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3'-Azido-3'-deoxythymidine (AZT) is the most widely used and evaluated chemotherapeutic agent for the treatment of persons with acquired immune deficiency syndrome (AIDS). Antiviral therapy is essential for treatment and prevention of AIDS in adults and children infected with human immunodeficiency virus (HIV), and to prevent mother-to-child transmission of HIV during pregnancy and labor. The studies described in this report were designed to determine possible long-term sequelae from AZT treatment, often used in combination with other antiviral drugs, such as lamivudine (3TC) and nevirapine (NVP) in preventing mother-to-child transmission of HIV. Male and female heterozygous F1 p53+/- mice were exposed to AZT, 3TC, NVP, or combinations of the chemicals in utero on gestation days (GD) 12 through 18, then administered the same chemical or combination of chemicals by gavage from postnatal day (PND) 1 through PND 28 and then observed until 45 weeks of age. Vehicle control mice received only an aqueous solution containing 0.2% methylcellulose and 0.1% Tween 80. Mice were dosed twice daily until PND 28. Genetic toxicology studies were conducted in mouse peripheral blood erythrocytes. The study compared three combination doses of AZT, 3TC and NVP (AZT/3TC/NVP-L, AZT/3TC/NVP-M, and AZT/3TC/NVP-H) with the vehicle controls, and compared the individual components with each other at the highest dose (AZT-H, 3TC-H, NVP-H, AZT/3TC-H and AZT/3TC/NVP-H). Because exposure to AZT/3TC/NVP-M and AZT/3TC/NVP-H reduced pup survival, additional litters were required to provide sufficient pups to load the 45-week study. 45-WEEK STUDY: In general, survival was relatively high once the pup exposure phase had been completed, with at least 75% of the mice surviving to terminal sacrifice in all groups. For males, survival was significantly greater in the AZT/3TC/NVP-L and AZT/3TC/NVP-M groups relative to the vehicle control group. There were no significant differences in survival between high dose groups of the constituent chemicals in either sex; however, survival of females in the AZT/3TC-H group was significantly less than that in the vehicle control group. Early deaths were predominantly associated with occurrences of malignant lymphoma, mammary gland tumors, and osteosarcomas. In the combination dose comparison, males and females dosed with the AZT/3TC/NVP-H combination had significantly decreased body weights compared to the vehicle control groups from PND 11 when individual monitoring began until 20 (males) or 11 (females) weeks. In addition, mean body weights for the male and female AZT/3TC/NVP-M groups were significantly less than those of the vehicle control groups until 14 weeks. In the high dose comparison, mean body weights of the male and female AZT-H groups were significantly less than those of the vehicle control groups during some of the early weeks of dosing. In male and female mice, absolute brain weights of the combination dose groups decreased with increasing dose and, except in low dose males, the absolute brain weights of the dosed groups were significantly less than those of the vehicle control groups. When the high doses of the constituent chemicals were compared, absolute brain weights of the male and female AZT-H and AZT/3TC/NVP-H groups were significantly less than those of the vehicle control groups. However, relative brain weights were not significantly altered. Relative liver weights of male combination dose groups followed a positive trend with dose. When the high dose groups were compared, increases in relative liver weights of male mice appeared to be associated with AZT exposure. In combination dose groups, the absolute heart weight of AZT/3TC/NVP-H females was significantly greater than that of the vehicle control group, and there was a positive trend in absolute heart weights. There was also a positive trend for relative heart weights in these combination dose groups, though no individual group relative weight was significantly greater than that of the vehicle control group. In females, absolute heart weight was also significantly increased in the AZT/3TC-H group relative to the vehicle control group. A small but statistically significant increase in serum alanine aminotransferase activity was observed in the male AZT/3TC/NVP-H group compared to the vehicle control group. In the combination dose comparison, the incidences of hepatocellular adenoma and hepatocellular adenoma or carcinoma (combined) in the liver of all groups of males dosed with AZT/3TC/NVP were significantly increased compared to the vehicle control group. In the high dose comparison, the incidences of hepatocellular adenoma in males in the AZT-H group and hepatocellular adenoma and hepatocellular adenoma or carcinoma (combined) in males in the AZT/3TC-H and AZT/3TC/NVP-H groups were significantly greater than those in the vehicle control group; the incidences of these lesions in the 3TC-H and NVP-H groups were significantly less than those in the AZT/3TC/NVP-H group. The incidences of malignant lymphoma in males administered AZT-H or AZT/3TC-H and in females administered AZT/3TC/NVP-M, AZT/3TC/NVP-H, NVP-H, or AZT/3TC-H were slightly greater than those in the vehicle control groups. The incidence of mammary gland adenoacanthoma or adenocarcinoma (combined) in females administered 3TC-H was slightly greater than that in the vehicle control group. In the peripheral blood of 1-day-old male and female mice, the percentage of total reticulocytes (RETs) was significantly decreased in groups exposed to doses that contained AZT. In addition, the percentages of micronucleated normochromatic erythrocytes (NCEs) and micronucleated RETs were generally significantly increased in groups exposed to doses containing AZT, but not in the 3TC-H or NVP-H groups. The percentages of micronucleated NCEs in the AZT/3TC/NVP-H groups were greater than in the AZT-H and the AZT/3TC-H groups. In peripheral blood of male pups evaluated at PND 28, both the percentage of micronucleated RETs and the percentage of micronucleated NCEs were significantly increased in the group where 3TC was coadministered with AZT compared to the group administered only AZT. Under the conditions of this gavage study, there was clear evidence of carcinogenic activity of AZT alone in male heterozygous F1 p53+/- mice based on increased incidences of hepatocellular adenoma. There was clear evidence of carcinogenic activity of AZT in combination with 3TC, and AZT in combination with 3TC and NVP in male heterozygous F1 p53+/- mice based on increased incidences of hepatocellular adenoma and hepatocellular adenoma or carcinoma (combined). The occurrence of malignant lymphoma may have been related to treatment with AZT alone and with AZT in combination with 3TC. There was no evidence of carcinogenic activity of 3TC alone in male heterozygous F1 p53+/- mice administered 150 mg/kg. There was no evidence of carcinogenic activity of NVP alone in male heterozygous F1 p53+/- mice administered 168 mg/kg. There was equivocal evidence of carcinogenic activity of NVP alone, AZT in combination with 3TC, and AZT in combination with 3TC and NVP in female heterozygous F1 p53+/- mice based on the occurrence of malignant lymphoma. There was equivocal evidence of carcinogenic activity of 3TC alone in female heterozygous F1 p53+/- mice based on the occurrence of mammary gland adenoacanthoma or adenocarcinoma (combined). There was no evidence of carcinogenic activity of AZT alone in female heterozygous F1 p53+/- mice administered 240 mg/kg. Synonyms: (3'-AZIDO-3'-DEOXYTHYMIDINE) 3'-azido-2',3'-dideoxythymidine; azidodeoxythymidine; azidothymidine; 3'-azidothymidine; AZT; BW A509U; Compound S; 3'-deoxy-3'-azidothymidine; 3'-deoxy-(8CI) (9CI); ZDV; zidovudine. Trade name: Retrovir® [Combivir® with 3TC] Synonyms: (2',3'-DIDEOXY-3'-THIACYTIDINE) 3TC; 4-amino-1-[(2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-1,2-dihydropyrimidin-2-one; L-2',3'-dideoxy-3'-thiacytidine; lamivudine Trade name: Epivir® [Combivir® with AZT] Synonyms: (NEVIRAPINE) NVP; 11-cyclopropyl-4-methyl-5,11-dihydro-6H- dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one Trade name: Viramune®

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Distraction osteogenesis has been broadly used to treat various structural bone deformities and defects. However, prolonged healing time remains a major problem. Various approaches including the use of low-intensity pulsed ultrasound, parathyroid hormone, and bone morphogenetic proteins (BMPs) have been studied to shorten the treatment period with limited success. Our previous studies of rats have reported that the transcutaneous application of CO2 accelerates fracture repair and bone-defect healing in rats by promoting angiogenesis, blood flow, and endochondral ossification. This therapy may also accelerate bone generation during distraction osteogenesis, but, to our knowledge, no study investigating CO2 therapy on distraction osteogenesis has been reported. We aimed to investigate the effect of transcutaneous CO2 during distraction osteogenesis in rabbits, which are the most suitable animal as a distraction osteogenesis model for a lengthener in terms of limb size. We asked: Does transcutaneous CO2 during distraction osteogenesis alter (1) radiographic bone density in the distraction gap during healing; (2) callus parameters, including callus bone mineral content, volumetric bone mineral density, and bone volume fraction; (3) the newly formed bone area, cartilage area, and angiogenesis, as well as the expression of interleukin-6 (IL-6), BMP-2, BMP-7, hypoxia-inducible factor (HIF) -1α, and vascular endothelial growth factor (VEGF); and (4) three-point bend biomechanical strength, stiffness, and energy? Forty 24-week-old female New Zealand white rabbits were used according to a research protocol approved by our institutional ethical committee. A distraction osteogenesis rabbit tibia model was created as previously described. Briefly, an external lengthener was applied to the right tibia, and a transverse osteotomy was performed at the mid-shaft. The osteotomy stumps were connected by adjusting the fixator to make no gap. After a 7-day latency phase, distraction was continued at 1 mm per day for 10 days. Beginning the day after the osteotomy, a 20-minute transcutaneous application of CO2 on the operated leg using a CO2 absorption-enhancing hydrogel was performed five times per week in the CO2 group (n = 20). Sham treatment with air was administered in the control group (n = 20). Animals were euthanized immediately after the distraction period (n = 10), 2 weeks (n = 10), and 4 weeks (n = 20) after completion of distraction. We performed bone density quantification on the plain radiographs to evaluate consolidation in the distraction gap with image analyzing software. Callus parameters were measured with micro-CT to assess callus microstructure. The newly formed bone area and cartilage area were measured histologically with safranin O/fast green staining to assess the progress of ossification. We also performed immunohistochemical staining of endothelial cells with fluorescein-labeled isolectin B4 and examined capillary density to evaluate angiogenesis. Gene expressions in newly generated callus were analyzed by real-time polymerase chain reaction. Biomechanical strength, stiffness, and energy were determined from a three-point bend test to assess the mechanical strength of the callus. Radiographs showed higher pixel values in the distracted area in the CO2 group than the control group at Week 4 of the consolidation phase (0.98 ± 0.11 [95% confidence interval 0.89 to 1.06] versus 1.19 ± 0.23 [95% CI 1.05 to 1.34]; p = 0.013). Micro-CT demonstrated that bone volume fraction in the CO2 group was higher than that in the control group at Week 4 (5.56 ± 3.21 % [95% CI 4.32 to 6.12 %] versus 11.90 ± 3.33 % [95% CI 9.63 to 14.25 %]; p = 0.035). There were no differences in any other parameters (that is, callus bone mineral content at Weeks 2 and 4; volumetric bone mineral density at Weeks 2 and 4; bone volume fraction at Week 2). At Week 2, rabbits in the CO2 group had a larger cartilage area compared with those in the control group (2.09 ± 1.34 mm [95% CI 1.26 to 2.92 mm] versus 5.10 ± 3.91 mm [95% CI 2.68 to 7.52 mm]; p = 0.011). More newly formed bone was observed in the CO2 group than the control group at Week 4 (68.31 ± 16.32 mm [95% CI 58.19 to 78.44 mm] versus 96.26 ± 19.37 mm [95% CI 84.25 to 108.26 mm]; p < 0.001). There were no differences in any other parameters (cartilage area at Weeks 0 and 4; newly formed bone area at Weeks 0 and 2). Immunohistochemical isolectin B4 staining showed greater capillary densities in rabbits in the CO2 group than the control group in the distraction area at Week 0 and surrounding tissue at Weeks 0 and 2 (distraction area at Week 0, 286.54 ± 61.55 /mm [95% CI 232.58 to 340.49] versus 410.24 ± 55.29 /mm [95% CI 361.78 to 458.71]; p < 0.001; surrounding tissue at Week 0 395.09 ± 68.16/mm [95% CI 335.34 to 454.83] versus 589.75 ± 174.42/mm [95% CI 436.86 to 742.64]; p = 0.003; at Week 2 271.22 ± 169.42 /mm [95% CI 122.71 to 419.73] versus 508.46 ± 49.06/mm [95% CI 465.45 to 551.47]; p < 0.001 respectively). There was no difference in the distraction area at Week 2. The expressions of BMP -2 at Week 2, HIF1-α at Week 2 and VEGF at Week 0 and 2 were greater in the CO2 group than in the control group (BMP -2 at Week 2 3.84 ± 0.83 fold [95% CI 3.11 to 4.58] versus 7.32 ± 1.63 fold [95% CI 5.88 to 8.75]; p < 0.001; HIF1-α at Week 2, 10.49 ± 2.93 fold [95% CI 7.91 to 13.06] versus 20.74 ± 11.01 fold [95% CI 11.09 to 30.40]; p < 0.001; VEGF at Week 0 4.80 ± 1.56 fold [95% CI 3.43 to 6.18] versus 11.36 ± 4.82 fold [95% CI 7.13 to 15.59]; p < 0.001; at Week 2 31.52 ± 8.26 fold [95% CI 24.27 to 38.76] versus 51.05 ± 15.52 fold [95% CI 37.44 to 64.66]; p = 0.034, respectively). There were no differences in any other parameters (BMP-2 at Week 0 and 4; BMP -7 at Weeks 0, 2 and 4; HIF-1α at Weeks 0 and 4; IL-6 at Weeks 0, 2 and 4; VEGF at Week 4). In the biomechanical assessment, ultimate stress and failure energy were greater in the CO2 group than in the control group at Week 4 (ultimate stress 259.96 ± 74.33 N [95% CI 167.66 to 352.25] versus 422.45 ± 99.32 N [95% CI 299.13 to 545.77]; p < 0.001, failure energy 311.32 ± 99.01 Nmm [95% CI 188.37 to 434.25] versus 954.97 ± 484.39 Nmm [95% CI 353.51 to 1556.42]; p = 0.003, respectively). There was no difference in stiffness (216.77 ± 143.39 N/mm [95% CI 38.73 to 394.81] versus 223.68 ± 122.17 N/mm [95% CI 71.99 to 375.37]; p = 0.92). Transcutaneous application of CO2 accelerated bone generation in a distraction osteogenesis model of rabbit tibias. As demonstrated in previous studies, CO2 treatment might affect bone regeneration in distraction osteogenesis by promoting angiogenesis, blood flow, and endochondral ossification. The use of the transcutaneous application of CO2 may open new possibilities for shortening healing time in patients with distraction osteogenesis. However, a deeper insight into the mechanism of CO2 in the local tissue is required before it can be used in future clinical practice.

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Roxarsone is a veterinary drug used as a growth promoter and as an anticoccidial agent and for treatment of swine dysentery. Toxicology and carcinogenesis studies were conducted by administering roxarsone (greater than 99.4% pure) in feed to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 weeks, or 2 years. Fourteen-Day and Thirteen-Week Studies: In the 14-day studies, the diets fed to rats contained 0 or 100-1,600 ppm roxarsone, and those fed to mice contained 0 or 60-1,000 ppm. Deaths occurred in rats and mice that received the highest doses. Rats that received 800 or 1,600 ppm lost weight. Male mice that received 1,000 ppm and female mice that received 500 ppm lost weight. In the first 13-week studies, roxarsone was fed to rats and mice at dietary concentrations of 0 or 50-800 ppm. Decreases (more than 10%) in final mean body weights of dosed rats relative to those of controls were observed for males that received 200, 400, or 800 ppm and for females that received 400 or 800 ppm. Deaths occurred in groups that received 800 ppm. Clinical signs of toxicity (trembling, ataxia, and pale skin) were seen primarily in rats that received 800 ppm. Kidney lesions were observed in rats that received 800 ppm. These lesions were characterized by tubular necrosis and mineralization in the rats that died during the studies and by tubular dilatation and casts, interstitial inflammation, and tubular epithelial cell regeneration in the rats that lived to the end of the studies. Additional 13-week studies were conducted in rats at dietary concentrations of 0, 100, or 400 ppm to demonstrate the absorption of roxarsone from the gastrointestinal tract; to determine its distribution in liver, kidney, and blood; and to study its effects on various hematologic and clinical chemical values. No deaths occurred. Renal lesions of minimal severity observed in male rats that received 400 ppm were characterized by tubular epithelial cell degeneration and regeneration, tubular casts, and mineralization. Arsenic levels in urine, blood, kidney, and liver of dosed rats increased (140%-300%) with time on study and were proportional to the dietary concentrations of roxarsone. No compound-related hematologic or clinical chemical effects were observed in rats. In the first 13-week studies, final mean body weights of mice that received 800 ppm were 11%-18% lower than those of controls. Deaths occurred in males and females receiving 400 and 800 ppm. No compound-related gross or histopathologic lesions were observed. In the second 13-week studies in mice, no compound-related hematologic or clinical chemical effects were observed. At the end of the studies, arsenic concentrations in dosed mice ranged from 0.45 to 0.99 ug/g of liver and from 0.85 to 2.98 ug/g of kidney. No arsenic was detected in the liver or kidney of control mice. Because of kidney lesions, lower body weight gain, and increased mortality in rats and lower body weight gain and increased mortality in mice in the short-term studies, dietary concentrations of roxarsone selected for the 2-year studies were 0, 50, or 100 ppm for rats and 0, 100, or 200 ppm for mice. Body Weight and Survival in the Two-Year Studies: Mean body weights of dosed rats were generally within 5% of those of controls. No significant differences in survival were observed between any groups of rats of either sex, although survival in males was lower than usual (final survival--male: control, 24/50; low dose, 18/50; high dose, 18/50; female: 27/50; 35/50; 32/50). The average feed consumption by high dose rats was 95% that of controls for males and 88% for females. The average amount of roxarsone consumed per day was approximately 2 mg/kg for low dose rats and 4 mg/kg for high dose rats. Mean body weights of high dose male mice were generally 5%-8% higher than those of the controls, whereas those of female mice were generally 6%-15% lower than those of the controls. The survival of the control group of male mice was lower than that of the low dose group after month 22; survival for females was low (final survir than that of the low dose group after month 22; survival for females was low (final survival--male: 27/50; 40/50; 33/50; female: 14/50; 18/50; 17/50). The low survival in females was due in part to utero-ovarian infection, with more than 50% of the animals in each dose group having suppurative inflammation at this site. The average daily feed consumption by dosed mice was 105%-110% that by the controls. The average amount of roxarsone consumed per day was approximately 21 or 43 mg/kg for low dose or high dose male mice and 27 or 54 mg/kg for low dose or high dose female mice. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Although the incidence of adenomas of the exocrine pancreas in high dose male rats was not statistically greater than that in the controls (control, 1/50; low dose, 1/50; high dose, 5/50), it was greater than that seen in any historical control group of male F344/N rats. The historical rate is 1/437 (0.2%) for the study laboratory and 5/1,871 (0.3%) throughout the Program. The incidences of hyperplasia were 2/50; 0/50; 3/50. No hyperplasia oradenomas were observed in the exocrine pancreas of female rats. Clitoral gland adenomas in female rats occurred with a marginally positive trend (1/44; 3/47; 6/48; P=0.049). One carcinoma was also observed in each of the groups. The incidences of adenomas or of adenomas or carcinomas (combined) in the dosed groups were not significantly different from those in the controls. This marginal effect was not considered to be related to roxarsone administration. No chemical-related increases in neoplastic or nonneoplastic lesions occurred in male or female mice. Lymphomas in female mice occurred with a negative trend; the incidences in the dosed groups were lower than that in the controls (13/50; 2/50; 3/50; P≤0.01). Genetic Toxicology: Roxarsone was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 with or without metabolic activation. Roxarsone induced trifluorothymidine (Tft) resistance in mouse lymphoma L5178Y cells in the absence of metabolic activation; it was not tested with activation. Exposure of adult male Drosophila melanogaster to roxarsone by injection or by feeding did not cause an increase in sex--linked recessive lethal mutations. Audit: The data, documents, and pathology materials from the 2-year studies of roxarsone 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 equivocal evidence of carcinogenic activity of roxarsone for male F344/N rats, as indicated by a marginally increased incidence of adenomas of the exocrine pancreas. There was no evidence of carcinogenic activity for female F344/N rats fed diets containing 50 or 100 ppm roxarsone for 2 years. There was no evidence of carcinogenic activity for male or female B6C3F1 mice fed diets containing 100 or 200 ppm roxarsone for 2 years. Synonyms: 4-hydroxy-3-nitrophenylarsonic acid; 4-hydroxy-3-nitrobenzenearsonic acid; 2-nitro-1-hydroxybenzene-4-arsonic acid; nitrophenolarsonic acid; 3-nitro-4-hydroxybenzenearsonic acid; 3-nitro-4-hydroxyphenylarsonic acid Trade Names: Ristat; Ren-O-sal; 3-nitro; 3-nitro-10; 3-nitro-20; 3-nitro-50; 3-nitro-80

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Pain among children and adolescents has been identified as an important public health problem. Most studies evaluating recurrent or chronic pain conditions among children have been limited to descriptions of pain intensity and duration. The effects of pain states and their impact on daily living have rarely been studied. The objective of this study was to investigate the impact of perceived pain on the daily lives and activities of children and adolescents. In addition, we sought to delineate self-perceived triggers of pain among children and adolescents. In this study, we (1) document the 3-month prevalence of painful conditions among children and adolescents, (2) delineate their features (location, intensity, frequency, and duration), (3) describe their consequences (restrictions and health care utilization), and (4) elucidate factors that contribute to the occurrence of pain episodes among young subjects. The study was conducted in 1 elementary school and 2 secondary schools in the district of Ostholstein, Germany. Children and adolescents, as well as their parents/guardians, were contacted through their school administrators. The teachers distributed an information leaflet, explaining the conduct and aim of the study, to the parents a few days before the official enrollment of the youths in the study. Parents of children in grades 1 to 4 of elementary school were asked to complete the pain questionnaire for their children at home, whereas children from grade 5 upward completed the questionnaire on their own during class, under the supervision of their teachers. The response rate was 80.3%. As previously stated, chronic pain was defined as any prolonged pain that lasted a minimum of 3 months or any pain that recurred throughout a minimal period of 3 months. The children and adolescents were surveyed with the Luebeck Pain-Screening Questionnaire, which was specifically designed for an epidemiologic study of the characteristics and consequences of pain among children and adolescents. The questionnaire evaluates the prevalence of pain in the preceding 3 months. The body area, frequency, intensity, and duration of pain are addressed by the questionnaire. In addition, the questionnaire inquires about the private and public consequences of pain among young subjects. Specifically, the questionnaire aims to delineate the self-perceived factors for the development and maintenance of pain and the impact of these conditions on daily life. Of the 749 children and adolescents, 622 (83%) had experienced pain during the preceding 3 months. A total of 30.8% of the children and adolescents stated that the pain had been present for >6 months. Headache (60.5%), abdominal pain (43.3%), limb pain (33.6%), and back pain (30.2) were the most prevalent pain types among the respondents. Children and adolescents with pain reported that their pain caused the following sequelae: sleep problems (53.6%), inability to pursue hobbies (53.3%), eating problems (51.1%), school absence (48.8%), and inability to meet friends (46.7%). The prevalence of restrictions in daily living attributable to pain increased with age. A total of 50.9% of children and adolescents with pain sought professional help for their conditions, and 51.5% reported the use of pain medications. The prevalence of doctor visits and medication use increased with age. Weather conditions (33%), illness (30.7%), and physical exertion (21.9%) were the most frequent self-perceived triggers for pain noted by the respondents. A total of 30.4% of study participants registered headache as the most bothersome pain, whereas 12.3% cited abdominal pain, 10.7% pain in the extremities, 8.9% back pain, and 3.9% sore throat as being most bothersome. A total of 35.2% of children and adolescents reported pain episodes occurring > or =1 time per week or even more often. Health care utilization because of pain differed among children and adolescents according to the location of pain. Children and adolescents with back pain (56.7%), limb pain (55.0%), and abdominal pain (53.3%) visited a doctor more often than did those with headache (32.5%). In contrast, children and adolescents with headache (59.2%) reported taking medication because of pain more often than did those with back pain (16.4%), limb pain (22.5%), and abdominal pain (38.0%). The prevalence of self-reported medication use and doctor visits because of pain increased significantly with age (chi2 test). The prevalence of self-reported medication use was significantly higher among girls than among boys of the same age, except between the ages of 4 and 9 years (chi2 test). The prevalence of restrictions in daily activities varied among children and adolescents with different pain locations; 51.1% of children and adolescents with abdominal pain and 43.0% with headache but only 19.4% with back pain reported having been absent from school because of pain. The prevalence of restrictions attributable to pain was significantly higher among girls than among boys of the same age, except between the ages of 4 and 9 years (chi2 test). The self-reported triggers for pain varied between girls and boys. Girls stated more often than boys that their pain was triggered by weather conditions (39% vs 25%), illness (eg, common cold or injury) (35.9% vs 23.9%), anger/disputes (20.9% vs 11.9%), family conditions (12.1% vs 5.2%), and sadness (11.9% vs 3.4%). In contrast, boys stated more often than girls that their pain was triggered by physical exertion (28% vs 17.2%). We used a logistic regression model to predict the likelihood of a child paying a visit to the doctor and/or using pain medication. Health care utilization was predicted by increasing age, greater intensity of pain, and longer duration of pain but not by the frequency of pain. We used a logistic regression model to predict restrictions in daily activities. Only the intensity of pain was predictive of the degree of restrictions in daily life attributable to pain; the duration of pain and the frequency of pain episodes had no bearing on the degree to which the daily lives of the children were restricted because of pain. More than two thirds of the respondents reported restrictions in daily living activities attributable to pain. However, 30 to 40% of children and adolescents with pain reported moderate effects of their pain on school attendance, participation in hobbies, maintenance of social contacts, appetite, and sleep, as well as increased utilization of health services because of their pain. Restrictions in daily activities in general and health care utilization because of pain increased with age. Girls > or =10 years of age reported more restrictions in daily living and used more medications for their pain than did boys of the same age. We found gender-specific differences in self-perceived triggers for pain. Pain intensity was the most robust variable for predicting functional impairment in > or =1 areas of daily life. Increasing age of the child and increasing intensity and duration of pain had effects in predicting health care utilization (visiting a doctor and/or taking medication), whereas restrictions in daily activities were predicted only by the intensity of pain. Our results underscore the relevance of pediatric pain for public health policy. Additional studies are necessary and may enhance our knowledge about pediatric pain, to enable parents, teachers, and health care professionals to assist young people with pain management, allowing the young people to intervene positively in their conditions before they become recurrent or persistent.

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Glyceryl Dilaurate, Glyceryl Diarachidate, Glyceryl Dibehenate, Glyceryl Dierucate, Glyceryl Dihydroxystearate, Glyceryl Diisopalmitate, Glyceryl Diisostearate, Glyceryl Dilinoleate, Glyceryl Dimyristate, Glyceryl Dioleate, Glyceryl Diricinoleate, Glyceryl Dipalmitate, Glyceryl Dipalmitoleate, Glyceryl Distearate, Glyceryl Palmitate Lactate, Glyceryl Stearate Citrate, Glyceryl Stearate Lactate, and Glyceryl Stearate Succinate are diacylglycerols (also known as diglycerides or glyceryl diesters) that function as skin conditioning agents - emollients in cosmetics. Only Glyceryl Dilaurate (up to 5%), Glyceryl Diisostearate (up to 43%), Glyceryl Dioleate (up to 2%), Glyceryl Distearate (up to 7%), and Glyceryl Stearate Lactate (up to 5%) are reported to be in current use. Production proceeds from fully refined vegetable oils, which are further processed using hydrogenation and fractionation techniques, and the end products are produced by reacting selected mixtures of the partly hydrogenated, partly fractionated oils and fats with vegetable-derived glycerine to yield partial glycerides. In the final stage of the production process, the products are purified by deodorization, which effectively removes pesticide residues and lower boiling residues such as residues of halogenated solvents and aromatic solvents. Diglycerides have been approved by the Food and Drug Administration (FDA) for use as indirect food additives. Nominally, these ingredients are 1,3-diglycerides, but are easily isomerized to the 1,2-diglycerides form. The 1,3-diglyceride isomer is not a significant toxicant in acute, short-term, subchronic, or chronic animal tests. Glyceryl Dilaurate was a mild primary irritant in albino rabbits, but not a skin sensitizer in guinea pig maximization tests. Diacylglycerol Oil was not genotoxic in the Ames test, in mammalian Chinese hamster lung cells, or in a rodent bone marrow micronucleus assay. An eye shadow containing 1.5% Glyceryl Dilaurate did not induce skin irritation in a single insult patch test, but mild skin irritation reactions to a foundation containing the same concentration were observed. A trade mixture containing an unspecified concentration of Glyceryl Dibehenate did not induce irritation or significant cutaneous intolerance in a 48-h occlusive patch test. In maximization tests, neither an eye shadow nor a foundation containing 1.5% Glyceryl Dilaurate was a skin sensitizer. Sensitization was not induced in subjects patch tested with 50% w/w Glyceryl Dioleate in a repeated insult, occlusive patch test. Glyceryl Palmitate Lactate (50% w/v) did not induce skin irritation or sensitization in subjects patch tested in a repeat-insult patch test. Phototoxicity or photoallergenicity was not induced in healthy volunteers tested with a lipstick containing 1.0% Glyceryl Rosinate. Two diacylglycerols, 1-oleoyl-2-acetoyl-sn-glycerol and 1,2-dipalmitoyl-sn-glycerol, did not alter cell proliferation (as determined by DNA synthesis) in normal human dermal fibroblasts in vitro at doses up to 10 microg/ml. In the absence of initiation, Glyceryl Distearate induced a moderate hyperplastic response in randomly bred mice of a tumor-resistant strain, and with 9,10-dimethyl-1,2-benzanthracene (DMBA) initiation, an increase in the total cell count was observed. In a glyceryl monoester study, a single application of DMBA to the skin followed by 5% Glyceryl Stearate twice weekly produced no tumors, but slight epidermal hyperplasia at the site of application. Glyceryl Dioleate induced transformation in 3-methylcholanthrene-initiated BALB/3T3 A31-1-1 cloned cells in vitro. A tumor-promoting dosing regimen that consisted of multiple applications of 10 mumol of a 1,2-diacylglycerol (sn-1,2-didecanoylglycerol) to female mice twice daily for 1 week caused more than a 60% decrease in protein kinase C (PKC) activity and marked epidermal hyperplasia. Applications of 10 micromol sn-1,2-didecanoylglycerol twice weekly for 1 week caused a decrease in cytosolic PKC activity, an increase in particulate PKC activity, and no epidermal hyperplasia. In studies of the tumor-promoting activity of 1,2-diacylglycerols, dose and the exposure regimen by which the dose is delivered play a role in tumor promotion. The 1,2-diacylglycerol-induced activation of PKC may also relate to the saturation of the fatty acid in the 1 or 2 position; 1,2-Diacylglycerols with two saturated fatty acids are less effective. Also, the activity of 1,2-diacylglycerols may be reduced when the fatty acid moiety in the structure is a long-chain fatty acid. A histological evaluation was performed on human skin from female volunteers (18 to 56 years old) who had applied a prototype lotion or placebo formulation, both containing 0.5% Glyceryl Dilaurate, consecutively for 16 weeks or 21 weeks. Skin irritation was not observed in any of the subjects tested. Biopsies (2 mm) taken from both legs of five subjects indicated no recognizable abnormalities of the skin; the epidermis was normal in thickness, and there was no evidence of scaling, inflammation, or neoplasms in any of the tissues that were evaluated. The Cosmetic Ingredient Review (CIR) Expert Panel considered that the available safety test data indicate that diglycerides in the 1,3-diester form do not present any significant acute toxicity risk, nor are these ingredients irritating, sensitizing, or photosensitizing. Whereas no data are available regarding reproductive or developmental toxicity, there is no reason to suspect any such toxicity because the dermal absorption of these chemicals is negligible. The Panel noted that these nominally 1,3-diglycerides contain 1,2-diglycerides, raising the concern that 1,2-diglycerides could potentially induce hyperplasia. Data regarding the induction of PKC and the tumor promotion potential of 1,2-diacylglycerols increased the level of concern. Most of the diglycerides considered in this safety assessment, however, have fatty acid chains longer than 14 carbons and none have mixed saturated/unsaturated fatty acid moieties. The Panel considered it particularly important that a 21-week use study of a prototype lotion containing 0.5% Glyceryl Dilaurate (a 14-carbon chain fatty acid) indicated no evidence of scaling, inflammation, or neoplasms in biopsy specimens. Also, DNA synthesis assays on Glyceryl Dilaurate and Glyceryl Distearate indicated that neither chemical altered cell proliferation (as determined by DNA synthesis) in normal human dermal fibroblasts in vitro at doses up to 10 microg/ml. The Panel understands that use testing is a common practice in industry and, if histopathology data are collected, the Panel believes that such an approach can demonstrate an absence of epidermal hyperplasia. Because the concentration of these ingredients can vary (up to 43% for Glyceryl Diisostearate in lipstick), the frequency of application can be several times daily, and the proportion of diglycerides that are inactive 1,3 isomers versus potentially biologically active 1,2 isomers is unknown, the Panel believes that each use should be examined to ensure the absence of epidermal hyperplasia during product development and testing. In the absence of inhalation toxicity data on the Glyceryl Diesters in this safety assessment, the Panel determined that these ingredients can be used safely in aerosolized products because they are not respirable. The Panel recognizes that certain ingredients in this group are reportedly used in a given product category, but the concentration of use is not available. For other ingredients in this group, information regarding use concentration for specific product categories is provided, but the number of such products is not known. In still other cases, an ingredient is not in current use, but may be used in the future. Although there are gaps in knowledge about product use, the overall information available on the types of products in which these ingredients are used and at what concentration indicate a pattern of use. Within this overall pattern of use, the CIR Expert Panel considers all ingredients in this group to be safe.

