was some evidence of carcinogenic activity of p-chloroaniline hydrochloride for male B6C3F1 mice, as indicated by increased incidences of hepatocellular neoplasms and of hemangiosarcomas of the liver or spleen. There was no evidence of carcinogenic activity of p-chloroaniline hydrochloride for female B6C3F1 mice administered 3, 10, or 30 mg/kg by gavage for 2 years. The incidences of mononuclear cell leukemia in male and female rats and of malignant lymphomas in male and female mice were decreased by administration of p-chloroaniline hydrochloride. Compound-related splenic fibrosis was present in male and female rats. Synonyms: 1-amino-4-chlorobenzene hydrochloride; 4-chlorophenylamine hydrochloride; 4-chlorobenzeneamine hydrochloride

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Urethane, a byproduct of fermentation found in alcoholic beverages, is carcinogenic in rodents and is classified by the International Agency for Research on Cancer as a possible human carcinogen. The United States Food and Drug Administration nominated urethane for study because of the widespread exposure of humans through the consumption of fermented foods and beverages and because of a lack of adequate dose-response data about the carcinogenicity of urethane with and without the coadministration of ethanol. Comparative studies of urethane in drinking water and in 5% ethanol were conducted to investigate possible effects of ethanol on urethane toxicity. Toxicokinetic studies of urethane in drinking water and in 5% ethanol and genetic toxicity studies of urethane in vivo and in vitro were also conducted. Groups of 10 male and 10 female F344/N rats and B6C3F1 mice, 6 weeks of age, received 0, 110, 330, 1,100, 3,300, or 10,000 ppm urethane in drinking water or in 5% ethanol for 13 weeks. Toxicokinetic evaluations were performed for urethane in the plasma of male mice after 13 weeks of administration in drinking water or 5% ethanol. The mutagenicity of urethane in Salmonella typhimurium strains TA97, TA98, TA100, TA1535, and TA1537 with and without S9 was tested at doses up to 16,666 micrograms/plate; urethane was also tested for induction of sister chromatid exchanges and chromosomal aberrations in cultured Chinese hamster ovary cells and sex-linked recessive lethal mutations and chromosomal reciprocal translocations in Drosophila melanogaster. The frequency of micronucleated erythrocytes induced in peripheral blood and bone marrow cells of mice by urethane in drinking water and in 5% ethanol was also evaluated. In rats that received urethane in drinking water, seven males and four females administered 10,000 ppm and one female administered 3,300 ppm died before the end of the study; body weight gains were reduced at these concentrations. Two males and all females given 10,000 ppm urethane in 5% ethanol died during the study, and the body weight gains of males and females that received 3,300 ppm were lower than those of the controls. Relative right kidney, liver, and lung weights of males and females and relative right testis weights of males administered 1,100 ppm or greater were generally higher than those of the controls in each study. Leukopenia and lymphopenia were observed in rats receiving urethane in either drinking water or ethanol and occurred in males receiving 330 ppm or greater and females receiving 110 ppm or greater. Other differences in hematology and clinical chemistry variables were not considered to be biologically significant. Lymphoid depletion of the spleen, lymph nodes, and thymus was observed in male and female rats receiving 1,100, 3,300, or 10,000 ppm urethane in drinking water. Cellular depletion of the bone marrow occurred in males and females in the 10,000 ppm groups. Hepatocellular fatty changes and clear cell foci of alteration were noted in the liver of males and females that received 3,300 or 10,000 ppm. The incidences of nephropathy were significantly increased in female rats that received 1,100 ppm or greater; the severity of this lesion in exposed males and females was greater than that in the controls. Females that received 330 ppm or greater had higher incidences of cardiomyopathy than the controls; the severity of this lesion was greater in males in the 10,000 ppm group and females in the 3,300 and 10,000 ppm groups than in the controls. In rats that received urethane in 5% ethanol, lymphoid depletion occurred in males and females in the 3,300 and 10,000 ppm groups. Cellular depletion of the bone marrow was observed in males and females in the 10,000 ppm groups. Only males in the 10,000 ppm group had hepatocellular fatty change (8/10) and clear cell foci (1/10); the incidence and severity of nephropathy in males and females and cardiomyopathy in males were similar to those in rats administered urethane in drinking water; however, no cardiomyopathy was observed in females receiving urethane in ethanol. The estrous cycle length of females receiving urethane in ethanol appeared to be longer than that of females receiving urethane in drinking water. Because cycle length was longer in the 10,000 ppm groups than in the controls in both the drinking water and ethanol vehicle studies, this difference may represent an exacerbation of the toxicity of urethane. A longer estrous cycle may be a sign of reproductive impairment and correlates with a decrease in female fecundity. All mice administered 10,000 ppm urethane in either vehicle died. All mice that received 3,300 ppm urethane in drinking water died, while only one male and four females receiving 3,300 ppm urethane in 5% ethanol died. Body weight gains of males and females in all 1,100 ppm groups were less than those of the respective controls, but the weight gains of mice receiving 1,100 ppm urethane in 5% ethanol were greater than those of mice receiving urethane in drinking water. The mean body weights of the lower exposure groups were similar to those of the respective controls, and there were no other differences between the body weights of mice receiving urethane in drinking water and those receiving urethane in 5% ethanol. Fluid consumption, and therefore total urethane intake, appeared lower in mice receiving the 5% ethanol vehicle than in those receiving the water vehicle. The relative right kidney, liver, and lung weights of males and females administered urethane in drinking water or ethanol were generally greater than those of the controls. Clearance of urethane from the plasma of male mice was complete within 2 hours after urethane was administered in water, but urethane was not cleared 12 hours after administration in 5% ethanol. At the end of 13 weeks of urethane administration, the plasma urethane elimination half-life was 0.8 hours; the kinetics were similar for concentrations of 110, 330, and 1,100 ppm urethane in water and in ethanol. However, at each exposure level, the plasma urethane concentration was four times greater for urethane administered in 5% ethanol than for urethane administered in drinking water, indicating a possible inhibition of urethane metabolism by ethanol. Kinetic measurements for elimination by female mice could not be obtained from the data collected. In mice administered urethane in drinking water, lung inflammation occurred in males and females that received 1,100 ppm or greater. Alveolar epithelial hyperplasia occurred in the lungs of males in the 330 and 1,100 ppm groups and females in the 1,100 ppm group; one male mouse in the 330 ppm group had an alveolar/bronchiolar adenoma (see the following summary table). Mice receiving urethane in 5% ethanol had lower incidences and severity of lung inflammation but generally greater incidences and severity of alveolar epithelial hyperplasia than mice receiving the same concentrations of urethane in drinking water. Alveolar/bronchiolar adenomas occurred in four males and one female administered urethane in ethanol. [table: see text] Nephropathy was observed in males and females that received urethane in either vehicle, and the lesions in female mice were more severe than those in male mice; ethanol did not appear to increase the incidence or severity of nephropathy. Cardiomyopathy occurred in males and females that received 1,100 or 3,300 ppm urethane in drinking water and in females that received 3,300 ppm urethane in ethanol. Lymphoid depletion occurred in mice that received 3,300 or 10,000 ppm urethane; 5% ethanol did not appear to enhance these effects. However, urethane in 5% ethanol induced ovarian atrophy; the incidence of this lesion was lower in females receiving urethane in drinking water. A concentration of 1,100 ppm urethane in either drinking water or ethanol effectively stopped estrous cycling. Urethane is clearly genotoxic in vitro and in vivo. In vitro, urethane induced mutations in Salmonella typhimurium strain TA1535 in the presence of liver S9 enzymes. Sister chromatid exchanges were induced in cultured Chinese hamster ovary (CHO) cells with and without S9. However, no induction of chromosomal aberrations was observed in CHO cells treated with urethane, with or without S9. In vivo, urethane induced sex-linked recessive lethal mutations and reciprocal translocations in germ cells of adult male Drosophila melanogaster fed urethane. Significantly increased frequencies of micronucleated erythrocytes were observed in peripheral blood obtained from male and female mice after 45 days of exposure and in bone marrow and peripheral blood obtained after 13 weeks of exposure to urethane in drinking water. There appeared to be no significant difference in the magnitude of the response in the peripheral blood micronucleus test between mice administered urethane in drinking water and mice administered urethane in 5% ethanol. In summary, concentrations of 1,100 ppm urethane or greater in drinking water caused lymphoid and bone marrow cell depletion and hepatocellular lesions and increased the severity of nephropathy and cardiomyopathy in male and female rats. The lethal effects of 10,000 ppm urethane were slightly exacerbated by 5% ethanol in female rats. Urethane administered in drinking water induced lung inflammation, alveolar and bronchiolar hyperplasia, alveolar/bronchiolar adenomas, nephropathy, cardiomyopathy, lymphoid and bone marrow cell depletion, seminiferous tubule degeneration, and ovarian atrophy and follicular degeneration in mice. In female mice, 5% ethanol appeared to exacerbate ovarian atrophy. Mice administered urethane in 5% ethanol consumed less fluid, and therefore less urethane, than mice receiving urethane in drinking water. Coadministration of urethane and ethanol inhibited the clearance of urethane from plasma. (ABSTRACT TRUNCATED)

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WHY A TASK FORCE ON THE FAMILY? The practice of pediatrics is unique among medical specialties in many ways, among which is the nearly certain presence of a parent when health care services are provided for the patient. Regardless of whether parents or other family members are physically present, their influence is pervasive. Families are the most central and enduring influence in children's lives. Parents are also central in pediatric care. The health and well-being of children are inextricably linked to their parents' physical, emotional and social health, social circumstances, and child-rearing practices. The rising incidence of behavior problems among children attests to some families' inability to cope with the increasing stresses they are experiencing and their need for assistance. When a family's distress finds its voice in a child's symptoms, pediatricians are often parents' first source for help. There is enormous diversity among families-diversity in the composition of families, in their ethnic and racial heritage, in their religious and spiritual orientation, in how they communicate, in the time they spend together, in their commitment to individual family members, in their connections to their community, in their experiences, and in their ability to adapt to stress. Within families, individuals are different from one another as well. Pediatricians are especially sensitive to differences among children-in their temperaments and personalities, in their innate and learned abilities, and in how they view themselves and respond to the world around them. It is remarkable and a testament to the effort of parents and to the resilience of children that most families function well and most children succeed in life. Family life in the United States has been subjected to extensive scrutiny and frequent commentary, yet even when those activities have been informed by research, they tend to be influenced by personal experience within families and by individual and cultural beliefs about how society and family life ought to be. The process of formulating recommendations for pediatric practice, public policy, professional education, and research requires reaching consensus on some core values and principles about family life and family functioning as they affect children, knowing that some philosophic disagreements will remain unresolved. The growing multicultural character of the country will likely heighten awareness of our diversity. Many characteristics of families have changed during the past 3 to 5 decades. Families without children younger than 18 years have increased substantially, and they are now the majority. The average age at marriage has increased, and a greater proportion of births is occurring to women older than 30 years. Between 1970 and 2000, the proportion of children in 2-parent families decreased from 85% to 69%, and more than one quarter (26%) of all children live with a single parent, usually their mother. Most of this change reflects a dramatic increase in the rate of births to unmarried women that went from 5.3% in 1960 to 33.2% in 2000. Another factor in this change is a slowly decreasing but still high divorce rate that is roughly double what it was in the mid-1950s. Family income is strongly related to children's health, and the financial resources that families have available are closely tied to changes in family structure. Family income in real dollars has trended up for many decades, but the benefits have not been shared equally. For example, the median income of families with married parents has increased by 146% since 1970, but female-headed households have experienced a growth of 131%. More striking is that in 2000, the median income of female-headed households was only 47% of that of married-couple families and only 65% of that of families with 2 married parents in which the wife was not employed. Not surprising, the proportion of children who live in poverty is approximately 5 times greater for female-headed families than for married-couple families. The comped families than for married-couple families. The composition of children's families and the time parents have for their children affect child rearing. Consequent to the increase in female-headed households, rising economic and personal need, and increased opportunities for women, the proportion of mothers who are in the workforce has climbed steadily over the past several decades. Currently, approximately two thirds of all mothers with children younger than 18 years are employed. Most families with young children depend on child care, and most child care is not of good quality. Reliance on child care involves longer days for children and families, the stress imposed by schedules and created by transitions, exposure to infections, and considerable cost. An increasing number and proportion of parents are also devoting time previously available to their children to the care of their own parents. The so-called "sandwich generation" of parents is being pulled in multiple directions. The amount and use of family time also has changed with a lengthening workday, including the amount of commuting time necessary to travel between work and home, and with the intrusion of television and computers into family life. In public opinion polls, most parents report that they believe it is more difficult to be a parent now than it used to be; people seem to feel more isolated, social and media pressures on and enticements of their children seem greater, and the world seems to be a more dangerous place. Social and public policy has not kept up with these changes, leaving families stretched for time and stressed to cope and meet their responsibilities. What can and what should pediatrics do to help families raise healthy and well-adjusted children? How can individual pediatricians better support families? FAMILY PEDIATRICS: The American Academy of Pediatrics (AAP) Board of Directors appointed the Task Force on the Family to help guide the development of public policy and recommend how to assist pediatricians to promote well-functioning families (see Appendix). The magnitude of the assigned work required task force members to learn a great deal from research and researchers in the fields of social and behavioral sciences. A review of some critical literature was completed by a consultant to the task force and accompanies this report. That review identified a convergence of pediatrics and research on families by other disciplines. The task force found that a great deal is known about family functioning and family circumstances that affect children. With this knowledge, it is possible to provide pediatric care in a way that promotes successful families and good outcomes for children. The task force refers to that type of care as "family-oriented care" or "family pediatrics" and strongly endorses policies and practices that promote the adoption of this 2-generational approach as a hallmark of pediatrics. During the past decade, family advocates have successfully promoted family-centered care, "the philosophies, principles and practices that put the family at the heart or center of services; the family as the driving force." Most pediatricians report that they involve families in the decision making regarding the health care of their child and make an effort to understand the needs of the family as well as the child. Family pediatrics, like family-centered care, requires an active, productive partnership between the pediatrician and the family. But family pediatrics extends the responsibilities of the pediatrician to include screening, assessment, and referral of parents for physical, emotional, or social problems or health risk behaviors that can adversely affect the health and emotional or social well-being of their child. FAMILY CONTEXT OF CHILD HEALTH: The power and importance of families to children arises out of the extended duration for which children are dependent on adults to meet their basic needs. Children's needs for which only a family can provide include social support, socialization, and coping and life skills. Their self-esteem grows from being cared for, loved, and valued and feeling that they are part of a social unit that shares values, communicates openly, and provides companionship. Families transmit and interpret values to their children and often serve as children's connection to the larger world, especially during the early years of life. Although schools provide formal education, families teach children how to get along in the world. Often, efforts to discuss families and make recommendations regarding practice or policy stumble over disagreements about the definition of a family. The task force recognized the diversity of families and chose not to operate from the position of a fixed definition. Rather, the task force, which was to address pediatrics, decided to frame its deliberations and recommendations around the functions of families and how various aspects of the family context influence child rearing and child health. One model of family functioning that implicitly guided the task force is the family stress model (Fig 1). Stress of various sorts (eg, financial or health problems, lack of social support, unhappiness at work, unfortunate life events) can cause parents emotional distress and cause couples conflict and difficulty with their relationship. These responses to stress then disrupt parenting and the interactions between parent and child and can lead to short-term or lasting poor outcomes. The earlier these events transpire and the longer that the disruption lasts, the worse the outcomes for children. The task force favors efforts to encourage and support marriage yet recognizes that every family constellation can produce good outcomes for children and that none is certain to yield bad ones. (ABSTRACT TRUNCATED)

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Two strands of change are suggested by this review, one maturational, the other therapeutic or developmental (Hartmann and Kris, 1945). By "maturational" I mean to suggest energies that infuse the individual from earliest life in a manner that includes object relations, but for the healthy exercise of which object relations per se need not be of central and crucial importance. Within wide limits such energies may be delayed until growth conditions prevail without significant distortion of certain of the organism's ego functions. Therapeutic change is analogous to developmental change in that both involve the crucial presence of another to release energies. In therapeutic change these are energies that have been repressed beyond the reach of developmental dynamics. In everyday development crisis and synthesis alternate in conjunction with new and emerging objects to add to the psychological structures brought to the fore by maturation. In many instances, as we see with John, over time and in a less focussed manner, developmental changes can approximate therapeutic change and visa versa. Freud-Dann in their "experiment" pursued one line, in which the equipmental delay brought on by extremely adverse living circumstances was redressed by providing an interpersonally enriching, loving, developmentally facilitating milieu. The sketches of individual children and John's subsequent story provide a perspective into what becomes the stuff of growth and what remains the stuff of neurosis. The developmental reserves and ego resilience of these children were impressive but probably not extraordinary. Usual growth ensued as soon as they were provided with the rich soil of Bulldogs Bank instead of the desert sand of the Tereszin concentration camp. However, no one can escape such adverse circumstances without having taken in the stuff of neurosis. Affects and percepts that were not assimilatable or even available to consciousness at the time remain buried in the unconscious. Pain deprived of meaning is buried as neurosis. As we see in John's story, experience that cannot be integrated at the time is locked away from whatever developmental progression has occurred. Intolerable affects and ideas require particular circumstances of object relation and verbalization such as are found in the context of psychoanalysis and arrived at through psychoanalytic interpretation. Or, as in John's case, they may give way only slowly and irregularly over long stretches of time, when subjected to life experiences in the company of new object relations. Broadly stated, the Freud-Dann paper helps us to appreciate that there are several pathways of protection and growth in the ego that involve the discovery or construction of new objects. Family-romance fantasies are a common manifestation of new-object phenomena. Transitional object phenomena are also related. For some individuals at a particular time or over a span of time, providing the right circumstances for the resumption of maturational and developmental growth is all it takes to make them whole. Changes in the adaptive ego are sufficient to alleviate the conflicts stemming from the neurotic ego. For others, depending upon the degree of their neurotic impairment, or for the same individual under other circumstances, therapeutic change in the deepest sense demands the relatively unconditional presence of the interactive and interpreting other. Children of the storm who come in for shelter and warmth may thrive, but they also require a means of getting at the storm in their core that has been internalized as part of the ego's survival mechanism. What can be extracted from the poignant story of the Bulldogs Bank children about current child-analytic technique? The psychoanalytic piano now may be more formally conceptualized as having white as well as black keys. Most analyses, adult and child, have been conducted as though the "black keys"--pressure to mastery through repetition and its subsequent interpretation in relation to the transference--were the sole agents of therapeutic change. Reviewing maturation and development in relation to the resumption of psychological growth suggests that the provision of a beneficient environment, the "white keys," may lead to the resumption of maturational growth and change. The difference between the two modalities would be in the relative need for a significant other to bring about such change. Expanding on Hartmann and Kris, we can say that maturation requires a certain level of human stimulation and a supportive environment to unfold. At times in our work we encounter a psychoanalysis of and about maturation rather than primarily transference and interpretation. By and large the structure and functions of the ego that have been impeded in their exercise by traumatic circumstances in the environment are reactivated by a generalized holding environment rather than a relationship. In the practice of psychoanalysis this means that the child analyst may be more relaxed about the nonverbal play and relational aspects of the work; he need not fear that dynamics not captured in secondary process are lost to change. To the extent that the analysis provides an opportunity for maturational expression, growth will occur. When growth has been impeded by direct and significant interpersonal factors, the standard interpretative clarifications of defense, drive, and object relations in the context of removing the transference distortions regarding the analyst (and the world) are essential for recovery. Where the sequence of repetition through practice to mastery has become frozen by thwarting and stunting relationships, these potentially dead-end examples of neurotic object constancy must be played out on the "black keys." The amalgamation of the black of transference developments and the white of maturational emergence is paradigmatic for the discovery of new objects and new senses of self. In everyday life and analysis, maturation may lead to dramatic change that has hitherto been poorly identified and conceptualized. In child analysis, play is the medium for picking the lock of both arrested maturation and stultified development. Realizing that should permit the child analyst to engage more freely with the child in their own style of play without being overly concerned about the presence or absence of relational dynamic material. Non-dynamic play may not usually be defensive play, though it has often been misinterpreted as such. It may represent activity supporting renewed maturation--practice play in the service of memory, motility, or small or large motor function rather than in the service of the playful, repetitive externalization of threatening introjects. Dynamic play highlights the stagnant or emerging functions of the ego with regard to defense and affect management, which may then be interpreted using the play as key or using words as key to unlock the troubled relationship that is being dramatized. The analyst remains in a non-defensive stance, assigned by the analysand as audience or benign participant. Similarly, in adult analyses some individuals come pre-programmed not so much for interpretation as to discover the analyst as new object. They are in search of near psychobiological maturational closure on an object, already constituted in fantasy, that is respectful, attentive, objective, interested, and sometimes enlightening in their attempts at analytic understanding and developmental homeostasis. This phenomenon is akin to love at first sight, though without the flagrant libidinal romantic element. It occurs as the analytic narrative unfolds and the patient comes to a new sense of self, often around some developmental role or mix of roles, such as spouse, lover, mother, student, sibling, or worker. The point is that playing on the black and white keys of development and maturation leads to the appreciation of a psychoanalytic instrument that is at once more complex and yet easier to get music out of. And development continues from early objects to new objects. New and renewed understandings of analytic events necessarily guide the analyst in the timing of his traditional activities of attending, listening, talking, and relating. A contemporary surge of clinical understanding has led to a more active and informed relatedness on the part of the analyst that allows for a more compassionate approach to verbalization, whether with adults or children. We now know that not every word and every dynamic needs to be funneled through interpretation. The spontaneous powers for recovery that are stimulated by the analytic ground and the analytic process may come to be more accepted as a component of therapeutic gain. Appreciation of the balance of power between the verbal and nonverbal aspects of the analytic process in bringing about therapeutic change has increased. This has led to a greater parity of power and responsibility in the therapeutic alliance. The idea of a "tilted partnership" in which both members work for or against the powerful forces of the analytic process, or of a reciprocal relationship between analyst and analysand has become available to replace the former emphasis on the "tilted relationship." The analyst need no longer be so much in charge of the proceedings whether through deep interpretations of the unconscious or by obsessive attention to associational detail. The ongoing process of developing a body of theoretical and technical understanding that is both reliable and plastic demands an openness that at times flies in the face of the imperative needs of our patients and our profession for clinical confidence and certainty. The analytic clinician, part artist and part scientist, is forever struggling to balance the interminable task of culling new understanding from experience while imposing previously derived understandings that while sure are yet subject to changes stimulated by analytic experience. (ABSTRACT TRUNCATED)

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The article series provides a written and pictorial account of the Danish pharmaceutical industry's products from their introduction until about 1950. Part 8 deals with products from Lundbeck. Lundbeck which today is known as a considerable international pharmaceutical company could in 2015 celebrate its 100 years' jubilee. Among the early Danish medicinal companies H. Lundbeck &amp; Co. is in many ways an exception as the company was not originally established as a pharmaceutical company. Not until several years after the foundation the company began to import foreign ready-made medicinal products and later-on to manufacture these medicinal products in own factory and even later to do research and development of own innovative products. When Lundbeck was established in 1915 several Danish medicinal companies, not only the well-known such as Alfred Benzon and Løvens kemiske Fabrik (LEO Pharma), but also Skelskør Frugtplantage, Ferrin and Ferraton, had emerged due to the respective enterprising pharmacy owners who had expanded their traditional pharmacy business and even with commercial success. Other medicinal companies, such as C.R. Evers &amp; Co., Leerbeck &amp; Holms kemiske Fabriker, Chr. F. Petri, Erslevs kemiske Laboratorium, Edward Jacobsen, Th. Fallesen-Schmidt, and yet other companies which were named after the founder had all been established by pharmacists with the primary intention to manufacture and sell medicinal products. Also for the limited companies Medicinalco, Ferrosan, Pharmacia, and GEA the primary task was to manufacture and sell medicinal products, and also in these companies pharmacists were involved in the foundation. Not until 1924, fully 9 years after the foundation, Lundbeck started to be interested in medicinal products and initiated import and sale of foreign medicinal products manufactured by a.o. German and French companies which had not established their own sales companies in Denmark. Almost all contemporary Danish manufacturers of medicinal products could exclusively determine own proprietary names of the articles and could themselves make their own homogeneous and easily recognisable design, a.o. by frequent use of prefixes as Afa, Asa, Gea, Ido, Leo, and Meco which associated to for instance the company name. However, it goes without saying that Lundbeck had to market the articles in commission according to the different contracts with their partners. Consequently their range of products appeared heterogeneously. The international financial crisis and the consequent unemployment in the 1920s and 1930s had in Denmark a.o. resulted in national regulation in order to complicate import of ready-made goods and thus support the domestic manufacture of such articles. This was one of the reasons why Lundbeck decided to initiate its own manufacture of medicinal products in Denmark instead of continuing only with the import business which had been obstructed by the authorities. This article does not mention all Lundbeck's medicinal products which were marketed in Denmark until 1955 where a new Pharmacy Act came into force though undoubtedly a lot of interest can be written about all of them. The products mentioned in this article have been carefully selected, not only because they are representative for Lundbeck's development during the first decades, but also because the Danish Collection of the History of Pharmacy has acquired consumer packages of many of the articles. Several of these packages include patient information leaflets with an instruction for use and/or other information, and especially these leaflets represent a source material which has not previously been given much attention. It does not appear from the available source material whether these earliest medicinal products from Lundbeck were assembled in Danish packages on the production sites, or whether they were repacked in Copenhagen. It is not unlikely that the assembling originally was finalized abroad, and that instructions for the production of packaging material with Danish text were supplied by Lundbeck to the respective manufacturers. However, it is not unlikely either that the currency restrictions which were made after 1932 encouraged Lundbeck, where possible, first of all to import raw materials and bulk products and then manufacture the finished products in Valby. This was the case with Anusol, which Lundbeck certainly emphazised in the advertisement. It has to be pointed out that at that time there were no legal requirements regarding dating, neither of the user instructions nor of advertisements. Thus it is not due to mistakes or omissions made by Lundbeck that these materials are undated. The user instructions which Lundbeck had inserted in the packages were made and distributed at a time where no legal restrictions were in force neither regarding form nor content of such. The user instructions for products marketed after 1932 had probably been presented to the Pharmacopoeia Commission as this was statutory. It is, however, uncertain whether the Commission has dealt with the contents and the look of the user instructions. The most important task of the Commission was besides of the work with maintaining the Pharmacopoeia to look after the economic interests of the pharmacies so that only new drug substances could be marketed by the pharmaceutical industry, cf. below. In order to find out whether, and if so to which extent, the Pharmacopoeia Commission has been occupied in evaluating the informative and promoting printed matters of the industry, would require studies of the unprinted files of the Commission, and that is outside the scope of this article. At that time it was not against the law to inform in a user instruction that in case of a longer period of treatment, it would be more economical for the patient to buy a larger package. If you look at these patient information leaflets with today's eyes in the light of the present detailed, comprehensive and rigid regulations which the EU Commission has stated regarding patient information leaflets, you will find that Lundbeck's patient information leaflets were both simple and easy to read. On a free sample of Gelonida meant for the prescribing physician Lundbeck stated, besides of indication, dosage and warnings, also that the article was "Manufactured in Denmark". At that time it was not required to print information of production sites on packaging materials, however, it was not unusual to use this sales promoting claim in times of unemployment. In 1949 the original packaging material for Beatin was modified because certain text elements, the therapeutic indications were removed as it appeared that they since 1933 had violated the Pharmacy Act against advertisements for medicinal products aimed at the public. The packaging material for Beatin is a model example of the possibilities to combine practical information about the use of a medicinal product with sales claims in a reliable way. The above text modification and thus the legalisation of the packaging material took place upon request from the company as the violation of the advertising rules of the Pharmacy Act apparently had not resulted in any legal problems. Studies of unpublished files from the National Board of Health may possibly explain the background of this sequence of events, however, that is outside the scope of this article. The paragraph of the Pharmacy Act of 1932, stating that a medicinal product containing a common commodity as the active ingredient could not be marketed as a proprietary medicinal product, was meant to protect the pharmacies against the increasing competition from the industry. At first the paragraph did put a strain on the industry which from then on either had to manufacture own originator products or to copy other originator products without breaking patents. In the long run it has probably caused that not only Lundbeck, but also other Danish pharmaceutical companies became research-oriented and thus have been able to develop a relatively large number of originator products. In this context a product like Lucamid can hardly be regarded as an example of such a compulsory development of an originator product, an acetylsalicylic acid analogue. There were already such products on the market, but the wish to develop a better active ingredient has probably been bigger. From the three first editions of The Tariff of Medicines from 1935, 1937 and 1939 respectively it appears how Lundbeck's business within the area of medicines developed during the last half of the 1930s. In 1935 Lundbeck had placed 36 different medicinal products on the market, and all of them were in-licensing products. 4 years later, in 1939 Lundbeck had placed 40 different medicinal products on the market, and the number of in-licensing products had been reduced to 18 and 22 products were Lundbeck products. However, the increased focus on the development of own new medicinal products as Epicutan and Klianyl did not stop the in-licensing activities. Varex which Lundbeck brought on the market in 1942 came from a German pharmaceutical company with which Lundbeck had not previously collaborated. In Denmark Lundbeck had the intention to market 4 of Goedecke's 6 different medicinal products which all had Gelonida as part of the proprietary name. However, only one of these products got a longer life and with a simplified name, namely Gelonida. The fixed combination with three compounds of acetylsalicylic acid, phenacetin and codeine was without doubt effective, however, already at the end of the 1950s concern was raised about the safety of phenacetin. The Card Index of Medicines is a primary source of knowledge of how Lundbeck marketed the earliest medicinal products to the prescribing physicians. (ABSTRACT TRUNCATED)

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Methylene blue trihydrate has a variety of biomedical and biologically therapeutic applications. Methylene blue trihydrate was nominated by the National Cancer Institute (NCI) for carcinogenicity testing based on the numerous uses of this compound and the lack of long-term toxicity data, including epidemiological studies of methylene blue trihydrate, as well as the inadequate animal data on this compound. Male and female F344/N rats and B6C3F1 mice were administered methylene blue trihydrate in 0.5% aqueous methylcellulose by gavage for 1 month, 3 months, or 2 years. Genetic toxicology studies were conducted using Salmonella typhimurium, Escherichia coli, cultured Chinese hamster ovary cells, mouse bone marrow cells, and mouse peripheral blood erythrocytes. 1-MONTH STUDY IN RATS: Groups of 10 male and 10 female core study rats and groups of 10 male and 10 female clinical pathology study rats were administered methylene blue trihydrate in 0.5% aqueous methylcellulose solution by gavage at doses of 0, 125, 250, 500, 1,000, or 2,000 mg/kg, 5 days per week for 5 weeks. In the 500 mg/kg groups, one male died the first week of the study and one male and four females died the second week of the study. All rats in the 1,000 mg/kg group died by study day 10, and all rats in the 2,000 mg/kg group died by study day 6. Final mean body weights of male and female rats in the 250 and 500 mg/kg groups were significantly less than those of the vehicle controls. Dosed rats developed methemoglobinemia and a regenerative Heinz body anemia. Significant increases in spleen weights occurred in all surviving dosed groups. There were also significant decreases in the thymus weights of 250 and 500 mg/kg males and 125 and 250 mg/kg females. Spleen lesions associated with methylene blue trihydrate administration included hematopoietic cell proliferation, pigmentation, lymphoid depletion of the lymphoid follicles, and capsular fibrosis. Hyperplasia of the bone marrow occurred in all dosed groups of rats. Liver lesions associated with methylene blue exposure included centrilobular necrosis in rats dying early, hematopoietic cell proliferation, and Kupffer cell pigmentation with erythrophagocytosis. 1-MONTH STUDY IN MICE: Groups of 10 male and 10 female core study mice were administered methylene blue trihydrate in 0.5% aqueous methylcellulose solution by gavage at doses of 0, 125, 250, 500, 1,000, or 2,000 mg/kg, 5 days per week for 5 weeks. None of the mice in the 500, 1,000, and 2,000 mg/kg groups survived to the end of the study. In the 250 mg/kg groups, two females died on days 16 and 18 and two males died on days 6 and 13. Mean body weights of surviving dosed mice were similar to those of the vehicle controls. Thinness, abnormal respiration, hypothermia, lethargy, ataxia, and ruffled fur were observed in a few surviving animals in the 250 mg/kg groups. Hypothermia and abnormal posture were observed in mice in the 500, 1,000, and 2,000 mg/kg groups. Dosed mice developed methemoglobinemia and a regenerative Heinz body anemia. Significant increases in spleen weights occurred in all surviving dosed groups of mice compared to vehicle controls. Significant decreases occurred in the thymus weights of 250 mg/kg males and females. The heart weights of 125 and 250 mg/kg females were significantly increased. Lesions in the spleen associated with methylene blue trihydrate administration included hematopoietic cell proliferation, pigmentation, and congestion. Liver lesions associated with methylene blue trihydrate administration included periportal degeneration, hematopoietic cell proliferation, and Kupffer cell pigmentation with erythrophagocytosis. The incidences of bone marrow pigmentation were significantly increased in all dosed groups of mice. Forestomach lesions that were related to methylene blue trihydrate administration included focal ulcer, inflammation, and squamous hyperplasia. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female core study rats and groups of 20 male and 20 female clinical pathology study rats were administered methylene blue trihydrate in 0.5% aqueous methylcellulose solution by gavage at doses of 0, 25, 50, 100 or 200 mg/kg, 5 days per week for 14 weeks. Mean body weights of males in the 200 mg/kg group were significantly less than those of the vehicle controls. Dosed rats developed methemoglobinemia and a regenerative Heinz body anemia. Significant increases in spleen weights occurred in males and females administered 50 mg/kg or greater. Thymus and lung weights of 50, 100, and 200 mg/kg males (except relative lung weight at 100 mg/kg) were significantly less than those of the vehicle controls. Spleen lesions in dosed rats included hematopoietic cell proliferation, congestion, lymphoid depletion of the lymphoid follicles, and capsular fibrosis. The incidences of bone marrow hyperplasia were significantly increased in groups administered 50 mg/kg or greater. There were no consistent effects of methylene blue trihydrate administration on reproductive system measures in male or female rats. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female core study mice and groups of 20 male and 20 female clinical pathology study mice were administered methylene blue trihydrate in 0.5% aqueous methylcellulose solution by gavage at doses of 0, 25, 50, 100, or 200 mg/kg, 5 days per week for 14 weeks. Mean body weights of all dosed groups were similar to or only slightly less than those of the vehicle control groups. Dosed mice developed methemoglobinemia and a regenerative Heinz body anemia. Spleen weights of 100 and 200 mg/kg males and 50 mg/kg or greater females were significantly greater than those of the vehicle control groups. Heart weights were significantly increased in 200 mg/kg males. In females, there were significant decreases in thymus weights at 50 mg/kg or greater. Males had decreased sperm motility and increased epididymal sperm counts at 200 mg/kg. In all dosed groups, the incidences of hematopoietic cell proliferation and pigmentation in the spleen were significantly greater than those in the vehicle controls. In the liver, the incidences of hematopoietic cell proliferation were significantly increased in males and females in the 100 and 200 mg/kg groups, and the incidences of Kupffer cell pigmentation were significantly increased in groups administered 50 mg/kg or greater. The incidences of bone marrow pigmentation were significantly increased in all dosed groups of mice except 25 mg/kg females. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were administered methylene blue trihydrate in 0.5% aqueous methylcellulose solution by gavage at doses of 0, 5, 25, or 50 mg/kg, 5 days per week for 2 years. Additional groups of 10 male and 10 female rats were administered the same doses for up to 18 months and were evaluated at 2 weeks and 3, 12, and 18 months for hematology. Survival of all dosed groups of rats was similar to that of the vehicle controls. Mean body weights of 25 and 50 mg/kg male rats were less than those of the vehicle controls after weeks 29 and 21, respectively. In the 25 and 50 mg/kg females, mean body weights were less after weeks 73 and 53. Dosed male and female rats developed methemoglobinemia, and females developed a regenerative Heinz body anemia. The incidences of pancreatic islet cell adenoma and adenoma or carcinoma (combined) were increased in all dosed groups of males, were significantly increased in 25 mg/kg males, and exceeded the historical range in controls (all routes). The incidence of pancreatic islet cell hyperplasia was significantly increased in the 50 mg/kg males. In the spleen, the incidence of hematopoietic cell proliferation in 50 mg/kg males was significantly increased; the incidences of capsular fibrosis were significantly increased in all dosed groups of males and in 5 and 50 mg/kg females. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were administered methylene blue trihydrate in a 0.5% aqueous methylcellulose solution by gavage at doses of 0, 2.5, 12.5, or 25 mg/kg, 5 days per week for 2 years. Additional groups of 30 male and 30 female mice were administered the same doses for up to 18 months and were evaluated at 2 weeks and 3, 12, or 18 months for hematology. Survival of dosed male and female groups exceeded that of the vehicle controls in a generally dose-related manner. Mean body weights of dosed female mice began to increase after weeks 29, 61, and 85, reaching final values that were 113%, 111%, and 106% of vehicle controls for the 2.5, 12.5, and 25 mg/kg groups, respectively. Dosed mice developed methemoglobinemia and a regenerative Heinz body anemia. The incidences of carcinoma and of adenoma or carcinoma (combined) of the small intestine occurred with a positive trend in males. The incidences of malignant lymphoma occurred with a positive trend in females, and the incidence in 25 mg/kg males exceeded the historical control range. The incidences of hematopoietic cell proliferation of the spleen were significantly increased in 12.5 and 25 mg/kg males and in 25 mg/kg females. The incidences of inflammation of the nose were significantly increased in 12.5 and 25 mg/kg females. Methylene blue trihydrate was mutagenic in Salmonella typhimurium strains TA98 and TA100 with and without rat or hamster liver S9 activation enzymes; mutagenicity was also observed in Escherichia coli strain WP2 uvrA/pKM101 with and without rat liver S9. In cytogenetic tests with cultured Chinese hamster ovary cells, methylene blue trihydrate induced sister chromatid exchanges and chromosomal aberrations with and without S9. (ABSTRACT TRUNCATED).

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The Republic of Kazakhstan is situated in the northern hemisphere on the boundary of two continents--Europe and Asia--at a longitude of 45 degrees E--87 degrees E and a latitude of 40 degrees N--55 degrees N. The total area of the republic is 2,724,900 square kilometers. Kazakhstan shares a border with the Russian Federation to the north-west, north and east: the border between the two countries is almost 6500 km long. To the south, Kazakhstan shares a border with the Central Asian states of Turkmenistan (380 km), Uzbekistan (2300 km) and Kyrgystan (980 km). To the south-east, it shares a border with China (1460 km): to the west is the Caspian Sea (600 km). Thus, the total length of Kazakhstan's external borders is 12,000 km. Because of the geographical, natural and climatic features prevailing throughout most of the Republic, there is a potential danger that local transmission of malaria may begin again if the disease is imported from abroad. The areas most at risk are the Panfilov and Uigur raions of Almaty oblast, which share a border with malaria-endemic regions of China, and the Saryagash and Makhtaral' raions of South Kazakhstan oblast along the border with Uzbekistan. The Government of the Republic of Kazakhstan places particular emphasis on malaria prevention and control, taking into account the historical data about the prevalence of malaria from the late 1920s to the early 1940s, amounting to hundreds of thousands of cases every year. Government Decree No. 840 entitled "Urgent Measures to Protect the Population from Blood-Sucking Insects and Ticks Dangerous to Humans", which lays down measures for the control of malarial mosquitoes in the areas most susceptible to malaria resurgence, was adopted in 1996. The Ministry of Health of the Republic of Kazakhstan issued instructions in 1998 and 1999 which were designed to motivate all health facilities in the field of malaria prevention and control. At present, as part of the directives developed by the Republican Health Epidemiology Posts, work is being done on the planning of malaria control measures in Kazakhstan for the period 2001-2003. In 1994 a programme of epidemiological malaria surveillance was introduced, which has enabled us to improve our monitoring of the epidemiological situation of malaria. The number of cases of imported malaria has declined: in 1997, there were 102 cases, in 1998-87 and in 1999-52. There have been occasional local cases in some years, and in 1998 there were four local cases in the south and north-west of the country: two cases in Almaty oblast, one case in Zhambyl oblast and one in West Kazakhstan oblast (see Fig. 1). Most malaria infections are imported from Tajikistan and Azerbaijan, with occasional cases from Pakistan, India, Turkey and Afghanistan. Analysis of the occupational status of patients shows that around 45% are military personnel who have served on the Tajik-Afghan border. The others are refugees, merchants, unemployed people or students. The overall aetiological structure of malaria cases is dominated by P. vivax malaria. For example, in 1999, there were 48 cases of P. vivax malaria (90.5% of the total), one case of tropical malaria (1.9%), two cases of quartan malaria (3.8%) and two cases of P. vivax + P. malariae (3.8%). In order to prevent indigenous malaria occurring within the country, a system of malaria screening has been set up; screening is carried out every year on groups who have visited neighbouring or more distant malaria-endemic countries and for patients with a persistent fever who are suspected of suffering from malaria. The area of water throughout the country within communities or within a 3-5 km radius of them which is susceptible to colonization by the Anopheles mosquito amounts to over 5000 hectares, according to the certification system in force. In addition, approximately 70,000 hectares in three oblasts used for rice cultivation also provide a habitat for Anopheles. The main malaria vector, An. messeae, is found throughout the country: in a few areas An. hyrcanus and An. claviger are found and, in the south, An. pulcherrimus. Data from recent years show the presence of An. superpictus, An. plumbeus and An. algeriensis. In 1999, from data collected during systematic observations of the phenology and seasonal variations in the number of Anopheles at 114 observation posts, the average seasonal numerical indicators for the mosquito imago reached a maximum of between 21 and 46.5 adult mosquitoes per cattle shed, up to 2.7-3.3 adult mosquitoes per residential building and 30-67.3 larvae per square metre of surface water. According to the results of large scale trapping programmes (486 communities were screened in 1999), the maximum value of the numerical indicator was 16.8-74.1 adult mosquitoes per cattle shed and 4.1-3.8 adult mosquitoes per residential building. In 1999, compared with 1998, the number of malarial mosquitoes detected throughout the country declined encouragingly, or stayed at the same level, which is one of the factors responsible for the country's favourable epidemiological situation with regard to malaria. According to data going back many years, there has been a significant increase in the number of mosquitoes at some observation posts in Almaty, East Kazakhstan and Kyzlorda oblasts. There is a tendency everywhere for the numbers of imagos detected in residential buildings to increase, which presents a definite epidemiological risk that indigenous malaria will re-emerge if the disease is imported into Kazakhstan from countries which suffer from it. If we consider the species of mosquito present in the country and the temperature factor (the number of days in the year when the average daily temperature is over 16 degrees C), the country can be divided, on the basis of incomplete 1999 data, into zones at very high risk of re-emergence of malaria (Almaty, Zhambyl and South Kazakhstan oblasts), high risk (Karaganda oblasts and Almaty city), medium risk (Aktyubinsk and Akmolinsk oblasts), and low risk (Kostanay oblast). The malaria risk of the other oblasts has been calculated using data from earlier years (map attached) [Translator's Note: map missing]. Preventive malaria control measures in Kazakhstan are divided into three categories to suit three different groups of communities. One hundred and seventy-nine communities have been allocated to the first group, at high risk of malaria resurgence; 1377 communities to the second group, at medium risk; and the remainder to the third group, at little or no risk of malaria resurgence. The following factors were used to categorize communities according to the risk that malaria might become reestablished if the disease should be imported from elsewhere: species of malarial mosquito present; changes in mosquito numbers and in the area of water susceptible to population by Anopheles; temperature conditions and, consequently, the length of the malaria transmission season and the season of effective susceptibility of the mosquito to infection; population migration; quality of laboratory testing for the diagnosis of malaria. Measures aimed at the destruction of mosquitoes are intended to reduce the numbers of Anopheles in the communities most at risk of malaria resurgence, i.e. those in group 1 above and the actual foci of malaria infection. Because of the economic crisis and financial difficulties, fewer areas have been treated in recent years. In 1999, 1387 hectares of water and 450,000 square metres of buildings were treated (see Fig. 2). Measures to control biting flies in health establishments, recreation areas, etc. Certainly also help to protect people from malarial mosquitoes. In 1999, 12,501 hectares of water and land were treated from the ground or the air (see Fig. 3). In the present situation, the main reasons for the difficulties affecting the malaria control and prevention campaign are as follows. Staff numbers in the Republic's parasitology service have been unjustifiably reduced. For example, the number of entomologists and entomology assistants employed is 58% and 48%, respectively, of the number laid down in Ministry of Health directives. At the health epidemiology posts, the number of disinfectors has been reduced to a minimum, and practically all engineer/water engineer posts have been abolished. The country does not possess the necessary education base for initial training or continuing education of staff for the parasitology service. The lack of basic scientific information about the problems of malaria control and prevention and parasitology in general. There is no research to test or introduce the most effective, safe and low-cost malaria control products and insecticides. The methodological literature required to use certain modern insecticides is not available. Entomologists are not provided with specialist insect control equipment. Entomological surveys are left incomplete because of shortages of transport and fuel at the health epidemiology posts. Because of the economic crisis and the high cost of the radical water engineering measures necessary to combat malaria, these measures cannot be implemented on the scale required. The equipment and materials stocks of the parasitology laboratories are highly inadequate: there is a lack of modern laboratory equipment, as well as a lack of opportunities for high-level professional training for staff. The exchange of information between the CIS countries is unsatisfactory, and there is no common information space: nor is there any systematic data available from other foreign countries. In the period 2000-2003, Kazakhstan plans to carry out malaria control activities (mosquito destruction) over an area of 2000 hectares of water and 1.5 million square metres of buildings.

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This report from the Medical Advisory Secretariat (MAS) was intended to evaluate the clinical utility of vitamin D testing in average risk Canadians and in those with kidney disease. As a separate analysis, this report also includes a systematic literature review of the prevalence of vitamin D deficiency in these two subgroups.This evaluation did not set out to determine the serum vitamin D thresholds that might apply to non-bone health outcomes. For bone health outcomes, no high or moderate quality evidence could be found to support a target serum level above 50 nmol/L. Similarly, no high or moderate quality evidence could be found to support vitamin D's effects in non-bone health outcomes, other than falls. VITAMIN D: Vitamin D is a lipid soluble vitamin that acts as a hormone. It stimulates intestinal calcium absorption and is important in maintaining adequate phosphate levels for bone mineralization, bone growth, and remodelling. It's also believed to be involved in the regulation of cell growth proliferation and apoptosis (programmed cell death), as well as modulation of the immune system and other functions. Alone or in combination with calcium, Vitamin D has also been shown to reduce the risk of fractures in elderly men (≥ 65 years), postmenopausal women, and the risk of falls in community-dwelling seniors. However, in a comprehensive systematic review, inconsistent results were found concerning the effects of vitamin D in conditions such as cancer, all-cause mortality, and cardiovascular disease. In fact, no high or moderate quality evidence could be found concerning the effects of vitamin D in such non-bone health outcomes. Given the uncertainties surrounding the effects of vitamin D in non-bone health related outcomes, it was decided that this evaluation should focus on falls and the effects of vitamin D in bone health and exclusively within average-risk individuals and patients with kidney disease. Synthesis of vitamin D occurs naturally in the skin through exposure to ultraviolet B (UVB) radiation from sunlight, but it can also be obtained from dietary sources including fortified foods, and supplements. Foods rich in vitamin D include fatty fish, egg yolks, fish liver oil, and some types of mushrooms. Since it is usually difficult to obtain sufficient vitamin D from non-fortified foods, either due to low content or infrequent use, most vitamin D is obtained from fortified foods, exposure to sunlight, and supplements. CONDITION AND TARGET POPULATION Vitamin D deficiency may lead to rickets in infants and osteomalacia in adults. Factors believed to be associated with vitamin D deficiency include: darker skin pigmentation,winter season,living at higher latitudes,skin coverage,kidney disease,malabsorption syndromes such as Crohn's disease, cystic fibrosis, andgenetic factors.Patients with chronic kidney disease (CKD) are at a higher risk of vitamin D deficiency due to either renal losses or decreased synthesis of 1,25-dihydroxyvitamin D. Health Canada currently recommends that, until the daily recommended intakes (DRI) for vitamin D are updated, Canada's Food Guide (Eating Well with Canada's Food Guide) should be followed with respect to vitamin D intake. Issued in 2007, the Guide recommends that Canadians consume two cups (500 ml) of fortified milk or fortified soy beverages daily in order to obtain a daily intake of 200 IU. In addition, men and women over the age of 50 should take 400 IU of vitamin D supplements daily. Additional recommendations were made for breastfed infants. A Canadian survey evaluated the median vitamin D intake derived from diet alone (excluding supplements) among 35,000 Canadians, 10,900 of which were from Ontario. Among Ontarian males ages 9 and up, the median daily dietary vitamin D intake ranged between 196 IU and 272 IU per day. Among females, it varied from 152 IU to 196 IU per day. In boys and girls ages 1 to 3, the median daily dietary vitamin D intake was 248 IU, while among those 4 to 8 years it was 224 IU. VITAMIN D TESTING: Two laboratory tests for vitamin D are available, 25-hydroxy vitamin D, referred to as 25(OH)D, and 1,25-dihydroxyvitamin D. Vitamin D status is assessed by measuring the serum 25(OH)D levels, which can be assayed using radioimmunoassays, competitive protein-binding assays (CPBA), high pressure liquid chromatography (HPLC), and liquid chromatography-tandem mass spectrometry (LC-MS/MS). These may yield different results with inter-assay variation reaching up to 25% (at lower serum levels) and intra-assay variation reaching 10%. The optimal serum concentration of vitamin D has not been established and it may change across different stages of life. Similarly, there is currently no consensus on target serum vitamin D levels. There does, however, appear to be a consensus on the definition of vitamin D deficiency at 25(OH)D &lt; 25 nmol/l, which is based on the risk of diseases such as rickets and osteomalacia. Higher target serum levels have also been proposed based on subclinical endpoints such as parathyroid hormone (PTH). Therefore, in this report, two conservative target serum levels have been adopted, 25 nmol/L (based on the risk of rickets and osteomalacia), and 40 to 50 nmol/L (based on vitamin D's interaction with PTH). ONTARIO CONTEXT: VOLUME #ENTITYSTARTX00026; COST: The volume of vitamin D tests done in Ontario has been increasing over the past 5 years with a steep increase of 169,000 tests in 2007 to more than 393,400 tests in 2008. The number of tests continues to rise with the projected number of tests for 2009 exceeding 731,000. According to the Ontario Schedule of Benefits, the billing cost of each test is $51.7 for 25(OH)D (L606, 100 LMS units, $0.517/unit) and $77.6 for 1,25-dihydroxyvitamin D (L605, 150 LMS units, $0.517/unit). Province wide, the total annual cost of vitamin D testing has increased from approximately $1.7M in 2004 to over $21.0M in 2008. The projected annual cost for 2009 is approximately $38.8M. EVIDENCE-BASED ANALYSIS: The objective of this report is to evaluate the clinical utility of vitamin D testing in the average risk population and in those with kidney disease. As a separate analysis, the report also sought to evaluate the prevalence of vitamin D deficiency in Canada. The specific research questions addressed were thus: What is the clinical utility of vitamin D testing in the average risk population and in subjects with kidney disease?What is the prevalence of vitamin D deficiency in the average risk population in Canada?What is the prevalence of vitamin D deficiency in patients with kidney disease in Canada?Clinical utility was defined as the ability to improve bone health outcomes with the focus on the average risk population (excluding those with osteoporosis) and patients with kidney disease. A literature search was performed on July 17th, 2009 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing &amp; Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 1998 until July 17th, 2009. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search. Articles with unknown eligibility were reviewed with a second clinical epidemiologist, then a group of epidemiologists until consensus was established. The quality of evidence was assessed as high, moderate, low or very low according to GRADE methodology. Observational studies that evaluated the prevalence of vitamin D deficiency in Canada in the population of interest were included based on the inclusion and exclusion criteria listed below. The baseline values were used in this report in the case of interventional studies that evaluated the effect of vitamin D intake on serum levels. Studies published in grey literature were included if no studies published in the peer-reviewed literature were identified for specific outcomes or subgroups. Considering that vitamin D status may be affected by factors such as latitude, sun exposure, food fortification, among others, the search focused on prevalence studies published in Canada. In cases where no Canadian prevalence studies were identified, the decision was made to include studies from the United States, given the similar policies in vitamin D food fortification and recommended daily intake. Studies published in EnglishPublications that reported the prevalence of vitamin D deficiency in CanadaStudies that included subjects from the general population or with kidney diseaseStudies in children or adultsStudies published between January 1998 and July 17(th) 2009 EXCLUSION CRITERIA: Studies that included subjects defined according to a specific disease other than kidney diseaseLetters, comments, and editorialsStudies that measured the serum vitamin D levels but did not report the percentage of subjects with serum levels below a given threshold Prevalence of serum vitamin D less than 25 nmol/LPrevalence of serum vitamin D less than 40 to 50 nmol/LSerum 25-hydroxyvitamin D was the metabolite used to assess vitamin D status. Results from adult and children studies were reported separately. Subgroup analyses according to factors that affect serum vitamin D levels (e.g., seasonal effects, skin pigmentation, and vitamin D intake) were reported if enough information was provided in the studies The quality of the prevalence studies was based on the method of subject recruitment and sampling, possibility of selection bias, and generalizability to the source population. The overall quality of the trials was examined according to the GRADE Working Group criteria. (ABSTRACT TRUNCATED)

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These documents have been archived because they contain outdated information. They should not be consulted for clinical use, but for historical research only. Please visit the journal website for the most recent guidelines. The Use of Magnetic Resonance Imaging in the Obstetric Patient [J Obstet Gynaecol Can 36 (2014) 349-355] AUTHORS Yves Patenaude, MD, Sherbrooke, QC Denise Pugash, MD, Vancouver, BC Kenneth Lim, MD, Vancouver, BC Lucie Morin, MD, Montreal, QC The Role of Surgery in Endometrial Cancer [J Obstet Gynaecol Can 35 (2013) 370-371] AUTHORS Christopher Giede, MD, Saskatoon, SK Tien Le, MD, Ottawa, ON Patti Power, MD, St John's, NL Female Genital Cutting [J Obstet Gynaecol Can 35 (2013) 1028-1045] AUTHORS Liette Perron, MSW, Ottawa, ON Vyta Senikas, MD, Ottawa, ON Margaret Burnett, MD, Winnipeg, ON Victoria Davis, MD, Scarborough, ON Technical Update on Pessary Use [J Obstet Gynaecol Can 35 (2013) 664-674] AUTHORS Magali Robert, MD, Calgary, AB Jane A. Schulz, MD, Edmonton, AB Marie-Andrée Harvey, MD, Kingston, ON Cancer Chemotherapy and Pregnancy [J Obstet Gynaecol Can 35 (2013) 263-278] AUTHORS Gideon Koren, MD, Toronto, ON Nathalie Carey, BSc, Toronto, ON Robert Gagnon, MD, Montréal, QC Cynthia Maxwell, MD, Toronto, ON Irena Nulman, MD, Toronto, ON Vyta Senikas, MD, Ottawa, ON Current Status in Non-Invasive Prenatal Detection of Down Syndrome, Trisomy 18, and Trisomy 13 Using Cell-Free DNA in Maternal Plasma [J Obstet Gynaecol Can 35 (2013) 177-181] AUTHORS Sylvie Langlois, MD, Vancouver, BC Jo-Ann Brock, MD, Halifax, NS Mifepristone [J Obstet Gynaecol Can 25 (2003) 235] The Presence of a Third Party During Breast and Pelvic Examinations [J Obstet Gynaecol Can 25 (2003) 237] Midwifery [J Obstet Gynaecol Can 25 (2003) 239] Emergency Contraception [J Obstet Gynaecol Can 25 (2003) 673-678] Tension-Free Vaginal Tape (TVT) Procedure [J Obstet Gynaecol Can 25 (2003) 692-694] Uterine Fibroid Embolization (UFE) [J Obstet Gynaecol Can 26 (2004) 899-911] AUTHORS Guylaine G. Lefebvre, MD, Toronto, ON George Vilos, MD, Toronto, ON Murray Asch, MD, Oshawa, ON The Prevention of Early-Onset Neonatal Group B Streptococcal Disease [J Obstet Gynaecol Can 26 (2004) 826-832] AUTHORS Deborah M. Money, MD, FRCSC, Vancouver, BC Simon Dobson, MD, FRCPC, Vancouver, BC Cell-Free Fetal DNA in the Maternal Circulation and its Future Uses in Obstetrics [J Obstet Gynaecol Can 27 (2005) 54-57] AUTHOR R. Douglas Wilson, MD, Philadelphia, PA Cystic Fibrosis Carrier Testing in Pregnancy in Canada [J Obstet Gynaecol Can 24 (2002) 644-647] Amniocentesis and Women with Hepatitis B, Hepatitis C, or Human Immunodeficiency Virus [J Obstet Gynaecol Can 25 (2003) 145-148] Fetal Health Surveillance in Labour [J Obstet Gynaecol Can 24 (2002) 250-262] Management of the Third Stage of Labour to Prevent Postpartum Hemorrhage [J Obstet Gynaecol Can 25 (2003) 952-953] Cervical Cancer Prevention in Low-Resource Settings [J Obstet Gynaecol Can 26 (2004) 205-206] Hirsutism: Evaluation and Treatment [J Obstet Gynaecol Can 24 (2002) 62-67] Breast Cancer, Pregnancy, and Breastfeeding [J Obstet Gynaecol Can 24 (2002) 164-171] Parvovirus B19 Infection in Pregnancy [J Obstet Gynaecol Can 24 (2002) 727-734] Diversity [J Obstet Gynaecol Can 25 (2003) 1042] Conflict of Interest [J Obstet Gynaecol Can 25 (2003) 1044] Canadian Contraception Consensus [J Obstet Gynaecol Can 26 (2004) 347-387] School-Based and School-Linked Sexual Health Education and Promotion in Canada [J Obstet Gynaecol Can 26 (2004) 596-600] Gestational Trophoblastic Disease [J Obstet Gynaecol Can 24 (2002) 434-439] FIGO Professional and Ethical Responsibilities Concerning Sexual and Reproductive Rights [J Obstet Gynaecol Can 26 (2004) 1097-1099] FIGO / ICM Global Initiative to Prevent Post-Partum Hemorrhage [J Obstet Gynaecol Can 26 (2004) 1102] Intimate Partner Violence Consensus Statement [J Obstet Gynaecol Can 27 (2005) 365-388] The Management of Nausea and Vomiting of Pregnancy [J Obstet Gynaecol Can 24 (2002) 817-823] Canadian Contraception Consensus [J Obstet Gynaecol Can 26 (2004) 143-156] Present Role of Stem Cells for Fetal Genetic Therapy [J Obstet Gynaecol Can 27 (2005) 1038-1042] Amended Canadian Guideline for Prenatal Diagnosis (2005) Change to 2005-Techniques for Prenatal Diagnosis [J Obstet Gynaecol Can 27 (2005) 1048-1054] Umbilical Cord Blood Banking: Implications for Perinatal Care Providers [J Obstet Gynaecol Can 27 (2005) 263-274] Breast Cancer and Abortion [J Obstet Gynaecol Can 27 (2005) 491] AUTHOR Robert H. Lea, MD, Halifax, NS Postural Health in Women: The Role of Physiotherapy [J Obstet Gynaecol Can 27 (2005) 493-500] AUTHORS S.J. Britnell, BScPT, Vancouver, BC J.V. Cole, BScPT, Vancouver, BC L. Isherwood, BScPT, Vancouver, BC M.M. Sran, PT, BScPT, Vancouver, BC N. Britnell, BScPT, Vancouver, BC S. Burgi, BScPT, Vancouver, BC G. Candido, BScPT, Vancouver, BC L. Watson, BScPT, Vancouver, BC The Management of Uterine Leiomyomas [J Obstet Gynaecol Can 25 (2003) 396-405] Guidelines for Vaginal Birth after Previous Caesarean Birth [J Obstet Gynaecol Can 26 (2004) 660-670] Fetal Health Surveillance in Labour [J Obstet Gynaecol Can 24 (2002) 342-348] Number of Births to Maintain Competence [J Obstet Gynaecol Can 24 (2002) 359] Sexual Abuse by Physicians [J Obstet Gynaecol Can 25 (2003) 862] The Use of First Trimester Ultrasound [J Obstet Gynaecol Can 25 (2003) 864-869] Use of Hormonal Replacement Therapy After Treatment of Breast Cancer [J Obstet Gynaecol Can 26 (2004) 49-54] Obstetric Ultrasound Biological Effects and Safety [J Obstet Gynaecol Can 27 (2005) 572-575] Fetal Soft Markers in Obstetric Ultrasound [J Obstet Gynaecol Can 27 (2005) 592-612] Maternal Transport Policy [J Obstet Gynaecol Can 27 (2005) 956-959] Choice of Surgery for Stress Incontinence [J Obstet Gynaecol Can 27 (2005) 964-971] The Use of Fetal Doppler in Obstetrics [J Obstet Gynaecol Can 25 (2003) 601-607] Screening for Gestational Diabetes Mellitus [J Obstet Gynaecol Can 24 (2002) 894-903] Hormone Replacement Therapy and Cardiovascular Disease [J Obstet Gynaecol Can 24 (2002) 577-579] Providing Opinion for Medico-Legal Cases [J Obstet Gynaecol Can 24 (2002) 590-592] Antenatal Corticosteroid Therapy for Fetal Maturation [J Obstet Gynaecol Can 25 (2003) 45-48] Mastalgia [J Obstet Gynaecol Can 28 (2006) 49-57] AUTHORS Vera Rosolowich, RN, SCM, IBCLC, Winnipeg, MB Elizabeth Saettler, MD, Winnipeg, MB Beth Szuck, BA, HEc, CACE, RD, Winnipeg, MB Pregnancy Outcomes After Assisted Reproductive Technology [J Obstet Gynaecol Can 28 (2006) 220-233] AUTHORS Victoria M. Allen, MD, MSc, Halifax, NS R. Douglas Wilson, MD, MSc, Philadelphia, PA Canadian Contraception Consensus-Update on Depot Medroxyprogesterone Acetate (DMPA) [J Obstet Gynaecol Can 28 (2006) 305-308] AUTHOR Amanda Black, MD, Ottawa, ON Guidelines for Training Requirements in Colposcopy and its Related Treatment Modalities [J Obstet Gynaecol Can 28 (2006) 314-316] AUTHOR Susan M. McFaul, MD, Ottawa, ON Pelvic Examinations by Medical Trainees [J Obstet Gynaecol Can 28 (2006) 320-321] AUTHORS Kimberly E. Liu, MD, Edmonton, AB Deborah Robertson, MD, Montréal, QC Glenn Posner, MDCM, Ottawa, ON Sukhbir S. Singh, MD, London, ON Lawrence Oppenheimer, MD, Ottawa, ON Stillbirth and Bereavement: Guidelines for Stillbirth Investigation [J Obstet Gynaecol Can 28 (2006) 540-545] AUTHOR Line Leduc, MD, Montréal, QC Progesterone-Only and Non-Hormonal Contraception in the Breast Cancer Survivor: Joint Review and Committee Opinion of the Society of Obstetricians and Gynaecologists of Canada and the Society of Gynecologic Oncologists of Canada [J Obstet Gynaecol Can 28 (2006) 616-626] AUTHORS Jenna McNaught, MD, Winnipeg, MB Robert L. Reid, MD, Kingston, ON Breast Self-Examination [J Obstet Gynaecol Can 28 (2006) 728-730] AUTHOR Vera Rosolowich, RN, SCM, IBCLC, Winnipeg, MB The Physician Expert in Legal Proceedings [J Obstet Gynaecol Can 28 (2006) 913-915] AUTHORS Titus Owolabi, MD, Toronto, ON George Vilos, MD, Toronto, ON Induced Abortion Guidelines [J Obstet Gynaecol Can 28 (2006) 1014-1027] AUTHOR Victoria Jane Davis, MD Health Professionals Working With First Nations, Inuit, and Métis Consensus Guideline [J Obstet Gynaecol Can 35 (2013) S1-S4] AUTHORS Don Wilson, MD, FRCSC (Co-chair), Hellisuk Nation, Comox, BC Sandra de la Ronde, MD, FRCSC (Co-chair), Ottawa, ON Simon Brascoupé, Kitigan Zibi Anishinabeg, Ottawa, ON Alisha Nicole Apale, MSc, Ottawa, ON Lucy Barney, RN, MSN, Lillooet Nation, Vancouver, BC Bing Guthrie, MD, FRCSC, Yellowknife, NT Elizabeth Harrold, RN, Vancouver, BC Ojistoh Horn, MD, CCFP, Mohawk, Kahnawake, QC Robin Johnson, MD, FRCSC, Esdilagh, First Nation, Williams Lake, BC Darrien Rattray, MD, Tahltan, Halifax, NS Nicole Robinson, MA, Ottawa, ON Introduction [J Obstet Gynaecol Can 35 (2013) S5-S6] Chapter 1 Definitions [J Obstet Gynaecol Can 35 (2013) S7-S8] Chapter 2 Demographics [J Obstet Gynaecol Can 35 (2013) S9-S12] Chapter 3 Social Determinants of Health Among First Nations, Inuit, and Métis [J Obstet Gynaecol Can 35 (2013) S13-S23] Chapter 4 Health Systems, Policies, and Services for First Nations, Inuit, and Métis [J Obstet Gynaecol Can 35 (2013) S24-S27] Chapter 5 First Nations, Inuit, and Métis Women's Sexual and Reproductive Health [J Obstet Gynaecol Can 35 (2013) S28-S32] Chapter 6 First Nations, Inuit, and Métis Maternal Health [J Obstet Gynaecol Can 35 (2013) S33-S36] Chapter 7 Mature Women's Health [J Obstet Gynaecol Can 35 (2013) S37] Chapter 8 Changing Outcomes Through Culturally Competent Care [J Obstet Gynaecol Can 35 (2013) S38-S41] Chapter 9 Conclusion [J Obstet Gynaecol Can 35 (2013) S42-S43] Chapter 10 Case Studies [J Obstet Gynaecol Can 35 (2013) S44-S47] Appendix 1. Apology for the Forced Relocation of Inukjuak and Pond Inlet Families [J Obstet Gynaecol Can 35 (2013) S48] Appendix 2. Apology for the Residential School System [J Obstet Gynaecol Can 35 (2013) S49] Appendix 3. Avoiding Re-Traumatization of Sexual Abuse/Assault Victims During the Birthing Process [J Obstet Gynaecol Can 35 (2013) S50].