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The aim of this review was to assess the clinical utility of portable bladder ultrasound. TARGET POPULATION AND CONDITION Data from the National Population Health Survey indicate prevalence rates of urinary incontinence are 2.5% in women and 1.4 % in men in the general population. Prevalence of urinary incontinence is higher in women than men and prevalence increases with age. Identified risk factors for urinary incontinence include female gender, increasing age, urinary tract infections (UTI), poor mobility, dementia, smoking, obesity, consuming alcohol and caffeine beverages, physical activity, pregnancy, childbirth, forceps and vacuum-assisted births, episiotomy, abdominal resection for colorectal cancer, and hormone replacement therapy. For the purposes of this review, incontinence populations will be stratified into the following; the elderly, urology patients, postoperative patients, rehabilitation settings, and neurogenic bladder populations. Urinary incontinence is defined as any involuntary leakage of urine. Incontinence can be classified into diagnostic clinical types that are useful in planning evaluation and treatment. The major types of incontinence are stress (physical exertion), urge (overactive bladder), mixed (combined urge and stress urinary incontinence), reflex (neurological impairment of the central nervous system), overflow (leakage due to full bladder), continuous (urinary tract abnormalities), congenital incontinence, and transient incontinence (temporary incontinence). Postvoid residual (PVR) urine volume, which is the amount of urine in the bladder immediately after urination, represents an important component in continence assessment and bladder management to provide quantitative feedback to the patient and continence care team regarding the effectiveness of the voiding technique. Although there is no standardized definition of normal PVR urine volume, measurements greater than 100 mL to 150 mL are considered an indication for urinary retention, requiring intermittent catheterization, whereas a PVR urine volume of 100 mL to 150 mL or less is generally considered an acceptable result of bladder training. Urinary retention has been associated with poor outcomes including UTI, bladder overdistension, and higher hospital mortality rates. The standard method of determining PVR urine volumes is intermittent catheterization, which is associated with increased risk of UTI, urethral trauma and discomfort. Portable bladder ultrasound products are transportable ultrasound devices that use automated technology to register bladder volume digitally, including PVR volume, and provide three-dimensional images of the bladder. The main clinical use of portable bladder ultrasound is as a diagnostic aid. Health care professionals (primarily nurses) administer the device to measure PVR volume and prevent unnecessary catheterization. An adjunctive use of the bladder ultrasound device is to visualize the placement and removal of catheters. Also, portable bladder ultrasound products may improve the diagnosis and differentiation of urological problems and their management and treatment, including the establishment of voiding schedules, study of bladder biofeedback, fewer UTIs, and monitoring of potential urinary incontinence after surgery or trauma. To determine the effectiveness and clinical utility of portable bladder ultrasound as reported in the published literature, the Medical Advisory Secretariat used its standard search strategy to retrieve international health technology assessments and English-language journal articles from selected databases. Nonsystematic reviews, nonhuman studies, case reports, letters, editorials, and comments were excluded. Of the 4 included studies that examined the clinical utility of portable bladder ultrasound in the elderly population, all found the device to be acceptable. One study reported that the device underestimated catheterized bladder volume In patients with urology problems, 2 of the 3 studies concerning portable bladder ultrasound found the device acceptable to use. However, one study did not find the device as accurate for small PVR volume as for catheterization and another found that the device overestimated catheterized bladder volume. In the remaining study, the authors reported that when the device's hand-held ultrasound transducers (scanheads) were aimed improperly, bladders were missed, or lateral borders of bladders were missed resulting in partial bladder volume measurements and underestimation of PVR measurements. They concluded that caution should be used in interpreting PVR volume measured by portable bladder ultrasound machines and that catheterization may be the preferred assessment modality if an accurate PVR measurement is necessary. All 3 studies with post-operative populations found portable bladder ultrasound use to be reasonably acceptable. Two studies reported that the device overestimated catheter-derived bladder volumes, one by 7% and the other by 21 mL. The third study reported the opposite, that the device underestimated catheter bladder volume by 39 mL but that the results remained acceptable In rehabilitation settings, 2 studies found portable bladder ultrasound to underestimate catheter-derived bladder volumes; yet, both authors concluded that the mean errors were within acceptable limits. In patients with neurogenic bladder problems, 2 studies found portable bladder ultrasound to be an acceptable alternative to catheterization despite the fact that it was not as accurate as catheterization for obtaining bladder volumes. Lastly, examinations concerning avoidance of negative health outcomes showed that, after use of the portable bladder ultrasound, unnecessary catheterizations and UTIs were decreased. Unnecessary catheterizations avoided ranged from 16% to 47% in the selected articles. Reductions in UTI ranged from 38% to 72%. In sum, all but one study advocated the use of portable bladder ultrasound as an alternative to catheterization. An economic analysis estimating the budget-impact of BladderScan in complex continuing care facilities was completed. The analysis results indicated a $192,499 (Cdn) cost-savings per year per facility and a cost-savings of $2,887,485 (Cdn) for all 15 CCC facilities. No economic analysis was completed for long-term care and acute care facilities due to lack of data. Rapid diffusion of portable bladder ultrasound technology is expected. Recently, the IC5 project on improving continence care in Ontario's complex continuing care centres piloted portable bladder ultrasound at 12 sites. Preliminary results were promising. Many physicians and health care facilities already have portable bladder ultrasound devices. However, portable bladder ultrasound devices for PVR measurement are not in use at most health care facilities in Ontario and Canada. The Verathon Corporation (Bothell, Wisconsin, United States), which patents BladderScan, is the sole licensed manufacturer of the portable bladder ultrasound in Canada. Field monopoly may influence the rising costs of portable bladder ultrasound, particularly when faced with rapid expansion of the technology. Several thousand residents of Ontario would benefit from portable bladder ultrasound. The number of residents of Ontario that would benefit from the technology is difficult to quantify, because the incidence and prevalence of incontinence are grossly under-reported. However, long-term care and complex continuing care institutions would benefit greatly from portable bladder ultrasound, as would numerous rehabilitation units, postsurgical care units, and urology clinics. The cost of the portable bladder ultrasound devices ranges from $17,698.90 to $19,565.95 (Cdn) (total purchase price per unit as quoted by the manufacturer). Additional training packages, batteries and battery chargers, software, gel pads, and yearly warranties are additional costs. Studies indicate that portable bladder ultrasound is a cost-effective technology, because it avoids costs associated with catheterization equipment, saves nursing time, and reduces catheter-related complications and UTIs. The use of portable bladder ultrasound device will affect the patient directly in terms of health outcomes. Its use avoids the trauma related to the urinary tract that catheterization inflicts, and does not result in UTIs. In addition, patients prefer it, because it preserves dignity and reduces discomfort.

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Previous studies have examined changes in heart rate variability (HRV*) and repolarization associated with increased particulate matter (PM) concentrations on the same and previous few days. However, few studies have examined whether these health responses to PM occur within a few hours or even less. Moreover, it is not clear whether exposure of subjects to ambient or-controlled PM concentrations both lead to similar health effects or whether any of the subjects' individual characteristics modify any of their responses to PM. The aims of the cur- rent study were to investigate whether exposure to PM was associated with rapid changes (< 60 minutes or con- current hour up to a delay of 6 hours) in markers of car- diac rhythni or changes in total antioxidant capacity (a marker of protection against oxidative stress) and whether any PM effects on cardiac rhythm markers were modified by total antioxidant capacity, age, obesity, smoking, hypertension, exertion, prior myocardial infarction (MI), or medication. We obtained data from a completed study in Augsburg, Germany (a panel study in N= 109 subjects, including a group with type 2 diabetes or impaired glucose tolerance [IGT; also known as prediabetes]) and a group of other- wise healthy subjects with a potential genetic susceptibil- ity to detoxifying and inflammatory pathways (Hampel et al. 2012b), as well as three completed studies in Rochester, New York (the REHAB panel study of N= 76 postinfarction patients in a cardiac rehabilitation pro- gram [Rich et al. 2012b]; the UPDIABETES study of con- trolled exposure to ultrafine particles [UFPs, particles with an aerodynamic diameter < 100 nm] of N = 19 patients with type 2 diabetes [Stewart et al. 2010; Vora et al. 2014j; and the UPCON controlled-exposure study of concentrated UFP exposure in N = 20 young, healthy, life- time nonsmokers). Data included 5-minute and 1-hour values for HRV and repolarization parameters from elec- trocardiogram (ECG) recordings and total antioxidant capacity measured in stored blood samples. Ambient con- centrations of UFPs, accumulation-mode particles (AMP, particles with an aerodynamic diameter of 100-500 nm), fine PM (PM2.5, particles with an aerodynamic diameter 2.5 pm), and black carbon (BC) were also available. We first conducted factor analyses in each study to find subgroups of correlated ECG outcomes and to reduce the number of outcomes examined in our statistical models. We then restricted the statistical analyses to the factors and representative.outcomes that were common to all four studies, including total HRV (measured as the standard deviation of normal-to-normal [NN] beat intervals [SDNNj), parasympathetic modulation (measured as the root mean square of the successive differences [RMSSD between adjacent NN beat intervals), and T-wave morphol- ogy (measured as T-wave complexity). Next, we used addi- tive mixed models to estimate the change in each outcome associated with increased pollutant concentrations in the . concurrent and previous 6 hours and with 5-minute inter- vals up to the previous 60 minutes, accounting for the correlation of repeated outcome measures for each subject and adjusting for time trend, hour of the day, temperature, relative humidity, day of the week, month, and visit number. Because multiple comparisons were an issue in our. analyses, we used a discovery-and-replication approach to draw conclusions across studies for each research question. In the Augsburg study, interquartile range (IQR) increases in UFP concentrations lagged 2 to 5 hours were associated with 1%-3% decreases in SDNN (e.g., lagged 3 hours in the group with a genetic susceptibility: -2.26%; 95% confidence interval [CI], -3.98% to -0.53%). In the REHAB study, similarly, IQR increases in UFP concentra- tions in the previous 5 hours were associated with < 3% decreases in SDNN (e.g., lagged 1 hour: -2.69%; 95% CI, -5.13% to -0.26%). We also found decreases in SDNN associated with IQR increases in total particle count-(a surrogate for UFP) in the UPDIABETES study (lagged 1 hour: -13.22%; 95% CI, -24.11% to -2.33%) but not in the UPCON study. In the Augsburg study, IQR increases in PM2.5 concen- trations in the concurrent hour and lagged 1-5 hours, AMP concentrations lagged 1 and 3 hours, and BC con- centrations lagged 1-5 hours were associated with -1%-5% decreases in SDNN (e.g., PM2.5 lagged 2 hours in the group with diabetes or IGT: -4.59%; 95% CI, -7.44% to -1.75%). In the REHAB study, IQR increases in PM2.5 concentrations lagged 5 and 6 hours and AMP concentra- tions in the concurrent hour and lagged up to 5 hours were associated with 1%-2% decreases in SDNN (e.g., PM2.5 lagged 4 hours: -2.13%; 95% CI, -3.91% to -0.35%). In the Augsburg study, IQR increases in PM2.5 concen- trations in the concurrent hour and BC lagged 1 and 6 hours were associated with 3%-7% decreases in RMSSD (e.g., PM2.5 concurrent hour in the group with diabetes or IGT: -7.20%; 95% CI, -12.11% to -2.02%). In the REHAB study, similarly, increases in PM2.5 concen- trations lagged 4 to 6 hours-though not AMP or BC con- centrations at any lag hour-were associated with -2.5%-3.5% decreases in RMSSD (e.g., PM2.5 lagged 5 hours: -3.49%; 95% CI, -6.13% to -0.84%). We did not find consistent evidence of any pollutant effects on T-wave complexity in 1-hour recordings. For 5-minute record- ings, there was no consistent evidence of UFP effects on SDNN, RMSSD, or T-wave complexity at any 5-minute interval within 60 minutes. We further concluded that these replicated hourly effects of UFP and PM2.5 on short-term measures of SDNN and RMSSD generally did not differ between the groups in the studies (i.e., type 2 diabetes, pre-diabetes/IGT, post- infarction, and healthy subjects). Last, we found no con- sistent evidence of effects of any pollutant on total anti- oxidant capacity and no consistent evidence of modification of our PM2.5-outcome associations by any of the potential effect modifiers. Increased UFP concentrations were associated with decreased SDNN in both of the panel studies and one of the two controlled-exposure studies. We also found that decreased SDNN was associated with both increased PM2.5 and AMP concentrations in the previous 6 hours in the panel studies and that decreased RMSSD was associ- ated with increased PM2.5 concentrations in the previous 6 hours in the panel studies. We therefore concluded that the research questions were replicated. Our findings suggest that both UFPs and PM2.5 are associated with autonomic dysfunction within hours of exposure, which may in part. explain the previously reported risk of acute cardiovascular events associated with increased PM in the previous few hours. Despite the heterogeneity of the study populations,and protocols, our findings provided consistent evidence for the induction of rapid pathophysiological responses by UFPs and PM2.5- The absence of consistent associations between UFPs, PM2.5, and these outcomes when examining shorter time intervals indicates that the 5- to 60-minute responses may be less pronounced than the responses occurring within hours. However, the findings from the 5-minute intervals may have been affected by the variety of proto- cols and conditions from study to study as well as by the potential effects of underlying diseases (e.g., healthy indi- viduals versus individuals with diabetes or a recent cor- onary artery. event), physical activity, circadian rhythms, stress, and/or medications.

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The semisynthetic ergotine dopamine agonist pergolide has demonstrated activity at pre- and postsynaptic dopamine D2 receptors in vitro and in vivo animal studies. However, unlike other dopamine agonists such as bromocriptine, pergolide also has agonist activity at dopamine D1 receptors. Certain other pharmacological effects of pergolide, such as reduction of dopamine turnover and effects on free radical scavenging enzymes, may be relevant in the early treatment of Parkinson's disease but this has not been conclusively determined. Short and long term noncomparative studies show that pergolide is an effective adjunct to levodopa therapy in patients with advancing Parkinson's disease, reducing the adverse effects of long term levodopa monotherapy and often enabling a reduction in levodopa dosage. In placebo comparisons pergolide was generally more effective than placebo and was associated with benefits similar to those seen in noncomparative studies. Longitudinal comparisons in individual patients indicate that the antiparkinsonian efficacy of pergolide is similar to that of mesulergine, lergotrile and lisuride, and may be superior to that of bromocriptine. Controlled comparisons with bromocriptine tend to support this latter finding. Studies evaluating the efficacy of pergolide as monotherapy early in the course of Parkinson's disease have shown the drug to be effective, but opinion is divided as to the value of early treatment with dopamine agonists (as opposed to levodopa monotherapy). Thus, pergolide is an effective adjunct to levodopa therapy in patients with advanced Parkinson's disease and may have a role in the treatment of early disease if its postulated beneficial effects on disease progression are proven. Pergolide is a semisynthetic ergoline dopamine agonist used in the treatment of Parkinson's disease. It has potent activity at presynaptic dopamine D2 receptors but is also active at postsynaptic D2 and dopamine D1 receptors. In vitro, pergolide suppressed D2-mediated prolactin release from rat anterior pituitary fragments and inhibited potassium-mediated dopamine or acetylcholine release from rat caudate slices. Pergolide-induced activation of rat striatal D1 receptors has been shown to stimulate adenylate cyclase activity which, in turn, increased production of cyclic AMP. The majority of receptor binding studies indicate that pergolide is considerably more selective for D2 than for D1 receptors. In vivo, pergolide has been shown to induce contralateral turning in rats with right-side nigrostriatal lesions; it also induced climbing in rats selected on the basis of a climbing response to apomorphine. Pergolide had similar actions to those of selective D2 agonists in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced hemiparkinsonian monkeys but was more potent than selective D1 agonists. Pergolide improved parkinsonian symptoms in another study in this model. Its effects were more marked, but of shorter duration, than those of bromocriptine or cabergoline. One theory regarding the cause of Parkinson's disease is that metabolism of dopamine produces free radicals which damage nigral neurons. Its effects on oxygen radical scavenging enzymes are unclear; the drug induced Superoxide dismutase in one in vivo animal study but had no effect in another (but did induce catalase and glutathione peroxidase). Single 1, 2, 5 and 10mg doses of pergolide produced mean peak plasma concentrations (Cmax) of 2.09, 4.57, 20.3 and 26 μg/L, respectively, in rhesus monkeys (administration of therapeutic doses to volunteers was considered unethical). The time to Cmax ranged between 2.4 and 2.7 hours at all dose levels. Mean steady-state pergolide plasma concentrations of 0.0275 to 1.167 μg/L were recorded during treatment with pergolide 2.25 to 9 mg/day in patients with Parkinson's disease; extensive interpatient variability was noted. 55% of a 0.138mg radiolabelled oral dose of pergolide was excreted in the urine of volunteers; a further 40 to 50% of radioactivity appeared in the faeces and approximately 3% appeared in expired air. Analysis of urine and faecal extracts indicated the formation of 10 or more metabolites. A large noncomparative Japanese study has evaluated the short term efficacy of pergolide in combination with levodopa ± carbidopa (n = 314) or as monotherapy (n = 86). Addition of pergolide allowed a significant reduction in levodopa dosage and about 65% of patients experienced at least a mild improvement in wearing off and on-off phenomena. 45.3% of monotherapy recipients experienced at least moderate improvement according to a final global rating scale (vs 52.9% of combination therapy recipients). Additional noncomparative studies in Australian, Thai, Chinese and Italian patients also reported adjunctive pergolide therapy to be effective. Early noncomparative long term studies reported an initial response to pergolide but the rate of clinical improvement tended to peak after 2 to 12 months, then decline. However, it does appear that the efficacy of pergolide, despite waning, can be maintained at a satisfactory level for several years. A long term continuation of the Japanese study discussed above reported a final global improvement rate that was at least moderate in 51.4% of adjunctive pergolide therapy recipients treated for at least 1 year, although the drug tended to become less effective after this time. 62 monotherapy recipients were included in this long term continuation; final global improvement rates were similar (moderate or greater in 61.3% of monotherapy recipients vs 51.4% in the combination therapy group). Results from a large 6-month multicentre double-blind placebo comparison have confirmed the result of earlier, smaller placebo comparisons. Pergolide recipients (n = 189) experienced a significantly greater improvement in many subjective measures of disease severity than placebo recipients. Pergolide allowed a 24.7% reduction in levodopa dosage compared with an approximate 5% reduction with placebo. On the basis of longitudinal sequential comparisons in individual patients, pergolide was considered to have similar utility to mesulergine, lergotrile and lisuride and appeared to be more effective than bromocriptine. In addition, a number of controlled studies reported that although both drugs were useful, pergolide tended to allow a greater reduction in levodopa dosage than bromocriptine. The sole available comparison of pergolide and bromocriptine as monotherapy reported the 2 drugs to be similarly effective. Postural hypotension occurs quite frequently in patients starting pergolide therapy but usually diminishes over time. In a recent placebo comparison, adverse events occurring significantly more frequently in pergolide recipients included dyskinesia (62% in the pergolide group vs 25% in placebo recipients), nausea (24 vs 13%), hallucinations (14 vs 3%), drowsiness (10 vs 3%), insomnia (8 vs 3%), nasal congestion (7 vs 1%), dyspepsia (6 vs 2%) and dyspnoea (5 vs 1%). ECG changes and palpitations have been noted in some patients receiving pergolide during clinical trials and close observation may be needed in patients with concomitant heart disease; limited data indicate that addition of domperidone attenuates these cardiac adverse events. Rarely, abrupt withdrawal of pergolide therapy can cause confusion or hallucinations; thus, when required, cessation of pergolide therapy should be gradual. To avoid first dose hypotension and other adverse effects such as nausea and vomiting, pergolide therapy must be initiated at a low dosage (often 0.05 mg/day for 2 days). The dose should be slowly increased until maximum clinical benefit is achieved with no or minimal adverse effects. The drug is administered in divided doses, usually 3 or 4 times per day, and the most frequent effective total daily dose is 3 to 4mg; however, mean effective dosages were somewhat lower in Japanese studies.

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Since the first U.S. infant conceived with assisted reproductive technology (ART) was born in 1981, both the use of ART and the number of fertility clinics providing ART services have increased steadily in the United States. ART includes fertility treatments in which eggs or embryos are handled in the laboratory (i.e., in vitro fertilization [IVF] and related procedures). Women who undergo ART procedures are more likely than women who conceive naturally to deliver multiple-birth infants. Multiple births pose substantial risks to both mothers and infants, including obstetric complications, preterm delivery, and low birthweight infants. This report provides state-specific information for the United States (including the District of Columbia and Puerto Rico) on ART procedures performed in 2014 and compares birth outcomes that occurred in 2014 (resulting from ART procedures performed in 2013 and 2014) with outcomes for all infants born in the United States in 2014. 2014. In 1996, CDC began collecting data on ART procedures performed in fertility clinics in the United States as mandated by the Fertility Clinic Success Rate and Certification Act of 1992 (FCSRCA) (Public Law 102-493). Data are collected through the National ART Surveillance System (NASS), a web-based data collection system developed by CDC. This report includes data from 52 reporting areas (the 50 states, the District of Columbia, and Puerto Rico). In 2014, a total of 169,568 ART procedures (range: 124 in Wyoming to 21,018 in California) with the intent to transfer at least one embryo were performed in 458 U.S. fertility clinics and reported to CDC. These procedures resulted in 56,028 live-birth deliveries (range: 52 in Wyoming to 7,230 in California) and 68,782 infants born (range: 64 in Wyoming to 8,793 in California). Nationally, the total number of ART procedures performed per million women of reproductive age (15-44 years), a proxy measure of the ART usage rate, was 2,647 (range: 364 in Puerto Rico to 6,726 in Massachusetts). ART use exceeded the national average in 13 reporting areas (Connecticut, Delaware, the District of Columbia, Hawaii, Illinois, Maryland, Massachusetts, New Hampshire, New Jersey, New York, Pennsylvania, Rhode Island, and Virginia). Eight reporting areas (Connecticut, the District of Columbia, Hawaii, Illinois, Maryland, Massachusetts, New Jersey, and New York) had rates of ART use exceeding 1.5 times the national average. Nationally, among ART transfer procedures in patients using fresh embryos from their own eggs, the average number of embryos transferred increased with increasing age of the woman (1.7 among women aged <35 years, 1.9 among women aged 35-37 years, and 2.3 among women aged >37 years). Among women aged <35 years, who typically are considered to be good candidates for elective single embryo transfer (eSET) procedures, the national eSET rate was 28.5% (range: 4.3% in Puerto Rico to 67.9% in Delaware). In 2014, ART contributed to 1.6% of all infants born in the United States (range: 0.4% in Puerto Rico to 4.7% in Massachusetts) and 18.3% of all multiple-birth infants (range: 5.5% in Alaska and West Virginia to 37.3% in Hawaii), including 18.0% of all twin infants (range: 5.2% in some states to 36.2% in Hawaii) and 26.4% of all triplets and higher-order infants (range: 0% in some states to 65.2% in Hawaii). Percentages of live births that were multiple-birth deliveries were higher among infants conceived with ART (39.4%; range: 11.5% in Delaware to 55.6% in Puerto Rico) than among all infants born in the total birth population (3.5%; range: 2.2% in Puerto Rico to 4.4% in New Jersey). Approximately 38.0% of ART-conceived infants were twin infants, and 2.0% were triplets and higher-order infants. ART-conceived twins accounted for approximately 95.3% of all ART-conceived infants born in multiple deliveries. Nationally, infants conceived with ART contributed to 5.5% of all low birthweight (<2,500 g) infants (range: 1.2% in West Virginia to 14.2% in Massachusetts). Among ART-conceived infants, 27.8% were low birthweight (range: 10.6% in Delaware to 44.4% in Puerto Rico), compared with 8.0% among all infants (range: 5.9% in Alaska to 11.3% in Mississippi). ART-conceived infants contributed to 4.7% of all preterm (<37 weeks) infants (range: 1.2% in Puerto Rico to 13.4% in Massachusetts). Percentages of preterm births were higher among infants conceived with ART (33.2%; range: 18.9% in the District of Columbia to 45.9% in Puerto Rico) than among all infants born in the total birth population (11.3%; range: 8.5% in California to 16.0% in Mississippi). The percentage of ART-conceived infants who were low birthweight was 8.9% (range: 3.2% in some states to 16.1% in Vermont) among singletons and 55.2% (range: 38.5% in Delaware to 77.8% in Alaska) among twins; the corresponding percentages of low birthweight infants among all infants born were 6.3% for singletons (range: 4.6% in Alaska, North Dakota, and Oregon to 9.5% in Puerto Rico) and 55.2% for twins (range: 46.1% in Alaska to 65.6% in Mississippi). The percentage of ART-conceived infants who were preterm was 13.2% (range: 7.5% in Rhode Island to 23.4% in West Virginia) among singletons and 62.2% (range: 33.3% in some states to 81.4% in Mississippi) among twins; the corresponding percentages of preterm infants among all infants were 9.7% for singletons (range: 1.7% in the District of Columbia to 14.2% in Mississippi) and 56.6% for twins (range: 47.2% in Vermont to 66.9% in Wyoming). The percentage of infants conceived with ART varied considerably by reporting area. Multiple births from ART contributed to a substantial proportion of all twins, triplets, and higher-order infants born. Low birthweight and preterm infant birth rates were disproportionately higher among ART-conceived infants than among the overall birth population. Although women aged <35 years are typically considered good candidates for eSET, on average two embryos were transferred per ART procedure with women in this group. Compared with ART-conceived singletons, ART-conceived twins were approximately five times more likely to be born preterm and approximately six times more likely to be born with low birthweight. Singleton infants conceived with ART had higher percentages of preterm birth and low birthweight than all singleton infants born in the United States. ART use per population unit was geographically variable, with 13 reporting areas showing ART use higher than the national rate. Of the four states (Illinois, Massachusetts, New Jersey, and Rhode Island) with comprehensive statewide-mandated health insurance coverage for ART procedures (i.e., coverage for at least four cycles of IVF), three (Illinois, Massachusetts, and New Jersey) had rates of ART use exceeding 1.5 times the national rate. This type of mandated insurance has been associated with greater use of ART and likely accounts for some of the difference in per capita ART use observed among states. Reducing the number of embryos transferred and increasing use of eSET when clinically appropriate could help reduce multiple births and related adverse health consequences. Because twins account for the majority of ART-conceived multiple births, improved provider practices and patient education and counseling on the maternal and infant health risks of having twins are needed. Although ART contributes to high percentages of multiple births, other factors not investigated in this report (e.g., delayed childbearing and use of non-ART fertility treatments) also contribute to multiple births and warrant further study.

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In July 2009, the Medical Advisory Secretariat (MAS) began work on Non-Invasive Cardiac Imaging Technologies for the Diagnosis of Coronary Artery Disease (CAD), an evidence-based review of the literature surrounding different cardiac imaging modalities to ensure that appropriate technologies are accessed by patients suspected of having CAD. This project came about when the Health Services Branch at the Ministry of Health and Long-Term Care asked MAS to provide an evidentiary platform on effectiveness and cost-effectiveness of non-invasive cardiac imaging modalities.After an initial review of the strategy and consultation with experts, MAS identified five key non-invasive cardiac imaging technologies for the diagnosis of CAD. Evidence-based analyses have been prepared for each of these five imaging modalities: cardiac magnetic resonance imaging, single photon emission computed tomography, 64-slice computed tomographic angiography, stress echocardiography, and stress echocardiography with contrast. For each technology, an economic analysis was also completed (where appropriate). A summary decision analytic model was then developed to encapsulate the data from each of these reports (available on the OHTAC and MAS website).The Non-Invasive Cardiac Imaging Technologies for the Diagnosis of Coronary Artery Disease series is made up of the following reports, which can be publicly accessed at the MAS website at: www.health.gov.on.ca/mas or at www.health.gov.on.ca/english/providers/program/mas/mas_about.htmlSINGLE PHOTON EMISSION COMPUTED TOMOGRAPHY FOR THE DIAGNOSIS OF CORONARY ARTERY DISEASE: An Evidence-Based AnalysisSTRESS ECHOCARDIOGRAPHY FOR THE DIAGNOSIS OF CORONARY ARTERY DISEASE: An Evidence-Based AnalysisSTRESS ECHOCARDIOGRAPHY WITH CONTRAST FOR THE DIAGNOSIS OF CORONARY ARTERY DISEASE: An Evidence-Based Analysis64-Slice Computed Tomographic Angiography for the Diagnosis of Coronary Artery Disease: An Evidence-Based AnalysisCARDIAC MAGNETIC RESONANCE IMAGING FOR THE DIAGNOSIS OF CORONARY ARTERY DISEASE: An Evidence-Based AnalysisPease note that two related evidence-based analyses of non-invasive cardiac imaging technologies for the assessment of myocardial viability are also available on the MAS website:POSITRON EMISSION TOMOGRAPHY FOR THE ASSESSMENT OF MYOCARDIAL VIABILITY: An Evidence-Based AnalysisMAGNETIC RESONANCE IMAGING FOR THE ASSESSMENT OF MYOCARDIAL VIABILITY: an Evidence-Based AnalysisThe Toronto Health Economics and Technology Assessment Collaborative has also produced an associated economic report entitled:The Relative Cost-effectiveness of Five Non-invasive Cardiac Imaging Technologies for Diagnosing Coronary Artery Disease in Ontario [Internet]. Available from: http://theta.utoronto.ca/reports/?id=7 OBJECTIVE: The objective of this analysis was to determine the diagnostic accuracy of cardiac magnetic resonance imaging (MRI) for the diagnosis of patients with known/suspected coronary artery disease (CAD) compared to coronary angiography. Stress cardiac MRI is a non-invasive, x-ray free imaging technique that takes approximately 30 to 45 minutes to complete and can be performed using to two different methods, a) perfusion imaging following a first pass of an intravenous bolus of gadolinium contrast, or b) wall motion imaging. Stress is induced pharmacologically with either dobutamine, dipyridamole, or adenosine, as physical exercise is difficult to perform within the magnet bore and often induces motion artifacts. Alternatives to stress cardiac perfusion MRI include stress single-photon emission computed tomography (SPECT) and stress echocardiography (ECHO). The advantage of cardiac MRI is that it does not pose the radiation burden associated with SPECT. During the same sitting, cardiac MRI can also assess left and right ventricular dimensions, viability, and cardiac mass. It may also mitigate the need for invasive diagnostic coronary angiography in patients with intermediate risk factors for CAD. EVIDENCE-BASED ANALYSIS: A literature search was performed on October 9, 2009 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 2005 to October 9, 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 relevant studies not identified through the search. Articles with unknown eligibility were reviewed with a second clinical epidemiologist and 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. Given the large amount of clinical heterogeneity of the articles meeting the inclusion criteria, as well as suggestions from an Expert Advisory Panel Meeting held on October 5, 2009, the inclusion criteria were revised to examine the effectiveness of cardiac MRI for the detection of CAD. Inclusion CriteriaExclusion CriteriaHeath technology assessments, systematic reviews, randomized controlled trials, observational studies≥20 adult patients enrolled.Published 2004-2009Licensed by Health CanadaFor diagnosis of CAD:Reference standard is coronary angiographySignificant CAD defined as ≥ 50% coronary stenosisPatients with suspected or known CADReported results by patient, not segmentNon-English studiesGrey literaturePlanar imagingMUGAPatients with recent MI (i.e., within 1 month)Patients with non-ischemic heart diseaseStudies done exclusively in special populations (e.g., women, diabetics) Sensitivity and specificityArea under the curve (AUC)Diagnostic odds ratio (DOR) SUMMARY OF FINDINGS: Stress cardiac MRI using perfusion analysis yielded a pooled sensitivity of 0.91 (95% CI: 0.89 to 0.92) and specificity of 0.79 (95% CI: 0.76 to 0.82) for the detection of CAD.Stress cardiac MRI using wall motion analysis yielded a pooled sensitivity of 0.81 (95% CI: 0.77 to 0.84) and specificity of 0.85 (95% CI: 0.81 to 0.89) for the detection of CAD.Based on DORs, there was no significant difference between pooled stress cardiac MRI using perfusion analysis and pooled stress cardiac MRI using wall motion analysis (P=0.26) for the detection of CAD.Pooled subgroup analysis of stress cardiac MRI using perfusion analysis showed no significant difference in the DORs between 1.5T and 3T MRI (P=0.72) for the detection of CAD.One study (N=60) was identified that examined stress cardiac MRI using wall motion analysis with a 3T MRI. The sensitivity and specificity of 3T MRI were 0.64 (95% CI: 0.44 to 0.81) and 1.00 (95% CI: 0.89 to 1.00), respectively, for the detection of CAD.The effectiveness of stress cardiac MRI for the detection of CAD in unstable patients with acute coronary syndrome was reported in only one study (N=35). Using perfusion analysis, the sensitivity and specificity were 0.72 (95% CI: 0.53 to 0.87) and 1.00 (95% CI: 0.54 to 1.00), respectively, for the detection of CAD. According to an expert consultant, in Ontario: Stress first pass perfusion is currently performed in small numbers in London (London Health Sciences Centre) and Toronto (University Health Network at the Toronto General Hospital site and Sunnybrook Health Sciences Centre).Stress wall motion is only performed as part of research protocols and not very often.Cardiac MRI machines use 1.5T almost exclusively, with 3T used in research for first pass perfusion.On November 25 2009, the Cardiac Imaging Expert Advisory Panel met and made the following comments about stress cardiac MRI for perfusion analysis: Accessibility to cardiac MRI is limited and generally used to assess structural abnormalities. Most MRIs in Ontario are already in 24-hour, constant use and it would thus be difficult to add cardiac MRI for CAD diagnosis as an additional indication.The performance of cardiac MRI for the diagnosis of CAD can be technically challenging. The quality of the body of evidence was assessed according to the GRADE Working Group criteria for diagnostic tests. For perfusion analysis, the overall quality was determined to be low and for wall motion analysis the overall quality was very low.

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Inhaled corticosteroids (ICS) are the first-line treatment for children with persistent asthma. Their potential for growth suppression remains a matter of concern for parents and physicians. To assess whether increasing the dose of ICS is associated with slower linear growth, weight gain and skeletal maturation in children with asthma. We searched the Cochrane Airways Group Specialised Register of trials (CAGR) and the ClinicalTrials.gov website up to March 2014. Studies were eligible if they were parallel-group randomised trials evaluating the impact of different doses of the same ICS using the same device in both groups for a minimum of three months in children one to 17 years of age with persistent asthma. Two review authors ascertained methodological quality independently using the Cochrane Risk of bias tool. The primary outcome was linear growth velocity. Secondary outcomes included change over time in growth velocity, height, weight, body mass index and skeletal maturation. Among 22 eligible trials, 17 group comparisons were derived from 10 trials (3394 children with mild to moderate asthma), measured growth and contributed data to the meta-analysis. Trials used ICS (beclomethasone, budesonide, ciclesonide, fluticasone or mometasone) as monotherapy or as combination therapy with a long-acting beta2 -agonist and generally compared low (50 to 100 μg) versus low to medium (200 μg) doses of hydrofluoroalkane (HFA)-beclomethasone equivalent over 12 to 52 weeks. In the four comparisons reporting linear growth over 12 months, a significant group difference was observed, clearly indicating lower growth velocity in the higher ICS dose group of 5.74 cm/y compared with 5.94 cm/y on lower-dose ICS (N = 728 school-aged children; mean difference (MD)0.20 cm/y, 95% confidence interval (CI) 0.02 to 0.39; high-quality evidence): No statistically significant heterogeneity was noted between trials contributing data. The ICS molecules (ciclesonide, fluticasone, mometasone) used in these four comparisons did not significantly influence the magnitude of effect (X(2) = 2.19 (2 df), P value 0.33). Subgroup analyses on age, baseline severity of airway obstruction, ICS dose and concomitant use of non-steroidal antiasthmatic drugs were not performed because of similarity across trials or inadequate reporting. A statistically significant group difference was noted in unadjusted change in height from zero to three months (nine comparisons; N = 944 children; MD 0.15, 95% CI -0.28 to -0.02; moderate-quality evidence) in favour of a higher ICS dose. No statistically significant group differences in change in height were observed at other time points, nor were such differences in weight, bone mass index and skeletal maturation reported with low quality of evidence due to imprecision. In prepubescent school-aged children with mild to moderate persistent asthma, a small but statistically significant group difference in growth velocity was observed between low doses of ICS and low to medium doses of HFA-beclomethasone equivalent, favouring the use of low-dose ICS. No apparent difference in the magnitude of effect was associated with three molecules reporting one-year growth velocity, namely, mometasone, ciclesonide and fluticasone. In view of prevailing parents' and physicians' concerns about the growth suppressive effect of ICS, lack of or incomplete reporting of growth velocity in more than 86% (19/22) of eligible paediatric trials, including those using beclomethasone and budesonide, is a matter of concern. All future paediatric trials comparing different doses of ICS with or without placebo should systematically document growth. Findings support use of the minimal effective ICS dose in children with asthma. Does altering the dose of inhaled corticosteroids make a difference in growth among children with asthma? Asthma guidelines recommend inhaled corticosteroids (ICS) as the first choice of treatment for children with persistent asthma that is not well controlled when only a reliever inhaler is used to treat symptoms. Steroids work by reducing inflammation in the lungs and are known to control underlying symptoms of asthma. However, parents and physicians remain concerned about the potential negative effect of ICS on growth. Does altering the dose of inhaled corticosteroids make a difference in the growth of children with asthma? WHAT EVIDENCE DID WE FIND?: We studied whether a difference could be seen in the growth of children with persistent asthma who were using different doses of the same ICS molecule and the same delivery device. We found 22 eligible trials, but only 10 of them measured growth or other measures of interest. Overall, 3394 children included in the review combined 17 group comparisons (i.e. 17 groups of children with mild to moderate asthma using a particular dose and type of steroid in 10 trials). Trials used different ICS molecules (beclomethasone, budesonide, ciclesonide, fluticasone or mometasone) either on their own or in combination with a long-acting beta2 -agonist (a drug used to open up the airways) and generally compared low doses of corticosteroids (50 to 100 μg) with low to medium (200 μg) doses of corticosteroids (converted in μg HFA-beclomethasone equivalent) over 12 to 52 weeks. We found a small but statistically significant group difference in growth over 12 months between these different doses clearly favouring the lower dose of ICS. The type of corticosteroid among newer molecules (ciclesonide, fluticasone, mometasone) did not seem to influence the impact on growth over one year. Differences in corticosteroid doses did not seem to affect the change in height, the gain in weight, the gain in bone mass index and the maturation of bones. QUALITY OF THE EVIDENCE: This review is based on a small number of trials that reported data and were conducted on children with mild to moderate asthma. Only 10 of 22 studies measured the few outcomes of interest for this review, and only four comparisons reported growth over 12 months. Our confidence in the quality of evidence is high for this outcome, however it is low to moderate for several other outcomes, depending on the number of trials reporting these outcomes. Moreover, a few outcomes were reported only by a single trial; as these findings have not been confirmed by other trials, we downgraded the evidence for these outcomes to low quality. An insufficient number of trials have compared the effect of a larger difference in dose, for example, between a high dose and a low dose of ICS and of other popular molecules such as budesonide and beclomethasone over a year or longer of treatment. We report an evidence-based ICS dose-dependent reduction in growth velocity in prepubescent school-aged children with mild to moderate persistent asthma. The choice of ICS molecule (mometasone, ciclesonide or fluticasone) was not found to affect the level of growth velocity response over a year. The effect of corticosteroids on growth was not consistently reported: among 22 eligible trials, only four comparisons reported the effects of corticosteroids on growth over one year. In view of parents' and clinicians' concerns, lack of or incomplete reporting of growth is a matter of concern given the importance of the topic. We recommend that growth be systematically reported in all trials involving children taking ICS for three months or longer. Until further data comparing low versus high ICS dose and trials of longer duration are available, we recommend that the minimal effective ICS dose be used in all children with asthma.

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Structured diagnostic interviews, which evolved along the development of classification's systems, are now widely used in adult psychiatry, in the fields of clinical trials, epidemiological studies, academic research as well as, more recently, clinical practice. These instruments improved the reliability of the data collection and interrater reliability allowing greater homogenisation of the subjects taking part in clinical research, essential factor to ensure the reproducibility of the results. The diagnostic instruments, conversely to the clinical traditional diagnostic processes allow a systematic and exhaustive exploration of disorders, diagnostic criteria but also severity levels, and duration. The format of the data collection, including the order of exploration of the symptoms, is fixed. The formulation of the questions is tested to be univocal, in order to avoid confusions. In child and adolescent, researches in pharmacology and epidemiology increased a lot in the last decade and the standardisation of diagnostic procedures is becoming a key feature. This Article aims to make an assessment, a selection, and a description of the standardized instruments helping psychiatric diagnosis currently available in the field of child and adolescent's psychiatry. Medline and PsycINFO databases were exhaustively checked and the selection of the instruments was based on the review of four main criteria: i) compatibility with international diagnostic systems (DSM IV and/or ICD-10); ii) number of disorders explored; iii) peer reviewed Journals and iv) richness of psychometric data. After the analysis of the instruments described or mentioned in the literature, 2 structured interviews [the Diagnostic Interview Schedule for Children (DISC) and the Children's Interview for Psychiatric Syndromes (ChIPS)] and 4 diagnostic semi-structured interviews [the Schedule for Affective Disorders and Schizophrenia for School-Age Children (Kiddie-SADS), the Diagnostic Interview for Children and Adolescent (DICA), the Child and Adolescent Psychiatric Assessment (CAPA) and the Interview Schedule for Children and Adolescents ISCA)] were retained according to the 3 first criteria. All can be administered by clinicians, and x out of 6 can also be administered by lay-interviewers. All include a child/adolescent version and a parent version. Two instruments evaluate the presence of DSM IV axe II disorders: The ISCA explores the criteria of the Antisocial Personality Disorder. The CAPA evaluates Borderline, Obsessional-compulsive, Histrionic and Schizotypic Personality Disorders. Regarding the psychometric quality criterion, the selection was much more difficult because of the lack of data and the weakness of the samples studied in reliability studies. Interrater reliability appeared to be good for the 6 instruments, with kappas ranging from 0.5 to 1. This is usual in such instruments. The test-retest reliability was found to vary from bad to excellent depending on the instruments, the "informant" status (child/adolescent or parent), and the disorder explored, kappas ranging from 0.32 to 1. The worst results concerned face-to-face reliability studies which showed weak concordances for the diagnoses, whatever the procedure implemented: Diagnostic interview vs. i) Another diagnostic interview, vs. ii) An expert diagnosis or vs. iii) Scales and questionnaires. Overall, the K-SADS-PL appeared to be the instrument that has the best test-retest reliability for Anxious Disorders and Affective Disorders (the value kappa showing good to excellent reliabilities). Several important methodological observations emerged from this review. Firstly, the metrological data corresponding to the diagnoses according to DSM IV or ICD-10 criteria's were lacking. The face validity was globally satisfactory, but the data concerning their face-to-face validities and their test-retest reliability, although better than in the former versions, were limited because they were tested on small sample. In fact, it appeared that the agreements depend on the informant, the sample studied, the various diagnostic categories and the instrument used. Since the studies carried out by Cohen et al., with now obsolete versions of the DISC and K-SADS, no other study establishing a comparison between two EDS have been conducted. Consequently, the clinicians must be very careful before comparing DSM or ICD diagnoses generated by different instruments. The second point was the length of the interviews that appeared sometimes longer than instruments used in adults, considering the fact that diagnostic procedure implies two independent interviews, one with the child/adolescent and one with the adult referent. The minimum duration was found to be 1 h 30 for the Chips in clinical setting, while it could reach 4 h or more for the DISC IV or the ISCA. The interviews had to be often carried out in several sessions, so the assessment became very difficult in easily tired and/or distractible subjects. The third point referred to the necessity to consider multiple data sources in young patients during the diagnostic procedure, and the weakness of the levels of agreement generally reported between sources. Empirically, it was observed that the investigator granted more weight to the report of the children than to the parent's one, when the clinical judgement was necessary to synthesize the data. On another level, studies showed a high agreement on the factual contents or on the specific events (ex: hospitalization), like on the obvious symptoms (ex: enuresis). The parents report more problems of behaviour, school and relational difficulties, whereas the children report more fear, anxiety, obsessions and compulsions, or delusional ideas. In other words, it appeared that children were better informants in describing their mental states (internalised disorders), and that adults would bring more reliable information in describing externalised disorders. Like McClellan and Werry, we think that further researches are needed to clarify if and when this is the case. The last major point concerned the problem of language. These instruments must be used in the maternal language of the interviewees and they were developed for most of them into English only. For example, there is only one instrument available into French (the Kiddie SADS). Nowadays, it remains difficult to conduct international studies in child and adolescent psychiatry and/or to compare data is this domain. To conclude, the use of the EDS and EDSS brings many benefits, in academic researches as well as in clinical practice, but a more systematic use is limited by a certain number of parameters. The instruments currently available in child and adolescent are far from being optimal in terms of quality and quantity. It seems necessary and useful to contribute to their development and their improvement. In particular, the following points should be considered: drastic reduction of the length of the interviews; simplification in the use of these instruments, during the interviews, but also in the treatment of the data collected during the final phase of diagnosis generation, the clinician having to carry out ceaseless returns to check the presence or not of each diagnostic criterion; reduction of the duration of the highly necessary training, which can be easily solved by the global simplification of the instruments; quantitative and qualitative improvements of psychometric properties, in particular in terms of sensitivity, specificity and face-to-face validity. Finally, it is highly necessary to continue to develop structured diagnostic interviews adapted to the assessment of child and adolescent psychiatric diagnoses keeping in mind simplicity, feasibility and reliability. Developing this kind of instruments is hard, expensive, and sometimes tiresome but it remains the inescapable stage to produce high quality data in the future.

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Mitochondrial fusion plays an essential role in mitochondrial calcium homeostasis, bioenergetics, autophagy and quality control. Fusion is quantified in living cells by photo-conversion of matrix targeted photoactivatable GFP (mtPAGFP) in a subset of mitochondria. The rate at which the photoconverted molecules equilibrate across the entire mitochondrial population is used as a measure of fusion activity. Thus far measurements were performed using a single cell time lapse approach, quantifying the equilibration in one cell over an hour. Here, we scale up and automate a previously published live cell method based on using mtPAGFP and a low concentration of TMRE (15 nm). This method involves photoactivating a small portion of the mitochondrial network, collecting highly resolved stacks of confocal sections every 15 min for 1 hour, and quantifying the change in signal intensity. Depending on several factors such as ease of finding PAGFP expressing cells, and the signal of the photoactivated regions, it is possible to collect around 10 cells within the 15 min intervals. This provides a significant improvement in the time efficiency of this assay while maintaining the highly resolved subcellular quantification as well as the kinetic parameters necessary to capture the detail of mitochondrial behavior in its native cytoarchitectural environment. Mitochondrial dynamics play a role in many cellular processes including respiration, calcium regulation, and apoptosis. The structure of the mitochondrial network affects the function of mitochondria, and the way they interact with the rest of the cell. Undergoing constant division and fusion, mitochondrial networks attain various shapes ranging from highly fused networks, to being more fragmented. Interestingly, Alzheimer's disease, Parkinson's disease, Charcot Marie Tooth 2A, and dominant optic atrophy have been correlated with altered mitochondrial morphology, namely fragmented networks. Often times, upon fragmentation, mitochondria become depolarized, and upon accumulation this leads to impaired cell function. Mitochondrial fission has been shown to signal a cell to progress toward apoptosis. It can also provide a mechanism by which to separate depolarized and inactive mitochondria to keep the bulk of the network robust. Fusion of mitochondria, on the other hand, leads to sharing of matrix proteins, solutes, mtDNA and the electrochemical gradient, and also seems to prevent progression to apoptosis. How fission and fusion of mitochondria affects cell homeostasis and ultimately the functioning of the organism needs further understanding, and therefore the continuous development and optimization of how to gather information on these phenomena is necessary. Existing mitochondrial fusion assays have revealed various insights into mitochondrial physiology, each having its own advantages. The hybrid PEG fusion assay, mixes two populations of differently labeled cells (mtRFP and mtYFP), and analyzes the amount of mixing and colocalization of fluorophores in fused, multinucleated, cells. Although this method has yielded valuable information, not all cell types can fuse, and the conditions under which fusion is stimulated involves the use of toxic drugs that likely affect the normal fusion process. More recently, a cell free technique has been devised, using isolated mitochondria to observe fusion events based on a luciferase assay. Two human cell lines are targeted with either the amino or a carboxy terminal part of Renilla luciferase along with a leucine zipper to ensure dimerization upon mixing. Mitochondria are isolated from each cell line, and fused. The fusion reaction can occur without the cytosol under physiological conditions in the presence of energy, appropriate temperature and inner mitochondrial membrane potential. Interestingly, the cytosol was found to modulate the extent of fusion, demonstrating that cell signaling regulates the fusion process. This assay will be very useful for high throughput screening to identify components of the fusion machinery and also pharmacological compounds that may affect mitochondrial dynamics. However, more detailed whole cell mitochondrial assays will be needed to complement this in vitro assay to observe these events within a cellular environment. A technique for monitoring whole-cell mitochondrial dynamics has been in use for some time and is based on a mitochondrially-targeted photoactivatable GFP (mtPAGFP). Upon expression of the mtPAGFP, a small portion of the mitochondrial network is photoactivated (10-20%), and the spread of the signal to the rest of the mitochondrial network is recorded every 15 minutes for 1 hour using time lapse confocal imaging. Each fusion event leads to a dilution of signal intensity, enabling quantification of the fusion rate. Although fusion and fission are continuously occurring in cells, this technique only monitors fusion as fission does not lead to a dilution of the PAGFP signal. Co-labeling with low levels of TMRE (7-15 nM in INS1 cells) allows quantification of the membrane potential of mitochondria. When mitochondria are hyperpolarized they uptake more TMRE, and when they depolarize they lose the TMRE dye. Mitochondria that depolarize no longer have a sufficient membrane potential and tend not to fuse as efficiently if at all. Therefore, active fusing mitochondria can be tracked with these low levels of TMRE. Accumulation of depolarized mitochondria that lack a TMRE signal may be a sign of phototoxicity or cell death. Higher concentrations of TMRE render mitochondria very sensitive to laser light, and therefore great care must be taken to avoid overlabeling with TMRE. If the effect of depolarization of mitochondria is the topic of interest, a technique using slightly higher levels of TMRE and more intense laser light can be used to depolarize mitochondria in a controlled fashion (Mitra and Lippincott-Schwartz, 2010). To ensure that toxicity due to TMRE is not an issue, we suggest exposing loaded cells (3-15 nM TMRE) to the imaging parameters that will be used in the assay (perhaps 7 stacks of 6 optical sections in a row), and assessing cell health after 2 hours. If the mitochondria appear too fragmented and cells are dying, other mitochondrial markers, such as dsRED or Mitotracker red could be used instead of TMRE. The mtPAGFP method has revealed details about mitochondrial network behavior that could not be visualized using other methods. For example, we now know that mitochondrial fusion can be full or transient, where matrix content can mix without changing the overall network morphology. Additionally, we know that the probability of fusion is independent of contact duration and organelle dimension, is influenced by organelle motility, membrane potential and history of previous fusion activity. In this manuscript, we describe a methodology for scaling up the previously published protocol using mtPAGFP and 15 nM TMRE in order to examine multiple cells at a time and improve the time efficiency of data collection without sacrificing the subcellular resolution. This has been made possible by the use of an automated microscope stage, and programmable image acquisition software. Zen software from Zeiss allows the user to mark and track several designated cells expressing mtPAGFP. Each of these cells can be photoactivated in a particular region of interest, and stacks of confocal slices can be monitored for mtPAGFP signal as well as TMRE at specified intervals. Other confocal systems could be used to perform this protocol provided there is an automated stage that is programmable, an incubator with CO2, and a means by which to photoactivate the PAGFP; either a multiphoton laser, or a 405 nm diode laser.

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Prominent cognitive deficits have been documented in bipolar disorder, and multiple studies suggest that these deficits can be observed among non-affected first-degree relatives of those with bipolar disorder. Although there is variability in the degree of cognitive deficits, these deficits are robustly relevant for functional outcomes. A separate literature documents clear difficulties in emotionality, emotion regulation, and emotion-relevant impulsivity within bipolar disorder, and demonstrates that these emotion-relevant variables are also central to outcome. Although cognitive and emotion domains are typically studied independently, basic research and emergent findings in bipolar disorder suggest that there are important ties between cognitive deficits and the emotion disturbances observed in bipolar disorder. Understanding these relationships has relevance for fostering more integrative research, for clarifying relevant aspects related to functionality and vulnerability within bipolar disorder, and for the development of novel treatment interventions. Bipolar disorder (BD) is a severe psychiatric illness that has been ranked as one of the 20 leading medical causes of disability (WHO, 2011). BD has been shown to be the psychiatric disorder with the highest rates of completed suicide across two major cohort studies (Ilgen et al., 2010; Nordentoft, Mortensen, & Pedersen, 2011). In a cross-national representative sample, one in four persons diagnosed with bipolar I disorder reported a suicide attempt (Merikangas et al., 2011). Rates of relapse remain high despite available treatments (Gitlin, Swendsen, Heller, & Hammen, 1995), and in the year after hospitalization for manic episode, two-thirds of patients do not return to work (Strakowski et al., 1998). Poverty, homelessness, and incarceration are all too common (Copeland et al., 2009). Despite the often poor outcomes, there is also evidence for outstanding accomplishments and creativity among those with milder forms of the disorder and their family members (Coryell et al., 1989; Jamison, 1993; Murray & Johnson, 2010). Some individuals appear to achieve more than the general population, suggesting the importance of understanding the variables that predict differential outcome within bipolar disorder. Within this paper, we focus on two key predictors of outcomes within bipolar disorder: cognition and emotionality. We review evidence that problems in cognition and emotionality are prominent among those diagnosed with the disorder, are not artifacts of symptom state, and relate substantively to poorer outcomes. Although traditionally studied separately, new work points toward the idea that cognition and emotionality are intricately linked within bipolar disorder. Drawing from research within bipolar disorder as well as outside of bipolar disorder, we build a model of how cognition and emotionality might be tied within bipolar disorder. We then provide suggestions for future research. Before considering findings, it is worth noting that there are several forms of the disorder, defined by varying degrees and duration of manic symptoms (APA, 2013; WHO, 1993). Manic episodes are defined by abnormally elevated or irritable mood, accompanied by increased activity and at least three symptoms (four if mood is only irritable) such as decreased need for sleep, increased self-confidence, racing thoughts or flight of ideas, rapid speech, distractibility, goal-directed activity, and engagement in pleasurable activities without regard to potential negative consequences. To meet criteria for mania, these symptoms must persist for at least one week or require hospitalization, and must lead to difficulties with functioning. If functional impairment is not more than mild and duration is between 4 and 6 days, the episode is considered a hypomanic episode. Bipolar I disorder (BD I) is diagnosed on the basis of at least one lifetime manic episode within the DSM-5 and by at least two episodes within the ICD, whereas bipolar II disorder is diagnosed on the basis of at least one hypomanic episode (and no manic episodes) as well as major depressive episodes. Cyclothymic disorder is defined by chronic but milder fluctuations between manic and depressive symptoms. Most research focuses on BD I. In addition to diagnosed samples, research has focused on those at high risk for bipolar disorder, including first-degree relatives of those with BD. This work draws on the evidence for extremely high heritability of BD I, with estimates from community-based twin studies of 0.85 (Kieseppä, Partonen, Haukka, Kaprio, & Lönnqvist, 2014). Other research has considered high risk for BD by virtue of lifetime subsyndromal symptoms, as measured by scales such as the Hypomanic Personality Scale (Eckblad & Chapman, 1986) or the General Behavior Inventory (Depue, Krauss, Spoont, & Arbisi, 1989). The study of high-risk individuals provides a way to decipher whether deficits are present before the onset of the disorder, of importance given models suggesting that episodes of the disorder may change brain function (Chang, Steiner, & Ketter, 2000; Strakowski, 2012) as well as individuals' perceptions of their emotion regulation. Beyond defining BD, it is worth defining some of the many different neuropsychological tasks that have been widely studied in BD. Perhaps no area has received more attention than executive function. Executive function is related to three core functions: 1) inhibition, the ability to suppress irrelevant information in working memory in order to accomplish an established goal; 2) working memory, the ability to hold and manipulate information in mind; and 3) cognitive flexibility, the ability to shift strategies in response to feedback (Diamond, 2013; Miyake et al., 2000). Attention (defined as the process of selecting information reception from internal or external cues) is implicated in all three of these aspects of executive function. Much of the literature we will discuss focuses on response inhibition, or the ability to suppress a prepotent response, which is considered a subtype of inhibition. Some tests measure multiple facets of executive function; for example the Trails B test likely requires working memory and cognitive flexibility (Sánchez-Cubillo et al., 2009). Aside from executive function, multiple other facets of cognition have been widely studied in bipolar disorder. Verbal and non-verbal memory are related to the ability to register, store and retrieve verbal or visual information (Lezak, 1995). Verbal fluency is measured as the number of verbal responses a person can generate to a given target, such as a specific semantic category (e.g., animals, furniture) or phonetic category (e.g., words that begin with letter F) (Diamond, 2013). Although cognitive tasks have been designed to evaluate these specific functions, it is important to note that most measures are highly inter-correlated and may assess multiple overlapping functions to some extent (for example, the Trails B test is often described as an "executive function" task, although this task likely involves both working memory and cognitive flexibility. Not surprisingly, then, some authors label the function of certain tests differently, and this is particularly evident in meta-analyses of cognition. As we describe findings in this paper, we will use the terms proposed by the authors but will also identify key tests used to define a cognitive construct. With this background in mind, we turn to a discussion of cognitive deficits, then of emotion-related traits. Our hope is that those concise summaries provide evidence for the importance of both domains, but also specificity regarding the facets of emotion and cognition that are most impaired in BD. This specificity then guides our consideration of models that integrate cognition and emotion.

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The Multicenter Ozone Study of oldEr Subjects (MOSES) was a multi-center study evaluating whether short-term controlled exposure of older, healthy individuals to low levels of ozone (O<sub3</sub) induced acute changes in cardiovascular biomarkers. In MOSES Part 1 (MOSES 1), controlled O<sub3</sub exposure caused concentration-related reductions in lung function with evidence of airway inflammation and injury, but without convincing evidence of effects on cardiovascular function. However, subjects' prior exposures to indoor and outdoor air pollution in the few hours and days before each MOSES controlled O<sub3</sub exposure may have independently affected the study biomarkers and/or modified biomarker responses to the MOSES controlled O<sub3</sub exposures. MOSES 1 was conducted at three clinical centers (University of California San Francisco, University of North Carolina, and University of Rochester Medical Center) and included healthy volunteers 55 to 70 years of age. Consented participants who successfully completed the screening and training sessions were enrolled in the study. All three clinical centers adhered to common standard operating procedures and used common tracking and data forms. Each subject was scheduled to participate in a total of 11 visits: screening visit, training visit, and three sets of exposure visits consisting of the pre-exposure day, the exposure day, and the post-exposure day. After completing the pre-exposure day, subjects spent the night in a nearby hotel. On exposure days, the subjects were exposed for 3 hours in random order to 0 ppb O<sub3</sub (clean air), 70 ppb O<sub3</sub, and 120 ppm O<sub3</sub. During the exposure period the subjects alternated between 15 minutes of moderate exercise and 15 minutes of rest. A suite of cardiovascular and pulmonary endpoints was measured on the day before, the day of, and up to 22 hours after each exposure. In MOSES Part 2 (MOSES 2), we used a longitudinal panel study design, cardiopulmonary biomarker data from MOSES 1, passive cumulative personal exposure samples (PES) of O<sub3</sub and nitrogen dioxide (NO<sub2</sub) in the 72 hours before the pre-exposure visit, and hourly ambient air pollution and weather measurements in the 96 hours before the pre-exposure visit. We used mixed-effects linear regression and evaluated whether PES O<sub3</sub and NO<sub2</sub and these ambient pollutant concentrations in the 96 hours before the pre-exposure visit confounded the MOSES 1 controlled O<sub3</sub exposure effects on the pre- to post-exposure biomarker changes (Aim 1), whether they modified these pre- to post-exposure biomarker responses to the controlled O<sub3</sub exposures (Aim 2), whether they were associated with changes in biomarkers measured at the pre-exposure visit or morning of the exposure session (Aim 3), and whether they were associated with differences in the pre- to post-exposure biomarker changes independently of the controlled O<sub3</sub exposures (Aim 4). Ambient pollutant concentrations at each site were low and were regularly below the National Ambient Air Quality Standard levels. In Aim 1, the controlled O<sub3</sub exposure effects on the pre- to post-exposure biomarker differences were little changed when PES or ambient pollutant concentrations in the previous 96 hours were included in the model, suggesting these were not confounders of the controlled O<sub3</sub exposure/biomarker difference associations. In Aim 2, effects of MOSES controlled O<sub3</sub exposures on forced expiratory volume in 1 second (FEV<sub1</sub) and forced vital capacity (FVC) were modified by ambient NO<sub2</sub and carbon monoxide (CO), and PES NO<sub2</sub, with reductions in FEV<sub1</sub and FVC observed only when these concentrations were "Medium" or "High" in the 72 hours before the pre-exposure visit. There was no such effect modification of the effect of controlled O<sub3</sub exposure on any other cardiopulmonary biomarker. As hypothesized for Aim 3, increased ambient O<sub3</sub concentrations were associated with decreased pre-exposure heart rate variability (HRV). For example, high frequency (HF) HRV decreased in association with increased ambient O<sub3</sub concentrations in the 96 hours before the pre-exposure visit (-0.460 ln[ms<sup2</sup]; 95% CI, -0.743 to -0.177 for each 10.35-ppb increase in O<sub3</sub; <iP</i = 0.002). However, in Aim 4 these increases in ambient O<sub3</sub were also associated with increases in HF and low frequency (LF) HRV from pre- to post-exposure, likely reflecting a "recovery" of HRV during the MOSES O<sub3</sub exposure sessions. Similar patterns across Aims 3 and 4 were observed for LF (the other primary HRV marker), and standard deviation of normal-to-normal sinus beat intervals (SDNN) and root mean square of successive differences in normal-to-normal sinus beat intervals (RMSSD) (secondary HRV markers). Similar Aim 3 and Aim 4 patterns were observed for FEV<sub1</sub and FVC in association with increases in ambient PM with an aerodynamic diameter ≤ 2.5 μm (PM<sub2.5</sub), CO, and NO<sub2</sub in the 96 hours before the pre-exposure visit. For Aim 3, small decreases in pre-exposure FEV<sub1</sub were significantly associated with interquartile range (IQR) increases in PM<sub2.5</sub concentrations in the 1 hour before the pre-exposure visit (-0.022 L; 95% CI, -0.037 to -0.006; <iP</i = 0.007), CO in the 3 hours before the pre-exposure visit (-0.046 L; 95% CI, -0.076 to -0.016; <iP</i = 0.003), and NO<sub2</sub in the 72 hours before the pre-exposure visit (-0.030 L; 95% CI, -0.052 to -0.008; <iP</i = 0.007). However, FEV<sub1</sub was not associated with ambient O<sub3</sub or sulfur dioxide (SO<sub2</sub), or PES O<sub3</sub or NO<sub2</sub (Aim 3). For Aim 4, increased FEV<sub1</sub across the exposure session (post-exposure minus pre-exposure) was marginally significantly associated with each 4.1-ppb increase in PES O<sub3</sub concentration (0.010 L; 95% CI, 0.004 to 0.026; <iP</i = 0.010), as well as ambient PM<sub2.5</sub and CO at all lag times. FVC showed similar associations, with patterns of decreased pre-exposure FVC associated with increased PM<sub2.5</sub, CO, and NO<sub2</sub at most lag times, and increased FVC across the exposure session also associated with increased concentrations of the same pollutants, reflecting a similar recovery. However, increased pollutant concentrations were not associated with adverse changes in pre-exposure levels or pre- to post-exposure changes in biomarkers of cardiac repolarization, ST segment, vascular function, nitrotyrosine as a measure of oxidative stress, prothrombotic state, systemic inflammation, lung injury, or sputum polymorphonuclear leukocyte (PMN) percentage as a measure of airway inflammation. Our previous MOSES 1 findings of controlled O<sub3</sub exposure effects on pulmonary function, but not on any cardiovascular biomarker, were not confounded by ambient or personal O<sub3</sub or other pollutant exposures in the 96 and 72 hours before the pre-exposure visit. Further, these MOSES 1 O<sub3</sub effects were generally not modified, blunted, or lessened by these same ambient and personal pollutant exposures. However, the reductions in markers of pulmonary function by the MOSES 1 controlled O<sub3</sub exposure were modified by ambient NO<sub2</sub and CO, and PES NO<sub2</sub, with reductions observed only when these pollutant concentrations were elevated in the few hours and days before the pre-exposure visit. Increased ambient O<sub3</sub concentrations were associated with reduced HRV, with "recovery" during exposure visits. Increased ambient PM<sub2.5</sub, NO<sub2</sub, and CO were associated with reduced pulmonary function, independent of the MOSES-controlled O<sub3</sub exposures. Increased pollutant concentrations were not associated with pre-exposure or pre- to post-exposure changes in other cardiopulmonary biomarkers. Future controlled exposure studies should consider the effect of ambient pollutants on pre-exposure biomarker levels and whether ambient pollutants modify any health response to a controlled pollutant exposure.

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What is the role of transcriptional-enhanced associate (TEA) domain family member 4 (TEAD4) in trophectoderm (TE) differentiation during human embryo preimplantation development in comparison to mouse? TEAD4 regulates TE lineage differentiation in the human preimplantation embryo acting upstream of caudal-type homeobox protein 2 (CDX2), but in contrast to the mouse in a GATA-binding protein 3 (GATA3)-independent manner. Tead4 is one of the earliest transcription factors expressed during mouse embryo preimplantation development and is required for the expression of TE-associated genes. Functional knock-out studies in mouse, inactivating Tead4 by site-specific recombination, have shown that Tead4-targeted embryos have compromised development and expression of the TE-specific Cdx2 and Gata3 is downregulated. Cdx2 and Gata3 act in parallel pathways downstream of Tead4 to induce successful TE differentiation. Downstream loss of Cdx2 expression, compromises TE differentiation and subsequent blastocoel formation and leads to the ectopic expression of inner cell mass (ICM) genes, including POU Class 5 homeobox 1 (Pou5f1) and SRY-box transcription factor (Sox2). Cdx2 is a more potent regulator of TE fate in mouse as loss of Cdx2 expression induces more severe phenotypes compared with loss of Gata3 expression. The role of TEAD4 and its downstream effectors during human preimplantation embryo development has not been investigated yet. The clustered regularly interspaced short palindromic repeats-clustered regularly interspaced short palindromic repeats (CRISPR)-associated genes (CRISPR-Cas9) system was first introduced in pronuclei (PN)-stage mouse zygotes aiming to identify a guide RNA (gRNA), yielding high editing efficiency and effective disruption of the Tead4 locus. Three guides were tested (gRNA1-3), each time targeting a distinct region of Exon 2 of Tead4. The effects of targeting on developmental capacity were studied in Tead4-targeted embryos (n = 164-summarized data from gRNA1-3) and were compared with two control groups; sham-injected embryos (n = 26) and non-injected media-control embryos (n = 51). The editing efficiency was determined by next-generation sequencing (NGS). In total, n = 55 (summarized data from gRNA1-3) targeted mouse embryos were analysed by NGS. Immunofluorescence analysis to confirm successful targeting by gRNA1 was performed in Tead4-targeted embryos, and non-injected media-control embryos. The downregulation of secondary TE-associated markers Cdx2 and Gata3 was used as an indirect confirmation of successful Tead4-targeting (previously shown to be expressed downstream of Tead4). Additional groups of gRNA1 Tead4-targeted (n = 45) and media control (n = 36) embryos were cultured for an extended period of 8.5 days, to further assess the developmental capacity of the Tead4-targeted group to develop beyond implantation stages. Following the mouse investigation, human metaphase-II (MII) oocytes obtained by IVM were microinjected with gRNA-Cas9 during ICSI (n = 74) to target TEAD4 or used as media-control (n = 33). The editing efficiency was successfully assessed in n = 25 TEAD4-targeted human embryos. Finally, immunofluorescence analysis for TEAD4, CDX2, GATA3 and the ICM marker SOX2 was performed in TEAD4-targeted (n = 10) and non-injected media-control embryos (n = 29). A ribonucleoprotein complex consisting of a gRNA-Cas9 mixture, designed to target Exon 2 of Tead4/TEAD4, was microinjected in mouse PN stage zygotes or human IVM MII oocytes along with sperm. Generated embryos were cultured in vitro for 4 days in mouse or 6.5 days in human. In mouse, an additional group of Tead4-targeted and media-control embryos was cultured in vitro for an extended period of 8.5 days. Embryonic development and morphology were assessed daily, during culture in vitro of mouse and human embryos and was followed by a detailed scoring at late blastocyst stage. Targeting efficiency following gRNA-Cas9 introduction was assessed via immunostaining and NGS analysis. NGS analysis of the Tead4-targeted locus revealed very high editing efficiencies for all three guides, with 100% of the mouse embryos (55 out of 55) carrying genetic modifications resulting from CRISPR-Cas9 genome editing. More specifically, 65.22% (15 out 23) of the PN zygotes microinjected with gRNA1-Cas9, which exhibited the highest efficiency, carried exclusively mutated alleles. The developmental capacity of targeted embryos was significantly reduced (data from gRNA1), as 44.17% of the embryos arrested at the morula stage (2.5 days post coitum), coincident with the initiation of TE lineage differentiation, compared with 8.51% in control and 12.50% in sham control groups. High-quality blastocyst formation rates (Grade 3) were 8.97% in the gRNA1-targeted group, compared with 87.23% in the media-control and 87.50% in the sham group. Immunofluorescence analysis in targeted embryos confirmed downregulation of Tead4, Cdx2, and Gata3 expression, which resulted from successful targeting of the Tead4 locus. Tead4-targeted mouse embryos stained positive for the ICM markers Pou5f1 and Sox2, indicating that expression of ICM lineage markers is not affected. Tead4-targeted embryos were able to cavitate and form a blastocoel without being able to hatch. Extended embryo culture following zona pellucida removal, revealed that the targeted embryos can attach and form egg-cylinder-like structures in the absence of trophoblast giant cells. In human embryos, Exon 2 of TEAD4 was successfully targeted by CRISPR-Cas9 (n = 74). In total, 25 embryos from various developmental stages were analysed by NGS and 96.00% (24 out of 25) of the embryos carried genetic modifications because of gRNA-Cas9 editing. In the subgroup of the 24 edited embryos, 17 (70.83%) carried only mutant alleles and 11 out of these 17 (64.70%) carried exclusively frameshift mutations. Six out of 11 embryos reached the blastocyst stage. In contrast to mice, human-targeted embryos formed blastocysts at a rate (25.00%) that did not differ significantly from the control group (23.81%). However, blastocyst morphology and TE quality were significantly compromised following TEAD4-targeting, showing grade C TE scores, with TE containing very few cells. Immunofluorescence analysis of TEAD4-targeted embryos (n = 10) confirmed successful editing by the complete absence of TEAD4 and its downstream TE marker CDX2, but the embryos generated retained expression of GATA3, which is in contrast to what we have observed and has previously been reported in mouse. In this regard, our results indicate that GATA3 acts in parallel with TEAD4/CDX2 towards TE differentiation in human. N/A. CRISPR-Cas9 germline genome editing, in some cases, induces mosaic genotypes. These genotypes are a result of inefficient and delayed editing, and complicate the phenotypic analysis and developmental assessment of the injected embryos. We cannot exclude the possibility that the observed differences between mouse and human are the result of variable effects triggered by the culture conditions, which were however similar for both mouse and human embryos in this study. Furthermore, this study utilized human oocytes obtained by IVM, which may not fully recapitulate the developmental behaviour of in vivo matured oocytes. Elucidation of the evolutionary conservation of molecular mechanisms that regulate the differentiation and formation of the trophoblast lineage can give us fundamental insights into early implantation failure, which accounts for ∼15% of human conceptions. The research was funded by the FWO-Vlaanderen (Flemish fund for scientific research, Grant no. G051516N), and Hercules funding (FWO.HMZ.2016.00.02.01) and Ghent University (BOF.BAS.2018.0018.01). G.C. is supported by FWO-Vlaanderen (Flemish fund for scientific research, Grant no. 11L8822N). A.B. is supported by FWO-Vlaanderen (Flemish fund for scientific research, Grant no. 1298722 N). We further thank Ferring Pharmaceuticals (Aalst, Belgium) for their unrestricted educational grant. The authors declare no competing interests. N/A.