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The work reported in the preceding sections justifies, we think, a number of definite conclusions. In addition to this, some of the experiments indicate a line of thought which may lead to considerable alteration in our conceptions, both of phenomena of bacterial hypersensitiveness and of infection. 1. In guinea pigs two fundamentally different types of intradermal reactions may be observed. One of these is the immediate, transitory reaction which develops in animals sensitized against proteins (horse serum, etc.) and may be regarded as one of the manifestations of general protein hypersensitiveness, or anaphylaxis; the other is the tuberculin type of skin reaction which develops more slowly, leads to a more profound injury of the tissues and is independent of anaphylaxis as ordinarily conceived. 2. The tuberculin type of hypersensitiveness (as well as probably the typhoidin, mallein, abortin reactions, etc.) does not develop at all in guinea pigs sensitized with proteins, like horse serum, etc. While this form of hypersensitiveness may eventually be induced with materials not bacterial in origin, it has been observed up to date only as a reaction of bacterial infection. 3. Methods of treatment with protein material from bacterial cultures which sensitize guinea pigs to anaphylactic reactions with the bacterial extracts, do not sensitize them to the tuberculin type of reaction. Such sensitization is easily accomplished only by infecting the animals with living organisms. No reliable method of sensitizing guinea pigs to such reactions with dead bacterial material has as yet been worked out, though a few hopeful experiments have been obtained with massive injections of large amounts of the acid-precipitable substances (nucleoproteins?) from bacterial extracts. 4. In animals made hypersensitive to the tuberculin type of reaction by infection with living bacteria, the reaction may be elicited by intradermal injections of bacterial extracts from which all coagulable proteins, nucleoproteins, and Bence-Jones proteins have been removed, as well as this can be done by boiling with acid, etc. This proteose residue alone suffices to elicit such reactions. The exact chemical nature of the so called proteose residue must be further studied and analyzed when we have had opportunity to produce bacterial extracts in large quantity. These points seem incontrovertible on the basis of our own experiments, as well as those of other workers. There thus seem to develop two definite forms of hypersensitiveness in guinea pigs infected with bacteria, typical anaphylaxis in which the protein material of the bacterial cells is concerned, which develops late and which can be induced by repeated injections of dead bacterial material, and a hypersensitiveness to non-protein constituents which differs from the former, both in the laws that govern sensitization and in the manifestations which follow injections into the sensitized animals. While there is virtual agreement among immunologists concerning the essential mechanism of protein anaphylaxis, its dependence upon an antigen-antibody reaction, and the dominating rôle played by the sessile antibodies, the mechanism of hypersensitiveness to tuberculin and similar bacterial substances is still a problem of much uncertainty. The most striking difference between the two phenomena lies, as we have seen, in the criteria of sensitization, in that hypersensitiveness to the tuberculin type of reaction can hardly ever be induced by any of the ordinary methods of preparation with the constituents of dead bacteria, but develops promptly (7 to 10 days) in the course of actual infection with living organisms. The considerable specificity of such reactions forces the conclusion that the sensitizing substance must, in some way, be derived from the infecting microorganisms. The idea that the failure of sensitization with dead culture materials is perhaps due to the elaboration in the body of infected animals of bacterial products not represented in extracts of test-tube cultures is rendered unlikely by the fact that in the tuberculin-sensitive, infected animals, we can produce the reactions by the application of such dead extracts. It is neither logical nor in keeping with biological experience to assume that one substance will sensitize to reaction with another. This mistake was made early in the study of anaphylaxis in another connection and caused considerable delay of progress. Krause has shown that tuberculin sensitiveness may be blunted in infected animals by massive, but sublethal injections of tuberculin, and we have obtained some indications of the same thing. Moreover, others as well as ourselves have seen tuberculin reactivity decline in guinea pigs and in man in the stages of very severe infection. These facts would eliminate any assumption of mere cumulative injury as explaining this type of reaction, and stamp it as a mechanism at least analogous to ordinary anaphylaxis. The only remaining possibility to explain the difference between infected animals and those treated with dead bacterial constituents would be to assume that the difference must lie in the manner in which the sensitizing substance is administered to the animals, and that sensitization with the proteose residue materials depends upon criteria of sensitization differing in regard to the time and quantity factors from those governing protein sensitization. If one considers the relatively simpler chemical structure and perhaps physically greater diffusibility of the materials concerned in this reaction, one might readily expect such differences in the methods needed for sensitization. In keeping with such a line of reasoning our experiments have shown that the tuberculin active materials are constantly and rapidly being diffused out into the culture fluid from growing organisms, in quantities greater than can be extracted from similar amounts of the dead bacteria. It seems reasonable to assume from this that the same thing may happen in the animal body harboring a growing focus. And it would seem quite likely that the association of the tuberculin type of reaction with actual infection may depend upon the fact that sensitization to these non-protein substances depends upon a constant steady absorption of large amounts of the material. Moreover, the only hopeful experiments on the artificial production of tuberculin sensitiveness in guinea pigs obtained by us were those in which massive doses of the nucleoprotein material injected into guinea pigs gave rise to a moderate skin sensitiveness. Does the so called proteose residue form antibodies, and, if so, are substances analogous to antibodies involved in the tuberculin type of hypersensitiveness? The failure to transfer passively this form of hypersensitiveness to normal animals with the blood and tissues of tuberculin-sensitive ones would suggest that no antibodies are involved. But this is not conclusive on the basis of available experimental facts. We are inclined to believe that antibodies of a sort are involved, for the following reasons: (a) In our experiments with the uteri of highly sensitive extract-treated guinea pigs and of tuberculous guinea pigs, we have occasionally had positive reactions when the proteose residue alone was used. (b) We believe that these proteose substances are entirely analogous to the substances studied by Avery and Dochez (22) in the urine and blood of typhoid and pneumonia patients. They obtained precipitin reactions against homologous immune sera with the urine of infected cases concentrated by evaporation after boiling with acetic acid to remove coagulable proteins. (c) Petroff, with whom we discussed this proteose residue early in our work, has produced it, and tells us that he has obtained precipitin reactions with it by titrating it against the serum of a sheep treated for a long time with tubercle bacillus products. In suggesting an antibody response to a non-protein antigen we are aware that we are opposing what has been regarded as a well established doctrine in immunity; this is justified, or at least mitigated, we believe, by the consideration that reactions of the antigen-antibody type are the only explanation of specificity; and tuberculin, mallein, and typhoidin reactions are to a considerable degree specific. If such reaction bodies cannot be produced by precisely the same methods of administration as to time and quantity which are successful in calling forth protein antibodies, this should not astonish us, since, after all, the substances that we are dealing with are simpler in chemical structure than are the proteins, and physically are probably of relatively greater diffusibility. It may be that the greater diffusibility of the proteose-like substances transfers much of the actual reaction phenomena to an intracellular location, and that this to some extent influences the presence of circulating antibodies. It may also be that these more diffusible non-protein antigens are more rapidly eliminated from the animal body than are the proteins. Indeed, the above mentioned observations of Avery and Dochez, and the recent work of Wildbolz (23), Lanz (24), Imhof (25), and Gibson and Carroll (26), who demonstrated tuberculin active antigens in the urine of active cases, would corroborate such a view. The evidence available at the present time, however, concerning antibody formation to these non-protein substances is, we recognize, largely indirect, at least as far as our own work is concerned, and we present it in the present connection purely as a working hypothesis. Finally, perhaps the most important theoretical consideration indicated by our experiments is the following. We have in the tuberculin reaction a form of hypersensitiveness which seems to be (in guinea pigs, at least) analogous entirely to the typhoidin reaction, the mallein reaction, and the abortin reaction. (ABSTRACT TRUNCATED)

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The objective of this review is to identify studies reporting on lay health worker- or volunteer-led community-based programs for blood pressure screening and cardiovascular awareness in order to determine if these programs contribute to changes in blood pressure among participants over time.The specific question for this review is: What are the changes in blood pressure among adult users of community-based blood pressure screening and awareness programs operated by lay health workers or volunteers as measured by the differences in systolic and diastolic blood pressure between the user's first visit to the program and their last visit to the program? Cardiovascular diseases, such as stroke and heart disease, are quickly becoming global diseases manifesting in countries and communities where they traditionally had not been widespread. The World Health Organization (WHO) has reported that "in the Asia/Pacific region, [cardiovascular disease] has become increasingly prevalent in recent decades, and now accounts for about one third of all deaths". One risk factor that can lead to cardiovascular disease is hypertension. Based on WHO data from 2008, hypertension is now a global problem affecting 27% of the population 25 years of age or older.The risk for cardiovascular disease also appears to be higher among people in urban areas. A recent United Nations population report indicates that in the next 40 years we could see an increase in the world's population by 2.3 billion people. The majority of these people will be residing in urban areas, particularly in developing nations. Between 2011 and 2050, "the population living in urban areas is projected to gain 2.6 billion, passing from 3.6 billion in 2011 to 6.3 billion in 2050". Population growth in urban areas is therefore not only projected to include the expected population growth but also expected to include a shift of rural population to urban centers and "most of the population growth expected in urban areas will be concentrated in the cities and towns of the less developed regions". This growth of urban areas has the potential to put enormous pressures on health care systems that are already struggling to cope with the rapid increase in diseases thought to be more prevalent in Western societies, such as cardiovascular diseases.Hypertension may be difficult to treat due to a number of factors. Globally, access to antihypertensive medications, hypertension screening, and access to medical care vary from one country to another. Lifestyle factors, such as salt and alcohol consumption, stress, smoking, body weight, and exercise, are risk factors for hypertension that may be influenced by culture, which can in turn support or hinder lifestyle decisions that could significantly affect blood pressure. Hypertension, however, is easy to detect. A trained person with access to a low-cost sphygmomanometer can detect abnormal blood pressures quickly; however, access to trained personnel is not universally guaranteed. Globally - according to one model of skilled health care worker density and total requirement offered for discussion by the Global Health Workforce Alliance and WHO - there could currently be an estimated shortage of over seven million skilled health care workers (midwifes, nurses and physicians), as measured against a theoretical density of skilled health care workers to population. The shortage of skilled health care workers in this model could grow to over 12 million by 2035 if the assumptions of the model and population growth estimates are valid. Through rapid urbanization the potential for inequities in access to healthcare is also increased.Over the last few years, a number of community-based blood pressure screening and education initiatives have been established. These initiatives have been created either as part of research, as part of community outreach programs by publicly funded agencies, or as part of an outreach by not-for-profit organizations with a particular interest in reducing cardiovascular disease in specific hard-to-reach populations. Several systematic reviews have been conducted to assess different models for delivering services to people living with high blood pressure to assess community-based programs with a focus on cardiovascular disease, and to assess effectiveness of community health workers (CHW) in a variety of settings. These systematic reviews point to the importance of distinguishing between different categories of health care providers, their training and their roles in program delivery when assessing studies for possible inclusion in a systematic review.In a systematic review of studies from the US by Brownstein et al. focusing on the effectiveness of community health workers (CHWs) in the care of people with hypertension, this category of health care providers went under many different names. Community health workers in this review were defined as "any health workers who carried out functions related to health care deliver, were trained as part of an intervention, had no formal paraprofessional or professional designation, and had a relationship with the community being served". One of the findings from this review was the wide variety of formal training of the CHWs. In other parts of the world, a CHW might be defined differently. In their review of CHW-based programs focusing on children's health, Bhattacharyya, Winch, LeBan and Tien found that "in general CHWs are not paid salaries because the MOH (Ministry of Health) or donors do not consider salaries to be sustainable. Yet CHWs are often held accountable and supervised as if they were employees. Community health worker programs must recognize that CHWs are volunteers (emphasis in original), even if they receive small monetary or nonmonetary incentives. They are volunteering their time to serve the community". One Canadian model for delivering a cardiovascular awareness program designed to reach older adults through their primary care provider is based on volunteers with basic training to perform blood pressure measurements and cardiovascular health information.In a global review of a wide range of public health and health promotion initiatives operated by lay health workers from 2005, Lewin et al. identified over 40 different names or terms for a lay health worker. However, the definition of a lay health worker used by Lewin et al. is very similar to the definition of CHWs offered by Brownstein et al. Lewin et al.'s systematic review was the only study with a global focus that was located that reviewed studies of programs with a cardiovascular component using lay health workers. In this study, the sample size of studies focusing on lay health workers and cardiovascular disease was small (N=3) and the results from two of the studies were inconclusive to the point where the authors felt they could not pool the results.While a lay health worker may or may not receive some compensation for their work, volunteers in higher income areas of the world such as in North America typically do not receive any compensation. Volunteers, as observed by Bhattacharyya et al., are common in many parts of the world, and in some areas they provide delivery of programs and services that reach hundreds of thousands of individuals. One challenge for this systematic review will therefore be to isolate those programs that are delivered by lay health workers or volunteers who receive little or no compensation and programs where staff is paid. The importance of this distinction is on one hand related to cost - as observed by Bhattacharyya et al., many organizations responsible for delivery of community-based programs do not have funding for salaried staff. On the other hand there might be other factors in the relationship between a community being served by a program and the staff delivering the program. One such factor could be linked to the role of the person delivering the program as either a paid health care professional or an unpaid lay health worker or volunteer.Through this proposed JBI systematic review, the reviewers will focus on community-based blood pressure screening and health information programs delivered by either lay health workers or volunteers. Previous systematic reviews have indicated that programs focusing on blood pressure reduction delivered in a variety of settings and delivered by a variety of health care professionals might lower blood pressure among program participants over time. This systematic review will be limited to community-based programs rather than hospital or research facility-based programs, and to programs delivered by lay health workers or volunteers rather than programs delivered by paid community health workers, nurses or teams of health care providers under direction of a primary care provider. Compared to other recent systematic reviews which focused on studies with comparison groups and included few studies where lay health workers were involved, this systematic review will attempt to fill this gap in knowledge about programs delivered by lay health workers or volunteers by focusing on non-randomized controlled studies which report blood pressure changes over time in programs targeting the general population. Community-based programs might have a variety of designs with a number of different interventions, and where possible these designs and interventions will be identified and subgroup analysis conducted as appropriate. It is hoped that this systematic review can extend the work by Lewin et al. by identifying additional studies globally, focusing on programs delivered by lay health workers or volunteers but limited to studies reporting changes in blood pressure over time. Where possible, a meta-analysis of the changes in blood pressure over time among participants in these programs will be conducted. (ABSTRACT TRUNCATED)

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The objective of this review was to assess the safety and effectiveness of metal on metal (MOM) hip resurfacing arthroplasty for young patients compared with that of total hip replacement (THR) in the same population. Total hip replacement has proved to be very effective for late middle-aged and elderly patients with severe degenerative diseases of the hips. As indications for THR began to include younger patients and those with a more active life style, the longevity of the implant became a concern. Evidence suggests that these patients experience relatively higher rates of early implant failure and the need for revision. The Swedish hip registry, for example, has demonstrated a survival rate in excess of 80% at 20 years for those aged over 65 years, whereas this figure was 33% by 16 years in those aged under 55 years. Hip resurfacing arthroplasty is a bone-conserving alternative to THR that restores normal joint biomechanics and load transfer. The technique has been used around the world for more than 10 years, specifically in the United Kingdom and other European countries. Metal-on-metal hip resurfacing arthroplasty is an alternative procedure to conventional THR in younger patients. Hip resurfacing arthroplasty is less invasive than THR and addresses the problem of preserving femoral bone stock at the initial operation. This means that future hip revisions are possible with THR if the initial MOM arthroplasty becomes less effective with time in these younger patients. The procedure involves the removal and replacement of the surface of the femoral head with a hollow metal hemisphere, which fits into a metal acetabular cup. Hip resurfacing arthroplasty is a technically more demanding procedure than is conventional THR. In hip resurfacing, the femoral head is retained, which makes it much more difficult to access the acetabular cup. However, hip resurfacing arthroplasty has several advantages over a conventional THR with a small (28 mm) ball. First, the large femoral head reduces the chance of dislocation, so that rates of dislocation are less than those with conventional THR. Second, the range of motion with hip resurfacing arthroplasty is higher than that achieved with conventional THR. A variety of MOM hip resurfacing implants are used in clinical practice. Six MOM hip resurfacing implants have been issued licences in Canada. A search of electronic bibliographies (OVID Medline, Medline In-Process and Other Non-Indexed Citations, Embase, Cochrane CENTRAL and DSR, INAHTA) was undertaken to identify evidence published from Jan 1, 1997 to October 27, 2005. The search was limited to English-language articles and human studies. The literature search yielded 245 citations. Of these, 11 met inclusion criteria (9 for effectiveness, 2 for safety). The result of the only reported randomized controlled trial on MOM hip resurfacing arthroplasty could not be included in this assessment, because it used a cemented acetabular component, whereas in the new generation of implants, a cementless acetabular component is used. After omitting this publication, only case series remained.   HEALTH OUTCOMES: The Harris hip score and SF-12 are 2 measures commonly used to report health outcomes in MOM hip resurfacing arthroplasty studies. Other scales used are the Oxford hip score and the University of California Los Angeles hip score. The case series showed that the mean revision rate of MOM hip resurfacing arthroplasty is 1.5% and the incidence of femoral neck fracture is 0.67%. Across all studies, 2 cases of osteonecrosis were reported. Four studies reported improvement in Harris hip scores. However, only 1 study reported a statistically significant improvement. Three studies reported improvement in SF-12 scores, of which 2 reported a significant improvement. One study reported significant improvement in UCLA hip score. Two studies reported postoperative Oxford hip scores, but no preoperative values were reported. None of the reviewed studies reported procedure-related deaths. Four studies reported implant survival rates ranging from 94.4% to 99.7% for a follow-up period of 2.8 to 3.5 years. Three studies reported on the range of motion. One reported improvement in all motions including flexion, extension, abduction-adduction, and rotation, and another reported improvement in flexion. Yet another reported improvement in range of motion for flexion abduction-adduction and rotation arc. However, the author reported a decrease in the range of motion in the arc of flexion in patients with Brooker class III or IV heterotopic bone (all patients were men). SAFETY OF METAL-ON-METAL HIP RESURFACING ARTHROPLASTY: There is a concern about metal wear debris and its systemic distribution throughout the body. Detectable metal concentrations in the serum and urine of patients with metal hip implants have been described as early as the 1970s, and this issue is still controversial after 35 years. Several studies have reported high concentration of cobalt and chromium in serum and/or urine of the patients with metal hip implants. Potential toxicological effects of the elevated metal ions have heightened concerns about safety of MOM bearings. This is of particular concern in young and active patients in whom life expectancy after implantation is long. Since 1997, 15 studies, including 1 randomized clinical trial, have reported high levels of metal ions after THR with metal implants. Some of these studies have reported higher metal levels in patients with loose implants. Because patients who receive a MOM hip arthroplasty are shown to be exposed to high concentrations of metallic ions, the Medical Advisory Secretariat searched the literature for reports of adverse biological effects of cobalt and chromium. Cobalt and chromium make up the major part of the metal articulations; therefore, they are a focus of concern. To date, only one study has examined the incidence of cancer after MOM and polyethylene on metal total hip arthroplasties. The results were compared to that of general population in Finland. The mean duration of follow-up for MOM arthroplasty was 15.7 years; for polyethylene arthroplasty, it was 12.5 years. The standardized incidence ratio for all cancers in the MOM group was 0.95 (95% CI, 0.79-1.13). In the polyethylene on metal group it was 0.76 (95% CI, 0.68-0.86). The combined standardized incidence ratio for lymphoma and leukemia in the patients who had MOM THR was 1.59 (95% CI, 0.82-2.77). It was 0.59 (95% CI, 0.29-1.05) for the patients who had polyethylene on metal THR. Patients with MOM THR had a significantly higher risk of leukemia. All patients who had leukemia were aged over than 60 years.   EPIDEMIOLOGICAL STUDIES OF MYOCARDIOPATHY OF BEER DRINKERS: An unusual type of myocardiopathy, characterized by pericardial effusion, elevated hemoglobin concentrations, and congestive heart failure, occurred as an epidemic affecting 48 habitual beer drinkers in Quebec City between 1965 and 1966. This epidemic was directly related the consumption of a popular beer containing cobalt sulfate. The epidemic appeared 1 month after cobalt sulfate was added to the specific brewery, and no further cases were seen a month after this specific chemical was no longer used in making this beer. A beer of the same name is made in Montreal, and the only difference at that time was that the Quebec brand of beer contained about 10 times more cobalt sulphate. Cobalt has been added to some Canadian beers since 1965 to improve the stability of the foam but it has been added in larger breweries only to draught beer. However, in small breweries, such as those in Quebec City, separate batches were not brewed for bottle and draught beer; therefore, cobalt was added to all of the beer processed in this brewery. In March 1966, a committee was appointed under the chairmanship of the Deputy Minister of Health for Quebec that included members of the department of forensic medicine of Quebec's Ministry of Justice, epidemiologists, members of Food and Drug Directorate of Ottawa, toxicologists, biomedical researchers, pathologists, and members of provincial police. Epidemiological studies were carried out by the Provincial Ministry of Health and the Quebec City Health Department. The association between the development of myocardiopathy and the consumption of the particular brand of beer was proven. The mortality rate of this epidemic was 46.1% and those who survived were desperately ill, and recovered only after a struggle for their lives. Similar cases were seen in Omaha (Nebraska). The epidemic started after a cobalt additive was used in 1 of the beers marketed in Nebraska. Sixty-four patients with the clinical diagnosis of alcoholic myocardiopathy were seen during an 18-month period (1964-1965). Thirty of these patients died. The first patient became ill within 1 month after cobalt was added to the beer, and the last patient was seen within 1 month of withdrawal of cobalt. A similar epidemic occurred in Minneapolis, Minnesota. Between 1964 and 1967, 42 patients with acute heart failure were admitted to a hospital in Minneapolis, Minnesota. Twenty of these patients were drinking 6 to 30 bottles per day of a particular brand of beer exclusively. The other 14 patients also drank the same brand of beer, but not exclusively. The mortality rate from the acute illness was 18%, but late deaths accounted for a total mortality rate of 43%. Examination of the tissue from these patients revealed markedly abnormal changes in myofibrils (heart muscles), mitochondria, and sarcoplasmic reticulum. In Belgium, a similar epidemic was reported in 1966, in which, cobalt was used in some Belgian beers. (ABSTRACT TRUNCATED)

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This study was undertaken to improve the performance of a Chemotherapy Treatment Unit by increasing the throughput and reducing the average patient's waiting time. In order to achieve this objective, a scheduling template has been built. The scheduling template is a simple tool that can be used to schedule patients' arrival to the clinic. A simulation model of this system was built and several scenarios, that target match the arrival pattern of the patients and resources availability, were designed and evaluated. After performing detailed analysis, one scenario provide the best system's performance. A scheduling template has been developed based on this scenario. After implementing the new scheduling template, 22.5% more patients can be served. 1. CancerCare Manitoba is a provincially mandated cancer care agency. It is dedicated to provide quality care to those who have been diagnosed and are living with cancer. MacCharles Chemotherapy unit is specially built to provide chemotherapy treatment to the cancer patients of Winnipeg. In order to maintain an excellent service, it tries to ensure that patients get their treatment in a timely manner. It is challenging to maintain that goal because of the lack of a proper roster, the workload distribution and inefficient resource allotment. In order to maintain the satisfaction of the patients and the healthcare providers, by serving the maximum number of patients in a timely manner, it is necessary to develop an efficient scheduling template that matches the required demand with the availability of resources. This goal can be reached using simulation modelling. Simulation has proven to be an excellent modelling tool. It can be defined as building computer models that represent real world or hypothetical systems, and hence experimenting with these models to study system behaviour under different scenarios.1, 2 A study was undertaken at the Children's Hospital of Eastern Ontario to identify the issues behind the long waiting time of a emergency room.3 A 20---day field observation revealed that the availability of the staff physician and interaction affects the patient wait time. Jyväskylä et al.4 used simulation to test different process scenarios, allocate resources and perform activity---based cost analysis in the Emergency Department (ED) at the Central Hospital. The simulation also supported the study of a new operational method, named "triage-team" method without interrupting the main system. The proposed triage team method categorises the entire patient according to the urgency to see the doctor and allows the patient to complete the necessary test before being seen by the doctor for the first time. The simulation study showed that it will decrease the throughput time of the patient and reduce the utilisation of the specialist and enable the ordering all the tests the patient needs right after arrival, thus quickening the referral to treatment. Santibáñez et al.5 developed a discrete event simulation model of British Columbia Cancer Agency"s ambulatory care unit which was used to study the impact of scenarios considering different operational factors (delay in starting clinic), appointment schedule (appointment order, appointment adjustment, add---ons to the schedule) and resource allocation. It was found that the best outcomes were obtained when not one but multiple changes were implemented simultaneously. Sepúlveda et al.6 studied the M. D. Anderson Cancer Centre Orlando, which is a cancer treatment facility and built a simulation model to analyse and improve flow process and increase capacity in the main facility. Different scenarios were considered like, transferring laboratory and pharmacy areas, adding an extra blood draw room and applying different scheduling techniques of patients. The study shows that by increasing the number of short---term (four hours or less) patients in the morning could increase chair utilisation. Discrete event simulation also helps improve a service where staff are ignorant about the behaviour of the system as a whole; which can also be described as a real professional system. Niranjon et al.7 used simulation successfully where they had to face such constraints and lack of accessible data. Carlos et al. 8 used Total quality management and simulation - animation to improve the quality of the emergency room. Simulation was used to cover the key point of the emergency room and animation was used to indicate the areas of opportunity required. This study revealed that a long waiting time, overload personnel and increasing withdrawal rate of patients are caused by the lack of capacity in the emergency room. Baesler et al.9 developed a methodology for a cancer treatment facility to find stochastically a global optimum point for the control variables. A simulation model generated the output using a goal programming framework for all the objectives involved in the analysis. Later a genetic algorithm was responsible for performing the search for an improved solution. The control variables that were considered in this research are number of treatment chairs, number of drawing blood nurses, laboratory personnel, and pharmacy personnel. Guo et al. 10 presented a simulation framework considering demand for appointment, patient flow logic, distribution of resources, scheduling rules followed by the scheduler. The objective of the study was to develop a scheduling rule which will ensure that 95% of all the appointment requests should be seen within one week after the request is made to increase the level of patient satisfaction and balance the schedule of each doctor to maintain a fine harmony between "busy clinic" and "quiet clinic". Huschka et al.11 studied a healthcare system which was about to change their facility layout. In this case a simulation model study helped them to design a new healthcare practice by evaluating the change in layout before implementation. Historical data like the arrival rate of the patients, number of patients visited each day, patient flow logic, was used to build the current system model. Later, different scenarios were designed which measured the changes in the current layout and performance. Wijewickrama et al.12 developed a simulation model to evaluate appointment schedule (AS) for second time consultations and patient appointment sequence (PSEQ) in a multi---facility system. Five different appointment rule (ARULE) were considered: i) Baily; ii) 3Baily; iii) Individual (Ind); iv) two patients at a time (2AtaTime); v) Variable Interval and (V---I) rule. PSEQ is based on type of patients: Appointment patients (APs) and new patients (NPs). The different PSEQ that were studied in this study were: i) first--- come first---serve; ii) appointment patient at the beginning of the clinic (APBEG); iii) new patient at the beginning of the clinic (NPBEG); iv) assigning appointed and new patients in an alternating manner (ALTER); v) assigning a new patient after every five---appointment patients. Also patient no show (0% and 5%) and patient punctuality (PUNCT) (on---time and 10 minutes early) were also considered. The study found that ALTER---Ind. and ALTER5---Ind. performed best on 0% NOSHOW, on---time PUNCT and 5% NOSHOW, on---time PUNCT situation to reduce WT and IT per patient. As NOSHOW created slack time for waiting patients, their WT tends to reduce while IT increases due to unexpected cancellation. Earliness increases congestion whichin turn increases waiting time. Ramis et al.13 conducted a study of a Medical Imaging Center (MIC) to build a simulation model which was used to improve the patient journey through an imaging centre by reducing the wait time and making better use of the resources. The simulation model also used a Graphic User Interface (GUI) to provide the parameters of the centre, such as arrival rates, distances, processing times, resources and schedule. The simulation was used to measure the waiting time of the patients in different case scenarios. The study found that assigning a common function to the resource personnel could improve the waiting time of the patients. The objective of this study is to develop an efficient scheduling template that maximises the number of served patients and minimises the average patient's waiting time at the given resources availability. To accomplish this objective, we will build a simulation model which mimics the working conditions of the clinic. Then we will suggest different scenarios of matching the arrival pattern of the patients with the availability of the resources. Full experiments will be performed to evaluate these scenarios. Hence, a simple and practical scheduling template will be built based on the indentified best scenario. The developed simulation model is described in section 2, which consists of a description of the treatment room, and a description of the types of patients and treatment durations. In section 3, different improvement scenarios are described and their analysis is presented in section 4. Section 5 illustrates a scheduling template based on one of the improvement scenarios. Finally, the conclusion and future direction of our work is exhibited in section 6. 2. A simulation model represents the actual system and assists in visualising and evaluating the performance of the system under different scenarios without interrupting the actual system. Building a proper simulation model of a system consists of the following steps. Observing the system to understand the flow of the entities, key players, availability of resources and overall generic framework.Collecting the data on the number and type of entities, time consumed by the entities at each step of their journey, and availability of resources.After building the simulation model it is necessary to confirm that the model is valid. (ABSTRACT TRUNCATED)

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Introgen and its wholly owned European subsidiary Gendux AB are developing an adenoviral p53 gene therapy as a treatment for cancer in the US and Europe, respectively. Phase III trials in patients with head and neck cancer are ongoing, and a number of clinical trials in other cancer indications have been completed. INGN 201 is being reviewed by the EMEA for approval in Li-Fraumeni syndrome (LFS) under the provisions of exceptional circumstance; the therapy is available on a compassionate use basis to eligible LFS cancer patients under a protocol authorised by the US FDA. The p53 tumour suppressor gene is deleted or mutated in many tumour cells and is one of the most frequently mutated genes in human tumours. The p53 protein is one of the most intricate elements in the apoptotic signalling cascade, and a mutation in the gene encoding it is believed to result in a decreased ability of a cell to apoptose. Thus replacing this gene via adenovirally-mediated p53 gene therapy is hoped to result in increased apoptosis where it is administered.INGN 201 is available for licensing, although Introgen favours retaining partial or full rights to the therapy in the US. Introgen entered into a license agreement with The University of Texas System and MD Anderson Cancer Center in 1994. The technologies licenced include p53 and fus1 (INGN 401). The collaboration has yielded exclusive patent and licensing rights to numerous technologies. Introgen entered into a collaboration with Rhône-Poulenc Rorer Pharmaceuticals (now sanofi-aventis) to develop therapeutics based on p53 inhibition in October 1994. However, in June 2001 this relationship was restructured and Introgen assumed responsibility for the worldwide development of all p53 products including INGN 201, and acquired all marketing and commercialisation rights with respect to those products. Introgen initiated two phase III trials in head and neck cancer (in June 2000 and May 2001) at about 80 sites in the US, Canada and Europe; the first is a comparative study of INGN 201 and IV methotrexate in 240 patients with refractory head and neck cancer. The second is for the combination of INGN 201 and standard chemotherapy, compared with standard chemotherapy alone, in 288 patients with recurrent squamous cell carcinoma of the head and neck. Introgen expects to complete regulatory filings for advanced recurrent head and neck cancer in the US and EU within 2007. Favourable phase II data of INGN 201 in a subpopulation of patients with recurrent, unresectable head and neck cancer (SCCHN) prompted Introgen to seek accelerated approval for INGN 201 in December 2004. The company has filed a request with the FDA to accept a 'rolling Biologics License Application', the first regulatory step in the accelerated approval process. Introgen requested immediate initiation of the Accelerated Approval rolling BLA, with completion of the filing process expected before the end of 2005. Introgen had presented combined results from three multicentre (US and Europe) phase II studies of INGN 201 in 217 patients with recurrent squamous cell carcinoma of the head and neck confirming previous safety and efficacy results of the treatment. In April 2004, the Southwest Oncology Group initiated a similar clinical trial using INGN 201 for the treatment of stage III or IV squamous cell carcinoma of the oral cavity, or oropharynx, that is able to be removed surgically. The study assessed the feasibility, efficacy and safety of administering INGN 201 at the time of surgery for suppression of remaining tumour cells, followed by a combination of chemotherapy and radiation therapy. The previous trial was a phase II study that afforded Introgen access to surgical specialists in cancer and complemented the company's ongoing pivotal phase III studies in advanced recurrent disease. Sixty patients with head and neck cancer will undergo surgery at ten US sites and receive INGN 201 intraoperatively (and not postoperatively as used in the former trial) followed by a combination of chemo- and radiotherapy. In September 2003, INGN 201 was granted designation as a Fast Track Drug Product development programme by the FDA for prolonging survival and delaying time to disease progression in patients with recurrent, unresectable squamous cell carcinoma of the head and neck. Previously, in February 2003, INGN 201 received orphan drug designation from the FDA for head and neck cancer. Phase I trials in the US for the treatment of non-small-cell lung cancer have been completed. Sanofi-aventis (formerly Rhône-Poulenc Rorer Gencell) initiated phase II trials in the US, Europe and Canada for non-small-cell lung cancer. Intratumoral injection of RPR/INGN 201 in patients with recurrent glioblastomas was safe and resulted in expression of the p53 protein. Direct administration of RPR/INGN 201 to the lower airways of patients with bronchioalveolar cell lung carcinoma resulted in symptomatic improvement and improved lung function in some patients. In November 2003, according to a Clinical Trials Agreement between the Division of Cancer Treatment and Diagnosis (DCTD) of the National Cancer Institute (NCI) and Introgen, a 6-month phase I/II study with p53 gene therapy administered in the form of an oral rinse or mouthwash for patients with oral premalignancies has been initiated. This is the first trial to investigate the effect of this treatment on oral lesions that are at high risk for developing into full blown cancers. In September 2006, the EMEA granted orphan drug status to INGN 201 for the treatment of LFS, following Gendux's application for the designation. The company intends to provide the therapy on a compassionate use basis to qualifying patients in Europe.INGN 201 has been successfully used in the treatment of a LFS patient on a compassionate use basis under a protocol authorised by the FDA. Based on these interim findings, Introgen has decided to continue making the therapy available through a compassionate use programme to eligible LFS patients who have relapsed after standard treatment as part of physician-sponsored protocols at qualifying institutions in the US.A worldwide, exclusive license to a family of US patents covering a combination therapy comprised of INGN 201 in combination with several inhibitors of epidermal growth factor receptors (EGFr) such as Erbituxtrade mark Vectibixtrade mark and Tarcevatrade mark was granted to Introgen by The University of Texas MD Anderson Cancer Center in November 2006. In February 2006, Introgen exclusively licenced a broad patent (US Patent No. 6 989 375), originally issued to to the Board of Regents of The University of Texas System; the patent covers any therapeutic gene-based therapy when applied in combination with conventional cancer therapy such as radiation or chemotherapy. Introgen Therapeutics was awarded a patent from the US Patent and Trademark Office in June 2005 that directly covers many of the special features of its INGN 201 molecular therapy. US Patent No. 6,905,873 is one of a family of patents that cover INGN 201 that have been issued to the Board of Regents of The University of Texas System and exclusively licensed to Introgen. To date, Introgen controls 30 issued patents relevant to the product covering compositions, therapeutic methods of administering the product in virtually any form, alone and in conjunction with the most widely used chemotherapeutic and radiation treatments, as well as its production, and has a large number of pending patent applications in the US and in foreign countries relating to its ADVEXIN((R)) therapy. In December 2004, the US Patent and Trademark Office issued Patent No. 6,830,749 entitled Recombinant p53 Adenovirus Methods and Compositions. Importantly, the patent is the broadest adenoviral p53 patent to date, covering any adenovirus carrying the p53 gene under the control of any promoter. Previously, Patent No. 6,805,858 covering methods for the administration of INGN 201 to cancer patients including virtually all of those routes currently being used for adenoviral delivery was awarded. In addition, US Patent No. 6,740,320, which broadly covers adenoviral vectors with the tumour suppressor p53 in pharmaceutical compositions, was awarded. This patent extends Introgen's patent coverage for its adenoviral p53 gene therapy product to the year 2021, not taking into account possible patent extensions. In February 2003, the US Patent and Trademark Office issued patent No. 6,511,847, entitled Recombinant p53 Adenovirus Methods and Compositions, covering any adenoviral DNA molecule that encodes the p53 gene positioned under the control of a promoter.US patents issued in 2002 include Patent No. 6,410,010, broadly covering all adenoviral p53 compositions (including ADVEXIN((R))) that express adequate p53 in amounts sufficient to suppress the growth of or kill cancer cells in patients. The patent also covers adenoviral p53, which incorporates a specific type of promoter that helps cells to express the p53 tumour suppressor gene. Introgen has a number of US patents that relate to the clinical use of adenoviral p53 gene therapy in cancer as monotherapy or in combination with one or more chemotherapeutic drugs, radiation therapies or other agents that have a damaging effect on the DNA or survival of (i.e. 2-methoxyestradiol, Patent No. 6,410,029) cancer cells.A patent with broad claims directed to combination therapy with the p53 gene and conventional chemotherapy or radiation was issued in China in August 2005. Patent No. ZL95192776.0, entitled Compositions Comprising DNA Damaging Agents and p53, was issued to the Board of Regents of The University of Texas System and was exclusively licenced to Introgen. (ABSTRACT TRUNCATED)

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Genistein is a naturally occurring isoflavone that interacts with estrogen receptors and multiple other molecular targets. Human exposure to genistein is predominantly through consumption of soy products, including soy-based infant formula and dietary supplements. Consumption of soy and genistein has been associated with a variety of beneficial effects in animals and humans, but concerns have also been raised concerning potential adverse effects of genistein, particularly with regard to reproductive toxicity and the induction or potentiation of carcinogenesis, due primarily to its weak estrogenic activity. Because of these concerns, genistein was selected as one of the compounds to be examined in a protocol utilizing Sprague-Dawley rats to evaluate the effects of multigenerational and long-term exposures to doses of estrogenic agents that produce subtle reproductive tract lesions in developmentally exposed Sprague-Dawley rat pups. Results from the multigenerational reproductive toxicology feed study are reported in this report, and results of the 2-year feed study are reported separately (NTP, 2008a). Data from a preliminary reproductive dose range-finding feed study (NTP, 2007) that utilized exposure concentrations of up to 1,250 ppm genistein were used to select dietary exposure concentrations of 0, 5, 100, and 500 ppm for the current study. These dietary doses resulted in ingested genistein doses of approximately 0, 0.3, 7, or 35 mg genistein/kg body weight per day for males and 0, 0.5, 10, or 51 mg/kg per day for females during the time that the rats were directly consuming dosed feed. The current study was a multigenerational study (F(0) through F(4), with F(5) litters terminated at weaning) focused on reproductive endpoints. Animals were continuously exposed to genistein from the time that the F(0) generation was 6 weeks old through weaning of the F(3) generation, and animals of the F(0) through F(4) generations were sacrificed and necropsied on postnatal day 140 (PND 140). Dosed feed was removed from the F(3) pups at the time of weaning, and this generation and subsequent generations were maintained on control feed for the remainder of the study. For this study, 140 animals of each sex were obtained from the NCTR CD (Sprague-Dawley) rat colony at weaning and placed on a soy- and alfalfa-free diet that was used throughout the study in an attempt to maintain consistently low background exposure to phytoestrogens. Thirty-five animals per sex were assigned to exposure groups by a weight-ranked randomization procedure prior to the start of dietary exposure of the parental (F(0)) generation at 6 weeks of age. At the time of mating, males were paired with females from the same exposure group, and they were housed together until evidence of successful mating was detected or for a maximum of 14 days. Litters were randomly standardized to four males and four females on PND 2, and 25 litters per exposure group and their associated sires and dams were randomly selected to continue on study to produce the next generation and then necropsied at termination at 20 weeks of age (PND 140). Similar procedures were used to produce each generation. Results of the current study are summarized below. In the postweaning period, exposure to 500 ppm genistein reduced body weights predominantly in females of generations in which rats were ingesting the compound throughout adulthood (F(0) through F(2)). In the unexposed F(4) generation, female body weight was also depressed, although to a lesser extent than in the earlier generations. In the F(1) generation, postweaning body weights were reduced in all 100 and 500 ppm groups, with a more pronounced effect in the females. While pup birth weights were not significantly affected by genistein in the F(1) through F(4) generations (with the exception of 100 ppm males in the F(1) generation), both sexes showed depressed body weight gains during the preweaning period in the 500 ppm groups in all of these generations. Male pup preweaning body weight gains were also depressed in the 5 and 100 ppm groups in the F(1) generation. In the unexposed F(5) generation, pup birth weights in all exposed groups of both sexes were significantly lower than those in the controls, although it seems likely that this is a chance observation rather than a carryover effect from exposures in earlier generations. Measures of fertility were not adversely affected by genistein except for litter size. Litter size of the 500 ppm group in the F(2) generation was significantly smaller than that in the corresponding control group. The litter sizes in the F(1), F(2), and F(3) generations showed negative exposure concentration trends. Male and female 500 ppm pups in the F(1) generation had slightly reduced anogenital distances (AGDs) relative to controls when covaried by body weight. Female pups also had reduced AGDs in the F(2) (500 ppm) and F(3) (100 ppm) generations, although the statistical significance was dependent on the analysis method applied. Females exposed to 500 ppm showed an accelerated time of vaginal opening (approximately 3 days) in the F(1) and F(2) generations, while the 5 ppm group showed an earlier time of vaginal opening (1.3 days) in the F(3) generation. Body weight at vaginal opening was lower in 500 ppm females of the F(1) through F(3) generations and in the 5 ppm females of the F(1) generation. When examined shortly after vaginal opening, estrous cycles of 500 ppm females in the F(1) and F(2) generations were significantly longer (approximately 3 days and 1 day, respectively) than those of their respective control groups. Other estrous cycle disturbances (with the exception of decreased time in diestrus for 100 ppm females in the F(4) generation) were confined to the 500 ppm group of the F(1) generation and included reduced time in proestrus and an increase in the number and percentage of aberrant cycles. When the estrous cycles of older animals were examined prior to termination, the sole significant effects were a decreased time in estrus and increased time in diestrus in 5 ppm females of the F(2) generation and an increased number of abnormal cycles in 500 ppm females of the F(3) generation. No effects of genistein on male sexual development were noted with the exception of an increased time to testicular descent in 500 ppm males of the F(3) generation. Significant organ weight effects in both sexes were largely confined to single exposed groups in single generations; no clear patterns indicating toxicity to reproductive or nonreproductive organs were observed. Exposure-related microscopic lesions were confined to males, with the mammary gland and kidney affected. Incidences of mammary gland alveolar/ductal hyperplasia were significantly increased in 500 ppm males in the F(0) through F(2) generations and in 100 ppm males in the F(1) and F(2) generations. In the F(3) generation, a significant positive linear exposure concentration trend in the incidences of mammary gland hyperplasia occurred, but no exposed group differed significantly from the controls in pairwise comparisons. The more pronounced effect of genistein on the incidences of male mammary gland hyperplasia in the continuously exposed F(1) and F(2) generations as compared to the late adolescent and adult exposures of the F(0) generation and the preweaning-only exposure of the F(3) generation indicates that both developmental and adult exposures contribute to the maintenance of this effect into adulthood. Statistically significant effects of genistein on the incidences of generally minimal to mild kidney lesions in males were confined to the continuously exposed F(1) and F(2) generations. Incidences of renal tubule mineralization were significantly increased in 100 and 500 ppm males in the F(1) and F(2) generations, and incidences of inflammation and renal tubule regeneration were significantly increased in 500 ppm males in the F(1) generation. In addition to the results reported above for animals from the main study, ancillary studies were conducted with pups derived from the current study or from animals treated under similar conditions. These results have been reported elsewhere (Appendix P) and are not presented in detail in this report. Of particular importance are the data on blood and tissue genistein concentrations obtained from adult animals in the F(1) generation (Chang et al., 2000), from dams and fetuses (Doerge et al., 2001), and from dams and nursing pups (Doerge et al., 2006). These data provide measures of the internal dose resulting from the dietary exposure concentrations used in the current study and indicate that while fetal and adult exposures to genistein were at concentrations relevant to the full range of human exposures, only very low exposures were achieved during the early neonatal period when the pups were receiving exposures exclusively from the milk. The minimal exposure to genistein during this critical developmental period must be considered in the interpretation of the data derived from the current study. In summary, although genistein did show adverse effects with dietary exposures of 100 or 500 ppm, there were no clear adverse effects on the reproductive or developmental parameters measured at genistein concentrations ranging from less than 1 ppm (control diet) to 100 ppm, a range of doses producing serum concentrations achievable from the phytoestrogen content of human diets. There were few clear, overtly toxic effects that carried over across directly exposed generations or appeared to be imprinted to carry over into unexposed descendents under the conditions of exposure in this study. (ABSTRACT TRUNCATED).