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During recent years significant progress has been made in the treatment of HIV-1, at least in part due to the availability of potent antiretroviral drugs. The goal of the current treatment strategies is to inhibit the viral replication as completely as possible by using a combination of 3 or more antiretroviral drugs. This Highly Active Antiretroviral Therapy (HAART) has radically changed the clinical outcome of HIV, leading to decreased mortality and morbidity, at least in developed countries. Additionally to the advent of new and potent drugs, demonstrations of the prognostic value of the CD4 cell count and the plasma viral load were of major importance in the development of therapeutic strategies. Especially the ability of viral load assays to assess accurately the true level of viral replication, led to a better understanding of the pathogenesis of the disease. HIV proved to be a highly dynamic infection even during the period of clinical latency. The initial enthusiasm that HAART could radically change the outcome of HIV was cooled off in face of the difficulties in real life associated with the complex treatment strategies. Besides long-term side effects and suboptimal drug potency, the emergence of resistant virus and the necessity of perfect therapy adherence are major concerns for obtaining a sustained control of viral replication. In this study we focused on HIV resistance, which remains one of the major threats for a sustained response to antiretroviral therapy. HIV proved to be able to develop resistance to all currently used antiretroviral drugs. The high replication rate of the virus together with the low fidelity of the viral reverse transcriptase, from the basis for the presence of enormous amounts of viral variants. Whenever viral replication is ongoing in the presence of antiretroviral drugs, these variants that escape the inhibitory effects of the drugs will be selected. Although the knowledge in the field of HIV resistance has expanded enormously, many issues need to be answered. Genotypic and phenotypic resistance patterns are evolving continuously, due to changes in the treatment strategies. Moreover the relation between drug resistance and therapy failure needs further investigation, in order to prove the relevance of performing resistance testing in the follow-up of HIV-infected patients. The wide availability of antiretroviral drugs has led to the transmission of resistant HIV. Infection with HIV resistant to one or more antiretroviral drugs has been observed to occur through the different transmission routes. In a first study we assessed the prevalence of genotypic resistance to antiretroviral drugs in Belgian antiretroviral-naïve HIV-infected patients. We observed that HIV strains with resistance-related mutations to one or more classes of antiretroviral drugs are not uncommon in the Belgian naïve patients. Furthermore the inclusion of samples from patients visiting the Belgian hospitals for the first time in 1995, 1997 and 1998, showed that the overall prevalence of baseline genotypic resistance remains rather constant (26-30%). The increasing trend in genotypic baseline resistance to 3TC (2% to 6.3%) and PIs (4.4% to 9.9%) as well as the decrease in ZDV-resistance (13.3% to 5.4%), reflect the change in treatment strategies, and resistance to these drugs is most probably caused by transmission of variants with resistance mutations selected during therapy. The presence of NNRTI-related mutations (around 16%) is likely to reflect the occurrence of baseline polymorphisms, since NNRTI-related mutations can occur without a replication deficit for the virus. Moreover, despite the rather recent introduction of NNRTIs into the clinic from 1997 onwards, no clear trend in NNRTI baseline resistance over time is observed. The best current therapeutic strategy for HIV-infected patients is to start antiretroviral therapy with HAART in order to avoid the accumulation of resistance towards drugs in less suppressive regimens. In a second study, we showed that the start of HAART in antiretroviral-naive HIV-patients in daily clinical practice could prevent viral breakthrough for up to 44 months in 60% of patients (n = 25). Six of 10 patients with virologic failure developed resistance to the drugs included in their treatment regimens. In comparison to patients with a sustained virologic response, patients with virologic failure were in a later disease stage when starting therapy and showed lower PI drug-levels, what can be an indication of poor adherence. Despite a poor virologic response for some of them, a rise in CD4 cell count was observed for all patients during the study period. A large number of HIV-infected patients started treatment in the pre-HAART period. The use of NRTIs is mono- or bitherapy was not able to prevent the development of resistant virus. In a third study we studied the prevalence and characteristics of 2 patterns of multinucleoside resistance (MNR) in European patients (n = 755). In patients without NRTI-exposure or with exposure to only one NRTI, no MNR was observed. MNR was present in low prevalence (each pattern &lt; 2%) in patients pretreated with multiple NRTIs. Despite this low prevalence, MNR should be closely monitored, since it results in broad cross-resistance to NRTIs in vitro and a poor therapy response in vivo. We also assessed the predictive value of baseline resistance on the virologic response to later added drugs. The genotype of patients starting or changing a therapy consisting solely of NRTIs was analyzed at baseline and 6 months later. In patients without genotypic mutations towards the added drug the virologic response was significantly better compared to patients with baseline resistance. At 6 months however, both patient groups showed a rise in viral load due to the accumulation of NRTI-related mutations under the presence of poorly suppressive regimens, although the difference between the two groups remained significant. In this study, and also in studies reported by others, the presence of baseline resistance has a high predictive value for therapy failure, while the absence of resistance is not predictive for therapy response. Suboptimal adherence may be one of the reasons of the poor predictive value of the absence of baseline resistance for a good therapy response. In a last observational study, we investigated the relation between adherence, the presence and development of genotypic resistance and the virologic response in patients during HAART therapy. Adherence to 1 protease inhibitor was monitored using Electronic Event Monitoring. Patients with perfect therapy adherence and in particular without drug holidays, can control viral replication provided that the activity of the drugs included in the combination is not entirely compromised by the presence of baseline resistance mutations. In our patient population, reduced adherence resulted in therapy failure, mostly associated with a subsequent accumulation of resistance mutations. In conclusion, the outcome of the HIV disease has been revolutionarily changed with the advent of HAART. Both resistance and treatment adherence are crucial factors in determining the therapy response. Retrospective studies, such as ours, and a limited number of prospective trials already proved the short-term benefit of therapy switch based on the results of resistance tests in addition to standard of care. To ultimately define the role of tools as resistance testing and adherence monitoring with eventual adherence interventions, more prospective trials are needed as well in treatment-naïve as in experienced patients.

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Malaria in humans is caused by intraerythrocytic protozoa of the genus Plasmodium. These parasites are transmitted by the bite of an infective female Anopheles species mosquito. Most malaria infections in the United States and its territories occur among persons who have traveled to regions with ongoing malaria transmission. However, among persons who have not traveled out of the country, malaria is occasionally acquired through exposure to infected blood or tissues, congenital transmission, nosocomial exposure, or local mosquitoborne transmission. Malaria surveillance in the United States and its territories provides information on its occurrence (e.g., temporal, geographic, and demographic), guides prevention and treatment recommendations for travelers and patients, and facilitates rapid transmission control measures if locally acquired cases are identified. This report summarizes confirmed malaria cases in persons with onset of illness in 2018 and trends in previous years. Malaria cases diagnosed by blood smear microscopy, polymerase chain reaction, or rapid diagnostic tests are reported to local and state health departments through electronic laboratory reports or by health care providers or laboratory staff members directly reporting to CDC or health departments. Case investigations are conducted by local and state health departments, and reports are transmitted to CDC through the National Malaria Surveillance System (NMSS), the National Notifiable Diseases Surveillance System (NNDSS), or direct CDC clinical consultations. CDC reference laboratories provide diagnostic assistance and conduct antimalarial drug resistance marker testing on blood specimens submitted by health care providers or local or state health departments. This report summarizes data from the integration of all cases from NMSS and NNDSS, CDC clinical consultations, and CDC reference laboratory reports. CDC received reports of 1,823 confirmed malaria cases with onset of symptoms in 2018, including one cryptic case and one case acquired through a bone marrow transplant. The number of cases reported in 2018 is 15.6% fewer than in 2017. The number of cases diagnosed in the United States and its territories has been increasing since the mid-1970s; the number of cases reported in 2017 was the highest since 1972. Of the cases in 2018, a total of 1,519 (85.0%) were imported cases that originated from Africa; 1,061 (69.9%) of the cases from Africa were from West Africa, a similar proportion to what was observed in 2017. Among all cases, P. falciparum accounted for most infections (1,273 [69.8%]), followed by P. vivax (173 [9.5%]), P. ovale (95 [5.2%]), and P. malariae (48 [2.6%]). For the first time since 2008, an imported case of P. knowlesi was identified in the United States and its territories. Infections by two or more species accounted for 17 cases (&lt;1.0%). The infecting species was not reported or was undetermined in 216 cases (11.9%). Most patients (92.6%) had symptom onset &lt;90 days after returning to the United States or its territories from a country with malaria transmission. Of the U.S. civilian patients who reported reason for travel, 77.0% were visiting friends and relatives. Chemoprophylaxis with antimalarial medications are recommended for U.S. residents to prevent malaria while traveling in countries where it is endemic. Fewer U.S. residents with imported malaria reported taking any malaria chemoprophylaxis in 2018 (24.5%) than in 2017 (28.4%), and adherence was poor among those who took chemoprophylaxis. Among the 864 U.S. residents with malaria for whom information on chemoprophylaxis use and travel region were known, 95.0% did not adhere to or did not take a CDC-recommended chemoprophylaxis regimen. Among 683 women with malaria, 19 reported being pregnant. Of these, 11 pregnant women were U.S. residents, and one of whom reported taking chemoprophylaxis to prevent malaria but her adherence to chemoprophylaxis was not reported. Thirty-eight (2.1%) malaria cases occurred among U.S. military personnel in 2018, more than in 2017 (26 [1.2%]). Among all reported malaria cases in 2018, a total of 251 (13.8%) were classified as severe malaria illness, and seven persons died from malaria. In 2018, CDC analyzed 106 P. falciparum-positive and four P. falciparum mixed species specimens for antimalarial resistance markers (although certain loci were untestable in some specimens); identification of genetic polymorphisms associated with resistance to pyrimethamine were found in 99 (98.0%), to sulfadoxine in 49 (49.6%), to chloroquine in 50 (45.5%), and to mefloquine in two (2.0%); no specimens tested contained a marker for atovaquone or artemisinin resistance. The importation of malaria reflects the overall trends in global travel to and from areas where malaria is endemic, and 15.6% fewer cases were imported in 2018 compared with 2017. Of imported cases, 59.3% were among persons who had traveled from West Africa. Among U.S. civilians, visiting friends and relatives was the most common reason for travel (77.1%). The best way for U.S. residents to prevent malaria is to take chemoprophylaxis medication before, during, and after travel to a country where malaria is endemic. Adherence to recommended malaria prevention strategies among U.S. travelers would reduce the number of imported cases. Reported reasons for nonadherence include prematurely stopping after leaving the area where malaria was endemic, forgetting to take the medication, and experiencing a side effect. Health care providers can make travelers aware of the risks posed by malaria and incorporate education to motivate them to be adherent to chemoprophylaxis. Malaria infections can be fatal if not diagnosed and treated promptly with antimalarial medications appropriate for the patient's age, pregnancy status, medical history, the likely country of malaria acquisition, and previous use of antimalarial chemoprophylaxis. Antimalarial use for chemoprophylaxis and treatment should be determined by the CDC guidelines, which are frequently updated. In April 2019, intravenous (IV) artesunate became the first-line medication for treatment of severe malaria in the United States and its territories. Artesunate was approved by the Food and Drug Administration (FDA) in 2020 and is commercially available (Artesunate for Injection) from major U.S. drug distributors (https://amivas.com). Stocking IV artesunate locally allows for immediate treatment of severe malaria once diagnosed and provides patients with the best chance of a complete recovery and no sequelae. With commercial IV artesunate now available, CDC will discontinue distribution of non-FDA-approved IV artesunate under an investigational new drug protocol on September 30, 2022. Detailed recommendations for preventing malaria are online at https://www.cdc.gov/malaria/travelers/drugs.html. Malaria diagnosis and treatment recommendations are also available online at https://www.cdc.gov/malaria/diagnosis_treatment. Health care providers who have sought urgent infectious disease consultation and require additional assistance on diagnosis and treatment of malaria can call the Malaria Hotline 9:00 a.m.-5:00 p.m. Eastern Time, Monday-Friday, at 770-488-7788 or 855-856-4713 or after hours for urgent inquiries at 770-488-7100. Persons submitting malaria case reports (care providers, laboratories, and state and local public health officials) should provide complete information because incomplete reporting compromises case investigations and public health efforts to prevent future infections and examine trends in malaria cases. Molecular surveillance of antimalarial drug resistance markers enables CDC to track, guide treatment, and manage drug resistance in malaria parasites both domestically and globally. A greater proportion of specimens from domestic malaria cases are needed to improve the completeness of antimalarial drug resistance analysis; therefore, CDC requests that blood specimens be submitted for any case of malaria diagnosed in the United States and its territories.

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Sodium dichromate dihydrate is one of a number of inorganic compounds containing hexavalent chromium (CR VI) found in drinking water supplies as a contaminant resulting from various industrial processes including electroplating operations, leather tanning, and textile manufacturing. Because of the lack of adequate experimental data on the toxicity and carcinogenicity of hexavalent chromium ingested orally, and because hexavalent chromium has been found in human drinking water supplies, the California Congressional delegation and the California Environmental Protection Agency nominated hexavalent chromium to the NTP for study. In study 1, male and female F344/N rats and B6C3F1 mice were exposed to sodium dichromate dihydrate (greater than 99% pure) in drinking water for 3 months. In study 2, sodium dichromate dihydrate was administered in drinking water to male B6C3F1, BALB/c, and am3-C57BL/6 mice for 3 months. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, and mouse peripheral blood erythrocytes. In study 1, groups of 10 male and 10 female F344/N rats and B6C3F1 mice were given drinking water containing 0, 62.5, 125, 250, 500, or 1,000 mg sodium dichromate dihydrate/L for 3 months (equivalent to average daily doses of approximately 5, 10, 17, 32, or 60 mg sodium dichromate dihydrate/kg body weight to rats and 9, 15, 26, 45, or 80 mg/kg to mice). On a molecular weight basis, these doses are equivalent to approximately 1.7, 3.5, 5.9, 11.2, and 20.9 mg hexavalent chromium/kg body weight per day to rats and 3.1, 5.2, 9.1, 15.7, and 27.9 mg/kg per day to mice. Additional groups of 10 rats per sex were exposed to the same concentrations of sodium dichromate dihydrate for 4 weeks. All rats and mice survived to the end of the study. Reduced body weights occurred in 500 and 1,000 mg/L male rats, 1,000 mg/L female rats, and in male and female mice exposed to 125 mg/L or greater. Water consumption by male and female rats exposed to 250 mg/L or greater and male and female mice exposed to 125 mg/L or greater was generally less than that by the control groups, and decreases in urine volume and increases in urine specific gravity in rats were related to reduced water consumption. Exposure to sodium dichromate dihydrate caused a microcytic hypochromic anemia in rats and mice, but the severity was less in mice. Serum cholesterol and triglyceride concentrations were decreased in rats. Increased bile acid concentrations in exposed groups of rats may have been due to altered hepatic function. The incidences of histiocytic cellular infiltration were generally significantly increased in the duodenum of rats and mice, the liver of female rats, and the mesenteric lymph node of mice exposed to 125 mg/L or greater. Significantly increased nonneoplastic lesions (focal ulceration, regenerative epithelial hyperplasia, and squamous epithelial metaplasia) occurred in the glandular stomach of male and female rats exposed to 1,000 mg/L. Incidences of epithelial hyperplasia of the duodenum were significantly increased in all exposed groups of mice. In study 2, sodium dichromate dihydrate was administered in drinking water to groups of 10 male B6C3F1, 10 male BALB/c, and five male am3-C57BL/6 mice for 3 months at exposure concentrations of 0, 62.5, 125, or 250 mg/L (equivalent to average daily doses of approximately 8, 15, or 25 mg/kg sodium dichromate dihydrate or 2.8, 5.2, or 8.7 mg/kg chromium to B6C3F1, BALB/c, and am3-C57BL/6 mice). All mice in study 2 survived until study termination. Mean body weights of 125 and 250 mg/L B6C3F1 and BALB/c mice and all exposed groups of am3-C57BL/6 mice were less than those of the control groups. Mice exposed to 250 mg/L consumed less water than the control groups. Exposure concentration-related decreases in mean red cell volumes and mean red cell hemoglobin values were observed in all three mouse strains. Erythrocyte counts were increased in exposed B6C3F1 and BALB/c mice but not in am3-C57BL/6 mice. Changes in organ weights were generally consistent with reduced body weights in exposed groups in all mouse strains. No biologically significant differences in reproductive parameters were observed in any strain. Histiocytic cellular infiltration and epithelial hyperplasia of the duodenum occurred in most mice exposed to 125 or 250 mg/L, and the incidences of these lesions were increased in the 62.5 mg/L group compared to controls. Secretory depletion was present in the pancreas of most mice exposed to 125 or 250 mg/L. The incidences of glycogen depletion of the liver were significantly increased in male B6C3F1 mice exposed to 125 or 250 mg/L and in all exposed groups of male am3-C57BL/6 mice. The incidence of histiocytic cellular infiltration in the mesenteric lymph node was significantly increased in the 250 mg/L group of male am3-C57BL/6 mice. Sodium dichromate dihydrate was mutagenic in S. typhimurium strains TA100 and TA98 and in E. coli strain WP2 uvrA pKM101 with and without induced rat liver S9 enzymes. The results of four micronucleus tests conducted in the three strains of mice from studies 1 and 2 were mixed. In study 1, no significant increases were seen in micronucleated normochromatic erythrocytes in peripheral blood samples from male or female B6C3F1 mice; there was a decrease in the percentage of polychromatic erythrocytes among total erythrocytes (an indication of bone marrow toxicity), but the changes were small and not well correlated with exposure concentrations. In study 2, a significant exposure concentration-related increase (P&lt;0.001) in micronucleated normochromatic erythrocytes was seen in am3-C57BL/6 male mice. An equivocal increase in micronucleated erythrocytes was noted in male B6C3F1 mice, based on a small increase in micronucleated normochromatic erythrocytes that did not reach statistical significance. No increase in micronucleated normochromatic erythrocytes was observed in male BALB/c mice. No significant effect of sodium dichromate dihydrate exposure on the percentage of polychromatic erythrocytes was observed in any of the three micronucleus tests conducted in study 2. In summary, administration of sodium dichromate dihydrate in the drinking water to F344/N rats and B6C3F1 mice resulted in focal ulceration, hyperplasia, and metaplasia in the glandular stomach at the limiting ridge in rats in the 1,000 mg/L group and evidence of increased histiocytic infiltration in the liver (female), duodenum of the small intestine, and/or pancreatic lymph nodes at concentrations as low as 62.5 mg/L, the lowest concentration studied. In addition, a microcytic, hypochromic anemia occurred at all exposure concentrations and was considered evidence of a toxic response resulting from absorption of Cr VI following oral ingestion in rats. A similar, but less severe, anemia was evident in mice receiving drinking water containing sodium dichromate dihydrate; histiocytic infiltration was noted in the duodenum of all three strains studied (B6C3F1, BALB/c, and am3-C57BL/6) at all concentrations employed, in the mesenteric lymph nodes at 125 mg/L or greater in the B6C3F1 strain, and at 250 mg/L in the am3-C57BL/6 strain. There was no consistent evidence of hepatocyte injury in mice in any of the strains tested. Variations in glycogen content were considered more likely related to diminished food intake than to the toxicity of sodium dichromate dihydrate. Synonyms: Chromic acid; dichromic acid; disodium salt, dihydrate; disodium dichromate dihydrate; chromium VI.

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Until recently diphtheria " toxin " was supposed to be a single definite substance and to have a definite toxicity in animals and neutralizing power for antitoxin. A fatal dose of toxin, without regard to the conditions under which it was produced or preserved, was supposed to require always the same quantity of antitoxin to neutralize it. Ehrlich's researches have completely done away with this theory, and have substituted for it one which assumes the toxin to be only at its origin a single definite chemical compound with definite physiological and antitoxic properties. According to Ehrlich the toxin is an unstable substance which readily loses its toxicity, while at the same time its affinity for antitoxin may be either increased or decreased. Its neutralization by antitoxin he considers to be due to a chemical union between the toxin and the antitoxin. The results of our experiments as detailed in this paper are fully in accord with those published by Ehrlich, as to the varying neutralizing value of a minimal fatal dose of " toxin "; they, however, go further and indicate roughly a general law in accordance with which these changes occur. The neutralizing value of a fatal dose of toxin is at its lowest in the culture fluid when the first considerable amounts of toxin have been produced. After a short period, during which the quantity of toxin in the fluid is increasing, the neutralizing value of the fatal dose begins to increase, at first rapidly, then more slowly. While the culture is still in vigorous growth and new toxin is being produced, the neutralizing value of the fatal dose fluctuates somewhat, but with a generally upward tendency. After the cessation of toxin production the neutralizing value of the fatal dose increases steadily until it becomes five to ten times its original amount. In our experiments the greatest value for L(+) was 126, the least 27. As at 6 hours L(+) was only 72 and at 28 hours only 91, we doubt whether L(+) ever reaches above 150, and therefore hardly expect Ehrlich's figures of 200 to be realized. When we seek to analyze the above-described process, we find certain facts which seem partly to explain it. Experiments have shown that filtered toxin, preserved for any length of time in conditions under which access of air occurs, gradually loses in both its toxicity and neutralizing power, and that it loses more rapidly in the former property than in the later. Thus, while the fatal dose of a toxin preserved for one year rose from .01 cc. to .55 cc., it lost only half as much in neutralizing value, one unit neutralizing at first 1 cc., at the end of the year 25 cc. These processes take place more rapidly at room temperature than in the ice chest, and in the incubator than in the room. In the fluid holding the living bacilli we have, therefore, after the first few hours of toxin formation, a double process going on, one of deterioration in the toxin already accumulated, which tends to increase the neutralizing value of the fatal dose, the other of new toxin formation, which probably tends to diminish the neutralizing value. The chemical changes produced by the growth of the bacilli in the bouillon tend to aid one or the other of these processes and so to make from hour to hour slight changes in the value of the fatal dose. Later, with the period of cessation of toxin production, the gradual deterioration of the toxicity alone continues, and the fatal dose gradually and steadily increases in its neutralizing value. Ehrlich's theories, as to the splitting up of " toxin " into toxoids having little or no toxicity but on the average full neutralizing power for antitoxin, have not in our opinion been substantiated by the results of these experiments. The difference between the amount of toxin mixed with a unit of antitoxin which causes the first symptoms and that causing death upon the fourth day would be, it is true, explained by his theory, but the failure of this difference to be greater where, by his theories, epitoxoids should be in great abundance prevents our acceptance of his views. The fact of the greater neutralization value of a fatal dose of a deteriorated toxin would be accounted for on his protoxoid theory. This, however, is not proof of its correctness, as other theories, such as the production by the diphtheria bacillus of two or more closely allied toxins, similar to the allied alkaloids produced by plants, would equally account for it, if we supposed the one which had the greater neutralization value was more resistant to destruction than the other. We only advance this theory to call attention to the fact that many theories can on paper explain a process without necessarily being thereby established. Even if his theories prove partially correct, we feel certain that his formula for standardizing toxins is founded upon error and cannot be employed for the purpose intended by him. While we do not believe, therefore, that he has changed the principles of testing antitoxin, yet we believe he has contributed greatly to uniformity in results by calling attention to the necessity of selecting a suitable toxin and by employing and distributing an antitoxin as a standard to test toxins by. In this way smaller testing stations can make their results correspond with those of the central station. In spite of the great variations in the neutralizing value of a fatal dose in different toxins, we do not believe there has been any such great difference in the toxins used by the different stations for testing purposes. Most laboratories have taken the culture fluid at about the time of its greatest toxicity, and the neutralizing value of a fatal dose of this toxin would seldom vary more than 10 per cent above or below the standard now adopted in Germany by the government testing station, this latter being presumably as close as possible to that used to establish the original Behring-EhrIich unit. Where error has been made, it has usually been by taking too old culture fluids, which would cause the antitoxin strength of samples tested to be estimated below and not above its real value. Culture 8, which is used not only by us but by many other laboratories in the United States and Europe, fortunately produces on the 6th day, the time at which the culture is usually removed, a toxin which grades Elirlich's antitoxin within five per cent of the strength given by him. We believe that by using such a bacillus, we can, after gaining a fuller knowledge of its characteristics, obtain a toxin of a known and suitable neutralizing value, and thus always correctly standardize an antitoxic serum. Meanwhile a fairly permanent antitoxin, such as Ehrlich provides, is of immense value in insuring a uniform though not necessarily correct standard among the different testing stations and in allowing of comparison between them.

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The development of modern materials science has led to a growing need to understand the phenomena determining the properties of materials on an atomistic level. As the behavior of atoms and electrons is governed by the laws of quantum mechanics, accurate and efficient techniques for solving the basic quantum-mechanical equations for very complex many-atom, many-electron systems are required. The development of density-functional theory (DFT) represents a decisive step forwards in our efforts to develop tools for ab initio atomistic simulations of complex materials, preparing the way towards computational materials design. The development of these ab initio simulation methods, whose aim is to model processes in materials by solving the coupled Newtonian equations of motion of the atoms and the Schrödinger equation for the electrons from first principles without any other input than the atomic numbers of the constituents, is part of fundamental research. Hence, for a long time the development and application of DFT methods has been a domain of academic research. Only during the past decade, based on the development of increasingly sophisticated codes and better computer performance, has the impact of DFT-based simulation methods has spread from academia to industry. New opportunities are opening for innovative materials research across physics, chemistry, surface science and nanotechnology extending even to earth sciences and molecular biology. In 1998 we organized, at the Vienna University of Technology, a first workshop entitled 'Electronic Structure Calculations for Industry and Basic Sciences' (short title 'Theory meets Industry') to celebrate the start of the European Science Foundation (ESF) research program 'Electronic Structure Calculations for Elucidating the Complex Atomistic Behavior of Solids and Surfaces', known as the Ψ(k)-network. At this workshop, researchers from academia presented recent results in the development of ab initio simulation methods and their application to key areas of condensed matter physics. Researchers from industry mainly focused on challenges arising from applied industrial research; contributions describing successful applications of DFT techniques to industrial problems were more scarce. Progress during the last decade has been very fast. The ESF research program has been renewed under the much bolder title 'Towards Computational Materials Design' and is now approaching the end of this second funding period. Due to the development of accurate, efficient and stable software packages for ab initio simulations, DFT-based techniques are now routinely used in many industrial laboratories worldwide. It was therefore considered timely to organize a second 'Theory meets Industry' workshop. The meeting took place between 12-14 June 2007 at the Erwin-Schrödinger-Institute (ESI) for Mathematical Physics in Vienna (Austria). It was sponsored by the Universität Wien through the VASP (Vienna Ab-initio Simulation Program) project, the Center for Computational Materials Science Vienna, the Erwin-Schrödinger-Institute and the ESF Program 'Towards Computational Materials Design'. The program of the workshop was decided by an international advisory board consisting of Ryoji Asahi (Toyota Central Research and Development Laboratory), Risto Nieminen (Helsinki University of Technology), Herve Toulhoat (Institut Français du Pétrole), Erich Wimmer (Materials Design Inc.), Chris Wolverton (Ford Motor Co. and Northwestern University) and Jürgen Hafner (Universität Wien). The 35 invited talks presented at the meeting were divided equally between researchers from academia and from industry. The contributions from academia concentrated on a wide range of new developments in DFT and post-DFT simulations (with contributions from the developers of leading software packages for ab initio simulations), as well as on applications in front-line materials research. In contrast to the first workshop nine years ago, all industrial speakers presented results of extensive ab initio studies in key areas of modern technology, concentrating on catalysis and chemical processing, information technologies, automotive engineering and energy. The proceedings assemble full papers summarizing 23 of the invited talks, abstracts of the remaining invited talks and abstracts of all the poster contributions. It is complemented by a conference summary written by Erich Wimmer. Erich is certainly excellently qualified for this task, because for many years he has played the role of mediator between academia and industry. I shall not anticipate his summary here, but I think that it is fair to say that tremendous progress has been made since the first workshop. Ab initio DFT simulations are now a well established tool for industrial research and, due to the availability of cheap high-performance server clusters, their use is no longer the reserve of large corporate laboratories equipped with supercomputers, but are also accessible to medium-sized enterprises. The basic methodology is still developed by the leading academic research groups. These groups urgently need support from funding agencies and/or industry not only for the basic code development, but also to bring their research codes up to industrial standards of programming, stability, user-friendliness and documentation. The fundamental challenge to theory, however, remains the same: more accurate total energies, application to larger and even more complex systems, and access to new materials properties. Responding to these challenges will require substantial effort at various levels. Achieving greatly improved accuracy of calculated total energies demands an improved description of electronic exchange and correlation. Possible routes (hybrid functionals for solids, dynamical mean field theory (DMFT), many-body perturbation theory (GW), quantum Monte-Carlo) have been presented at this meeting. Access to larger systems could be realized either by codes achieving O (N)-scaling or by adopting a strategy of multi-scale simulations. At least two different O (N)-codes have been discussed at the workshop. But even if these approaches allow ab initio calculations to be performed for ten times as many atoms as before, in terms of linear dimensions, the accessible systems size increases only by a factor of two. Therefore, multi-scale simulations strategies remain a very important issue. Access to new materials properties requires adding new routines to the basic codes. Again, this meeting has highlighted important new developments: evolutionary crystal structure predictions, transport properties of semiconductors and insulators, and calculations of free-energy reaction barriers to name only a few. The task of providing a full 'tool-box' of routines for fast and efficient calculation of many different materials properties evidently exceeds the capacity of a single group of developers. Here, collaboration is necessary between the developers of the basic DFT codes and the expert users of these codes pushing the application of the methodology to new frontiers. Again, it will be important to bring the newly developed routines into a stable, well documented form and to make them accessible to a wide range of users, both in academia and industry. Supporting these efforts is also a challenge to industry. The academic research needs industry's support in many ways. Industry has to make governmental and funding agencies aware of the vital role of our research for future technological development-and a very persuasive way to do that is to invest directly into leading academic groups. As the workshop organizer and editor of the proceedings, I would like to thank all contributors (especially those who accepted the burden of writing a full paper), the members of the Advisory Board for helping to organize such a good program, and the Institute of Physics for their help in the preparation of the proceedings.