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In this report the various elements of the safety and nutritional assessment procedure for genetically modified (GM) plant derived food and feed are discussed, in particular the potential and limitations of animal feeding trials for the safety and nutritional testing of whole GM food and feed. The general principles for the risk assessment of GM plants and derived food and feed are followed, as described in the EFSA guidance document of the EFSA Scientific Panel on Genetically Modified Organisms. In Section 1 the mandate, scope and general principles for risk assessment of GM plant derived food and feed are discussed. Products under consideration are food and feed derived from GM plants, such as maize, soybeans, oilseed rape and cotton, modified through the introduction of one or more genes coding for agronomic input traits like herbicide tolerance and/or insect resistance. Furthermore GM plant derived food and feed, which have been obtained through extensive genetic modifications targeted at specific alterations of metabolic pathways leading to improved nutritional and/or health characteristics, such as rice containing beta-carotene, soybeans with enhanced oleic acid content, or tomato with increased concentration of flavonoids, are considered. The safety assessment of GM plants and derived food and feed follows a comparative approach, i.e. the food and feed are compared with their non-GM counterparts in order to identify intended and unintended (unexpected) differences which subsequently are assessed with respect to their potential impact on the environment, safety for humans and animals, and nutritional quality. Key elements of the assessment procedure are the molecular, compositional, phenotypic and agronomic analysis in order to identify similarities and differences between the GM plant and its near isogenic counterpart. The safety assessment is focussed on (i) the presence and characteristics of newly expressed proteins and other new constituents and possible changes in the level of natural constituents beyond normal variation, and on the characteristics of the GM food and feed, and (ii) the possible occurrence of unintended (unexpected) effects in GM plants due to genetic modification. In order to identify these effects a comparative phenotypic and molecular analysis of the GM plant and its near isogenic counterpart is carried out, in parallel with a targeted analysis of single specific compounds, which represent important metabolic pathways in the plant like macro and micro nutrients, known anti-nutrients and toxins. Significant differences may be indicative of the occurrence of unintended effects, which require further investigation. Section 2 provides an overview of studies performed for the safety and nutritional assessment of whole food and feed. Extensive experience has been built up in recent decades from the safety and nutritional testing in animals of irradiated foods, novel foods and fruit and vegetables. These approaches are also relevant for the safety and nutritional testing of whole GM food and feed. Many feeding trials have been reported in which GM foods like maize, potatoes, rice, soybeans and tomatoes have been fed to rats or mice for prolonged periods, and parameters such as body weight, feed consumption, blood chemistry, organ weights, histopathology etc have been measured. The food and feed under investigation were derived from GM plants with improved agronomic characteristics like herbicide tolerance and/or insect resistance. The majority of these experiments did not indicate clinical effects or histopathological abnormalities in organs or tissues of exposed animals. In some cases adverse effects were noted, which were difficult to interpret due to shortcomings in the studies. Many studies have also been carried out with feed derived from GM plants with agronomic input traits in target animal species to assess the nutritive value of the feed and their performance potential. Studies in sheep, pigs, broilers, lactating dairy cows, and fish, comparing the in vivo bioavailability of nutrients from a range of GM plants with their near isogenic counterpart and commercial varieties, showed that they were comparable with those for near isogenic non-GM lines and commercial varieties. In Section 3 toxicological in vivo, in silico, and in vitro test methods are discussed which may be applied for the safety and nutritional assessment of specific compounds present in food and feed or of whole food and feed derived from GM plants. Moreover the purpose, potential and limitations of the 90-day rodent feeding trial for the safety and nutritional testing of whole food and feed have been examined. Methods for single and repeated dose toxicity testing, reproductive and developmental toxicity testing and immunotoxicity testing, as described in OECD guideline tests for single well-defined chemicals are discussed and considered to be adequate for the safety testing of single substances including new products in GM food and feed. Various in silico and in vitro methods may contribute to the safety assessment of GM plant derived food and feed and components thereof, like (i) in silico searches for sequence homology and/or structural similarity of novel proteins or their degradation products to known toxic or allergenic proteins, (ii) simulated gastric and intestinal fluids in order to study the digestive stability of newly expressed proteins and in vitro systems for analysis of the stability of the novel protein under heat or other processing conditions, and (iii) in vitro genotoxicity test methods that screen for point mutations, chromosomal aberrations and DNA damage/repair. The current performance of the safety assessment of whole foods is mainly based on the protocols for low-molecular-weight chemicals such as pharmaceuticals, industrial chemicals, pesticides, food additives and contaminants. However without adaptation, these protocols have limitations for testing of whole food and feed. This primarily results from the fact that defined single substances can be dosed to laboratory animals at very large multiples of the expected human exposure, thus giving a large margin of safety. In contrast foodstuffs are bulky, lead to satiation and can only be included in the diet at much lower multiples of expected human intakes. When testing whole foods, the possible highest concentration of the GM food and feed in the laboratory animal diet may be limited because of nutritional imbalance of the diet, or by the presence of compounds with a known toxicological profile. The aim of the 90-days rodent feeding study with the whole GM food and feed is to assess potential unintended effects of toxicological and/or nutritional relevance and to establish whether the GM food and feed is as safe and nutritious as its traditional comparator rather than determining qualitative and quantitative intrinsic toxicity of defined food constituents. The design of the study should be adapted from the OECD 90-day rodent toxicity study. The precise study design has to take into account the nature of the food and feed and the characteristics of the new trait(s) and their intended role in the GM food and feed. A 90-day animal feeding trial has a large capacity (sensitivity and specificity) to detect potential toxicological effects of single well defined compounds. This can be concluded from data reported on the toxicology of a wide range of industrial chemicals, pharmaceuticals, food substances, environmental, and agricultural chemicals. It is possible to model the sensitivity of the rat subchronic feeding study for the detection of hypothetically increased amount of compounds such as anti-nutrients, toxicants or secondary metabolites. With respect to the detection of potential unintended effects in whole GM food and feed, it is unlikely that substances present in small amounts and with a low toxic potential will result in any observable (unintended) effects in a 90-day rodent feeding study, as they would be below the no-observed-effect-level and thus of unlikely impact to human health at normal intake levels. Laboratory animal feeding studies of 90-days duration appear to be sufficient to pick up adverse effects of diverse compounds that would also give adverse effects after chronic exposure. This conclusion is based on literature data from studies investigating whether toxicological effects are adequately identified in 3-month subchronic studies in rodents, by comparing findings at 3 and 24 months for a range of different chemicals. The 90-day rodent feeding study is not designed to detect effects on reproduction or development other than effects on adult reproductive organ weights and histopathology. Analyses of available data indicate that, for a wide range of substances, reproductive and developmental effects are not potentially more sensitive endpoints than those examined in subchronic toxicity tests. Should there be structural alerts for reproductive/developmental effects or other indications from data available on a GM food and feed, then these tests should be considered. By relating the estimated daily intake, or theoretical maximum daily intake per capita for a given whole food (or the sum of its individual commercial constituents) to that consumed on average per rat per day in the subchronic 90-day feeding study, it is possible to establish the margin of exposure (safety margin) for consumers. Results obtained from testing GM food and feed in rodents indicate that large (at least 100-fold) 'safety' margins exist between animal exposure levels without observed adverse effects and estimated human daily intake. Results of feeding studies with feed derived from GM plants with improved agronomic properties, carried out in a wide range of livestock species, are discussed. The studies did not show any biologically relevant differences in the parameters tested between control and test animals. (ABSTRACT TRUNCATED)

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Five hundred and sixty patients began renal replacement therapy in 2006, giving an incidence of 117.51 pmp; in 2007 there were 579 new patients, for an incidence rate of 120.01 pmp. Analysis of the incidence between 1998 and 2007 for both raw and age-standardized data (based on the 2001 census) shows a slow, gradual increase that is statistically significant. Most of the patients were between 55 and 85 years old; the modal class for males was between 65 and 70, and between 75 and 80 for females. The median age of the population beginning replacement therapy is clearly over 65 years old. The year 2000 was particularly significant because the incidence of new patients undergoing renal replacement therapy over the age of 75 definitively exceeded that of the next younger class (65-74 years old), a trend that remained constant until 2007. In 2006 and 2007, males account for 64.4% and 66.4%, respectively, of new patients, a proportion that is constant over the years. The greater incidence of males is also to be found across the other age groups and tends to be even more noticeable in the oldest age class. Incidence by province is highly variable, however, there is a constant trend within provinces during these years, since the incidence in some provinces is lower than the regional average and higher in others. After adjusting for age, there are no significant differences in the incidence between provinces: the age structure of the population accounts for the variability of the incidence of terminal uremia across the Veneto provinces. The conditions most responsible for renal insufficiency requiring replacement therapy are vascular diseases, diabetes and nephropathies of unknown origin. Although diabetic and vascular nephropathies are subject to wide fluctuations, they remain stable over the years, whereas the frequency of nephropathy of unknown origin appears to be on the rise. The first treatment for most of the patients is hemodialysis. In 2006, 436 patients (78%) were given extracorporeal dialysis as first treatment, compared to 122 patients (22%) who were given peritoneal dialysis and 2 (0.35%) who received live-donor kidney transplant. In 2007 the situation was very similar, with 435 patients treated with extracorporeal dialysis, 142 with peritoneal dialysis and 1 by a live-donor transplant. The proportion between patients treated with hemodialysis and peritoneal dialysis was constant from 1998 to 2007. The choice between hemodialysis or peritoneal dialysis as the initial treatment modality depends on many factors, ranging from clinical indications to cultural attitudes at the facility to individual patient preferences. Logistic regression of the factors influencing the choice of dialysis treatment shows that peritoneal dialysis is offered primarily to patients between the ages of 45 and 65 who do not have an underlying systemic or nephropathy of unknown origin and who do not have any comorbidities. This confirms the positive selection made with regard to these patients, widely described in the literature. Initial treatment by transplant is an exceptional event: starting from 2003, it was used in only 1 or 2 patients per year. Seventy-two percent of patients starting replacement therapy present with at least one comorbidity. Thirty-six percent of patients also present with more than one associated disease. The RVDT has been gathering data on the vascular access used for new dialysis patients since 2006. Roughly 43% of patients start treatment with an arteriovenous fistula, 38% with a temporary catheter, less than 1% with a prosthesis, 9% with a tunneled catheter, and 10% with a peritoneal catheter. Logistic regression was used to evaluate what role age, primary nephropathies and comorbidities present at the start of treatment play in determining the choice of a temporary catheter. The logistic model estimates a 29% probability of starting treatment with a temporary access. This probability decreases if the patient suffers from a familiar or hereditary nephropathy but increases if the patient has secondary glomerulonephritis or is affected by a group of various diseases (multiple myeloma or other pathologies) or if the patient suffers at the same time from cardiac insufficiency or an infection. The estimated probability of starting hemodialysis with a mature fistula is 40%, but this figure diminishes significantly in female patients, if the patient has secondary glomerulonephritis, cardiac insufficiency or infections. As of December 31, 2006, there were 4,071 patients being treated with extracorporeal or peritoneal dialysis or by kidney transplant, leading to a prevalence of 852.82 patients pmp; as of December 31, 2007, there were 4,200 patients treated, with a corresponding prevalence of 869.14 pmp. The breakdown in prevalence by age group shows that the increase in prevalence is highly significant in the top two age classes, namely, between 65 and 75 years of age and over 75, while remaining negligible in the other classes. Between 1998 and 2007, the prevalence increased by 40% in patients over 75 and increased by 20% in the class of 65-to-75 year olds. The elderly contribute a greater weight in the renal replacement therapy population, reflected in the gradual increase of the median age of the prevalent population from 1998 to 2007. During 2006 and 2007, males made up 63.99% and 64.36% of the patients, respectively. This relative frequency mirrors the findings for incidence and is constant over the years. The distribution of primary diseases is very different in the prevalent population compared to findings in the incident patients. Primary glomerulonephritis, at fourth place among incident patients, is the most frequent disease in the prevalent population (although there is a clearly downward trend over the years). The percentages of diabetes and vascular disease, on the other hand, are lower compared to what is observed in the incident population. The prevalence expressed by treatment modality pmp increased for all three types. In analyzing the annual percentage rise in prevalence, using 1998 as the baseline, the most significant figure regards transplant patients, whose prevalence increased by over 60% between 1998 and 2007. Prevalence of hemodialysis patients rose moderately by only slightly over 10%. Peritoneal dialysis shows a rather linear increase, similar to the transplant trend. Our study used longitudinal regression models to analyze factors predictive of a patient starting and continuing to undergo the same type of treatment over the years. The results show that a patient has a greater probability of being treated with hemodialysis based on several primary nephropathies, when aged &gt; 45, and in the presence of the main comorbidities. The predictive factors for peritoneal dialysis mentioned earlier have a diametrically opposed role. The presence of comorbidities (except high blood pressure), the type of nephropathy, and age &gt; 65 lead to a lower probability of receiving a transplant. We analyzed peritoneal dialysis failures - defined as changing over to extracorporeal dialysis for any reason (clinical, psychological or social) - and the cumulative incidence of failure, taking into account the two competing outcomes of transplant and death. The only variable associated with peritoneal dialysis failure was the presence of infections. Older patients, patients with peripheral vascular disease, and those with neoplasia are less frequently taken off peritoneal dialysis to receive a transplant, an event occurring more frequently, however, in patients with hypertension. Death is dependent on age, on the presence of peripheral vascular disease and is less frequent in hypertensives. As is the case for peritoneal dialysis, the natural history of kidney transplant can have two competing outcomes: return to dialysis and death. The risk factors associated with return to dialysis are the presence of peripheral vascular disease, hypertension and infections; risk factors associated with death include age, the presence of cerebral vascular disease and neoplasia. From 1998 to 2007, the prevalence of hepatitis C virus-antibody-positive patients decreased by almost one third. The number of antigen-positive hepatitis B patients is declining slowly, but the levels remain in any case very low. The association between the two infections is disappearing: already at very low levels in 1998, that figure was halved by 2007. MORTALITY AND SURVIVAL: The mortality of uremic patients on renal replacement therapy was calculated both as a cumulative incidence, expressed as the number of deaths over patients at risk (alive at the beginning of the study year) and as a mortality rate, expressed as the number of deaths per patients/year. The figure was constant over the years, at around 10%. The mortality of males was no different from that of females; this finding differs from what is observed in the general population where male mortality is markedly higher than that of females. The mortality rate is dependent on the age group of the patient at start of treatment and shows an upward trend that is growing exponentially. The mortality rate in hemodialysis patients remained stable at 15% between 2000 and 2007, while the mortality rate in peritoneal dialysis patients gradually decreased down to 13%. The mortality rate for transplant patients was low and constant, at under 2%. The trend for the various causes of death is stable over the years and shows that the main cause of death is cardiac, accounting for between 30% and 35%, while mortality due to vascular, neoplastic, infection or cachexia-related causes are all roughly at the same rate, between 10% and 15%. (ABSTRACT TRUNCATED)

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The ESCALA* project (Estudio de Salud y Contaminación del Aire en Latinoamérica) is an HEI-funded study that aims to examine the association between exposure to outdoor air pollution and mortality in nine Latin American cities, using a common analytic framework to obtain comparable and updated information on the effects of air pollution on several causes of death in different age groups. This report summarizes the work conducted between 2006 and 2009, describes the methodologic issues addressed during project development, and presents city-specific results of meta-analyses and meta-regression analyses. The ESCALA project involved three teams of investigators responsible for collection and analysis of city-specific air pollution and mortality data from three different countries. The teams designed five different protocols to standardize the methods of data collection and analysis that would be used to evaluate the effects of air pollution on mortality (see Appendices B-F). By following the same protocols, the investigators could directly compare the results among cities. The analysis was conducted in two stages. The first stage included analyses of all-natural-cause and cause-specific mortality related to particulate matter &lt; or = 10 pm in aerodynamic diameter (PM10) and to ozone (O3) in cities of Brazil, Chile, and México. Analyses for PM10 and O3 were also stratified by age group and O3 analyses were stratified by season. Generalized linear models (GLM) in Poisson regression were used to fit the time-series data. Time trends and seasonality were modeled using natural splines with 3, 6, 9, or 12 degrees of freedom (df) per year. Temperature and humidity were also modeled using natural splines, initially with 3 or 6 df, and then with degrees of freedom chosen on the basis of residual diagnostics (i.e., partial autocorrelation function [PACF], periodograms, and a Q-Q plot) (Appendix H, available on the HEI Web site). Indicator variables for day-of-week and holidays were used to account for short-term cyclic fluctuations. To assess the association between exposure to air pollution and risk of death, the PM10 and O3 data were fit using distributed lag models (DLMs). These models are based on findings indicating that the health effects associated with air pollutant concentrations on a given day may accumulate over several subsequent days. Each DLM measured the cumulative effect of a pollutant concentration on a given day (day 0) and that day's contribution to the effect of that pollutant on multiple subsequent (lagged) days. For this study, exposure lags of up to 3, 5, and 10 days were explored. However, only the results of the DLMs using a 3-day lag (DLM 0-3) are presented in this report because we found a decreasing association with mortality in various age-cause groups for increasing lag effects from 3 to 5 days for both PM10 and O3. The potential modifying effect of socioeconomic status (SES) on the association of PM10 or O3 concentration and mortality was also explored in four cities: Mexico City, Rio de Janeiro, São Paulo, and Santiago. The methodology for developing a common SES index is presented in the report. The second stage included meta-analyses and metaregression. During this stage, the associations between mortality and air pollution were compared among cities to evaluate the presence of heterogeneity and to explore city-level variables that might explain this heterogeneity. Meta-analyses were conducted to combine mortality effect estimates across cities and to evaluate the presence of heterogeneity among city results, whereas meta-regression models were used to explore variables that might explain the heterogeneity among cities in mortality risks associated with exposures to PM10 (but not to O3). The results of the mortality analyses are presented as risk percent changes (RPC) with a 95% confidence interval (CI). RPC is the increase in mortality risk associated with an increase of 10 microg/m3 in the 24-hour average concentration of PM10 or in the daily maximum 8-hour moving average concentration of O3. Most of the results for PM10 were positive and statistically significant, showing an increased risk of mortality with increased ambient concentrations. Results for O3 also showed a statistically significant increase in mortality in the cities with available data. With the distributed lag model, DLM 0-3, PM10 ambient concentrations were associated with an increased risk of mortality in all cities except Concepci6n and Temuco. In Mexico City and Santiago the RPC and 95% CIs were 1.02% (0.87 to 1.17) and 0.48% (0.35 to 0.61), respectively. PM10 was also significantly associated with increased mortality from cardiopulmonary, respiratory, cardiovascular, cerebrovascular-stroke, and chronic obstructive lung diseases (COPD) in most cities. The few nonsignificant effects generally were observed in the smallest cities (Concepción, Temuco, and Toluca). The percentage increases in mortality associated with ambient O3 concentrations were smaller than for those associated with PM10. All-natural-cause mortality was significantly related to O3 in Mexico City, Monterrey, São Paulo and Rio de Janeiro. Increased mortality risks for some specific causes were also observed in these cities and in Santiago. In the analyses stratified by season, different patterns in mortality and O3 were observed for cold and warm seasons. Risk estimates for the warm season were larger and significant for several causes of death in São Paulo and Rio de Janeiro. Risk estimates for the cold season were larger and significant for some causes of death in Mexico City, Monterrey, and Toluca. In an analysis stratified by SES, the all-natural-cause mortality risk in Mexico City was larger for people with a medium SES; however we observed that the risk of mortality related to respiratory causes was larger among people with a low SES, while the risk of mortality related to cardiovascular and cerebrovascular-stroke causes was larger among people with medium or high SES. In São Paulo, the all-natural-cause mortality risk was larger in people with a high SES, while in Rio de Janeiro the all-natural-cause mortality risk was larger in people with a low SES. In both Brazilian cities, the risks of mortality were larger for respiratory causes, especially for the low- and high-SES groups. In Santiago, all-natural-cause mortality risk did not vary with level of SES; however, people with a low SES had a higher respiratory mortality risk, particularly for COPD. People with a medium SES had larger risks of mortality from cardiovascular and cerebrovascular-stroke disease. The effect of ambient PM10 concentrations on infant and child mortality from respiratory causes and lower respiratory infection (LRI) was studied only for Mexico City, Santiago, and São Paulo. Significant increased mortality risk from these causes was observed in both Santiago (in infants and older children) and Mexico City (only in infants). For O3, an increased mortality risk was observed in Mexico City (in infants and older children) and in São Paulo (only in infants during the warm season). The results of the meta-analyses confirmed the positive and statistically significant association between PM10 and all-natural-cause mortality (RPC = 0.77% [95% CI: 0.60 to 1.00]) using the random-effects model. For mortality from specific causes, the percentage increase in mortality ranged from 0.72% (0.54 to 0.89) for cardiovascular disease to 2.44% (1.36 to 3.59) for COPD, also using the random-effects model. For O3, significant positive associations were observed using the random-effects model for some causes, but not for all natural causes or for respiratory diseases in people 65 years or older (&gt; or = 65 years), and not for COPD and cerebrovascular-stroke in the all-age and the &gt; or = 65 age groups. The percentage increase in all-natural-cause mortality was 0.16% (-0.02 to 0.33). In the meta-regression analyses, variables that best explained heterogeneity in mortality risks among cities were the mean average of temperature in the warm season, population percentage of infants (&lt; 1 year), population percentage of children at least 1 year old but &lt; 5 years (i.e., 1-4 years), population percentage of people &gt; or = 65 years, geographic density of PM10 monitors, annual average concentrations of PM10, and mortality rates for lung cancer. The ESCALA project was undertaken to obtain information for assessing the effects of air pollutants on mortality in Latin America, where large populations are exposed to relatively high levels of ambient air pollution. An important goal was to provide evidence that could inform policies for controlling air pollution in Latin America. This project included the development of standardized protocols for data collection and for statistical analyses as well as statistical analytic programs (routines developed in R by the ESCALA team) to insure comparability of results. The analytic approach and statistical programming developed within this project should be of value for researchers carrying out single-city analyses and should facilitate the inclusion of additional Latin American cities within the ESCALA multicity project. Our analyses confirm what has been observed in other parts of the world regarding the effects of ambient PM10 and 03 concentrations on daily mortality. They also suggest that SES plays a role in the susceptibility of a population to air pollution; people with a lower SES appeared to have an increased risk of death from respiratory causes, particularly COPD. Compared with the general population, infants and young children appeared to be more susceptible to both PM10 and O3, although an increased risk of mortality was not observed in these age groups in all cities. (ABSTRACT TRUNCATED)

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Long stays are often thought to result from outdated methods of treatment, so that modernization should bring them to an end. The purpose of this work is to find out whether old and new long stay patients are to be found in French psychiatric institutions, as they have been in several other countries, and if so, describe some characters of the patients, in order to give a better understanding of the situation. As early as 1972, Wing and Hailey were able to study old and new long stay patients in the Camberwell register. In 1987, Kastrup published the results from the Danish national cohort; among other conclusions, she was able to show that some patients experienced a long stay when admitted for the first time, while others only did so later during the course of their treatment. In 1994, Lelliott and Wing, published the results of a British national audit of new long stay patients; they reiterated that the closing of psychiatric hospitals should go along with the opening of specialised long stay and rehabilitation facilities. Trieman, Leff, and several other researchers members of the Team for the Assessment of Psychiatric Services (TAPS) published many articles describing the follow-up of patients staying in two large hospitals undergoing closure near London. One of these papers concludes that "difficult to place patients will not disappear with the closure of the psychiatric hospitals..., they continue to arise from the population of patients recently diagnosed". At the end of 1998, a national survey was organised according to the recommendations of the United Nations and of the World Health Organisation by the French National Institute of Statistics and of Economic Studies (INSEE). Its general purpose was to describe disabilities in the French population on a census day. To that end, information was also recorded about schooling, employment, income, lodging, family relations, etc. Persons who were notable to answer by themselves were included; if not, many severe cases would have been excluded. A follow-up survey of the same persons took place 2 years later. Interviews were carried out by trained interviewers of the INSEE. Medical information was recorded from what the patients themselves knew or could say. The survey included a random sample of inpatients in psychiatric institutions. We study here specialised hospitals: this does not include psychiatric wards in general hospitals, nor private hospitals. Compared to what had been planned, the proportion of successful interviews in psychiatric institutions was 75%. The 1180 persons who answered the questionnaire bring information about the estimated 33,600 who were in these psychiatric institutions at the end of 1998. Information about where the persons were by 2000 could be collected about almost all of them. This paper deals with length of stay, sex, age, marital status, age at admission, place of residence before entering hospital and outcome at the end of year 2000 All data relating to age and duration were studied by splitting groups into quartiles. No multivariate analysis was made, since information about diagnosis and disabilities was not included. Among the 33,600 in-patients, six out of ten were men. A quarter were under 32 years of age, half under 43. Two thirds of the patients were bachelors. One patient out of ten had been in hospital for 15 days, and one out of five for 30 days; half had been in hospital for 7 months; the duration of stay was over 1 year for 41%, over 5 years for 23% and over 18 years for 10%. Before being admitted, more than four patients out of ten (44%) lived in an independent home, one out of six (16%) lived with his-her parents more than one out of four (28%) lived in another institution. When they were admitted, one patient out of four was 26 years of age or younger, and one out of two was two was 38 or younger. Men, bachelors, and patients between 43 and 54 years of age had longer lengths of stay than the average. Patients admitted before the age of 26, and in particular those admitted before they were 18, had the longest length of stay. Patients who lived in an independent home were in hospital for a much shorter time than those who lived with parents before being admitted. Patients coming from institutions for the elderly had lengths of stay very much similiar to those patients who lived in an independent home before being admitted. In these cases, hospital was for the most part normal place for treatment. Patients coming from institutions for disabled persons had very long lengths of stay. Among the 33,600 patients, one out of ten was living in an institution for disabled persons before being admitted and had been in hospital more than a year. The follow-up showed that among those who had been in hospital for less 16 days by the end of 1998, 6% were in the same institution two years later. For those who had been there for less 41 days, the proportion was 11%. On the other hand, an those who had been in hospital for more than 4 years by the end of 1998, 7% were in an independent home 2 years later. Before being admitted, 44% of the patients lived in an independent home, but only 34% were in such a setting by the end of year 2000. An important minority (43%) was in the same hospital by the end of 2000. The proportion of patients who were in the same hospital 2 years later was higher at younger ages, among those who lived previously with parents, or who came from institutions for disabled persons, or who were admitted before the age of 26. had been in hospital for over 4 years by the end of 1998 and who were in the same hospital 2 years later were admitted at younger ages (eight out of ten were admitted before the age of 38); a large minority (31%) lived previously in an institution for disabled persons. The global death rate in two years was 7%, with a standardised mortality ratio of 4. Patients who lived in an institution for adult disabled persons before being admitted in hospital had a standardised mortality ratio of 10. These data very much suggest that many patients in French psychiatric institutions suffer from severe problems that prevent them from living in an independent home or even in an institution for disabled persons. A large number of persons seem to have been admitted in hospital at a time when it was not anymore possible for them to go on living in the previous setting: after treatment, they were not able to go back to where they came from. Indeed, a survey organised on a census day will over represent the longer stays and the more severe patients. On the other hand, outpatient treatment is very much organised in French public sectorised services, so that it is mainly those who suffer from severe problems who will go to hospital. The data also show that old long stay patients are slowly being replaced by new ones. The splitting of all groups into quartiles shows that there is no clear cut between short and long stay patients. The usual definition (over a year) is simple and convenient, yet is not a definite boundary between 2 separate groups. The analysis of allthese data can be organisedalong2 lines: one approach describes the patients, a complementary one provides information about services. The first approach will underscore the many social abilities that are necessary in order to live in an independent home. Younger age at outset will often be related with more serious mental illness. Considering that marriage usually happens later in our modern society, social withdrawal associated with mental illness will less often be balanced by the family and by relatives, so that patients may tend to stay longer with their parents. On the other hand, the fact that some patients who have been in hospital for a long or a very long time may nevertheless be found in an independent home two years later shows that long stay patients are not neglected. The second approach, about services, draws on the history of French psychiatric institutions: in the past, specialised wards for children were very poorly staffed and received patients with most severe problems. Some of these patients have now become adults and live in the hospital where they were admitted as children. Another question is about how services should be organised so that patients will be able to stay out of hospital despite their severe problems in daily life. A third question is about institutions for disabled persons, who are supposed to provide shelter for patients with disabilities, yet fail to do so for a number of them, so that these persons are admitted to a psychiatric hospital, then cannot leave it. This first French national random survey in psychiatric institutions, with two-year follow up, shows that old and new long stay patients are found in French psychiatric institutions. The results provide information about the patients; they can also help planners in order to improve appropriate services.

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The objective of this health technology policy assessment was to evaluate the clinical utility and cost-effectiveness of sleep studies in Ontario. TARGET POPULATION AND CONDITION Sleep disorders are common and obstructive sleep apnea (OSA) is the predominant type. Obstructive sleep apnea is the repetitive complete obstruction (apnea) or partial obstruction (hypopnea) of the collapsible part of the upper airway during sleep. The syndrome is associated with excessive daytime sleepiness or chronic fatigue. Several studies have shown that OSA is associated with hypertension, stroke, and other cardiovascular disorders; many researchers believe that these cardiovascular disorders are consequences of OSA. This has generated increasing interest in recent years in sleep studies. There is no 'gold standard' for the diagnosis of OSA, which makes it difficult to calibrate any test for diagnosis. Traditionally, polysomnography (PSG) in an attended setting (sleep laboratory) has been used as a reference standard for the diagnosis of OSA. Polysomnography measures several sleep variables, one of which is the apnea-hypopnea index (AHI) or respiratory disturbance index (RDI). The AHI is defined as the sum of apneas and hypopneas per hour of sleep; apnea is defined as the absence of airflow for ≥ 10 seconds; and hypopnea is defined as reduction in respiratory effort with ≥ 4% oxygen desaturation. The RDI is defined as the sum of apneas, hypopneas, and abnormal respiratory events per hour of sleep. Often the two terms are used interchangeably. The AHI has been widely used to diagnose OSA, although with different cut-off levels, the basis for which are often unclear or arbitrarily determined. Generally, an AHI of more than five events per hour of sleep is considered abnormal and the patient is considered to have a sleep disorder. An abnormal AHI accompanied by excessive daytime sleepiness is the hallmark for OSA diagnosis. For patients diagnosed with OSA, continuous positive airway pressure (CPAP) therapy is the treatment of choice. Polysomnography may also used for titrating CPAP to individual needs. In January 2005, the College of Physicians and Surgeons of Ontario published the second edition of Independent Health Facilities: Clinical Practice Parameters and Facility Standards: Sleep Medicine, commonly known as "The Sleep Book." The Sleep Book states that OSA is the most common primary respiratory sleep disorder and a full overnight sleep study is considered the current standard test for individuals in whom OSA is suspected (based on clinical signs and symptoms), particularly if CPAP or surgical therapy is being considered. Polysomnography in a sleep laboratory is time-consuming and expensive. With the evolution of technology, portable devices have emerged that measure more or less the same sleep variables in sleep laboratories as in the home. Newer CPAP devices also have auto-titration features and can record sleep variables including AHI. These devices, if equally accurate, may reduce the dependency on sleep laboratories for the diagnosis of OSA and the titration of CPAP, and thus may be more cost-effective. Difficulties arise, however, when trying to assess and compare the diagnostic efficacy of in-home PSG versus in-lab. The AHI measured from portable devices in-home is the sum of apneas and hypopneas per hour of time in bed, rather than of sleep, and the absolute diagnostic efficacy of in-lab PSG is unknown. To compare in-home PSG with in-lab PSG, several researchers have used correlation coefficients or sensitivity and specificity, while others have used Bland-Altman plots or receiver operating characteristics (ROC) curves. All these approaches, however, have potential pitfalls. Correlation coefficients do not measure agreement; sensitivity and specificity are not helpful when the true disease status is unknown; and Bland-Altman plots measure agreement (but are helpful when the range of clinical equivalence is known). Lastly, receiver operating characteristics curves are generated using logistic regression with the true disease status as the dependent variable and test values as the independent variable. Thus, each value of the test is used as a cut-point to measure sensitivity and specificity, which are then plotted on an x-y plane. The cut-point that maximizes both sensitivity and specificity is chosen as the cut-off level to discriminate between disease and no-disease states. In the absence of a gold standard to determine the true disease status, ROC curves are of minimal value. At the request of the Ontario Health Technology Advisory Committee (OHTAC), MAS has thus reviewed the literature on PSG published over the last two years to examine new developments. There is a large body of literature on sleep studies and several reviews have been conducted. Two large cohort studies, the Sleep Heart Health Study and the Wisconsin Sleep Cohort Study, are the main sources of evidence on sleep literature. To examine new developments on PSG published in the past two years, MEDLINE, EMBASE, MEDLINE In-Process &amp; Other Non-Indexed Citations, the Cochrane Database of Systematic Reviews and Cochrane CENTRAL, INAHTA, and websites of other health technology assessment agencies were searched. Any study that reported results of in-home or in-lab PSG was included. All articles that reported findings from the Sleep Heart Health Study and the Wisconsin Sleep Cohort Study were also reviewed. DIFFUSION OF SLEEP LABORATORIES: To estimate the diffusion of sleep laboratories, a list of sleep laboratories licensed under the Independent Health Facility Act was obtained. The annual number of sleep studies per 100,000 individuals in Ontario from 2000 to 2004 was also estimated using administrative databases. A total of 315 articles were identified that were published in the past two years; 227 were excluded after reviewing titles and abstracts. A total of 59 articles were identified that reported findings of the Sleep Heart Health Study and the Wisconsin Sleep Cohort Study. Based on cross-sectional data from the Wisconsin Sleep Cohort Study of 602 men and women aged 30 to 60 years, it is estimated that the prevalence of sleep-disordered breathing is 9% in women and 24% in men, on the basis of more than five AHI events per hour of sleep. Among the women with sleep disorder breathing, 22.6% had daytime sleepiness and among the men, 15.5% had daytime sleepiness. Based on this, the prevalence of OSA in the middle-aged adult population is estimated to be 2% in women and 4% in men. Snoring is present in 94% of OSA patients, but not all snorers have OSA. Women report daytime sleepiness less often compared with their male counterparts (of similar age, body mass index [BMI], and AHI). Prevalence of OSA tends to be higher in older age groups compared with younger age groups. DIAGNOSTIC VALUE OF POLYSOMNOGRAPHY: It is believed that PSG in the sleep laboratory is more accurate than in-home PSG. In the absence of a gold standard, however, claims of accuracy cannot be substantiated. In general, there is poor correlation between PSG variables and clinical variables. A variety of cut-off points of AHI (&gt; 5, &gt; 10, and &gt; 15) are arbitrarily used to diagnose and categorize severity of OSA, though the clinical importance of these cut-off points has not been determined. Recently, a study of the use of a therapeutic trial of CPAP to diagnose OSA was reported. The authors studied habitual snorers with daytime sleepiness in the absence of other medical or psychiatric disorders. Using PSG as the reference standard, the authors calculated the sensitivity of this test to be 80% and its specificity to be 97%. Further, they concluded that PSG could be avoided in 46% of this population. OBSTRUCTIVE SLEEP APNEA AND OBESITY: Obstructive sleep apnea is strongly associated with obesity. Obese individuals (BMI &gt;30 kg/m(2)) are at higher risk for OSA compared with non-obese individuals and up to 75% of OSA patients are obese. It is hypothesized that obese individuals have large deposits of fat in the neck that cause the upper airway to collapse in the supine position during sleep. The observations reported from several studies support the hypothesis that AHIs (or RDIs) are significantly reduced with weight loss in obese individuals. OBSTRUCTIVE SLEEP APNEA AND CARDIOVASCULAR DISEASES: Associations have been shown between OSA and comorbidities such as diabetes mellitus and hypertension, which are known risk factors for myocardial infarction and stroke. Patients with more severe forms of OSA (based on AHI) report poorer quality of life and increased health care utilization compared with patients with milder forms of OSA. From animal models, it is hypothesized that sleep fragmentation results in glucose intolerance and hypertension. There is, however, no evidence from prospective studies in humans to establish a causal link between OSA and hypertension or diabetes mellitus. It is also not clear that the associations between OSA and other diseases are independent of obesity; in most of these studies, patients with higher values of AHI had higher values of BMI compared with patients with lower AHI values. A recent meta-analysis of bariatric surgery has shown that weight loss in obese individuals (mean BMI = 46.8 kg/m(2); range = 32.30-68.80) significantly improved their health profile. Diabetes was resolved in 76.8% of patients, hypertension was resolved in 61.7% of patients, hyperlipidemia improved in 70% of patients, and OSA resolved in 85.7% of patients. This suggests that obesity leads to OSA, diabetes, and hypertension, rather than OSA independently causing diabetes and hypertension. (ABSTRACT TRUNCATED)

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2,3-Dibromo-l-propanol, a colorless liquid, has been used as a flame retardant, as an intermediate in the preparation of the flame retardant tris(2,3-dibromopropyl) phosphate, and as an intermediate in the manufacture of pesticides and pharmaceutical preparations. Toxicology and carcinogenicity studies were conducted by applying 2,3-dibromo-1-propanol (approximately 98% pure) in ethanol to the subscapular area of the skin of male and female F344/N rats and B6C3F1 mice 5 days per week for 16 days, 13 weeks, 48 to 51 weeks (male rats), 52 to 55 weeks (female rats), 36 to 39 weeks (male mice), or 39 to 42 weeks (female mice). Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, Drosophila melanogaster, mouse Iymphoma cells, and mouse bone marrow cells. 16-DAY STUDY IN RATS Groups of five male and five female rats received dermal applications of 0, 44, 88, 177, 375, or or 750 mg/kg 2,3-dibromo-1-propanol 5 days per week for 16 days. One male and one female receiving 750 mg/kg died before the end of the study. The mean body weight gains and final mean body weights of dosed rats were similar to those of the controls. There were no clinical findings or gross lesions associated with chemical application. 16-DAY STUDY IN MICE Groups of five male and five female mice received dermal applications of 0, 44, 88, 177, 375, or 750 mg/kg 2,3-dibromo-1-propanol 5 days per week for 16 days. Four males and one female receiving 750 mg/kg died before the end of the study. The mean body weight gains and final mean body weights of dosed mice were similar to those of the controls. There were no clinical findings or gross lesions associated with chemical application. 13-WEEK STUDY IN RATS Groups of 10 male and 10 female rats received dermal applications of 0, 44, 88, 177, 375, or 750 mg/kg 2,3-dibromo-1-propanol 5 days per week for 13 weeks. All rats survived until the end of the for 16 days. One male and one female receiving study. For rats in the 750 mg/kg groups, the mean 750 mg/kg died before the end of the study. The body weight gain was 11% lower than that of the controls for males and 13% lower for females. The mean liver weights and liver-weight-to-body-weight ratios of males receiving 375 or 750 mg/kg and of females receiving 750 mg/kg were increased. Chemical-related lesions occurred in the kidney of male rats and in the liver of female rats. The average severity of nephropathy was slightly increased in males receiving dermal applications of 750 mg/kg, while individual cell necrosis was observed in the liver of all female rats in the 750 mg/kg group. 13-WEEK STUDY IN MICE Groups of 10 male and 10 female mice received dermal applications of 0, 44, 88, 177, 375, or 750 mg/kg 2,3-dibromo-1-propanol 5 days per week for 13 weeks. Eight male mice receiving 750 mg/kg died during the study, while all female mice survived. The final mean body weights of dosed and control mice were similar. The mean liver weights and liver weight-to-body-weight ratios of males receiving 375 or 750 mg/kg and of females receiving 750 mg/kg were increased. Chemical-related lesions occurred in the liver and lung of mice. Centrilobular hepatocellular necrosis occurred in all males in the 750 mg/kg group that died during the study, while individual cell necrosis was observed in the liver of females receiving 177, 375, or 750 mg/kg. Pleomorphism of the epithelium in pulmonary bronchioles occurred with a dose related increased incidence in males and females. Necrosis of the bronchiolar epithelium was observed in males receiving 750 mg/kg. LONG-TERM STUDY IN RATS Originally planned to last for 2 years, the chronic study in rats was terminated early because of reduced survival in the high-dose groups related to chemical induced neoplasms and because of the detection of antibodies to Iymphocytic choriomeningitis virus in sentinel mice. Groups of 50 male and 50 female rats received dermal applications of 0,188, or 375 mg/kg 2,3-dibromo-1-propanol 5 days per week for 48 to 51 weeks (males) or 52 to 55 weeks (females). Su5 weeks (females). Survival, Body Weights, and Clinical Findings The survival of 375 mg/kg male and female rats was significantly lower than that of the controls (males: 50/50, 41/50,16/50; females: 48/50, 38/50, 24/50). In the 375 mg/kg groups, the final mean body weight was 23&amp;percnt; lower than that of the controls for males and 14&amp;percnt; lower for females. There were no chemical related clinical findings. Pathology Findings Application of 2,3-dibromo-1-propanol to the skin produced significant dose-related increases in the incidences of neoplasms at numerous sites in male and female rats. Almost all dosed rats had malignant neoplasms; only one control male and one control female had malignant neoplasms. In male rats, the incidences of benign or malignant neoplasms of the skin, nose, Zymbal's gland, oral mucosa, esophagus, and small and large intestines were significantly increased in the low- and high-dose groups, while the incidences of neoplasms of the forestomach and liver were significantly increased only in the high-dose group. Neoplasms of the kidney, vascular neoplasms of the spleen, and mesotheliomas in males occurred with a significant positive trend. In female rats, the incidences of benign or malignant neoplasms of the nose, Zymbal's gland, oral mucosa, esophagus, large intestine, and liver were significantly increased in the low- and high-dose groups, while the incidences of neoplasms of the skin, forestomach, small intestine, mammary gland, and clitoral gland were significantly increased in the high-dose group only. Neoplasms of the kidney in females occurred with a significant positive trend. LONG-TERM STUDY IN MICE Originally planned to last for 2 years, the chronic study in mice was terminated early because of the detection of antibodies to lymphocytic choriomeningitis virus in sentinel mice. Groups of 50 male and 50 female mice received dermal applications of 0, 88, or 177 mg/kg 2,3-dibromo-1-propanol 5 days per week for 36 to 39 weeks (males) or 39 to 42 weeks (females). Survival, Body Weights, and Clinical Findings All mice (except two low-dose females) survived until study termination. Mean body weights of control and dosed mice were similar throughout the study, and there were no clinical findings attributed to 2,3-dibromo-l-propanol. Pathology Findings Application of 2,3-dibromo-1-propanol to the skin produced significant dose-related increases in the incidences of neoplasms at several sites in male and female mice. Benign or malignant neoplasms were observed in 40&amp;percnt; of the low-dose males, 66&amp;percnt; of the high-dose males, 52&amp;percnt; of the low-dose females, and 56&amp;percnt; of the high-dose females. In control groups, neoplasms occurred in 6&amp;percnt; of the males and 10&amp;percnt; of the females. In male and female mice, the incidences of benign or malignant neoplasms of the forestomach were significantly increased in the low- and high-dose groups, while the incidences of neoplasms of the skin were significantly increased only in the high-dose groups. The incidences of liver and lung neoplasms were increased in high-dose males. GENETIC TOXICOLOGY 2,3-Dibromo-l-propanol was mutagenic in a variety of short-term tests, independent of exogenous metabolic activation (S9). It induced gene mutations in three strains of Salmonella typhimurium (TA98, TA100, and TA1535) and was positive in the mouse Iymphoma assay for induction of trifluorothymidine resistance in L5178Y cells. 2,3-Dibromo-l-propanol induced sister chromatid exchanges and chromosomal aberrations in cultured Chinese hamster ovary cells. In germ cells of male Drosophila melanogaster, 2,3-dibromo-1-propanol induced sex-linked recessive lethal mutations and reciprocal translocations. Results of an in vivo bone marrow micronucleus assay in male mice treated with 2,3-dibromo-1-propanol were negative. CONCLUSIONS Under the conditions of these long-term dermal studies, there was clear evidence of carcinogenic activity of 2,3-dibromo-1-propanol in male F344/N rats based on increased incidences of neoplasms of the skin, nose, oral mucosa, esophagus, forestomach, small and large intestine, Zymbal's gland, liver, kidney, tunica vaginalis, and spleen. There was clear evidence of carcinogenic activity of 2,3-dibromo-1-propanol in female F344/N rats based on increased incidences of neoplasms of the skin, nose, oral mucosa, esophagus, forestomach, small and large intestine, Zymbal's gland, liver, kidney, clitoral gland, and mammary gland. There was clear evidence of carcinogenic activity of 2,3-dibromo-1-propanol in male B6C3F1 mice based on increased incidences of neoplasms of the skin, forestomach, liver, and lung. There was clear evidence of carcinogenic activity of 2,3-dibromo-1-propanol in female B6C3F1 mice based on increased incidences of neoplasms of the skin and the forestomach. The increased incidences of alveolar/bronchiolar adenomas in female mice may have been related to chemical administration. In rats, 2,3-dibromo-1-propanol caused increased incidences of hyperkeratosis in the skin, forestomach, and esophagus, epithelial dysplasia in the nose, pleomorphism and basophilic and clear cell changes in the liver, and nuclear enlargement in the kidney. There were also chemical-related increases in the incidences of forestomach ulcers and acanthosis, angiectasis in the liver, and renal hyperplasia in male rats and epithelial dysplasia of the forestomach and bile duct hyperplasia in the liver in female rats. Chemical-related increases occurred in the incidences of hyperplasia in the skin, epithelial dysplasia of the forestomach, and bronchiolar epithelial pleomorphism and hyperplasia in male and female mice and in the incidence of eosinophilic cytoplasmic change in the liver in males. Synonyms: 2,3-dibromopropanol; 2,3-dibromopropyl alcohol.

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In recent years, much attention has been given to review reports on the early effects of air pollution on health, measured through daily series of deaths and/or hospital admissions. A number of large planned meta-analyses (in which methods for data retrieval and processing are commonly planned a priori for all participating centers) are on going both in the US and in Europe. The National Mortality, Morbidity and Air Pollution Study included data from 90 US cities, whereas APHEA (Air Pollution and Health, a European Approach) considers data from about 30 european cities. The present paper summarizes methods and findings of MISA, a meta-analysis of data from 8 Italian cities. It belongs to an ad hoc supplement of Epidemiologia &amp; Prevenzione (Epidemiol Prev 2001; 25 (2) Suppl: 1-72), the official Journal of the Italian Association of Epidemiology, which contains a full description of the study. MISA was launched on March 2000, within the project "Statistics, Environment and Health" (GRASPA), funded by the Italian Ministry of Education. Additional support was given by the Authorities of the 8 participating cities (from North to South: Turin, Milan, Verona, Ravenna, Bologna, Florence, Rome and Palermo). DAILY HEALTH DATA: Deaths certificate and hospital admission data have been collected respectively from the Local Health Authority and regional files. The same programme for retrieval of data on selected hospital admissions for acute conditions was used in the 8 cities. Main data are summarized in Table 1. DAILY CONCENTRATION OF POLLUTANTS: Most data were obtained from Regional Environmental Protection Agencies, which are responsible for environmental monitoring since 1993. Verona, Palermo and Milan (1990-94) data were obtained from local sources. Monitors with more than 25% of missing data were excluded. Meteorological data were collected by the same monitors and completed with data from monitors situated in the suburbs or (in Milan and Bologna) in the airport. The monitors were selected by a group of experts to ensure comparability. For SO2 and NO2 daily averages of hourly measurements were used, whereas concentrations of ozone and CO were estimated as the maximum 8 hours moving average. Total suspended particulate or PM10 were measured as 24 hours deposition. All analyses used the whole range of observed values (Table 2). Daily data were considered as missing when more than 25% of hourly data were not available. Missing data in one monitor were imputed as average of data from the remaining monitors weighted by the ratio between the specific monitor's year average and the general year average of all the selected city monitors. Missing data in one day were imputed as average of four days (preceding and following day, the same day of the previous and following weeks). In the city of Florence and Palermo PM10 concentrations were available. For the other cities we applied a conversion factor from PTS to PM10 (0.6 for Turin and 0.8 for all the others) estimated through validation studies. Ozone concentrations were used only where background monitors were available (Turin, Verona, Bologna and Florence) and limited to the warm season (May through September). A common protocol for the city-specific analyses was defined on the basis of a structured exploratory analysis. The adopted basic model was a Generalized Additive Model for Poisson data. Effect estimates were age-adjusted (0-64, 65-74, 75+) and formal tests of interaction pollutant-age were conducted. In the first two age groups, indicator variables for seasonality were specified, and cubic splines with fixed number of degree of freedom were specified for the last age group and for all age groups for the morbidity data. Model adequacy was checked by residual analysis and inspection of the partial autocorrelation function. In a sensitivity analysis non linear pollutant effects were considered and overdispersed [table: see text] transitional models were fitted; the analysis was conducted for all lags 0-3 and some distributed lags (0-1, 1-2, 0-3); no multipollutant models were fitted. The same model was fitted to the city data. No model selection was done: Table 3 describes the steps in model building. In the meta-analysis, for each outcome, the estimates for each pollutant and for each city were combined using fixed and random effects models. Heterogeneity of effects was tested according to DerSimonian and Laird. Results were checked using a hierarchical bayesian model, which was used to investigate heterogeneity across cities in a meta-regression phase. Non informative priors were used. Posterior distributions of parameters of interest have been obtained with WinBUGS. 10,000 iterations (excluding [table: see text] the first 2000) were retained, while for the meta-regression 100,000 iterations (excluding the first 4000) were stored. To approximate the marginal posteriors only one sample out of five were used. Achieved convergence was assessed using the Gelman and Rubin approach. In the meta-regression the models specified were the following: [formula: see text] i denotes city, j calendar period (1990-1994; 1995-1999). The first model includes only period as effect modifier, while the second model other potential variables. The ui terms (which do not vary with j) represent city specific random effects. For each pollutant, the meta-analysis detected a statistically significant association with mortality for natural causes. But for ozone, positive associations were commonly found for death and hospital admissions for both cardiovascular and respiratory diseases. Indeed, the only estimates whose lower 95% confidence limit bore a negative sign regarded the association between PM10 and mortality from respiratory diseases. Ozone in the warm season was positively and significantly associated with daily mortality and mortality for cardiovascular diseases whereas other estimates did not reach statistical significance and some were negative (only lag 0-1 for external comparability are reported in Table 4). Risks were highest (up to 4%) for respiratory conditions (Table 4). They were more pronounced at lag 1-2 for mortality, and at lag 0-3 for hospital admissions. Age was an effect modifier for mortality, the elderly being more susceptible. In the random effect meta-analysis, at lag 1-2, excess risks for unit increase of the pollutants at age 75+ and at age 0-64 were respectively: 4.9% and -0.4% for SO2, 1.7% and 0.6% for NO2; 2.3% and 0.2% for CO. Corresponding figures for PM10 at lag 0-1 were 1.1% and 0.2%. The effect of PM10 on mortality [table: see text] was greater during the warm season (2.8% vs 0.8%). A complete analysis is reported in the Italian text. Here we provide some details on the effects of PM10, about which the residual heterogeneity across cities was highest (Table 4). In addition, the epidemiological evidence on the hazards from this fraction of particulate matter is more controversial. Table 5 reports the excess risk estimated through the meta-analysis in 1995-99 for a 10 micrograms/m3 increase of PM10 for some outcomes. Proper prior distributions (overdispersed normal and inverse gamma) were adopted in the final bayesian analyses. The sensitivity of results to the choice of the priors were investigated (we defined proper and improper uniform, student's t), obtaining comparable results. Total natural mortality was significantly heterogeneous across cities (Q = 18.96, 5 df, p &lt; 0.001). City-specific estimates are represented graphically in Fig. 1. As expected, the confidence (credibility) intervals are widest [table: see text] for bayesian estimates, intermediate for those obtained under a random effects model, and narrowest for those found under a fixed effects model. Nevertheless, differences in point estimates are negligible. A North-South gradient in risk is obvious. Table 6 shows, for the cities for which mortality data were available, the improvement in precision and the shrinkage of effect estimates toward the overall mean introduced by the bayesian modelling. In the meta-regression, total mortality and a deprivation score were associated with greater effects. The excess risks on hospital admission were modified by the deprivation score and by the NO2/PM10 ratio. Overall, the risk estimates were greater in the calendar period 1995-99 and there was a North-South gradient, with larger effects in cities located in Central and Southern Italy (Florence, Rome, Palermo). The meta-analysis of the Italian studies on short-term effects of air pollution in 8 cities, MISA, exhibits the following features: With the exception of Naples, all greatest Italian cities were included; overall a population of 7 million was enrolled. The study protocol was accurate with regard to the selection of hospital admissions for acute conditions. Monitored data of concentration of pollutant were carefully evaluated before their inclusion in the meta-analysis. City specific analyses were carried out according to a common protocol controlling for seasonality, influenza epidemics, age and meterological variables; [table: see text] the protocol derived from a structured exploratory analysis. The meta-analysis was done using fixed and random effects models; a hierarchical bayesian model was fitted in a sensitivity analysis. The heterogeneity of effects across cities was investigated using a hierarchical bayesian model for meta-regression. While mortality data are of good quality, hospital admission data are more problematic. Since the filing criteria for the latter changed around 1995, comparability of results before and after such date is limited. Moreover, hospital admissions rely on availability of beds, the offer of which may be restricted during the warm season. Comparability of pollutant concentration estimates among cities may have been influenced by differences in monitor characteristics. (ABSTRACT TRUNCATED)

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Rates of obesity are increasing worldwide, as is the incidence of inflammatory bowel disease (IBD). Obesity is now considered an inflammatory state. Visceral adiposity in particular may be associated with a more severe inflammatory phenotype in IBD. The aim of this review article is to summarise the current literature on the association between visceral adiposity and outcomes in inflammatory bowel disease METHODS: To collect relevant articles, PubMed/MEDLINE and Embase searches were performed using Boolean search phrases. Grey literature and manual searches were also performed. Abstracts were selected by two independent reviewers based on pre-determined criteria. Full text articles were reviewed, and data extracted and assessed. One hundred twenty-seven abstracts were obtained through the initial search, with 85 abstracts reviewed and 22 full text articles included. Characteristics are included in Table 1. Most of these were retrospective studies and of moderate or weak quality. Studies suggested visceral fat content is higher in Crohn's disease than in healthy controls. Visceral adiposity was associated with an increased risk of complex Crohn's disease phenotype (OR 26.1 95% CI 2-75.4; p = 0.02). Post-operative recurrence was higher in patients with higher visceral fat indices (RR 2.1; CI 1.5-3; p = 0.012). There were conflicting data regarding the effect of visceral adiposity on post-operative complications and the efficacy of medical therapy. Table 1 Study characteristics Author Year Country Study type Study numbers Control group Disease type Methodology e.g. CT Body composition measurements Results Argeny [24] 2018 Austria Retrospective cohort N = 95 N/A Crohn's disease CT; L3 level Visceral fat area (cm<sup2</sup) Visceral fat index (VFA/m<sup2</sup) No association between VFA or VFI and short-term post-operative outcomes Bryant [30] 2018 Australia Prospective cohort N = 110 N/A Crohn's disease and UC DXA Visceral adipose tissue (VAT) (cm<sup3</sup) Visceral adipose tissue (grams) VAT/height index (cm<sup3</sup/m<sup2</sup) VAT:subcutaneous adipose tissue ratio Fat mass index (kg/m<sup2</sup) VAT and VHI increased significantly over 24 months Bryant [13] 2018 Australia Prospective cohort N = 72 N/A Crohn's disease; female DXA Visceral adipose tissue (VAT) (cm<sup3</sup) Visceral adipose tissue (grams) VAT/height index (cm<sup3</sup/m<sup2</sup) VAT:subcutaneous adipose tissue ratio VAT:SAT positively associated with stricturing disease Adiposity not associated with fistulising disease phenotype VAT:SAT significantly associated with faecal calprotectin in L3 phenotype VAT:SAT significantly negatively associated with VHI and QoL over 24 months Buning [25] 2015 Germany Case control N = 50 N = 19 healthy controls Crohn's disease MRI US VAT Thickness of abdominal fat Distance to posterior wall of aorta Area of inferior part of perirenal fat VAT accumulation was higher in CD patients vs healthy controls VAT and VAT/fat mass ratio higher in patients in short-term remission vs long-term remission VAT/FM higher in stricturing/fistulising disease vs inflammatory subtype No association between VAT/FM and CDAI, HBI or anti-TNF treatment Connolly [26] 2014 US Retrospective cohort N = 143 N/A Crohn's disease CT (L1-L5 level) Visceral/intra-abdominal adiposity (VA) Subcutaneous adiposity (SA) VA not associated with post-operative morbidity Decreased SA and increased visceral/subcutaneous ratio were predictive of post-op complications. (p = 0.02; p &lt; 0.001) Cravo [27] 2017 Portugal Retrospective cohort N = 71 N/A Crohn's disease CT (L3 level) Smooth muscle area (cm<sup2</sup) Visceral fat area (cm<sup2</sup) Subcutaneous fat area (cm<sup2</sup) Visceral fat index Muscle radiation attenuation L2 phenotype associated with lower muscle attenuation and higher visceral fat index (non-significant) B2/B3/surgery - significantly lower muscle attenuation. VFI associated with increased risk of complicated phenotype. (OR 26.1; 95% CI 1-75; p = 0.02) Ding [17] 2016 US Retrospective cohort N = 164 N/A Crohn's disease CT (L3 level) Visceral fat area (cm<sup2</sup) Subcutaneous fat area Total fat area Visceral obesity associated with longer duration of surgery, increased intra-operative blood loss and longer length of bowel resected Higher complication rates in patients with visceral obesity (p &lt; 0.001) VFA independent risk factor of adverse post-op outcomes Ding [14] 2017 Retrospective cohort N = 106 N/A Crohn's disease CT (L3 level) Visceral fat area Subcutaneous fat area Skeletal muscle area Skeletal muscle index Visceral obesity and myopenic obesity not significantly associated with risk of primary non-response Body composition factors not associated with secondary loss of response Erhayiem [18] 2011 UK Retrospective cohort N = 50 N/A Crohn's disease CT (L4 level) Mesenteric fat index (visceral:subcutaneous area ratio)N = 50 Mesenteric fat index was significantly higher in complicated Crohn's disease. ROC analysis for MFI in identifying complicated Crohn's disease: AUC = 0.95 (95% CI 0.89-1.0) Feng [28] 2018 China Retrospective cohort N = 80 Non-IBD GI patients Crohn's disease CT-energy spectral Visceral fat area (cm<sup2</sup) Subcutaneous fat area (cm<sup2</sup) Mesenteric fat index No significant difference in VFA between Crohn's disease cohort and control group. (p = 0.669). ROC analysis: detection of disease based on VFA and MFI: AUC 0.776 Sensitivity 77.5% Specificity 67.5% Hafraoui [16] 1998 France/Belgium Prospective N = 43 Healthy volunteers n = 13 Intestinal resection n = 9 Crohn's disease MRI (umbilicus) Total abdominal fat (cm<sup2</sup) Intra-abdominal fat (cm<sup2</sup) Subcutaneous fat (cm<sup2</sup) Ratio of intra-abdominal:total fat area was significantly higher in patients with Crohn's vs controls. (p = 0.012) No correlation between abdominal fat tissue and disease activity, duration or steroid therapy Holt [29] 2017 Australia/New Zealand RCT N = 44 N = 11 placebo group Crohn's disease CT/MRI (L3, L4-5 levels) Visceral adipose tissue area Subcutaneous adipose tissue area Skeletal muscle area Visceral adipose tissue/height index VHI &gt; 1.5 times gender mean was specific for endoscopic recurrence (100%) with sensitivity of 29%. PPV = 1 (0.59-1.00) There was no significant difference in disease activity at 18 months post-resection based on VHI &gt; 1.5 gender mean Li [31] 2015 China Retrospective cohort N = 72 N/A Crohn's disease CT (umbilicus) Visceral fat area (cm<sup2</sup) Subcutaneous fat area (cm<sup2</sup) Mesenteric fat index Post-op recurrence was more frequent with high VFA values. (p = 0.019) VFA and MFI were independent risk factors for post-operative recurrence. (p = 0.013 and p = 0.028, respectively) High VFA and high MFI were significantly higher in patients with endoscopic activity (p = 0.023) Liu [32] 2016 Retrospective case-control N = 59 N = 30 (&lt; 15% increase VFA) IBD with IPAA CT (L3) Visceral fat area Subcutaneous fat area No difference in pouchitis, pouch sinus formation and composite adverse pouch outcomes between the 2 groups with and without VFA increase &gt; 15%. Excessive VAT gain was an independent risk factor for the composite adverse pouch outcomes. (OR 12.6 (95% CI 1.19-133.5) Magro [33] 2018 Brazil Cross-sectional study N = 78 N = 28 Health control Crohn's disease DEXA Fat and lean masses Visceral fat (kg) Visceral fat/BMI Visceral fat per %body fat VF was higher in Crohn's disease group (p = 0.004) compared to controls Parmentier-Decrucq [34] 2009 Prospective study N = 132 N/A Crohn's disease MRI Subcutaneous fat Visceral fat Total abdominal fat increased 18% in Crohn's disease patients treated with infliximab induction therapy Shen [35] 2018 China Retrospective N = 97 N/A Crohn's disease CT (umbilicus) Subcutaneous fat area Visceral fat area Mesenteric fat index VFA and MFI were significantly lower in patients with mucosal healing (post-infliximab). (p &lt; 0.0001) SFA was not significantly different VFA correlated with CDAI (p &lt; 0.001) and was an independent predictive factor for mucosal healing Stidham [15] 2015 Retrospective N = 269 N/A Crohn's disease CT(T10-L5) Subcutaneous fat volume Visceral fat volume No significant difference in visceral fat volume between patients with surgical complications Thiberge [36] 2018 France Retrospective N = 149 N/A Crohn's disease CT (L3 level) Skeletal muscle index Visceral adiposity index Subcutaneous adiposity index SAI and VAI were significantly lower in patients who underwent surgery or who died in 6 months post-CT(p = 0.009 and p &lt; 0.001) VanDerSloot [37] 2017 Cohort study N/A Crohn's disease CT (T11-S5) Visceral adipose tissue volume Non-significant trend toward increased risk of surgery and penetrating disease with increasing VAT Wei [38] 2018 China Retrospective N = 86 N/A IBD post-resection CT (L3 level) Visceral adipose volume Subcutaneous adipose volume Increased visceral:subcutaneous fat ratio was associated with increased procalcitonin levels on post-op days 1, 3 and 5 Yadav [39] 2017 India Prospective N = 97 N/A IBD CT (L4 level) Visceral fat area Subcutaneous fat area No statistically significant correlation between visceral fat and disease behaviour in Crohn's disease N/A not applicable, VFA visceral fat area, VFI visceral fat index, VAT visceral adipose tissue, VHI visceral adipose tissue to height index, SAT subcutaneous adipose tissue, DXA dual-energy X-ray absorptiometry, CT computer tomography, MRI magnetic resonance imaging, US ultrasound, CDAI Crohn's disease activity index, HBI Harvey-Bradshaw Index, anti-TNF anti-tumour necrosis factor, SA subcutaneous adiposity, ROC receiver operating curve, AUC area under the curve, MFI mesenteric fat index, SAI subcutaneous adiposity index, PPV positive predictive value CONCLUSION: Visceral adiposity appears to be increased in Crohn's disease with some evidence that it is also associated with more complex disease phenotypes. There is also a signal that post-operative recurrence rates are affected by increasing mesenteric adiposity. There is a relative lack of data in UC patients and further high-quality studies are necessary to elucidate the relationship between visceral adiposity and IBD and the implications for patient outcomes.