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Ampligen [polyI:polyC12U] is a mismatched double-stranded RNA that acts by inducing interferon production (immunomodulator) and by activating an intracellular enzyme (RNase-L) against viral RNA transcripts (antiviral). Ampligen, currently under development by Hemispherx Biopharma in the US, acts on the immunological system through T-lymphocyte stimulation and is indicated for the treatment of chronic fatigue syndrome and acquired immunodeficiency deficiency syndrome (AIDS), as part of the combined therapy. Ampligen is available for licensing worldwide. In February 2004, Fujisawa Deutschland GmbH, a subsidiary of Fujisawa Pharmaceutical Co., entered into an option agreement with Hemispherx Biopharma with the intent of becoming a distributor for Ampligen for the potential treatment of chronic fatigue syndrome in Germany, Switzerland and Austria. An option fee of 400,000 euros was paid pursuant to the terms of the option agreement and upon execution of the Distribution Agreement, Fujisawa will pay Hemispherx fees and milestone payments with a potential worth of several millions of dollars. In September 2003, Hemispherx Biopharma Inc. entered into an agreement with Guangdong Medicine Group Corporation to organise clinical trials, marketing, sales and distribution for both of its lead compounds, Ampligen and Alferon N in the People's Republic of China. The agreement stipulates that the Guangdong Medicine Group Corporation (GMC) will conduct clinical trials with Ampligen for the treatment of HIV. All costs related to the trials are to be covered by GMC. Additionally, GMC has to develop and implement marketing and promotional programmes. In May 2003, Hemispherx Biopharma and the Center for Cell and Gene Therapy entered into a research project agreement that will see Ampligen implemented in a protocol used in patients with relapsed EBV-positive Hodgkin's Lymphoma. In March 2002, Esteve and Hemispherx Biopharma entered into a collaborative agreement under which Esteve will be the sole distributor of Ampligen in Spain, Portugal and Andorra for the treatment of chronic fatigue syndrome. Under this agreement, in addition to other terms, Esteve will also collaborate in the drug product development by conducting clinical studies in Spain in patients coinfected with HIV/HCV. In July 2001 Hemispherx Biopharma announced that it had formed a strategic alliance with Empire Health Resources for clinical trials of Ampligen in the treatment of HIV and hepatitis C virus infections. Empire Health Resources, a healthcare management firm, will be responsible for accrual and retention of patients for HIV trials, and protocols for trials in patients with hepatitis C or both HIV and hepatitis C infections. Hemispherx has entered into a collaboration with RED Laboratories, and RED Laboratories NV expects that this will facilitate the continued development of Ampligen. Hemispherx has also entered into an agreement with Schering Plough to use a Schering facility as its principal manufacturing platform in the US. This agreement may be expanded to include other territories. Hemispherx and AOP Orphan Pharmaceuticals have signed a marketing agreement for Ampligen for the treatment of chronic fatigue syndrome for Austria, the Czech Republic, Poland and Hungary. In an arrangement between Hemispherx and Bioclones, Bioclones has certain marketing rights for Ampligen in the Southern Hemisphere, UK and Ireland. In the US, Ampligen has been granted orphan drug status for the treatment of AIDS, renal cell carcinoma (phase II, completed), chronic fatigue syndrome (phase III) and invasive/metastatic malignant melanoma (phase II). In August 2004, Hemispherx announced that it intends to use the proceeds from the private placement of company stock to complete the clinical work for its immunotherapeutics/ antivirals Ampligen and Oragens. Previously, Hemispherx submitted an application to the EMEA for the approval of Ampligen for the treatment of chronic fatigue syndrome; the first stage of th;) for the treatment of chronic fatigue syndrome; the first stage of the regulatory review has been cleared. In 2000, Hemispherx Europe (Hemispherx) obtained orphan drug status for Ampligen for the treatment of chronic fatigue syndrome in the EU, providing Hemispherx with 10 years of marketing exclusivity following the launch of the drug, as well as potential financial research benefits for the agent. In February 2000, Crystaal Corporation (now Biovail Pharmaceuticals Canada) acquired exclusive marketing rights to Ampligen in Canada, where it submitted an NDA for the agent for the treatment of chronic fatigue syndrome. In the meantime, Ampligen has been available since May 1996 under the Canadian Emergency Drug Release Programme for the treatment of chronic fatigue syndrome and immune dysfunction syndrome by Rivex Pharma (Helix BioPharma). Bioclones has initiated clinical studies with Ampligen for the treatment of chronic fatigue syndrome in Australia. The active substance for Ampligen is manufactured by F.H. Faulding Ltd. Clinical treatment programmes for chronic fatigue syndrome in other Pacific Rim countries are planned. Ampligen is available for severe chronic fatigue syndrome on a named patient, cost-recovery basis in South Africa. Hemispherx has developed a 'ready-to-use' liquid formulation of the drug and has begun treating patients with chronic fatigue syndrome in ongoing clinical trials. Hemispherx has also developed an oral version of the drug (Oragen), which is undergoing preclinical evaluation. In February 2001, Hemispherx Biopharma announced that it was initiating phase II/III trials of Ampligen in the treatment of late-stage, multidrug-resistant strains of HIV in the European Union. Patients treated in these studies will have exhausted all other treatment options. In July 2001, Hemispherx stated that Ampligen was being evaluated in a phase IIb trial in patients with HIV in the US. The trial, comprising two studies, REARMI and REARMII (Research/Evaluation of Ampligen for Retroviral Mutations I and II), will evaluate the ability of Ampligen to prevent the emergence of mutated, drug-resistant strains of the virus. 'Several hundred' patients currently on antiretroviral therapy and at risk of viral relapse will be enrolled at centres in Connecticut, New York, Florida and California. A second phase IIb study evaluating the effect of Ampligen on structured treatment interruptions (STI) is also underway. Final results from this study were reported in December 2002. NIH sponsored studies of potential therapies for SARS have identified Ampligen as having unusually high and consistent antiviral activity against human coronavirus, the pathogen implicated as the causative agent of the disease. Ampligen demonstrated very high potency at very low concentrations (0.4 microg/mL) and had a favourable safety profile. In October 2003, Hemispherx announced that, based on these promising new results, the company will stockpile injectible and/or oral formats of Ampligen and Alferon N. Independent researchers have demonstrated the antiviral activity of Ampligen against flaviviruses (West Nile virus, Equine Encephalitis virus, Dengue fever virus and Japanese Encephalitis virus) as well as virus classes associated with bioterrorism. In an animal study, Ampligen was shown to prevent destruction of nerve cells, reduce virus concentrations in the brain and blood stream and increase survival rates. Researchers at the Rega Institute in Belgium have published results from an animal study demonstrating that Ampligen was superior at protecting mice against coxsackie B3 virus-induced myocarditis compared with pegylated interferon. In May 2004 Hemispherx announced that it had filed an expanded US patent application covering the use of Ampligen for the potential treatment and prevention of severe acute respiratory syndrome (SARS) and dreaded emerging viruses.

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In view of the effective traditional Chinese medicine (TCM) in the treatment of clinical depression, the mechanism is not clear, this study attempts to research the cause of depression in a complex situation to lay the foundation for the next step of TCM curative effect evaluation. Based on the brain wave of 120 depression patients and 40 ordinary person, the change regulation of acetylcholine, dopamine, norepinephrine, depression neurotransmitters and excited neurotransmitters in the whole and various encephalic regions' multi-neurotransmitters of depression patients-serotonin are analysed by search of encephalo-telex (SET) system, which lays the foundation for the diagnosis of depression. The result showed that: contrased with the normal person group, the mean value of the six neurotransmitters in depression patients group are: (1) in the whole encephalic region of depression patients group the dopamine fall (P &lt; 0.05), and in the double centralregions, right temporal region and right parietal region distinct fall (P &lt; 0.01); (2) in the right temporal region of depression patients group the serotonin rise (P &lt; 0.05); (3) in the right central region, left parietal region of depression patients group the acetylcholine fall (P &lt; 0.05), left rear temporal region fall obviously (P &lt; 0.01). The correlation research between antagonizing pairs of neurotransmitters and neurotransmitters: (1) the three antagonizing pairs of neurotransmitters-serotonin and dopamine, acetylcholine and norepinephrine, depression neurotransmitters and excited neurotransmitters, in ordinary person group and depression patients group are characterizeed by middle or strong negative correlation. Serotonin and dopamine, which are characterized by weak negative correlation in the right rear temporal region of ordinary person group, are characterized by strong negative correlation in the other encephalic regions and the whole encephalic (ordinary person group except the right rear temporal region: the range of [r] is [0.82, 0.92], P &lt; 0.01)/(depression patients group:the range of [r] is [0.88, 0.94], P &lt; 0.01); acetylcholine and norepinephrine, in the whole and various encephalic region are characterized by middle negative correlation(ordinary person group:the range of [r] is [0.39, 0.76], P &lt; 0.01 or P &lt; 0.05)/(depression patients group: the range of [Ir] is [0.56, 0.64], P &lt; 0.01); depression neurotransmitters and excited neurotransmitters are characterized by middle strong negative correlation (ordinary person group: the range of [r] is [0.57, 0.80], P &lt; 0.01)/(depression patients group: the range of [r] is [0.68, 0.78], P &lt; 0.01). (2) The two neurotransmitters which are not antagonizing pairs of neurotransmitters, serotonin and excited neurotransmitters, or acetylcholine and depression neurotra-nsmitters, or dopamine and depression neurotransmitters in the various encephalic regions are characterized by weak negative correlation. Serotonin and excited neurotransmitters are characterizeed by weak negative correlation (ordinary person group: in the right central region, left parietal region, double front temporal regions, right rear temporal region, the range of [r] is [0.25, 0.50], P &lt; 0.01 or P &lt; 0.05)/(depression patients group: in the whole encephalic regions, double parietal regions, double occipital regions, right front temporal region, left central region, left frontal region, the range of [r] is [0.18, 0.37], P &lt; 0.01 or P &lt; 0.05); acetylcholine and depression, neurotransmitters are characterized by weak negative correlation (ordinary person group: in the double frontal regions, left parietal region, left front temporal region, right rear temporal region, the range of [r] is [0.31, 0.46], P &lt; 0.01 or P &lt; 0.05)/(depression patients group: in double rear temporal regions, right front temporal region, double occipital regions, left central region, the range of [r] is [0.20, 0.32] , P &lt; 0.01 or P &lt; 0.05); do-pamine and depression neurotransmitters are characterized by weak middle negative correlation (ordinary person group: in left parietal region, right central region, left frontal region, left occipital region, double front temporal regions, the range of [r] is [0.33, 0.68], P &lt; 0.01 or P &lt; 0.05)/(depression patients group: in the whole region and other various regions except the left frontal region, right central region, the range of Irl is [0.21, 0.34], P &lt; 0.01 or P &lt; 0.05). Dopamine and acetylcholine or norepinephrine and serotonin are characterized by weak positive correlation in all encephalic regions. Dopamine and acetylcholine are characterized by weak positive correlation (ordinary person group: in left frontal region, right parietal region, left front temporal region and left rear temporal region, the range of [r] is [0.37, 0.46], P &lt; 0.01)/(depression patients group: in the whole region and the orther various regions except the double central regions, the range of [r] is [0.23, 0.5], P &lt; 0.01 or P &lt; 0.05); norepinephrine and serotonin are characterized by weak positive correlation (ordinary person group: in double front temporal regions, double rear temporal regions, right frontal region and left parietal region, the range of [r] is [0.34, 0.48], P &lt; 0.01 or P &lt; 0.05)/(depression patients group: in the whole and various regions, the range of [r] is [0.18, 0.42], P &lt; 0.01). The main differences between the depression patients group and ordinary person group are: (1) In the whole regin, left frontal region and right central region of depression patients group, the six neurotransmitters all fall normally (P &lt; 0.05). (2) The percent of dopamine falling or including dopamine falling, or including dopamine falling and serotonin rising in depression patients group increases. The percent of dopamine falling or including dopamine falling in the whole region, right frontal region, right central region increases (P &lt; 0.01), such as dopamine decreasing, serotonin increasing dopamine decreasing, serotonin increasing acetylcholine decreasing dopamine decreasing, dopamine decreasing norepinephrine increasing depression neurotransmitters decreasing, serotonin increasing acetylcholine decreasing dopamine decreasing neurotransmitters increasing and so on. (3) The percent of acetylcholine falling, or including acetylcholine falling, or including acetylcholine falling and neurotransmitters (beta)-receptor)rising in depression patients group increases. The percent of acetylcholine falling, or including acetylcholine falling in the right temporal region, double central regions increases (P &lt; 0.05 or P &lt; 0.01), such as acetylcholine decreasing, acetylcholine decreasing neurotransmitters increaseng, acetylcholine decreasing neurotransmitters increasing depression neurotransmitters decreasing, serotonin increasing acetylcholine decreasing dopamine decreasing neurotransmitters increasing and so on. It's showed in research that depression patients' brain are characterized by multi-neurotransmitters abnormal, the synchronous change of multi-neurotransmitters has some certain regularities, which are not the simple linear relation. It's conformed that the three antagonizing pairs, neurotransmitters-serotonin and dopamine, acetylcholine and norepinephrine, depression eurotransmitters and excited neurotransmitters of ordinary person group and depression patients group, are both characterized by strong antagonizing relation, that the two neurotransmitters which are not antagonizing pairs of neurotransmitters are characterized by weak positive correlation or negative correlation, prompt maybe has the indirect causal relationship. And the change of six neurotransmitters in depression patients' various encephalic regions is rather complex. It's conformed preliminarily that the right frontal region and right central region are characterized by dopamine decreasing, acetylcholine decreasing, serotonin increasing dopamine decreasing, serotonin increasing acetylcholine decreasing dopamine decreasing, dopamine decreasing norepinephrine increasing excited neurotransmitters decreasing, serotonin increasing acetylcholine decreasing dopamine decreasing neurotransmitters increasing, acetylchoine decreasing neurotransmitters increasing, acetylcholine decreasing neurotransmitters increasing excited neurotransmitters decreasing and so on. Contrasted with the ordinary person group, the depression patients group have the notable difference.

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Ostegenesis imperfecta (OI) is a hereditary disease of the connective tissue caused by mutations to, mainly, the genes that are involved in the biosynthesis of collagen type 1. Patients are grouped according to clinical severity and mode of inheritance according to Sillence's classification (originally 1979, updated 2014). According to our data, the population prevalence of OI in Denmark was 10.3 per 100,000, with 575 patients registered with an OI diagnosis in the National Patient Register and alive at the end of 2012 out of a total population of 5,602,628 persons. Hallmarks of the disease are multiple fractures, blue sclera and varying degrees of bone deformities. Collagen type 1 is the most abundant collagen in the body and is an important part of the structure and function of the heart and lungs, the skeleton and many other organs. We hypothesize that patients with OI will have increased prevalence and risk of fractures throughout life, lower bone mineral density (BMD), impaired bone microstructure and bone geometry and increased risk of cardiovascular diseasesthus increased risk of all cause mortality compared to the general population. 
This thesis is a systematic search and narrative review covering the four main areas of interest of the PhD scholarship (risk and causes of death, fracture rates, bone mineral density, -geometry and -microstructure and cardiovascular diseases in OI). In addition to the review the thesis include the following four studies:
 1) Study 1 aimed to investigate the main causes of death and the risk of premature death in patients with OI in Denmark. We used a nationwide, registry-based, cohort study design, and included all patients registered in the National Patient Register with an OI diagnosis and a matched reference population randomly selected from the Danish Civil Service Register (matched 5:1, on gender and month and year of birth for each OI patient). We identified 687 patients with OI (25,615 person years at risk) and a reference population of 3,435 (132,131 person years at risk). One hundred and twelve patients with OI and 257 persons in the reference population died during the observation period from 1977 to 2013. The all-cause mortality hazard ratio between the OI cohort and the reference population was 2.90. The median survival time for men with OI was 72.4 years, compared to 81.9 in the reference population. The median survival time for women with OI was 77.4 years, compared to 84.5 years in the reference population. Patients with OI had a higher risk of death from respiratory diseases, gastrointestinal diseases and trauma.
 Conclusion: The all-cause hazard ratio for premature death in OI was 2.9 compared to the reference population. There was an increased risk of death due to respiratory diseases, gastrointestinal diseases and death following trauma. 
2) Study 2 aimed to compare the fracture rates across the lifespan of patients with OI with that of the general population. Using a nationwide, registry-based, cohort study design, we counted all fractures registered from 1995 in the National Patient Register. The study included the same population as in study 1, but patients who died before 1995 were excluded. We identified 644 patients
 
(55.6% females) in the OI cohort through the Danish National Patient Register and 3,361 persons (55.2% females), randomly selected from the Civil Registry System. A total of 416 patients with OI experienced a total of 1,566 fractures during the observation period of median 17.9 years (IQ-range: 12.4-18.0), adding up to 10,137 person years. In comparison, 709 persons in the reference population experienced a total of 1,018 fractures during follow-up. Both male and female patients with OI had an increased fracture rate throughout their life. The fracture rate ratio for participants aged 0-19 years was 10.7, for participants aged 20-54 years 17.2, and for participants aged 55 years and over 4.1 when compared to the reference population. The highest fracture rate was seen in males with OI aged 0-19 years (257 fractures per 1,000 person years). The fractures appear to follow the same pattern as in the general population, with a peak during the toddler and adolescent years (IR (incidence rates) 233.9 per 1,000 person years), fewer fractures during adulthood (IR 84.5 per 1000 person years), and increased fracture rate in older women (IR 111.9 per 1,000 person years).
 Conclusion: Patients with OI have increased risk of fractures throughout life compared to the general population. The relative risk of fractures generally declines with age, however, increases in older women. 
3) Study 3 aimed to evaluate the bone mineral density (BMD) and bone geometry and -microarchitecture in patients with OI type I using a cross-sectional study design and evaluating the participants using HRpQCT. The study included 39 patients with OI type I, and 39 healthy age and gender matched non-OI individuals. The patients were shorter than the reference group (159 ± 10 cm versus 170 ± 9 cm, p &lt; 0.001), but had similar body weight. In patients with OI, areal bone mineral density (aBMD) was 8% lower at the hip (p &lt; 0.05) and 13% lower at the spine (p &lt; 0.001) compared with the reference group. The trabecular volumetric bone mineral density (vBMD) was 28% lower in radius (p &lt; 0.001) and 38% lower in tibia (p &lt; 0.001) in patients with OI compared with the reference group. At radius, total bone area was 5% lower in OI patients than in controls (p &lt; 0.05). In the tibia, cortical bone area was 18% lower in patients with OI (p &lt; 0.001). In both radius and tibia the number of trabeculae was lower in patients compared to the reference group (35% and 38%, respectively, p &lt; 0.001 at both sites). Furthermore, trabecular spacing was 55% higher in OI patients in both tibia and radius (p &lt; 0.001 at both sites) when compared with reference group.
 Conclusion: Patients with type I OI have lower aBMD, vBMD, bone area, and trabecular number when compared with healthy age- and gender-matched individuals. 
4) Study 4 aimed to evaluate the risk of valvulopathies, atrial arrhythmias, heart failure and vascular dissections in patients with OI using a nationwide, registry-based, cohort study design. The study included the same population as in study 1. As patients with OI have increased risk of premature death, the risk of cardiovascular diseases is biased by the competing risk of death. We corrected for this increased risk by using a competing risk regression model. We found that the OI population had increased relative risk of mitral valve regurgitation (sub hazard ratio (SHR) 6.3), aortic valve regurgitation (SHR 4.5), atrial fibrillation/flutters (SHR 1.7) and heart failure (SHR 2.3) compared to the reference population. There was no difference in the risk of arterial aneurisms or arterial dissections.
 Conclusion: Patients with OI have increased risk of valvulopathies, atrial arrhythmias and heart failure when compared to the reference population, even after adjusting for risk factors for these car-diovascular diseases - indicating that the quantitative or qualitative defects of collagen type 1 synthesis seen in OI influence the risk of these cardiovascular diseases in patients with OI.

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Chapter 2: Screening and assessment for unhealthy alcohol use Screening Screening for unhealthy alcohol use and appropriate interventions should be implemented in general practice (Level A), hospitals (Level B), emergency departments and community health and welfare settings (Level C). Quantity-frequency measures can detect consumption that exceeds levels in the current Australian guidelines (Level B). The Alcohol Use Disorders Identification Test (AUDIT) is the most effective screening tool and is recommended for use in primary care and hospital settings. For screening in the general community, the AUDIT-C is a suitable alternative (Level A). Indirect biological markers should be used as an adjunct to screening (Level A), and direct measures of alcohol in breath and/or blood can be useful markers of recent use (Level B). Assessment Assessment should include evaluation of alcohol use and its effects, physical examination, clinical investigations and collateral history taking (Level C). Assessment for alcohol-related physical problems, mental health problems and social support should be undertaken routinely (GPP). Where there are concerns regarding the safety of the patient or others, specialist consultation is recommended (Level C). Assessment should lead to a clear, mutually acceptable treatment plan which specifies interventions to meet the patient's needs (Level D). Sustained abstinence is the optimal outcome for most patients with alcohol dependence (Level C). Chapter 3: Caring for and managing patients with alcohol problems: interventions, treatments, relapse prevention, aftercare, and long term follow-up Brief interventions Brief motivational interviewing interventions are more effective than no treatment for people who consume alcohol at risky levels (Level A). Their effectiveness compared with standard care or alternative psychosocial interventions varies by treatment setting. They are most effective in primary care settings (Level A). Psychosocial interventions Cognitive behaviour therapy should be a first-line psychosocial intervention for alcohol dependence. Its clinical benefit is enhanced when it is combined with pharmacotherapy for alcohol dependence or an additional psychosocial intervention (eg, motivational interviewing) (Level A). Motivational interviewing is effective in the short term and in patients with less severe alcohol dependence (Level A). Residential rehabilitation may be of benefit to patients who have moderate-to-severe alcohol dependence and require a structured residential treatment setting (Level D). Alcohol withdrawal management Most cases of withdrawal can be managed in an ambulatory setting with appropriate support (Level B). Tapering diazepam regimens (Level A) with daily staged supply from a pharmacy or clinic are recommended (GPP). Pharmacotherapies for alcohol dependence Acamprosate is recommended to help maintain abstinence from alcohol (Level A). Naltrexone is recommended for prevention of relapse to heavy drinking (Level A). Disulfiram is only recommended in close supervision settings where patients are motivated for abstinence (Level A). Some evidence for off-label therapies baclofen and topiramate exists, but their side effect profiles are complex and neither should be a first-line medication (Level B). Peer support programs Peer-led support programs such as Alcoholics Anonymous and SMART Recovery are effective at maintaining abstinence or reductions in drinking (Level A). Relapse prevention, aftercare and long-term follow-up Return to problematic drinking is common and aftercare should focus on addressing factors that contribute to relapse (GPP). A harm-minimisation approach should be considered for patients who are unable to reduce their drinking (GPP). Chapter 4: Providing appropriate treatment and care to people with alcohol problems: a summary for key specific populations Gender-specific issues Screen women and men for domestic abuse (Level C). Consider child protection assessments for caregivers with alcohol use disorder (GPP). Explore contraceptive options with women of reproductive age who regularly consume alcohol (Level B). Pregnant and breastfeeding women Advise pregnant and breastfeeding women that there is no safe level of alcohol consumption (Level B). Pregnant women who are alcohol dependent should be admitted to hospital for treatment in an appropriate maternity unit that has an addiction specialist (GPP). Young people Perform a comprehensive HEEADSSS assessment for young people with alcohol problems (Level B). Treatment should focus on tangible benefits of reducing drinking through psychotherapy and engagement of family and peer networks (Level B). Aboriginal and Torres Strait Islander peoples Collaborate with Aboriginal or Torres Strait Islander health workers, organisations and communities, and seek guidance on patient engagement approaches (GPP). Use validated screening tools and consider integrated mainstream and Aboriginal or Torres Strait Islander-specific approaches to care (Level B). Culturally and linguistically diverse groups Use an appropriate method, such as the "teach-back" technique, to assess the need for language and health literacy support (Level C). Engage with culture-specific agencies as this can improve treatment access and success (Level C). Sexually diverse and gender diverse populations Be mindful that sexually diverse and gender diverse populations experience lower levels of satisfaction, connection and treatment completion (Level C). Seek to incorporate LGBTQ-specific treatment and agencies (Level C). Older people All new patients aged over 50 years should be screened for harmful alcohol use (Level D). Consider alcohol as a possible cause for older patients presenting with unexplained physical or psychological symptoms (Level D). Consider shorter acting benzodiazepines for withdrawal management (Level D). Cognitive impairment Cognitive impairment may impair engagement with treatment (Level A). Perform cognitive screening for patients who have alcohol problems and refer them for neuropsychological assessment if significant impairment is suspected (Level A). Chapter 5: Understanding and managing comorbidities for people with alcohol problems: polydrug use and dependence, co-occurring mental disorders, and physical comorbidities Polydrug use and dependence Active alcohol use disorder, including dependence, significantly increases the risk of overdose associated with the administration of opioid drugs. Specialist advice is recommended before treatment of people dependent on both alcohol and opioid drugs (GPP). Older patients requiring management of alcohol withdrawal should have their use of pharmaceutical medications reviewed, given the prevalence of polypharmacy in this age group (GPP). Smoking cessation can be undertaken in patients with alcohol dependence and/or polydrug use problems; some evidence suggests varenicline may help support reduction of both tobacco and alcohol consumption (Level C). Co-occurring mental disorders More intensive interventions are needed for people with comorbid conditions, as this population tends to have more severe problems and carries a worse prognosis than those with single pathology (GPP). The Kessler Psychological Distress Scale (K10 or K6) is recommended for screening for comorbid mental disorders in people presenting for alcohol use disorders (Level A). People with alcohol use disorder and comorbid mental disorders should be offered treatment for both disorders; care should be taken to coordinate intervention (Level C). Physical comorbidities Patients should be advised that alcohol use has no beneficial health effects. There is no clear risk-free threshold for alcohol intake. The safe dose for alcohol intake is dependent on many factors such as underlying liver disease, comorbidities, age and sex (Level A). In patients with alcohol use disorder, early recognition of the risk for liver cirrhosis is critical. Patients with cirrhosis should abstain from alcohol and should be offered referral to a hepatologist for liver disease management and to an addiction physician for management of alcohol use disorder (Level A). Alcohol abstinence reduces the risk of cancer and improves outcomes after a diagnosis of cancer (Level A).

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Taking into account the incidence and the severity of electrocutions, we consider it extremely necessary to find effective, appropriate and particularized therapeutic solutions aimed at improving the survival, decreasing the mortality, ensuring a superior functional and aesthetic effect and facilitating the social reintegration. Given the severity of the general condition of the electrically injured patient and the fact that any worsening of the lesions has a systemic echo, the selection of the timing for re-excision is very important. The postponement of the surgical timing can break the precarious metabolic equilibrium and can hasten the installation of the multisystem organ failure (MSOF). The study is intended to establish a possible connection between the clinical evolution of the electrically injured patient and the dynamics of three important biological parameters, able to provide data concerning the therapeutic attitude to be followed. The patients with a diagnostic of high-voltage electrocution, who will be admitted to the Clinic, will be followed for a period of 2 years. The parameters to be followed daily will be: - Creatin-kinase, as a marker of muscular damage. - Hemoglobin, as a marker of tissue oxygenation. - Leukocytes, as an indicator of a possible septic evolution. The therapeutic alternatives, including the administration of antiplatelet drugs will be studied. In the period October 2010-June 2013 a total of 12 cases of high-voltage electrocution were admitted in our clinic. Among these, some could be placed in the study of 7 cases, as the remaining patients died within the first 24 hours of hospitalization due to the endured lesions. All the patients were admitted to the ICU ward that supported the treatment and monitoring until their stabilization, at which time they were transferred to the ward. All the patients received anti-thromboxane treatment from their admission (injectable NSAIDs associated with antisecretory drugs). By mutual agreement with ICU service, Dipyridamole was not introduced because of the "steal effect" in the viable areas to the detriment of the already ischemic areas, the drug effect being obvious in vitro, but hard to be proven in the clinical case. The relationship between the CK level and the clinical appearance of the ischemic areas is relative. We cannot conclude that an increased level of CK is equivalent to an enlarged ischemic area and even less it does not provide us direct information concerning the best time for re-excision. The presence of a viable blood supply around the necrotic tissue will lead to an important resorption of degradation products in that area, a quasinormal level of CK having no value. The sealing of the necrosis areas and the lack of immediate resorption does not have a positive prognostic value. Taking into account that the electrocutions are mostly multiple injuries, the CK level can increase even after some muscular damages, fractures, independent of the actual electrocution lesion. In one case, the patient suffered from electrocution at both thoracic limbs. With the carbonization of the hands and grifa installed up to the level of the elbow fold, he stayed for 6 hours at the accident site until he had been recovered. At the moment of presentation to the hospital, his consciousness condition was satisfactory but the CK level was of over 20000 IU, becoming rapidly non-detectable, in combination with black urine. The patient's condition deteriorated quickly, and, although the bilateral shoulder disarticulation has been carried out, he died in the next 12 hours. As a conclusion, the CK level did not prove itself a prognostic for the surgical timing or the actual surgical attitude and could be influenced by a whole series of factors, dependent or not on the electrocution lesion. A radical attitude is to be preferred in cases with established ischemia; the prognostic being the more reserved the larger the damage and the longer the period of time from the event. The established treatment is of renal support and treatment of acute renal injury (AKI) subsequently installed. An increased level of leukocytes is always present as in any severe trauma, even if there are no immediate signs of infection of the electrocution lesions. Taking into account that the electrocution lesion as well as the one caused by burning destroys the natural defense barrier represented by the skin, the infection risk is major and that is why the therapeutic protocol stipulates the immediate establishment of a treatment with broad-spectrum antibiotics or with an association of antibiotics. The increase of the leukocytes level under antibiotics treatment involves either the contamination with a germ that is not sensitive to the respective antibiotic or the persistence of necrosis areas which secondarily infect, and where antibiotic penetration is very low. Therefore, the excision of the compromised tissues is an absolute necessity. In terms of prognostic, the increase of the leukocytes number signified an insufficient excision and indicated the resuming and deepening of the excisions. Taking into account that the patient has been admitted through the ICU service, the risk of contracting severe infections with selected germs is real. Another risk is that of infection with Clostridium difficile following the prolonged utilization of broad-spectrum antibiotics, especially in patients with associated diseases and reduced immunity per primam. The existence of completely separate circuits should solve the problem of contamination with bacteria of selected species; unfortunately, in our cases, we have faced this problem and the utilization of last choice antibiotics (Imipenem, Vancomycin, Targocid, etc.) as well as the association of immunoglobulins was necessary. All the patients admitted in the study received anti-thromboxane drugs in order to limit the ischemic process at tissue level. Despite the efforts we have made, the lack of blood and its derivatives or simply the negligence in patient monitoring, allowed the decrease, even transient of the Hb level, sometimes only for a few hours, but enough to allow the deepening of the ischemic lesions. Excisions were carried out in all the patients in emergency or even amputations of the extremities, with the wish to limit the extension of the ischemic lesions and the resorption of cell degradation products. The amputations performed in emergency did not always represent a saving solution; however, they remained the most effective measures when they were carried out immediately after the accident and obviously in viable tissue. The increase of CK is not an indicative factor itself in making re-excisions but orients the therapeutic approach, the utilization of the dialysis when the values do not decrease by treatment for renal support and the forcing of diuresis is required. The normalization of CK indicates the time when we can start the covering of the defects resulted as a consequence of the excisions. The level of the leukocytes represents both a prognostic factor and an indicative factor for the re-excision of the ischemic areas. An increased level under antibiotic therapy signifies either an incomplete excision or the contamination with flora resisting to the antibiotic that has been used. In the light of findings in the caring of the patients with electrocutions, I propose several caring/assessment protocols for the severe electrically injured patient.

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A nonlinear selection index (NL) method was compared with restricted linear index (RI) using two experiments of upward selection for the weight/(lenght)(n) ratio in Tribolium castaneum. The first experiment was designed to increase pupal weight/(pupal length)(2) , while the second experiment was intended to improve larval weight/(larval length)(3) . Larval and pupal traits were measured at 14 and 21 days after adult emergence, respectively. There were four generations of selection in each of three replicates, the proportion selected being 20 %. The selection criterion in the NL lines was (m(1) + Ĝ(1) )/(m(2) + Ĝ(2) )(n) , where m(1) and m(2) are the population means for the numerator and denominator traits, Ĝ(1) and Ĝ(2) are the estimated additive genetic values, and n is 2 (experiment 1) or 3 (experiment 2). The restricted linear index used as the selection criterion in the RI lines was calculated to increase the numerator trait and hold the denominator constant. Responses observed for the ratios differed significantly between lines (P &lt; .05) in both experiments, the NL lines having the greatest responses. In experiment 1, the observed response for increasing the numerator was significant in the NL line, while the observed responses were positive and significant for both traits in the RI line; lines differed significantly pupal length (P &lt; .01). The response obtained for the ratio in experiment 2 was due to decreases in both component traits. Results of these experiments showed that the nonlinear selection indices increased ratios that included quadratic and cubic terms in the denominator. Restricted linear indices holding the denominator constant were a less efficient alternative. ZUSAMMENFASSUNG: Experimentelle Studie über die relative Wirksamkeit nicht-linearer und beschränkter Selektionsindexe für Quotienten mit quadratischen und kubischen Größen Ein nicht-linearer Selektionsindex (NL) wurde mit einem linearen Index mit Restriktion (RI) bei Tribolium mittels eines Selektionexperiments zugunsten des Quotienten Gewicht/(Länge)(n) verglichen. Das erste Experiment zielte auf Erhöhung von Gewicht der Puppe/(Länge der Puppe)(2) , während das zweite Experiment der Verbesserung von Gewicht der Larve/(Länge der Larve)(3) diente. Merkmale von Larve una Puppe wurden jeweils nach 14 und 21 Tagen gemessen in drei Wiederholungen und vier Selektionsgenerationen mit je 20% Selektion. Das Auswahlkriterium der Linien NL war (m(1) + Ĝ(1) )/(m(2) + Ĝ(2) )(n) , wobei m(1) und m(2) den Durchschnitt für Zähler- und Nennercharakteristika darstellen, Ĝ(1) und Ĝ(2) die angenommenen Werte sind und n 2 (Experiment 1) oder 3 (Experiment 2) ist. Der bei den Linien RI als Selektionskriterium verwendete Beschränkungsindex wurde zur Erhöhung des Zählers und zur Konstanthaltung des Nenners angenommen. Die Ergebnisse für den Quotienten waren bei beiden Experimenten zwischen Linien (P &lt; .05) signifikant unterschiedlich, wobei die Reaktion der NL-Linien größer war. Beim Experiment 1 war die Reaktion der Linie NL im Zähler signifikant, während sie bei der Linie RI für beide Charakteristika positiv und signifikant war, die Linien waren signifikant verschieden hinsichtlich Länge der Puppe (P &lt; .01). Das beim Experiment 2 erzielte Ergebnis für den Quotienten ergab sich aufgrund der Abnahme der beiden charakteristischen Komponenten. Die Ergebnisse dieser Experimente zeigten, daß die nicht-linearen Indexe die Quotienten erhöhten, welche im Nenner quadratische oder kubische Termini beinhalteten. Die linearen Indexe mit Restriktion für den Nenner des Quotienten stellten eine weniger wirksame Alternative dar. RESUMEN: Estudio experimental de la eficiencia relativa de indices de selección no lineales y con restricción para cocientes que incluyen cuadrados y cubos Un índice no lineal de selección (NL) fue comparado con un índice lineal con restricción (RI) en Tribolium, usando dos experimentos de selección a favor del cociente peso/(longitud)(n) . El primer experimento fue diseñado para incrementar peso de pupa/(longitud de pupa)(2) , mientras que el segundo experimento trataba de mejorar peso de larva/(longitud de larva)(3) . Los caracteres de larva y de pupa se midieron a los 14 y a los 21 días respectivamente. Había cuatro generaciones de selección en cada una de tres repeticiones, siendo la proporción seleccionada el 20 %. El criterio de selección en las líneas NL fue (m(1) +Ĝ(1) /(m(2) +Ĝ(2) )(n) , donde m(1) y m(2) son las medias para los caracteres numerador y denominador, Ĝ(1) y Ĝ(2) son los valores aditivos estimados, y n es 2 (experimento 1) o 3 (experimento 2). El índice con restricción usado como criterio de selección en las líneas RI fue calculado para incrementar el numerador y mantener constante el denominador. Las respuestas observadas para el cociente diferían significativamente entre líneas (P &lt; .05) en ambos experimentos, teniendo mayor respuesta las líneas NL. En el experimento 1, la respuesta observada en el numerador fue significativa en la línea NL, mientras que fue positiva y significativa para ambos caracteres en la línea RI; las líneas diferían significativamente para longitud de pupa (P &lt; .01). La respuesta obtenida para el cociente en el experimento 2 fue debida a la disminución de ambos caracteres componentes. Los resultados de estos experimentos mostraban que los indices no lineales incrementaban cocientes que incluían en el denominador términos cuadráticos o cúbicos. Los índices lineales con restricción para el denominador del cociente eran una alternativa menos eficiente. RÉSUMÉ: Etude expérimentale de l'efficacité relative des indices de sélection non linéares y avec restriction pour des quotients qui comportent des carrés et des cubes Nous avons comparé un index non linéaire de sélection (NL) avec un index linéaire avec restriction (RI) à Tribolium, on utilisant deux expériences de sélection en faveur du quotient poids/(Longueur)(n) . La première expérience fut conçue pour augmenter le poids de la pupe/(Longueur de pupe)(2) , tandis que la deuxième expérience essayait d'améliorer le poids de la larve/(Longueur de larve)(3) . Les caractères de larve et de pupe furent mesurés au bout de 14 et de 21 jours respectivement. Il y avait quatre générations de sélection dans chacune des trois répétitions et la proportion choisie fut celle de 20 %. On prit (m(1) + Ĝ(1) )/(m(2) + Ĝ(2) )(n) come critére de sélection dans les lignes NL, m(1) et m(2) étant les moyennes pour les caractères numérateur et dénominateur, Ĝ(1) et Ĝ(2) les valeurs additives estimées et n étant 2 (expérience 1) ou 3 (expérience 2). Le index avec restriction employé comme critère de sélection dans les lignes RI a été calculé pour augmenter le numérateur et maintenir le dénominateur constant. Les réponses obtenues pour le quotient étaient significativement différentes entre les lignes (P &lt; .05) dans les deux expériences, la réponse plus grande étant celle de la ligne NL. Dans l'expérience 1, la réponse observée dans le numérateur fût significative dans la ligne NL, tandis qu'elle fut positive et significative pour les deux caracteres dans la ligne RI; les lignes étaient significativemcnt différentes pour la longueur de pupe (P &lt; .01). La réponse obtenue pour le quotient dans l'expérience 2 a été due à la diminution des deux caractères composants. Les résultats de ces expériences ont montré que les indices non linéares augmentaient les quotients qui incluaient dans le dénominateur des termes quadratiques ou cubiques. Les indiceslinéaires avec restriction pour le dénominateur du quotient ont été une alternative moins efficace.

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What are the psychosocial experiences of women with breast cancer across the lifespan, including similarities and differences in the psychosocial experiences of younger, middle-aged and older women with breast cancer? The experience of a life threatening illness, such as cancer, requires a person to consider an array of emotional, medical, social and existential demands. Specific to breast cancer, research shows that the experience of diagnosis and treatment of breast cancer may result in considerable distress.It is also known that a diagnosis of invasive breast cancer propels women into a time of uncertainty, that brings fear and emotional work. This disease oftentimes challenges a woman's identity, self-esteem, body image and relationships. However, even with these commonly felt distresses, most women adjust well to a breast cancer diagnosis and the treatments experienced, particularly if they do not experience a recurrence of cancer. Protective factors for distress include supportive care networks, such as family and support groups and professional resources provided by clinical staff, such as timely referrals to specialized services.Although most women adjust well to breast cancer, understanding distressing experiences among this population is crucial because, when experienced, the negative psychosocial impacts can be significant. Women who do experience distress due to breast cancer are at a risk of distress accompanying them through the breast cancer journey and impacting their long-term quality of life.Although literature suggests that the psychosocial experience of a breast cancer diagnosis may be different across the lifespan, less is known about the similarities and differences in the psychosocial experience between younger and older women with breast cancer. However, this studyexamines the experience of one age group and no comparisons between different age groups in this or other studies have been found at this time. Among what is known, younger women with breast cancer are at a heightened risk of anxiety and depression in comparison to older women and younger women experience more worries about their careers and finances than older women. There is also evidence that young women perceive their quality of life to be lower than older women as a result of breast cancer. This may be attributed to poorer emotional wellbeing, specific cancer-related concerns, depression and intrusive thoughts for this younger group. On the other hand, older women with breast cancer experience more health problems than younger women in survivorship, independent of receiving chemotherapy. In general, older breast cancer survivors experience overall better quality of life and mental health than their younger counterparts, but they tend to have poorer physical health and health-related quality of life due to comorbid conditions. Another risk factor for psychosocial distress is low income, which may be particularly salient for older women who are more likely to be on a fixed income than their younger counterparts. However, literature suggests that a higher degree of psychosocial adaptation can be found among older women with breast cancer because these women have had more life experience, including prior experiences with the health care system, witnessing the diagnosis of others with cancer, and having few competing demands. It is thought that these factors contributed to coping and successful adaption to the disease among older women.When studying how women acclimatize to breast cancer in the early stages of the cancer journey, it has been found that the main concerns for these women were concepts connected to identity. Breast cancer threatens women's self-integrity and the restructuring of life after a cancer diagnosis calls for the new experiences and feelings to be integrated into a revised self-narrative, sometimes referred to as 'meaning-making'. Little is understood about the differences between younger and older women in their construction of identity or how they make meaning in the context of breast cancer. What is known is that, for younger women, the diagnosis of cancer is shocking, and is an opportunity to contemplate mortality. Older women are more likely to approach their diagnoses in a matter-of-fact manner associated with the expected process of aging.The concept of body image can be found as a focus of breast cancer literature which describes the level of investment women put into their body in order to help them determine their wellbeing. The disruption of body image in breast cancer is attributed to hair loss, as well as changes in the breast and weight. Studies show younger women do seek normality in their breasts following mastectomy, and seek breast reconstruction more often than older women. Regarding older women with breast cancer, little is known about the experience of specific body image concerns, such as short- or long-term changes in the body due to treatment. It is known that older women with cancer experience body dissatisfaction and may even experience higher levels of dissatisfaction than younger women, possibly due to more persistent problems with the physical functioning of their body.It is also known that the diagnosis and treatment of breast cancer affect relationships including spousal relationships, and relationships with children and older parents. As a woman with breast cancer experiences vulnerabilities, so too does her family. Spouses and partners of women with breast cancer work to adjust roles and to balance added household responsibilities, particularly during times of treatment. Children of women with breast cancer are impacted by the level of interaction with their mothers, with increased positive mother-child interactions associated with the increased wellbeing of family members. On the other hand, children are impacted negatively by a negative change in the mother's mood or marital tension. Lastly, parents of women with breast cancer are also affected since, they too, need to come to terms with the early timing of their daughters' diagnoses.Family relationships are vital for women with cancer because these relationships provide a high degree of social support, including emotional, tangible, informational and experiential support. Literature shows family relationships are improved for both younger and older breast cancer survivors. However, the intimate relationships of younger women are more likely to be strained in comparison to the intimate relationships of older women in the context of breast cancer survivorship. Also, younger adults with cancer experience increased loneliness, and a greater sense of isolation from peer and support networks than older adults perhaps because they perceive themselves to be different from their peers as a result of cancer.This incomplete understanding of the psychosocial experience of women with breast cancer across the lifespan requires an urgent need for research to facilitate a greater understanding of the psychosocial needs of these women. To allow for the effective delivery of appropriate cancer care support to these populations, a greater understanding of the unmet needs of these women must occur, including an understanding of the similarities and differences of younger and older women with this disease. A synthesis of literature from multiple contexts of the psychosocial experiences of younger and older women with breast cancer will add to the understanding of the experiences of these women. No systematic review on this topic was found when searching Cochrane Database of Systematic Reviews, PROSPERO and the JBI Database of Systematic Reviews and Implementation Reports.

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In June 2008, the Medical Advisory Secretariat began work on the Diabetes Strategy Evidence Project, an evidence-based review of the literature surrounding strategies for successful management and treatment of diabetes. This project came about when the Health System Strategy Division at the Ministry of Health and Long-Term Care subsequently asked the secretariat to provide an evidentiary platform for the Ministry's newly released Diabetes Strategy.After an initial review of the strategy and consultation with experts, the secretariat identified five key areas in which evidence was needed. Evidence-based analyses have been prepared for each of these five areas: insulin pumps, behavioural interventions, bariatric surgery, home telemonitoring, and community based care. For each area, an economic analysis was completed where appropriate and is described in a separate report.To review these titles within the Diabetes Strategy Evidence series, please visit the Medical Advisory Secretariat Web site, http://www.health.gov.on.ca/english/providers/program/mas/mas_about.html,DIABETES STRATEGY EVIDENCE PLATFORM: Summary of Evidence-Based AnalysesContinuous Subcutaneous Insulin Infusion Pumps for Type 1 and Type 2 Adult Diabetics: An Evidence-Based AnalysisBehavioural Interventions for Type 2 Diabetes: An Evidence-Based AnalysisBARIATRIC SURGERY FOR PEOPLE WITH DIABETES AND MORBID OBESITY: An Evidence-Based SummaryCommunity-Based Care for the Management of Type 2 Diabetes: An Evidence-Based AnalysisHome Telemonitoring for Type 2 Diabetes: An Evidence-Based AnalysisApplication of the Ontario Diabetes Economic Model (ODEM) to Determine the Cost-effectiveness and Budget Impact of Selected Type 2 Diabetes Interventions in Ontario The objective of this report is to determine the efficacy of specialized multidisciplinary community care for the management of type 2 diabetes compared to usual care. TARGET POPULATION AND CONDITION Diabetes (i.e. diabetes mellitus) is a highly prevalent chronic metabolic disorder that interferes with the body's ability to produce or effectively use insulin. The majority (90%) of diabetes patients have type 2 diabetes. (1) Based on the United Kingdom Prospective Diabetes Study (UKPDS), intensive blood glucose and blood pressure control significantly reduce the risk of microvascular and macrovascular complications in type 2 diabetics. While many studies have documented that patients often do not meet the glycemic control targets specified by national and international guidelines, factors associated with glycemic control are less well studied, one of which is the provider(s) of care. Multidisciplinary approaches to care may be particularly important for diabetes management. According guidelines from the Canadian Diabetes Association (CDA), the diabetes health care team should be multi-and interdisciplinary. Presently in Ontario, the core diabetes health care team consists of at least a family physician and/or diabetes specialist, and diabetes educators (registered nurse and registered dietician). Increasing the role played by allied health care professionals in diabetes care and their collaboration with physicians may represent a more cost-effective option for diabetes management. Several systematic reviews and meta-analyses have examined multidisciplinary care programs, but these have either been limited to a specific component of multidisciplinary care (e.g. intensified education programs), or were conducted as part of a broader disease management program, of which not all were multidisciplinary in nature. Most reviews also do not clearly define the intervention(s) of interest, making the evaluation of such multidisciplinary community programs challenging. What is the evidence of efficacy of specialized multidisciplinary community care provided by at least a registered nurse, registered dietician and physician (primary care and/or specialist) for the management of type 2 diabetes compared to usual care? [Henceforth referred to as Model 1]What is the evidence of efficacy of specialized multidisciplinary community care provided by at least a pharmacist and a primary care physician for the management of type 2 diabetes compared to usual care? [Henceforth referred to as Model 2] English language full-reportsPublished between January 1, 2000 and September 28, 2008Randomized controlled trials (RCTs), systematic reviews and meta-analysesType 2 diabetic adult population (≥18 years of age)Total sample size ≥30Describe specialized multidisciplinary community care defined as ambulatory-based care provided by at least two health care disciplines (of which at least one must be a specialist in diabetes) with integrated communication between the care providers.Compared to usual care (defined as health care provision by non-specialist(s) in diabetes, such as primary care providers; may include referral to other health care professionals/services as necessary)≥6 months follow-up Studies where discrete results on diabetes cannot be abstractedPredominantly home-based interventionsInpatient-based interventions The primary outcomes for this review were glycosylated hemoglobin (rHbA1c) levels and systolic blood pressure (SBP). A literature search was performed on September 28, 2008 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 between January 1, 2000 and 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 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. Given the high clinical heterogeneity of the articles that met the inclusion criteria, specific models of specialized multidisciplinary community care were examined based on models of care that are currently being supported in Ontario, models of care that were commonly reported in the literature, as well as suggestions from an Expert Advisory Panel Meeting held on January 21, 2009. The initial search yielded 2,116 unique citations, from which 22 RCTs trials and nine systematic reviews published were identified as meeting the eligibility criteria. Of these, five studies focused on care provided by at least a nurse, dietician, and physician (primary care and/or specialist) model of care (Model 1; see Table ES 1), while three studies focused on care provided by at least a pharmacist and primary care physician (Model 2; see Table ES 2). Based on moderate quality evidence, specialized multidisciplinary community care Model 2 has demonstrated a statistically and clinically significant reduction in HbA1c of 1.0% compared with usual care. The effects of this model on SBP, however, are uncertain compared with usual care, based on very-low quality evidence. Specialized multidisciplinary community care Model 2 has demonstrated a statistically and clinically significant reduction in both HbA1c of 1.05% (based on high quality evidence) and SBP of 7.13 mm Hg (based on moderate quality evidence) compared to usual care. For both models, the evidence does not suggest a preferred setting of care delivery (i.e., primary care vs. hospital outpatient clinic vs. community clinic). Table ES1:Summary of Results of Meta-Analyses of the Effects of Multidisciplinary Care Model 1OutcomeEstimate of effect(95% CI)Heterogeneity I(2)(p-value)GRADEGlycosylated Hemoglobin (HbA1c [%])-1.00 [-1.27, -0.73]4% (p=0.37)Moderate-quality     Subgroup: Moderate-to-High Quality-0.91 [-1.19, -0.62]0% (p=0.74)Systolic Blood Pressure (mm Hg)-2.04 [-13.80, 9.72]89% (p=0.002)Very-low quality*Mean change from baseline to follow-up between intervention and control groupsTable ES2:Summary of Results of Meta-Analyses of the Effects of Multidisciplinary Care Model 2OutcomeEstimate of effect(95% CI)Heterogeneity I(2)(p-value)GRADEGlycosylated Hemoglobin (HbA1c [%])-1.05 [-1.57, -0.52]0% (p=0.75)High-qualitySystolic Blood Pressure (mm Hg)-7.13 [-11.78, -2.48]46% (p=0.17)Moderate quality*Mean change from baseline to follow-up between intervention and control groups.

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Adis CommentsAVAX Technologies is developing a therapeutic melanoma vaccine [M-Vax, DNP-VACC] consisting of autologous tumour cells conjugated to a highly immunogenic hapten, dinitrophenyl, which makes the cancer cells more easily recognised by the immune system. AVAX licensed the autologous cell vaccine technology (AC Vaccine) from Thomas Jefferson University in Philadelphia, USA, where it was originally developed. M-Vax was launched in Australia in the first half of 2000, but was withdrawn from this market in September 2002 due to financial constraints faced by the company and its need to focus its resources on initiatives that provide the greatest return. Although AVAX applied for Federal Government price reimbursement in Australia through the Medical Services Advisory Committee during 2001, the vaccine is not reimbursed in Australia. Obtaining Federal Government reimbursement was a step AVAX considered essential for the success of the M-Vax. AVAX has not ruled out re-entering the Australian market again at a later date. AVAX will now concentrate on gaining approval in the US and Europe. M-Vax has received orphan drug designation from the US FDA. M-Vax is in preregistration in Germany, Japan and The Netherlands for treatment of stage III melanoma. In September 1999, the company announced that it expected to market M-Vax for treatment of stage III melanoma in Germany, Japan and the Netherlands. This announcement came after AVAX's continuing dialogue with senior regulatory authorities in several pharmaceutical markets. The commercial availability of M-Vax in Germany, Japan and The Netherlands will be subject to meeting certain requirements specified by the regulatory agency in each country. Phase II data have been submitted for regulatory approval in these countries; phase III data may not be required because the vaccine contains autologous tumour cells. This was the case with the Australian approval of M-Vax, which was on the basis of data from phase II trials. Clinical development: M-Vax was in a pivotal phase III trial for treatment of stage III melanoma in the US, and a multicentre phase II trial in the US for treatment of patients with stage IV melanoma with lung metastases. However, in late March 2001, AVAX announced that the FDA had suspended these trials until the agency had further reviewed them. Subsequently, AVAX received written communication from the FDA indicating that the suspension is related to manufacturing issues. These events triggered the resignations of AVAX's executive Vice-President and Vice-President of operations, at the request of the company's board of directors. AVAX met with the FDA in October 2001 to discuss the clinical holds on M-Vax and O-Vax. AVAX's proposed improvements involving a frozen vaccine were also discussed at the meeting. Following the meeting AVAX was told by the FDA that selected characterisation work would have to be carried out on the new products, and new INDs submitted. In December 2001 AVAX announced that the development of a frozen vaccine and changes to various policies and procedures would ensure that the company complied with the FDA regulations. A new IND was submitted to the FDA for M-Vax in September 2002. In August 2002, AVAX had been unsure whether following approval of its new IND it would re-initiate clinical development for both M-Vax and O-Vax in parallel, or advance one of the agents and wait for further funding for the other. However, in September it indicated that clinical trials of both vaccines would be conducted following approval of the IND. A total of 42 patients are to be enrolled in each trial. In October 2002, AVAX announced that the US FDA had no outstanding issues regarding the IND. AVAX can now proceed with clinical trials as planned. AVAX Technologies was enrolling patients with stage III melanoma in the pivotal US phase III trial for registration of M-Vax trade ed, multicentre trial designed to compare the efficacy of the vaccine against high-dose interferon-alpha, the standard post-surgical treatment for stage III melanoma. The two end-points are rate of melanoma tumour recurrence and overall survival. The dosing regimen chosen for this study is that which was found from several clinical studies to be most effective at eliciting a positive delayed-type hypersensitivity skin response to autologous melanoma cells. The study was being conducted at more than 20 US sites. A low dose of M-Vax was also being evaluated in a phase II study at Thomas Jefferson University in the US. On 16 March 2000, AVAX announced promising interim results from this study, which revealed that 65% of 23 evaluated patients developed an immune response of the same magnitude as that observed with higher doses of M-Vax in previous studies. The study was to enroll a total of 46 patients, who were to receive seven doses of M-Vax over 7 weeks. The advantage of using a low dose of M-Vax is that it requires a smaller amount of the patient's tumour tissue to produce the vaccine (approximately half that required in previous studies) and therefore more patients would be eligible for treatment. On the basis of these results, AVAX modified the pivotal phase III trial to use the low dose of M-Vax to treat additional patients with smaller tumours. On 29 March 2000, AVAX announced that it had initiated a multicentre phase II study in the US in patients with stage IV melanoma and lung metastases. Patients were receiving seven doses of M-Vax at weekly intervals and a booster at 6 months. AVAX initiated the study because of promising results in a study of stage IV melanoma patients with lung metastases in which patients treated with M-Vax had tumour regression and prolonged survival. Commercial agreements: In June 1999, AVAX announced its first international commercialisation opportunity for M-Vax, in Australia, where the company subsequently launched the vaccine (now withdrawn) in the first half of 2000. AVAX formed a subsidiary, AVAX Australia, which was co-marketing M-Vax in Australia together with Australian Vaccine Technologies (formerly Neptunus International Holdings). Under the terms of this agreement, Australian Vaccine Technologies purchased dollars A10 million in shares, a 50% interest, in AVAX Australia. The final dollars A3 million installment was made in August 2000. AVAX had an option to purchase up to 5% of shares in Australian Vaccine Technologies. In August 2002, AVAX extended and expanded an existing production agreement with Medigene for approximately 1 year. Under the terms of the agreement, Genopoietic (Medigene) in France will process clinical samples of M-Vax. In October 2002, AVAX signed a distribution agreement with Ferrer International, SA (Grupo Ferrer) for sales and distribution of the AC Vaccines, including M-Vax and O-Vax. The agreement covers Europe, Latin America and certain Asian territories. Under the terms of the agreement AVAX will retain manufacturing rights and will sell the vaccine to Ferrer. In return, Ferrer will make payments to AVAX for the product as well as certain milestone payments for marketing and registration goals. M-Vax was manufactured in Australia by Bioenterprises, a subsidiary of Biotech Australia. However, in 2002, the manufacturer underwent an acquisition with significant changes, which resulted in its decision to discontinue manufacturing M-Vax.

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SUMMARYIn the last decade, our understanding of posttraumatic stress disorder (PTSD) has progressed from studies of war veterans and specific disaster victims to studies that examine the epidemiology of PTSD in the United States (USA) population. Epidemiologic data on PTSD in developing countries is an understudied area with the majority of studies were developed in the USA and other developed countries. Of the few epidemiological surveys undertaken in other countries, most of them have focused its interest on the prevalence rates of PTSD and its risk factors for following specific traumatic events. Besides increasing the international normative and descriptive data base on PTSD, an examination of prevalence rates and risk factors for PTSD in a socio-political and cultural context (that is markedly different to established market economies) can deepen our understanding of the phenomenology and determinants of PTSD. Although many psychiatric diagnoses can be related with previous traumatic experiences, PTSD has been identified as a disorder that requires a previous traumatic exposure for its diagnosis. A growing literature strongly suggests that early exposure to traumatic events disrupts crucial normal stages of childhood development and predisposes children to subsequent psychiatric sequelae. A series of epidemiological studies has demonstrated that childhood sexual abuse is associated with a range of psychiatric disorders in adulthood that includes mood, anxiety, and substance use disorders, even after adjusting for possible confounds, such as family factors and parental psychopathological disorders or other childhood adversities. There is little evidence of diagnostic specificity of childhood sexual abuse, although a consistent finding has been that alcohol and drug disorders are more strongly related to childhood sexual abuse than other psychiatric disorders. Other forms of childhood traumas have been less well studied.This article reviews the findings of an epidemiological study that took place in Chile and examined prevalence rates of PTSD, traumatic events most often associated with PTSD, comorbidity of PTSD with other lifetime psychiatric disorders, gender differences in PTSD as well as trauma exposure in a representative sample of Chileans. This article also reported a comparison of prevalence rates of various psychiatric disorders among persons who reported the first trauma during their childhood, those who reported the first trauma during their adulthood, and those with no trauma history.The study was based on a household-stratified sample of people defined by the health service system to be adults (aged 15 years and older). The study was designed to represent the population of Chile. This analysis is limited to three geographically distinct provinces, chosen as being representative of the distribution of much of the population. The interviews were administered to a representative sample of 2390 persons aged 15 to over 64 years.The measures used were the DSM-III-R PTSD and antisocial personality disorder modules from the Diagnostic Interview Schedule and modules for a range of DSM-III-R diagnoses from the Composite International Diagnostic. Traumatic events were categorized into one of 11 categories: military combat, rape, physical assault, seeing someone hurt or killed, disaster, threat, narrow escape, sudden injury/ accident, news of a sudden death or accident, other event (e.g. kidnapping, torture), or other experience. The translation into Spanish was conducted using the protocol outlined by the World Health Organization. The interviewers were all university students in their senior year studying social sciences.Taylor series linearization method was used to estimate the standard errors due to the sample design and the need for weighting. The analysis was conducted using procedures without replacement for non-respondents. The region, province, comuna, and district selected were used as the defined strata. Logistic regression with the corresponding 95% confidence interval was used to examine associations among PTSD, demographic risk factors, and trauma type. To examine whether the association between PTSD and gender could be explained by other risk factors, multivariate logistic regression analyses were also conducted.The first analysis found that the lifetime prevalence of PTSD was 4.4% (2.5% for men and 6.2% for women). Among the traumatic events, rape was most strongly associated with PTSD diagnosis. Among those exposed to traumas, women were significantly more likely to develop PTSD than men, after controlling for assaultive violence. The second analysis revealed that exposure to a lifetime trauma was associated with a higher probability of psychiatric morbidity in comparison with no trauma exposure.Traumas with childhood onset were significantly related to lifetime panic disorder, independent of number of lifetime traumas and demographic differences.This revealed that women had more probabilities than men of developing PTSD once they are exposed to trauma, independent of previous traumas, experiences of sexual assault, other violent experiences or level of education. Some authors have proposed that women have a higher vulnerability than men to develop PTSD and that there are sex differences in brain morphology, in the social interpretation of trauma, or/and in the peritraumatic dissociative experience. Although many theories have been proposed to explain this gender difference in PTSD, more research is needed to evaluate them empirically.This study highlights the importance of investigating the prevalence of PTSD, the patterns of comorbidity of PTSD, as well as gender differences of PTSD in non-English speaking countries. Although Chile has a different historical and socio-cultural context with respect to other countries in which the epidemiology of PTSD has been examined, in general, this study achieved similar results as those found in other studies.The results showed that PTSD is not an uncommon psychiatric illness, it is associated with a high degree of psychiatric comorbidity, it is more likely to predate other psychiatric disorders. Also, the results showed that men are more likely to be exposed to traumas than women, women are more likely than men to develop PTSD, and that PTSD is associated with relatively high treatment utilization.However, compared to another country in Latin America, such as Mexico, Chile has a lower prevalence of PTSD and trauma exposure, which may due to socio-economic factors, such as less inequity between the wealthy and the poor and less violence, crime, and poverty in Chile than Mexico. These studies also suggest that traumatic events that occur in childhood are related to specific disorders rather than those that occurred later in life.Individuals with childhood interpersonal trauma exposure are more likely to suffer from lifetime panic disorder, agoraphobia or PTSD compared to those who experience interpersonal trauma as an adult. However, research should examine the specificity of these disorders in relation to various types of childhood traumas.Limitations of the current study include the use of lay interviewers who, despite acceptable levels of reliability and validity, may be less accurate than clinicians as interviewers.Also the retrospective recall of lifetime disorders is likely to be less accurate than a more recent time frame. The sample used in this study does not show nation wide perspective, because the Southern portion of the country which includes much of the indigenous population was excluded. This study, like most epidemiological studies, did not use an-depth or validated index of trauma, which may have diluted findings. Since this study was cross-sectional, a direct cause-effect relationship cannot be assumed between trauma exposure and subsequent disorders.

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Alport syndrome (AS) is a progressive renal disease that is characterised by hematuria and progressive renal failure, and often accompanied by progressive high-tone sensorineural hearing loss and ocular changes in form of macular flecks and lenticonus. AS is a genetic heterogenous disease, and X-linked dominant in about 85% of the families. The autosomal recessive and dominant forms constitute about 15% of the cases. In the first part of the study is a multipoint linkage analysis of 12 families suspected of X-linked AS. The aim of that part of the study was to map a number of X-chromosomal polymorphic markers in relation to the locus for AS, in order to be able to perform carrier detection and prenatal diagnosis in the families. In addition, a more precise map of the region could form the basis for positional cloning of the gene for X-linked AS. In 1990 it was found that the X-linked form of AS is caused by mutation in the COL4A5 gene located at Xq22, and encoding the alpha 5-chain of type IV-collagen. The COL4A5 gene is a very large gene spanning 257 kb with a transcript of 6.5 kb distributed on 51 exons. In addition, two alternatively transcribed exons have been identified. In the second part of the study methods were set up for detection and characterisation of mutations in the COL4A5 gene in 135 patients suspected of AS. The aims of that part of the study were to develop an efficient and reliable approach for mutation detection, and to implement the results of the mutation analysis in clinical practice for carrier detection and prenatal diagnosis, in order to be able to offer a better genetic counselling to the families. Knowledge of a possible correlation between genotype and phenotype can be of help in predicting the prognosis. Samples from 135 probands suspected of AS and 359 of their relatives were collected, together with available clinical information. Southern blotting analysis and multiplex ligation-dependent probe amplification (MLPA) were used to screen for larger structural rearrangements (deletions and duplications). cDNA probes covering the entire coding region of the COL4A5 gene were hybridised on restriction enzyme digested genomic DNA on Southern blots. Three different rearrangements were found by Southern blotting, two of which were caused by single base substitutions, and also detected by the PCR-SSCP analysis. One larger rearrangement was found, an inversion of 21 Mb with a proximal breakpoint in COL4A5 intron 8 at Xq22.3, and a distal breakpoint in the RAB33A gene at Xq26.1. This rearrangement was exclusively ascertained by the Southern blotting analysis. Three deletions of &gt;or= 2 exons were detected by MLPA. One of these was detected in a female proband. A deletion in heterozygous form will not be detected by PCR-SSCP or direct sequencing. A method based on the PCR-SSCP technique was set up for screening of the COL4A5 gene exon-by-exon for mutation. All 51 COL4A5 exons with flanking intronic sequences were screened by this technique. The two alternatively transcribed exons 41A and 41B were directly sequenced. The PCR-SSCP method was compared to direct sequencing in 15 of the cases. No difference in mutation detection rates were found. Finally, a method based on RT-PCR analysis of mRNA extracted from cultured skin fibroblasts was established. A mutation in a patient previously screened by PCR-SSCP analysis with normal result, was detected. Another advantage of analysing a skin biopsy is that it is also possible to perform immunostaining for the alpha 5(IV)-chain in the epidermal basement membrane on sections from the biopsy. Absence of the alpha 5(IV)-chain support a diagnosis of X-linked AS. A total of 64 different and putative disease causing mutations were found in 72 of the families. Half of the mutations identified were missense mutations. The most frequent mutations in AS were glycine substitutions in the Gly-Xaa-Yaa repeat sequence in the collagenous domain of the alpha 5(IV)-chain, accounting for 47% of all mutations and 89% if the missense mutations. Frame-shift mutations accounted for 17% of the mutations, splice site mutations for 13%, nonsense mutations for 11%, in-frame deletions for 4%, and larger structural rearrangements for 6%. In addition, 5 different non-pathogenic sequence variations, polymorphisms and mutations of unknown effect on the phenotype, were found. Nineteen of the mutations are new and have not previously been published, and 55 of the mutations have exclusively been detected in this material. Two of the mutations (3%) are de novo mutations, and it has been possible to trace the mutation back in six of the families, and to determine the parental origin of the mutation in these six families. The origin of the mutation was found to be paternal in 4 of the families (67%), and maternal in 2 of the families (33%). We have demonstrated a highly efficient and sensitive molecular diagnostic approach for analysing the COL4A5 gene in putative AS cases. Based on the present results and the litterature, an algorithm for molecular genetic analysis of the COL4A5 gene is suggested. The overall mutation detection rate was found to be 53%. The mutation detection rate was 72% in patients fulfilling &gt;or= 3 of the clinical criteria for AS, and 82% in families clearly demonstrating X-linked inheritance. No COL4A5 mutation could be detected in 63 (47%) of the families. X-linked inheritance could be excluded in seven of these families solely based on a pedigree analysis, and a diagnosis of Epstein syndrome was established in one of the patients by MYH9 mutation analysis. We found that the underlying COL4A5 mutation, truncating or non-truncating, can significantly predict the age at ESRD in male patients. Truncating mutations, comprising nonsense mutations, frame-shifts, and larger structural rearrangements, were found to cause a juvenile form of the disease with a mean age at ESRD of 21.6 years, compared to 33.1 years in patients with a non-truncating mutation. The effect of non-truncating mutations is, however, less clear-cut. Glycine substitutions in the collagenous domain of the alpha 5(IV)-chain will result in an adult form of AS with a mean age at ESRD of 35.8 years. Missense mutations in the NC1-domain and in-frame deletions result in a juvenile form of the disease with a mean age at ESRD of 23.3 and 20.3 years, respectively, but the number of patients in each group is limited. We found no significant differences in the presence of hearing defects or ocular manifestations between patients with the different types of mutations. The lack of distinct genotype-phenotype correlations implies that the usefulness of the result of the COL4A5 mutation analysis to predict the prognosis is limited. Future technological improvements e.g. automated sequencing strategies and implementation of microarray technology , may increase the mutation detection rates, and lower the time and costs of the analyses. Functional studies are hampered by the restricted expression of the type IV collagen chains. The many different animal models for AS are obvious and promising targets for functional studies, and an important resource for gene therapy studies. This makes AS a reliable candidate for future gene therapy in humans.