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1,4-Dichlorobenzene is commonly used as a space deodorant in toilets and for moth control. Because of its extensive production and use and the absence of carcinogenicity data, carcinogenesis studies were conducted by administering 1,4-dichlorobenzene (greater than 99% pure) in corn oil by gavage (5 days per week) to male F344/N rats at doses of 0, 150, or 300 mg/kg and to female F344/N rats and male and female B6C3F1 mice at doses of 0, 300, or 600 mg/kg per day for 2 years (50 animals per group). Fourteen-day and 13-week studies were performed to characterize the toxicity, identify affected sites, and set doses for the 2-year studies. Clinical chemistry and hematologic studies were performed during the 13-week studies to assess the effects of 1,4-dichlorobenzene on the liver, kidney, and hematopoietic system and to assess whether the compound produced hepatic porphyria. Two 13-week studies were performed in rats. In the first study, rats were dosed with 300-1,500 mg/kg 1,4-dichlorobenzene. Because histologic changes were observed in the kidney of male rats at all doses, a second 13-week study was performed at doses of 38-600 mg/kg. In the 13-week studies, survival was decreased in groups of male rats given 1,200 or 1,500 mg/kg and in female rats given 1,500 mg/kg. Weight gain was decreased in male rats receiving doses of 300 mg/kg or more and in female rats given doses of 1,200 or 1,500 mg/kg. Doses of 1,200 or 1,500 mg/kg produced degeneration and necrosis of hepatocytes, hypoplasia of the bone marrow, lymphoid depletion of the spleen and thymus, and epithelial necrosis of the nasal turbinates in male and female rats. Renal tubular cell degeneration was observed in male rats receiving 300 mg/kg or more in the first study, but only slight changes were seen at 300 mg/kg in the second study. Liver weight to brain weight ratios were increased at 900 mg/kg or more for both male and female rats. The kidney weight to brain weight ratio was increased in male rats receiving doses of 600 mg/kg or more. Administration of 1,4-dichlorobenzene to rats for 13 weeks produced slight but statistically significant decreases in the hematocrit, red blood cell count, and hemoglobin level in all males receiving doses of 300-1,200 mg/kg. No clear hematologic changes were observed in female rats. 1,4-Dichlorobenzene produced minimal changes in clinical chemistry parameters in the 13-week studies. Serum cholesterol levels were increased by doses of 600 mg/kg or more in male rats and 900 mg/kg or more in female rats. Serum triglycerides were reduced by doses of 300 mg/kg or more in male rats. The blood urea nitrogen level was increased slightly in male rats dosed with 900 mg/kg or more. Urinary porphyrins were increased slightly in male rats administered 1,200 or 1,500 mg/kg and female rats receiving 1,200 mg/kg. However, these increases were modest and indicative of a mild porphyrinuria rather than hepatic porphyria. Liver porphyrins were not increased at any dose. Two 13-week studies were performed in mice. The doses selected for the first study were 600-1,800 mg/kg. Survival was decreased in male and female mice receiving doses of 1,500 mg/kg or more, and body weight gain was decreased at all doses. Hepatocellular degeneration was observed in both sexes at all doses, and the liver weight to brain weight ratio was increased at doses of 900 mg/kg or more. Serum cholesterol levels were increased in male mice at doses of 900 mg/kg or more, whereas serum protein and triglycerides were increased at doses of 1,500 mg/kg or more. These relatively modest clinical chemistry changes probably reflect the hepatic effects of this compound. The white blood cell count was reduced significantly in male mice receiving doses of 600 mg/kg or more and female mice receiving 1,000 mg/kg or more, but this effect was not dramatic. Hepatic porphyria was not found in mice at any dose in the 13-week study. Because hepatic effects were seen in all dose groups in the first study, a second 13-week study was performed at doses of 85-900 mg/kg. In this study, hepatocellularellular cytomegaly was observed im male and female mice at doses of 675 mg/kg or more but not at 338 mg/kg. Renal damage was not observed in mice in either 13-week study. Based on the histopathologic findings in the kidney of male rats and in the liver of both sexes of rats and mice in the 13-week studies, the doses selected for the 2-year studies were 150 and 300 mg/kg for male rats and 300 and 600 mg/kg for female rats and male and female mice. In the 2-year studies, survival of female rats and of both sexes of mice was comparable to that of the vehicle controls; survival of high dose male rats was significantly lower than that of the vehicle controls (vehicle control, 32/50; low dose, 31/50; high dose, 20/50). Mean body weights of high dose male rats were 5&amp;percnt;-8&amp;percnt; lower than those of vehicle controls after week 38, and those of high dose female rats were 5&amp;percnt;-7&amp;percnt; lower than those of vehicle controls after week 55. Mean body weights of mice dosed with 1,4-dichlorobenzene were comparable to those of vehicle controls throughout the studies. Administration of 1,4-dichlorobenzene to male rats increased the average seveity of nephropathy and caused epithelial hyperplasia of the renal pelvis (1/50; 30/50; 31/50), mineralization of the collecting tubules in the renal medulla (4/50; 46/50; 47/50), and focal hyperplasia of renal tubular epithelium (0/50; 1/50; 9/50). There were increased incidences of nephropathy in both low and high dose female rats compared with vehicle controls (21/49; 32/50; 41/49). 1,4-Dichlorobenzene produced a dose-related increase in the incidence of tubular cell adenocarcinomas of the kidney in male rats (1/50; 3/50; 7/50); one tubular cell adenoma was observed in a high dose male rat. These malignant tumors are uncommon in male F344/N rats. They have been diagnosed in only 4/1,098 (0.4&amp;percnt;) corn oil gavage controls in previous NTP studies. There were no tubular cell tumors in dosed or vehicle control female rats. There was a marginal increase in the incidence of mononuclear cell leukemia in dosed male rats compared with that in vehicle controls (5/50; 7/50; 11/50). 1,4-Dichlorobenzene increased the incidences of nonneoplastic liver lesions in male and female mice, including alteration in cell size (cytomegaly and karyomegaly), hepatocellular degeneration, and individual cell necrosis. 1,4-Dichlorobenzene also increased the incidences of nephropathy in male mice and renal tubular regeneration in female mice. 1,4-Dichlorobenzene increased the incidences of hepatocellular carcinomas in high dose male (14/50; 11/49; 32/50) and female (5/50; 5/48; 19/50) mice and hepatocellular adenomas in dosed male (5/50; 13/49; 16/50) and high dose female (10/50; 6/48; 21/50) mice. Hepatoblastomas were observed in four high dose male mice but not in vehicle controls. This rare tumor has not occurred in 1,091 male vehicle control mice in NTP studies. An increase in thyroid gland follicular cell hyperplasia was observed in dosed male mice (1/47; 4/48; 10/47), and there was a marginal positive trend in the incidence of follicular cell adenomas of the thyroid gland in female mice (0/48; 0/45; 3/46). Pheochromocytomas (benign or malignant, combined) of the adrenal gland occurred with a positive trend in dosed male mice, and the incidence in the high dose group was significantly greater than in vehicle controls (0/47; 2/48; 4/49). The incidence of adrenal gland medullary hyperplasia in male mice was 2/47; 4/48; and 4/49. Focal hyperplasia of the adrenal gland capsule was also observed in dosed male mice (11/47;21/48; 28/49). 1,4-Dichlorobenzene was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 with or without activation by Aroclor 1254-induced male Sprague-Dawley rat or male Syrian hamster liver S9 when tested according to a preincubational protocol at concentrations up to 100 ug/plate. 1,4-Dichlorobenzene did not induce forward mutations in the mouse lymphoma L5178Y/TK&amp;plusmn; assay in the absence of exogenous metabolic activation; however, the results were equivocal in this system in the presence of metabolic activation. 1,4-Dichlorobenzene did not produce an increase in sister-chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells in culture with or without exogenous metabolic activation. No increase in micronucleated cells was seen in erythrocytes of mice from the first 13-week studies. An audit of the experimental data was conducted for the 2-year studies of 1,4-dichlorobenzene. No data discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year gavage studies, 1,4-dichlorobenzene produced clear evidence of carcinogenicity for male F344/N rats, as shown by an increased incidence of renal tubular cell adenocarcinomas. There was no evidence of carcinogenicity for female F344/N rats receiving doses of 300 or 600 mg/kg. There was clear evidence of carcinogenicity for both male and female B6C3F1 mice, as shown by increased incidences of hepatocellular carcinomas and hepatocellular adenomas. Marginal increases were observed in the incidences of pheochromocytomas of the adrenal gland in male mice. Nonneoplastic effects in the kidney of male and female rats, in the liver of male and female mice, and in the thyroid gland and adrenal gland of male mice were also associated with the administration of 1,4-dichlorobenzene. Synonyms: p-dichlorobenzene; para-dichlorobenzene; para-chlorophenyl chloride

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MedImmune Vaccines (formerly Aviron) has developed a cold-adapted live influenza virus vaccine [FluMist] that can be administered by nasal spray. FluMist is the first live virus influenza vaccine and also the first nasally administered vaccine to be marketed in the US. The vaccine will be formulated to contain live attenuated (att) influenza virus reassortants of the strains recommended by the US Public Health Service for each 'flu season. The vaccine is termed cold-adapted (ca) because the virus has been adapted to replicate efficiently at 25 degrees C in the nasal passages, which are below normal body temperature. The strains used in the seasonal vaccine will also be made temperature sensitive (ts) so that their replication is restricted at 37 degrees C (Type B strains) and 39 degrees C (Type A strains). The combined effect of the antigenic properties and the att, ca and ts phenotypes of the influenza strains contained in the vaccine enables the viruses to replicate in the nasopharynx to produce protective immunity. The original formulation of FluMist requires freezer storage throughout distribution. Because many international markets do not have distribution channels well suited to the sale of frozen vaccines, Wyeth and MedImmune are collaborating to develop a second generation, refrigerator-stable, liquid trivalent cold-adapted influenza vaccine (CAIV-T), which is in phase III trials. Initially, the frozen formulation will only be available in the US. For the 2003-2004 season, FluMist will contain A/New Caledonia/20/99 (H1N1), A/Panama/2007/99 (H3N2) (A/Moscow/10/99-like) and B/Hong Kong/330/2001. Aviron was acquired by MedImmune on 15 January 2002. Aviron is now a wholly-owned subsidiary of MedImmune and is called MedImmune Vaccines. Aviron acquired FluMist in March 1995 through a Co-operative Research and Development Agreement (CRADA) with the US NIAID, and a licensing agreement with the University of Michigan, Ann Arbor, USA. In June 2000, the CRADA was extended through to June 2003. Aviron holds exclusive worldwide rights to the vaccine except for Japan, where Kaketsuken Pharmaceuticals (also known as Chemo-Sero-Therapeutic Research Institute) is the licensee. Aviron signed a development and licensing agreement with Sang-A in Korea, which was to manufacture and market FluMist in South Korea. However, in 2000, Aviron terminated all rights and licences to Sang-A relating to FluMist. Sang-A responded by filing a suit against Aviron in August 2000, for breach of contract and unfair and deceptive business practices. Aviron filed a counter claim denying the allegations in late Sept 2001. In 1999, Aviron entered into an agreement with Wyeth-Lederle Vaccines for worldwide collaboration in the marketing of FluMist. Under the $US400 million agreement, Aviron granted Wyeth-Lederle Vaccines exclusive worldwide rights to market FluMist. Wyeth-Lederle Vaccines and Aviron (now Med-Immune Vaccines) will co-promote FluMist in the US, while Wyeth-Lederle Vaccines will have the exclusive right to market the product ex-US. Wyeth will hold marketing rights for up to 11 years. The collaboration excludes Korea, Australia, New Zealand and certain South Pacific countries. The companies will collaborate on the regulatory, clinical and marketing programmes for FluMist and both will manufacture liquid FluMist. MedImmune Vaccines is to receive an average of 40% of revenues from FluMist; the percentage will be higher in the US and lower in other markets. Aviron received a $US15 million upfront payment upon initiation of the agreement. In December 2000, Aviron received a $US15.5 million milestone payment from American Home Products (now Wyeth) after the US FDA accepted the BLA for FluMist. MedImmune Vaccines will receive a $US20 million milestone payment upon US FDA approval. Aviron also received an additional $US20 million in milestone payments for expaory body recommendations. MedImmune Vaccines is entitled to receive a $US10 million payment for submitting a licence application in Europe, a $US27.5 million payment for approval of a refrigerator-stable liquid formulation of FluMist and as much as $US50 million for licensing of FluMist internationally. In July 2003 MedImmune announced that it had received approximately $US28 million in milestone payments during Q2 of 2003 for the approval of FluMist. CSL Ltd of Australia will collaborate on the development, sale and distribution of MedImmune Vaccine's vaccine in Australia, New Zealand and certain countries in the South Pacific. MedImmune is to acquire vaccine research programmes in respiratory syncytial virus and cytomegalovirus from MedImmune Vaccines. The company's primary interest is in FluMist. In May 2002, MedImmune licensed exclusive rights to Crucell's proprietary human cell line PER.C6 for use in its influenza vaccine programmes. On 11 March 2002, American Home Products changed its name and the names of its subsidiaries Wyeth-Ayerst and Wyeth-Lederle to Wyeth. Wyeth's vaccines division is called Wyeth Vaccines. On 29 September 2000, Aviron announced that it had been awarded a $US2.7 million Challenge Grant from NIAID for development of vaccines against pandemic strains of influenza based on FluMist intranasal technology. The cold-adapted live influenza vaccine has been widely evaluated in the US and Japan since 1975 in clinical trials involving several thousand people. Aviron completed phase II clinical trials in adults in the US and phase III trials in US children aged 15-71 months. Additional phase III trials in adults and the elderly are ongoing. Aviron also commenced phase III trials to test the safety of its intranasal live vaccine in children with moderate to severe asthma. The vaccine is delivered using the AccuSpray nasal delivery system by Becton Dickinson, which will supply the system for FluMist through the 2001-2002 influenza season under an agreement with Aviron made in August 1998. On 7 March 2000, Aviron announced that Wyeth-Lederle Vaccines (now Wyeth Vaccines) had begun a phase II bridging study with a refrigerator-stable liquid formulation of FluMist in the Southern Hemisphere. The randomised single-blind trial is being conducted together with Aviron (now MedImmune Vaccines) and is intended to demonstrate clinical equivalence between frozen and liquid FluMist. At the time of the announcement, more than 500 children aged 1-3 years had been enrolled to receive either frozen or liquid FluMist. The final study population is approximately 1300. If clinical equivalence of the two forms of FluMist is demonstrated in this study, MedImmune Vaccines will be able to use data from trials of frozen FluMist in licence applications for international markets. Aviron submitted a Biologics Licence Application (BLA) to the US FDA in July 1998. The FDA rejected this application on the grounds of a lack of data on manufacturing, validation and stability. In June 1999, Aviron announced that it had completed a bridging study on FluMist designed to provide some of the manufacturing data required by the US FDA on FluMist prepared at one of two manufacturing sites. Preliminary analysis indicated that the results had met the company's objectives. The primary endpoint of the study was to demonstrate that the batch of FluMist blended and filled at Packaging Coordinators, Inc. in Philadelphia had similar immunogenicity for all three 1997-98 influenza strains as the vaccine used in earlier clinical trials, which was manufactured by Medeva Pharma (now Evans Vaccines, a subsidiary of PowderJect Pharmaceuticals) in England. The secondary endpoint was to show that these lots of FluMist had similar safety and tolerability profiles. Aviron then submitted a BLA in October 2000. However, in late July 2001, an FDA advisory committee declined to recommend approval of the vaccine, citing concerns with safety. Aviron subsequently received a Complete Response Letter from the FDA requesting additional clinical and manufacturing data. Aviron stated that it should be able to provide these data without conducting further clinical trials. In January 2002, Aviron submitted additional clinical and manufacturing data on FluMist to the US FDA. MedImmune received a second Complete Response Letter from the US FDA on 10 July 2002, requesting clarification and additional data relating to previously submitted information. One of the most significant issues raised by the US FDA was the exacerbated rate of asthma and wheezing in 18-35-month-old patients using FluMist. MedImmune is considering two options to address this issue; to either exclude patients with asthma and wheezing from the label, or to exclude 18- to 30-month-old patients from the proposed indication. On 26 August 2002, MedImmune reported that it had completed the submission of information requested by the US FDA for FluMist. On 17 December 2002, the US FDA's Vaccination and Related Biologicals Products Advisory Committee (VRBPAC) recommended that the FDA approve FluMist to prevent influenza in healthy children, adolescents and adults (ages 5-49 years). Even though the VRBPAC voted in favour of the product's safety in the 50- to 64-year age group, they believed that the data set on efficacy for this age group was insufficient. The committee has also recommended that head-to-head studies should be conducted comparing FluMist to the marketed trivalent inactivated vaccine. Additional clinical trials suggested by the VRBPAC were shedding studies to more clearly define the probability of transmitting the influenza vaccine virus to a high-risk patient and annual revaccination studies. On 30 January 2003, MedImmune announced that it had received a Complete Response Letter from the US FDA requesting clarification and additional information relating to data previously submitted. No additional clinical trials were requested. The company responded to the five questions contained in the letter on 7 February 2003. (ABSTRACT TRUNCATED)

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Dibromoacetic acid is a water disinfection by-product. Dibromoacetic acid was nominated to the National Toxicology Program by the United States Environmental Protection Agency for toxicity and carcinogenicity studies in rats and mice because of widespread human exposure and because a related dihaloacetate, dichloroacetate, was found to be carcinogenic to the liver of rats and mice. Drinking water was selected as the route of exposure to mimic human exposure to this chemical. Male and female F344/N rats and B6C3F1 mice were exposed to dibromoacetic acid (greater than 99% pure) in drinking water for 2 weeks, 3 months, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and peripheral blood erythrocytes of exposed mice. 2-WEEK STUDY IN RATS: Groups of five male and five female rats were exposed to 0, 125, 250, 500, 1,000, or 2,000 mg/L dibromoacetic acid in drinking water for 2 weeks, equivalent to average daily doses of approximately 17, 32, 67, 134, 270 (males), or 257 (females) mg dibromoacetic acid/kg body weight. All rats survived to the end of the study. Mean body weight gains of 1,000 mg/L males and of 500 mg/L females were significantly greater than those of the controls. Water consumption by exposed and control groups was similar. Liver weights of exposed males and females were significantly increased. Right testis weights of males exposed to 500 mg/L or greater were significantly decreased. The incidences of hepatocytic cytoplasmic alteration were significantly increased in males exposed to 500 mg/L or greater and in 2,000 mg/L females. Testicular lesions, characterized by a delay in spermiation and retained spermatids, were noted in males exposed to 500 mg/L or higher concentrations. 2-WEEK STUDY IN MICE: Groups of five male and five female mice were exposed to 0, 125, 250, 500, 1,000, or 2,000 mg/L dibromoacetic acid (equivalent to average daily doses of approximately 24, 47, 95, 178, or 370 mg/kg to males and 22, 53, 88, 166, or 309 mg/kg to females) in drinking water for 2 weeks. All mice survived to the end of the study. Mean body weight gains of 250 and 500 mg/L males were significantly greater than those of the controls. Water consumption by exposed and control groups was similar. Liver weights of males and females in the 1,000 and 2,000 mg/L groups were significantly increased. Thymus weights of males and females in the 1,000 and 2,000 mg/L groups were significantly less than those of controls. The incidences of thymus atrophy were significantly increased in 1,000 and 2,000 mg/L males and 2,000 mg/L females. The incidences of morphological changes to the germinal epithelium of the testes were increased in males exposed to 1,000 or 2,000 mg/L. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were exposed to 0, 125, 250, 500, 1,000, or 2,000 mg/L dibromoacetic acid (equivalent to average daily doses of approximately 10, 20, 40, 90, and 166 mg/kg to males and 12, 23, 48, 93, and 181 mg/kg to females) in drinking water for 3 months. All rats survived to the end of the study. Mean body weights of male and female rats in the 2,000 mg/L group were significantly less than those of controls. Water consumption by the 2,000 mg/L males at weeks 1 and 13 and by females at week 13 was less than that by controls. Small decreases in the erythron and platelet counts occurred in rats exposed to 2,000 mg/L; minimally impaired erythropoiesis was also seen in 1,000 mg/L rats. Liver weights of all exposed groups of males and females were significantly increased. Male rats in the 2,000 mg/L group had significantly decreased testis weights. Testicular atrophy was noted in the 2,000 mg/L group, and retained spermatids were observed in the 500 and 1,000 mg/L groups. In the pituitary gland of male rats exposed to 2,000 mg/L, the incidence of cellular hypertrophy was significantly increased. The incidences of hepatocellular vacuolization were significantly increased in males exposed to 500 mg/L or greater and in females exposed to 2,000 mg/L. Hematopoietic cell proliferation was noted in females in the 2,000 mg/L group. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female mice were exposed to 0, 125, 250, 500, 1,000, or 2,000 mg/L dibromoacetic acid (equivalent to average daily doses of approximately 16, 30, 56, 115, and 230 mg/kg to males and 17, 34, 67, 132, and 260 mg/kg to females) in drinking water for 3 months. All mice survived to the end of the study. Mean body weights and body weight gains of female mice in the 2,000 mg/L group and the mean body weight gain of 2,000 mg/L males were significantly less than those of controls. Water consumption by males in the 2,000 mg/L group was decreased at weeks 1 and 13 relative to controls. Small decreases in mean cell hemoglobin and platelet counts occurred in 2,000 mg/L male mice. Liver weights of males and females exposed to 500 mg/L or greater were significantly increased. Hepatocellular cytoplasmic vacuolization was present in most mice and the severity was increased in 1,000 and 2,000 mg/L males and females. The incidences of abnormal testicular morphology were significantly increased in 1,000 and 2,000 mg/L males. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were exposed to drinking water containing 0, 50, 500, and 1,000 mg/L dibromoacetic acid for 2 years (equivalent to average daily doses of approximately 2, 20, and 40 mg/kg to males and 2, 25, and 45 mg/kg to females). Survival of exposed rats was similar to that of the control groups. Mean body weights of 1,000 mg/L males and females were less than those of the controls after weeks 29 and 53, respectively, and those of 500 mg/L males and females were less after weeks 57 and 85, respectively. Water consumption by males and females exposed to 1,000 mg/L was less than that by controls during year 2 of the study. The incidence of malignant mesothelioma was significantly increased in 1,000 mg/L male rats. A positive trend in the incidence of mononuclear cell leukemia occurred in female rats, and the incidence in 1,000 mg/L females was significantly increased. The incidences of mononuclear cell leukemia were increased in 50 and 500 mg/L males. The incidences of cystic degeneration of the liver were significantly increased in all exposed groups of male rats. The incidences of alveolar epithelial hyperplasia were significantly increased in 500 and 1,000 mg/L females, and the incidences of nephropathy were significantly increased in all exposed groups of females. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were exposed to drinking water containing 0, 50, 500, and 1,000 mg/L dibromoacetic acid for 2 years (equivalent to average daily doses of approximately 4, 45, and 87 mg/kg to males and 4, 35, and 65 mg/kg to females). Survival of exposed mice was similar to that of the controls. Mean body weights of 50 and 500 mg/L male mice were greater than those of the controls after week 85. Water consumption by exposed mice was generally similar to that by controls throughout the study. The incidences of liver neoplasms occurred with positive trends in male and female mice. The incidences of multiple hepatocellular adenoma and hepatocellular adenoma or carcinoma (combined) were significantly increased in all exposed groups of males and in 500 and 1,000 mg/L females. The incidences of hepatoblastoma were significantly increased in 500 and 1,000 mg/L males, and the incidences of hepatocellular carcinoma were significantly increased in 1,000 mg/L males and 500 mg/L females. The incidences of alveolar/bronchiolar adenoma occurred with positive trends in males and females, and the incidence in 500 mg/L male mice was significantly greater than that in controls. Dibromoacetic acid was mutagenic in Salmonella typhimurium strain TA100 with and without rat or hamster liver metabolic activation enzymes (S9); no activity was detected in strain TA98, with or without S9. Increased frequencies of micronucleated normochromatic erythrocytes were observed in peripheral blood samples from male, but not female, mice administered dibromoacetic acid in drinking water for 3 months. Under the conditions of these studies, there was some evidence of carcinogenic activity of dibromoacetic acid in male rats based on an increased incidence of malignant mesothelioma. The increased incidences of mononuclear cell leukemia in male rats may have been related to dibromoacetic acid exposure. There was some evidence of carcinogenic activity of dibromoacetic acid in female rats based on an increased incidence and positive trend of mononuclear cell leukemia. There was clear evidence of carcinogenic activity of dibromoacetic acid in male and female mice based on increased incidences of hepatocellular neoplasms and hepatoblastoma (males only). Increased incidences of lung neoplasms in male mice were also considered to be exposure related. The slight increased incidence of lung neoplasms in female mice may have been related to dibromoacetic acid exposure. Exposure to dibromoacetic acid for 2 years caused increased incidences of cystic degeneration of the liver in male rats, increased incidences of alveolar epithelial hyperplasia and nephropathy in female rats, and increased incidences of splenic hematopoiesis in male mice.

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For cases of acute respiratory distress syndrome (ARDS) and progressive chronic respiratory failure, the first choice or treatment is mechanical ventilation. For decades, this method has been used to support critically ill patients in respiratory failure. Despite its life-saving potential, however, several experimental and clinical studies have suggested that ventilator-induced lung injury can adversely affect the lungs and patient outcomes. Current opinion is that by reducing the pressure and volume of gas delivered to the lungs during mechanical ventilation, the stress applied to the lungs is eased, enabling them to rest and recover. In addition, mechanical ventilation may fail to provide adequate gas exchange, thus patients may suffer from severe hypoxia and hypercapnea. For these reasons, extracorporeal lung support technologies may play an important role in the clinical management of patients with lung failure, allowing not only the transfer of oxygen and carbon dioxide (CO(2)) but also buying the lungs the time needed to rest and heal. The objective of this analysis was to assess the effectiveness, safety, and cost-effectiveness of extracorporeal lung support technologies in the improvement of pulmonary gas exchange and the survival of adult patients with acute pulmonary failure and those with end-stage chronic progressive lung disease as a bridge to lung transplantation (LTx). The application of these technologies in primary graft dysfunction (PGD) after LTx is beyond the scope of this review and is not discussed. CLINICAL APPLICATIONS OF EXTRACORPOREAL LUNG SUPPORT: Extracorporeal lung support technologies [i.e., Interventional Lung Assist (ILA) and extracorporeal membrane oxygenation (ECMO)] have been advocated for use in the treatment of patients with respiratory failure. These techniques do not treat the underlying lung condition; rather, they improve gas exchange while enabling the implantation of a protective ventilation strategy to prevent further damage to the lung tissues imposed by the ventilator. As such, extracorporeal lung support technologies have been used in three major lung failure case types: As a bridge to recovery in acute lung failure - for patients with injured or diseased lungs to give their lungs time to heal and regain normal physiologic function.As a bridge to LTx - for patients with irreversible end stage lung disease requiring LTx.As a bridge to recovery after LTx - used as lung support for patients with PGD or severe hypoxemia. EX-VIVO LUNG PERFUSION AND ASSESSMENT: Recently, the evaluation and reconditioning of donor lungs ex-vivo has been introduced into clinical practice as a method of improving the rate of donor lung utilization. Generally, about 15% to 20% of donor lungs are suitable for LTx, but these figures may increase with the use of ex-vivo lung perfusion. The ex-vivo evaluation and reconditioning of donor lungs is currently performed at the Toronto General Hospital (TGH) and preliminary results have been encouraging (Personal communication, clinical expert, December 17, 2009). If its effectiveness is confirmed, the use of the technique could lead to further expansion of donor organ pools and improvements in post-LTx outcomes. EXTRACORPOREAL LUNG SUPPORT TECHNOLOGIES: ECMO: The ECMO system consists of a centrifugal pump, a membrane oxygenator, inlet and outlet cannulas, and tubing. The exchange of oxygen and CO(2) then takes place in the oxygenator, which delivers the reoxygenated blood back into one of the patient's veins or arteries. Additional ports may be added for haemodialysis or ultrafiltration. TWO DIFFERENT TECHNIQUES MAY BE USED TO INTRODUCE ECMO: venoarterial and venovenous. In the venoarterial technique, cannulation is through either the femoral artery and the femoral vein, or through the carotid artery and the internal jugular vein. In the venovenous technique cannulation is through both femoral veins or a femoral vein and internal jugular vein; one cannula acts as inflow or arterial line, and the other as an outflow or venous line. Venovenous ECMO will not provide adequate support if a patient has pulmonary hypertension or right heart failure. Problems associated with cannulation during the procedure include bleeding around the cannulation site and limb ischemia distal to the cannulation site. ILA: Interventional Lung Assist (ILA) is used to remove excess CO(2) from the blood of patients in respiratory failure. The system is characterized by a novel, low-resistance gas exchange device with a diffusion membrane composed of polymethylpentene (PMP) fibres. These fibres are woven into a complex configuration that maximizes the exchange of oxygen and CO(2) by simple diffusion. The system is also designed to operate without the help of an external pump, though one can be added if higher blood flow is required. The device is then applied across an arteriovenous shunt between the femoral artery and femoral vein. Depending on the size of the arterial cannula used and the mean systemic arterial pressure, a blood flow of up to 2.5 L/min can be achieved (up to 5.5 L/min with an external pump). The cannulation is performed after intravenous administration of heparin. Recently, the first commercially available extracorporeal membrane ventilator (NovaLung GmbH, Hechingen, Germany) was approved for clinical use by Health Canada for patients in respiratory failure. The system has been used in more than 2,000 patients with various indications in Europe, and was used for the first time in North America at the Toronto General Hospital in 2006. EVIDENCE-BASED ANALYSIS: The research questions addressed in this report are: Does ILA/ECMO facilitate gas exchange in the lungs of patients with severe respiratory failure?Does ILA/ECMO improve the survival rate of patients with respiratory failure caused by a range of underlying conditions including patients awaiting LTx?What are the possible serious adverse events associated with ILA/ECMO therapy?To address these questions, a systematic literature search was performed on September 28, 2009 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing &amp; Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 2005 to September 28, 2008. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search. Articles with an unknown eligibility were reviewed with a second clinical epidemiologist and then a group of epidemiologists until consensus was established. Studies in which ILA/ECMO was used as a bridge to recovery or bridge to LTxStudies containing information relevant to the effectiveness and safety of the procedureStudies including at least five patients Studies reporting the use of ILA/ECMO for inter-hospital transfers of critically ill patientsStudies reporting the use of ILA/ECMO in patients during or after LTxAnimal or laboratory studiesCase reports Reduction in partial pressure of CO(2)Correction of respiratory acidosisImprovement in partial pressure of oxygenImprovement in patient survivalFrequency and severity of adverse eventsThe search yielded 107 citations in Medline and 107 citations in EMBASE. After reviewing the information provided in the titles and abstracts, eight citations were found to meet the study inclusion criteria. One study was then excluded because of an overlap in the study population with a previous study. Reference checking did not produce any additional studies for inclusion. Seven case series studies, all conducted in Germany, were thus included in this review (see Table 1). Also included is the recently published CESAR trial, a multicentre RCT in the UK in which ECMO was compared with conventional intensive care management. The results of the CESAR trial were published when this review was initiated. In the absence of any other recent RCT on ECMO, the results of this trial were considered for this assessment and no further searches were conducted. A literature search was then conducted for application of ECMO as bridge to LTx patients (January, 1, 2005 to current). A total of 127 citations on this topic were identified and reviewed but none were found to have examined the use of ECMO as bridge to LTx. To grade the quality of evidence, the grading system formulated by the GRADE working group and adopted by MAS was applied. The GRADE system classifies the quality of a body of evidence as high, moderate, low, or very low according to four key elements: study design, study quality, consistency across studies, and directness. TRIALS ON ILA: Of the seven studies identified, six involved patients with ARDS caused by a range of underlying conditions; the seventh included only patients awaiting LTx. All studies reported the rate of gas exchange and respiratory mechanics before ILA and for up to 7 days of ILA therapy. Four studies reported the means and standard deviations of blood gas transfer and arterial blood pH, which were used for meta-analysis. Fischer et al. reported their first experience on the use of ILA as a bridge to LTx. In their study, 12 patients at high urgency status for LTx, who also had severe ventilation refractory hypercapnea and respiratory acidosis, were connected to ILA prior to LTx. Seven patients had a systemic infection or sepsis prior to ILA insertion. Six hours after initiation of ILA, the partial pressure of CO(2) in arterial blood significantly decreased (P &lt; .05) and arterial blood pH significantly improved (P &lt; .05) and remained stable for one week (last time point reported). (ABSTRACT TRUNCATED)

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The objectives were to identify the components of a program to deliver early defibrillation that optimizes the effectiveness of automated external defibrillators (AEDs) in out-of-hospital and hospital settings, to determine whether AEDs are cost-effective, and if cost-effectiveness was determined, to advise on how they should be distributed in Ontario. Survival in people who have had a cardiac arrest is low, especially in out-of-hospital settings. With each minute delay in defibrillation from the onset of cardiac arrest, the probability of survival decreases by 10%. (1) Early defibrillation (within 8 minutes of a cardiac arrest) has been shown to improve survival outcomes in these patients. However, in out-of-hospital settings and in certain areas within a hospital, trained personnel and their equipment may not be available within 8 minutes. This implies that "first responders" should take up the responsibility of delivering shock. The first responders in out-of-hospital settings are usually bystanders, firefighters, police, and community volunteers. In hospital settings, they are usually nurses. These first responders are not trained in reading electrocardiograms and identifying abnormal heart rhythms restorable by defibrillation. An AED is a device that can analyze a heart rhythm and deliver a shock if needed. Thus, AEDs can be used by first responders to deliver early defibrillation in out-of-hospital and hospital settings. However, simply providing an AED would not likely improve survival outcomes. Rather, AEDs have a role in strengthening the "chain of survival," which includes prompt activation of the 911 telephone system, early cardiopulmonary resuscitation (CPR), rapid defibrillation, and timely advanced life support. In the chain of survival, the first step for a witness of a cardiac arrest in an out-of-hospital setting is to call 911. Second, the witness initiates CPR (if she or he is trained in CPR). If the witness cannot initiate CPR, or the first responders of the 911 system (e.g., firefighters/police) have arrived, the first responders initiate CPR. Third, the witness or first responders apply an AED to the patient. The device reads the patient's heart rhythm and prompts for shock when indicated. Fourth, the patient is handed over to the advanced life-support team with subsequent admission to an intensive care unit in a hospital. The use of AEDs requires developing and implementing a program at sites where the cardiac arrest rate is high, where a number of potential first responders are trained and retained, and where patients are transferred to an advanced care facility after initiating resuscitation. Obviously, placing an AED at a site where no cardiac arrests are likely to occur would be futile, as would placing an AED at a site where no one knows how to use it. Moreover, abandoning patients after initial resuscitation by not transferring them to an advanced care facility would negate all earlier efforts. Thus, it is important to identify the essential components of an AED program that might also optimize the effectiveness of AED use. There is a large body of literature on the use of AEDs in various settings ranging from closed environments such as hospitals, airlines, and casinos to open places such as sports fields and highways. There is little doubt regarding the effectiveness and safety of AEDs to treat people in cardiac arrest. It is intuitive that these devices should be provided in hospitals in areas that are not readily accessible to the traditional responders, the "code blue team." Similarly, it is intuitive to provide AEDs in out-of-hospital settings where the risk of cardiac arrest is high and a response plan involving trained first responders in the use of AEDs is in place. Thus, the Medical Advisory Secretariat reviewed the literature and focused on the components of an AED program in out-of-hospital settings that maximize the effectiveness and cost-effectiveness of the program in the management of cardiac arrest. Search engines included MEDLINE, EMBASE, EconLit and Web sites of other agencies that assess health technologies. Any study that reported results of an AED program in an out-of-hospital setting was included. Studies that did not use AEDs, had a physician-assisted emergency response plan, did not have a program for the use of AEDs, or did not include cardiac arrest as an outcome were excluded. A total of 133 articles were identified; 62 were excluded after reviewing titles and abstracts. Of the 71 articles reviewed, 8 reported findings of 2 large studies, the Ontario Prehospital Advanced Life Support (OPALS) study and the Public Access Defibrillation (PAD) trial. These studies examined the effect of a community program to respond to cardiac arrest with and without the use of AEDs. Their authors had reported a significant reduction in overall mortality from cardiac arrest with the use of AEDs. Factors That Improve the Effectiveness of an AED Program The PAD trial investigators reported a significant improvement in survival (P = .03) after providing AEDs in public access areas and training volunteers in CPR compared with training volunteers in CPR only. The OPALS study investigators reported odds ratios (ORs) and 95% confidence intervals (CIs) for significant predictors of survival, which were age (OR [age per 10 year], 0.8; CI, 0.8-0.9), arrest witnessed by bystander (OR, 3.9; CI, 2.7-5.5), CPR initiated by bystander (OR, 3.7; CI, 2.6-5.1), CPR initiated by first responder (OR, 1.6; CI, 1.1-2.3), and emergency medical service response within 8 minutes (OR, 3.0; CI, 1.8-5.1). The last 3 variables are modifiable and thus may improve the effectiveness of an AED program. For example, the rate of bystander-initiated CPR was only 14% in the OPALS study, but it was 100% in the PAD trial. This was because PAD trial investigators trained community volunteers whereas the OPALS study investigators did not. Cost-Effectiveness A systematic review of the literature suggests that cost-effectiveness varies from setting to setting. Most of the studies have estimated cost-effectiveness in American settings from a societal perspective; therefore, the results are not applicable to this report. However, results from this review suggest that the incidence of cardiac arrest in out-of-hospital setting in Ontario is 59 per 100,000 people. The mean age of cardiac arrest patients is 69 years. Eighty-five percent of these cardiac arrests occur in homes. Of all the cardiac arrests, 37% have heart rhythm abnormalities (ventricular tachycardia or ventricular fibrillation) that are correctable by delivering shock through an AED. Thus, in an out-of-hospital setting, general use of AEDs by laypersons would not be cost-effective. Special programs are needed in the out-of-hospital setting for cost-effective use of AEDs. One model for the use of AEDs in out-of-hospital settings was examined in the OPALS study. Firefighters and police were trained and provided with AEDs. The total initial cost (in US dollars) of this program was estimated to be $980,000. The survival rate was 3.9% before implementing the AED program and 5.2% after its implementation (OR, 1.33; 95% CI, 1.03-1.7; P = .03). Applying these estimates to cardiac arrest rates in Ontario in 2002, one would expect 54 patients of the total 1,395 cardiac arrests to survive without AEDs compared with 73 patients with AEDs; thus, 19 additional lives might be saved each year with an AED program. It would initially cost $51,579 to save each additional life. In subsequent years, however, total cost would be lower (about $50,000 per year), when it would cost $2,632 to save each additional life per year. One limitation of the OPALS study was that the authors combined emergency medical service response time and application of an AED into a single variable. Thus, it was not possible to tease out the independent effects of reduction in response time and application of an AED on the small improvement in survival. Nevertheless, the PAD study found that when response time was fixed, the application of AED improved survival. There are other delivery models for AEDs in casinos, sports arenas, and airports. The proportion of cardiac arrest at these sites out of the total cardiac arrests in Ontario is between 0.05% and 0.4%. Thus, an AED placed at these sites would likely not be used at all. Of the 85% cardiac arrests that occur in homes, 56% occur in single residential dwellings (houses), 23% occur in multi-residential dwellings (apartments/condominiums), and 6% occur in nursing homes. There is no program in place except the 911 system to reach these patients. Accordingly, the Medical Advisory Secretariat examined the cost-effectiveness of providing AEDs in hospitals, office buildings, apartments/condominiums, and houses. The results suggested that deployment of AEDs in hospitals would be cost-effective in terms of cost per quality adjusted life year gained. Conversely, deployment of AEDs in office buildings, apartments, and houses was not cost-effective. An exception, however, was noted for people at high risk of sudden cardiac arrest; these were patients with a left ventricular ejection fraction less than or equal to 0.35. The OPALS study model appears cost-effective, and effectiveness can be further enhanced by training community volunteers to improve the bystander-initiated CPR rates. Deployment of AEDs in all public access areas and in houses and apartments is not cost-effective. Further research is needed to examine the benefit of in-home use of AEDs in patients at high risk of cardiac arrest.

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EXECUTIVE SUMMARY: Across the developed world, we are witnessing an increasing emphasis on the need for more closely coordinated forms of health and social care provision. Integrated care pathways (ICPs) have emerged as a response to this aspiration and are believed by many to address the factors which contribute to service integration. ICPs map out a patient's journey, providing coordination of services for users. They aim to have: 'the right people, doing the right things, in the right order, at the right time, in the right place, with the right outcome'. The value for ICPs in supporting the delivery of care across organisational boundaries, providing greater consistency in practice, improving service continuity and increasing collaboration has been advocated by many. However, there is little evidence to support their use, and the need for systematic evaluations in order to measure their effectiveness has been widely identified. A recent Cochrane review assessed the effects of ICPs on functional outcome, process of care, quality of life and hospitalisation costs of inpatients with acute stroke, but did not specifically focus on service integration or its derivatives. To the best of our knowledge, no such systematic review of the literature exists. • To systematically review all high-quality studies which have evaluated the impact of care pathway technologies on 'service integration' and its derivatives in stroke care • To examine how elements of service integration are defined in such studies • To examine the type of evidence utilised to measure service integration • To analyse the weight of evidence used to support claims about the effectiveness of ICPs on improving service integration • To produce recommendations for ICP developers, users and evaluators. Types of participants The review focused on the care of adult patients who had suffered a stroke. It included the full spectrum of services - acute care, rehabilitation and long-term support - in hospital and community settings. Types of intervention(s)/phenomena of interest Integrated care pathways were the intervention of interest, defined for the purpose of this review as 'a multidisciplinary tool to improve the quality and efficiency of evidence based care and is used as a communication tool between professionals to manage and standardise the outcome orientated care' Here 'multidisciplinary' is taken to refer to the involvement of two or more disciplines. Types of outcomes 'Service integration' was the outcome of interest however, this was defined and measured in the selected studies. Types of studies This review was concerned with how 'service integration' was defined in evaluations of ICPs; the type of evidence utilised in measuring the impact of the intervention and the weight of evidence to support the effectiveness of care pathway technologies on 'service integration'. Studies that made an explicit link between ICPs and service integration were included in the review. Evidence generated from randomised controlled trials, quasi-experimental, qualitative and health economics research was sought. The search was limited to publications after 1980, coinciding with the emergence of ICPs in the healthcare context. Assessment for inclusion of foreign papers was based on the English-language abstract, where available. These were included only if an English translation was available. This review excluded studies that: • focused only on a single aspect of stroke care (e.g. dysphasia) • evaluated ICPs as part of a wider program of service development • did not make an explicit link between ICPs and service integration • did not meet the definition of ICP utilised for the purposes of the review • focused exclusively on the outcomes of variance analysis In order to avoid replication, the Joanna Briggs Institute for Evidence Based Nursing and Midwifery Database and the Cochrane Library were searched to establish that no systematic reviews existed and none were in progress. A three-stage search strategy was then used to identify both published and unpublished studies (see Appendix III). Our search strategy located 2123 papers, of which 39 were retrieved for further evaluation. We critically appraised seven papers, representing five studies. These were all evaluation studies and, as is typical in this field, comprised a range of study designs and data collection methods. Owing to the diversity of the study types included in the review, we developed a single-appraisal checklist and data-extraction tool which could be applied to all research designs.(32) The tool drew on the Joanna Briggs Institute (JBI) appraisal checklists for experimental studies and interpretive and critical research, and also incorporated specific information and issues which were relevant for our purposes (see Appendix VI). This extends the thinking outlined in Lyne et al.(31) in which, drawing on Campbell and Stanley's classic paper, the case is made for developing an appraisal tool which is applicable to all types of evaluation, irrespective of study design. In assessing the quality of the papers, we were sympathetic to the methodological challenges of evaluating complex interventions such as ICPs. We were also cognisant of the very real constraints in which service evaluations are frequently undertaken in healthcare contexts. In accordance with the aims of this particular review, we have included studies, which are methodologically weaker than is typical of many systematic reviews because, in our view, in the absence of stronger evidence, they yield useful information. Given the heterogeneity of the included studies, meta-analysis and/or qualitative synthesis was not possible. A narrative summary of the study findings is presented. 1 ICPs can be effective in ensuring that patients receive relevant clinical interventions and/or assessments in a timely manner, although these improvements may reflect better documentation rather than actual changes in practice. 2 ICPs can be effective in improving the documentation of rehabilitation goals, documentation of communication with patients, carers (diagnosis, prognosis and follow-up arrangements) and documentation of notification of primary care physicians of discharge. However, this can create additional burdens of work for staff. 3 Early studies of ICP-managed care in the acute stroke context have demonstrated reduced length of stay without any associated adverse effects on discharge destination, morbidity or mortality. These effects do not reach statistical significance, however, and may reflect wider changes in service provision and a general trend towards reduced length of hospital stay. While later studies in the acute and rehabilitation contexts do not reveal any significant reduction in length of stay, they do report greater documented use of certain clinical interventions and assessments, suggesting that ICPs can be effective in mobilising hospital resources around the patient. 4 ICPs implemented in the context of acute stroke care can be effective in reducing the occurrence of urinary tract infections, although we do not know whether this can be attributed to improved service integration. 5 ICP management in stroke rehabilitation may not be flexible enough to meet diverse patient needs and can result in insufficient attention to higher-level functioning and carer needs influencing perceptions of quality of life. 6 ICP management may assist in clarifying role boundaries and a shared understanding of the work, but this can result in some members of the disciplinary team perceiving that their contribution is not appropriately reflected in the documentation. 7 There is some evidence that ICPs may be effective in changing professional behaviours in the desired direction where there is scope for improvement, but in situations in which multidisciplinary working is effective, their positive effects may be limited. Furthermore, it is far from clear what the active ingredients of ICPs actually are. Kwan et al. suggest that it was the process of ICP development that had most impact on behaviours rather than the use of the artefact per se.(20) 8 None of the studies assessed the balance of costs and benefits of ICP use. Therefore, we do not know whether the costs of ICP development and implementation are justified by any of the reported benefits. Implications for practice There is some evidence that ICPs may support certain elements of service integration in the context of stroke care. This seems to be as a result of their ability to support the timely implementation of clinical interventions and the mobilisation of resources around the patient without incurring additional increases in length of stay. ICPs appear to be most successful in improving service coordination in the acute stroke context where patient care trajectories are predictable. Their value in the context of rehabilitation settings in which recovery pathways are more variable is less clear. There is some evidence that ICPs may be effective in bringing about behavioural changes in contexts where deficiencies in service provision have been identified. Their value in contexts where inter-professional working is well established is less clear. While earlier before and after studies show a reduction in length of stay in ICP-managed care, this may reflect wider healthcare trends, and the failure of later studies to demonstrate further reductions suggests that there may be limits as to how far this can continue to be reduced. There is some evidence to suggest that ICPs bring about improvements in documentation, but we do not know how far documented practice reflects actual practice. It is unclear how ICPs have their effects and the relative importance of the process of development and the artefact in use. (ABSTRACT TRUNCATED)

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In the last 12 - 18 months nearly all ultrasound manufacturers have arrived to implement ultrasound shear wave elastography modality in their equipment for the assessment of chronic liver disease; the few remaining players are expected to follow in 2016.When all manufacturers rush to a new technology at the same time, it is evident that the clinical demand for this information is of utmost value. Around 1990, there was similar demand for color Doppler ultrasound; high demand for contrast-enhanced ultrasonography was evident at the beginning of this century, and around 2010 demand increased for strain elastography. However, some issues regarding the new shear wave ultrasound technologies must be noted to avoid misuse of the resulting information for clinical decisions. As new articles are expected to appear in 2016 reporting the findings of the new technologies from various companies, we felt that the beginning of this year was the right time to present an appraisal of these issues. We likewise expect that in the meantime EFSUMB will release a new update of the existing guidelines 1 2.The first ultrasound elastography method became available 13 years ago in the form of transient elastography with Fibroscan(®) 3. It was the first technique providing non-invasive quantitive information about the stiffness of the liver and hence regarding the amount of fibrosis in chronic liver disease 3. The innovation was enormous, since a non-invasive modality was finally available to provide findings otherwise achievable only by liver biopsy. In fact, prior to ultrasound elastography, a combination of conventional and Doppler ultrasound parameters were utilized to inform the physician about the presence of cirrhosis and portal hypertension 4. However, skilled operators were required, reproducibility and diagnostic accuracy were suboptimal, and it was not possible to differentiate the pre-cirrhotic stages of fibrosis. All these limitations were substantially improved by transient elastography, performed with Fibroscan(®), a technology dedicated exclusively to liver elastography. Since then, more than 1300 articles dealing with transient elastography have been listed in PubMed, some describing results with more than 10,000 patients 5. The technique has been tested in nearly all liver disease etiologies, with histology as the reference standard. Meta-analysis of data, available in many etiologies 6, showed good performance and reproducibility as well as some situations limiting reliability 5. Thresholds for the different fibrosis stages (F0 to F4) have been provided by many large-scale studies utilizing histology as the reference standard 7. Transient elastography tracks the velocity of shear waves generated by the gentle hit of a piston on the skin, with the resulting compression wave traveling in the liver along its longitudinal axis. The measurement is made in a 4 cm long section of the liver, thus able to average slightly inhomogeneous fibrotic deposition.In 2008 a new modality became available, Acoustic Radiation Force Impulse (ARFI) quantification, and classified by EFSUMB 1 as point shear wave elastography (pSWE), since the speed of the shear wave (perpendicular to the longitudinal axis) is measured in a small region (a "point", few millimeters) at a freely-choosen depth within 8 cm from the skin. This technology was the first to be implemented in a conventional ultrasound scanner by Siemens(®) 8. Several articles have been published regarding this technology, most with the best reference standards 9, some including findings on more than 1000 hepatitis C patients 10 or reporting meta-analysis of data 11. Although the correlation between Siemens pSWE and transient elastography appeared high 12 13, the calculated thresholds for the different fibrosis stages and the stiffness ranges between the two techniques are not superimposable.Interestingly, pSWE appears to provide greater applicability than transient elastography for measuring both liver 13 and spleen stiffness, which is a new application of elastography 14, of interest for the prediction of the degree of portal hypertension 15 16.Nowadays other companies have started producing equipment with pSWE technology, but only very few articles have been published so far, for instance describing the use of Philips(®) equipment, which was the second to provide pSWE. These articles show preliminary good results also in comparison with TE 17 18. Not enough evidence is currently available in the literature about the elastographic performance of the products most recently introduced to the market. Furthermore, with some products the shear wave velocities generated by a single ultrasound acoustic push pulse can be measured in a bidimensional area (a box in the range of 2 - 3 cm per side) rather than in a single small point, producing a so-called bidimensional 2D-SWE 1. The stiffness is depicted in color within the area and refreshing of the measurement occurs every 1 - 2 seconds. Once the best image is acquired, the operator chooses a Region Of Interest (ROI) within the color box, where the mean stiffness is then calculated. 2D-SWE can be performed as a "one shot" technique or as a semi-"real-time" technique for a few seconds (at about 1 frame per second) in order to obtain a stable elastogram. With either technique, there should be no motion/breathing during image acquisition. A bidimensional averaged area should overcome the limitation of pSWE to inadvertently investigate small regions of greater or lesser stiffness than average. A shear wave quality indicator could be useful to provide real-time feedback and optimize placement of the sampling ROIs, a technology recently presented by Toshiba(®), but which is still awaiting validation in the literature.Supersonic Imagine by Aixplorer(®) which works with a different modality of insonation and video analysis compared to the the previously-mentioned three techniques (i. e., transient elastography, pSWE and 2D-SWE), leading to a bidimensional assessment of liver stiffness in real time up to 5 Hz and in larger regions; thus this technique is also termed real-time 2 D SWE. It has been available on the market for a few years 19 20, and many articles have been published showing stiffness values quite similar to those of Fibroscan(®) 21; likewise, defined thresholds based on histological findings have appeared in several articles 19 20 21.After this brief summary of the technological state of the art we would like to mention the following critical issues that we believe every user should note prior to providing liver stiffness reports. · The thresholds obtained from the "oldest" techniques for the various fibrosis stages based on hundreds of patients with histology as reference standard cannot be straightforwardly applied to the new ultrasound elastography techniques, even if based on the same principle (e. g. pSWE). In fact, the different manufacturers apply proprietary patented calculation modes, which might result in slightly to moderately different values. It should be kept in mind that the range for intermediate fibrosis stages (F1 to F3) is quite narrow, in the order of 2 - 3 kilopascal (over a total range spanning 2 to 75 kPa with Fibroscan), so that slightly different differences in outputs could shift the assessment of patients from one stage to another. Comparative studies using phantoms and healthy volunteers, as well as patients, are eagerly awaited. In fact, the equipment might not produce linear correlations of measurements at different degrees of severity of fibrosis. As a theoretical example, some equipment might well correlate in their values with an older technique, such as transient elastography, at low levels of liver fibrosis, but not as well in cases of more advanced fibrosis or vice versa. Consequentely, when elastography data are included in a report, the equipment utilized for the measurement should be clearly specified, and conclusions about the fibrosis stage should be withheld if an insufficient number of comparative studies with solid reference standards are available for that specific equipment.. · Future studies using histology as a reference might be biased in comparison to previous studies, since nowadays fewer patients with chronic hepatitis C or hepatitis B undergo biopsy. In fact, due to wide availability of effective drugs as well as the use of established elastography methods for patients with viral hepatitis, most cases submitted to biopsy today have uncertain etiology or inconsistent and inconclusive clinical data. Therefore, extrapolated thresholds from such inhomogeneous populations applied to more ordinary patients with viral hepatitis might become problematic in the future, although no better solution is currently anticipated. This situation might lead to the adoption of a standard validated elastographic method as reference, but this has to be agreed-upon at an international level.. · Ultrasound elastography embedded in conventional scanners usually allows the choice of where to place the ROI within the color stiffness box and whether to confirm or exclude each single measurement when determining the final value. Thus, the operator has a greater potential to influence the final findings than with Fibroscan®, where these choices are not available. This has to be kept in mind to avoid the possibility that an operator could, even inadvertently, tend to confirm an assumption about that specific patient or to confirm the patient's expectations.. · Quality criteria for the new technologies following transient elastography are absent (depending on the manufacturer) or have not been satisfactorily defined, so that the information potentially inserted in a report cannot currently be judged for its reliability by the clinician.. (ABSTRACT TRUNCATED)

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DIOXIN TOXIC EQUIVALENCY FACTOR EVALUATION OVERVIEW: Polyhalogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) have the ability to bind to and activate the ligand-activated transcription factor, the aryl hydrocarbon receptor (AhR). Structurally related compounds that bind to the AhR and exhibit biological actions similar to TCDD are commonly referred to as "dioxin-like compounds" (DLCs). Ambient human exposure to DLCs occurs through the ingestion of foods containing residues of DLCs that bioconcentrate through the food chain. Due to their lipophilicity and persistence, once internalized they accumulate in human tissues, mainly adipose, resulting in chronic lifetime human exposure. Since human exposure to DLCs always involves a complex mixture, the toxic equivalency factor (TEF) methodology has been developed as a mathematical tool to assess the health risk posed by complex mixtures of these compounds. The TEF methodology is a relative potency scheme that ranks the dioxin-like activity of a compound relative to TCDD, which is the most potent congener. This allows for the estimation of the potential dioxin-like activity of a mixture of chemicals, based on a common mechanism of action involving an initial binding of DLCs to the AhR. The toxic equivalency of DLCs was nominated for evaluation because of the widespread human exposure to DLCs and the lack of data on the adequacy of the TEF methodology for predicting relative potency for cancer risk. To address this, the National Toxicology Program conducted a series of 2-year bioassays in female Harlan Sprague-Dawley rats to evaluate the chronic toxicity and carcinogenicity of DLCs and structurally related polychlorinated biphenyls (PCBs) and mixtures of these compounds. 2,3,4,7,8-Pentachlorodibenzofuran (PeCDF) is not manufactured commercially other than for scientific research purposes. The main sources of PeCDF releases into the environment are from combustion and incineration sources. PeCDF was selected for study by the National Toxicology Program as a part of the dioxin TEF evaluation to assess the cancer risk posed by complex mixtures of polychlorinated dibenzodioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and PCBs. The dioxin TEF evaluation includes conducting multiple 2-year rat bioassays to evaluate the relative chronic toxicity and carcinogenicity of DLCs, structurally related PCBs, and mixtures of these compounds. While one of the aims of the dioxin TEF evaluation was a comparative analysis across studies, in this Technical Report only the results of the present PeCDF study are presented and discussed. Female Harlan Sprague-Dawley rats were administered PeCDF (at least 97% pure) in corn oil:acetone (99:1) by gavage for 14, 31, or 53 weeks or 2 years. 2-YEAR STUDY: Groups of 81 female rats were administered 6, 20, 44, 92, or 200 ng PeCDF/kg body weight in corn oil:acetone (99:1) by gavage, 5 days per week, for up to 105 weeks; a group of 81 vehicle control female rats received the corn oil/acetone vehicle alone. Up to 10 rats per group were evaluated at 14, 31, and 53 weeks. A stop-exposure group was administered 200 ng/kg PeCDF in corn oil:acetone (99:1) by gavage for 30 weeks and then the vehicle for the remainder of the study. The PeCDF in this study was at least 97% pure. Survival of dosed groups was similar to that of the vehicle control group. Mean body weights of the 200 ng/kg core and stop-exposure groups were less than those of the vehicle controls during year 2 of the study. Thyroid Hormone Concentrations: Alterations in serum thyroid hormone levels were evaluated at the 14-, 31- and 53-week interim evaluations. There were significant decreases in total serum thyroxine (T(4)) levels at the 14-week interim evaluation. There were no significant differences observed in serum free T(4), total triiodothyronine (T(3)), or thyroid stimulating hormone (TSH) at 14 weeks. At both 31 and 53 weeks, there were treatment-related decreases in free and total T(4) concentrations and increases in serum T(3) levels. Serum TSH levels in dosed groups at 31 and 53 weeks were not significantly different than in the vehicle controls. Hepatic Cell Proliferation Data: To evaluate hepatocyte replication, analysis of labeling of replicating hepatocytes with 5-bromo-2'-deoxyuridine (BrdU) was conducted at the 14-, 31-, and 53-week interim evaluations. At 14 and 53 weeks, hepatocyte BrdU-labeling indices were significantly higher in the 200 ng/kg groups compared to time-matched vehicle controls. No significant differences were observed between the dosed groups and vehicle controls at 31 weeks. Cytochrome P450 Enzyme Activities: To evaluate the expression of known dioxin-responsive genes, CYP1A1-associated 7-ethoxyresorufin-O-deethylase (EROD) activity and CYP1A2-associated acetanilide-4-hydroxylase (A4H) activity were evaluated at the 14-, 31-, and 53-week interim evaluations. Hepatic EROD and A4H activities were significantly higher in all groups administered PeCDF relative to the vehicle controls at all three interim evaluations. Pulmonary EROD was also significantly higher in all dosed groups compared to vehicle controls at 14, 31, and 53 weeks. Determinations of PeCDF Concentrations in Tissues: The tissue disposition of PeCDF was analyzed in the liver, lung, fat, and blood of all animals at the 14-, 31-, and 53-week interim evaluations, and in 10 animals per group at the end of the 2-year study (105 weeks). In the liver of vehicle controls, PeCDF concentrations were detectable at 105 weeks. Measurable concentrations of PeCDF were not detected in fat or lung from vehicle control rats at any of the interim evaluations or at 105 weeks. Hepatic and fat concentrations were higher in groups with increasing doses of PeCDF, demonstrating a dose-related increase in tissue burden of PeCDF at each time point. No measurable concentrations of PeCDF were detected in the lungs of vehicle controls or any of the dosed groups at 14 weeks or in the lungs of the vehicle control group at 31, 53, and 105 weeks, or the 6 ng/kg group at 31 and 53 weeks. In groups with measurable levels, PeCDF concentrations were higher with respect to increasing doses. Mean levels of PeCDF in the liver, fat, lung, and blood in the 200 ng/kg group at the end of the 2-year study were 500 ng/g, 7.75 ng/g, 0.28 ng/g and 0.04 ng/mL, respectively. Negligible PeCDF concentrations were observed in blood of the 200 ng/kg group at 53 weeks and the 92 and 200 ng/kg groups at 105 weeks. In liver and fat from the stop-exposure group, the PeCDF concentrations were between the levels observed in the 6 and 20 ng/kg groups. In the stop-exposure group, PeCDF concentration in lung was comparable to levels observed in the 6 ng/kg group. No measurable concentrations were observed in blood from the stop-exposure group. Pathology and Statistical Analyses: There were dose-dependent increases in both absolute and relative liver weights at 4, 31, and 53 weeks, and these tended to correlate with increased incidences of hepatocellular hypertrophy. In the liver at 14 weeks, the only significant effect was an increase in the incidences of hepatocellular hypertrophy. At 53 weeks, there were significant increases in the incidences of hepatocellular hypertrophy and pigmentation. At 2 years, there were significant dose-dependent trends for increased incidences of hepatocellular adenoma and cholangiocarcinoma of the liver. A significant dose-dependent increase in hepatic toxicity was observed and was characterized by increased incidences of numerous nonneoplastic lesions including hepatocellular hypertrophy, multinucleated hepatocytes, oval cell hyperplasia, diffuse fatty change, pigmentation, nodular hyperplasia, eosinophilic foci, hepatocellular necrosis, bile duct hyperplasia, bile duct fibrosis, cholangiofibrosis, and toxic hepatopathy. At 2 years, three gingival squamous cell carcinomas of the oral mucosa were seen in the 200 ng/kg core and stop-exposure groups, two occurred in the 6 ng/kg group, and one occurred in each of the vehicle control, 20 ng/kg, and 92 ng/kg groups. Gingival squamous hyperplasia occurred in all groups including the vehicle controls, with increasing incidences in groups administered 44 ng/kg or greater. The incidence of carcinoma of the uterus was marginally increased in the 92 ng/kg group at 2 years. Increased incidences of chronic active inflammation of the uterus were observed in all dosed groups, and the incidence in the 200 ng/kg stop-exposure group was greater than those in the vehicle control and 200 ng/kg core study groups. Increased incidences of squamous metaplasia of the uterus occurred in all dosed groups. In the 200 ng/kg stop-exposure group, the incidence of squamous metaplasia was significantly greater than that in the vehicle controls, but was lower than that in the 200 ng/kg core study group. At 14-weeks, lung weights were significantly increased in the 200 ng/kg group compared to the vehicle controls. A single occurrence of a multiple cystic keratinizing epithelioma of the lung was observed in the 200 ng/kg core study group. There were increases in the incidences of bronchiolar metaplasia of the alveolar epithelium and sporadic incidences of squamous metaplasia. One pancreatic acinar adenoma and one pancreatic acinar carcinoma were each observed in the 92 ng/kg group and in the 200 ng/kg stop-exposure group at 2 years. Significantly increased incidences of acinar cytoplasmic vacuolization and arterial chronic active inflammation and increased severity of chronic active inflammation were observed in the 200 ng/kg core study group. Numerous nonneoplastic effects were seen in other organs including thyroid follicular cell hypertrophy, thymic atrophy, adrenal cortex cystic degeneration, nephropathy, cardiomyopathy, and squamous hyperplasia of the forestomach.

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Dear Editor, Next to focal neurological symptoms, epileptic seizures and head aches, brain tumors can less frequently bring about cognitive changes, slowed speech, difficulty sustaining mental functioning and psychiatric symptoms of personality changes and. loss of interest in daily activities, these symptoms may be evaluated as anxiety or depression. Depression is known to be a complication of brain tumours and may sometimes be seen after the presentation of neurological symptoms linked to brain tumours, and sometimes after tumor treatment (Oğuz et al. 2005, Litofsky et al. 2004, Moise and Madhusoodanan 2006, Oreskovic M et al. 2007, Rooney A et al. 2010). The dorsolateral prefrontal, orbitofrontal and medial frontal circuits constitute the three subcortical neuronal circuits in the frontal cortex. The dorsolateral prefrontal circuit is associated with planning and operational functions and lesions on it may give rise to apathy, abulia, perseveration, personality changes and planning disorder. Lesions involving the orbitofrontal circuit, which is associated with response suppression and disinhibition, may involve emotional lability and memory problems. Whereas lesions affecting the right orbitofrontal circuit give rise to elevated mood, lesions on the left orbitofrontal circuit lead to depressed mood. In cases with medial frontal circuit involvement, akinetic mutism may result from lesions in the superior medial region and anteroretrograde amnesia and confabulation are observed with lesions in the inferior medial region (Tosun et al. 2016, Chirchiglia 2018). A diagnosis of psychiatric disorder may be given during the first examination of patieants with primary brain tumours, especially if localized in the frontal lobe. Thorough history taking and physical examination are necessary for early diagnosis. The case reported here concerns a 29-year-old university graduate female patient, living with her partner and children, who consulted the clinic with complaints of tendency to frequent crying, anhedonia, having difficulty with speech fluency, forgetfulness and distractedness that had presented suddenly, 2 months previously, without any causative stressor. In her mental status examination, she appeared having normal self-care with appearance at her actual age. She was fully conscious and oriented, not willing to cooperate with the interview, had distinct difficulty in maintaining attention and with fluency of speech. Her mood was depressive. She described loss of appetite, fatigue and energy loss. Her difficulty in paying attention was pronounced. She did not have a history of psychotropic medication use or family history of psychiatric disease. She did not smoke or use alcohol or substance. After evaluating the clinical interview, a preliminary diagnosis of major depressive disorder was considered on the basis of the DSM-5 criteria. Routine blood tests were requested. Given the continuation of her complaints, the difficulty with fluent speech and the increase in tendency to sleep at the first week follow up, cranial MRI was planned. The MRI results showed on the right, in the frontal lobe a multilocular mass with precallosal extension, undiscernable margins with the right lateral aspect of the corpus callosum genu and dispersed cystic-necrotic areas with T2 signal series. The dimensions of the mass were nearly 5 x 3 cm causing a 1-cm right-to-left shift of the midline (Figure 1) DEPRESSION AS THE FIRST SYMPTOM OF FRONTAL LOBE GRADE 2 MALIGNANT GLIOMA 2 Türk Psikiyatri Dergisi 2 Turkish Journal of Psychiatry Letter to the Editor 143 144 The patient was referred for surgery with the preliminary diagnosis of high-grade glial tumour. Pathology results identified a grade 2 glioma. It was learned that radiotherapy sessions were begun after surgery. The patient did not have any symptoms of psychopathology during the 2 monthly psychiatric interviews made after surgery. Brain tumours generally indicate their presence with headache, seizures and other neurological symptoms and very rarely with depression as seen in the case of our patient. It should be kept in mind that atypical psychiatric symptoms may have an underlying organic lesion and subtle neurological symptoms should be investigated in detail. A recent meta-analysis on 37 observational studies determined a 21.7% prevalence of depression in a total of 4518 patients with intracranial tumours. Comorbidity of depression with brain tumor was demonstrated to worsen the quality of life, increase suicidal risk and lower the chance of survival (Huang et al. 2017). The possibility of psychiatric symptoms being the clinical clues for brain cancer was noted and the necessity of neuroimaging tests in cases of recent-onset psychosis or mood disorder symptoms, atypical personality changes and anorexia without body dysmorphic disorder was emphasized (Madhusoodanan et al. 2015). Loss of interest, tendency to frequent weeping, introversion and anhedonia were the sole complaints in the case discussed here. The increase in psychomotor retardation and slowing down of movements at the very first weekly control follow up necessitated neuroimaging. Despite the reports in the literature on the frequent association of unpreventable excessive behavior, disinhibition and irritability with right frontal injury and lesions (Okumuş and Hocaoğlu 2018), depression was the dominant symptom in the case presented here. There are differences between primary major depression and depression presenting with underlying somatic diseases which is known to occur at later ages (Rouchell et al. 2002). However, our patient was aged 29 years. Also, cases of depression due to somatic disease are less associated with family history of depression and suicidal ideation and attempts, while cognitive symptoms come to the foreground during mental status examination. (Sertöz and Mete 2004, Rouchell et al. 2002). Our patient did not have suicidal ideation or attempts, or a family history of depression. In apathy, which may be explained as emotional blunting, indifference or detachment from the external world, targeted behavior is also reduced next to the lack of emotional expression. The individual discussed here was learned not to sit at the table or change the television channel unless reminded to do so. When the reason was asked, she could not think of one. The reduction in emotional expression accompanies reduced insight, abulia and lack of empathy (Sözeri Varma et al. 2019). In depression, apathy is defined as 'sorrowless depression'. Our patient cried but had very blunted mimics and gestures. She explained that she could not help weeping even at times when she did not feel internally distressed. The seriousness of apathy, as a symptom difficult to differentiate from depression, is still not understood. Neuroimaging Figure 1- Cranial MRI of the patient 145 Received: 16.08.2020, Accepted: 04.12.2020, Available Online Date: 05.10.2021 1MD., Antalya Kepez State Hospital, Department of Psychiatry, Antalya, 2MD., Ordu University Training and Research Hospital, Department of Psychiatry, Ordu, Turkey e-mail: [email protected] https://doi.org/10.5080/u25957 studies indicate apathy to be a reflect of impaired frontal-subcortical circuits and the functional disorder of the connections between the ventromedial prefrontal cortex and the basal ganglia (Chase 2011). Comparison of 45 individuals with depression due to aging and 43 healthy individuals showed apathy to be associated with fronto-limbic gray and white matter abnormalities which continued after antidepressant treatment. The structural anomalies of the posterior subgenual cingulate gyrus and the uncinate fasciculus were discussed (Yuen 2014). The case discussed here is presented to emphasize the importance of brain imaging methods and detailed investigation of atypical symptoms for diagnostic approaches to psychiatric disorders. Especially, complaints at young age of depression with psychomotor retardation, reduced fluency of speech and sudden onset withdrawal without stressors should be a warning of secondary depression. Yours sincerely... Şerif Bora Nazlı1 , Muhammet Sevindik2 REFERENCES Chase TN (2011) Apathy in Neuropsychiatric Disease: Diagnosis, Pathophysiology, and Treatment. Neurotox Res 19:266-78. Chirchiglia D (2018) Pseudodepression as an Anticipatory Symptom of Frontal Lobe Brain Tumors. Int J Depress Anxiety 1:007. Huang J, Zeng C, Xiao J et al (2017) Association between depression and brain tumor: a systematic review and meta-analysis. Oncotarget 8:94932-43. Litofsky NS, Farace E, Anderson F et al (2004) Depression in patients with high-grade glioma: Results of the glioma outcomes project. Neurosurgery 54:358-67. Madhusoodanan S, Ting MB, Farah T et al (2015) Pyschiatric aspects of brain tumors: A review. World J Psychiatry 5:273-85. Moise D, Madhusoodanan S (2006) Psychiatric symptoms associated with brain tumors: a clinical enigma. CNS Spectr 2006;11:28-31. Oğuz N, Ilnem C, Yener F (2005) Psychiatric symptoms in brain tumors: Case reports. Bulletin of Clinical Psychopharmacology 15:18-21. Hocaoğlu Ç, Okumuş B (2018) Psychiatric manifestations and brain tumor: A case report and brief review. The Medical Journal of Mustafa Kemal University 9:42-9. Oreskovic NM, Strother CG, Zibners LM (2007) An unusual case of a central nervous system tumor presenting as a chief complaint of depression. Pediatric Emergency Care 23:486-8. Rooney A, Carson A, Grant R (2011) Depression in cerebral glioma patients: a systematic review of observational studies. J Natl Cancer Inst103:61-76. Rouchell AM, Pounds R, Tierney JG (2002) Depression Textbook of Consultation-Liaison Psychiatry, 2nd Edition, Volume 1. MG Wise, JR Rundell (Ed), Washington DC American Psychiatric Publishing, Inc, p.307-38. Özen SÖ, Hayriye ME (2004) Bedensel Hastalıklarda Depresyon. Klinik Psikiyatri Ek 2:63-9. Sözeri Varma G , Bingöl C , Topak O et al (2019) Relationship of apathy with depressive symptom severity and cognitive functions in geriatric depression. Arch Neuropsychiatry 56:133-8. Yuen GS, Gunning FM, Woods E et al (2014) Neuroanatomical correlates of apathy in late-life depression and antidepressant treatment response. J Affect Disord 166:179-86.

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Toxicology studies of pentachlorophenol, a biocide used primarily as a wood preservative, were conducted by feeding diets containing a technical-grade composite, Dowicide EC-7 (a technical grade formulation), or pure pentachlorophenol to groups of B6C3F1 mice for 30 days. These three grades plus another commercial grade of pentachlorophenol (DP-2) were used in 6-month studies. These studies were followed by 2-year carcinogenicity studies of technical-grade pentachlorophenol and of Dowicide EC-7 in feed. Genetic toxicology studies were conducted in Salmonella typhimurium and in Chinese hamster ovary (CHO) cells. Thirty-Day and Sixteen-Month Studies: Groups of 19 male mice and 5-15 female mice were fed diets containing 0, 20, 100, 500, 2,500, or 12,500 ppm technical-grade pentachlorophenol, Dowicide EC-7, or pure pentachlorophenol for 30 consecutive days. Necropsies and histopathologic examinations were performed on all animals. Selected organs were weighed. Supplemental analyses included hematology, serum chemistry, urinalysis, immunology, and hepatic enzyme induction. Compound-related deaths were observed at the highest dose (12,500 ppm) with all three materials and at 2,500 ppm with EC-7 and pure pentachlorophenol (males only). Decreases in body weight gain were also observed in the groups in which deaths occurred. Diffuse centrilobular cytomegaly, karyomegaly, nuclear atypia, degeneration, or necrosis of the liver were compound-related lesions observed in all groups that received pure pentachlorophenol, technical-grade pentachlorophenol, or EC-7 at 500 ppm and above. Serum enzymes associated with liver injury were increased. In the 6-month studies, groups of 10 male and 10 female mice were given diets containing the various grades of pentachlorophenol at the following dietary concentrations: 200, 600, or 1,800 ppm technical-grade pentachlorophenol; 200, 600, or 1,200 ppm DP-2 (not used in the 30-day studies); 200, 600, or 1,200 ppm EC-7; or 200, 500, or 1,500 ppm pure pentachlorophenol for 26-27 weeks. Common control groups of 10 male and 10 female mice were fed control diets. Additional groups of male mice were examined for behavioral, histopathologic, clinical pathology, biochemical, and immunologic effects. All mice exposed at the highest dose of technical-grade pentachlorophenol died, as did 2/10 male mice exposed at the highest dose of DP-2. No deaths were observed in mice exposed to EC-7 or pure pentachlorophenol. Markedly lower final body weights were observed in the high dose groups only (all grades of pentachlorophenol). No chemical-relatedclinical signs were observed at sublethal doses. No major behavioral changes were observed after 5 weeks' exposure, but increased motor activity and heightened startle responses were present at the end of the study in female mice exposed to all four grades of pentachlorophenol. All grades of pentachlorophenol caused increases in serum enzymes associated with liver injury. All grades of pentachlorophenol also resulted in a dose-related induction of aryl hydrocarbon hydroxylase and an increase in cytochrome P450. However, the technical grade was a more powerful inducer than the other grades of pentachlorophenol. Pure pentachlorophenol had no effect on humoral or cell-mediated immunity. However, DP-2 and particularly technical-grade pentachlorophenol depressed humoral immune function. A dose-related increase in liver weight was observed in mice exposed to all grades of pentachlorophenol. A dose-related increase in spleen weight was observed in male mice exposed to all grades of pentachlorophenol; a decrease in spleen weight was observed in female mice exposed to all grades of pentachlorophenol except pure. After 6 months' exposure, histopathologic examination consistently revealed effects in the liver and urinary bladder. The liver lesions were present at all doses with all four grades of pentachlorophenol but were less severe at comparable doses in the mice exposed to pure pentachlorophenol; they consisted of hepatocellular karyomegaly, cytomegaly, and degeneration. The changes in the urinary bladder consisted of a brown granular pigment in the cells of the surface epithelium. No inflammation or proliferative response was associated with the pigment. Based primarily on the liver lesions observed in the 6-month studies, diets chosen for the 2-year studies contained 0, 100, or 200 ppm technical-grade pentachlorophenol or 0, 100, 200, or 600 ppm EC-7, fed to groups of 50 male and 50 female mice. DP-2 and pure pentachlorophenol were not chosen for the 2-year studies because of economic considerations and because the clinicopathologic syndrome observed in the 6-month studies was similar to that observed with EC-7. Body Weights and Survival in the Two-Year Studies: Mean body weights of mice exposed to technical-grade pentachlorophenol and EC-7 were comparable to those of controls until weeks 36-82. Thereafter, a 4&amp;percnt;-22&amp;percnt; dose-related decrease was observed in the mid and high dose mice exposed to EC-7 and in high dose mice exposed totechnical-grade pentachlorophenol. Females were more affected than males. Feed consumption by exposed mice was similar to that by controls. The average daily doses of technical-grade pentachlorophenol were approximately 17-18 or 35 mg/kg compared with 17-18, 34-37, or 114-118 mg/kg of EC-7. Survival of mice did not appear to be affected by exposure to either technical-grade pentachlorophenol or EC-7 at the doses used in these studies. Neoplastic and Nonneoplastic Effects in the Two-Year Studies: The incidences of hepatocellular adenomas and carcinomas were increased (dose related) in male and female mice exposed to either technical-grade pentachlorophenol or EC-7, although the increase was less marked in females exposed to technical-grade pentachlorophenol (adenomas or carcinomas, combined: technical-grade: male-- control, 7/32, 22&amp;percnt;; low dose, 26/47, 55&amp;percnt;; high dose, 37/48, 77&amp;percnt;; female--3/33, 9&amp;percnt;; 9/49, 18&amp;percnt;; 9/50, 18&amp;percnt;; EC-7: male--control, 6/35, 17&amp;percnt;; low dose, 19/48, 40&amp;percnt;; mid dose, 21/48, 44&amp;percnt;; high dose, 34/49, 69&amp;percnt;; female-- 1/34, 3&amp;percnt;; 4/50, 8&amp;percnt;; 6/49, 12&amp;percnt;; 31/48, 65&amp;percnt;). The incidences of pheochromocytomas in male mice were significantly greater than those in controls for both technical-grade pentachlorophenol (0/31; 10/45, 22&amp;percnt;; 23/45, 51&amp;percnt;) and EC-7 (1/34, 3&amp;percnt;; 4/48, 8&amp;percnt;; 21/48, 44&amp;percnt;; 45/49, 92&amp;percnt;). These neoplasms were also increased in female mice exposed to EC-7 at the highest dose (0/35; 2/49, 4&amp;percnt;; 2/46, 4&amp;percnt;; 38/49, 78&amp;percnt;) but not in those exposed to technical-grade pentachlorophenol (2/33, 6&amp;percnt;; 2/48, 4&amp;percnt;; 1/49, 2&amp;percnt;). Hyperplasia of the adrenal medulla was observed at increased incidences in mice that received either technical-grade pentachlorophenol (male: 1/31; 10/45; female: 0/33; 4/48; 2/49) or EC-7 (male: 1/34; 19/48; 13/48; 1/49; female: 2/35; 1/49; 5/46; 17/49). The incidences of hemangiosarcomas in the spleen and/or liver were significantly greater than those in controls for high dose female mice that received technical-grade pentachlorophenol (0/35; 3/50, 6&amp;percnt;; 6/50, 12&amp;percnt;) or EC-7 (0/35; 1/50, 2&amp;percnt;; 3/50, 6&amp;percnt;; 8/49, 16&amp;percnt;). Compound-related nonneoplastic lesions occurred in the liver, spleen, and nose in mice exposed to either technical-grade pentachlorophenol or EC-7. The lesions in the liver included dose-related increased incidences of clear cell foci, chronic active inflammation, pigmentation, necrosis, cytomegaly, proliferation of hematopoietic cells, and bile duct hyperplasia. Increased amounts of extramedullary hematopoiesis of the splenic red pulp were observed at increased incidences in dosed male and high dose female mice that received technical-grade pentachlorophenol (male: 5/30; 15/23; 18/46; female: 2/33; 4/13; 11/47). Acutefocal inflammation of the nasal mucosa and focal metaplasia of the olfactory epithelium were observed at increased incidences in high dose mice that received EC-7 (inflammation--male: 4/35; 1/13; 3/16; 47/49; female: 0/35; 0/14; 2/5; 46/48; focal metaplasia-- male: 2/35; 1/13; 2/16; 46/49; female: 1/35; 0/14; 2/5; 45/48) but not in mice exposed to technical-grade pentachlorophenol. Genetic Toxicology: Pentachlorophenol (91.6&amp;percnt; pure; equivalent in purity to the technical-grade pentachlorophenol used in the toxicology studies) was not mutagenic in S. typhimurium strains TA98, TA100, TA1535, or TA1537 when tested in the presence or absence of exogenous metabolic activation (S9). In cytogenetic studies with cultured CHO cells, pentachlorophenol produced an increase in chromosomal aberrations in the presence but not the absence of S9 metabolic activation; conversely, sister chromatid exchanges (SCEs) were induced only in the absence of S9. Audit: The data, documents, and pathology materials from the 2-year studies of pentachlorophenol have been audited. The audit findings show that the conduct of the studies is documented adequately and support the data and results given in this Technical Report. Conclusions: Under the conditions of these 2-year feed studies, there was clear evidence of carcinogenic activity for male B6C3F1 mice fed diets containing technical-grade pentachlorophenol, as shown by increased incidences of adrenal medullary and hepatocellular neoplasms. There was some evidence of carcinogenic activity for female B6C3F1 mice exposed to technical-grade pentachlorophenol, as shown by increased incidences of hemangiosarcomas and hepatocellular neoplasms. There was clear evidence of carcinogenic activity for male B6C3F1 mice exposed to pentachlorophenol, EC-7, as shown by increased incidences of adrenal medullary and hepatocellular neoplasms. There was clear evidence of carcinogenic activity for female B6C3F1 mice exposed to pentachlorophenol, EC-7, as shown by increased incidences of adrenal medullary and hepatocellular neoplasms and hemangiosarcomas. Chemically related increased incidences of nonneoplastic lesions in mice of each sex included hepatocellular cytomegaly, necrosis, inflammation, pigmentation, and clear cell foci and intrahepatic bile duct hyperplasia. Synonyms or Common Names: chlorophen; PCP; penchlorol; penta; pentachlorofenol; pentachlorofenolo; pentachlorphenol; 2,3,4,5,6-pentachlorophenol Trade Names: Acutox; Chem-Penta; Chem-Tol; Cryptogil ol; Dowicide 7; Dowicide EC-7; Dow Pentachlorophenol DP-2 Antimicrobial; Durotox; EP 30; Fungifen; Fungol; Glazd Penta; Grundier Arbezol; Lauxtol; Lauxtol A; Liroprem; Moosuran; Pentacon; Penta-Kil; Pentasol; Penwar; Peratox; Permacide; Permagard; Permasan;Permatox; Priltox; Permite; Santophen; Santophen 20; Sinituho; Term-i-Trol; Thompson's Wood Fix; Weedone; Witophen P

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Propargyl alcohol is a commercially available acetylenic primary alcohol. It is also a by-product in the industrial synthesis of butynediol from acetylene and formaldehyde with copper acetylide as catalyst. Propargyl alcohol is used as a reactant/chemical intermediate, pharmaceutical intermediate, agricultural chemical intermediate, soil fumigant, corrosion inhibitor, solvent stabilizer, and polymer modifier. It has also been used to prevent the hydrogen embrittlement of steel. Propargyl alcohol was nominated by the National Cancer Institute for study because of the potential for human exposure in occupational settings through inhalation and dermal contact. Male and female F344/N rats and B6C3F1 mice were exposed to propargyl alcohol (greater than 99% pure) by inhalation for 2 weeks, 3 months, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and mouse peripheral blood erythrocytes. 2-WEEK STUDY IN RATS: Groups of five male and five female rats were exposed to propargyl alcohol vapor at concentrations of 0, 31.3, 62.5, 125, 250, or 500 ppm, 6 hours plus T(90 )(12 minutes) per day, 5 days per week for 16 days. All males exposed to 125 ppm or greater and all females exposed to 250 or 500 ppm died by the end of day 3 of the study, and one 125 ppm female died on day 5. Mean body weights were significantly decreased in 62.5 ppm males and 125 ppm females. Clinical findings in the 125 and 250 ppm groups included lethargy, ataxia, abnormal breathing, and nasal/eye discharge. Right kidney weights of 62.5 and 125 ppm females and liver weights of 125 ppm females were significantly greater than those of the chamber controls. All 250 and 500 ppm males and females had moderate to marked periportal necrosis, congestion, and erythrophagocytosis of the liver. 2-WEEK STUDY IN MICE: Groups of five male and five female mice were exposed to propargyl alcohol vapor at concentrations of 0, 31.3, 62.5, 125, 250, or 500 ppm, 6 hours plus T(90) (12 minutes) per day, 5 days per week for 17 days. All mice exposed to 125 ppm or greater died by day 3 of the study. Mean body weights of mice exposed to 62.5 ppm were significantly less than those of the chamber controls. Clinical findings in the 62.5 and/or 125 ppm groups included abnormal breathing, nasal/eye discharge, thinness, and lethargy. Right kidney weights of 31.3 ppm mice were significantly greater, and thymus weights of 62.5 ppm males were significantly less than those of the chamber controls. The livers of all males and females exposed to 250 or 500 ppm exhibited marked periportal necrosis, congestion, and erythrophagocytosis; these lesions also occurred in all 125 ppm males with less severity. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were exposed to propargyl alcohol vapor at concentrations of 0, 4, 8, 16, 32, or 64 ppm, 6 hours plus T(90) (12 minutes) per day, 5 days per week for 14 weeks. All rats survived to the end of the study. Mean body weights of all exposed groups were similar to those of the chamber control groups. The incidences of minimal to mild hyperplasia of respiratory epithelium of the nose were significantly increased in all exposed groups except 8 ppm males and 4 ppm females. Squamous metaplasia of the respiratory epithelium was noted in a few males and most females exposed to 64 ppm. Necrosis of olfactory epithelium was present in half of the males and females exposed to 64 ppm and in a few males and females exposed to 32 ppm. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female mice were exposed to propargyl alcohol vapor at concentrations of 0, 4, 8, 16, 32, or 64 ppm, 6 hours plus T(90) (12 minutes) per day, 5 days per week for 14 weeks. All mice survived to the end of the study. Mean body weights of males exposed to 8 ppm or greater and 32 and 64 ppm females were significantly less than those of the chamber control groups. Histopathologic changes occurred in the nasal cavity of mice and involved both the respiratory and olfactory epithelium in groups exposed to 16 ppm or greater. Lesions included minimal to moderate suppurative inflammation, minimal to moderate squamous metaplasia of the respiratory epithelium, minimal to mild hyaline degeneration (accumulation) in the respiratory epithelium, minimal to moderate olfactory epithelial atrophy, minimal to moderate hyperplasia of glands in the olfactory region, minimal necrosis of olfactory epithelium, and minimal to moderate turbinate atrophy. There were no biologically significant differences in organ weights between exposed and chamber control groups. Reproductive tissue parameters of exposed males were similar to those of the chamber controls. Only 2/9 female mice in the 64 ppm group exhibited regular estrous cyclicity compared to 6/10 in the controls. Females exposed to 16 ppm differed from chamber controls in the relative time in the estrous stages, and 64 ppm females had a significantly increased probability of extended estrus. No gross lesions were observed at necropsy. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were exposed to propargyl alcohol vapor at concentrations of 0, 16, 32, or 64 ppm, 6 hours plus T(90) (14 minutes) per day, 5 days per week for 105 weeks. Survival of 32 and 64 ppm males was significantly less than that of the chamber control group. Mean body weights of males exposed to 64 ppm were less than those of the chamber controls after week 24 of the study. Nasal respiratory epithelial adenomas were present in three 64 ppm males and one 32 ppm female; the incidence in 64 ppm males exceeded the historical control ranges. A spectrum of nonneoplastic lesions occurred in the respiratory and olfactory epithelium of rats at all exposure concentrations. The incidences of respiratory epithelial hyperplasia, respiratory glandular hyperplasia, and olfactory basal cell hyperplasia were significantly increased in all exposed groups of rats. The incidences of lesions of the olfactory epithelium including hyperplasia, glandular hyperplasia, atrophy, respiratory metaplasia, degeneration, necrosis, hyaline droplet accumulation, and chronic active inflammation were significantly increased in one or more exposed groups of males and/or females. The incidence of mononuclear cell leukemia was significantly increased in males exposed to 64 ppm, and the incidence exceeded the historical control ranges. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were exposed to propargyl alcohol vapor at concentrations of 0, 8, 16, or 32 ppm, 6 hours plus T(90) (14 minutes) per day, 5 days per week for 105 weeks. Survival of exposed groups was similar to that of the chamber control groups. Mean body weights of 16 and 32 ppm females were less than those of the chamber control group after weeks 73 and 21, respectively. Eye abnormality (unspecified) was observed after one full year of exposure with the incidence increasing in an exposure concentration-related manner. The incidences of nasal respiratory epithelial adenoma increased with a positive trend and were significantly increased in groups exposed to 32 ppm. A spectrum of nonneoplastic lesions occurred in the nasal respiratory and olfactory epithelium of mice at all exposure concentrations. The incidences of respiratory epithelial hyperplasia, respiratory glandular hyperplasia, and squamous metaplasia were significantly increased in most exposed groups of mice. Suppurative inflammation was often associated with the squamous metaplasia, and turbinate atrophy was present in all exposed mice (except one 16 ppm male). The incidences of olfactory epithelial atrophy and respiratory metaplasia were increased in the 16 and 32 ppm groups. Significantly increased incidences of Harderian gland adenoma occurred in 8 and 32 ppm males. Propargyl alcohol was mutagenic in Salmonella typhimurium strain TA100 in the absence of liver S9 activation enzymes only; no mutagenicity was observed in TA100 in the presence of S9 enzymes, in TA1535 without S9, or in TA98 with or without S9. In vivo, no significant increases in the frequencies of micronucleated normochromatic erythrocytes were observed in peripheral blood samples from male mice exposed by inhalation to propargyl alcohol for 3 months. In female mice, propargyl alcohol exposure produced a small increase in micronucleated erythrocytes that was judged to be equivocal. No significant changes in the percentage of polychromatic erythrocytes were seen in either male or female mice after 3 months of exposure to propargyl alcohol. Under the conditions of these 2-year inhalation studies, there was some evidence of carcinogenetic activity of propargyl alcohol in male F344/N rats based on increased incidences of nasal respiratory epithelial adenoma and mononuclear cell leukemia. There was no evidence of carcinogenic activity of propargyl alcohol in female F344/N rats exposed to 16, 32, or 64 ppm. There was some evidence of carcinogenic activity of propargyl alcohol in male and female B6C3F1 mice based on increased incidences of nasal respiratory epithelial adenoma. The increased incidences of Harderian gland adenoma in male B6C3F1 mice may have been related to exposure to propargyl alcohol. Exposure to propargyl alcohol resulted in increased incidences of nonneoplastic nasal lesions in male and female rats and mice. Synonyms: Ethynylcarbinol; 1-hydroxy-2-propyne; 3-hydroxy-1-propyne; PA; 1-propyn-3-ol; 1-propyn-3-yl alcohol; 2-propynol; 3-propynol; propynyl alcohol; 2-propynyl alcohol.

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The impact of study design on the results of medical research has long been an area of both substantial debate and a smaller body of empirical research. Examples come from many disciplines within clinical and public health research. Among the early major contributions in the 1970s was work by Mosteller and colleagues (Gilbert et al., 1997), who noted that innovations in surgery and anesthesia showed greater gains than standard therapy when nonrandomized, controlled trials were evaluated compared with the gains reported in randomized, controlled trials. More recently, we and others have evaluated the impact of design in medical and surgical research, and concluded that the mean gain comparing new therapies to established therapies was biased by study design in nonrandomized trials (Colditz et al., 1989; Miller et al., 1989). Benson and Hartz (2000) conducted a study in which they focused only on studies reported after 1985. On the basis of 136 reports of 19 diverse treatments, Benson and Hartz concluded that in only 2 of the 19 analyses did the combined data from the observational studies lie outside the 95% confidence interval for the combined data from the randomized trials. A similar study drew only on data reported from 1991 to 1995, which showed remarkably similar results among observational studies and randomized, controlled trials (Concato et al., 2000). These more recent data suggest that advancing the study design and analytic methods may reduce bias in some evaluations of medical and public health interventions. Such methods apply not only to the original studies, but also to the approaches that are taken to quantitatively combine results by using meta-analytic approaches such as random effects meta-regression, Bayesian meta-analysis, and the like (Normand, 1999). By focusing attention on thorough data analysis, design issues can be understood and their impact or bias can be estimated, on average, and then ideally accounted for in the interpretation of data. Before discussing dietary data, let us first consider some of the more clearly delineated preventive exposures. Issues of study design have been addressed in terms of combining randomized trials and observational studies in evaluating preventive interventions such as Bacillus Calmette-Guerin vaccination (Colditz et al., 1994) and mammography screening (Desmissie et al., 1998). When one is interpreting the apparent heterogeneity in the results, it is important to step back and ask what is the relationship being evaluated under these different study designs? For example, a randomized, controlled trial uses the intention-to-treat analysis to preserve the merit of randomization. Such an analysis does not evaluate the exposure-disease relationship, but rather examines the impact of offering a new therapy versus an alternative therapy (regardless of adherence to the intervention, or control or placebo). On the other hand, a case-control study or a prospective cohort study will evaluate the impact of the screening test among those participants who were screened as compared with those who were never screened. In prevention studies, the design raises major issues of the timing of the exposure in the natural history of disease and also the adherence to therapy by healthy research volunteers. Case-control studies of preventive interventions such as screening mammography and prospective population-based studies of pap smears have capitalized on this variation in time since the last screen to evaluate the protective interval for a screening test (IARC Work Group, 1986). In contrast, a trial must choose a level of exposure, such as annual mammography screenings or colon screenings every 10 years with a colonoscopy, regardless of the evolving evidence on the duration of protection after a negative screening test. Continuing with the mammography example, a detailed study by Demissie and colleagues (1998) combined data from seven randomized trials and six case-control studies that investigated the association between participation in breast cancer screening programs and breast cancer mortality. The authors showed that if one assumes noncompliance with mammography (approaching 30%) and 20% of the control group is screened, then the benefit of mammography in terms of reduced mortality is comparable in randomized, controlled trials and epidemiologic studies after adjusting for nonadherence (Demissie et al., 1998). Thus, the different designs fundamentally measure different constructs of the impact of screening. Zelen (1988) considered the challenges of primary prevention trials and addressed both compliance and models of carcinogenesis as major impediments to the use of randomized, controlled trials to evaluate cancer prevention strategies. It is important to contrast these issues in both treatment trials and prevention trials. In treatment trials, recently diagnosed patients, who are often in life-threatening situations, are typically offered the option to participate in a trial of a new therapy compared with standard therapy or placebo. Compliance or adherence to therapy is usually very high among these highly motivated patients and their outcomes are generally in the short- to mid-term. In contrast, prevention trials recruit large numbers of healthy participants, offer them a therapy, and then follow them over many years because the chronic diseases being prevented are relatively rare. With substantial noncompliance (often in the range of 20% to 40% over the duration of the trial), an intention-to-treat analysis is no longer unbiased, but rather gives a biased estimate of the effect, typically underestimating the magnitude of the association that is seen in observation studies in which those participants who have had exposure to a particular lifestyle component are compared with those without such an exposure. There are additional challenges for nutritional interventions, including the timing of diet as a preventive agent in the disease process and the range of nutrient intakes in the population. In retrospective case-control studies, recall bias of past diet is an additional issue with which to contend. Unlike smoking or screening tests in which the exposure is finite and can be completely stopped and started, one's diet, physical activity, and weight change cannot go to zero for prolonged periods and sustain life. The range of nutrient intake is a major issue when enrolling participants into prevention trials and observational studies. Health-conscious volunteers are more often identified and screened as eligible for a trial. The epidemiology of diet and colon cancer has been extensively studied. For example, Cho et al. (2004) conducted a combined analysis of prospective dietary studies of calcium and vitamin D intake data from 10 cohorts. The dose-response relationship for calcium showed that the greatest benefit for increasing calcium intake was for those participants who had a reported daily intake below 1000 mg/d. Increasing the intake of those individuals with low intake to the level of 1000 mg/day would yield a 20% reduction in risk. Beyond this level of intake, there was little additional reduction in the risk of colon cancer. In the Women's Health Initiative, participants had a mean calcium intake of 1150 mg/d at baseline and increased this intake in the intervention arm to 2250 mg/d on average. This magnitude of increase was of limited association in the combined, prospective, cohort studies and was not related to risk in the randomized trial (Wactawski-Wende et al., 2006). Similar findings apply to the interpretation of the vitamin D intervention and highlight the role of dietary intake at randomization when evaluating dietary components. Returning to the time frame of exposure in the carcinogenic process, the null randomized, controlled trials of fiber (Alberts et al., 2000) and fruit and vegetables (Schatzkin et al., 2000) for the prevention of polyp recurrence amply illustrate Zelen's concerns regarding the timing of the preventive intervention in the disease process. The extent of DNA damage accumulated across the colonic mucosa at the time of detecting the "eligibility polyp" was certainly not limited only to the removed polyp. Rather, these observations beg the question that at what stage in the disease process may fiber play a role in protecting against colon cancer? This contrasts with the richness of epidemiologic studies that can address exposure over the life course and relate such exposure to disease risk. Perhaps the best-known example is the radiation follow-up effects cohort in Japan in which a radiation dose was estimated for each woman who had been exposed to the effects of the atomic bombs on Hiroshima and Nagasaki and followed-up over 40 years. The results of this study showed a clear and strong relationship between the increased risk of breast cancer with higher exposure among those participants who were exposed before the age of 20 years (Land et al., 2003). Retrospective assessment of diet after disease diagnosis has been demonstrated to introduce bias into the evaluation of exposure-disease relationships. For example, Giovannucci et al. (1993) evaluated retrospective recall of diet after breast cancer diagnosis within the ongoing Nurses' Health Study. In contrast with the prospective analysis in which no relationship between dietary fat and breast cancer was observed, the retrospective analysis yielded a positive relationship for total fat and saturated fat (Giovannucci et al., 1993). By comparing the top quintile versus the bottom quintile of reported intake, the retrospective assessment yielded odds ratios of 1.43 for total fat and 1.38 for saturated fat. Therefore, the magnitude of bias was sufficient to distort evaluation of the diet-disease relationship. (ABSTRACT TRUNCATED)

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To review the evidence on the effectiveness and cost-effectiveness of balloon kyphoplasty for the treatment of vertebral compression fractures (VCFs). Vertebral compression fractures are one of the most common types of osteoporotic fractures. They can lead to chronic pain and spinal deformity. They are caused when the vertebral body (the thick block of bone at the front of each vertebra) is too weak to support the loads of activities of daily living. Spinal deformity due to a collapsed vertebral body can substantially affect the quality of life of elderly people, who are especially at risk for osteoporotic fractures due to decreasing bone mass with age. A population-based study across 12 European centres recently found that VCFs have a negative impact on health-related quality of life. Complications associated with VCFs are pulmonary dysfunction, eating disorders, loss of independence, and mental status change due to pain and the use of medications. Osteoporotic VCFs also are associated with a higher rate of death. VCFs affect an estimated 25% of women over age 50 years and 40% of women over age 80 years. Only about 30% of these fractures are diagnosed in clinical practice. A Canadian multicentre osteoporosis study reported on the prevalence of vertebral deformity in Canada in people over 50 years of age. To define the limit of normality, they plotted a normal distribution, including mean and standard deviations (SDs) derived from a reference population without any deformity. They reported a prevalence rate of 23.5% in women and a rate of 21.5% in men, using 3 SDs from the mean as the limit of normality. When they used 4 SDs, the prevalence was 9.3% and 7.3%, respectively. They also found the prevalence of vertebral deformity increased with age. For people older than 80 years of age, the prevalence for women and men was 45% and 36%, respectively, using 3 SDs as the limit of normality. About 85% of VCFs are due to primary osteoporosis. Secondary osteoporosis and neoplasms account for the remaining 15%. A VCF is operationally defined as a reduction in vertebral body height of at least 20% from the initial measurement. It is considered mild if the reduction in height is between 20% and 25%; moderate, if it is between 25% and 40%; and severs, if it is more than 40%. The most frequently fractured locations are the third-lower part of the thorax and the superior lumbar levels. The cervical vertebrae and the upper third of the thorax are rarely involved. Traditionally, bed rest, medication, and bracing are used to treat painful VCFs. However, anti-inflammatory and narcotic medications are often poorly tolerated by the elderly and may harm the gastrointestinal tract. Bed rest and inactivity may accelerate bone loss, and bracing may restrict diaphragmatic movement. Furthermore, medical treatment does not treat the fracture in a way that ameliorates the pain and spinal deformity. Over the past decade, the injection of bone cement through the skin into a fractured vertebral body has been used to treat VCFs. The goal of cement injection is to reduce pain by stabilizing the fracture. The secondary indication of these procedures is management of painful vertebral fractures caused by benign or malignant neoplasms (e.g., hemangioma, multiple myeloma, and metastatic cancer). Balloon kyphoplasty is a modified vertebroplasty technique. It is a minimally invasive procedure that aims to relieve pain, restore vertebral height, and correct kyphosis. During this procedure, an inflatable bone tamp is inserted into the collapsed vertebral body. Once inflated, the balloon elevates the end plates and thereby restores the height of the vertebral body. The balloon is deflated and removed, and the space is filled with bone cement. Creating a space in the vertebral body enables the application of more viscous cement and at a much lower pressure than is needed for vertebroplasty. This may result in less cement leakage and fewer complications. Balloons typically are inserted bilaterally, into each fractured vertebral body. Kyphoplasty usually is done under general anesthesia in about 1.5 hours. Patients typically are observed for only a few hours after the surgery, but some may require an overnight hospital stay. Health Canada has licensed KyphX Xpander Inflatable Bone Tamp (Kyphon Inc., Sunnyvale, CA), for kyphoplasty in patients with VCFs. KyphX is the only commercially available device for percutaneous kyphoplasty. The KyphX kit uses a series of bone filler device tubes. Each bone filler device must be loaded manually with cement. The cement is injected into the cavity by pressing an inner stylet. In the United States, the Food and Drug Administration cleared the KyphX Inflatable Bone Tamp for marketing in July 1998. CE (Conformité European) marketing was obtained in February 2000 for the reduction of fracture and/or creation of a void in cancellous bone. The aim of this literature review was to evaluate the safety and effectiveness of balloon kyphoplasty in the treatment of painful VCFs. INAHTA, Cochrane CCTR (formerly Cochrane Controlled Trials Register), and DSR were searched for health technology assessment reports. In addition, MEDLINE, EMBASE, and MEDLINE In-Process &amp; Other Non-Indexed Citations were searched from January 1, 2000 to September 21, 2004. The search was limited to English-language articles and human studies. The positive end points selected for this assessment were as follows: Reduction in pain scoresReduction in vertebral height lossReduction in kyphotic (Cobb) angleImprovement in quality of life scoresThe search did not yield any health technology assessments on balloon kyphoplasty. The search yielded 152 citations, including those for review articles. No randomized controlled trials (RCTs) on balloon kyphoplasty were identified. All of the published studies were either prospective cohort studies or retrospective studies with no controls. Eleven studies (all case series) met the inclusion criteria. There was also a comparative study published in German that had been translated into English. The results of the 1 comparative study (level 3a evidence) that was included in this review showed that, compared with conservative medical care, balloon kyphoplasty significantly improved patient outcomes. Patients who had balloon kyphoplasty reported a significant reduction in pain that was maintained throughout follow-up (6 months), whereas pain scores did not change in the control group. Patients in the balloon kyphoplasty group did not need pain medication after 3 days. In the control group, about one-half of the patients needed more pain medication in the first 4 weeks after the procedure. After 6 weeks, 82% of the patients in the control group were still taking pain medication regularly. Adjacent fractures were more frequent in the control group than in the balloon kyphoplasty group. The case series reported on several important clinical outcomes. Pain: Four studies on osteoporosis patients and 1 study on patients with multiple myeloma/primary cancers used the Visual Analogue Scale (VAS) to measure pain before and after balloon kyphoplasty. All of these studies reported that patients had significantly less pain after the procedure. This was maintained during follow-up. Two other studies on patients with osteoporosis also used the VAS to measure pain and found a significant improvement in pain scores; however, they did not provide follow-up data. Vertebral body height: All 5 studies that assessed vertebral body height in patients with osteoporosis reported a significant improvement in vertebral body height after balloon kyphoplasty. One study had 1-year follow-up data for 26 patients. Vertebral body height was significantly better at 6 months and 1 year for both the anterior and midline measurements. Two studies reported that vertebral body height was restored significantly after balloon kyphoplasty for patients with multiple myeloma or metastatic disease. In another study, the researchers reported complete height restoration in 9% of patients, a mean 56% height restoration in 60% of patients, and no appreciable height restoration in 31% of the patients who received balloon kyphoplasty. Kyphosis correction: Four studies that assessed Cobb angle before and after balloon kyphoplasty in patients with osteoporosis found a significant reduction in degree of kyphosis after the procedure. In these studies, the differences between preoperative and postoperative Cobb angles were 3.4°, 7°, 8.8°, and 9.9°. Only 1 study investigated kyphosis correction in patients with multiple myeloma or metastatic disease. The authors reported a significant improvement (5.2°) in local kyphosis. Quality of life: Four studies used the Short Form 36 (SF-36) Health Survey Questionnaire to measure the quality of life in patients with osteoporosis after they had balloon kyphoplasty. A significant improvement in most of the domains of the SF-36 (bodily pain, social functioning, vitality, physical functioning, mental health, and role functioning) was observed in 2 studies. One study found that general health declined, although not significantly, and another found that role emotional declined. Both studies that used the Oswestry Disability Index found that patients had a better quality of life after balloon kyphoplasty. In one study, this improvement was statistically significant. In another study, researchers found that quality of life after kyphoplasty improved significantly, as measured with the Roland-Morris Disability Questionnaire. Yet another study used a quality of life questionnaire and found that 62% of the patients that had balloon kyphoplasty had returned to normal activities, whereas 2 patients had reduced mobility. (ABSTRACT TRUNCATED)

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To assess the effectiveness and cost-effectiveness of hylan G-F 20 as a substitute for existing treatments for pain due to osteoarthritis (OA) of the knee, other viscosupplementation devices, and/or as an adjunct to conventional therapy. Hylan G-F 20 (brand name Synvisc, which is manufactured by Genzyme) is a high molecular weight derivative of hyaluronan, a component of joint synovial fluid. It acts as a lubricant and shock absorber. It is administered by injection into the joint space to treat pain associated with OA of the knee. Although the injection procedure is an insured service in Ontario, the device, hylan G-F 20, is not. Osteoarthritis is prevalent in 10% to 12% of Ontario adults, and exceeds 40% in Ontario residents aged 65 years and older. About one-half of these people have mild, moderate, or severe OA of the knee. Conventional treatment involves a combination of nonpharmacological management (e.g., weight loss, exercise, social support, and patient education), drugs, (e.g., acetaminophen, COX-2 inhibitors, nonsteroidal anti-inflammatory drugs with/without misoprostol, intra-articular glucocorticoids, opioids, and topical analgesics) and surgical interventions, such as debridement and total knee replacement, when pharmacological management fails. The growing burden of OA of the knee in the aging Ontario population combined with recent safety concerns about COX-2 inhibitors and long wait times for total joint replacement is placing pressure on the demand for new, effective technologies to manage the pain of OA. Hylan G-F 20 is derived from rooster comb hyaluronan (HA). At the time of writing, eight viscosupplement hyaluronic products are licensed in Canada. Hylan G-F 20 is distinguished from the other products by its chemical structure (i.e., cross-linked hyaluronan, hence hylan) and relatively higher molecular weight, which may bestow greater therapeutic viscoelastic properties. A complete treatment cycle of hylan G-F 20 involves an intra-articular injection of 2 ml of hylan G-F 20 once a week for 3 weeks. It is licensed for use for patients in all stages of joint pathology, but should not be used in infected or severely inflamed joints, in joints with large effusion, in patients that have skin diseases or infections in the area of the injection site, or in patients with venous stasis. It is also contraindicated in patients with hypersensitivities to avian proteins. The Medical Advisory Secretariat used its standard search protocol to review the literature for evidence on the effectiveness of intra-articular hylan G-F 20 compared with placebo, as a substitute for alternate active treatments, or as an adjunct to conventional care for treatment of the pain of OA of the knee. All English-language journal articles and reviews with clearly described designs and methods (i.e., those sufficient to assign a Jadad score to) published or released between 1966 and February 2005 were included. Two more recently published meta-analyses were also included. The databases searched were Ovid MEDLINE, EMBASE, the Cochrane database and leading international organizations for health technology assessments, including the International Network of Agencies for Health Technology Assessments. The search terms were as follows: hyaluronan, hyaluronate adj sodium, hylan, hylan G-F 20 (Synvisc), Synvisc, Hyalgan, Orthovisc, Supartz, Artz, Artzal, BioHY, NASHA, NRD101, viscosupplementation, osteoarthritis, knee, knee joint. The primary outcome of interest was a clinically significant difference, defined as greater than 10 mm on 100 mm visual analogue scale, or a change from baseline of more than 20% in the mean magnitude of pain relief experienced among patients treated with hylan G-F 20 compared with those treated with the control intervention. One clinical epidemiologist reviewed the full-text reports and extracted data using an extraction form. Key variables included, but were not limited to, the characteristics of the patients, method of randomization, type of control intervention, outcome measures for effectiveness and safety, and length of follow-up. The quality of the studies and level of the evidence was initially scored by one clinical epidemiologist using the Jadad scale and GRADE approach. Level of quality depends on the amount of certainty about the magnitude of effect and is based on study designs, extent of methodological limitations, consistency of results and applicability (i.e. directness) to the Ontario clinical context. The GRADE approach also permits comment on the strength of recommendations resulting from the evidence, based on estimates of the magnitude of effect relative to the magnitude of risk and burden and the level of certainty around these estimates. The quality assessments were subsequently peer-reviewed. The literature search revealed 2 previous health technology assessments, 3 meta-analyses of placebo-controlled trials, 1 Cochrane review and meta-analysis encompassing 18 randomized controlled trials (RCTs) that compared hylan G-F 20 to either placebo or active treatments, 11 RCTs of hylan G-F 20 (all included in the Cochrane review), and 10 observational studies. Given the preponderance of evidence, the Medical Advisory Secretariat's analysis focused on studies with Level 1 evidence of effectiveness (i.e., the meta-analyses of RCTs and the RCTs). Only safety data from the observational studies were included. The authors of the 2 health technology assessments concluded that the data were sparse and poor quality. There was some evidence that hylan G-F 20 delivered a small, clinical benefit at 3 to 6 months after treatment on a magnitude comparable to NSAIDs and intra-articular steroids. Hylan G-F 20 appeared to carry a risk of a local adverse reaction of in the range of 3% to 18% per 100 injections, but there was no apparent risk of a severe adverse event, although the data were limited. Each of the 3 meta-analyses of placebo-controlled trials of intra-articular hyaluronans had only 3 trials involving hylan G-F 20. There results were inconsistent, with one study concluding that intra-articular hyaluronans were efficacious, whereas the 2 other analyses concluded the effect size was small (0.32) and probably not clinically significant. The risk of a minor adverse event ranged from 8% to 19% per 100 injections. Major adverse events were rare. The authors of the Cochrane review concluded that a pooled analysis supported the efficacy of hyaluronans, including hylan G-F 20. The 5- to 13-week post-injection period showed an improvement from baseline of 11% to 54% for pain and 9% to 15% for function. Comparable efficacy was noted against NSAIDs, and longer-term benefits were noted in against steroids. Few adverse events were noted. When the Medical Advisory Secretariat applied the criterion of clinical significance to the magnitude of pain relief reported in the RCTs on hylan G-F 20, the following was noted:There was inconsistent evidence that hylan G-F 20 was clinically superior to placebo at 5 to 26 weeks after treatment.There was consistent evidence that, in terms of delivering pain relief, hylan G-F 20 was no better or worse than NSAIDs or intra-articular steroids at 5 to 26 weeks after treatment.There was consistent evidence that hylan G-F 20 was not clinically superior to other hyaluronic products.There was consistent evidence that hylan G-F 20 delivered a small magnitude of clinical benefit at 12 to 52 weeks post-injection when administered as an adjunct to conventional care.There were limitations to the methods in many of the RCTs involving hylan G-F 20. When only the results from the higher-quality studies were considered, there was level 2 evidence that hylan G-F 20 was not clinically superior to placebo (or another hyaluronan) at 1 to 26 weeks after treatment in older patients with advanced disease for whom total knee replacement was indicated. There was level 2 evidence that hylan G-F 2- was comparable to NSAIDs at 4 to 13 weeks after treatment, and level 2 evidence that hylan G-F 20 was superior to placebo as an adjunct to conventional care 4 to 26 weeks after treatment. With respect to safety, overall, hylan G-F 20 carries a risk of a minor, local adverse event rate of about 8% to 19% per 100 injections. Incidents of moderate-severe post-injection inflammatory joint reactions have been reported, but the likelihood appears to be low (0.15% of patients). Case-costing estimates suggest that the annual cost of 2 treatment cycles of hylan G-F 20 (plus analgesics for breakthrough pain) is almost equivalent to the annual cost of taking a NSAID (with a gastroprotective agent) and is more expensive that taking intra-articular corticosteroids (plus analgesics for breakthrough pain). The estimated cost of funding hylan G-F 20 as an adjunct to conventional therapy (i.e., any of analgesics, NSAIDs, intra-articular steroids, physiotherapy, and surgery) is $700 per patient per year. Given the huge burden of mild to moderate OA among adults who seek medical care for it in Ontario (about 300,000), funding hylan G-F 20 as an adjunct to existing treatment could be expensive, depending on its diffusion and uptake. If only 10% to 30% of patients choose this option, then the estimated budget impact would be $21 million to $63 million (Cdn) per year. When the benefits relative to the risks and costs are considered, NSAIDs and hylan G-F 20 appear comparable, as the table shows. Consequently, there's little evidence on which to recommend hylan G-F 20 over NSAIDs, except perhaps for patients who cannot tolerate NSAIDs, although this evidence is indirect, since no studies looked specifically at this population. (ABSTRACT TRUNCATED)

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t -Butyl alcohol is widely used in the manufacture of perfumes and a variety of cosmetics. It is also used as a raw material in the production of isobutylene, which may be used to produce methyl tertiary butyl ether, a common gasoline additive, or to produce butyl elastomers used in the production of automobile tires. Male and female F344/N rats and B6C3F1 mice were given t -butyl alcohol (greater than 99% pure) in drinking water for 13 weeks or 2 years. The genetic toxicity of t -butyl alcohol was assessed by testing the ability of the chemical to induce mutations in various strains of Salmonella typhimurium and in L5178Y mouse lymphoma cells, sister chromatid exchanges and chromosomal aberrations in cultured Chinese hamster ovary cells, and by measuring the frequency of micronucleated erythrocytes in mouse peripheral blood. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were given 0, 2.5, 5, 10, 20, or 40 mg/mL t -butyl alcohol in drinking water for 13 weeks. All males and six females given 40 mg/mL died during the study. Final mean body weights of 10 and 20 mg/mL males and of 40 mg/mL females were 12%, 17%, or 21% less than those of the corresponding controls, respectively. Serum sorbitol dehydrogenase activities in 10 and 20 mg/mL males were greater than that in the controls after 13 weeks. Serum alanine aminotransferase activity in 40 mg/mL females was greater than that in the controls after 2 weeks and greater in all exposed females after 13 weeks. Urine volumes of 10, 20, and 40 mg/mL males and females decreased, and urine specific gravity values increased. Transitional epithelial hyperplasia and inflammation of the urinary bladder were observed in 20 and 40 mg/mL males and 40 mg/mL females. Absolute and relative liver weights of all exposed groups of females and relative liver weights of 5, 10, and 20 mg/mL males were significantly greater than those of the controls. Absolute and relative kidney weights of all exposed groups of males and females were significantly greater than those of the controls. Incidences of mineralization of the kidney were significantly increased in 10, 20, and 40 mg/mL males. The severity of nephropathy in 2.5, 5, 10, and 20 mg/mL males was significantly greater than that of the controls as was the accumulation of hyaline droplets in the kidney of 5, 10, and 20 mg/mL males. The incidences of nephropathy in 10, 20, and 40 mg/mL females were significantly greater than that of the controls. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were given 0, 2.5, 5, 10, 20, or 40 mg/mL t -butyl alcohol in drinking water for 13 weeks. The deaths of two males and one female in the 40 mg/mL group were attributed to exposure to t -butyl alcohol. The final mean body weights of 20 and 40 mg/mL males and 40 mg/mL females were significantly lower than those of the controls. There were no biologically significant differences in hematology parameters of exposed and control groups of mice. Transitional epithelial hyperplasia and inflammation were observed in the urinary bladder of 20 and 40 mg/mL males and 40 mg/mL females. 2-YEAR STUDY IN RATS: Groups of 60 F344/N rats were given 0, 1.25, 2.5, or 5 mg/mL t -butyl alcohol (males) or 0, 2.5, 5, or 10 mg/mL t -butyl alcohol (females) in drinking water for 2 years. These correspond to average daily doses of approximately 90, 200, or 420 mg t -butyl alcohol/kg body weight for males and approximately 180, 330, or 650 mg t -butyl alcohol/kg body weight for females. Ten rats per group were evaluated after 15 months of chemical administration. Survival, Body Weights, and Water Consumption: Survival rates of 5 mg/mL males and 10 mg/mL females were significantly lower than those of the controls. The final mean body weights of exposed groups of males were 15% to 24% lower than that of the controls, and the final mean body weight of 10 mg/mL females was 21% lower than that of the controls. Water consumption by males increased with dose; water consumption by females decreased with dose. Hematology and Urinalysis: At the 15-month inte. Hematology and Urinalysis: At the 15-month interim evaluation, there were no significant differences in hematology parameters in males and females, and there were no significant differences in urinalysis parameters in males. Females given 5 or 10 mg/mL had increased urine specific gravities and decreased urine volumes. Pathology Findings: At the 15-month interim evaluation, relative kidney weights of 2.5 and 5 mg/mL males and absolute and relative kidney weights of 2.5, 5, and 10 mg/mL females were significantly greater than those of the controls. At 2 years, the incidence of mineralization in the kidney increased with dose and that of 5 mg/mL males was significantly greater than that of the controls. In the standard evaluation at the end of the study, the incidences of focal renal tubule hyperplasia and of adenoma were increased in exposed males and a carcinoma was observed in one 5 mg/mL male. Renal tubule hyperplasia occurred in one 10 mg/mL female. An extended evaluation of the kidney identified additional male rats with hyperplasia (control, 11/50; 1.25 mg/mL, 13/50; 2.5 mg/mL, 11/50; 5 mg/mL, 19/50) and renal tubule adenoma (7/50, 8/50, 15/50, 10/50); renal tubule carcinomas were identified in two 1.25 mg/mL males and in one 2.5 mg/mL male. Renal tubule adenoma was identified in one 5 mg/mL male from the 15-month extended evaluation. In the standard and extended evaluations combined, there were dose-related increased incidences of hyperplasia and adenoma. The severity of nephropathy and the incidence and severity of transitional cell hyperplasia of the kidney were increased in exposed male and female rats. Linear foci of mineralization were present in the renal papilla of exposed males. 2-YEAR STUDY IN MICE: Groups of 60 male and 60 female B6C3F1 mice were given 0, 5, 10, or 20 mg/mL t -butyl alcohol in drinking water for 2 years. Exposure levels of 5, 10, or 20 mg/mL delivered average daily doses of approximately 540, 1,040, or 2,070 mg t -butyl alcohol/kg body weight to males and approximately 510, 1,020, or 2,110 mg/kg to females. Survival, Body Weights, and Water Consumption: Survival of 20 mg/mL males was significantly lower than that of the controls. The final mean body weights of exposed groups of males were similar to those of the controls. The mean body weights of females given 20 mg/mL were 10&amp;percnt; to 15&amp;percnt; lower than those of the controls from week 13 to the end of the study. Water consumption by exposed groups of males and females was similar to that by the controls. Pathology Findings: Incidences of thyroid gland follicular cell hyperplasia were significantly increased in all exposed groups of males and in 10 and 20 mg/mL females. The incidence of follicular cell adenoma or carcinoma (combined) was marginally increased in 10 mg/mL males (0 mg/mL, 1/60; 5 mg/mL, 0/59; 10 mg/mL, 4/59; 20 mg/mL, 2/57). The incidence of follicular cell adenoma was significantly increased in 20 mg/mL females (2/58, 3/60, 2/59, 9/59). The incidences of chronic inflammation and transitional epithelial hyperplasia of the urinary bladder were increased in 20 mg/mL males and to a lesser extent in 20 mg/mL females. GENETIC TOXICOLOGY: t -Butyl alcohol was tested for induction of genetic damage in vitro and in vivo, and all results were negative. In vitro, t -butyl alcohol was negative in Salmonella typhimurium and mouse lymphoma cell mutation tests, and it did not induce sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells. These in vitro studies were conducted with and without metabolic activation (S9). In vivo, no increase in micronucleated erythrocytes was observed in peripheral blood samples from mice administered t -butyl alcohol in drinking water for 13 weeks. CONCLUSIONS: Under the conditions of these 2-year drinking water studies, there was some evidence of carcinogenic activity of t -butyl alcohol in male F344/N rats based on increased incidences of renal tubule adenoma or carcinoma (combined). There was no evidence of carcinogenic activity in female F344/N rats receiving 2.5, 5, or 10 mg/mL t -butyl alcohol. There was equivocal evidence of carcinogenic activity of t -butyl alcohol in male B6C3F1 mice based on the marginally increased incidences of follicular cell adenoma or carcinoma (combined) of the thyroid gland. There was some evidence of carcinogenic activity of t -butyl alcohol in female B6C3F1 mice based on increased incidences of follicular cell adenoma of the thyroid gland. Exposure to t -butyl alcohol was associated with mineralization and renal tubule hyperplasia in male rats, transitional epithelial hyperplasia and increased severity of nephropathy of the kidney in male and female rats, follicular cell hyperplasia of the thyroid gland in male and female mice, and chronic inflammation and hyperplasia of the urinary bladder in male mice and to a lesser extent in female mice. Synonyms: 2-Methyl-2-propanol, 2-methylpropan-2-ol, TBA, t -butanol, tertiary butyl alcohol, t -butyl hydroxide, trimethyl carbinol, trimethyl methanol

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Androstenedione is an androgen steroid that is normally synthesized within men and women and may be metabolized to a more potent androgen or estrogen hormone. It was nominated to the National Toxicology Program for study due to concern for adverse health effects associated with its chronic use as a dietary supplement by athletes (prior to the banning of its over the counter sales). In order to evaluate its subchronic and chronic toxicity, male and female F344/N rats and B6C3F1 mice were administered androstenedione (98% pure) by gavage for 2 weeks, 3 months, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, rat bone marrow cells, and mouse peripheral blood erythrocytes. 2-WEEK STUDY IN RATS: groups of five male and five female rats were administered 0, 1, 5, 10, 20, or 50 mg androstenedione/kg body weight in a 0.5% aqueous methylcellulose solution by gavage, 5 days per week for 12 days. All rats survived to the end of the study, and the mean body weights of dosed groups were similar to those of the vehicle control groups. The development of cytoplasmic vacuoles within centrilobular hepatocytes in male rats was the only treatment-related effect observed. 2-WEEK STUDY IN MICE: groups of five male and five female mice were administered 0, 1, 5, 10, 20, or 50 mg androstenedione/kg body weight in a 0.5% aqueous methylcellulose solution by gavage, 5 days per week for 12 days. One vehicle control female, one 20 mg/kg female, and one 50 mg/kg female died early due to gavage accidents. There were no significant chemical-related histopathological or mean body weight changes. 3-MONTH STUDY IN RATS: groups of 10 male and 10 female core study rats were administered 0, 1, 5, 10, 20, or 50 mg androstenedione/kg body weight in a 0.5% aqueous methylcellulose solution by gavage, 5 days per week for 14 weeks; additional groups of 10 male and 10 female clinical pathology study rats received the same doses for 23 days. All rats survived to the end of the study. The mean body weights of the 20 mg/kg female group was significantly greater than those of the vehicle control group and there was significant increased weight gain in the 1, 20, and 50 mg/kg female groups. Female thymus weights were significantly increased in the 20 and 50 mg/kg groups, which may be related to the increase in mean body weight. The numbers of sperm per mg cauda epididymis in the 10, 20, and 50 mg/kg male groups and the total number of sperm per cauda epididymis in 50 mg/kg males were significantly less than those of the vehicle controls. No treatment-related histological lesions were observed in males or females. 3-MONTH STUDY IN MICE: groups of 10 male and 10 female mice were administered 0, 1, 5, 10, 20, or 50 mg androstenedione/kg body weight in a 0.5% aqueous methylcellulose solution by gavage, 5 days per week for 14 weeks. Except for one 10 mg/kg female that died early due to a dosing accident, all mice survived to the end of the study. The mean body weights of dosed groups were similar to those of the vehicle control groups. The number of spermatids per mg testis and the total number of spermatids per testis in 20 mg/kg males were significantly greater than those of the vehicle controls. Sperm motility in 50 mg/kg males was significantly lower than that in the vehicle controls. The incidences of x-zone atrophy of the adrenal cortex, an androgen-sensitive endpoint, were significantly increased in females administered 5 mg/kg or greater. There were also significant decreases in the incidences of x-zone cytoplasmic vacuolization in 20 and 50 mg/kg females. The incidences of bone marrow hyperplasia were significantly increased in 5 and 50 mg/kg males. 2-YEAR STUDY IN RATS: groups of 50 male and 50 female rats were administered 0, 10, 20, or 50 mg androstenedione/kg body weight in a 0.5% aqueous methylcellulose solution by gavage, 5 days per week for at least 104 weeks. Survival of 10 mg/kg males was significantly greater than that of the vehicle controls. The mean body weights of 20 and 50 mg/kg females were greater than those of the vehicle controls after weeks 17 and 9, respectively. The incidences of mononuclear cell leukemia were significantly increased in 20 and 50 mg/kg females and significantly decreased in 20 and 50 mg/kg males. Incidences of alveolar/bronchiolar adenoma and alveolar/bronchiolar adenoma or carcinoma (combined) were significantly increased in 20 mg/kg males. The incidence of testicular interstitial cell adenoma (including bilateral) was significantly decreased in 50 mg/kg males. In females, the incidences of mammary gland fibroadenoma were significantly decreased in the 20 and 50 mg/kg groups, the incidences of mammary gland hyperplasia were significantly decreased in all dosed groups, and the incidences of mammary gland cyst were significantly decreased in the 10 and 50 mg/kg groups. In the liver of males, the incidences of basophilic focus in all dosed groups, the incidence of clear cell focus in the 20 mg/kg group, and the incidence of eosinophilic focus in the 50 mg/kg group were significantly increased. The incidences of pancreatic islet hyperplasia and atrophy of the exocrine pancreas were significantly increased in 50 mg/kg females. 2-YEAR STUDY IN MICE: groups of 50 male and 50 female mice were administered 0, 2 (females only), 10, 20 (males only), or 50 mg androstenedione/kg body weight in a 0.5% aqueous methylcellulose solution by gavage, 5 days per week for at least 104 weeks. Survival of dosed groups was similar to that of the vehicle control groups. Mean body weights of 10 and 50 mg/kg females were generally less than those of the vehicle controls after weeks 81 and 17, respectively. The incidences of hepatocellular adenoma in males and females were significantly increased in the 50 mg/kg groups. In females, the incidences of hepatocellular carcinoma were significantly increased in all dosed groups. Incidences of hepatocellular adenoma or carcinoma (combined) in males and females were significantly increased in the 50 mg/kg groups. Incidences of hepatoblastoma were marginally increased in dosed males. Incidences of multiple hepatocellular adenomas and carcinomas were significantly increased in 10 and 50 mg/kg males, and there was an increased incidence of multiple hepatocellular adenomas in 50 mg/kg females. The incidence of eosinophilic focus was significantly increased in 50 mg/kg males, and the incidences of mixed cell focus and cytoplasmic vacuolization were significantly increased in 50 mg/kg females. There was a marginally increased incidence of pancreatic islet adenoma in 50 mg/kg males and in 10 and 50 mg/kg females, with an earlier day of first incidence in males. The incidences of clitoral gland hyperplasia and clitoral gland duct dilatation were significantly increased in 10 and 50 mg/kg females. The incidence of glomerular metaplasia of the kidney was significantly increased in 50 mg/kg females, and the incidences of cytoplasmic alteration of the submandibular salivary gland were significantly increased in all dosed female groups. The increased incidences of cytoplasmic alteration of the submandibular salivary gland and glomerular metaplasia of the kidney in female mice indicated a masculinizing effect from androstenedione treatment. In 50 mg/kg females, the incidence of malignant lymphoma was significantly decreased. androstenedione was not mutagenic in either of two independent bacterial mutation assays conducted with and without exogenous metabolic activation. No significant increases in the frequencies of micronucleated polychromatic erythrocytes, indicators of chromosomal damage, were observed in bone marrow of male rats administered androstenedione by gavage once daily for 3 consecutive days. Results of a peripheral blood erythrocyte micronucleus test in mice, in which androstenedione was administered by gavage for 3 months, were negative in males but judged to be equivocal in females due to a small increase (twofold over background) in micronucleated normochromatic erythrocytes observed at the highest dose administered (50 mg/kg). under the conditions of these 2-year gavage studies, there was equivocal evidence of carcinogenic activity of androstenedione in male F344/N rats based on increased incidences of alveolar/bronchiolar adenoma and alveolar/bronchiolar adenoma or carcinoma (combined). There was equivocal evidence of carcinogenic activity of androstenedione in female F344/N rats based on increased incidences of mononuclear cell leukemia. There was clear evidence of carcinogenic activity of androstenedione in male B6C3F1 mice based on increased incidences of multiple hepatocellular adenoma and hepatocellular carcinoma and increased incidence of hepatoblastoma. There was clear evidence of carcinogenic activity of androstenedione in female B6C3F1 mice based on increased incidences of hepatocellular adenoma and hepatocellular carcinoma. Increased incidences of pancreatic islet adenoma in male and female mice were also considered chemical related. Androstenedione administration caused increased incidences in nonneoplastic lesions of the liver in male and female rats and mice; pancreatic islets and exocrine pancreas of female rats; and clitoral gland, kidney, and submandibular salivary gland of female mice. Decreases in the incidences of testicular interstitial cell adenoma in male rats, mammary gland fibroadenoma, cysts, and hyperplasia in female rats, and malignant lymphoma in female mice were considered related to androstenedione administration. Synonyms: Andro; androst-4-ene-3,17-dione; 4-androstene-3,17-dione; delta-4-androstene-3,17-dione; delta-4-androstenedione; 3,17-dioxoandrost-4-ene; 17-ketotestosterone; SKF 2170 Trade names: Androtex, Fecundin.