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<bObjective:</b To explore effects of dendritic epidermal T cells (DETCs) and Vγ4 T lymphocytes on proliferation and differentiation of mice epidermal cells and the effects in wound healing of mice. <bMethods:</b (1) Six C57BL/6 male mice aged 8 weeks were collected and divided into control group and wound group according to random number table (the same grouping method below), with 3 mice in each group. A 4 cm long straight excision with full-thickness skin defect was cut on back of each mouse in wound group, while mice in control group received no treatment. On post injury day (PID) 3, mice in 2 groups were sacrificed, and skin within 5 mm from the wound margin on back of mice in wound group and normal skin on corresponding part of mice in control group were collected to make single cell suspensions. The percentage of Vγ4 T lymphocyte expressing interleukin-17A (IL-17A) and percentage of DETCs expressing insulin-like growth factor Ⅰ (IGF-Ⅰ) were detected by flow cytometer. (2) Ten C57BL/6 male mice aged 8 weeks were collected and divided into control group and Vγ4 T lymphocyte depletion group with 5 mice in each group. Mice in Vγ4 T lymphocyte depletion group were injected with 200 g Vγ4 T lymphocyte monoclonal neutralizing antibody of Armenian hamster anti-mouse intraperitoneally, and mice in control group were injected with the same amount of Armenian hamster Ig intraperitoneally. One hole with full-thickness skin defect was made on each side of spine of back of each mice. The wound healing was observed on PID 1-8, and percentage of remaining wound area was calculated. (3) Six C57BL/6 male mice aged 8 weeks were grouped and treated in the same way as in experiment (2), with 3 mice in each group. On PID 3, expressions of IL-17A and IGF-Ⅰ in epidermis on margin of wound were detected with Western blotting. (4) Thirty C57BL/6 male mice aged 3 days were sacrificed, and epidermal cells were extracted. The keratin 14 positive cell rate was examined by flow cytometer (the same detecting method below). (5) Another batch of mouse epidermal cells were collected and divided into control group, IGF-Ⅰ group, and IL-17A group, with 3 wells in each group (the same well number below). Cells in IGF-Ⅰ group and IL-17A group were added with 1 mL recombinant mouse IGF-Ⅰ and IL-17A with final mass concentration of 100 ng/mL respectively, while cells in control group were added with the same amount of sterile phosphate buffered saline (PBS). On post culture day (PCD) 5, keratin 14 negative cell rate was examined. Another batch of mouse epidermal cells were collected, grouped, and treated in the same way as aforementioned experiment, and keratin 10 positive cell rate was examined on PCD 10. (6) Another batch of mouse epidermal cells were collected and added with 4 mmol/L 5(6)-carboxyfluorescein diacetate N-succinimidyl ester (CFSE) solution, and divided into control 0 d group, control 7 d group, IGF-Ⅰ group, and IL-17A group. Cells in IGF-Ⅰ group and IL-17A group were treated in the same way as the corresponding groups in experiment (5), and cells in control 0 d group and control 7 d group were treated in the same way as the control group in experiment (5). The CFSE fluorescence peaks were examined on PCD 0 of control 0 d group and PCD 7 of the other 3 groups. (7) Another batch of mouse epidermal cells were collected and divided into control group and IGF-Ⅰ group. Cells in IGF-Ⅰ group were added with 1 mL recombinant mouse IGF-Ⅰ with final mass concentration of 100 ng/mL, and cells in control group were added with the same amount of sterile PBS. On PCD 5, cells were underwent keratin 14 staining and CFSE staining as aforementioned, and keratin 14 negative cell rate of CFSE positive cells was examined. Another batch of mouse epidermal cells were collected and divided into control group and IL-17A group. Cells in IL-17A group were added with 1 mL recombinant mouse IL-17A with final mass concentration of 100 ng/mL, and cells in control group were added with the same amount of sterile PBS. On PCD 5, keratin 14 negative cell rate of CFSE positive cells was examined. Data were processed with one-way analysis of variance and <it</i test. <bResults:</b (1) On PID 3, percentage of DETC expressing IGF-Ⅰ in normal epidermis of control group was (9.9±0.8)%, significantly lower than (19.0±0.6)% of epidermis around margin of wound group (<it</i=8.70, <iP</i&lt;0.01); percentage of Vγ4 T lymphocyte expressing IL-17A in normal epidermis of control group was (0.123±0.024)%, significantly lower than (8.967±0.406)% of epidermis around margin of wound group (<it</i=21.77, <iP</i&lt;0.01). (2) On PID 1-4, there was obvious inflammatory reaction around wounds of mice in control group, and on PID 5-8, the wound area was still large. On PID 1-4, there was slight inflammatory reaction around wounds of mice in Vγ4 T lymphocyte depletion group, and on PID 5-8, the wound area was significantly reduced. On PID 3-7, percentages of residual wound area in Vγ4 T lymphocyte depletion group were significantly lower than those in control group (<it</i=5.92, 5.74, 7.17, 5.38, 5.57, <iP</i&lt;0.01), while percentages of residual wound area in two groups on PID 1, 2, 6 were similar (<it</i=1.46, 3.17, 3.10, <iP</i&gt;0.05). (3) On PID 3, compared with those in control group, expression of IL-17A and IGF-Ⅰ in epidermis around wound margin of mice in Vγ4 T lymphocyte depletion group was markedly decreased and increased respectively (<it</i=8.47, 19.24, <iP</i&lt;0.01). (4) The keratin 14 positive cell rate of mouse epidermal cells was 94.7%. (5) On PCD 5, the keratin 14 negative cell rate of mice in control group was markedly higher than that of IGF-Ⅰ group, while significantly lower than that of IL-17A group (<it</i=7.25, 5.64, <iP</i&lt;0.01). On PCD 10, the keratin 10 positive cell rate of mice in control group was significantly higher than that of IGF-Ⅰ group, while significantly lower than that of IL-17A group (<it</i=3.99, 10.82, <iP</i&lt;0.05 or <iP</i&lt;0.01). (6) Compared with that of control 0 d group, CFSE fluorescence peaks of mouse epidermal cells in control 7 d group, IGF-Ⅰ group, and IL-17A group on PCD 7 shifted to the left. Compared with that of control 7 d group, CFSE fluorescence peaks of mouse epidermal cells in IGF-Ⅰ group and IL-17A group on PCD 7 shifted to the left. (7) On PCD 5, keratin 14 negative cell rate of CFSE positive cells of mice in control group was significantly higher than that in IGF-Ⅰ group (<it</i=9.91, <iP</i&lt;0.01), and keratin 14 negative cell rate of CFSE positive cells of mice in control group was markedly lower than that in IL-17A group (<it</i=6.49, <iP</i&lt;0.01). <bConclusions:</b In the process of wound healing, IGF-Ⅰ secreted by DETC can promote the proliferation of mouse keratin 14 positive epidermal cells and inhibit their terminal differentiation, while IL-17A secreted by Vγ4 T lymphocyte can promote the proliferation and terminal differentiation of mouse keratin 14 positive epidermal cells, thus both IGF-Ⅰ and IL-17A can affect wound healing.

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1. General Principles: 'Application of the Statistical Theory of Rubber Elasticity to the Effect of Heat on Wheat Gluten', by R. Bale and H. G. Muller. 1. General Principles: 'Processing of Non-Newtonian Foods', by S. D. Holdworth (Fruit and Veg. Preserv. Res. Assoc., Chipping Camden, Glos., England), Process Biochem. 4 (10) (October, 1969), 15-21, 33. 1. General Principles: 'A Quick Method of Measuring the Surface Texture of Aggregate', by D. F. Orchid and W. O. Yondell (School of Highway Eng., Univ. of South Wales, Rendwick, N. S. W.), paper presented at the Australian Road Res. Board's 1970 Biennial Conf. 1. General Principles: 'The Deformation and Fracture Behaviour of the Binder in Bituminous Road Surfacing Materials under Traffic Loading', by E. J. Dickinson and H. P. Witt (Australian Road Research Board, 60 Denmark Street, Kew. Vic. 3101, Aust.), paper presented at the Australian Road Research Board, 1970 Biennial Conference. 2. Instrumentation and Methodology: 'Design and Evaluation of a Pressure Attachment for a Rotational Rheometer', by K. R. M. Vora, L. L. Augsburger, and R. F. Shangraw (Dept. of Pharmacy, School of Pharmacy, University of Maryland, Baltimore, Maryland 21201, U. S. A.), J. Pharm. Sci. 59 (1970), 1012-16. 2. Instrumentation and Methodology: 'Materials for Standardizing the FMC Tenderometer', by L. M. Staley (Univ. of British Columbia, Vancouver, B. C., Canada), Can. Inst. Food Technol. J. 3 (1970), 116-117. 2. Instrumentation and Methodology: 'An Electronic Recording Viscometer for Food Products', by P. W. Voisey and J. M. deMan (Eng. Res. Service, Res. Branch, Canada Dept. of Agr., Ottawa and Univ. of Guelph, Guelph, Canada), Can. Inst. Food Technol. J. 3 (1970), 130-135. 2. Instrumentation and Methodology: 'Test Cells for Objective Textural Measurements', by P. W. Voisey (Eng. Res. Service, Res. Branch, Canada Dept. of Agr., Ottawa), Can. Inst. Food Technol. J. 3 (1970), 93-102. 3. Objdve Measurements: 'An Empirical Equation Describing the Firming of the Crumb of Bread', by E. M. A. Willhoft (Lyons Central Labs, 149 Hammersmith Rd., London W14), Chem. Ind. 8 (1970), 1017. 3. Objdve Measurements: 'De la rhéologie des systèmes aqueux à base de gommes', by R. A. Schutz (Mulhouse-Dornach, France), Stärke 22 (1970), 116-125. 3. Objdve Measurements: 'Chopin Teleplastometer Study of Dough Consistency, Preliminary Tests', by J. J. Etienne and M. Dubois (Lab. Grands Moulins, Bobigny, France), Bull. Anciens Elèves Ecole Franç. Meunerie, No. 236 (1970), 94-100. 3. Objdve Measurements: 'The Rheological Evaluation of Semisolids', by L. H. Block and P. P. Lamy (Duquesne Univ. Pittsburgh, and Univ. of Maryland, Baltimore, Md., U. S. A.), J. Soc. Cosmet. Chem. 21 (1970), 645-660. 4. Factors Affecting Texture: 'Comparison of Tennet Curd Tension with Undenatured Whey Protein as a Measure of Heat Treatment', by U. S. Ashworth and Joseph Nebe (Washington State Univ., Pullman, Wash. 99163, U. S. A.), J. Dairy Sci. 53 (1970), 415-419. 4. Factors Affecting Texture: 'Gelation Temperatures of Starch as Influenced by Polyhydric and Monohydric Alcohols, Phenols, Carboxylic Acids and Some Other Additives', by S. Y. Gersma (Technical Univ. Delft, Julianalaan 67, Delft, Netherlands), Stärke 22 (1970), 3-9. 4. Factors Affecting Texture: 'Disodium Dihydrogen Pyrophosphate Blanch and the Texture of French Fries', by A. S. Jaswal (Res. Prod. Counc., Frederickton, New Brunswick, Canada), Am. Potato J. 47 (5) (1970), 145-7. 4. Factors Affecting Texture: 'Nonstarch Polysaccharides and the Texture of French Fried Potatoes', by A. S. Jaswal (Res. Prod. Counc., Fredericton, New Brunswick, Canada), Am. Potato J. 47 (1970), 311-316. 4. Factors Affecting Texture: 'Food Processing Characteristics of Soybean 11S and 7S Proteins. I. Effect of Difference of Protein Components Among Soybean Varieties on Formation of Tofu-Gel', by K. Saio, M. Kamiya, and T. Watanabe (Food Res. Inst., Ministry of Agric. and Forestry, Japan), Agr. Biol. Chem. 33 (1969), 1301-8. 4. Factors Affecting Texture: 'Modifying the Texture of Processed Apple Slices', by R. C. Wiley and Y. S. Lee (Univ. of Maryland, College Park, Md., U. S. A.), Food Technol. 24 (1970), 1168-70. 4. Factors Affecting Texture: 'Factors Influencing the Curd Tension of Rennet Coagulated Milk; Salt Balance', by J. J. S. Jen and U. S. Ashworth (Washington State Univ., Pullman, Wash., U. S. A.), J. Dairy Sci. 53 (1970), 1201-6. 4. Factors Affecting Texture: 'Physical and Chemical Properties of Epimysial Acid-Soluble Collagen From Meats of Varying Tenderness', by W. G. Kruggel, R. A. Field, and G. J. Miller (Univ. of Wyoming, Laramie, Wyo., U. S. A.), J. Food Sci. 35 (1970), 106-110. 4. Factors Affecting Texture: 'Cream Puffs Prepared with Frozen, Foam-Spray-Dried, Freeze-Dried, and Spray-Dried Eggs', by Kaye Funk, Mary E. Zabik, Gisele Charlebois, and Doris M. Downs (Departments of Institution, Administration and Foods and Nutrition, Michigan State Univ., East Lansing, U. S. A.), Cereal Chem. 47 (1970), 324-331. 4. Factors Affecting Texture: 'Effects of Amylases and Metals on the Pasting Properties of Wheat Flour, Determined by the Amylograph and by Hagberg's Falling-Number Method', by Peter Meredith (Wheat Research Institute, Department of Scientific and Industrial Research, Christchurch, New Zealand), Cereal Chem. 47 (1970), 483-491. 4. Factors Affecting Texture: 'Inactivation of Cereal Alpha-Amylase by Brief Acidification: The Pasting Strength of Wheat Flour', by Peter Meredith (Wheat Research Institute, Department of Scientific and Industrial Research, Christchurch, New Zealand), Cereal Chem. 47 (1970), 492-500. 4. Factors Affecting Texture: 'Effects of Fumigation on Wheat in Storage. I. Physical Measurements of Flour', by Ruth H. Matthews, C. C. Fifield, T. F. Hartsing, C. L. Storey, and N. M. Dennis (Human Nutrition Res. Div., ARS, USDA, Beltsville, Maryland, U. S. A.), Cereal Chem. 47 (1970), 579-586. 4. Factors Affecting Texture: 'Effects of Fumigation on Wheat in Storage. II. Physical and Eating Qualities of Breads and Rolls', by Ruth H. Matthews, C. C. Fifield, and T. F. Hartsing (Human Nutrition Res. Div., ARS, USDA, Beltsville, Maryland, U. S. A.), Cereal Chem. 47 (1970), 587-591. 4. Factors Affecting Texture: 'Gelation Phenomena of Soybean Globulins. I. Protein-Protein Interactions', by N. Catsimpoolas and E. W. Meyer (Protein Res. Lab., Central Soya-Chemurgy Div., Chicago, Illinois 60639, U. S. A.), Cereal Chem. 47 (1970), 559-570. 4. Factors Affecting Texture: 'Barley Starch. IV. A Study of the Cooking Viscosity Curves of Twelve Barley Genotypes', by K. J. Goering, Robert Eslick, and Bernice DeHaas, (Montana State Univ., Bozeman, Mont. 59715, U. S. A.), Cereal Chem. 47 (1970) 592-596. 4. Factors Affecting Texture: 'The Effect of Muscle Excision Before the Onset of Rigor Mortis on the Palatibility of Beef', by G. R. Schmidt and K. V. Gilbert (The Meat Industry Res. Inst. of New Zealand, Hamilton, New Zealand), J. Food Technol. 5 (1970), 331-338. 4. Factors Affecting Texture: 'Relation Between pH and Tenderness in Cooked Muscle', by Christine L. Miles and R. A. Lawrie (Food Science Laboratories, Dept. of Applied Biochemistry and Nutrition, Univ. of Nottingham, Sutton Bonington, Loughborough, Leics., England), J. Food Technol. S (1970), 325-330. 4. Factors Affecting Texture: 'Rigor Tensions and Gaping in Cod Muscle', by J. R. Burt, N. R. Jones, A. S. McGill, and G. D. Stroud (Torry Research Station, Ministry of Technology, Aberdeen, Scotland), J. Food Technol. S (1970), 339-351.

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<bObjective:</b To explore the application effects of bundle nursing of citric acid extracorporeal anticoagulation on continuous renal replacement therapy (CRRT) of severe burn patients. <bMethods:</b A non-randomized controlled study was conducted. Forty-six patients who met the inclusion criteria and received regular nursing of citric acid extracorporeal anticoagulation during CRRT in the First Affiliated Hospital of Army Medical University (the Third Military Medical University) from January to December 2017 were included in regular nursing group (30 males and 16 females, aged 42.0 (38.7,47.0) years, with 201 times of CRRT performed), and 48 patients who met the inclusion criteria and received bundle nursing of citric acid extracorporeal anticoagulation during CRRT in the same hospital from January to December 2018 were included in bundle nursing group (32 males and 16 females, aged 41.0 (36.0,46.0) years, with 164 times of CRRT performed). The clinical data of all the patients in the two groups were recorded, including the length of intensive care unit (ICU) stay, total cost of treatment in ICU, cost of CRRT, unplanned ending of treatment, ending of treatment due to operation (with the rates of unplanned ending of treatment and ending of treatment due to operation calculated), times of disposable hemodialysis filter and supporting pipeline filter (hereinafter referred to as filter) with use time&gt;24 h, times of CRRT, and lifetime of filter. For the patients in both groups who continuously received CRRT for 3 days or more from the first treatment, the prothrombin time (PT), activated partial thromboplastin time (APTT), international normalized ratio (INR), total calcium, ionic calcium (with the difference of total calcium or ionic calcium between before and after treatment calculated), creatinine, urea, β<sub2</sub microglobulin, cystatin C, platelet count, mean arterial pressure, pH value, oxygenation index, bicarbonate radical, and lactic acid levels before the first treatment (hereinafter referred to as before treatment) and 3 days after the first treatment (hereinafter referred to as after 3 days of treatment). The treatment-related complications of all patients in the two groups were recorded during hospitalization. Data were statistically analyzed with independent sample <it</i test, Mann-Whitney <iU</i test, and chi-square test. <bResults:</b Compared with those in regular nursing group, the length of ICU stay was significantly shortened (<iZ</i=-4.71, <iP</i&lt;0.01), the total cost of treatment in ICU was significantly reduced (<it</i=-1.39, <iP</i&lt;0.01), the cost of CRRT had no significant change (<iP</i&gt;0.05), the rates of unplanned ending of treatment and ending of treatment due to operation were both significantly decreased (with <iχ<sup2</sup</i values of 12.20 and 17.83, respectively, <iP</i&lt;0.01), the times of filter service time&gt;24 h was increased significantly (<iZ</i=-5.93, <iP</i&lt;0.01), the times of CRRT were significantly reduced (<iZ</i=-4.75, <iP</i&lt;0.01), and the filter service life was significantly prolonged (<iZ</i=-9.24, <iP</i&lt;0.01) among patients in bundle nursing group. Thirty-one patients in bundle nursing group and 28 patients in regular nursing group continuously received CRRT for 3 days or more from the first treatment. Before treatment, PT, APTT, and INR of patients in bundle nursing group were 24.10 (16.08, 39.20) s, 38.81 (32.32, 45.50) s, and 1.17 (1.12, 1.19), respectively, similar to 31.75 (22.99, 40.96) s, 41.82 (35.05, 48.06) s, and 1.15 (1.11, 1.19) of patients in regular nursing group (<iP</i&gt;0.05); the levels of total calcium and ionic calcium of patients in the two groups were similar (<iP</i&gt;0.05). After 3 days of treatment, PT, APTT, and INR of patients in bundle nursing group and regular nursing group were 29.06 (20.11, 39.46) s, 35.25 (30.06, 40.28) s, 1.13 (1.09, 1.17) and 36.51 (26.64, 42.92) s, 39.89 (34.81, 46.62) s, 1.14 (1.10, 1.18), respectively, similar to those before treatment (<iP</i&gt;0.05); the level of ionic calcium of patients in regular nursing group was significantly higher than that before treatment (<iZ</i=-2.08, <iP</i&lt;0.05); the levels of total calcium and ionic calcium of patients in bundle nursing group were both significantly higher than those before treatment (with <iZ</i values of -3.55 and -3.69, respectively, <iP</i&lt;0.01); compared with those in regular nursing group, APTT of patients was significantly shorter (<iZ</i=-2.29, <iP</i&lt;0.05), while the total calcium level of patients was significantly higher in bundle nursing group (<iZ</i=-2.26, <iP</i&lt;0.05). The difference of total calcium between before and after treatment of patients in bundle nursing group was significantly higher than that in regular nursing group (<iZ</i=-3.15, <iP</i&lt;0.01). The differences of ionic calcium between before and after treatment of patients in the two groups were similar (<iP</i&gt;0.05). Before treatment, the level of β<sub2</sub microglobulin of patients in bundle nursing group was significantly higher than that in regular nursing group (<iZ</i=-2.84, <iP</i&lt;0.01), the platelet count of patients in bundle nursing group was significantly lower than that in regular nursing group (<iZ</i=-2.44, <iP</i&lt;0.05), while the levels of creatinine, urea, cystatin C, mean arterial pressure, pH value, oxygenation index, bicarbonate radical, and lactic acid of patients in the two groups were similar (<iP</i&gt;0.05). After 3 days of treatment, the levels of creatinine, urea, β<sub2</sub microglobulin, cystatin C, pH value, bicarbonate radical, and lactic acid of patients were all significantly lower than those before treatment (with <iZ</i values of -2.10, -2.90, -3.11, -2.02, -2.34, -2.63, and -2.84, respectively, <iP</i&lt;0.05 or <iP</i&lt;0.01), while the levels of platelet count, oxygenation index, and mean arterial pressure of patients were all significantly higher than those before treatment in bundle nursing group (with <iZ</i values of -6.65 and -2.40, respectively, <it</i=-9.97, <iP</i&lt;0.05 or <iP</i&lt;0.01); the levels of creatinine, urea, β<sub2</sub microglobulin, cystatin C, platelet count, pH value, bicarbonate radical, and lactic acid of patients were all significantly lower than those before treatment (with <iZ</i values of -5.32, -2.31, -2.41, -2.21, -3.68, -2.93, -2.20, and -2.31, respectively, <iP</i&lt;0.05 or <iP</i&lt;0.01), while the oxygenation index and mean arterial pressure of patients were both significantly higher than those before treatment in regular nursing group (<iZ</i=-5.59, <it</i=-7.74, <iP</i&lt;0.01). After 3 days of treatment, compared with those in regular nursing group, the levels of creatinine, cystatin C, platelet count, oxygenation index, bicarbonate radical, and mean arterial pressure of patients were all significantly higher (with <iZ</i values of -2.93, -1.99, -6.39, -2.09, and -2.52, respectively, <it</i=-3.28, <iP</i&lt;0.05 or <iP</i&lt;0.01), while the levels of urea, β<sub2</sub microglobulin, pH value, and lactic acid of patients were all significantly lower (with <iZ</i values of -3.87, -2.58, -4.24, and -2.75, respectively, <iP</i&lt;0.05 or <iP</i&lt;0.01) in bundle nursing group. During hospitalization, there were no treatment-related bleeding events or hypernatremia related to citric acid treatment of patients in the two groups. The ratio of total calcium to ionic calcium in one patient in bundle nursing group was &gt;2.5, but there was no manifestation of citric acid accumulation poisoning; 1 patient had hypoionic calcemia, and 1 patient had severe metabolic alkalosis. Five patients had hypoionic calcemia and 2 patients had severe metabolic alkalosis in regular nursing group. <bConclusions:</b The implementation of bundle nursing of citric acid extracorporeal anticoagulation during CRRT for severe burn patients shortens the length of ICU stay, reduces the total cost of treatment in ICU and the occurrence of treatment-related complications, relieves the economic burden of patients, and improves the continuity and quality of treatment.

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The term 'lipid-based nutrient supplements' (LNS) refers generically to a range of fortified, lipid-based products, including products like Ready-to-Use Therapeutic Foods (RUTF) (a large daily ration with relatively low micronutrient concentration) as well as highly concentrated supplements (1-4 teaspoons/day, providing &lt;100 kcal/day) to be used for 'point-of-use' fortification. RUTF have been successfully used for the management of severe acute malnutrition (SAM) among children in emergency settings. Recent research on smaller doses of LNS for prevention of malnutrition has created interest in their potential use in emergency settings to ensure a more nutritionally adequate ration for the most vulnerable groups [e.g. infants and children between 6 and 24 months of age, and pregnant and lactating women (PLW)]. Currently, the main food and nutrition interventions in emergency settings include general food distribution (GFD) rations, which are provided to the affected population as a whole, and selective (or supplementary) feeding programs (SFP), which are to be provided to nutritionally vulnerable or malnourished individuals. In addition to logistical and operational challenges that may limit the intended effect of these programs, the nutritional quality of the food commodities provided may be insufficient to meet the needs of infants and young children and PLW. Because these subgroups have particularly high nutrient needs for growth and development, meeting these needs is challenging in settings where the ration is limited to a few food commodities, with little access to a diverse diet and bioavailable sources of micronutrients. In recent years, there has been increased attention to adding micronutrient interventions, on top of the other food-based interventions (such as GFDs and SFPs), to fill micronutrient gaps in diets in emergency settings. The focus of this document is the potential role of LNS in meeting the nutritional needs of these vulnerable subgroups, with the goal of preventing malnutrition in emergency-affected populations. The document addresses the desired nutritional formulation of LNS for these target groups, taking into account the expected bioavailability of relevant nutrients and toxicity concerns. It also discusses the recommended chemical forms of the fortificants in LNS; stability and shelf-life considerations; production, packaging and distribution of LNS in the context of emergencies; and cost implications of the addition of LNS to current GFD rations for vulnerable groups. To develop the desired nutritional formulation of LNS for these purposes, we calculated the current nutrient content of commonly provided GFD rations and determined the nutritional 'gaps' (of both micro- and macronutrients) of these rations for each of the target groups (i.e. children 6-35 months of age and PLW). For fat and protein, both quantity and quality were evaluated. Through an iterative process, we determined the formulation of a small dose of LNS that would best meet the recommended nutrient intakes for each group in combination with other foods in the GFD ration [composed of a grain, pulse, oil, sugar and salt, but excluding a fortified blended food (FBF)], as well as breast milk for children 6-24 months of age, while avoiding excess levels of any one nutrient to the extent possible. The composition of the LNS used for these calculations is based on an existing LNS product (Nutributter, Malaunay, France, Nutriset), but with less sugar and more oil. Two different approaches were used: (1) developing two different formulations of LNS, one to be used for infants and children 6-35 months of age and a separate one for PLW; and (2) developing a single formulation that could be used for all of these subgroups. We used commodity cost data to estimate the cost of adding an LNS product to the GFD ration. The results indicate that the typical GFD ration currently provided in emergency settings--based on cereals, pulse, an FBF such as corn-soy blend (CSB), oil, salt and sugar-does not meet the nutritional needs of infants and young children and PLW. The hypothetical intake from a ration composed of food aid commodities (based on the current USAID/USDA specifications for exported food aid commodities used in emergency settings), and including breast milk for children 6-24 months of age, provided less than 75% of the recommended intake for several micronutrients for certain age/physiologic groups, including calcium, iron, zinc, B vitamins such as riboflavin, B6 and B12, and fat-soluble vitamins such as D, E and K. It also generally contained lower than recommended levels of fat and essential fatty acids. The initial LNS formulation for each target group was designed to provide 100% of the recommended amount (RDA or RNI) for most micronutrients per daily dose (20 g, approximately 118 kcal) of LNS. This would ensure consumption of the recommended levels of each nutrient even if the 'base' diet changed. However, because such a formulation could provide excess amounts of certain nutrients when consumed in combination with the 'base' diet (especially when the 'base' diet contains fortified foods), we made adjustments in the LNS formulation when there was a risk of greatly exceeding the Upper Level for certain subgroups and there were relevant concerns about adverse effects from chronic consumption of such amounts. For most nutrients, consumption of toxic amounts is highly unlikely with the proposed LNS formulations. The 'one-size' LNS formulation was designed so that one 'dose' (20 g) would be provided to infants and young children and two 'doses' (i.e. 40 g/day) would be provided to PLW. This 'one-size' formulation was based on the LNS formulation developed for children 6-35 months of age. Although the resulting formulation is not a perfect match for the unique nutritional needs of each subgroup, there are several practical advantages to using such an approach. As anticipated, addition of LNS to the GFD ration, even after eliminating the FBF (e.g. CSB), increases the cost. The 'revised' ration without CSB but with LNS would cost 34-52% more (food only) than the 'typical' GFD diet for a hypothetical mother-infant pair, depending on how many LNS 'doses' were provided to the mother. However, depending on the contribution of food costs to overall program costs, the overall increase in costs may be significantly less. Although cost is an important consideration, options to improve the nutritional quality of foods provided in emergency settings should also be assessed with regard to effectiveness in maintaining and improving nutritional outcomes. Another consideration is whether a specialized product like LNS is more easily targeted to the individuals for whom it is intended, thus reducing inter- and intra-household sharing, a common concern with other fortified products such as CSB. This could have substantial cost implications because programs usually compensate for sharing by inflating the amount of FBF provided. This document is intended to be a starting point for considering the incorporation of LNS in the food packages provided in emergency settings. Our goal was to examine the potential nutritional benefits but also the challenges of adopting such a strategy. There are many different options for emergency nutrition programs, and there are also many considerations governing which option to choose. This document is intended to encourage further evaluation of all of these options.

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Maximum contaminant levels are used to control potential health hazards posed by chemicals in drinking water, but no primary national or international limits for aluminum (Al) have been adopted. Given the differences in toxicological profiles, the present evaluation derives total allowable concentrations for certain water-soluble inorganic Al compounds (including chloride, hydroxide, oxide, phosphate and sulfate) and for the hydrated Al silicates (including attapulgite, bentonite/montmorillonite, illite, kaolinite) in drinking water. The chemistry, toxicology and clinical experience with Al materials are extensive and depend upon the particular physical and chemical form. In general, the water solubility of the monomeric Al materials depends on pH and their water solubility and gastrointestinal bioavailability are much greater than that of the hydrated Al silicates. Other than Al-containing antacids and buffered aspirin, food is the primary source of Al exposure for most healthy people. Systemic uptake of Al after ingestion of the monomeric salts is somewhat greater from drinking water (0.28%) than from food (0.1%). Once absorbed, Al accumulates in bone, brain, liver and kidney, with bone as the major site for Al deposition in humans. Oral Al hydroxide is used routinely to bind phosphate salts in the gut to control hyperphosphatemia in people with compromised renal function. Signs of chronic Al toxicity in the musculoskeletal system include a vitamin D-resistant osteomalacia (deranged membranous bone formation characterized by accumulation of the osteoid matrix and reduced mineralization, reduced numbers of osteoblasts and osteoclasts, decreased lamellar and osteoid bands with elevated Al concentrations) presenting as bone pain and proximal myopathy. Aluminum-induced bone disease can progress to stress fractures of the ribs, femur, vertebrae, humerus and metatarsals. Serum Al ≥100 µg/L has a 75-88% positive predictive value for Al bone disease. Chronic Al toxicity is also manifest in the hematopoietic system as an erythropoietin-resistant microcytic hypochromic anemia. Signs of Al toxicity in the central nervous system (speech difficulty to total mutism to facial grimacing to multifacial seizures and dyspraxia) are related to Al accumulation in the brain and these symptoms can progress to frank encephalopathy. There are four groups of people at elevated risk of systemic Al intoxication after repeated ingestion of monomeric Al salts: the preterm infant, the infant with congenital uremia and children and adults with kidney disease. There is a dose-dependent increase in serum and urinary Al in people with compromised renal function, and restoration of renal function permits normal handling of systemically absorbed Al and resolution of Al bone disease. Clinical experience with 960 mg/day of Al(OH)(3) (~5 mg Al/kg-day) given by mouth over 3 months to men and women with compromised renal function found subclinical reductions in hemoglobin, hematocrit and serum ferritin. Following adult males and females with reduced kidney function found that ingestion of Al(OH)(3) at 2.85 g/day (~40 mg/kg-day Al) over 7 years increased bone Al, but failed to elicit significant bone toxicity. There was one report of DNA damage in cultured lymphocytes after high AlCl(3) exposure, but there is no evidence that ingestion of common inorganic Al compounds presents an increased carcinogenic risk or increases the risk for adverse reproductive or developmental outcomes. A number of studies of Al exposure in relation to memory in rodents have been published, but the results are inconsistent. At present, there is no evidence to substantiate the hypothesis that the pathogenesis of Alzheimer's Disease is caused by Al found in food and drinking water at the levels consumed by people living in North America and Western Europe. Attapulgite (palygorskite) has been used for decades at oral doses (recommended not to exceed two consecutive days) of 2,100 mg/day in children of 3-6 years, 4,200 mg/day in children of 6-12 years, and 9,000 mg/day in adults. Chronic ingestion of insoluble hydrated Al silicates (in kg) can result in disturbances in iron and potassium status, primarily as a result of clay binding to intestinal contents and enhanced fecal iron and zinc elimination. Sufficiently high doses of ingested Al silicates (≥50 g/day) over prolonged periods of time can elicit a deficiency anemia that can be corrected with oral Fe supplements. There is essentially no systemic Al uptake after ingestion of the hydrated Al silicates. Rats fed up to 20,000 ppm Ca montmorillonite (equivalent to 1,860 ppm total Al as the hydrated Al silicate) for 28 weeks failed to develop any adverse signs. The results of dietary Phase I and II clinical trials conducted in healthy adult volunteers over 14 days and 90 days with montmorillonite found no adverse effects after feeding up to 40 mg/kg-day as Al. Since the Al associated with ingestion of hydrated Al silicates is not absorbed into the systemic circulation, the hydrated Al silicates seldom cause medical problems unless the daily doses consumed are substantially greater than those used clinically or as dietary supplements. A no-observable-adverse-effect-level (NOAEL) of 13 mg/kg-day as total Al can be identified based on histologic osteomalacia seen in adult hemodialysis patients given Al hydroxide for up to 7 years as a phosphate binder. Following U.S. EPA methods for calculation of an oral reference dose (RfD), an intraspecies uncertainty factor of 10x was applied to that value results in a chronic oral reference dose (RfD) of 1.3 mg Al/kg-day; assuming a 70-kg adult consumes 2 L of drinking water per day and adjusting for a default 20% relative source contribution that value corresponds to a drinking water maximum concentration of 9 mg/L measured as total Al. A chronic NOAEL for montmorillonite as representative of the hydrated Al silicates was identified from the highest dietary concentration (20,000 ppm) fed in a 28-week bioassay with male and female Sprague-Dawley rats. Since young rats consume standard laboratory chow at ~23 g/day, this concentration corresponds to 56 mg Al/kg-day. Application of 3x interspecies uncertainty factor and a 3x factor to account for study duration results in a chronic oral RfD of 6 mg Al/kg-day. Of note, this RfD is 5-10 fold less than oral doses of Al silicates consumed by people who practice clay geophagy and it corresponds to a maximum drinking water concentration of 40 mg Al/L. To utilize the values derived here, the risk manager must recognize the particular product (e.g., alum) or source (e.g., groundwater, river water, clay or cement pipe) of the Al found in tap water, apply the appropriate analytical methods (atomic absorption, energy dispersive X-ray diffraction, infrared spectral analysis and/or scanning transmission electron microscopy) and compare the results to the most relevant standard. The drinking water concentrations derived here are greater than the U.S. EPA secondary maximum contaminant level (MCL) for total Al of 0.05-0.2 mg/L [40 CFR 143.3]. As such, domestic use of water with these concentrations is likely self-limiting given that its cloudy appearance will be greater than the maximum permitted (0.5-5.0 nephalometric turbidity units; 40 CFR Parts 141 and 142). Therefore, the organoleptic properties of Al materials in water determine public acceptance of potable water as contrast to any potential health hazard at the concentrations ordinarily present in municipal drinking water.