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On February 17, 2003, a congestion charging scheme (CCS*) was introduced in central London along with a program of traffic management measures. The scheme operated Monday through Friday, 7 AM to 6 PM. This program resulted in an 18% reduction in traffic volume and a 30% reduction in traffic congestion in the first year (2003). We developed methods to evaluate the possible effects of the scheme on air quality: We used a temporal-spatial design in which modeled and measured air quality data from roadside and background monitoring stations were used to compare time periods before (2001-2002) and after (2003-2004) the CCS was introduced and to compare the spatial area of the congestion charging zone (CCZ) with the rest of London. In the first part of this project, we modeled changes in concentrations of oxides of nitrogen (NOx), nitrogen dioxide (NO2), and PM10 (particles with a mass median aerodynamic diameter &lt; or = 10 microm) across the CCZ and in Greater London under different traffic and emission scenarios for the periods before and after CCS introduction. Comparing model results within and outside the zone suggested that introducing the CCS would be associated with a net 0.8-microg/m3 decrease in the mean concentration of PM10 and a net 1.7-ppb decrease in the mean concentration of NOx within the CCZ. In contrast, a net 0.3-ppb increase in the mean concentration of NO2 was predicted within the zone; this was partly explained by an expected increase in primary NO2 emissions due to the introduction of particle traps on diesel buses (one part of the improvements in public transport associated with the CCS). In the second part of the project, we established a CCS Study Database from measurements obtained from the London Air Quality Network (LAQN) for air pollution monitors sited to measure roadside and urban background concentrations. Fully ratified (validated) 15-minute mean carbon monoxide (CO), nitric oxide (NO), NO2, NOx, PM10, and PM2.5 data from each chosen monitoring site for the period from February 17, 2001, to February 16, 2005, were transferred from the LAQN database. In the third part of our project, these data were used to compare geometric means for the 2 years before and the 2 years after the CCS was introduced. Temporal changes within the CCZ were compared with changes, over the same period, at similarly sited (roadside or background) monitors in a control area 8 km distant from the center of the CCZ. The analysis was confined to measurements obtained during the hours and days on which the scheme was in operation and focused on pollutants derived from vehicles (NO, NO2, NOx, PM10, and CO). This set of analyses was based on the limited data available from within the CCZ. When compared with data from outside the zone, we did not find evidence of temporal changes in roadside measurements of NOx, NO, and NO2, nor in urban background concentrations of NOx. (The latter result, however, concealed divergent trends in NO, which fell, and NO2, which rose.) Although based upon fewer stations, there was evidence that background concentrations of PM10 and CO fell within the CCZ compared with outside the zone. We also analyzed the trends in background concentrations for all London monitoring stations; as distance from the center of the CCZ increased, we found some evidence of an increasing gradation in NO and PM10 concentrations before versus after the intervention. This suggests a possible intermediate effect on air quality in the area immediately surrounding the CCZ. Although London is relatively well served with air quality monitoring stations, our study was restricted by the availability of only a few monitoring sites within the CCZ, and only one of those was at a roadside location. The results derived from this single roadside site are not likely to be an adequate basis for evaluating this complex urban traffic management scheme. Our primary approach to assessing the impact of the CCS was to analyze the changes in geometric mean pollutant concentrations in the 2 years before and 2 years after the CCS was introduced and to compare changes at monitoring stations within the CCZ with those in a distant control area (8 km from the CCZ center) unlikely to be influenced by the CCS. We saw this as the most robust analytical approach with which to examine the CCS Study Database, but in the fourth part of the project we did consider three other approaches: ethane as an indicator of pollution dispersion; the cumulative sum (CUSUM) statistical technique; and bivariate polar plots for local emissions. All three were subsequently judged as requiring further development outside of the scope of this study. However, despite their investigative nature, each technique provided useful information supporting the main analyses. The first method used ethane as a dispersion indicator to remove the inherent variability in air pollutant concentrations caused by changes in meteorology and atmospheric dispersion. The technique had the potential to ascertain more accurately the likely impacts of the CCS on London's air quality. Although this novel method appeared promising over short time periods, a number of concerns arose about whether the spatial and temporal variability of ethane over longer time periods would be representative of meteorologic conditions alone. The major strength of CUSUM, the second method, is that it can be used to identify the approximate timing of changes that may have been caused by the CCS. This ability is weakened, however, by the effects of serial correlation (the correlation of data among measurements in successive time intervals) within air pollution data that is caused by seasonality and long-term meteorologic trends. The secure interpretation of CUSUM requires that the technique be adapted to take proper account of the underlying correlation between measurements without the use of smoothing functions that would obscure a stepped change in concentrations. Although CUSUM was not able to provide a quantitative estimation of changes in pollution levels arising from the introduction of the CCS, the strong signals that were identified were considered in the context of other results from the study. The third method, bivariate polar plots, proved useful. The plots revealed important characteristics of the data from the only roadside monitoring site within the CCZ and highlighted the importance of considering prevailing weather conditions when positioning a roadside monitor. The technique would benefit from further development, however, in transforming the qualitative assessment of change into a quantitative assessment and including an estimate of uncertainty. Research is ongoing to develop this method in air-quality time-series studies. Overall, using a range of measurement and modeling approaches, we found evidence of small changes in air quality after introduction of the CCS. These include small decreases in PM10, NO, and CO. The possibility that some of these effects might reflect more general changes in London's air quality is suggested by the findings of somewhat similar changes in geometric means for weekends, when the CCS was not operating. However, since some evidence suggests that the CCS also had an impact on traffic volume on weekends, the CCS remains as one possible explanation for the observed pattern of changes in pollutant concentrations. In addition, the CCS was just one of a number of traffic and emission reduction schemes introduced in London over the 4-year study period; if the other measures had an impact in central London, they might partly explain our findings. Although not the aim of this study, it is important to consider how the trends we observed might be translated into health effects. For example, given that London already has NO2 concentrations in excess of the permitted limit value, we do not know what the effects of an increase in NO2 created by diesel-exhaust after-treatment for particles might mean for health. Further, although it is not likely that NO affects health, the decrease in NO concentrations is likely associated with an increase in ozone concentrations (a pollutant associated with health effects), as has been seen in recent years in London. These and other similar issues require further investigation. Although the CCS is a relatively simple traffic management scheme in the middle of a major urban environment, analyzing its possible impact on air quality was found to be far from straightforward. Using a range of modeling and monitoring approaches to address the impact of the scheme revealed that each technique has its own advantages and limitations. The placement of monitoring sites and the availably of traffic count data were also identified as key issues. The most compelling lesson we take away from this study is that such work is impossible to undertake without a coherent multi-disciplinary team of skilled researchers. In conclusion, our study suggests that the introduction of the CCS in 2003 was associated with small temporal changes in air pollutant concentrations in central London compared with outer areas. However, attributing the cause of these changes to the CCS alone is not appropriate because the scheme was introduced at a time when other traffic and emissions interventions, which might have had a more concentrated effect in central London, were also being implemented.

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Systematic reviews and analyses of administrative data were performed to determine the appropriate use of bone mineral density (BMD) assessments using dual energy x-ray absorptiometry (DXA), and the associated trends in wrist and hip fractures in Ontario. DUAL ENERGY X-RAY ABSORPTIOMETRY BONE MINERAL DENSITY ASSESSMENT: Dual energy x-ray absorptiometry bone densitometers measure bone density based on differential absorption of 2 x-ray beams by bone and soft tissues. It is the gold standard for detecting and diagnosing osteoporosis, a systemic disease characterized by low bone density and altered bone structure, resulting in low bone strength and increased risk of fractures. The test is fast (approximately 10 minutes) and accurate (exceeds 90% at the hip), with low radiation (1/3 to 1/5 of that from a chest x-ray). DXA densitometers are licensed as Class 3 medical devices in Canada. The World Health Organization has established criteria for osteoporosis and osteopenia based on DXA BMD measurements: osteoporosis is defined as a BMD that is &gt;2.5 standard deviations below the mean BMD for normal young adults (i.e. T-score &lt;-2.5), while osteopenia is defined as BMD that is more than 1 standard deviation but less than 2.5 standard deviation below the mean for normal young adults (i.e. T-score&lt; -1 &amp; ≥-2.5). DXA densitometry is presently an insured health service in Ontario.   BURDEN OF DISEASE: The Canadian Multicenter Osteoporosis Study (CaMos) found that 16% of Canadian women and 6.6% of Canadian men have osteoporosis based on the WHO criteria, with prevalence increasing with age. Osteopenia was found in 49.6% of Canadian women and 39% of Canadian men. In Ontario, it is estimated that nearly 530,000 Ontarians have some degrees of osteoporosis. Osteoporosis-related fragility fractures occur most often in the wrist, femur and pelvis. These fractures, particularly those in the hip, are associated with increased mortality, and decreased functional capacity and quality of life. A Canadian study showed that at 1 year after a hip fracture, the mortality rate was 20%. Another 20% required institutional care, 40% were unable to walk independently, and there was lower health-related quality of life due to attributes such as pain, decreased mobility and decreased ability to self-care. The cost of osteoporosis and osteoporotic fractures in Canada was estimated to be $1.3 billion in 1993. With 2 exceptions, almost all guidelines address only women. None of the guidelines recommend blanket population-based BMD testing. Instead, all guidelines recommend BMD testing in people at risk of osteoporosis, predominantly women aged 65 years or older. For women under 65 years of age, BMD testing is recommended only if one major or two minor risk factors for osteoporosis exist. Osteoporosis Canada did not restrict its recommendations to women, and thus their guidelines apply to both sexes. Major risk factors are age greater than or equal to 65 years, a history of previous fractures, family history (especially parental history) of fracture, and medication or disease conditions that affect bone metabolism (such as long-term glucocorticoid therapy). Minor risk factors include low body mass index, low calcium intake, alcohol consumption, and smoking. The Ontario Health Insurance Program (OHIP) Schedule presently reimburses DXA BMD at the hip and spine. Measurements at both sites are required if feasible. Patients at low risk of accelerated bone loss are limited to one BMD test within any 24-month period, but there are no restrictions on people at high risk. The total fee including the professional and technical components for a test involving 2 or more sites is $106.00 (Cdn). This review consisted of 2 parts. The first part was an analysis of Ontario administrative data relating to DXA BMD, wrist and hip fractures, and use of antiresorptive drugs in people aged 65 years and older. The Institute for Clinical Evaluative Sciences extracted data from the OHIP claims database, the Canadian Institute for Health Information hospital discharge abstract database, the National Ambulatory Care Reporting System, and the Ontario Drug Benefit database using OHIP and ICD-10 codes. The data was analyzed to examine the trends in DXA BMD use from 1992 to 2005, and to identify areas requiring improvement. The second part included systematic reviews and analyses of evidence relating to issues identified in the analyses of utilization data. Altogether, 8 reviews and qualitative syntheses were performed, consisting of 28 published systematic reviews and/or meta-analyses, 34 randomized controlled trials, and 63 observational studies. Analysis of administrative data showed a 10-fold increase in the number of BMD tests in Ontario between 1993 and 2005.OHIP claims for BMD tests are presently increasing at a rate of 6 to 7% per year. Approximately 500,000 tests were performed in 2005/06 with an age-adjusted rate of 8,600 tests per 100,000 population.Women accounted for 90 % of all BMD tests performed in the province.In 2005/06, there was a 2-fold variation in the rate of DXA BMD tests across local integrated health networks, but a 10-fold variation between the county with the highest rate (Toronto) and that with the lowest rate (Kenora). The analysis also showed that:With the increased use of BMD, there was a concomitant increase in the use of antiresorptive drugs (as shown in people 65 years and older) and a decrease in the rate of hip fractures in people age 50 years and older.Repeat BMD made up approximately 41% of all tests. Most of the people (&gt;90%) who had annual BMD tests in a 2-year or 3-year period were coded as being at high risk for osteoporosis.18% (20,865) of the people who had a repeat BMD within a 24-month period and 34% (98,058) of the people who had one BMD test in a 3-year period were under 65 years, had no fracture in the year, and coded as low-risk.Only 19% of people age greater than 65 years underwent BMD testing and 41% received osteoporosis treatment during the year following a fracture.Men accounted for 24% of all hip fractures and 21 % of all wrist fractures, but only 10% of BMD tests. The rates of BMD tests and treatment in men after a fracture were only half of those in women.In both men and women, the rate of hip and wrist fractures mainly increased after age 65 with the sharpest increase occurring after age 80 years. SERIAL BONE MINERAL DENSITY TESTING FOR PEOPLE NOT RECEIVING OSTEOPOROSIS TREATMENT: A systematic review showed that the mean rate of bone loss in people not receiving osteoporosis treatment (including postmenopausal women) is generally less than 1% per year. Higher rates of bone loss were reported for people with disease conditions or on medications that affect bone metabolism. In order to be considered a genuine biological change, the change in BMD between serial measurements must exceed the least significant change (variability) of the testing, ranging from 2.77% to 8% for precisions ranging from 1% to 3% respectively. Progression in BMD was analyzed, using different rates of baseline BMD values, rates of bone loss, precision, and BMD value for initiating treatment. The analyses showed that serial BMD measurements every 24 months (as per OHIP policy for low-risk individuals) is not necessary for people with no major risk factors for osteoporosis, provided that the baseline BMD is normal (T-score ≥ -1), and the rate of bone loss is less than or equal to 1% per year. The analyses showed that for someone with a normal baseline BMD and a rate of bone loss of less than 1% per year, the change in BMD is not likely to exceed least significant change (even for a 1% precision) in less than 3 years after the baseline test, and is not likely to drop to a BMD level that requires initiation of treatment in less than 16 years after the baseline test. Seven published meta-analysis of randomized controlled trials (RCTs) and 2 recent RCTs on BMD monitoring during osteoporosis therapy showed that although higher increases in BMD were generally associated with reduced risk of fracture, the change in BMD only explained a small percentage of the fracture risk reduction.Studies showed that some people with small or no increase in BMD during treatment experienced significant fracture risk reduction, indicating that other factors such as improved bone microarchitecture might have contributed to fracture risk reduction.There is conflicting evidence relating to the role of BMD testing in improving patient compliance with osteoporosis therapy.Even though BMD may not be a perfect surrogate for reduction in fracture risk when monitoring responses to osteoporosis therapy, experts advised that it is still the only reliable test available for this purpose.A systematic review conducted by the Medical Advisory Secretariat showed that the magnitude of increases in BMD during osteoporosis drug therapy varied among medications. Although most of the studies yielded mean percentage increases in BMD from baseline that did not exceed the least significant change for a 2% precision after 1 year of treatment, there were some exceptions. A review of 3 published pooled analyses of observational studies and 12 prospective population-based observational studies showed that the presence of any prevalent fracture increases the relative risk for future fractures by approximately 2-fold or more. (ABSTRACT TRUNCATED)

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To the Editors: We have read with interest and some concern the recently published editorial, "We've Got a Treatment, but What's the Disease," by Rosenthal and Glatstein. This editorial enunciates these common anxieties (? "mid-life") about radiosurgery: A) that thedure as currently practiced worldwide, even in the United States, does not in all cases rely on the talents of radiation oncologists; B) that the technique disregards fundamental (? proven) principles about radiobiology, and C) that the authors of the editorial have chosen to ignore a tremendous body of historical and clinical literature relative to outcomes. In fact, long-term clinical data have been published in a wide variety of reports during the last ten years. Their reference list does not include a single article published beyond 1992. Now let's address the first issue. While it is true that the advantages obtained by closed skull focused stereotactic single session irradiation of a small but well-defined intracranial target volume (radiosurgery) were first espoused and practiced by neuosurgeons, the goal was not to impact upon the turf of the radiation oncologist. The goal was to provide a minimally invasive treatment for many problems deep within the brain for which traditional neurosurgical procedures were neither satisfactory nor effective. The tools that allowed neurosurgeons to accomplish this goal included focused particle beams or photon beams generated by the gamma knife or by linear accelerators. The technique also required highly precise (&lt;1 mm) intracranial guiding systems (stereotactic technology). The initial evolution of this technology was cautious. It was based on more than 30 years of experimental and clinical work that preceded its introduction into the worldwide medical community beginning in the mid-1980s. In the United States, the vast majority of centers provide this technology based on the multidisciplinary input of neurosurgeons, radiation oncologists and medical physicists. The team provides both the necessary experience as well as the different perspectives that facilitate safe intervention and effective outcomes. The issue of responsibility in this multidisciplinary medical team should not be obfuscated by individual socio-economic concerns (who's in charge, who gets paid?). The recent purchase of an expensive deice for fractionated frameless radiotherapy by Southwest Medical Center may impact on Rosenthal and Glatstein's recent publication. In fact, stereotactic fractionated radiotherapy is the expensive treatment in search of a disease to pay for it Of greater concern is the authors' misconceptions (misunderstanding?) about the goals of radiosurgery (the second issue). Initially, radiosurgery was created to provide small volume destruction (in this case, true necrosis) of small target volumes withinthe basal ganglia, thalamus, or internal capsule for the treatment of intractable movement disorders, chronic pain, or medically refractory neuroses. With the redesign of the technology, deep-seated neoplasms and vascular malformations became more appealing targets with an entirely different radiobiologic goal. Instead, the goal became radiobiological inactivation of the ability of a tumor cell to divide and multiply (for tumors) or progressive luminal closure induced by endothelial hyperplasia (in the case of vascular malformations). Preservation of the surrounding normal brain (a feature brought about by the very sharp fall-off of the radiation dose delivered to small volumes with precise technology) reduced the risk of complications to normal brain, especially in contrast to surgical extirpation. Fractionated radiation therapy has rarely been an alternative to the usage of radiosurgery for these conditions. For malignant tumors, radiosurgery is most often used in conjunction with fractionated radiation therapy to take advantage of the single fraction destructive effects of radiosurgery followed or preceded by conventional fractionated radiation therapy. Such an approach enhances the likelihood of a satisfactory response based on the standard 4 Rs of curret radiobiological thinking. Stereotactic radiosurgery is a single "fraction" treatment; fractionated stereotactic radiosurgery is an absolute oxymoron. Certainly, renewed interest in the risk-benefit of fractionated radiation therapy is a logical outgrowth of the current tremendousave of enthusiasm for radiosurgery. In fact, the growth of radiosurgery has made radiation oncologists re-think their own practice of conventional radiation therapy. Similarly, it has had a profound impact on procedure selection by neurological surgeons. The third issue is addressed by the enormous volume of literature relative to outcomes in vascular malformations, malignant tumors, and benign tumors. The usage of radiosurgical technology should continue to stimulate thoughtful investigators to advance outcomes in these difficult conditions and reduce the risks of standard surgical techniques. It must be based on a collegial and multidisciplinary approach. The timing of Rosenthal and Glatstein's editorial was a mystery, appearing almost atavistic, especially considering the enormous growth of understanding and experience accumulated in the ten-year interval since both linac and gamma knife radiosurgical tecnologies became available in North America. AUTHORS' RESPONSE: In response to the Letter to the Editor by Lunsford, Flickinger and Larson, our main objectives in writing that article were twofold. The first was to review those principles of fractionation derived from a near century's experience in clinical radiobioloy. We have learned over and over again that, in general, hypofractionation leads to poorer tumor control, and more frequent and severe normal tissue complications. We believe that this point was, perhaps, not as fully appreciated during the development of radiosurgery because of a more surgical rather than radiotherapeutic influence. The second objective regards the safety issues of the even more widespread use of radiosurgery for brain tumors during the period when long-term follow-up data (ten years or more) are still emerging. Radiosurgery is in common use at our institution, the University of Pennsylvania Medical Center. We in no way wish to diminish the established safety and effectiveness of radiosurgery for arteriovenous malformations (AVMs). Additionally, we wholeheartedly encourage continued investigation for benign and malignant intracranial tumors. Our chief concern is the objective scientific validation of radiosurgery for these latter applications in prospective trials which have adequate long-term follow-up to establish safety. The central nervous system is the most unforgiving organ in terms of late radiation effects. Are all patients undergoing radiosurgery for benign tumors being accurately informed of the good results of modern fractionated radiotherapy, and those who undergo it for malignant tumors, that objective phase III validation and long-term safety data are NOT yet available? It frightens us even more that Lunsford et al. state, "In fact, the growth of radiosurgery has made radiation oncologists re-think their own practice of conventional raiation therapy." Just when do we evaluate the new clothes for the emperor Lunsford et al. tell us that radiosurgery technology has been "re-designed" with ".an entirely different radiobiologic goal. (the) inability of a tumor cell to divide and multiply." Radiation oncologists have long been taught as residents that raiologists accept the definition of "radiobiologic cell death" as the loss of continual clonogenicity. We all strive to this end in the treatment of tumors, but we are concerned about the extrapolation of the accepted application of radiosurgery for AVM tumors. More than 10,000 patients have had radiosurgery for brain tumors. Many of these have been benign, and more than 1,000 patients were treated with protons at the Harvard Cyclotron Unit, mostly for pituitary adenoma. Their experience has established safety, but the data for photon radiosurgery is not as large or mature, and one wonders how much photon radiosurgery adds to the excellent results achievable by conventional fractionated radiotherapy, especially for patients with pituitary tumors. With respect to malignant primary tumors or metastases, there have been fewer patients so treated. We recognize that longer term follow-up is not as important an issue for this unfortunate patient population whose survival period is generally short. Nonetheless, we reiterate that: A) hypofractionation has historically been shown to lead both to decreased control and increased complications, and B) that the higher the grade of a brain tumor, the more difficulty we have in localizing its extensions, especially when a treatment volume is &lt;3 cc. There is absolutely no evidence that fractionated stereotactic treatment is an "oxymoron." Those data are only now beginning to emerge. It makes sense to encourage the investigation of radiosurgery as a boost followingonventional fractionated radiotherapy, or, for those who had the wherewithal to develop practical and cost-effective methods to treat with "fractionated radiosurgery" (read "stereotactic radiotherapy") to use those principles of clinical radiobiology twe have learned painstakingly over the last century to drive clinical investigation, and not rely solely on the impetus of new technology. Such investigation is ongoing at our institution, as we strive for the scientific evaluation of the comparative efficacy and long-term safety of radiosurgery for brain tumors. Had Coutard and Baclesse not pioneered fractionation, radiotherapy probably would have fallen into oblivion due to the morbidities of single shot treatment. Indeed, much of the first half of this century was spent learning that doses large enough to sterilize a mass of tumor cells (10 logs) cannot be predictably given safely. Instead, fractionation evolved which permitted us to exploit repopulation, redistribution, reoxygenation and repair. The use of these large single doses remains, at least in our minds, investigational in the treatment of especially malignant tumors. This is the way this subject is presented to patients here.

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As the first case-control study of malignant mesothelioma of the pericardium and the tunica vaginalis testis (mTVT), the paper by Marinaccio et al (1) is potentially an important epidemiologic contribution. A careful review of the paper, however, raises a number of methodological issues. Any case-control study can be viewed as being nested within a conceptual cohort, with controls being sampled from the at-risk cohort as cases arise over time. This view of case-control studies leads to the concept of incidence-density sampling of controls (eg, 2, 3). For Marinaccio et al (1) this would mean that, as cases were registered over the study period, each would be matched to an individual control or set of controls of the same gender, age, and region of the country (since asbestos exposure varies by time and region [4]). For example, if a case were 50 years old in 1995, then any matched control should be close to age 50 in 1995 and of the same gender and from the same region as the case. Matching for age in this fashion automatically results in matching for year of birth, which is essential in this context because birth-cohort effects are determinants of asbestos exposure and mesothelioma incidence (eg, 5-8). If Marinaccio et al (1) used this scheme for age-matching, one would expect to see similar distributions of cases (table 1) and controls (table S3 in the supplemental material) by period of birth. Among males, however, the distributions of mesothelioma cases (whether pericardial or mTVT) and controls by period of birth are clearly different (P&lt;0.001). Among females, the distributions of cases of pericardial mesothelioma and controls by birth year are less dissimilar (P≈0.05). Thus, the female cases of pericardial mesothelioma are better matched to controls on year of birth than are male cases of either mTVT or pericardial mesothelioma. We note also that the distributions of male and female controls by year of birth are distinctly different (P&lt;0.002), whereas the birth-year distributions of cases of mesothelioma by site and gender are not (P≈0.8). In the Marinaccio et al (1) sensitivity analysis restricted to subjects born before 1950, the distributions of cases and controls by period of birth remain significantly different. Therefore, based on the reported evidence, cases and controls were not matched on birth cohort, thereby possibly biasing the results. Similarly, bias may result from the lack of matching on geographic region; while cases were registered from across Italy, controls were selected from only six regions. Although a sensitivity analysis restricted cases and controls to those from only the six regions, a comparison of tables S1 and S3 indicates that the regional distribution of controls is different from that of person-time observed; that is, the controls do not appear to be representative of the underlying population at risk by region. The second major issue of concern has to do with ascertainment of asbestos exposure. Information on exposure for the cases was presumably obtained at the time of registration. The two sets of controls, obtained from previously unpublished case-control studies, were interviewed during 2014-2015 and 2014-2016; that is, many years after the exposure for most cases was ascertained (1993-2015). Few other details of the control groups are provided, except that participation by one set of controls was &lt;50%, raising additional concerns about selection bias. For details on the second set of controls, Marinaccio et al (1) reference a paper by Brandi et al (9). On review of that paper, however, we found no description of the control group, only references to three earlier papers. Marinaccio et al (1) present analyses only with both sets of controls combined; to evaluate potential sources of bias from the use of different sets of controls, they should also report results using each set of controls separately. The authors also did not detail their methods of exposure classification. For example, what does probable or possible exposure mean? The authors should at least present separate analyses of definite occupational exposure. Eighty cases of mTVT were registered, but only 68 were included in the analyses. Information on the 12 omitted cases (eg, age, year of birth, and region) would be helpful. Marinaccio et al (1) did not provide clear information on what occupations and/or industries they considered as exposed to asbestos. In an earlier study, Marinaccio et al (10) remarked on the absence of pericardial mesothelioma and mTVT in industries with the highest exposures to asbestos, saying, "[t]he absence of exposures in the shipbuilding, railway and asbestos-cement industries … for all the 67 pericardial and testicular cases is noteworthy but not easy to interpret." By contrast, Marinaccio et al (1) stated, "[t]he economic sectors more frequently associated with asbestos exposure were construction, steel mills, metal-working industry, textile industry and agriculture." The possibility of exposure in the "agriculture economic sector" was not mentioned in Marinaccio et al (10) and appears not to have been considered in previous epidemiologic studies in Italy. In general, epidemiologic studies indicate that farmers and agricultural workers are not at increased risk of developing mesothelioma (eg, 11-17). The fact that few, if any, cases of mTVT and pericardial mesothelioma occurred in industries traditionally associated with high asbestos exposure raises the possibility that the results of Marinaccio et al (1) are attributable to deficiencies in study design, very possibly bias in the selection of controls, and deficiencies in exposure assessment and classification as described above, leading to a spurious association of occupational exposure with mTVT and male pericardial mesothelioma. Conflict of interest This research has received no outside funding. All authors are employees of Exponent, Inc., an international scientific and engineering consulting company. All authors have worked as both consulting and testifying experts in litigation matters related to asbestos exposure and asbestos-related disease. References 1. Marinaccio A, Consonni D, Mensi C, Mirabelli D, Migliore E, Magnani C et al.; ReNaM Working Group. Association between asbestos exposure and pericardial and tunica vaginalis testis malignant mesothelioma: a case-control study and epidemiological remarks. Scand J Work Environ Health. 2020;46(6):609-617. https://doi.org/10.5271/sjweh.3895. 2. Rothman KJ, Greenland S, Lash TL. Modern Epidemiology. 2008; Philadelphia: Wolters Kluwer/Lippincott Williams &amp; Wilkins. 3. Richardson DB. An incidence density sampling program for nested case-control analyses. Occup Environ Med 2004 Dec;61(12):e59. https://doi.org/10.1136/oem.2004.014472. 4. Marinaccio A, Binazzi A, Marzio DD, Scarselli A, Verardo M, Mirabelli D et al.; ReNaM Working Group. Pleural malignant mesothelioma epidemic: incidence, modalities of asbestos exposure and occupations involved from the Italian National Register. Int J Cancer 2012 May;130(9):2146-54. https://doi.org/10.1002/ijc.26229. 5. La Vecchia C, Decarli A, Peto J, Levi F, Tomei F, Negri E. An age, period and cohort analysis of pleural cancer mortality in Europe. Eur J Cancer Prev 2000 Jun;9(3):179-84. https://doi.org/10.1097/00008469-200006000-00005. 6. Price B, Ware A. Mesothelioma trends in the United States: an update based on Surveillance, Epidemiology, and End Results Program data for 1973 through 2003. Am J Epidemiol 2004 Jan;159(2):107-12. https://doi.org/10.1093/aje/kwh025. 7. Moolgavkar SH, Meza R, Turim J. Pleural and peritoneal mesotheliomas in SEER: age effects and temporal trends, 1973-2005. Cancer Causes Control 2009 Aug;20(6):935-44. https://doi.org/10.1007/s10552-009-9328-9. 8. Moolgavkar SH, Chang ET, Mezei G, Mowat FS. Chapter 3. Epidemiology of mesothelioma. In Testa JR. Asbestos and mesothelioma; 2017. pp. 43-72. Cham, Switzerland: Springer International Publishing. 9. Brandi G, Di Girolamo S, Farioli A, de Rosa F, Curti S, Pinna AD et al. Asbestos: a hidden player behind the cholangiocarcinoma increase? Findings from a case-control analysis. Cancer Causes Control 2013 May;24(5):911-8. https://doi.org/10.1007/s10552-013-0167-3. 10. Marinaccio A, Binazzi A, Di Marzio D, Scarselli A, Verardo M, Mirabelli D et al. Incidence of extrapleural malignant mesothelioma and asbestos exposure, from the Italian national register. Occup Environ Med 2010 Nov;67(11):760-5. https://doi.org/10.1136/oem.2009.051466. 11. Teschke K, Morgan MS, Checkoway H, Franklin G, Spinelli JJ, van Belle G et al. Mesothelioma surveillance to locate sources of exposure to asbestos. Can J Public Health 1997 May-Jun;88(3):163-8. https://doi.org/10.1007/BF03403881. 12. Bouchardy C, Schüler G, Minder C, Hotz P, Bousquet A, Levi F et al. Cancer risk by occupation and socioeconomic group among men--a study by the Association of Swiss Cancer Registries. Scand J Work Environ Health 2002;28(1 Suppl 1):1-88. 13. Hemminki K, Li X. Time trends and occupational risk factors for pleural mesothelioma in Sweden. J Occup Environ Med 2003a Apr;45(4):456-61. https://doi.org/10.1097/01.jom.0000058341.05741.7e. 14. Hemminki K, Li X. Time trends and occupational risk factors for peritoneal mesothelioma in Sweden. J Occup Environ Med 2003b Apr;45(4):451-5. https://doi.org/10.1097/01.jom.0000052960.59271.d4. 15. Pukkala E, Martinsen JI, Lynge E, Gunnarsdottir HK, Sparén P, Tryggvadottir L et al. Occupation and cancer - follow-up of 15 million people in five Nordic countries. Acta Oncol 2009;48(5):646-790. https://doi.org/10.1080/02841860902913546. 16. Rolland P, Gramond C, Berron H, Ducamp S, Imbernon E, Goldberg M et al. Mesotheliome pleural: Professions et secteurs d'activite a risque chez les hommes [Pleural mesothelioma: Professions and occupational areas at risk among humans]. 2005; Institut de Veille Sanitaire, Departement Sante Travai, Saint-Maurice, France. 17. Rolland P, Gramond C, Lacourt A, Astoul P, Chamming's S, Ducamp S et al. PNSM Study Group. Occupations and industries in France at high risk for pleural mesothelioma: A population-based case-control study (1998-2002). Am J Ind Med 2010 Dec;53(12):1207-19. https://doi.org/10.1002/ajim.20895.

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There is emerging evidence, largely from studies in Europe and North America, that economic deprivation increases the magnitude of morbidity and mortality related to air pollution. Two major reasons why this may be true are that the poor experience higher levels of exposure to air pollution, and they are more vulnerable to its effects--in other words, due to poorer nutrition, less access to medical care, and other factors, they experience more health impact per unit of exposure. The relations among health, air pollution, and poverty are likely to have important implications for public health and social policy, especially in areas such as the developing countries of Asia where air pollution levels are high and many live in poverty. The aims of this study were to estimate the effect of exposure to air pollution on hospital admissions of young children for acute lower respiratory infection (ALRI*) and to explore whether such effects differed between poor children and other children. ALRI, which comprises pneumonia and bronchiolitis, is the largest single cause of mortality among young children worldwide and is responsible for a substantial burden of disease among young children in developing countries. To the best of our knowledge, this is the first study of the health effects of air pollution in Ho Chi Minh City (HCMC), Vietnam. For these reasons, the results of this study have the potential to make an important contribution to the growing literature on the health effects of air pollution in Asia. The study focused on the short-term effects of daily average exposure to air pollutants on hospital admissions of children less than 5 years of age for ALRI, defined as pneumonia or bronchiolitis, in HCMC during 2003, 2004, and 2005. Admissions data were obtained from computerized records of Children's Hospital 1 and Children's Hospital 2 (CH1 and CH2) in HCMC. Nearly all children hospitalized for respiratory illnesses in the city are admitted to one of these two pediatric hospitals. Daily citywide 24-hour average concentrations of particulate matter (PM) &lt; or =10 microm in aerodynamic diameter (PM10), nitrogen dioxide (NO2), and sulfur dioxide (SO2) and 8-hour maximum average concentrations of ozone (O3) were estimated from the HCMC Environmental Protection Agency (HEPA) ambient air quality monitoring network. Daily meteorologic information including temperature and relative humidity were collected from KTTV NB, the Southern Regional Hydro-Meteorological Center. An individual-level indicator of socioeconomic position (SEP) was based on the degree to which the patient was exempt from payment according to hospital financial records. A group-level indicator of SEP was based on estimates of poverty prevalence in the districts of HCMC in 2004, obtained from a poverty mapping project of the Institute of Economic Research in HCMC, in collaboration with the General Statistics Office of Vietnam and the World Bank. Poverty prevalence was defined using the poverty line set by the People's Committee of HCMC of 6 million Vietnamese dong (VND) annual income. Quartiles of district-level poverty prevalence were created based on poverty prevalence estimates for each district. Analyses were conducted using both time-series and case-crossover approaches. In the absence of measurement error, confounding, and other sources of bias, the two approaches were expected to provide estimates that differed only with regard to precision. For the time-series analyses, the unit of observation was daily counts of hospital admissions for ALRI. Poisson regression with smoothing functions for meteorologic variables and variables for seasonal and long-term trends was used. Case-crossover analyses were conducted using time-stratified selection of controls. Control days were every 7th day from the date of admission within the same month as admission. Large seasonal differences were observed in pollutant levels and hospital admission patterns during the investigation period for HCMC. Of the 15,717 ALRI admissions occurring within the study period, 60% occurred in the rainy season (May through October), with a peak in these admissions during July and August of each year. Average daily concentrations for PM10, O3, NO2, and SO2 were 73, 75, 22, and 22 microg/m3, respectively, with higher pollutant concentrations observed in the dry season (November through April) compared with the rainy season. As the time between onset of illness and hospital admission was thought to range from 1 to 6 days, it was not possible to specify a priori a single-day lag. We assessed results for single-day lags from lag 0 to lag 10, but emphasize results for an average of lag 1-6, since this best reflects the case reference period. Results were robust to differences in temperature lags with lag 0 and the average lag (1-6 days); results for lag 0 for temperature are presented. Results differed markedly when analyses were stratified by season, rather than simply adjusted for season. ALRI admissions were generally positively associated with ambient levels of PM10, NO2, and SO2 during the dry season (November-April), but not the rainy season (May-October). Positive associations between O3 and ALRI admissions were not observed in either season. We do not believe that exposure to air pollution could reduce the risk of ALRI in the rainy season and infer that these results could be driven by residual confounding present within the rainy season. The much lower correlation between NO2 and PM10 levels during the rainy season provides further evidence that these pollutants may not be accurate indicators of exposure to air pollution from combustion processes in the rainy season. Results were generally consistent across time-series and case-crossover analyses. In the dry season, risks for ALRI hospital admissions with average pollutant lag (1-6 days) were highest for NO2 and SO2 in the single-pollutant case-crossover analyses, with excess risks of 8.50% (95% CI, 0.80-16.79) and 5.85% (95% CI, 0.44-11.55) observed, respectively. NO2 and SO2 effects remained higher than PM10 effects in both the single-pollutant and two-pollutant models. The two-pollutant model indicated that NO2 confounded the PM10 and SO2 effects. For example, PM10 was weakly associated with an excess risk in the dry season of 1.25% (95% CI, -0.55 to 3.09); after adjusting for SO2 and O3, the risk estimate was reduced but remained elevated, with much wider confidence intervals; after adjusting for NO2, an excess risk was no longer observed. Though the effects seem to be driven by NO2, the statistical limitations of adequately addressing collinearity, given the high correlation between PM10 and NO2 (r = 0.78), limited our ability to clearly distinguish between PM10 and NO2 effects. In the rainy season, negative associations between PM10 and ALRI admissions were observed. No association with O3 was observed in the single-pollutant model, but O3 exposure was negatively associated with ALRI admissions in the two-pollutant model. There was little evidence of an association between NO2 and ALRI admissions. The single-pollutant estimate from the case-crossover analysis suggested a negative association between NO2 and ALRI admissions, but this effect was no longer apparent after adjustment for other pollutants. Although associations between SO2 and ALRI admissions were not observed in the rainy season, point estimates for the case-crossover analyses suggested negative associations, while time-series (Poisson regression) analyses suggested positive associations--an exception to the general consistency between case-crossover and time-series results. Results were robust to differences in seasonal classification. Inclusion of rainfall as a continuous variable and the seasonal reclassification of selected series of data did not influence results. No clear evidence of station-specific effects could be observed, since results for the different monitoring stations had overlapping confidence intervals. In the dry season, increased concentrations of NO2 and SO2 were associated with increased hospital admissions of young children for ALRI in HCMC. PM10 could also be associated with increased hospital admissions in the dry season, but the high correlation of 0.78 between PM10 and NO2 levels limits our ability to distinguish between PM10 and NO2 effects. Nevertheless, the results support the presence of an association between combustion-source pollution and increased ALRI admissions. There also appears to be evidence of uncontrolled negative confounding within the rainy season, with higher incidence of ALRI and lower pollutant concentrations overall. Exploratory analyses made using limited historical and regional data on monthly prevalence of respiratory syncytial virus (RSV) suggest that an unmeasured, time-varying confounder (RSV, in this case) could have, in an observational study like this one, created enough bias to reverse the observed effect estimates of pollutants in the rainy season. In addition, with virtually no RSV incidence in the dry season, these findings also lend some credibility to the notion that RSV could influence results primarily in the rainy season. Analyses were not able to identify differential effects by individual-level indicators of SEP, mainly due to the small number of children classified as poor based on information in the hospitals' financial records. Analyses assessing differences in effect by district-level indicator of SEP did not indicate a clear trend in risk across SEP quartiles, but there did appear to be a slightly higher risk among the residents of districts with the highest quartile of SEP. As these are the districts within the urban center of HCMC, results could be indicative of increased exposures for residents living within the city center. (ABSTRACT TRUNCATED)

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Fractures of the femoral shaft in children are relatively uncommon but serious injuries that disrupt the lives of children and their carers and can result in significant long-term disability. Treatment involves either surgical fixation, such as intramedullary nailing or external fixation, or conservative treatment involving prolonged immobilisation, often in hospital. To assess the effects (benefits and harms) of interventions for treating femoral shaft fractures in children and adolescents. We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (accessed 16 August 2013), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2013 Issue 7), MEDLINE (1946 to August Week 1 2013), EMBASE (1980 to 2012 week 9), CINAHL (16 August 2013), clinical trials registries, conference proceedings and reference lists; and contacted trial authors and experts in the field. Randomised and quasi-randomised controlled trials comparing conservative and surgical interventions for diaphyseal fractures of the femur in children under 18 years of age. Our primary outcomes were functional outcome measures, unacceptable malunion, and serious adverse events. Two authors independently screened and selected trials, assessed risk of bias and extracted data. We assessed the overall quality of the evidence for each outcome for each comparison using the GRADE approach. We pooled data using a fixed-effect model. We included 10 trials (six randomised and four quasi-randomised) involving a total of 527 children (531 fractures). All trials were at some risk of bias, including performance bias as care provider blinding was not practical, but to a differing extent. Just one trial was at low risk of selection bias. Reflecting both the risk of bias and the imprecision of findings, we judged the quality of evidence to be 'low' for most outcomes, meaning that we are unsure about the estimates of effect. Most trials failed to report on self-assessed function or when children resumed their usual activities. The trials evaluated 10 different comparisons, belonging to three main categories. Surgical versus conservative treatment. Four trials presenting data for 264 children aged 4 to 12 years made this comparison. Low quality evidence (one trial, 101 children) showed children had very similar function assessed using the RAND health status score at two years after surgery (external fixation) compared with conservative treatment (spica cast): mean 69 versus 68. The other three trials did not report on function. There was moderate quality evidence (four trials, 264 children, aged 4 to 12 years, followed up 3 to 24 months) that surgery reduced the risk of malunion (risk ratio (RR) 0.29, 95% confidence interval (CI) 0.15 to 0.59, 4 trials). Assuming an illustrative baseline risk of 115 malunions per 1000 in children treated conservatively, these data equate to 81 fewer (95% CI 47 to 97 fewer) malunions per 1000 in surgically-treated children. Conversely, low quality evidence indicated that there were more serious adverse events such as infections after surgery (RR 2.39, 95% CI 1.10 to 5.17, 4 trials). Assuming an illustrative baseline risk of 40 serious adverse events per 1000 for conservative treatment, these data equate to 56 more (95% CI 4 to 167 more) serious adverse events per 1000 children treated surgically. There was low quality evidence (one trial, 101 children) of similar satisfaction levels in children and parents with surgery involving external fixation and plaster cast only. However, there was low quality evidence (one trial, 46 children) that more parents were satisfied with intramedullary nailing than with traction followed by a cast, and that surgery reduced the time taken off from school. Comparisons of different methods of conservative treatment. The three trials in this category made three different comparisons. We are very unsure if unacceptable malunion rates differ between immediate hip spica versus skeletal traction followed by spica in children aged 3 to 10 years followed up for six to eight weeks (RR 4.0, 95% CI 0.5 to 32.9; one trial, 42 children; very low quality evidence). Malunion rates at 5 to 10 years may not differ between traction followed by functional orthosis versus traction followed by spica cast in children aged 5 to 13 years (RR 0.98, 95% CI 0.46 to 2.12; one trial, 43 children; low quality evidence). We are very unsure (very low quality evidence) if either function or serious adverse events (zero events reported) differ between single-leg versus double-leg spica casts (one trial, 52 young children aged two to seven years). Low quality evidence on the same comparison indicates that single-leg casts are less awkward to manage by parents, more comfortable for the child and may require less time off work by the caregiver. Comparisons of different methods of surgical treatment. The three trials in this category made three different comparisons. Very low quality evidence means that we are very unsure if the rates of malunion, serious adverse events, time to return to school or parental satisfaction actually differ in children whose fractures were fixed using elastic stable intramedullary nailing or external fixation (one trial, 19 children). The same applies to the rates of serious adverse events and time to resume full weight-bearing in children treated with dynamic versus static external fixation (one trial, 52 children). Very low quality evidence (one trial, 47 children) means that we do not know if malunion, serious adverse events and time to resume weight-bearing actually differ between intramedullary nailing versus submuscular plating. However, there could be more difficulties in plate removal subsequently. There is insufficient evidence to determine if long-term function differs between surgical and conservative treatment. Surgery results in lower rates of malunion in children aged 4 to 12 years, but may increase the risk of serious adverse events. Elastic stable intramedullary nailing may reduce recovery time. There is insufficient evidence from comparisons of different methods of conservative treatment or of different methods of surgical treatment to draw conclusions on the relative effects of the treatments compared in the included trials. Different methods of treating fractures of the shaft of the thigh bone in children and adolescents Although uncommon, fractures of the femoral shaft (thigh bone) in children may require prolonged treatment in hospital and sometimes surgery. This can cause significant discomfort and can disrupt the lives of the children and their familles. This review compared different methods of treating these fractures. Surgical treatment comprises different methods of fixing the broken bones, such as internally-placed nails, or pins incorporated into an external frame (external fixation). Non-surgical or conservative treatment usually involves different types of plaster casts with or without traction (where a pulling force is applied to the leg). We searched for studies in the medical literature until August 2013. The review includes 10 randomised or quasi-randomised controlled trials that recruited 527 children. Four trials compared different surgical versus non-surgical treatments; three compared different methods of non-surgical treatment and three compared different methods of surgical treatment. Generally we are unsure about the results of these trials because some were at risk of bias, some results were contradictory and usually there was too little evidence to rule out chance findings. Most trials failed to report on self-assessed function or when children resumed their usual activities. Comparing surgical versus non-surgical treatment. Low quality evidence (one trial, 101 children) showed children had similar function at two years after having surgery, involving external fixation, compared with those treated with a plaster cast. The other three trials did not report this outcome. There was moderate quality evidence (four trials, 264 children, aged 4 to 12 years, followed up for 3 to 24 months) that surgery reduced the risk of malunion (the leg is deformed) compared with non-surgical treatment. However, low quality evidence (four trials) indicated that there were more serious adverse events such as infections after surgery. There was low quality evidence (one trial, 101 children) of similar satisfaction levels in children and parents with surgery involving external fixation and plaster cast only. However, there was low quality evidence (one trial, 46 children) that more parents were satisfied with surgery involving an internal nail than with traction followed by a cast and that surgery reduced the time taken off from school. Comparing various non-surgical treatments. Very low quality evidence means that we are very unsure if the rates of malunion differ or not between children treated with immediate plaster casts versus with traction followed by plaster cast (one trial, 42 children), or between children treated with traction followed by either a functional orthosis (a brace or cast that allows some movement) or a cast (one trial, 43 children). We are very unsure if either function or serious adverse events differ between young children (aged two to seven years) immobilised in single-leg versus double-leg casts (one trial, 52 children). However, single-leg casts appear to be easier to manage by parents and more comfortable for the child. Comparing various surgical treatments Very low quality evidence means that we are very unsure if the rates of malunion, serious adverse events, time to return to school or parental satisfaction actually differ in children whose fractures were fixed using internal nails or external fixation (one trial, 19 children). (ABSTRACT TRUNCATED)

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Critical care is a multidisciplinary and interprofessional specialty providing comprehensive care to patients in an acute life-threatening, but treatable condition.<sup1</sup The aim is to prevent further physiological deterioration while the failing organ is treated. Patients admitted to a critical care unit normally need constant attention from specialist nursing and therapy staff at an appropriate ratio, continuous, uninterrupted physiological monitoring supervised by staff that are able to interpret and immediately act on the information, continuous clinical direction and care from a specialist consultant-led medical team trained and able to provide appropriate cover for each critical care unit, and artificial organ support and advanced therapies which are only safe to administer in the above environment. It is an important aspect of medical care within a hospital as it is an underpinning service without which a hospital would not be able to conduct most or all of its planned and unplanned activities. As such, critical care requires a very intensive input of human, physical, and financial resources.<sup2</sup It occupies a proportionately large fraction of a hospital's estate and infrastructure for a small number of patients. The resources that are invested into a critical care bed should therefore be valued against the activities and care throughout the hospital that the availability of that bed allows to happen. Given that demand for critical care beds will continue to grow, providing more critical care beds is unlikely to work on its own since experience has shown that additional capacity is soon absorbed within routine provision.<sup3</sup Attention must therefore be given to maximising the efficient and effective use of existing critical care beds, necessitating an ability to cope with peaks in demand. Historically the world over, the development of critical care units has been unplanned and haphazard and largely relied on the interest of local clinicians to drive development. However, there is now an eminent body of opinion that supports an alternative approach to critical care provision - namely through a managed Critical Care Network with an agenda of integrated working and the focus on facilitating safe quality care that is cost-effective and patient-focused for acutely and critically ill patients across the various constituent organisations of a healthcare system. The Critical Care Service in Hamad Medical Corporation (HMC) has developed rapidly to address the increasing demand linked to the population growth in the State of Qatar with the aim of meeting the vision of the National Health Strategy (NHS). It is paralleled with HMC's vision to improve the delivery of critical care to patients and their families in a way that meets the highest international standards such as those set by the Joint Commission International by whom the Corporation has been accredited since 2007.<sup4</sup For this reason, the organisation took the lead to perform a gap analysis with expert auditors from the United States of America and the United Kingdom who have experience in critical care service provision. The aim was to assess the Critical Care Service within HMC and identify potential short-term, medium-term, and long-term opportunities for improvement. This assessment focused on a very broad range of aspects such as: bed capacity, facilities and equipment, medical, nursing and allied healthcare staffing levels and their education, career development pathways, patient safety, quality metrics, clinical governance structure, clinical protocols and pathways, critical care outreach, and future planning for critical care at HMC. As a result of extensive review for the Critical Care Services at HMC, the Critical Care Network (CCNW) in the State of Qatar was established in 2014. It is a strategic and operational delivery network, which includes 12 hospitals across the country. The network functions through a combination of strategic programmes, working groups, and large multidisciplinary governance and professional development events. Through collaborative working with the leadership of the various facilities and critical care clinicians, the network reviews services and makes improvements where they are required, ensuring delivery of patient-focused care by appropriately educated and trained healthcare professionals as well as the appropriate utilisation of critical care beds for those patients who require such care. Detailed involvement and engagement from the clinical membership at every event and in the various working groups ensures that all decisions, reports, and improvement programmes are clinically-focused and benefit from a diversity of opinions that can be considered for implementation. All of this is carefully aligned to the requirements of the latest Qatar National Health Strategy.<sup5</sup It aims to adopt evidence-based best practices to deliver the safest, most effective and most compassionate care to our critical care patients by setting the most appropriate care pathway to transform Critical Care Services across HMC hospitals. The key aims of the CCNW as stated in its Terms of Reference document are listed in Table 1.<sup6</sup This enhances the quality and safety of patient care across HMC, promotes staff satisfaction, and improves customer service and patient outcome. The CCNW is structured in a way that involves all Critical Care Service stakeholders to maintain the stability and sustainability of delivering the best care to critically ill patients. The CCNW is steered by a multidisciplinary committee (Figure 1) that is empowered with the generative, managerial, and fiscal responsibilities to enable the required changes to take place. The committee oversees the HMC Critical Care Services through coordinating and standardising their activities and governance arrangements across the complete HMC healthcare system. It provides HMC clinical and managerial leadership at a corporate and local level, the opportunity to jointly develop critical care standards, policies, and operating procedures. In doing so, the CCNW decides on and implements recommendations on how to best plan and deliver critical care services using evidence-based practice set against the context of national and international practices. The HMC CCNW gives recommendations to various committees to improve the services in the following areas: <b1. <iDefining the level of care and critical care core standards for HMC</i:</b The CCNW standardises critical care across the Corporation regardless of where it is being delivered. As such it develops the critical care core standards for the critical care units and gives recommendations regarding future critical care core facility planning within HMC. The CCNW helps the Ministry of Public Health (MoPH) develop the National Critical Care Core Standards. <b2. <iQuality and safety</i:</b The CCNW works collaboratively with HMC leaders to ensure a culture of quality is embedded within all critical care services delivered within HMC. There is a continuous evaluation process in place to measure the quality of care for high performance critical care which is the goal. This is based upon ongoing observations, robust data collection and analysis, and a change management strategy implemented as required. <b3. <iClinical pathways, guidelines, and protocols</i:</b The CCNW develops, according to international best practice, clinical care pathways, guidelines, and protocols that govern critical care units throughout HMC. Critical care clinical practice is audited against these standards, compared with the international benchmark, and updated as required to ensure currency of all patient care aspects. <b4. <iTransfer and transportation of critically ill patients</i:</b The CCNW develops HMC-wide criteria for patient intramural, extramural, and international transfers, and sets standards of care during transportation in collaboration with the HMC Ambulance Service Transfer and Retrieval team. This includes HMC-wide bed management consideration with the senior consultants on call, review of the patient's condition and medical needs, and assessment of the mission associated risks and mitigating strategies. This involves significant planning on the part of the team, clear communication and handovers, and the use of checklists at several stages to ensure the provision of safe and efficient patient transfers. <b5. <iEducation</i:</b The CCNW develops educational plans and ensures corresponding courses accredited by the Qatar Council for Healthcare Practitioners (QCHP) are designed and delivered to address the training needs of clinicians. The portfolio of courses is regularly reviewed to meet identified needs so clinicians always possess the appropriate knowledge and skills to manage critically ill patients. <b6. <iResearch and Critical Care Data Registry development</i:</b Being a key player in an Academic Health System, HMC fosters a relatively young but growing research environment<sup4</sup of which the CCNW forms an integral part. Creating opportunities for epidemiological research and also fulfilling the needs for quality monitoring and benchmarking, the CCNW has enabled the creation of critical care data registries. Such registries provide a valuable source of information and have already been exploited at HMC to better understand the type of patients a service cares for and patient outcomes with respects various factors.<sup7</sup The establishment of a CCNW at a corporate level (with membership from local leaders across HMC) has provided a level of oversight and leadership which has significantly contributed to optimizing and reshaping the way acutely ill patients are cared for. It has enabled the adoption of evidence-based best practices across the various critical care services of HMC as well as created a multidisciplinary forum for dialogue and collaboration. Innovative work focusing on providing effective, up-to-date, and patient-focused care are ongoing as well as HMC's pursuit of various international accreditation awards by prestigious organisations and professional bodies.

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***ACUTE DAY HOSPITAL VERSUS ADMISSION FOR ACUTE PSYCHIATRIC DISORDERS*** Inpatient treatment is an expensive way of caring for people with acute psychiatric disorders. It has been proposed that many of those currently treated as inpatients could be cared for in acute psychiatric day hospitals. The aim of this review was to assess the effectiveness and feasibility of day hospital versus inpatient care for people with acute psychiatric disorders. Eligible studies were randomised controlled trials of day hospital versus inpatient care for people with acute psychiatric disorders. Studies were excluded if they were primarily concerned with elderly people, children, or patients with a diagnosis of organic brain disease or substance abuse. METHODS - DATA SOURCES: We searched the Cochrane Controlled Trials Register, MEDLINE, EMBASE, CINAHL, PsycLIT, and the reference lists of articles. Researchers were approached to identify unpublished studies. Trialists were asked to provide individual patient data. METHODS - DATA EXTRACTION: Data were extracted independently by two reviewers and cross-checked. METHODS - DATA SYNTHESIS: Relative risk (RR) and 95% confidence intervals (CIs) were calculated for dichotomous data. Weighted or standardised means were calculated for continuous data. Day hospital trials tend to present similar outcomes in slightly different formats, making it difficult to synthesise the data. Individual patient data were therefore sought so that outcomes could be re-analysed using a common format. Nine trials met the inclusion criteria (involving 1568 randomised patients and 2268 assessed for suitability of day hospital treatment). Individual patient data were obtained for four trials (involving 594 people). A sensitivity analysis of combined data suggested that day hospital treatment was feasible for at worst 23.2% (n = 2268; 95% CI, 21.2 to 25.2) and at best 37.5% (n = 1768; 95% CI, 35.2 to 39.8) of those currently admitted to inpatient care. Individual patient data from three trials showed no difference in the number of days in hospital (combining day hospital days and inpatient days) between day hospital patients and controls (n = 465; weighted mean difference (WMD) = -0.38 days/ month; 95% CI, -1.32 to 0.55). However, compared with controls, patients randomised to day hospital care spent significantly more days in day hospital care (n = 265; WMD = 2.34 days/month; 95% CI, 1.97 to 2.70) and significantly fewer days in inpatient care (n = 265; WMD = -2.75 days/month; 95% CI, -3.63 to -1.87). There was no difference between readmission rates for day hospital and control patients (n = 667; RR = 0.91; 95% CI, 0.72 to 1.15). Individual patient data from three trials showed a significant time-treatment interaction, indicating a more rapid improvement in mental state (n = 407; c2 = 9.66; p = 0.002), but not social functioning (n = 295; c2 = 0.006; p = 0.941) amongst day hospital patients. Four of five trials demonstrated that day hospital care was cheaper than inpatient care (with overall cost reductions ranging from 20.9% to 36.9%). Acute day hospitals are an attractive option in situations where demand for inpatient care is high and facilities exist that are suitable for conversion. They are a less attractive option when demand for inpatient care is low and where effective alternatives already exist. The interpretation of day hospital research would be enhanced if future trials made use of the common set of outcome measures used in this review. It is important to examine how acute day hospital care can be most effectively integrated into a modern community-based psychiatric service. ***VOCATIONAL REHABILITATION FOR PEOPLE WITH SEVERE MENTAL DISORDERS*** People who are disabled by severe mental disorders experience high rates of unemployment, but most want to work. Prevocational training (PVT) is the traditional approach to helping such people to return to work. PVT assumes that a period of preparation is required before those with a severe mental disorder can enter into competitive employment. Supported Employment (SEm) is a new approach that places clients in competitive employment without extended preparation. Both PVT and SEm are widely practised, but it is unclear which is the most effective. The overall objective of this review was to assess the effectiveness of PVT and SEm relative to each other and to standard care (in hospital or the community) for people with severe mental disorders. In addition, the review examined the effectiveness of: (1) special types of PVT ("clubhouse" model) and SEm (individual placement and support model); and (2) modifications for enhancing PVT (e.g. payment or psychological interventions). Eligible studies were randomised controlled trials (RCTs) examining the effectiveness of vocational rehabilitation approaches (PVT and SEm or modifications) for people of working age and suffering from a severe mental disorder. METHODS - DATA SOURCES: Relevant trials were identified from searches of the Cochrane Schizophrenia Group's specialised register, MEDLINE, EMBASE, CINAHL and PsycLIT, and the reference lists of all identified studies and review articles. Researchers who were active in the field were approached in order to identify unpublished studies. METHODS - DATA EXTRACTION: All data were extracted independently by two reviewers and cross-checked. Continuous data were excluded if they were collected by using an unpublished scale or were based on a subset of items from a scale. METHODS - DATA SYNTHESIS: For all comparisons, the primary outcome was the number of clients who were in competitive employment at various time points. Secondary outcomes were: other employment outcomes, clinical outcome and costs. The relative risk (RR) and number-needed-to-treat (NNT) were calculated for the relevant categorical outcomes. Continuous data were either presented as in the original trial reports or, where possible, combined across trials as a standardised mean difference score. Eighteen RCTs of reasonable quality were identified: PVT versus hospital controls, three RCTs, n = 172; PVT versus community controls, five RCTs, n = 1204; modified PVT, four RCTs, n = 423; SEm versus community controls, one RCT, n = 256; and SEm versus PVT, five RCTs, n = 491). The main finding was that, on the primary outcome (number in competitive employment), SEm was significantly more effective than PVT at all time points (e.g. at 12 months, SEm 34% employed, PVT 12% employed; RR of not being in competitive employment = 0.76, 95% confidence interval 0.69 to 0.84, NNT = 4.5). Clients in SEm also earned more and worked more hours per month than those in PVT. The main finding was that SEm was more effective than PVT for patients suffering from a severe mental disorder who wanted to work. There was no evidence that PVT was more effective than standard community care or hospital care. The implication of these findings is that people suffering from mental disorders who want to work should be offered the option of SEm. Commissioning agencies would be justified in encouraging vocational rehabilitation (VR) providers to develop more SEm schemes. From a research perspective, the cost-effectiveness of SEm should be examined in larger multicentre trials, both within and outside the USA. There is a case for countries outside the USA to survey their existing VR services to determine the extent to which the most effective interventions are being offered. ***DAY HOSPITAL VERSUS OUTPATIENT CARE FOR PATIENTS WITH PSYCHIATRIC DISORDERS*** This review considers the use of day hospitals as an alternative to outpatient care. Two typesof day hospital provision are covered: "day treatment programmes" and "day care centres". Day treatment programmes are day hospitals that are used to enhance the treatment of patients with anxiety or depressive disorders who have failed to respond to outpatient care. Day care centres are day hospitals that offer structured support to patients with long-term severe mental disorders who would otherwise be treated in an outpatient clinic. There were two objectives: first, to assess the effectiveness of day treatment programmes versus outpatient care for people with non-psychotic disorders; and, secondly, to assess the effectiveness of day care centres versus outpatient care for people with severe long-term disorders. Eligible studies were randomised controlled trials comparing day hospital care (either a day treatment programme or a day care centre) with outpatient care. Studies were ineligible if they were largely restricted to patients who were aged under 18 or over 65 years or who had a primary diagnosis of substance abuse or organic brain disorder. METHODS - DATA SOURCES: Relevant trials were identified from searches of the Cochrane Controlled Trials Register, MEDLINE, EMBASE, CINAHL, PsycLIT, and the reference lists of all identified studies and review articles. Researchers were approached to identify unpublished studies. Trialists were asked to provide individual patient data. METHODS - DATA EXTRACTION: All data were extracted independently by two reviewers and cross-checked. METHODS - DATA SYNTHESIS: Relative risks and 95% confidence intervals were calculated for dichotomous data. Standardised mean differences were calculated for continuous data. There was evidence from two of the five trials identified suggesting that day treatment programmes were superior to continuing outpatient care in terms of improving psychiatric symptoms. There was no evidence to suggest that day treatment programmes were better or worse than outpatient care on any other clinical or social outcome variable or on costs. (ABSTRACT TRUNCATED)

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Tribromomethane, a chemical intermediate and solvent, has been identified as a drinking water contaminant resulting from water chlorination. Toxicology and carcinogenesis studies were conducted by administering tribromomethane (95%-97% pure) in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex once or for 14 days, 13 weeks, or 2 years. Single-Administration, Fourteen-Day, and Thirteen-Week Studies: All rats that received 2,000 mg/kg and 3/5 males and 3/5 females that received 1,000 mg/kg tribromomethane died before the end of the single-administration studies. All mice that received 2,000 mg/kg, 4/5 males and 2/5 females that received 1,000 mg/kg, and 1/5 males that received 500 mg/kg died before the end of the studies. Shallow breathing was observed for rats and male mice that received 1,000 or 2,000 mg/kg tribromomethane. In the 14-day studies, all rats that received 600 or 800 mg/kg and 1/5 males that received 400 mg/kg tribromomethane died before the end of the studies. The final mean body weight of male rats that received 400 mg/kg was 14% lower than that of vehicle controls. One of five male mice that received 600 mg/kg and 1/5 female mice that received 800 mg/kg died before the end of the studies. Final mean body weights of dosed and vehicle control mice were comparable. None of the rats died before the end of the 13-week studies (doses ranged from 12 to 200 mg/kg). Final mean body weights were comparable for dosed and vehicle control rats. All male rats that received 100 or 200 mg/kg tribromomethane and all female rats that received 200 mg/kg were lethargic. The incidences of cytoplasmic vacuolization of hepatocytes in dosed male rats were slightly increased compared with that in vehicle controls. The severity of this lesion was increased in the 200 mg/kg group. One of 10 female mice that received 100 mg/kg tribromomethane died before the end of the 13-week studies. The final mean body weight of mice that received 400 mg/kg was 8% lower than that of vehicle controls for males and was comparable to that of vehicle controls for females. Cytoplasmic vacuolization of hepatocytes was observed in the liver of 5/10 male mice that received 200 mg/kg and in 8/10 male mice that received 400 mg/kg tribromomethane. Based on these results, 2-year studies of tribromomethane were conducted by administering 0, 100, or 200 mg/kg tribromomethane in corn oil by gavage, 5 days per week for 103 weeks, to groups of 50 F344/N rats of each sex and 50 female B6C3F1 mice. Male B6C3F1 mice were administered 0, 50, or 100 mg/kg tribromomethane on the same schedule. Body Weights and Survival in the Two-Year Studies: Mean body weights of high dose male and female rats were 10%-28% lower than those of vehicle controls throughout the second year of the studies. Survival of the high dose group of male rats was significantly lower than that of the vehicle controls after week 91; no significant differences in survival were observed between any groups of female rats (male: vehicle control, 34/50; low dose, 30/50; high dose, 11/50; female: 34/50; 28/50; 28/50). Reduced survival for male rats given 200 mg/kg tribromomethane lowered the sensitivity of this group to detect a carcinogenic response. Mean body weights of dosed and vehicle control male mice were comparable throughout the study. Mean body weights of dosed female mice were 5%-16% lower than those of vehicle controls from week 28 to the end of the study. No significant differences in survival were observed between any groups of male mice; the survival of both dosed groups of female mice was significantly lower than that of the vehicle controls after week 77 (male: 41/50; 37/50; 36/50; female: 25/49; 15/50; 20/50). Reduced survival in all groups of female mice was partly due to a utero-ovarian infection; nonetheless, survival of all groups of female mice was at least 50% by week 92. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Uncommon adenomatous polyps or adenocarcinomas (combined) of the large intestine (colon or rectum) were induced in three male ratarge intestine (colon or rectum) were induced in three male rats (vehicle control, 0/50; low dose, 0/50; high dose, 3/50) and in nine female rats (0/50; 1/50; 8/50); the historical incidence of neoplasms of the large intestine is less than 0.2&amp;percnt; in approximately 2,000 corn oil vehicle control male F344/N rats, and none has been observed in approximately 2,000 corn oil vehicle control female F344/N rats. Three of the neoplasms of the large intestine (one in the high dose male rats and two in the high dose female rats) were adenocarcinomas. Focal or diffuse fatty change of the liver was observed at increased incidences in dosed rats (male: 23/50; 49/50; 50/50; female: 19/50; 39/49; 46/50). Active chronic inflammation was observed at increased incidences in dosed male and high dose female rats (male: 0/50; 29/50; 23/50; female: 9/50; 8/49; 27/50). The incidence of necrosis of the liver was increased in high dose male rats (7/50; 3/50; 20/50) and decreased in dosed females (11/50; 3/49; 2/50). Mixed cell focus was observed at increased incidences in dosed female rats (8/50; 25/49; 28/50). Other nonneoplastic lesions observed at increased incidences in dosed rats included chronic active inflammation and squamous metaplasia of the ducts of the salivary gland (squamous metaplasia-- male: 0/50; 15/50; 31/48; female: 0/49; 10/49; 16/50; chronic active inflammation--male: 0/50; 16/50; 25/48; female: 0/49; 9/49; 18/50), squamous metaplasia of the prostate gland (2/49; 6/46; 12/50), ulcers of the forestomach (male: 1/49; 5/50; 10/50), and chronic active inflammation of the lung (male: 1/50; 7/50; 15/50). Pigmentation of the spleen was also observed at an increased incidence in high dose female rats. The salivary gland and lung lesions were characteristic of infection by rat coronavirus, a virus to which a positive serologic reaction was observed early in the studies. The incidence of follicular cell hyperplasia of the thyroid gland was increased in high dose female mice (5/49; 4/49; 19/47), and fatty change of the liver was increased in both dosed groups of female mice (1/49; 9/50; 24/50). No chemically related adverse effects were observed in male mice. Neoplastic lesions that occurred at lower incidences in dosed animals compared with those in vehicle controls included preputial gland neoplasms in male rats (10/41; 5/38; 1/34), uterine stromal polyps in female rats (10/49; 9/50; 2/50), anterior pituitary gland adenomas in male and female rats (male: 12/50; 12/48; 2/45; female: 29/48; 12/46; 16/48), mammary gland fibroadenomas in female rats (22/50; 17/50; 6/50), and alveolar/bronchiolar neoplasms in male mice (11/50; 7/50; 2/49). Other than concomitant decreases in body weights, no other reasons are obvious to correlate these decreases with chemical administration. Genetic Toxicology: Tribromomethane exhibited equivocal mutagenicity in Salmonella typhimurium strain TA100 in the absence of exogenous metabolic activation and in strains TA97 and TA98 when exposure occurred in the presence of hamster S9; tribromomethane produced no increases in revertant colonies in TA1535 or TA1537 with or without exogenous metabolic activation. Tribromomethane induced trifluorothymidine (Tft) resistance in mouse L5178Y cells with and without metabolic activation. When tested incultured Chinese hamster ovary (CHO) cells for cytogenetic effects, tribromomethane produced an increase in both sister chromatid exchanges (SCEs) and chromosomal aberrations in the absence, but not in the presence, of exogenous metabolic activation. Tribromomethane caused sex-linked recessive lethal mutations in Drosophila when administered to adult males by feeding; no induction of mutations was observed when tribromomethane was administered by abdominal injection. Results of tests for reciprocal translocations in adult male Drosophila exposed to tribromomethane by feeding were negative. In vivo tests for cytogenetic effects in bone marrow cells of male B6C3F1 mice demonstrated that intraperitoneal injection of tribromomethane induced an increase in SCEs but no increase in chromosomal aberrations. Intraperitoneal injection of tribromomethane also induced an increase in the incidence of micronucleated polychromatic erythrocytes in the bone marrow of B6C3F1 mice. Audit: The data, documents, and pathology materials from the 2-year studies of tribromomethane have been audited. The audit findings show that the conduct of the studies is documented adequately and support the data and results given in this Technical Report. Conclusions: Under the conditions of these 2-year gavage studies, there was some evidence of carcinogenic activity of tribromomethane for male F344/N rats and clear evidence of carcinogenic activity for female F344/N rats, based on increased incidences of uncommon neoplasms of the large intestine. Reduced survival for male rats given 200 mg/kg tribromomethane lowered the sensitivity of this group to detect a carcinogenic response. Chemically related nonneoplastic lesions included fatty change and active chronic inflammation of the liver in male and female rats, minimal necrosis of the liver in male rats, and mixed cell foci of the liver in female rats. There was no evidence of carcinogenic activity for male B6C3F1 mice given 50 or 100 mg/kg tribromomethane or for female B6C3F1 mice given 100 or 200 mg/kg; male mice might have been able to tolerate a higher dose. Survival of female mice was reduced, partly due to a utero-ovarian infection. Synonym: bromoform

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Allyl acetate, allyl alcohol, and acrolein are used in the manufacture of detergents, plastics, pharmaceuticals, and chemicals and as agricultural agents and food additives. Male and female F344/N rats and B6C3F(1) mice received allyl acetate, allyl alcohol, or acrolein by gavage for 14 weeks. Genetic toxicology studies were conducted in Salmonella typhimurium, Drosophila melanogaster, cultured Chinese hamster ovary cells, rat bone marrow erythrocytes, and mouse peripheral blood erythrocytes. Groups of 10 male and 10 female rats were administered 0, 6, 12, 25, 50, or 100 mg allyl acetate/kg body weight, 0, 1.5, 3, 6, 12, or 25 mg/kg allyl alcohol, or 0, 0.75, 1.25, 2.5, 5, or 10 mg/kg acrolein in 0.5% methylcellulose by gavage, 5 days per week for 14 weeks. Groups of 10 male and 10 female mice were administered 0, 8, 16, 32, 62.5, or 125 mg/kg allyl acetate, 0, 3, 6, 12, 25, or 50 mg/kg allyl alcohol, or 0, 1.25, 2.5, 5, 10, or 20 mg/kg acrolein in 0.5% methylcellulose by gavage, 5 days per week for 14 weeks. In the allyl acetate rat study, all males and females in the 100 mg/kg groups died or were killed moribund by day 8; there were no other deaths. In the allyl alcohol study, all rats survived to the end of the study except one 6 mg/kg female. In the acrolein rat study, eight males and eight females in the 10 mg/kg groups died by week 9 of the study. Two males in the 2.5 and 5 mg/kg groups and one or two females in the 1.25, 2.5, and 5 mg/kg groups also died early; two of these deaths were gavage accidents. In the allyl acetate mouse study, all males and females in the 125 mg/kg group died during the first week of the study. All other early deaths, except five 62.5 mg/kg males and one 32 mg/kg female, were gavage accidents. In the allyl alcohol mouse study, one 50 mg/kg female died due to a gavage accident; all other animals survived to the end of the study. In the acrolein mouse study, all males and females administered 20 mg/kg died during the first week of the study. All other early deaths, except one male and one female administered 10 mg/kg, were unrelated to chemical administration. The concentration of 3-hydroxypropyl mercapturic acid (3-HPM) in the urine of rats and mice was determined after the first dose of chemical and at the end of the 14-week study. At both time points, the concentrations of 3-HPM in the urine of animals that received allyl acetate or allyl alcohol increased linearly with dose. In animals dosed with acrolein, the concentrations of 3-HPM exhibited a nonlinear increase with dose at the first time point. At the end of the study, the concentration of 3-HPM in the urine of animals dosed with acrolein was linear with dose except at the highest concentration administered. Since urine volumes were not recorded during the urine collection, complete quantitation of these data was not possible. The final mean body weights and mean body weight gains of male rats administered 12 or 50 mg/kg allyl acetate and of male and female rats administered 10 mg/kg acrolein were significantly less than those of the vehicle controls. The mean body weight gain of male mice in the 50 mg/kg group in the allyl alcohol study was also less than that of the vehicle controls. Final mean body weights and mean body weight gains of dosed female rats and male and female mice in the allyl acetate studies, male and female rats and female mice in the allyl alcohol studies, and male and female mice in the acrolein studies were generally similar to those of the respective vehicle controls. Clinical findings related to allyl acetate administration included pallor, eye or nasal discharge, ruffled fur, lethargy, diarrhea, and thinness among rats in the 100 mg/kg groups and lethargy, abnormal breathing, thinness, and ruffled fur among mice that died early. In the acrolein study, clinical findings included abnormal breathing, eye or nasal discharge, ruffled fur, thinness, and lethargy in rats in the 10 mg/kg groups. The liver weights of male rats administered 25 mg/kg allyl alcohol, female rats administered 50 mg/kg allyl acetate or 5 or 10 mg/kg acrolein, and male mice administered 10 mg/kg acrolein were significantly greater than those of the vehicle controls. Female rats administered 10 mg/kg acrolein had significantly lower absolute and relative thymus weights than did the vehicle controls. Female rats administered 25 mg/kg allyl alcohol spent more time in diestrus and less time in metestrus than the vehicle controls. The estrous cycles of female mice dosed with 16 or 32 mg/kg allyl acetate were significantly longer than that of the vehicle controls. Gross lesions related to allyl acetate treatment were observed in the liver, forestomach, and thorax/abdomen of male and female rats in the 100 mg/kg groups. Microscopically, the incidences of forestomach squamous epithelial hyperplasia were significantly increased in male rats administered 12 mg/kg or greater, female rats administered 25 or 50 mg/kg, male mice administered 32 or 62.5 mg/kg, and female mice administered 16, 32, or 62.5 mg/kg. Forestomach necrosis, hemorrhage, and inflammation were present in most rats in the 100 mg/kg groups, and the incidence of hemorrhage in 125 mg/kg male mice was increased; male mice in the 62.5 and 125 mg/kg groups and 125 mg/kg female mice had significantly increased incidences of glandular stomach hemorrhage. Increased incidences of several liver lesions occurred in male or female rats administered 50 or 100 mg/kg, and to a lesser extent in 25 mg/kg rats, 62.5 mg/kg male mice, and 125 mg/kg male and female mice. Bone marrow hyperplasia, hemorrhage or depletion in the mediastinal, mandibular, and mesenteric lymph nodes, hemorrhage and necrosis of the thymus, and hematopoietic cell proliferation of the red pulp were also observed in 100 mg/kg rats. Increased incidences of necrosis in the mandibular and mesenteric lymph nodes, spleen, and thymus were observed in 62.5 and 125 mg/kg mice. Male and female rats administered 6 mg/kg allyl alcohol or greater and male and female mice administered 12 mg/kg allyl alcohol or greater had significantly increased incidences of squamous hyperplasia of the forestomach epithelium. Female rats in the 25 mg/kg group had significantly increased incidences of bile duct hyperplasia and periportal hepatocyte hypertrophy in the liver. Incidences of portal cytoplasmic vacuolization were significantly increased in 50 mg/kg male mice and female mice in the 25 and 50 mg/kg groups. Gross lesions related to acrolein treatment were observed in the forestomach and glandular stomach of male and female rats in the 10 mg/kg groups and 20 mg/kg female mice. Microscopically, the incidences of squamous hyperplasia of the forestomach epithelium were significantly increased in male rats in the 5 and 10 mg/kg groups, female rats administered 2.5 mg/kg or greater, and male and female mice administered 2.5, 5, or 10 mg/kg. Male and female rats in the 10 mg/kg groups and 20 mg/kg male and female mice had significantly increased incidences of glandular stomach hemorrhage. Female mice in the 20 mg/kg group also had significantly increased incidences of glandular stomach inflammation and epithelial necrosis. Allyl acetate was mutagenic in S. typhimurium strains TA100 and TA1535, in the absence of S9 activation. With S9, no mutagenicity was detected in these two strains; negative results were obtained in strains TA97 and TA98, with and without S9. Allyl alcohol was not mutagenic in four strains of S. typhimurium, with or without S9 metabolic activation. Acrolein, tested in a preincubation protocol, was weakly mutagenic in S. typhimurium strain TA100 in the presence of 10% induced rat liver S9. Equivocal results were obtained in strains TA100 and TA1535 with 10% induced hamster liver S9. Negative results were obtained with TA97, TA98, and TA1538 under all test conditions, and acrolein gave negative results in all four S. typhimurium strains tested for mutation induction under a vapor protocol. No induction of micronuclei was noted in bone marrow erythrocytes of male rats administered allyl acetate by gavage three times at 24-hour intervals. No significant increases in micronucleated erythrocytes were noted in bone marrow samples from male rats administered allyl alcohol by intraperitoneal injection for 3 days. A small, but significant increase in the frequency of micronucleated normochromatic erythrocytes was observed in the peripheral blood of female mice administered allyl acetate by gavage for 14 weeks; no increase was observed in male mice. No increases in the frequencies of micronucleated normochromatic erythrocytes were observed in the peripheral blood of male or female mice administered allyl alcohol or acrolein by gavage for 14 weeks. Acrolein induced sister chromatid exchanges in cultured Chinese hamster ovary cells in the absence, but not the presence, of S9; it did not induce chromosomal aberrations, with or without S9. Results of three independent Drosophila melanogaster sex linked recessive lethal tests in which acrolein was administered to adult flies via feeding or injection and to larvae via feeding were negative.

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The purpose of this review is to determine the effectiveness of 2 separate modalities, digital mammography (DM) and magnetic resonance imaging (MRI), relative to film mammography (FM), in the screening of women asymptomatic for breast cancer. A third analysis assesses the effectiveness and safety of the combination of MRI plus mammography (MRI plus FM) in screening of women at high risk. An economic analysis was also conducted. How does the sensitivity and specificity of DM compare to FM?How does the sensitivity and specificity of MRI compare to FM?How do the recall rates compare among these screening modalities, and what effect might this have on radiation exposure? What are the risks associated with radiation exposure?How does the sensitivity and specificity of the combination of MRI plus FM compare to either MRI or FM alone?What are the economic considerations? The effectiveness of FM with respect to breast cancer mortality in the screening of asymptomatic average- risk women over the age of 50 has been established. However, based on a Medical Advisory Secretariat review completed in March 2006, screening is not recommended for women between the ages of 40 and 49 years. Guidelines published by the Canadian Task Force on Preventive Care recommend mammography screening every 1 to 2 years for women aged 50 years and over, hence, the inclusion of such women in organized breast cancer screening programs. In addition to the uncertainty of the effectiveness of mammography screening from the age of 40 years, there is concern over the risks associated with mammographic screening for the 10 years between the ages of 40 and 49 years. The lack of effectiveness of mammography screening starting at the age of 40 years (with respect to breast cancer mortality) is based on the assumption that the ability to detect cancer decreases with increased breast tissue density. As breast density is highest in the premenopausal years (approximately 23% of postmenopausal and 53% of premenopausal women having at least 50% of the breast occupied by high density), mammography screening is not promoted in Canada nor in many other countries for women under the age of 50 at average risk for breast cancer. It is important to note, however, that screening of premenopausal women (i.e., younger than 50 years of age) at high risk for breast cancer by virtue of a family history of cancer or a known genetic predisposition (e.g., having tested positive for the breast cancer genes BRCA1 and/or BRCA2) is appropriate. Thus, this review will assess the effectiveness of breast cancer screening with modalities other than film mammography, specifically DM and MRI, for both pre/perimenopausal and postmenopausal age groups. International estimates of the epidemiology of breast cancer show that the incidence of breast cancer is increasing for all ages combined whereas mortality is decreasing, though at a slower rate. The observed decreases in mortality rates may be attributable to screening, in addition to advances in breast cancer therapy over time. Decreases in mortality attributable to screening may be a result of the earlier detection and treatment of invasive cancers, in addition to the increased detection of ductal carcinoma in situ (DCIS), of which certain subpathologies are less lethal. Evidence from the Surveillance, Epidemiology and End Results (better known as SEER) cancer registry in the United States, indicates that the age-adjusted incidence of DCIS has increased almost 10-fold over a 20 year period, from 2.7 to 25 per 100,000. There is a 4-fold lower incidence of breast cancer in the 40 to 49 year age group than in the 50 to 69 year age group (approximately 140 per 100,000 versus 500 per 100,000 women, respectively). The sensitivity of FM is also lower among younger women (approximately 75%) than for women aged over 50 years (approximately 85%). Specificity is approximately 80% for younger women versus 90% for women over 50 years. The increased density of breast tissue in younger women is likely responsible for the decreased accuracy of FM. Treatment options for breast cancer vary with the stage of disease (based on tumor size, involvement of surrounding tissue, and number of affected axillary lymph nodes) and its pathology, and may include a combination of surgery, chemotherapy and/or radiotherapy. Surgery is the first-line intervention for biopsy-confirmed tumors. The subsequent use of radiation, chemotherapy or hormonal treatments is dependent on the histopathologic characteristics of the tumor and the type of surgery. There is controversy regarding the optimal treatment of DCIS, which is considered a noninvasive tumour. Women at high risk for breast cancer are defined as genetic carriers of the more commonly known breast cancer genes (BRCA1, BRCA2 TP53), first degree relatives of carriers, women with varying degrees of high risk family histories, and/or women with greater than 20% lifetime risk for breast cancer based on existing risk models. Genetic carriers for this disease, primarily women with BRCA1 or BRCA2 mutations, have a lifetime probability of approximately 85% of developing breast cancer. Preventive options for these women include surgical interventions such as prophylactic mastectomy and/or oophorectomy, i.e., removal of the breasts and/or ovaries. Therefore, it is important to evaluate the benefits and risks of different screening modalities, to identify additional options for these women. This Medical Advisory Secretariat review is the second of 2 parts on breast cancer screening, and concentrates on the evaluation of both DM and MRI relative to FM, the standard of care. Part I of this review (March 2006) addressed the effectiveness of screening mammography in 40 to 49 year old average-risk women. The overall objective of the present review is to determine the optimal screening modality based on the evidence. EVIDENCE REVIEW STRATEGY: THE MEDICAL ADVISORY SECRETARIAT FOLLOWED ITS STANDARD PROCEDURES AND SEARCHED THE FOLLOWING ELECTRONIC DATABASES: Ovid MEDLINE, EMBASE, Ovid MEDLINE In-Process &amp; Other Non-Indexed Citations, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews and The International Network of Agencies for Health Technology Assessment database. The subject headings and keywords searched included breast cancer, breast neoplasms, mass screening, digital mammography, magnetic resonance imaging. The detailed search strategies can be viewed in Appendix 1. Included in this review are articles specific to screening and do not include evidence on diagnostic mammography. The search was further restricted to English-language articles published between January 1996 and April 2006. Excluded were case reports, comments, editorials, nonsystematic reviews, and letters. DIGITAL MAMMOGRAPHY: In total, 224 articles specific to DM screening were identified. These were examined against the inclusion/exclusion criteria described below, resulting in the selection and review of 5 health technology assessments (HTAs) (plus 1 update) and 4 articles specific to screening with DM. MAGNETIC RESONANCE IMAGING: In total, 193 articles specific to MRI were identified. These were examined against the inclusion/exclusion criteria described below, resulting in the selection and review of 2 HTAs and 7 articles specific to screening with MRI. The evaluation of the addition of FM to MRI in the screening of women at high risk for breast cancer was also conducted within the context of standard search procedures of the Medical Advisory Secretariat. as outlined above. The subject headings and keywords searched included the concepts of breast cancer, magnetic resonance imaging, mass screening, and high risk/predisposition to breast cancer. The search was further restricted to English-language articles published between September 2007 and January 15, 2010. Case reports, comments, editorials, nonsystematic reviews, and letters were not excluded. MRI PLUS MAMMOGRAPHY: In total, 243 articles specific to MRI plus FM screening were identified. These were examined against the inclusion/exclusion criteria described below, resulting in the selection and review of 2 previous HTAs, and 1 systematic review of 11 paired design studies. English-language articles, and English or French-language HTAs published from January 1996 to April 2006, inclusive.Articles specific to screening of women with no personal history of breast cancer.Studies in which DM or MRI were compared with FM, and where the specific outcomes of interest were reported.Randomized controlled trials (RCTs) or paired studies only for assessment of DM.Prospective, paired studies only for assessment of MRI. Studies in which outcomes were not specific to those of interest in this report.Studies in which women had been previously diagnosed with breast cancer.Studies in which the intervention (DM or MRI) was not compared with FM.Studies assessing DM with a sample size of less than 500. Digital mammography.Magnetic resonance imaging. COMPARATOR: Screening with film mammography. Breast cancer mortality (although no studies were found with such long follow-up).Sensitivity.Specificity.Recall rates. DIGITAL MAMMOGRAPHY: There is moderate quality evidence that DM is significantly more sensitive than FM in the screening of asymptomatic women aged less than 50 years, those who are premenopausal or perimenopausal, and those with heterogeneously or extremely dense breast tissue (regardless of age). It is not known what effect these differences in sensitivity will have on the more important effectiveness outcome measure of breast cancer mortality, as there was no evidence of such an assessment. Other factors have been set out to promote DM, for example, issues of recall rates and reading and examination times. (ABSTRACT TRUNCATED)

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Recent development of tuberculosis in Japan tends to converge on a specific high risk group. The proportion of tuberculosis developing particularly from the compromised hosts in the high risk group is especially high. At this symposium, therefore, we took up diabetes mellitus, gastrectomy, dialysis, AIDS and the elderly for discussion. Many new findings and useful reports for practical medical treatment are submitted; why these compromised hosts are predisposed to tuberculosis, tuberculosis diagnostic and remedial notes of those compromised hosts etc. It is an important question for the future to study how to prevent tuberculosis from these compromised hosts. 1. Tuberculosis in diabetes mellitus: aggravation and its immunological mechanism: Kazuyoshi KAWAKAMI (Department of Internal Medicine, Division of Infectious Diseases, Graduate School and Faculty of Medicine, University of the Ryukyus). It has been well documented that diabetes mellitus (DM) is a major aggravating factor in tuberculosis. The onset of this disease is more frequent in DM patients than in individuals with any underlying diseases. However, the precise mechanism of this finding remains to be fully understood. Earlier studies reported that the migration, phagocytosis and bactericidal activity of neutrophils are all impaired in DM patients, which is related to their reduced host defense to infection with extracellular bacteria, such as S. aureus and E. colli. Host defense to mycobacterial infection is largely mediated by cellular immunity, and Th1-related cytokines, such as IFN-gamma and IL-12, play a central role in this response. It is reported that serum level of these cytokines and their production by peripheral blood mononuclear cells (PBMC) are reduced in tuberculosis patients with DM, and this is supposed to be involved in the high incidence of tuberculosis in DM. Our study observed similar findings and furthermore indicated that IFN-gamma and IL-12 production by BCG-stimulated PBMC was lower in poorly-controlled DM patients than that in well-controlled DM patients and healthy subjects. Thus, these clinical data suggest that the high incidence of tuberculosis in DM patients is due to the impaired production of Th1-related cytokines. However, direct evidences to prove this possibility remain to be obtained. In 1980, Saiki and co-workers reported that host defense and delayed-type hypersensitivity response to M. tuberculosis was hampered in a mouse DM model established by injecting streptozotocin (Infect Immun. 1980; 28: 127-131). We followed their investigation with the similar observations. Interestingly, levels of IFN-gamma and IL-12 in serum, lung, liver and spleen after infection were significantly reduced in DM mice when compared with those in control mice. Considered collectively, these results strongly suggest that the reduced production of Th1-related cytokines leads to the susceptibility of DM to mycobacterial infection. However, it remains to be understood how DM hampers the synthesis of Th1-related cytokines. In our preliminary study, the production of these cytokines by PBMC from DM patients and healthy subjects was not affected under a high glucose condition. Thus, it is not likely that the increased level of glucose directly suppresses the cell-mediated immune responses. Further investigations are needed to make these points clear. 2. A study of gastrectomy cases in pulmonary tuberculosis patients: Takenori YAGI (Division of Thoracic Disease, National Chiba-Higashi Hospital). Patients who have undergone gastric resection are considered at increased risk of developing pulmonary tuberculosis. I have investigated the role played by gastrectomy in giving rise to pulmonary tuberculosis. Of 654 pulmonary tuberculosis patients admitted to National Chiba-Higashi Hospital from January 1999 to December 2001, 55 patients (31-84 years old, mean 63.5 +/- 12.5 years, 48 males and 7 females) had the history of gastric resection. The incidence of gastrectomy among patients with pulmonary tuberculosis was 8.4 percent. The mean age of gastric resection was 50.2 +/- 16.6 years, and the mean interval from gastrectomy to pulmonary tuberculosis was 13.6 +/- 11.0 years. On admission to our hospital, 34 out of 55 cases were smear positive by sputum examination for acid-fast bacilli and 39 cases had cavitary lesions on chest X-ray. Gastrectomy was done due to carcinoma of the stomach in 31 cases, gastric and/or duodenal ulcer in 21 cases, adenomatous polyp in two cases, and accidental injury in one case. 52 patients improved, but three cases died due to pulmonary tuberculosis. No one had recurrence of carcinoma of the stomach. Body weight, Body Mass Index, Prognostic Nutritional Index (PNI; 10x serum albumin concentration +0.005 x peripheral lymphocyte count) which was proposed by Onodera, serum albumin level and serum total cholesterol level were lower in the gastrectomy group than in the non-gastrectomy group. I calculated the odds of tuberculosis among gastrectomy patients to be 3.8 times that of appropriate controls. This study confirms that gastrectomy is one of the risk factor(s) of tuberculosis. However, whether gastrectomy in itself is a risk factor or whether it is secondarily associated with another risk factor such as underweight status and/or inadequate nutrition following surgery remains unclear. 3. Immunodefficiency and tuberculosis in dialysis patients: Hajime INAMOTO (Division of Dialysis, Keio University School of Medicine). The patients who have renal insufficiency is fatal, but they can live much longer by dialysis. The number of lymphocytes of the patients whose serum creatinine was 10 mg/dl or more has decreased to about 50% of the people who have normal kidney. When the lymphocyte was cultured after it was stimulated with PHA, the DNA synthesis of the patients' lymphocyte was much lower than that of the modest people's. In the dialysis food, the nutrient such as vitamins, minerals, etc. were lacked. The density of the serum albumin of the dialysis patient has decreased. Many of them were thin when their BMI was examined. The size of the patients' erythema by the tuberculin test has become small. There were many patients receiving dialysis with erythema but no induration. It means that the delayed skin reaction specific to Mycobacterium tuberculosis has decreased among the dialysis patients. The morbidity rate, the mortality rate and the prevalence of tuberculosis was much higher than the general population. The anamnesis of tuberculosis was also high. Most of those tuberculosis patients appear the disease from the period immediately before the beginning of dialysis to one year after that. That is also the period that patients' number of peripheral blood lymphocyte decreased and the tuberculin reaction positivity rate fell sharply. During the dialysis patients, pulmonary tuberculosis with cavities was minority and extrapulmonary tuberculosis and miliary tuberculosis were remarkably many. People with large reaction against the tuberculin test were better prognosis than those with smaller reaction. It was thought that anorexia, weakening, and a weight decrease were seen when the immunity decreased. At the end stage of renal failure, kidney shrink, vitamin D activation becomes difficult, and the low calcium blood syndrome appears. The calcification of tuberculoma is absorbed, soft tuberculoma becomes baring, the caseation abscess melts, and the endogenous infection occurs. The cell immunity has decreased, and tuberculosis attacks. It might be such circumstances that tuberculosis happen frequently at the dialysis introduction period. There are a lot of cases that the caseation necrosis is a little, and the formation of tuberculoma is bad in the pathology opinion. Due to the decrease in the cell immunity, cavities are not formed easily. It is easy to stay in the leaching lesion so that anti-tuberculosis drugs are much effective, and the patients recover easily. However, if the treatment is delayed, it is fatally because hematogenous metastasis are easy to occur and become miliary tuberculosis. 4. AIDS and tuberculosis: Hideaki NAGAI (Department of Respiratory Diseases, National Tokyo Hospital). With AIDS patients with tuberculosis, there are the following problems on the treatment. (1) The adverse reactions by antituberculosis drugs tend to occur in AIDS patients. Eleven of 33 AIDS patients with tuberculosis had the adverse reactions (skin rash, fever, liver dysfunction) considered to be due to antituberculosis drugs. It is a very large burden for the HIV infected persons to take simultaneously antituberculosis drugs, medicines for opportunistic infections, and anti-HIV medicines. Since many medicines are taken, it is difficult to determine which drug is the cause once an adverse reaction occurs and all medicines should be often stopped. (2) The combined use with rifampicin (RFP) is difficult for the protease inhibitors and nonnuclear acid reverse transcriptase inhibitors. RFP induces cytochrome P-450 in liver, accelerates the metabolism of some concomitant drug agents, and reduces blood concentration them remarkably. When starting the two above-mentioned medicines during tuberculosis treatment, RFP should be changed to rifabutin (RFB) which has less induction of P-450 than RFP. However, some procedures are required for acquisition of RFB and it is a little complicated in Japan. CDC mentioned the combined use with RFP and efavirenz (EFV) is possible. So, the treatment with EFV and RFP is recently chosen. However, the monitor of the blood concentration of EFV is required, and the dose of EFV should be increased if it is a low value. (3) When a highly active antiretroviral therapy (HAART) is given to AIDS patients with tuberculosis, transient worsening of tuberculosis may develop after about two weeks. (ABSTRACT TRUNCATED)

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The objective of the MAS evidence review was to conduct a systematic review of the available evidence on the safety, effectiveness, durability and cost-effectiveness of endovascular laser therapy (ELT) for the treatment of primary symptomatic varicose veins (VV). The Ontario Health Technology Advisory Committee (OHTAC) met on November 27, 2009 to review the safety, effectiveness, durability and cost-effectiveness of ELT for the treatment of primary VV based on an evidence-based review by the Medical Advisory Secretariat (MAS). CLINICAL CONDITION: VV are tortuous, twisted, or elongated veins. This can be due to existing (inherited) valve dysfunction or decreased vein elasticity (primary venous reflux) or valve damage from prior thrombotic events (secondary venous reflux). The end result is pooling of blood in the veins, increased venous pressure and subsequent vein enlargement. As a result of high venous pressure, branch vessels balloon out leading to varicosities (varicose veins). SYMPTOMS TYPICALLY AFFECT THE LOWER EXTREMITIES AND INCLUDE (BUT ARE NOT LIMITED TO): aching, swelling, throbbing, night cramps, restless legs, leg fatigue, itching and burning. Left untreated, venous reflux tends to be progressive, often leading to chronic venous insufficiency (CVI). A NUMBER OF COMPLICATIONS ARE ASSOCIATED WITH UNTREATED VENOUS REFLUX: including superficial thrombophlebitis as well as variceal rupture and haemorrhage. CVI often results in chronic skin changes referred to as stasis dermatitis. Stasis dermatitis is comprised of a spectrum of cutaneous abnormalities including edema, hyperpigmentation, eczema, lipodermatosclerosis and stasis ulceration. Ulceration represents the disease end point for severe CVI. CVI is associated with a reduced quality of life particularly in relation to pain, physical function and mobility. In severe cases, VV with ulcers, QOL has been rated to be as bad or worse as other chronic diseases such as back pain and arthritis. Lower limb VV is a common disease affecting adults and estimated to be the seventh most common reason for physician referral in the US. There is a strong familial predisposition to VV with the risk in offspring being 90% if both parents affected, 20% when neither is affected, and 45% (25% boys, 62% girls) if one parent is affected. Globally, the prevalence of VV ranges from 5% to 15% among men and 3% to 29% among women varying by the age, gender and ethnicity of the study population, survey methods and disease definition and measurement. The annual incidence of VV estimated from the Framingham Study was reported to be 2.6% among women and 1.9% among men and did not vary within the age range (40-89 years) studied. Approximately 1% of the adult population has a stasis ulcer of venous origin at any one time with 4% at risk. The majority of leg ulcer patients are elderly with simple superficial vein reflux. Stasis ulcers are often lengthy medical problems and can last for several years and, despite effective compression therapy and multilayer bandaging are associated with high recurrence rates. Recent trials involving surgical treatment of superficial vein reflux have resulted in healing and significantly reduced recurrence rates. ENDOVASCULAR LASER THERAPY FOR VV: ELT is an image-guided, minimally invasive treatment alternative to surgical stripping of superficial venous reflux. It does not require an operating room or general anesthesia and has been performed in outpatient settings by a variety of medical specialties including surgeons (vascular or general), interventional radiologists and phlebologists. Rather than surgically removing the vein, ELT works by destroying, cauterizing or ablating the refluxing vein segment using heat energy delivered via laser fibre. Prior to ELT, colour-flow Doppler ultrasonography is used to confirm and map all areas of venous reflux to devise a safe and effective treatment plan. The ELT procedure involves the introduction of a guide wire into the target vein under ultrasound guidance followed by the insertion of an introducer sheath through which an optical fibre carrying the laser energy is advanced. A tumescent anesthetic solution is injected into the soft tissue surrounding the target vein along its entire length. This serves to anaesthetize the vein so that the patient feels no discomfort during the procedure. It also serves to insulate the heat from damaging adjacent structures, including nerves and skin. Once satisfactory positioning has been confirmed with ultrasound, the laser is activated. Both the laser fibre and the sheath are simultaneously, slowly and continuously pulled back along the length of the target vessel. At the end of the procedure, homeostasis is then achieved by applying pressure to the entry point. Adequate and proper compression stockings and bandages are applied after the procedure to reduce the risk of venous thromboembolism, and to reduce postoperative bruising and tenderness. Patients are encouraged to walk immediately after the procedure and most patients return to work or usual activity within a few days. Follow-up protocols vary, with most patients returning 1-3 weeks later for an initial follow-up visit. At this point, the initial clinical result is assessed and occlusion of the treated vessels is confirmed with ultrasound. Patients often have a second follow-up visit 1-3 months following ELT at which time clinical evaluation and ultrasound are repeated. If required, sclerotherapy may be performed during the ELT procedure or at any follow-up visits. Endovascular laser for the treatment of VV was approved by Health Canada as a class 3 device in 2002. The treatment has been an insured service in Saskatchewan since 2007 and is the only province to insure ELT. Although the treatment is not an insured service in Ontario, it has been provided by various medical specialties since 2002 in over 20 private clinics. The MAS evidence-based review was performed as an update to the 2007 health technology review performed by the Australian Medical Services Committee (MSAC) to support public financing decisions. The literature search was performed on August 18, 2009 using standard bibliographic databases for studies published from January 1, 2007 to August 15, 2009. Search alerts were generated and reviewed for additional relevant literature up until October 1, 2009. English language full-reports and human studiesOriginal reports with defined study methodologyReports including standardized measurements on outcome events such as technical success, safety, effectiveness, durability, quality of life or patient satisfactionReports involving ELT for VV (great or small saphenous veins)Randomized controlled trials (RCTs), systematic reviews and meta-analysesCohort and controlled clinical studies involving &gt; 1 month ultrasound imaging follow-up Non systematic reviews, letters, comments and editorialsReports not involving outcome events such as safety, effectiveness, durability, or patient satisfaction following an intervention with ELTReports not involving interventions with ELT for VVPilot studies or studies with small samples ( &lt; 50 subjects) The MAS evidence search identified 14 systematic reviews, 29 cohort studies on safety and effectiveness, four cost studies and 12 randomized controlled trials involving ELT, six of these comparing endovascular laser with surgical ligation and saphenous vein stripping. Since 2007, 22 cohort studies involving 10,883 patients undergoing ELT of the great saphenous vein (GSV) have been published. Imaging defined treatment effectiveness of mean vein closure rates were reported to be greater than 90% (range 93%- 99%) at short term follow-up. Longer than one year follow-up was reported in five studies with life table analysis performed in four but the follow up was still limited at three and four years. The overall pooled major adverse event rate, including DVT, PE, skin burns or nerve damage events extracted from these studies, was 0.63% (69/10,883). The overall level of evidence of randomized trials comparing ELT with surgical ligation and vein stripping (n= 6) was graded as moderate to high. Recovery after treatment was significantly quicker after ELT (return to work median number of days, 4 vs. 17; p= .005). Major adverse events occurring after surgery were higher [(1.8% (n=4) vs. 0.4% (n = 1) 1 but not significantly. Treatment effectiveness as measured by imaging vein absence or closure, symptom relief or quality of life similar in the two treatment groups and both treatments resulted in statistically significantly improvements in these outcomes. Recurrence was low after both treatments at follow up but neovascularization (growth of new vessels, a key predictor of long term recurrence was significantly more common (18% vs. 1%; p = .001) after surgery. Although patient satisfaction was reported to be high (&gt;80%) with both treatments, patient preferences evaluated through recruitment process, physician reports and consumer groups were strongly in favour of ELT. For patients minimal complications, quick recovery and dependability of outpatient scheduling were key considerations. As clinical effectiveness of the two treatments was similar, a cost-analysis was performed to compare differences in resources and costs between the two procedures. A budget impact analysis for introducing ELT as an insured service was also performed. The average case cost (based on Ontario hospital costs and medical resources) for surgical vein stripping was estimated to be $1,799. Because of the uncertainties with resources associated with ELT, in addition to the device related costs, hospital costs were varied and assumed to be the same as or less than (40%) those for surgery resulting in an average ELT case cost of $2,025 or $1,602. (ABSTRACT TRUNCATED)

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Trichotillomania (TTM) is defined by the Diagnostics and Statistic Manual of Mental Disorders, 4th edition (DMS-IV) as hair loss from a patient`s repetitive self-pulling of hair. The disorder is included under anxiety disorders because it shares some obsessive-compulsive features. Patients have the tendency towards feelings of unattractiveness, body dissatisfaction, and low self-esteem (1,2). It is a major psychiatric problem, but many patients with this disorder first present to a dermatologist. An 11-year-old girl came to our department with a 2-month history of diffuse hair loss on the frontoparietal and parietotemporal area (Figure 1). She had originally been examined by a pediatrician with the diagnosis of alopecia areata. The patient`s personal history included hay fever and shortsightedness, and she suffered from varicella and mononucleosis. Nobody in the family history suffered from alopecia areata, but her father has male androgenetic alopecia (Norwood/Hamilton MAGA C3F3). The mother noticed that the child had had changeable mood for about 2 months and did not want to communicate with other persons in the family. The family did not have any pet at home. At school, her favorite subjects were Math and Computer Studies. She did not like Physical Education and did not participate in any sport activities during her free time. This was very strange because she was obese (body-mass index (BMI) 24.69). She was sometimes angry with her 13-year-old sister who had better results at school. The girl had suddenly started to wear a blue scarf. The parents did not notice that she pulled out her hair at home. Dermatological examination of the capillitium found a zone of incomplete alopecia in the frontoparietal and parietotemporal area, without inflammation, desquamation, and scaring. Hairs were of variable length (Figure 1). There was a patch of incomplete alopecia above the forehead between two stripes of hair of variable length (Figure 2). The hair pull test was negative along the edges of the alopecia. Mycological examination from the skin capillitium was negative. The trichoscopy and skin biopsy of the parietotemporal region of the capillitium (Figure 3) confirmed trichotillomania. Laboratory tests (blood count, iron, ferritin, transferrin, selenium, zinc, vitamin B12, folic acid, serology and hormones of thyroid gland) were negative. We referred the girl for ophthalmologic and psychological examination. Ophthalmologic examination proved that there was no need to add any more diopters. The psychological examination provided us with a picture in which she drew her family (Figure 4). The strongest authority in the family was the mother because she looked after the girls for most of the day. She was in the first place in the picture. The father had longer working hours and spent more time outside the home. He worked as a long vehicle driver. He was in the second place in the picture. There was sibling rivalry between the girls, but the parents did not notice this problem and preferred the older daughter. She was successful at school and was prettier (slim, higher, curly brown hair, without spectacles). Our 11-years-old patient noticed all these differences between them, but at her level of mental development was not able to cope with this problem. She wanted to be her sister's equal. The sister is drawn in the picture in the third place next to father, while the patient's own figure was drawn larger and slim even though she was obese. Notably, all three female figures had very nice long brown hair. It seemed that the mother and our patient had better quality of hair and more intense color than the sister in the drawing. The only hairless person in the picture was the father. The girl did not want to talk about her problems and feelings at home. Then it was confirmed that our patient was very sensitive, anxious, willful, and withdrawn. She was interested in her body and very perceptive of her physical appearance. From the psychological point of view, the parents started to pay more interest to their younger daughter and tried to understand and help her. After consultation with the psychiatrist, we did not start psychopharmacologic therapy for trichotillomania; instead, we started treatment with cognitive behavioral therapy, mild shampoo, mild topical steroids (e.g. hydrocortisone butyrate 0.1%) in solution and methionine in capsules. With parents' cooperation, the treatment was successful. The name trichotillomania was first employed by the French dermatologist Francois Henri Hallopeau in 1889, who described a young man pulling his hair out in tufts (3-5). The word is derived from the Greek thrix (hair), tillein (to pull), and mania (madness) (5). The prevalence of TTM in the general adult population ranges from 0.6% to 4%, and 2-4% of the general psychiatric outpatient population meet the criteria for TTM (2-5). The prevalence among children and adolescents has been estimated at less than 1% (5). The disease can occur at any age and in any sex. The age of onset of hair pulling is significantly later for men than for women (3). There are three subsets of age: preschool children, preadolescents to young adults, and adults. The mean age of onset is pre-pubertal. It ranges from 8 to 13 years (on average 11.3 years) (2-5). The occurrence of hair-pulling in the first year of life is a rare event, probably comprising &lt;1% of cases (5). The etiology of TTM is complex and may be triggered by a psychosocial stressor within the family, such as separation from an attachment figure, hospitalization of the child or parent, birth of a younger sibling, sibling rivalry, moving to a new house, or problems with school performance. It has been hypothesized that the habit may begin with "playing" with the hair, with later chronic pulling resulting in obvious hair loss (2). Environment is a factor because children usually pull their hair when alone and in relaxed surroundings. The bedroom, bathroom, or family room are "high-risk" situations for hair-pulling (5). Men and women also differed in terms of the hair pulling site (men pull hair from the stomach/back and the moustache/beard areas, while women pull from the scalp) (3). Pulling hair from siblings, pets, dolls, and stuffed animals has also been documented, often occurring in the same pattern as in the patient (5). Genetic factors contributing to the development of TTM are mutations of the SLITRK1 gene, which plays a role in cortex development and neuronal growth. The protein SAPAP3 has been present in 4.2% of TTM cases and patients with obsessive-compulsive disorder (OCD). It may be involved in the development of the spectrum of OCD. A significantly different concordance rate for TTM was found in monozygotic (38.1%) compared with dizygotic (0%) twins in 34 pairs (3). The core diagnostic feature is the repetitive pulling of hairs from one`s own body, resulting in hair loss. The targeted hair is mostly on the scalp (75%), but may also be from the eyebrows (42%), eyelashes (53%), beard (10%), and pubic area (17%) (3,5). There are three subtypes of hair pulling - early onset, automatic, and focused. Diagnostic criteria for TTM according to DSM-IV criteria are (2,3,5): 1) recurrent pulling of one`s hair resulting in noticeable hair loss; 2) an increasing sense of tension immediately prior to pulling out the hair or when attempting to resist the behavior; 3) pleasure, gratification, or relief when pulling out the hair; 4) the disturbance is not better accounted for by another mental disorder and is not due to a general medical condition (e.g., a dermatologic condition); 5) the disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning. The differential diagnosis includes alopecia areata (Table 1) (6), tinea capitis, telogen effluvium, secondary syphilis, traction alopecia, loose anagen syndrome, lichen planopilaris, alopecia mucinosa, and scleroderma (2-5). Biopsy of an involved area (ideally from a recent site of hair loss) can help to confirm the diagnosis (5). On histologic examination, there are typically increased numbers of catagen and telogen hairs without evidence of inflammation. Chronic hair pulling induces a catagen phase, and more hairs will be telogen hairs. Pigment casts and empty anagen follicles are often seen. Perifollicular hemorrhage near the hair bulb is an indicator of TTM (2). Complications of TTM are rare, but they comprise secondary bacterial infections with regional lymphadenopathy as a result of picking and scratching at the scalp. Many patients play with and ingest the pulled hairs (e.g. touching the hair to lips, biting, and chewing). Trichophagia (ingestion of the hair) can lead to a rare complication named trichobezoar (a "hair ball" in stomach). This habit is present in approximately 5% to 30% of adult patients, but it is less frequent in children. Patient with trichophagia present with pallor, nausea, vomiting, anorexia, and weight loss. Radiologic examination and gastroscopy should not be delayed (2,4,5). The management of the disease is difficult and requires strong cooperation between the physician, patient, and parents. The dermatologist cannot take part in the therapy, strictly speaking, but without the psychological, psychopharmacologic, and topic dermatologic treatment a vicious circle will be perpetuated.

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The NTP chose to initiate studies in fish as an exploration of alternate or additional models for examining chemical toxicity and carcinogenicity. The use of small fish species in carcinogenicity testing offered potential advantages as a bioassay test system, including significant savings in cost and time over rodent studies. Large numbers of small fish could be easily maintained in a limited area. The two species chosen for study were guppy (Poecilia reticulata) and medaka (Oryzias latipes), both of which are hardy, easily maintained, and have a low occurrence of background lesions. The three chemicals chosen for study in fish had already been studied by the NTP in rodents, permitting a comparison of results between the two models. Two of the chemicals used (2,2-bis(bromomethyl)-1,3-propanediol and 1,2,3-trichloropropane) were mutagenic and multisite carcinogens in rats and mice. The third chemical, nitromethane, was nonmutagenic with a more modest carcinogenic response in rodents. Male and female guppies and medaka were exposed to 2,2-bis(bromomethyl)- 1,3-propanediol (greater than 99% pure), nitromethane, (greater than 99% pure), or 1,2,3-trichloropropane (99% pure) in aquaria water for up to 16 months. OVERALL STUDY DESIGN: Groups of approximately 220 guppies (two replicates of 110) were maintained in aquaria water containing nominal concentrations of 0, 24, 60, or 150 mg/L 2,2-bis(bromomethyl)-1,3-propanediol; 0, 10, 30, or 70 mg/L nitromethane; or 0, 4.5, 9.0, or 18.0 mg/L 1,2,3-trichloropropane. Groups of approximately 340 medaka (two replicates of 170) were maintained in aquaria water containing 0, 24, 60, or 150 mg/L 2,2-bis(bromomethyl)-1,3-propanediol; 0, 10, 20, or 40 mg/L nitromethane; or 0, 4.5, 9.0, or 18.0 mg/L 1,2,3-trichloropropane. The overall study durations were 16 months for all guppy studies, 14 months for 2,2-bis(bromomethyl)-1,3-propanediol-exposed medaka, and 13 months for nitromethane- and 1,2,3-trichloropropane-exposed medaka. Ten guppies and 10 medaka from each group replicate were sacrificed at 9 months for histopathologic analysis. Approximately one third of the remaining fish from each group were placed in chemical-free water at 9 months and constituted a stop-exposure study component. The remainder of the fish were exposed for the duration of the study and constituted the core study component. A stop-exposure component was added to determine if stopping the exposure at 9 months and transferring to chemical-free aquaria might allow for better survival and tumor development. The sex of guppies and medaka was determined at histopathologic analysis. 2,2-BIS(BROMOMETHYL)-1,3-PROPANEDIOL - 16-MONTH STUDY IN GUPPIES: 2,2-Bis(bromomethyl)-1,3-propanediol was chronically toxic to guppies in the 60 and 150 mg/L core and stop-exposure groups. Due to mortality, exposure of core study animals in the 150 mg/L group was terminated on day 443, after approximately 64 weeks on study, and fish were maintained in 2,2-bis(bromomethyl)- 1,3-propanediol-free water in the exposure system until the end of the study at 69 weeks. Nominal exposure concentrations of 24, 60, and 150 mg/L provided actual aquaria water exposure concentrations of 20.0, 53.5, and 139.0 mg/L 2,2-bis(bromomethyl)- 1,3-propanediol, respectively. There were no treatment-related differences between the control and exposed groups in body weights or lengths. At 9 months, hepatocellular adenomas occurred in one 24 mg/L male and in one 150 mg/L male. In the core study, the incidence of hepatocellular adenoma or carcinoma (combined) in 150 mg/L males was greater than that in the controls; multiple adenomas occurred in two 150 mg/L males and in one 150 mg/L female. Cholangioma occurred in a small number of exposed males and females. In the stop-exposure study, incidences of hepatocellular adenoma (including multiple) and of hepatocellular carcinoma were greater in 150 mg/L males than in controls. One cholangioma and one cholangiocarcinoma occurred in the 150 mg/L female group. 14-MONTH STUDY IN MEDAKA: Exposure to 2,2-bis(bromomethyl)-1,3-propanediol did not result in any significant reduction in survival, although the mortality of fish was somewhat greater in the 60 and 150 mg/L core study groups than in the control and 24 mg/L groups. After reallocation, mortality of medaka in the 60 and 150 mg/L core groups was slightly increased over the corresponding stop-exposure groups. Nominal exposure concentrations of 24, 60, and 150 mg/L provided actual exposure concentrations of 19.4, 56.9, and 137.8 mg/L 2,2-bis(bromomethyl)- 1,3-propanediol, respectively. Core study animals in the 60 and 150 mg/L groups were significantly larger, in both body length and weight, than control group fish. In the core study, the incidence of hepatocellular adenoma or carcinoma (combined) was increased in 150 mg/L males. Cholangiocarcinomas occurred in a few exposed males and females, with all but one occurring in 150 mg/L fish. One cholangioma occurred in a 150 mg/L female, and one occurred in a control female. In the stop-exposure study, incidences of hepatocellular adenoma or carcinoma (combined) were marginally increased in the 150 mg/L group of males and in the 60 and 150 mg/L groups of females as compared with controls. Cholangiocarcinoma occurred in one male and one female in the 150 mg/L groups and in one control female. NITROMETHANE - 16-MONTH STUDY IN GUPPIES: Although the cause of death could not be confirmed in many cases, mortality in the 70 mg/L groups appeared to indicate that this level of nitromethane exposure was chronically toxic. This is confirmed by the similar survival rate of guppies from all treatments following removal from treatment aquaria and placement in stop-exposure. Due to the high mortality of fish in the 70 mg/L core study groups, these fish were removed from treatment (day 396) and fixed for histological analyses after approximately 57 weeks on study. The controls and other exposed groups were sacrificed at 70 weeks. Nominal exposure concentrations of 10, 30, and 70 mg/L provided actual exposure concentrations of 9.9, 28.7, and 66.4 mg/L nitromethane, respectively. There were no treatment-related differences between the control and exposed groups in body lengths or weights. 13-MONTH STUDY IN MEDAKA: Nitromethane in the aquaria supported a substantial microfaunal growth which, without frequent cleaning, affected water quality and treatment concentrations. To maintain acceptable water quality and treatment concentrations potentially affected by the rapid microfaunal growth, the study aquaria were brushed once and siphoned three times each day. Due to this frequent activity, a number of fish probably died due to mechanical injury. Unfortunately, the cause of death could not be confirmed in many cases; the mortality from this activity is believed to have been approximately uniform among treatments and should not have affected the comparison of survival between treatments. Based on mortality in this study and the previous life-span evaluation, the life phase of this study was terminated approximately 13.5 months after hatching. Nominal exposure concentrations of 10, 20, and 40 mg/L resulted in actual exposure concentrations of 9.3, 20.8, and 41.7 mg/L nitromethane, respectively. No differences between control and exposed groups were found in body lengths or weights at the 9-month interim evaluation. Due to mortality, unequal numbers of fish were distributed among the core study and stop-exposure aquaria at 9 months. Differences in lengths and weights were found at 13 months. The biological significance of this finding is unknown. At 9 months, a single cholangiocarcinoma occurred in a 40 mg/L male. Hepatocellular adenomas occurred in two 20 mg/L males and in one 40 mg/L female. In the core study, one cholangioma occurred in a 20 mg/L male, and cholangiocarcinomas were seen in a few exposed males, but none occurred in control males. 1,2,3-TRICHLOROPROPANE - 16-MONTH STUDY IN GUPPIES: The survival of exposed guppies was less than that of the control group at 9 months. Reduced survival was evident at 6 months in the 18.0 mg/L groups and at 7 months in the 4.5 and 9.0 mg/L groups. Survival was significantly reduced in the 18.0 mg/L core study group within 1 month of the 9-month interim evaluation, and mortality in this group was 42.6% between 9 months and study termination. Nominal exposure concentrations of 4.5, 9.0, and 18.0 mg/L resulted in actual exposure concentrations of 4.4, 8.8, and 18.2 mg/L 1,2,3-trichloropropane, respectively. Guppies in the 18.0 mg/L core study group were significantly longer and weighed more than the controls. Fish in the 18.0 mg/L stop-exposure group also weighed more than the controls. Mortality of fish during the study resulted in unequal numbers of individuals distributed to core study and stop-exposure aquaria at 9 months. This appears to have influenced the length and weight of fish measured at study termination (i.e., the smaller tank population allowed the fish to grow more). Observed differences in weight and length between controls and 18.0 mg/L fish was most likely an artifact of the reduced numbers of fish in the 18.0 mg/L aquaria. At 9 months, multiple hepatocellular adenomas occurred in one 4.5 mg/L male, and one hepatocellular adenoma occurred in a control male. In the core study, increased incidences of cholangiocellular (bile duct) and hepatocellular neoplasms occurred in exposed groups of males and females. Cholangioma and cholangiocarcinoma were seen in several exposed males and females. In the stop-exposure study, increased incidences of hepatocellular neoplasms occurred in 18.0 mg/L males and increased incidences of cholangiocellular (bile duct) neoplasms occurred in 18.0 mg/L females. (ABSTRACT TRUNCATED)

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3,3',4,4'-Tetrachloroazobenzene (TCAB) is not commercially manufactured but is formed as an unwanted by-product in the manufacture of 3,4-dichloroaniline and its herbicidal derivatives Propanil, Linuron, and Diuron. It occurs from the degradation of chloroanilide herbicides (acylanilides, phenylcarbamates, and phenylureas) in soil by peroxide-producing microorganisms; and is formed by the photolysis and biolysis of 3,4-dichloroaniline. Humans may be exposed to TCAB during the manufacture as well as the application of herbicides containing TCAB as a contaminant. TCAB was nominated by the United States Environmental Protection Agency for toxicity and carcinogenicity testing based on its structural and biological similarity to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and the potential for human exposure from the consumption of crops contaminated with 3,4-dichloroaniline-derived herbicides. Male and female Harlan Sprague-Dawley rats and B6C3F1 mice were administered TCAB (at least 97.8% pure) in corn oil:acetone (99:1) by gavage for 3 months (rats only) or 2 years. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female Harlan Sprague-Dawley rats were administered 0.1, 0.3, 1, 3, 10, 30, or 100 mg TCAB/kg body weight in corn oil:acetone (99:1) by gavage, 5 days a week, for 14 weeks; groups of 10 male and 10 female rats received the corn oil:acetone vehicle alone. Special study groups of 30 (dosed groups) or 6 (vehicle control group) female Harlan Sprague-Dawley rats were administered 0.1, 3, or 100 mg TCAB/kg body weight in corn oil:acetone (99:1) by gavage, 5 days a week, for 13 weeks; vehicle controls received the corn oil:acetone vehicle alone. All male and female rats survived to the end of the study. Terminal mean body weights of males were not significantly different from vehicle controls in any group. Terminal mean body weights of females administered 10 mg/kg or greater were significantly less than those of the vehicle controls. Mean body weight gains of all dosed groups of females were significantly less than those of the vehicle controls. The hematology results indicate that TCAB induced a microcytic normochromic responsive anemia in male Sprague-Dawley rats. Serum concentrations of total thyroxine (T4) and free T4 were significantly decreased in a dose-related manner in all dosed groups in both sexes compared to their respective vehicle controls; total triiodothyronine (T3) and thyroid stimulating hormone (TSH) concentrations were generally unaffected. There were no statistically significant differences in the BrdU labeling indices in the liver of males or females exposed to TCAB compared to their respective vehicle controls. Significant induction of hepatic 7-ethoxyresorufin-O-deethylase (EROD) and 7-pentoxyresorufin-O-deethylase activities was observed in all dosed groups of males and females. Significant induction of hepatic acetanilide-4-hydroxylase activity was observed in males exposed to 3 mg/kg or greater and all treated groups of females. EROD activities in the lung generally increased with increasing dose and were significantly greater in all treated groups of males and females compared to their respective vehicle controls. The highest concentrations of TCAB were observed in fat tissue with lower concentrations in the liver and lung. TCAB concentrations were significantly increased in a dose-dependent manner in all tissues from dosed groups relative to vehicle controls. At the end of the 3-month study, absolute and relative liver weights were significantly greater than those of the vehicle controls in all dosed groups of males and in females administered 10 mg/kg or greater. Absolute and relative lung weights were significantly greater in 100 mg/kg males and 3 mg/kg or greater females. Absolute and relative right kidney and spleen weights were generally significantly greater for all dosed groups of males. Absolute thymus weights of 10 mg/kg or greater males and absolute and relative thymus weights of 1 mg/kg or greater females were significantly less than those of the vehicle controls. In the liver, the incidences of midzonal to diffuse hepatocytic hypertrophy in males administered 1 mg/kg or greater and in females administered 10 mg/kg or greater were significantly greater than the vehicle control incidences. Hematopoietic cell proliferation occurred in most males administered 3 mg/kg or greater and most females administered 10 mg/kg or greater. The incidences of midzonal hepatocytic cytoplasmic fatty vacuolization were significantly increased in males administered 3 mg/kg or greater. In the lung, significantly increased incidences of bronchiolar metaplasia of the alveolar epithelium and interstitial mononuclear cell infiltration occurred in 10, 30, and 100 mg/kg males. The incidence of interstitial mononuclear cell infiltration was also significantly increased in 100 mg/kg females. Significantly increased incidences of hematopoietic cell proliferation of the spleen occurred in males administered 10 mg/kg or greater. The incidences of hemosiderin pigment of the spleen were significantly increased in 10 mg/kg or greater females. Atrophy in the thymus was significantly increased in all dosed groups of females, except the 0.1 mg/kg group, and in males administered 10 mg/kg or greater. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female Harlan Sprague-Dawley rats were administered 10, 30, or 100 mg TCAB/kg body weight in corn oil:acetone (99:1) by gavage, 5 days a week, for 2 years; groups of 50 male and 50 female rats received the corn oil:acetone vehicle alone. The survival of all dosed groups of males was significantly less than that of the vehicle controls. Mean body weights of 100 mg/kg males were less than those of the vehicle control group throughout the study. Mean body weights of 30 mg/kg males were 6% less than those of the vehicle control group after week 24, and those of 10 mg/kg males were 7% less than the vehicle control group after week 80. Mean body weights of 100 mg/kg females were less than those of the vehicle control group throughout the study, and those of 30 mg/kg females were 6% less than the vehicle control group after week 36. In the lung, the incidences of multiple cystic keratinizing epithelioma and single or multiple cystic keratinizing epithelioma (combined) in males and females were significantly increased in all dosed groups (except multiple epithelioma in 10 mg/kg females). Significantly increased incidences of pigmentation, alveolar epithelium squamous metaplasia (except 10 mg/kg females), and alveolar epithelium bronchiolar metaplasia occurred in all dosed groups of males and females. The incidences of histiocytic cellular infiltration in all dosed groups of males were significantly increased. In the liver, the incidences of cholangiocarcinoma (single or multiple) occurred in a positive trend in males and were significantly greater than that in the vehicle control group; the incidence in 100 mg/kg females was also increased. A significant dose-related increase in hepatic toxicity was observed in dosed rats and was characterized by increased incidences of numerous lesions including hepatocyte hypertrophy, centrilobular degeneration, hepatocellular necrosis, pigmentation, fatty change, bile duct hyperplasia, oval cell hyperplasia, nodular hyperplasia, hematopoietic cell proliferation, eosinophilic focus, mixed cell focus, multinucleated hepatocytes, bile duct cyst, toxic hepatopathy, and cholangiofibrosis. Significantly increased incidences of gingival squamous cell carcinoma within the oral mucosa occurred in 10 mg/kg males and 100 mg/kg males and females. The incidences of gingival squamous hyperplasia and cystic keratinizing hyperplasia in dosed groups of males and females were generally significantly increased. The incidences of follicular cell adenoma (single or multiple) of the thyroid gland in 30 and 100 mg/kg males were significantly greater than that in the vehicle control group. The incidences of follicular cell hypertrophy, follicular cell hyperplasia, and inflammation were significantly increased in 30 and 100 mg/kg males. Three incidences of single or multiple squamous cell papilloma of the forestomach occurred in 100 mg/kg females, and single incidences of squamous cell carcinoma of the forestomach occurred in 10 and 100 mg/kg females. Significantly increased incidences of epithelial hyperplasia occurred in all dosed groups of males and females. There were three incidences of malignant schwanomma in the thoracic cavity in 100 mg/kg males and a single incidence in 30 mg/kg males. In the adrenal cortex of 30 and 100 mg/kg females, there were slightly increased incidences of adenoma. In all dosed groups of males, the incidences of degeneration, cytoplasmic vacuolization, and hyperplasia of the zona fasciculata were significantly increased. Increased incidences and severities of necrosis occurred in 30 and 100 mg/kg males. Incidences of cytoplasmic vacuolation in 10 and 100 mg/kg females and hyperplasia of the zona fasciculata in 30 mg/kg females were significantly greater than those in the vehicle controls. Numerous nonneoplastic effects were seen in other organs including atrophy, acinar cytoplasmic vacuolization, and inflammation of the pancreas; blood vessel inflammation; lymphoid follicle atrophy and pigmentation of the spleen; pigmentation and atrophy of the mesenteric lymph node; germinal epithelial degeneration of the testes; and inflammation of the nose. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were administered 3, 10, or 30 mg TCAB/kg body weight in corn oil:acetone (99:1) by gavage, 5 days a week, for 2 years; groups of 50 male and 50 female rats received the corn oil:acetone vehicle alone. Survival of 10 and 30 mg/kg males and 30 mg/kg females was significantly less than that of vehicle controls. All 30 mg/kg males died before the end of the study. (ABSTRACT TRUNCATED)

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The aim of this systematic review is to establish the best available evidence of the effectiveness of health literacy interventions on the informed consent process for health care users. The specific review question is:What is the effectiveness of health literacy interventions on health care users' informed consent to health procedures processes? Informed consent is a fundamental principal in the health care context which nowadays includes the patient's capacity to judge and to be involved in the decision making concerning their care that ensures that the care received reflects their goals, preferences and values. The importance of obtaining a valid consent before any medical procedure is well-established. In a US court case in 1914, it was stated that it is the right of any adult with the capability of making decisions concerning his own body, and that any surgical operation without the patient's consent could be considered as an assault. In another US court case, the court stated that it is a doctor's duty to make a reasonable disclosure to his patient of the nature, probable consequences and dangers of the proposed treatment to the patient. The application of the doctrine of informed consent as a legal procedure may slightly differ from country to country or from state to state, and may have different forms even within the same country. For example in the UK, consent can be written, verbal or non-verbal/implied, and a written consent form is not the actual consent itself but merely serves as evidence that consent has been given. If the elements of voluntariness, appropriate information and capacity have not been satisfied, a signed informed consent form will not make the consent valid. Nowadays it is widely accepted that prior to the application of any medical procedure, its benefits, risks and alternatives must have been explained to the patient, and the competent patient should have voluntarily and understandingly consented. Hence, the informed consent refers both to the health professional's obligation of information disclosure to the patient and to the quality of the patient's understanding and decision making. In other words, it does not refer to the single moment of the agreement, but to the whole complex process of gaining information, deciding and consenting. Several factors may restrict informed consent, including the patient's competence, provision of limited information, ineffective communication between patients and professionals, the hospital environment itself and privacy problems.According to the World Health Organization (WHO), people are increasingly urged to make choices for themselves or for their family members in regards to health care use. However, at the same time, inadequate or problematic health literacy skills have been reported in approximately half of the adult population in eight European countries. "Health literacy is linked to literacy and entails people's knowledge, motivation and competences to access, understand, appraise and apply health information in order to make judgments and take decisions in everyday life concerning health care, disease prevention and health promotion to maintain or improve quality of life during the life course". There are many instruments measuring either health literacy in general or some dimensions of health literacy (e.g. numeracy), health literacy related to specific issues (e.g. nutrition, diabetes) or health literacy of specific populations (e.g. adolescents). The diversity of existing instruments, which includes diversity in terms of scoring and ranges, makes the comparison of the results of different studies difficult. Index thresholds and ranges for different levels of health literacy for most tools were set based either on that of other well established health literacy instruments used in the same study, or on experts' assessments of the required health literacy scores. Adequate health literacy could be considered as the capacity of successfully completing most tasks required to function in the health care setting.Low or inadequate health literacy has been found to have several adverse effects on health and health care use: reduced ability to take medications properly and to interpret labels and health messages, poorer overall health status and higher risk of mortality in seniors, increased emergency department and hospital use, and decreased use of preventive interventions.Most studies examining the relationship between health literacy and informed consent conclude that patients with low health literacy are less likely to participate in decision making concerning their health care. According to a recent literature review, health care users' literacy, together with other factors, were found to be important determinants of a patient's capacity to provide fully informed consent. According to this review, 21 to 86% of the patients were able to recall the potential risks and complications of their medical procedure. This percentage may be even lower because most of the included studies referred to self-reported recall, which may be a flawed measure. According to the literature, much of the written material related to the informed consent is too difficult for health care users to understand. In addition, in their study, McCarthy et al. observed that during consultations, physicians spoke and used significantly more complex language than their patients, which may result in inappropriate communication for the patients, mainly for those with limited literacy. The situations described above may raise a number of critical legal and ethical problems. Health professionals, who shape the conditions of interactions with the patient, are responsible for adapting appropriate interventions, such as communication approaches that take into account patients' health literacy. These interventions could have a major contribution to the improvement of the informed consent process.Sheridan et al. conducted a systematic review on interventions designed to reduce the effects of limited health literacy in general. Some of the outcomes of the included studies were comprehension and behavioral intent, outcomes which could be strongly related to the informed consent process. Without making any distinction of the studies referring to the informed consent process, they conclude that several health literacy interventions, for example, adding video to narrative, could improve an individual's comprehension. Schenker et al. conducted a systematic review on the interventions to improve patient comprehension of medical and surgical procedures, including articles published until 2008. One of their conclusions was that, in most studies, while particular attention is needed for interventions provided to patients with limited literacy, the literacy of the patients was not addressed or assessed.Since then, many articles on health literacy and informed consent have been published. According to a recent review on best practices and new models of health literacy for informed consent, which includes papers published from 2004 to 2014, over half of the collected articles were published since 2010. This review, which is limited to literature within the US and its territories, and does not focus on the evaluation of the recommended practices in the literature, concludes that different tactics for simplifying written documents and clarifying verbal exchanges, and the use of multimedia formats and computerized exchanges might ameliorate constraints to health literate communications required for informed consent.Studies have evaluated the effectiveness of health literacy interventions which aim to improve the informed consent process. Improvement of the informed consent process may refer not only to the patients' comprehension but also, for example, to the recall of the information provided, to their intention to ask for clarifications, or to their satisfaction with the procedure. Interventions described and tested in the literature focus on the improvement of the print material, the process (e.g. the communication of the appropriate information) or both. Davis et al. conducted a randomized controlled trial to compare two polio vaccine pamphlets written at a sixth grade level - an international standardized pamphlet and an easy-to-read pamphlet - for the comprehension and preference among parents. Although the parents in the intervention group (N=304) achieved significantly higher comprehension than the control group (N=306) (65% vs 60%, p&lt;0.005), the authors concluded that simplifying written material increases appeal but not the comprehension to an adequate level without use of instructional graphics. Similarly, Lorenzen et al. found that a reader friendly informed consent document to surgical procedures was more commonly read by the health care users as compared to the original consent document; however, no difference was found in terms of the participants' capacity to describe the procedure in their own words. Kang et al. evaluated recall and comprehension of orthodontic informed consent among pairs of children and their parents (N=90) applying three different informed consent procedures. According to this study, a combination of improving the readability of consent materials and the informed consent process (audio and visual cues) led to better recall for the patients and better recall and comprehension for their parents compared to an improved readability form or the usual informed consent form. Smith et al. used a randomized controlled trial to compare a decision aid (booklet and DVD) specifically designed for adults with low literacy skills (N=357) with a standard information booklet (N=173) on screening for bowel cancer. They found that the proportion of participants making an informed choice was 22% higher in the intervention group than in the control group (34% vs 12%, P&lt;0.001). Matsuyama et al. (ABSTRACT TRUNCATED)

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To assess the effectiveness and safety of low-density lipoprotein (LDL) apheresis performed with the heparin-induced extracorporeal LDL precipitation (HELP) system for the treatment of patients with refractory homozygous (HMZ) and heterozygous (HTZ) familial hypercholesterolemia (FH). BACKGROUND ON FAMILIAL HYPERCHOLESTEROLEMIA: Familial hypercholesterolemia is a genetic autosomal dominant disorder that is caused by several mutations in the LDL-receptor gene. The reduced number or absence of functional LDL receptors results in impaired hepatic clearance of circulating low-density lipoprotein cholesterol (LDL-C) particles, which results in extremely high levels of LDL-C in the bloodstream. Familial hypercholesterolemia is characterized by excess LDL-C deposits in tendons and arterial walls, early onset of atherosclerotic disease, and premature cardiac death. Familial hypercholesterolemia occurs in both HTZ and HMZ forms. Heterozygous FH is one of the most common monogenic metabolic disorders in the general population, occurring in approximately 1 in 500 individuals. Nevertheless, HTZ FH is largely undiagnosed and an accurate diagnosis occurs in only about 15% of affected patients in Canada. Thus, it is estimated that there are approximately 3,800 diagnosed and 21,680 undiagnosed cases of HTZ FH in Ontario. In HTZ FH patients, half of the LDL receptors do not work properly or are absent, resulting in plasma LDL-C levels 2- to 3-fold higher than normal (range 7-15mmol/L or 300-500mg/dL). Most HTZ FH patients are not diagnosed until middle age when either they or one of their siblings present with symptomatic coronary artery disease (CAD). Without lipid-lowering treatment, 50% of males die before the age of 50 and 25% of females die before the age of 60, from myocardial infarction or sudden death. In contrast to the HTZ form, HMZ FH is rare (occurring in 1 case per million persons) and more severe, with a 6- to 8-fold elevation in plasma LDL-C levels (range 15-25mmol/L or 500-1000mg/dL). Homozygous FH patients are typically diagnosed in infancy, usually due to the presence of cholesterol deposits in the skin and tendons. The main complication of HMZ FH is supravalvular aortic stenosis, which is caused by cholesterol deposits on the aortic valve and in the ascending aorta. The average life expectancy of affected individuals is 23 to 25 years. In Ontario, it is estimated that there are 13 to 15 cases of HMZ FH. An Ontario clinical expert confirmed that 9 HMZ FH patients have been identified to date. There are 2 accepted clinical diagnostic criterion for the diagnosis of FH: the Simon Broome FH Register criteria from the United Kingdom and the Dutch Lipid Network criteria from the Netherlands. The criterion supplement cholesterol levels with clinical history, physical signs and family history. DNA-based-mutation-screening methods permit a definitive diagnosis of HTZ FH to be made. However, given that there are over 1000 identified mutations in the LDL receptor gene and that the detection rates of current techniques are low, genetic testing becomes problematic in countries with high genetic heterogeneity, such as Canada. The primary aim of treatment in both HTZ and HMZ FH is to reduce plasma LDL-C levels in order to reduce the risk of developing atherosclerosis and CAD. The first line of treatment is dietary intervention, however it alone is rarely sufficient for the treatment of FH patients. Patients are frequently treated with lipid-lowering drugs such as resins, fibrates, niacin, statins and cholesterol absorption-inhibiting drugs (ezetimibe). Most HTZ FH patients require a combination of drugs to achieve or approach target cholesterol levels. A small number of HTZ FH patients are refractory to treatment or intolerant to lipid-lowering medication. According to clinical experts, the prevalence of refractory HTZ FH in Ontario is between 1 to 5%. Using the mean of 3%, it is estimated that there are approximately 765 refractory HTZ FH patients in Ontario, of which 115 are diagnosed and 650 are undiagnosed. Drug therapy is less effective in HMZ FH patients since the effects of the majority of cholesterol-lowering drugs are mediated by the upregulation of LDL receptors, which are often absent or function poorly in HMZ FH patients. Some HMZ FH patients may still benefit from drug therapy, however this rarely reduces LDL-C levels to targeted levels. EXISTING TECHNOLOGY: PLASMA EXCHANGE An option currently available in Ontario for FH patients who do not respond to standard diet and drug therapy is plasma exchange (PE). Patients are treated with this lifelong therapy on a weekly or biweekly basis with concomitant drug therapy. Plasma exchange is nonspecific and eliminates virtually all plasma proteins such as albumin, immunoglobulins, coagulation factors, fibrinolytic factors and HDL-C, in addition to acutely lowering LDL-C by about 50%. Blood is removed from the patient, plasma is isolated, discarded and replaced with a substitution fluid. The substitution fluid and the remaining cellular components of the blood are then returned to the patient. The major limitation of PE is its nonspecificity. The removal of HDL-C prevents successful vascular remodeling of the areas stenosed by atherosclerosis. In addition, there is an increased susceptibility to infections, and costs are incurred by the need for replacement fluid. Adverse events can be expected to occur in 12% of procedures. OTHER ALTERNATIVES: Surgical alternatives for FH patients include portocaval shunt, ileal bypass and liver transplantation. However, these are risky procedures and are associated with a high morbidity rate. Results with gene therapy are not convincing to date. LDL APHERESIS An alternative to PE is LDL apheresis. Unlike PE, LDL apheresis is a selective treatment that removes LDL-C and other atherogenic lipoproteins from the blood while minimally impacting other plasma components such as HDL-C, total serum protein, albumin and immunoglobulins. As with PE, FH patients require lifelong therapy with LDL apheresis on a weekly/biweekly basis with concomitant drug therapy. HEPARIN-INDUCED EXTRACORPOREAL LDL PRECIPITATION: Heparin-induced extracorporeal LDL precipitation (HELP) is one of the most widely used methods of LDL apheresis. It is a continuous closed-loop system that processes blood extracorporeally. It operates on the principle that at a low pH, LDL and lipoprotein (a) [Lp(a)] bind to heparin and fibrinogen to form a precipitate which is then removed by filtration. In general, the total duration of treatment is approximately 2 to 3 hours. Results from early trials indicate that LDL-C concentration is reduced by 65% to 70% immediately following treatment in both HMZ and HTZ FH and then rapidly begins to rise. Typically patients with HTZ FH are treated every 2 weeks while patients with HMZ FH require weekly therapy. Heparin-induced extracorporeal LDL precipitation also produces small transient decreases in HDL-C, however levels generally return to baseline within 2 days. After several months of therapy, long-term reductions in LDL-C and increases in HDL-C have been reported. In addition to having an impact on plasma cholesterol concentrations, HELP lowers plasma fibrinogen, a risk factor for atherosclerosis, and reduces concentrations of cellular adhesion molecules, which play a role in early atherogenesis. In comparison with PE, HELP LDL apheresis does not have major effects on essential plasma proteins and does not require replacement fluid, thus decreasing susceptibility to infections. One study noted that adverse events were documented in 2.9% of LDL apheresis treatments using the HELP system compared with 12% using PE. As per the manufacturer, patients must weigh at least 30kgs to be eligible for treatment with HELP. The H.E.L.P.® System (B.Braun Medizintechnologie GmbH, Germany) has been licensed by Health Canada since December 2000 as a Class 3 medical device (Licence # 26023) for performing LDL apheresis to acutely remove LDL from the plasma of 3 high-risk patient populations for whom diet has been ineffective and maximum drug therapy has either been ineffective or not tolerated. The 3 patient groups are as follows: Functional hypercholesterolemic homozygotes with LDL-C &gt;500 mg/dL (&gt;13mmol/L);Functional hypercholesterolemic heterozygotes with LDL-C &gt;300 mg/dL (&gt;7.8mmol/L);Functional hypercholesterolemic heterozygotes with LDL-C &gt;200 mg/dL (&gt;5.2mmol/L) and documented CADNo other LDL apheresis system is currently licensed in Canada. The Medical Advisory Secretariat systematically reviewed the literature to assess the effectiveness and safety of LDL apheresis performed with the HELP system for the treatment of patients with refractory HMZ and HTZ FH. A standard search methodology was used to retrieve international health technology assessments and English-language journal articles from selected databases. The GRADE approach was used to systematically and explicitly make judgments about the quality of evidence and strength of recommendations. The search identified 398 articles published from January 1, 1998 to May 30, 2007. Eight studies met the inclusion criteria. Five case series, 2 case series nested within comparative studies, and one retrospective review, were included in the analysis. A health technology assessment conducted by the Alberta Heritage Foundation for Medical Research, and a review by the United States Food and Drug Administration were also included. Large heterogeneity among the studies was observed. Studies varied in inclusion criteria, baseline patient characteristics and methodology. Overall, the mean acute relative decrease in LDL-C with HELP LDL apheresis ranged from 53 to 77%. The mean acute relative reductions ranged as follows: total cholesterol (TC) 47 to 64%, HDL-C +0. (ABSTRACT TRUNCATED)

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Barium chloride dihydrate, a white crystalline granule or powder, is used in pigments, aluminum refining, leather tanning and coloring, the manufacture of magnesium metal, ceramics, glass, and paper products, as a pesticide, and in medicine as a cardiac stimulant. Toxicology and carcinogenicity studies were conducted by administering barium chloride dihydrate (99% pure) in drinking water to F344/N rats and B6C3F1 mice for 15 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and mouse lymphoma cells. 15-DAY STUDY IN RATS: Groups of five males and five females received barium chloride dihydrate in the drinking water at concentrations of 0, 125, 250, 500, 1,000, or 2,000 ppm for 15 days, corresponding to average daily doses of 10, 15, 35, 60, or 110 mg barium/kg body weight to males and females. No chemical-related deaths, differences in final mean body weights, or clinical findings of toxicity were observed. Water consumption by male and female rats exposed to 2,000 ppm was slightly less (S16%) than controls during week 2. There were no significant differences in absolute or relative organ weights between exposed and control rats. No biologically significant differences in hematology, clinical chemistry, or neurobehavioral parameters occurred in rats. 15-DAY STUDY IN MICE: Groups of five males and five females received barium chloride dihydrate in the drinking water at concentrations of 0, 40, 80,173, 346, or 692 ppm for 15 days, corresponding to average daily doses of 5,10, 20, 40, or 70 mg barium/kg body weight to males and 5, 10, 15, 40, or 85 mg barium/kg body weight to females. No chemical-related deaths, differences in mean body weights or in water consumption, or clinical findings of toxicity were observed in mice. The relative liver weight of males receiving 692 ppm was significantly greater than that of the controls. The absolute and relative liver weights of females that received 692 ppm were significantly greater than those of the controls. No histopathologic evidence of toxicity was observed in mice. 13-WEEK STUDY IN RATS: Groups of 10 males and 10 females received barium chloride dihydrate in the drinking water at concentrations of 0, 125, 500, 1,000, 2,000, or 4,000 ppm for 13 weeks, corresponding to average daily doses of 10, 30, 65, 110, or 200 mg barium/kg body weight to males and 10, 35, 65, 115, or 180 mg barium/kg body weight to females. Three males and one female in the 4,000 ppm groups died during the last week of the study. The final mean body weights of male and female rats receiving 4,000 ppm were significantly lower (13% and 8%) than those of the controls. Water consumption by male and female rats in the 4,000 ppm groups was approximately 30% lower than that by the controls. No clearly chemical-related clinical findings of toxicity or neurobehavioral or cardiovascular effects were noted. Serum phosphorus levels in 2,000 and 4,000 ppm male and female rats were significantly higher than those in controls, but there were no biologically significant differences in hematology parameters or in serum sodium, potassium, or calcium levels. Renal tubule dilatation in the outer stripe of the outer medulla and cortex occurred in male and female rats receiving 4,000 ppm. 13-WEEK STUDY IN MICE: Groups of 10 males and 10 females received barium chloride dihydrate in the drinking water at concentrations of 0, 125, 500, 1,000, 2,000, or 4,000 ppm for 13 weeks, corresponding to average daily doses of 15, 55, 100, 205, or 450 mg barium/kg body weight to males and 15, 60, 110, 200, or 495 mg barium/kg body weight to females. Six males and seven females that received 4,000 ppm and one male that received 125 ppm died during the study. Final mean body weights of male and female mice receiving 4,000 ppm were significantly lower (&gt;30%) than those of controls. Water consumption by male mice in the 4,000 ppm group was 18% lower than that by the controls; water consumption by other exposed groups of male and female mice was similar to thatd groups of male and female mice was similar to that by the controls. Clinical findings of toxicity were limited to debilitation in the surviving male and female mice receiving 4,000 ppm. The absolute and/or relative liver weights of mice receiving 1,000, 2,000, and 4,000 ppm were significantly lower than those of the controls. Multifocal to diffuse nephropathy characterized by tubule dilatation, regeneration, and atrophy occurred in 4,000 ppm male and female mice. 2-YEAR STUDY IN RATS: Groups of 60 males and 60 females received barium chloride dihydrate in the drinking water at concentrations of 0, 500, 1,250, or 2,500 ppm for 104 (males) or 105 weeks (females), corresponding to average daily doses of 15, 30, or 60 mg barium/kg body weight for males and 15, 45, or 75 mg barium/kg body weight for females. The high dose of 2,500 ppm was selected based on decreased final mean body weights, mortality, decreased water consumption, and chemical-related kidney lesions observed in the 4,000 ppm groups in the 13-week study. Survival, Body Weights, Water Consumption, and Clinical Findings: Two-year survival of exposed male and female rats was similar to that of the controls. The final mean body weights of male and female rats that received 2,500 ppm were (5&amp;percnt; and 11&amp;percnt;) lower than those of controls. Beginning as early as week 5, water consumption by male and female rats receiving 2,500 ppm was substantially lower than that by controls (male: 11&amp;percnt; to 30&amp;percnt;; female: 19&amp;percnt; to 33&amp;percnt;). There were no chemical-related clinical findings. Hematology and Clinical Chemistry: There were no chemical-related differences in hematology or clinical chemistry parameters in male or female rats. Special Studies: At the 15-month interim evaluation, the plasma barium concentrations (mg/ml) were significantly increased in males receiving 1,250 and 2,500 ppm and in all exposed groups of females (male: 0 ppm, 0.98; 500 ppm, 1.00; 1,250 ppm, 1.23; 2,500 ppm, 1.68; female: 0 ppm, 0.74; 500 ppm, 0.99; 1,250 ppm, 0.97; 2,500 ppm, 1.43). Barium levels in bone in rats from the 2,500 ppm groups were about 400 times greater than those in the controls. Pathology Findings: At the end of 2 years, there were no increased incidences of neoplasms or nonneoplastic lesions that could be attributed to barium chloride dihydrate. However, there were dose-related decreased incidences of adrenal medulla pheochromocytomas and mononuclear cell leukemia in male rats. 2-YEAR STUDY IN MICE: Groups of 60 males and 60 females received barium chloride dihydrate in the drinking water at concentrations of 0, 500, 1,250, or 2,500 ppm for 103 (males) or 104 weeks (females), corresponding to average daily doses of 30, 75, or 160 mg barium/kg body weight for males and 40, 90, or 200 mg barium/kg body weight for females. The high dose of 2,500 ppm was selected based on decreased final mean body weights, mortality, decreased water consumption, and chemical-related kidney lesions observed in the 4,000 ppm groups in the 13-week study. Survival, Body Weights, Water Consumption, and Clinical Findings: Two-year survival of male and female mice receiving 2,500 ppm was significantly lower than that of the controls due to renal toxicity. Final mean body weights of 2,500 ppm males and females were 9% and 12% lower than those of controls. Water consumption by male and female mice receiving barium chloride was similar to that by the controls. There were no chemical-related clinical findings. Hematology and Clinical Chemistry: There were no differences in hematology or clinical chemistry parameters measured at the 15-month interim evaluation. Special Studies: At the 15-month interim evaluation, plasma barium concentrations (mg/mL) were significantly increased in all exposed groups of mice (male: 0 ppm, 0.62; 500 ppm, 0.77; 1,250 ppm, 0.89; 2,500 ppm, 1.49; female: 0 ppm, 0.52; 500 ppm, 0.74; 1,250 ppm, 1.01; 2,500 ppm, 1.35). Pathology Findings: At the end of the 2-year study, there were increased incidences of nephropathy in male and female mice (male: 1/50, 0/50, 2/48, 19/50; female: 0/50, 2/53, 1/50, 37/54). There were no chemical-related increased incidences of neoplasms in male or female mice. The incidence of hepatocellular adenoma was significantly decreased in male mice receiving 2,500 ppm. GENETIC TOXICOLOGY: Barium chloride dihydrate was not mutagenic in Salmonella typhimurium strains TA97, TA98, TA100, TA1535, or TA1537, with or without exogenous metabolic activation (S9). It was mutagenic in L5178Y mouse lymphoma cells in the presence of S9, but it did not induce sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells, with or without S9. CONCLUSIONS: Under the conditions of these 2-year drinking water studies, there was no evidence of carcinogenic activity of barium chloride dihydrate in male or female F344/N rats that received 500, 1,250, or 2,500 ppm. There was no evidence of carcinogenic activity of barium chloride dihydrate in male or female B6C3F1 mice that received 500, 1,250, or 2,500 ppm. There were chemical-related increased incidences of nephropathy in male and female mice.

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Chronic low back pain (CLBP) is one of the main causes of disability in the western world with a huge economic burden to society. As yet, no specific underlying anatomic cause has been identified for CLBP. Imaging often reveals degenerative findings of the disc or facet joints of one or more lumbar motion segments. These findings, however, can also be observed in asymptomatic people. It has been suggested that pain in degenerated discs may be caused by the ingrowth of nerve fibers into tears or clefts of the annulus fibrosus or nucleus pulposus, and by reported high levels of pro-inflammatory mediators. As this so-called discogenic pain is often exacerbated by mechanical loading, the concept of relieving pain by spinal fusion to stabilise a painful spinal segment, has been developed. For some patients lumbar spinal fusion indeed is beneficial, but its results are highly variable and hard to predict for the individual patient. To identify those CLBP patients who will benefit from fusion, many surgeons rely on tests that are assumed to predict the outcome of spinal fusion. The three most commonly used prognostic tests in daily practice are immobilization in a lumbosacral orthosis, provocative discography and trial immobilization by temporary external transpedicular fixation. Aiming for consensus on the indications for lumbar fusion and in order to improve its results by better patient selection, it is essential to know the role and value of these prognostic tests for CLBP patients in clinical practice. The overall aims of the present thesis were: 1) to evaluate whether there is consensus among spine surgeons regarding the use and appreciation of prognostic tests for lumbar spinal fusion; 2) to verify whether a thoracolumbosacral orthosisis (TLSO) truly minimises lumbosacral motion; 3) to verify whether a TLSO can predict the clinical outcome of fusion for CLBP; 4) to assess whether provocative discography of adjacent segments actually predicts the long-term clinical outcome fusion; 5) to determine the incidence of postdiscography discitis, and whether there is a need for routine antibiotic prophylaxis; 6) to assess whether temporary external transpedicular fixation (TETF) can help to predict the outcome of spinal fusion; 7) to determine the prognostic accuracy of the most commonly used tests in clinical practice to predict the outcome of fusion for CLBP. The results of a national survey among spine surgeons in the Netherlands were presented in Study I. The surgeons were questioned about their opinion on prognostic factors and about the use of predictive tests for lumbar fusion in CLBP patients. The comments were compared with findings from the prevailing literature. The survey revealed a considerable lack of uniformity in the use and appreciation of predictive tests. Prognostic factors known from the literature were not consistently incorporated in the surgeons' decision making process either. This heterogeneity in strategy is most probably caused by the lack of sound scientific evidence for current predictive tests and it was concluded that currently there is not enough consensus among spine surgeons in the Netherlands to create national guidelines for surgical decision making in CLBP. In Study II, the hypothesized working mechanism of a pantaloon cast (i.e., minimisation of lumbosacral joint mobility) was studied. In patients who were admitted for a temporary external transpedicular fixation test (TETF), infrared light markers were rigidly attached to the protruding ends of Steinman pins that were fixed in two spinal levels. In this way three-dimensional motion between these levels could be analysed opto-electronically. During dynamic test conditions such as walking, a plaster cast, either with or without unilateral hip fixation, did not significantly decrease lumbosacral joint motion. Although not substantiated by sound scientific support, lumbosacral orthoses or pantaloon casts are often used in everyday practice as a predictor for the outcome of fusion. A systematic review of the literature supplemented with a prospective cohort study was performed (Study III) in order to assess the value of a pantaloon cast in surgical decision-making. It appeared that only in CLBP patients with no prior spine surgery, a pantaloon cast test with substantial pain relief suggests a favorable outcome of lumbar fusion compared to conservative treatment. In patients with prior spine surgery the test is of no value. It is believed by many spine surgeons that provocative discography, unlike plain radiographs or magnetic resonance imaging, is a physiologic test that can truly determine whether a disc is painful and relevant in a patient's pain syndrome, irrespective of the morphology of the disc. It has been suggested that in order to achieve a successful clinical outcome of lumbar fusion, suspect discs should be painful and adjacent control discs should elicit no pain on provocative discography. For this reason, a cohort of patients in whom the decision to perform lumbar fusion was based on an external fixation (TETF) trial, was analysed retrospectively in Study IV. The results of preoperative discography of solely the levels adjacent to the fusion were compared with the clinical results after spinal fusion. It appeared that in this select group of patients the discographic status of discs adjacent to a lumbar fusion did not have any effect on the clinical outcome. The most feared complication of lumbar discography is discitis. Although low in incidence, this is a serious complication for a diagnostic procedure and prevention by the use of prophylactic antibiotics has been advocated. In search for clinical guidelines, the risk of postdiscography discitis was assessed in Study V by means of a systematic literature review and a cohort of 200 consecutive patients. Without the use of prophylactic antibiotics, an overall incidence of postdiscography discitis of 0.25% was found. To prove that antibiotics would actually prevent discitis, a randomised trial of 9,000 patients would be needed to reach significance. Given the possible adverse effects of antibiotics, it was concluded that the routine use of prophylactic antibiotics in lumbar discography is not indicated. In Study VI, the middle- and long-term results of external fixation (TETF) as a test to predict the clinical outcome of lumbar fusion were studied in a group of back pain patients for whom there was doubt about the indication for surgery. The test included a placebo trial, in which the patients were unaware whether the lumbar segmental levels were fixed or dynamised. Using strict and objective criteria of pain reduction on a visual analogue scale, the TETF test failed to predict clinical outcome of fusion in this select group of patients. Pin track infection and nerve root irritation were registered as complications of this invasive test. It was concluded that in chronic low back pain patients with a doubtful indication for fusion, TETF is not recommended as a supplemental tool for surgical decision-making. In Study VII, a systematic literature review was performed regarding the prognostic accuracy of tests that are currently used in clinical practice and that are presumed to predict the outcome of lumbar spinal fusion for CLBP. The tests of interest were magnetic resonance imaging (MRI), TLSO immobilisation, TETF, provocative discography and facet joint infiltration. Only 10 studies reporting on three different index tests (discography, TLSO immobilisation and TETF) that truly reported on test qualifiers, such as sensitivity, specificity and likelihood ratios, could be selected. It appeared that the accuracy of all prognostic tests was low, which confirmed that in many clinical practices patients are scheduled for fusion on the basis of tests, of which the accuracy is insufficient or at best unknown. As the overall methodological quality of included studies was poor, higher quality trials that include negatively tested as well as positively tested patients for fusion, will be needed. It was concluded that at present, best evidence does not support the use of any prognostic test in clinical practice. No subset of patients with low back pain could be identified, for whom spinal fusion is a reliable and effective treatment. In literature, several studies have reported that cognitive behavioural therapy or intensive exercise programs have treatment results similar to those of spinal fusion, but with considerably less complications, morbidity and costs. As the findings of the present thesis show that the currently used tests do not improve the results of fusion by better patient selection, these tests should not be recommended for surgical decision making in standard care. Moreover, spinal fusion should not be proposed as a standard treatment for chronic low back pain. Causality of nonspecific spinal pain is complex and CLBP should not be regarded as a diagnosis, but rather as a symptom in patients with different stages of impairment and disability. Patients should be evaluated in a multidisciplinary setting or Spine Centre according to the so-called biopsychosocial model, which aims to identify underlying psychosocial factors as well as biological factors. Treatment should occur in a stepwise fashion starting with the least invasive treatment. The current approach of CLBP, in which emphasis is laid on self-management and empowerment of patients to take an active course of treatment in order to prevent long-term disability and chronicity, is recommended.

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The objective of this analysis was to determine the diagnostic utility of oral fluid testing collected with the Intercept oral fluid collection device. TARGET POPULATION AND CONDITION Opioids (opiates or narcotics) are a class of drugs derived from the opium poppy plant that typically relieve pain and produce a euphoric feeling. Methadone is a long-acting synthetic opioid used to treat opioid dependence and chronic pain. It prevents symptoms of opioid withdrawal, reduces opioid cravings and blocks the euphoric effects of short-acting opioids such as heroin and morphine. Opioid dependence is associated with harms including an increased risk of exposure to Human Immunodeficiency Virus and Hepatitis C as well as other health, social and psychological crises. The goal of methadone treatment is harm reduction. Treatment with methadone for opioid dependence is often a long-term therapy. The Ontario College of Physicians and Surgeons estimates that there are currently 250 physicians qualified to prescribe methadone, and 15,500 people in methadone maintenance programs across Ontario. Drug testing is a clinical tool whose purpose is to provide objective meaningful information, which will reinforce positive behavioral changes in patients and guide further treatment needs. Such information includes knowledge of whether the patient is taking their methadone as prescribed and reducing or abstaining from using opioid and other drugs of abuse use. The results of drug testing can be used with behavior modification techniques (contingency management techniques) where positive reinforcements such as increased methadone take-home privileges, sustained employment or parole are granted for drug screens negative for opioid use, and negative reinforcement including loss of these privileges for drug screens positive for opioid used. Body fluids including blood, oral fluid, often referred to as saliva, and urine may contain metabolites and the parent drug of both methadone and drugs of abuse and provide a means for drug testing. Compared with blood which has a widow of detection of several hours, urine has a wider window of detection, approximately 1 to 3 days, and is therefore considered more useful than blood for drug testing. Because of this, and the fact that obtaining a urine specimen is relatively easy, urine drug screening is considered the criterion measure (gold standard) for methadone maintenance monitoring. However, 2 main concerns exist with urine specimens: the possibility of sample tampering by the patient and the necessity for observed urine collection. Urine specimens may be tampered with in 3 ways: dilution, adulteration (contamination) with chemicals, and substitution (patient submits another persons urine specimen). To circumvent sample tampering the supervised collection of urine specimens is a common and recommended practice. However, it has been suggested that this practice may have negative effects including humiliation experienced by patient and staff, and may discourage patients from staying in treatment. Supervised urine specimen collection may also present an operational problem as staff must be available to provide same-sex supervision. Oral fluid testing has been proposed as a replacement for urine because it can be collected easily under direct supervision without infringement of privacy and reduces the likelihood of sample tampering. Generally, the results of oral fluid drug testing are similar to urine drug testing but there are some differences, such as lower concentrations of substances in oral fluid than urine, and some drugs remain detectable for longer periods of time in urine than oral fluid. The Intercept Oral Specimen Collection Device (Ora-Sure Technologies, Bethlehem, PA) consists of an absorbent pad mounted on a plastic stick. The pad is coated with common salts. The absorbent pad is inserted into the mouth and placed between the cheek and gums for 3 minutes on average. The pad absorbs the oral fluid. After 3 minutes (range 2min-5 min) the collection device is removed from the mouth and the absorbent pad is placed in a small vial which contains 0.8mL of pH-balanced preservative, for transportation to a laboratory for analysis. It is recommended that the person undergoing oral fluid drug testing have nothing to eat or drink for a 10- minute period before the oral fluid specimen is collected. This will remove opportunity for adulteration. Likewise, it is recommended that the person be observed for the duration of the collection period to prevent adulteration of the specimen. An average of 0.4 mL of saliva can be collected. The specimen may be stored at 4C to 37C and tested within 21 days of collection (or within 6 weeks if frozen). The oral fluid specimen must be analyzed in a laboratory setting. There is no point-of-care (POC) oral fluid test kit for drugs of abuse (other than for alcohol). In the laboratory the oral fluid is extracted from the vial after centrifugation and a screening test is completed to eliminate negative specimens. Similar to urinalysis, oral fluid specimens are analyzed first by enzyme immunoassay with positive specimens sent for confirmatory testing. Comparable cut-off values to urinalysis by enzyme immunoassay have been developed for oral fluids   What is the diagnostic utility of the Intercept oral specimen device? Studies evaluating paired urine and oral fluid specimens from the same individual with the Intercept oral fluid collection device.The population studied includes drug users. Studies testing for marijuana (THC) only. Sensitivity and Specificity of oral fluid testing compared to urinalysis for methadone (methadone metabolite), opiates, cocaine, benzodiazepines, and alcohol. QUALITY OF THE BODY OF EVIDENCE: The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used to evaluate the overall quality of the body of evidence (defined as 1 or more studies) supporting the research questions explored in this systematic review. A description of the GRADE system is reported in Appendix 1. A total of 854 potential citations were retrieved. After reviewing titles and abstracts, 2 met the inclusion and exclusion criteria. Two other relevant studies were found after corresponding with the author of the 2 studies retrieved from the literature search. Therefore a total of 4 published studies are included in this analysis. All 4 studies carried out by the same investigator meet the definition of Medical Advisory Secretariat level III (not a-randomized controlled trial with contemporaneous controls) study design. In each of the studies, paired urine and oral fluid specimens where obtained from drug users. Urine collection was not observed in the studies however, laboratory tests for pH and creatinine were used to determine the reliability of the specimen. Urine specimens thought to be diluted and unreliable were removed from the evaluation. Urinalysis was used as the criterion measurement for which to determine the sensitivity and specificity of oral fluid testing by the Intercept oral fluid device for opiates, benzodiazepines, cocaine and marijuana. Alcohol was not tested in any of the 4 studies. From these 4 studies, the following conclusions were drawn: The evidence indicates that oral fluid testing with the Intercept oral fluid device has better specificity than sensitivity for opiates, benzodiazepines, cocaine and marijuana.THE SENSITIVITY OF ORAL FLUIDS TESTING WITH THE INTERCEPT ORAL FLUID DEVICE SEEMS TO BE FROM BEST TO WORST: cocaine &gt; benzodiazepines &gt;opiates&gt; marijuana.The sensitivity and specificity for opiates of the Intercept oral fluid device ranges from 75 to 90% and 97- 100% respectively.The consequences of opiate false-negatives by oral fluid testing with the Intercept oral fluid device need to be weighed against the disadvantages of urine testing, including invasion of privacy issues and adulteration and substitution of the urine specimen.The window of detection is narrower for oral fluid drug testing than urinalysis and because of this oral fluid testing may best be applied in situations where there is suspected frequent drug use. When drug use is thought to be less frequent or remote, urinalysis may offer a wider (24-48 hours more than oral fluids) window of detection.The narrow window of detection for oral fluid testing may mean more frequent testing is needed compared to urinalysis. This may increase the expense for drug testing in general.POC oral fluid testing is not yet available and may limit the practical utility of this drug testing methodology. POC urinalysis by immunoassay is available.The possible applications of oral fluid testing may include:Because of its narrow window of detection compared to urinalysis oral fluid testing may best be used during periods of suspected frequent or recent drug use (within 24 hours of drug testing). This is not to say that oral fluid testing is superior to urinalysis during these time periods.In situations where an observed urine specimen is difficult to obtain. This may include persons with "shy bladder syndrome" or with other urinary conditions limiting their ability to provide an observed urine specimen.When the health of the patient would make urine testing unreliable (e,g., renal disease)As an alternative drug testing method when urine specimen tampering practices are suspected to be affecting the reliability of the urinalysis test.Possible limiting Factors to Diffusion of Oral Fluid Technology No oral fluid POC test equivalent to onsite urine dips or POC analyzer reducing immediacy of results for patient care.Currently, physicians get reimbursed directly for POC urinalysis. (ABSTRACT TRUNCATED)

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HEALTH PROBLEM: Cervical cancer is a disease which is highly preventable by means of Pap test screening for the precancerous lesions, which can be easily treated. Furthermore, in the near future, control of the disease will be enhanced by the vaccination which prevents the infection of those human papillomavirus types that cause the vast majority of cervical cancers. The effectiveness of screening in drastically reducing cervical cancer incidence has been clearly demonstrated. The epidemiology of cervical cancer in industrialised countries is now determined mostly by the Pap test coverage of the female population and by the ability of health systems to assure appropriate follow up after an abnormal Pap test. Today there are two fully automated systems for computer-assisted Pap test: the BD FocalPoint and the Hologic Imager. Recently, the Hologic Integrated Imager, a semi-automated system, was launched. The two fully automated systems are composed of a central scanner, where the machine examines the cytologic slide, and of one or more review stations, where the cytologists analyze the slides previously centrally scanned. The softwares used by the two systems identify the fields of interest so that the cytologists can look only at those points, automatically pointed out by the review station. Furthermore, the FocalPoint system classifies the slides according to their level of risk of containing signs of relevant lesions. Those in the upper classes--about one fifth of the slides--are labelled as « further review », while those in the lower level of risk, i.e. slides that have such a low level of risk that they can be considered as negative with no human review, are labelled as « no further review ». The aim of computer-assisted Pap test is to reduce the time of slide examination and to increase productivity. Furthermore, the number of errors due to lack of attention may decrease. Both the systems can be applied to liquidbased cytology, while only the BD Focal Point can be used on conventional smears. Cytology screening has some critical points: there is a shortage of cytologists/cytotechnicians; the quality strongly depends on the experience and ability of the cytologist; there is a subjective component in the cytological diagnosis; in highly screened populations, the prevalence of lesions is very low and the activity of cytologists is very monotonous. On the other hand, a progressive shift to molecular screening using HPV-DNA test as primary screening test is very likely in the near future; cytology will be used as triage test, dramatically reducing the number of slides to process and increasing the prevalence of lesions in those Pap tests. In this Report we assume that the diagnostic accuracy of computer-assisted Pap test is equal to the accuracy of manual Pap test and, consequently, that screening using computer-assisted Pap test has the same efficacy in reducing cervical cancer incidence and mortality. Under this assumption, the effectiveness/ benefit/utility is the same for the two screening modes, i.e. the economic analysis will be a cost minimization study. Furthermore, the screening process is identical for the two modalities in all the phases except for slide interpretation. The cost minimization analysis will be limited to the only phase differing between the two modes, i.e. the study will be a differential cost analysis between a labour-intensive strategy (traditional Pap test) and a technology-intensive strategy (the computer-assisted Pap test). Briefly, the objectives of this HTA Report are: to determine the break even point of computer-assisted Pap test systems, i.e. the volume of slides processed per year at which putting in place a computer-assisted Pap test system becomes economically convenient; to quantify the cost per Pap test in different scenarios according to screening centre activity volume, productivity of cytologist, type of cytology (conventional smear or liquid-based, fully automated or semi-automated computer-assisted); to analyse the computer-assisted Pap test in the Italian context, through a survey of the centres using the technology, collecting data useful for the sensitivity analysis of the economic evaluation; to evaluate the acceptability of the technology in the screening services; to evaluate the organizational and financial impact of the computer-assisted Pap test in different scenarios; to illustrate the ideal organization to implement computer-assisted Pap test in terms of volume of activity, productivity, and human and technological resources. to produce this Report, the following process was adopted: application to the Ministry of health for a grant « Analysis of the impact of professional involvement in evidence generation for the HTA process »; within this project, the sub-project « Cost effectiveness evaluation of the computer-assisted Pap test in the Italian screening programmes » was financed; constitution of the Working Group, which included the project coordinator, the principal investigator, and the health economist; identification of the centres using the computer-assisted Pap test and which had published scientific reports on the subject; identification of the Consulting Committee (stakeholder), which included screening programmes managers, pathologists, economists, health policy-makers, citizen organizations, and manufacturers. Once the evaluation was concluded, a plenary meeting with Working Group and Consulting Committee was held. The working group drafted the final version of this Report, which took into account the comments received. the fully automated computer-assisted Pap test has an important financial and organizational impact on screening programmes. The assessment of this health technology reached the following conclusions: according to the survey results, after some distrust, cytologists accepted the use of the machine and appreciated the reduction in interpretation time and the reliability in identifying the fields of interest; from an economic point of view, the automated computer-assisted Pap test can be convenient only with conventional smears if the screening centre has a volume of more than 49,000 slides/year and the cytologist productivity increases about threefold. It must be highlighted that it is not sufficient to adopt the automated Pap test to reach such an increase in productivity; the laboratory must be organised or re-organised to optimise the use of the review stations and the person time. In the case of liquid-based cytology, the adoption of automated computer- assisted Pap test can only increase the costs. In fact, liquid-based cytology increases the cost of consumable materials but reduces the interpretation time, even in manual screening. Consequently, the reduction of human costs is smaller in the case of computer-assisted screening. Liquid-based cytology has other implications and advantages not linked to the use of computer-assisted Pap test that should be taken into account and are beyond the scope of this Report; given that the computer-assisted Pap test reduces human costs, it may be more advantageous where the cost of cytologists is higher; given the relatively small volume of activity of screening centres in Italy, computer-assisted Pap test may be reasonable for a network using only one central scanner and several remote review stations; the use of automated computer-assisted Pap test only for quality control in a single centre is not economically sustainable. In this case as well, several centres, for example at the regional level, may form a consortium to reach a reasonable number of slides to achieve the break even point. Regarding the use of a machine rather than human intelligence to interpret the slides, some ethical issues were initially raised, but both the scientific community and healthcare professionals have accepted this technology. The identification of fields of interest by the machine is highly reproducible, reducing subjectivity in the diagnostic process. The Hologic system always includes a check by the human eye, while the FocalPoint system identifies about one fifth of the slides as No Further Review. Several studies, some of which conducted in Italy, confirmed the reliability of this classification. There is still some resistance to accept the practice of No Further Review. A check of previous slides and clinical data can be useful to make the cytologist and the clinician more confident. Computer-assisted automated Pap test may be introduced only if there is a need to increase the volume of slides screened to cover the screening target population and sufficient human resources are not available. Switching a programme using conventional slides to automatic scanning can only lead to a reduction in costs if the volume of slides per year exceeds 49,000 slides/annum and cytologist productivity is optimised to more than 20,000 slides per year. At a productivity of 15,000 or fewer, the automated computer-assisted Pap test cannot be convenient. Switching from manual screening with conventional slides to automatic scanning with liquid-based cytology cannot generate any economic saving, but the system could increase output with a given number of staff. The transition from manual to computer assisted automated screening of liquid based cytology will not generate savings and the increase in productivity will be lower than that of the switch from manual/conventional to automated/conventional. The use of biologists or pathologists as cytologists is more costly than the use of cytoscreeners. Given that the automated computer-assisted Pap test reduces human resource costs, its adoption in a model using only biologists and pathologists for screening is more economically advantageous. (ABSTRACT TRUNCATED)

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