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Following the publication of the above paper, the authors realized that, in their follow‑up experiments, the STAT3 and p65 antibodies they used had already expired prior to the results being published. This affected the confidence that the authors could place in the results published in Figs. 1 and 3E. In addition, the findings were also inconsistent with Fig. 4A and B, potentially causing confusion for the readers. The authors therefore repeated some of these experiments with newly purchased antibodies; they also changed the RT-qPCR results. In the published manuscript, the authors investigated the expression of LYPD8 mRNA expression in tissues from stages I, II, and III whereas in the revised manuscript they have investigated stages II and IV. In addition, the authors have supplemented the manuscript with new transwell assays. The revised figures are presented on the next two pages (Figs 1-4). Repeating these particular experiments has resulted in the following changes being necessary to the text of the published paper (changes are highlighted in bold): i) The fourth sentence in the Abstract, on p. 2389, should read as follows: "The results revealed that the expression of LYPD8 was significantly reduced in the CRC tissue compared with that in precancerous tissue and normal tissue, particularly in stage IV tissue." ('III' has been changed to 'IV'). ii) In the Materials and methods section, "<iHistological analysis</i" subsection on p. 2390, the last three sentences should be replaced with the following text: "The histological sections were then stained with the DAB Kit (cat. no. PV‑9000; ZSGB‑BIO, Beijing, China). All sections were observed under a bright‑field microscope (Nikon Corporation, Tokyo, Japan)." iii) In the "<iCell culture</i" subsection in the right‑hand column, the first four sentences should be revised to the following: "Four CRC cell lines (SW480, SW620, HCT116 and RKO) were used. SW480 (ATCC<sup®</sup CCL‑228™, organism, human; tissue, colon; disease, colorectal adenocarcinoma), SW620 (ATCC<sup®</sup CCL‑227™, organism, human; tissue, colon; derived from metastatic site, lymph node; disease, colorectal adenocarcinoma), HCT116 (ATCC<sup®</sup CCL‑247™, organism, human; tissue, colon; disease, colorectal carcinoma) and RKO (ATCC<sup<sub®</sub</sup CRL‑2577™, organism, human; tissue, colon; disease, carcinoma) cells were purchased from the American Type Culture Collection (Manassas, VA, USA). The four cell lines within passages 10 were used in all experiments, and the cell lines were maintained at 37˚C in a humidified incubator containing 5% CO<sub2</sub". Also, in line 8 of p. 2391, the cell lines here should be changed to "SW480, SW620 and HCT116 cells", and on line 11, "HT29 cells" should be changed to "RKO cells". iv) In the Results section, the following changes to the text are necessary: In the "<iCorrelation of the expression of LYPD8 with STAT3/P65 phosphorylation and IL‑6/TNF‑α secretion in patients with CRC</i" subsection, in the second sentence, "immunofluorescence" should have been written as "immunohistochemistry", and the fourth sentence should have read as follows: "The results of the western blotting showed that the levels of p‑P65/P65 and p‑STAT3/STAT3 gradually increased between stage II and IV (Fig. 1B and C)." Then, the three sentences starting on line 7 on p. 2391 should now read as follows: "Following this, the gene expression levels of LYWPD8 in stage II and IV CRC tissue, precancerous tissue, and normal tissue were assessed using RT‑qPCR analysis (Fig. 2C). Compared with the precancerous tissue and normal tissue, the gene expression of LYPD8 was significantly reduced in stage II and IV tissues. Furthermore, the expression of LYPD8 was reduced in stage IV tissue compared with that in stage II tissue." v) In the subsequent subsection, "<iConstruction and overexpression of LYPD8 in CRC cells</i", the first sentence should have read as follows: "The plasmid DNA for overexpressing LYPD8 was constructed using the eukaryotic expression vector (pIRES2), as shown in Fig. 3A and B, and the relative expression levels of LYPD8 in the RTO, SW480 HCT116 and SW620 cells were examined by RT-qPCR analysis. vi) In the "<iOverexpression of LYPD8 inhibits CRC cell proliferation and migration</i" subsection, the penultimate sentence as it appears towards the foot of p. 2392 should now read as follows: "As shown in Fig. 4C and D, a more marked inhibitory effect on cell migration was observed in the LYPD8 OE group compared with that in the control, LYPD8 OE + IL‑6 and LYPD8 OE + TNF‑α groups." vi) In the Discussion, the sentence starting on p. 2394, right‑hand column, line 10 should read as follows: "By contrast, the expression of LYPD8 was significantly reduced in stage II and IV CRC tissues." vii) Finally, some revisions were necessary to the descriptions in the figure legends for Figs. 1, 2 and 4, as follows (only the affected text is included, and the changes are indicated in bold): Figure 1. STAT3 and P65 are activated in colonic tumor tissues from patients. (A) Representative immunohistochemistry images revealing activated STAT3 and P65 in colonic cancer tissue and precancerous tissue. Scale bar, 100 µm. (B) Representative western blotting revealing the expression of p‑P65, P65, p‑STAT3 and STAT3 in stages II and IV colonic tumor tissues. GAPDH was used as a control. (C) Band intensities of western blotting for p‑P65/P65 and p‑STAT3/STAT3 in stage II and IV tissues were analyzed. The data are reported as the mean ± standard deviation of experiments (n=4). <sup**</supP&lt;0.05, phosphorylation levels of STAT3 in stage II tissues vs. in stage IV tissues. Figure 2. Association between IL‑6/TNF‑α and the expression of LYPD8 in colonic tumor tissue, precancerous tissue and normal tissue at different stages. (A) IL‑6 and (B) TNF‑α secretion were analyzed by ELISA in stage II and IV colonic tumor tissue and precancerous tissue. (C) Gene expression of LYPD8 in stage II and IV colonic tumor tissue and precancerous tissue. β‑actin was used as a control. The data are reported as the mean ± standard deviation of experiments (n=6). <sup**</supP&lt;0.01, LYPD8 mRNA expression of normal tissue, precancerous tissue vs. colonic tumor tissue in stage II and IV tissues. Figure 4. Effects of the overexpression of LYPD8 on SW480 cell proliferation and migration. (A) Cell viability of the Control, LYPD, LYPD8 OE + IL‑6 and LYPD8 OE + TNF‑α groups of SW480 cells. (B) SW480 cells were treated with different concentrations (0.5, 1 and 2 <iµ</iM) of niclosamide and different concentrations (5, 15 and 30 <iµ</iM) of JSH‑23, respectively. (C) Numbers of migratory SW480 cells from the Control, LYPD8, LYPD8 OE + IL‑6 and LYPD8 OE + TNF‑α groups. (D) Transwell assay of SW480 cells from the (a) Control, (b) LYPD8 OE, (c) LYPD8 OE + IL‑6 and (d) LYPD8 OE + TNF‑α groups (magnification, ×200).  Note that the replacement of the original figures and these revisions made to the text do not drastically alter the overall conclusions reported in the study. The authors are very grateful to the Editor of <iOncology Reports</i for allowing them the opportunity to publish this Corrigendum; furthermore, they apologize for any inconvenience caused to the readership of the Journal. [the original articles was published in Oncology Reports 41: 2389‑2395, 2019; DOI: 10.3892/or.2019.7034].

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<bObjective:</b To investigate the effects of exosomes from human adipose-derived mesenchymal stem cells (ADSCs) on inflammatory response of mouse RAW264.7 cells and wound healing of full-thickness skin defects in mice. <bMethods:</b The experimental research methods were adopted. The discarded adipose tissue was collected from 3 female patients (aged 10-25 years) who underwent abdominal surgery in the First Affiliated Hospital of Air Force Medical University. ADSCs were extracted from the adipose tissue by collagenase Ⅰ digestion and identified with flow cytometry. Exosomes were extracted from the human ADSCs by differential ultracentrifugation, the morphology of the exosomes was observed by transmission electron microscopy, the particle diameter of the exosomes was detected by nanoparticle tracking analyzer, and the protein expressions of CD9, CD63, tumor susceptibility gene 101 (TSG101), and β-actin were detected by Western blotting. The human ADSCs exosomes (ADSCs-Exos) and RAW264.7 cells were co-cultured for 12 h, and the uptake of RAW264.7 cells for human ADSCs-Exos was observed. The RAW264.7 cells were divided into phosphate buffer solution (PBS) group stimulated with PBS for suitable time, endotoxin/lipopolysaccharide (LPS) stimulation 2 h group, LPS stimulation 4 h group, LPS stimulation 6 h group, LPS stimulation 12 h group, and LPS stimulation 24 h group stimulated with LPS for corresponding time, with 3 wells in each group, and the mRNA expressions of interleukin 1β (IL-1β), tumor necrosis factor α (TNF-α), IL-6, and IL-10 were detected by real-time fluorescence quantitative reverse transcription polymerase chain reaction (RT-PCR) method. The RAW264.7 cells were divided into PBS group, LPS alone group, and LPS+ADSCs-Exos group, with 3 wells in each group, which were dealt correspondingly for the time screened out in the previous experiment, the mRNA expressions of IL-1β, TNF-α, IL-6, IL-10, trasforming growth factor β (TGF-β,) and vascular endothelial growth factor (VEGF) were detected by real time fluorescence quantitative RT-PCR method, and the protein expressions of inducible nitric oxide synthase (iNOS) and arginase 1 (Arg1) were detected by Western blotting. Twenty-four 8-week-old male BALB/c mice were divided into PBS group and ADSCs-Exos group according to the random number table, with 12 mice in each group, and a full-thickness skin defect wound with area of 1 cm×1 cm was inflicted on the back of each mouse. Immediately after injury, the wounds of mice in the two groups were dealt correspondingly. On post injury day (PID) 1, the concentration of IL-1β and TNF-α in serum were detected by enzyme-linked immunosorbent assay, and the mRNA expressions of IL-1β, TNF-α, and IL-6 were detected by real time fluorescence quantitative RT-PCR method. On PID 3, 6, 9, 12, and 15, the wound healing was observed and the wound non-healing rate was calculated. On PID 15, the defect length of skin accessory and collagen volume fraction (CVF) were detected by hematoxylin eosin staining and Masson staining, respectively, the CD31 expression and neovascularization were detected by immunohistochemistry, and the ratio of Ki67 positive cells, the ratio of iNOS and Arg1 double positive cells, and the ratio of iNOS positive cells to Arg1 positive cells and their fluorescence intensities were detected by immunofluorescence method. The number of samples in animal experiments was 6. Data were statistically analyzed with analysis of variance for repeated measurement, one-way analysis of variance, and independent sample <it</i test. <bResults:</b At 12 h of culture, the cells exhibited a typical spindle shape, which were verified as ADSCs with flow cytometry. The exosomes with a vesicular structure and particle diameters of 29-178 nm, were positively expressed CD9, CD63, and TSG101 and negatively expressed β-actin. After 12 h of co-culture, the human ADSCs-Exos were endocytosed into the cytoplasm by RAW264.7 cells. The mRNA expressions of IL-1β, TNF-α, IL-6, and IL-10 of RAW264.7 cells in LPS stimulation 2 h group, LPS stimulation 4 h group, LPS stimulation 6 h group, LPS stimulation 12 h group, and LPS stimulation 24 h group were significantly higher than those in PBS group (with <it</i) values of 39.10, 14.55, 28.80, 4.74, 48.80, 22.97, 13.25, 36.34, 23.12, 18.71, 29.19, 41.08, 11.68, 18.06, 8.54, 43.45, 62.31, 22.52, 21.51, and 37.13, respectively, <iP</i&lt;0.01). The stimulation 12 h with significant expressions of all the inflammatory factors was selected as the time point in the following experiment. After stimulation of 12 h, the mRNA expressions of IL-1β, TNF-α, IL-6, and IL-10 of RAW264.7 cells in LPS alone group were significantly higher than those in PBS group (with <it</i values of 44.20, 51.26, 14.71, and 8.54, respectively, <iP</i&lt;0.01); the mRNA expressions of IL-1β, TNF-α, and IL-6 of RAW264.7 cells in LPS+ADSCs-Exos group were significantly lower than those in LPS alone group (with <it</i values of 22.89, 25.51, and 8.03, respectively, <iP</i&lt;0.01), while the mRNA expressions of IL-10, TGF-β, and VEGF were significantly higher than those in LPS alone group (with <it</i values of 9.89, 13.12, and 7.14, respectively, <iP</i&lt;0.01). After stimulation of 12 h, the protein expression of iNOS of RAW264.7 cells in LPS alone group was significantly higher than that in PBS group and LPS+ADSCs-Exos group, respectively (with <it</i values of 11.20 and 5.06, respectively, <iP</i&lt;0.05 or <iP</i&lt;0.01), and the protein expression of Arg1 was significantly lower than that in LPS+ADSCs-Exos group (<it</i=15.01, <iP</i&lt;0.01). On PID 1, the serum concentrations of IL-1β and TNF-α and the mRNA expressions of IL-1β, TNF-α, and IL-6 in wound tissue of mice in ADSCs-Exos group were significantly those in lower than PBS group (with <it</i values of 15.44, 12.24, 9.24, 7.12, and 10.62, respectively, <iP</i&lt;0.01). On PID 3, 6, 9, 12, and 15 d, the wound non-healing rates of mice in ADSCs-Exos group were (73.2±4.1)%, (53.8±3.8)%, (42.1±5.1)%, (24.1±2.8)%, and 0, which were significantly lower than (82.5±3.8)%, (71.2±4.6)%, (52.9±4.1)%, (41.5±3.6)%, and (14.8±2.5)% in PBS group, respectively (with <it</i values of 4.77, 8.93, 5.54, 7.63, and 7.59, respectively, <iP</i&lt;0.01). On PID 15, the defect length of skin accessory in wounds of mice in PBS group was significantly longer than that in ADSCs-Exos group (<it</i=9.50, <iP</i&lt;0.01), and the CVF was significantly lower than that in ADSCs-Exos group (<it</i=9.15, <iP</i&lt;0.01). On PID 15, the CD31 expression and the number of new blood vessels (<it</i=12.99, <iP</i&lt;0.01), in wound tissue of mice in ADSCs-Exos group were significantly more than those in PBS group, and the ratio of Ki67 positive cells was significantly higher than that in PBS group (<it</i=7.52, <iP</i&lt;0.01). On PID 15, the ratio of iNOS and Arg1 double positive cells in wound tissue of mice in PBS group was (12.33±1.97)%, which was significantly higher than (1.78±0.29)% in ADSCs-Exos group (<it</i=13.04, <iP</i&lt;0.01), the ratio of iNOS positive cells and the fluorescence intensity of iNOS were obviously higher than those of ADSCs-Exos group, and the ratio of Arg1 positive cells and the fluorescence intensity of Arg1 were obviously lower than those of ADSCs-Exos group. <bConclusions:</b The human ADSCs-Exos can alleviate inflammatory response of mouse RAW264.7 cells, decrease macrophage infiltration and secretion of the pro-inflammatory cytokines, increase the secretion of anti-inflammatory cytokines to promote neovascularization and cell proliferation in full-thickness skin defect wounds of mice, hence accelerating wound healing.

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Sodium dichromate dihydrate is one of a number of inorganic compounds containing hexavalent chromium (Cr VI) found in drinking water source supplies as a contaminant resulting from various industrial processes including electroplating operations, leather tanning, and textile manufacturing. Because of the lack of adequate experimental data on the toxicity and carcinogenicity of hexavalent chromium ingested orally and because hexavalent chromium has been found in drinking water source supplies, the California Congressional Delegation, the California Environmental Protection Agency, and the California Department of Health Services nominated hexavalent chromium to the National Toxicology Program for study. Results of 3 month toxicity studies in F344/N rats and B6C3F1, BALB/c, and am3-C57BL/6 mice were reported earlier in NTP Toxicity Report 72. In the current study, male and female F344/N rats and B6C3F1 mice were exposed to sodium dichromate dihydrate (greater than 99.7% pure) in drinking water for 2 years. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were exposed to drinking water containing 0, 14.3, 57.3, 172, or 516 mg/L sodium dichromate dihydrate (equivalent to 0, 5, 20, 60, or 180 mg/L chromium) for 2 years (equivalent to average daily doses of approximately 0.6, 2.2, 6, or 17 mg sodium dichromate dihydrate/kg body weight for males and 0.7, 2.7, 7, or 20 mg/kg for females). Survival of exposed groups was similar to that of the control groups. Mean body weights of 516 mg/L males and females were less than those of the controls throughout the study. The lower body weights were partly attributed to poor palatability of the dosed water and consequent reductions in water consumption. Water consumption by 172 and 516 mg/L rats was less than that by the controls throughout the study. Exposure to sodium dichromate dihydrate caused a microcytic hypochromic anemia in rats that ameliorated with time. Exposure to sodium dichromate dihydrate resulted in the development of neoplasms of the squamous epithelium that lines the oral mucosa and tongue. The incidences of squamous cell carcinoma in the oral mucosa of 516 mg/L male and female rats were significantly greater than those in the controls. The incidence in 172 mg/L females exceeded the historical control ranges for drinking water studies and for all routes of administration. The incidences of squamous cell papilloma or squamous cell carcinoma (combined) of the oral mucosa or tongue of 516 mg/L male and female rats were significantly greater than those in the controls. Exposure concentration-related nonneoplastic liver lesions were observed in males and females exposed to 57.3 mg/L or greater. These included histiocytic cellular infiltration, chronic inflammation, fatty change (females), basophilic focus (males), and clear cell focus (females). Increased incidences of histiocytic cellular infiltration also occurred in the small intestine (duodenum), mesenteric lymph node, and pancreatic lymph node of males and/or females exposed to 57.3 mg/L or greater. 2-YEAR STUDY IN MICE: Groups of 50 male mice were exposed to drinking water containing 0, 14.3, 28.6, 85.7, or 257.4 mg/L sodium dichromate dihydrate (equivalent to 0, 5, 10, 30, or 90 mg/L chromium) for 2 years (equivalent to average daily doses of approximately 1.1, 2.6, 7, or 17 mg sodium dichromate dihydrate/kg body weight). Groups of 50 female mice were exposed to drinking water containing 0, 14.3, 57.3, 172, or 516 mg/L sodium dichromate dihydrate (equivalent to 0, 5, 20, 60, or 180 mg/L chromium) for 2 years (equivalent to average daily doses of approximately 1.1, 3.9, 9, or 25 mg/kg). Survival of exposed groups was similar to that of the control groups. Mean body weights of 257.4 mg/L males were less than those of controls from months 2 through 6 of the study, but by the end of the study, the mean body weight of 257.4 mg/L males was only slightly less than that of the control group. Mean body weights of 172 mg/L females were less than those of the controls from months 3 through 12 of the study, and mean body weights of 516 mg/L females were less than those of the controls from month 2 until the end of the study. By the end of the study, the mean body weight of 172 mg/L females was 8% less than that of the controls, and the mean body weight of 516 mg/L females was 15% less than that of the controls. The lower body weights were partly attributed to poor palatability of the dosed water and consequent reductions in water consumption. Water consumption by 85.7 and 257.4 mg/L males and 172 and 516 mg/L females was less than that by the controls throughout the study. A treatment-related microcytosis occurred in exposed mice; the mice were less affected than the rats. The incidences of neoplasms of the small intestine (duodenum, jejunum, or ileum) were increased in exposed groups of male and female mice. The incidences of adenoma of the duodenum in 257.4 mg/L males and 172 and 516 mg/L females were significantly greater than those in the controls. The incidence of carcinoma of the duodenum was significantly increased in 516 mg/L females. The incidence of adenoma of the jejunum in 516 mg/L females was significantly increased compared to that in the controls. When the incidences of adenoma and carcinoma were combined for all sites of the small intestine, the incidences were significantly increased in 85.7 and 257.4 mg/L males and 172 and 516 mg/L females compared to those in the controls. The incidences in 57.3 mg/L females exceeded the historical control ranges for drinking water studies and for all routes of administration. The incidences of diffuse epithelial hyperplasia were significantly increased in the duodenum of all exposed groups of male and female mice. The incidences of histiocytic cellular infiltration were significantly increased in the duodenum of 85.7 and 257.4 mg/L males and in 172 and 516 mg/L females. In the jejunum, the incidences of diffuse epithelial hyperplasia and histiocytic cellular infiltration were significantly increased in 516 mg/L females. The incidences of histiocytic cellular infiltration of the liver in all exposed groups of females, of the mesenteric lymph node in all exposed groups of males and females, and of the pancreatic lymph node of 85.7 and 257.4 mg/L males and 172 and 516 mg/L females were significantly increased. Tissue distribution studies showed that total chromium concentrations tended to increase with increasing exposure concentration and duration of exposure. Under the conditions of these 2-year drinking water studies, there was clear evidence of carcinogenic activity of sodium dichromate dihydrate in male and female F344/N rats based on increased incidences of squamous cell neoplasms of the oral cavity. There was clear evidence of carcinogenic activity of sodium dichromate dihydrate in male and female B6C3F1 mice based on increased incidences of neoplasms of the small intestine (duodenum, jejunum, or ileum). Exposure to sodium dichromate dihydrate resulted in histiocytic cellular infiltration in the liver, small intestine, and pancreatic and mesenteric lymph nodes of rats and mice and diffuse epithelial hyperplasia in the small intestine of male and female mice.

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We revise the large Neotropical genus Operclipygus Marseul, in the histerid tribe Exosternini (Histeridae: Histerinae). We synonymize 3 species, move 14 species from other genera, sink the genus Tribalister Horn into Operclipygus, and describe 138 species as new, bringing the total to 177 species of Operclipygus. Keys are provided for the identification of all species, and the majority of the species are illustrated by habitus and male genitalia illustrations. The species are diverse throughout tropical South and Central America, with only a few species extending into the temperate parts of North America. The majority of species can be recognized by the presence of a distinct stria or sulcus along the apical margin of the pygidium, though it is not exclusive to the genus. Natural history details for species of Operclipygus are scant, as most specimens have been collected through the use of passive flight interception traps. Many are probably generally associated with decaying vegetation and leaf litter, where they prey on small arthropods. But a small proportion are known inquilines, with social insects such as ants and termites, and also with some burrowing mammals, such as Ctenomys Blainville. The genus now includes the following species groups and species: Operclipygus sulcistrius group [Operclipygus lucanoides sp. n., Operclipygus schmidti sp. n., Operclipygus simplistrius sp. n., Operclipygus sulcistrius Marseul, 1870], Operclipygus mirabilis group [Operclipygus mirabilis (Wenzel &amp; Dybas, 1941) comb. n., Operclipygus pustulifer sp. n., Operclipygus plaumanni sp. n., Operclipygus sinuatus sp. n., Operclipygus mutuca sp. n., Operclipygus carinistrius (Lewis, 1908) comb. n., Operclipygus parensis sp. n., Operclipygus schlingeri sp. n.], Operclipygus kerga group [Operclipygus kerga (Marseul, 1870), Operclipygus planifrons sp. n., Operclipygus punctistrius sp. n.], Operclipygus conquisitus group [Operclipygus bicolor sp. n., Operclipygus conquisitus (Lewis, 1902), Operclipygus friburgius (Marseul, 1864)], Operclipygus impuncticollis group [Operclipygus bickhardti sp. n., Operclipygus britannicus sp. n., Operclipygus impuncticollis (Hinton, 1935)], Operclipygus panamensis group [Operclipygus crenatus (Lewis, 1888), Operclipygus panamensis (Wenzel &amp; Dybas, 1941)], Operclipygus sejunctus group [Operclipygus depressus (Hinton, 1935), Operclipygus itoupe sp. n., Operclipygus juninensis sp. n., Operclipygus pecki sp. n., Operclipygus punctiventer sp. n., Operclipygus sejunctus (Schmidt, 1896) comb. n., Operclipygus setiventris sp. n.], Operclipygus mortavis group [Operclipygus ecitonis sp. n., Operclipygus mortavis sp. n., Operclipygus paraguensis sp. n.], Operclipygus dytiscoides group [Operclipygus carinisternus sp. n., Operclipygus crenulatus sp. n., Operclipygus dytiscoides sp. n., Operclipygus quadratus sp. n.], Operclipygus dubitabilis group [Operclipygus dubitabilis (Marseul, 1889), Operclipygus yasuni sp. n.], Operclipygus angulifer group [Operclipygus angulifer sp. n., Operclipygus impressifrons sp. n.], Operclipygus dubius group [Operclipygus andinus sp. n., Operclipygus dubius (Lewis, 1888), Operclipygus extraneus sp. n., Operclipygus intermissus sp. n., Operclipygus lunulus sp. n., Operclipygus occultus sp. n., Operclipygus perplexus sp. n., Operclipygus remotus sp. n., Operclipygus validus sp. n., Operclipygus variabilis sp. n.], Operclipygus hospes group [Operclipygus assimilis sp. n., Operclipygus belemensis sp. n., Operclipygus bulbistoma sp. n., Operclipygus callifrons sp. n., Operclipygus colombicus sp. n., Operclipygus communis sp. n., Operclipygus confertus sp. n., Operclipygus confluens sp. n., Operclipygus curtistrius sp. n., Operclipygus diffluens sp. n., Operclipygus fusistrius sp. n., Operclipygus gratus sp. n., Operclipygus hospes (Lewis, 1902), Operclipygus ibiscus sp. n., Operclipygus ignifer sp. n., Operclipygus impositus sp. n., Operclipygus incisus sp. n., Operclipygus innocuus sp. n., Operclipygus inquilinus sp. n., Operclipygus minutus sp. n., Operclipygus novateutoniae sp. n., Operclipygus praecinctus sp. n., Operclipygus prominens sp. n., Operclipygus rileyi sp. n., Operclipygus subterraneus sp. n., Operclipygus tenuis sp. n., Operclipygus tiputinus sp. n.], Operclipygus farctus group [Operclipygus atlanticus sp. n., Operclipygus bidessois (Marseul, 1889), Operclipygus distinctus (Hinton, 1935), Operclipygus distractus (Schmidt, 1896) comb. n., Operclipygus farctissimus sp. n., Operclipygus farctus (Marseul, 1864), Operclipygus gilli sp. n., Operclipygus impressistrius sp. n., Operclipygus inflatus sp. n., Operclipygus latemarginatus (Bickhardt, 1920) comb. n., Operclipygus petrovi sp. n., Operclipygus plicatus (Hinton, 1935) comb. n., Operclipygus prolixus sp. n., Operclipygus punctifrons sp. n., Operclipygus proximus sp. n., Operclipygus subrufus sp. n.], Operclipygus hirsutipes group [Operclipygus guianensis sp. n., Operclipygus hirsutipes sp. n.], Operclipygus hamistrius group [Operclipygus arquus sp. n., Operclipygus campbelli sp. n., Operclipygus chiapensis sp. n., Operclipygus dybasi sp. n., Operclipygus geometricus (Casey, 1893) comb. n., Operclipygus hamistrius (Schmidt, 1893) comb. n., Operclipygus impressicollis sp. n., Operclipygus intersectus sp. n., Operclipygus montanus sp. n., Operclipygus nubosus sp. n., Operclipygus pichinchensis sp. n., Operclipygus propinquus sp. n., Operclipygus quinquestriatus sp. n., Operclipygus rubidus (Hinton, 1935) comb. n., Operclipygus rufescens sp. n., Operclipygus troglodytes sp. n.], Operclipygus plicicollis group [Operclipygus cephalicus sp. n., Operclipygus longidens sp. n., Operclipygus plicicollis (Schmidt, 1893)], Operclipygus fossipygus group [Operclipygus disconnectus sp. n., Operclipygus fossipygus (Wenzel, 1944), Operclipygus foveipygus (Bickhardt, 1918), Operclipygus fungicolus (Wenzel &amp; Dybas, 1941), Operclipygus gibbulus (Schmidt, 1889) comb. n., Operclipygus olivensis sp. n., Operclipygus simplicipygus sp. n., Operclipygus subdepressus (Schmidt, 1889), Operclipygus therondi (Wenzel, 1976)], Operclipygus impunctipennis group [Operclipygus chamelensis sp. n., Operclipygus foveiventris sp. n., Operclipygus granulipectus sp. n., Operclipygus impunctipennis (Hinton, 1935) comb. n., Operclipygus latifoveatus sp. n., Operclipygus lissipygus sp. n., Operclipygus maesi sp. n., Operclipygus mangiferus sp. n., Operclipygus marginipennis sp. n., Operclipygus nicodemus sp. n., Operclipygus nitidus sp. n., Operclipygus pacificus sp. n., Operclipygus pauperculus sp. n., Operclipygus punctissipygus sp. n., Operclipygus subviridis sp. n., Operclipygus tripartitus sp. n., Operclipygus vorax sp. n.], Operclipygus marginellus group [Operclipygus ashei sp. n., Operclipygus baylessae sp. n., Operclipygus dentatus sp. n., Operclipygus formicatus sp. n., Operclipygus hintoni sp. n., Operclipygus marginellus (J.E. LeConte, 1860) comb. n., Operclipygus orchidophilus sp. n., Operclipygus selvorum sp. n., Operclipygus striatellus (Fall, 1917) comb. n.], incertae sedis: O. teapensis (Marseul, 1853) comb. n., Operclipygus punctulatus sp. n., Operclipygus lama Mazur, 1988, Operclipygus florifaunensis sp. n., Operclipygus bosquesecus sp. n., Operclipygus arnaudi Dégallier, 1982, Operclipygus subsphaericus sp. n., Operclipygus latipygus sp. n., Operclipygus elongatus sp. n., Operclipygus rupicolus sp. n., Operclipygus punctipleurus sp. n., Operclipygus falini sp. n., Operclipygus peregrinus sp. n., Operclipygus brooksi sp. n., Operclipygus profundipygus sp. n., Operclipygus punctatissimus sp. n., Operclipygus cavisternus sp. n., Operclipygus siluriformis sp. n., Operclipygus parallelus sp. n., Operclipygus abbreviatus sp. n., Operclipygus pygidialis (Lewis, 1908), Operclipygus faltistrius sp. n., Operclipygus limonensis sp. n., Operclipygus wenzeli sp. n., Operclipygus iheringi (Bickhardt, 1917), Operclipygus angustisternus (Wenzel, 1944), Operclipygus shorti sp. n. We establish the following synonymies: Phelisteroides miladae Wenzel &amp; Dybas, 1941 and Pseudister propygidialis Hinton, 1935e = Operclipygus crenatus (Lewis, 1888); Phelister subplicatus Schmidt, 1893b = Operclipygus bidessois (Marseul, 1889). We designate lectotypes for Operclipygus sulcistrius Marseul, 1870, Phelister carinistrius Lewis, 1908, Phelister kerga Marseul, 1870, Phelister friburgius Marseul, 1864, Phelister impuncticollis Hinton, 1935, Phelister crenatus Lewis, 1888, Phelister sejunctus Schmidt, 1896, Pseudister depressus Hinton, 1935, Epierus dubius Lewis, 1888, Phelister hospes Lewis, 1902, Phelister farctus Marseul, 1864, Phelister bidessois Marseul, 1889, Phelister subplicatus Schmidt, 1893, Phelister plicatus Hinton, 1935, Phelister distinctus Hinton, 1935, Phelister distractus Schmidt, 1896, Pseudister latemarginatus Bickhardt, 1920, Phelister hamistrius Schmidt, 1893, Phelister plicicollis Schmidt, 1893, Phelister gibbulus Schmidt, 1889, Phelister subdepressus Schmidt, 1889, Phelister teapensis Marseul, 1853, Phelister pygidialis Lewis, 1908, Phelister iheringi Bickhardt, 1917, and Phelister marginellus J.E. LeConte 1860. We designate a neotype for Operclipygus conquisitus Lewis, replacing its lost type specimen.

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Dear Editor, Ultraviolet (UV) radiation is a well-known physical hazard responsible for photoaging, photoallergic, and phototoxic reactions as well as carcinogenesis, including life-threatening melanomas (1,2). Overexposure to both natural and artificial UV radiation is a public health concern. 30% of cancers diagnosed worldwide are skin cancers. Approximately three million non-melanoma skin cancers and 132 000 new cases of melanomas are diagnosed globally each year (3). Sunburns, especially in childhood, are a very important risk factor for melanomas. Several studies demonstrated a positive association between sunbed use and an increased incidence of malignant melanoma (4). Current medical and cosmetology students will soon be knowledge providers about the risks of excessive exposure to UV radiation and prophylaxis of its consequences. Our aim was to evaluate their knowledge about the side effects of ultraviolet radiation and tanning behaviors. Details on the knowledge and habits of students were obtained during classes at the Poznan University of Medical Sciences. With approval from the Institutional Bioethical Committee, a 41-question anonymous survey was conducted in the spring of 2012 among 190 medical (1-6 year) and cosmetology students (1-5 year). The mean age of the study group was 22.3 years (standard deviation (SD) = 2.4 years), range 19-28 years. The survey was composed of closed and open-ended questions prepared by the authors. The first part of the form included demographic data: gender, age, degree course, and school year. The students were also asked about their reaction to sunlight, sunburns in childhood, and personal and family history of skin cancers or dysplastic nevus syndrome. The factual section of the survey contained questions evaluating responder knowledge about sunbeds and risk of UV radiation as well as their personal tanning habits. The open-ended questions asked responders to provide definitions of: skin phototype, sun protection factor (SPF), and tanorexia. The students were additionally asked to mention possible side effects of solar radiation and contraindications to sunbeds and drugs, which may induce photosensitivity. Statistical analysis was performed using The R Project for Statistical Computing. Chi-squared test was used to compare both sun-risk knowledge and tanning behaviors between medical and cosmetology students. P&lt;0.05 was considered statistically significant. We distributed 220 questionnaires and received 190 (86%) eligible for evaluation. Table 1 shows the study population. Gender distribution among groups was uneven, with significantly more male subjects in the medicine program group. We decided to include their answers in this study to provide an unbiased view of both of those programs. Where appropriate, we additionally provided comparisons between female subjects in both groups to prove that differences were not solely due to uneven gender distribution. When we asked students to define skin phototype, cosmetology students more frequently gave a correct definition. In the group of students who stated they knew the definition of skin phototype, medical students were significantly more frequently wrong when we asked them to explain the term in their own words. Cosmetology students correctly answered significantly more knowledge checking questions (Table 2). When we asked students to list photosensitizing agents, students of the cosmetology program gave twice as many correct answers per respondent as students of the medicine program (see Table 3). Cosmetology students more frequently listed retinoids, while medical students listed tetracyclines as the main photosensitizing drug. The most common answer in the cosmetology group was the herb of Hypericum perforatum, although it is not considered a drug. Psoralens were identified by only 4 medical students as a possible cause of phototoxicity. When students were asked to list adverse effects of sunbathing, we specifically looked for three responses (see Table 4). Cosmetology students listed those answers significantly more often than medical students. Students of the cosmetology program gave significantly more correct answers when asked to list contraindications for sunbathing. While medical students reported mainly pregnancy (as a contraindication for most medical procedures), cosmetology students reported history of skin cancer as the most frequent answer (Table 5). Cosmetology students (89.04%) stated they visited a tanning salon more often than medical students (46.55%) (P&lt;0.0001). When we restricted this analysis to only female subjects there still was a significant difference (P=0.0002) between cosmetology and medical female students. Cosmetology students reported lower incidence of sunscreen use (83.78% vs. 97.39%; P=0.0019). The age of the first tanning studio visit was also lower for cosmetology students (mean = 16.5 years) than medical students (mean = 17.2 years), (P=0.0290). Figure 1 illustrates the frequency of student tanning studio visits; the difference between groups was significant (P=0.0308). Skin cancers, dysplastic nevi syndrome, and precancerous lesions were reported in the family history by 19 students (10.00%). 12 of those students (63.16%) were also tanning salons users. 85 students (44.74%) reported a history of a sunburn in their childhood and over half of them continue visiting tanning salons. Some American (5) and French (6) studies assessed medical student knowledge and behaviors concerning sun risk and its prevention. The results of these studies indicated that medical school students did not have a satisfactory awareness about sun risk hazards. The French evaluation showed medical student knowledge was comparable to that of the French general population. Studies evaluating Polish student knowledge (7-9) showed ignorance of the term Fitzpatrick's skin phototype. We emphasize this because patients with phototype 1 and 2 are more susceptible to the development of skin cancers (10) and ignorance in this matter may be dangerous. UV rays may promote drug-induced photosensitivity reactions such as phototoxicity and photoallergy (1), with the most common causes being: non-steroidal anti-inflammatory agents (ketoprofen, ibuprofen, piroxicam, diclofenac), cardiovascular drugs (furosemid, amiodarone, thiazides), antibiotics (tetracyclines, ciprofloxacine, sulfonamides), psoralens, and oral contraceptives (11). Our study found deficient knowledge about drugs which may trigger photosensitivity reactions. Cosmetology students reported significantly more risky tanning behavior but did better in knowledge checking questions, which may be explained by their personal interest in this subject or by educational focus due to their major. We suggest that better knowledge about sunbathing in general is due to increased interest in this matter (not solely due to formal education) and this interest derives from a positive attitude towards a tanned appearance. It has been proven that sunbathing shows signs of addictive behavior (12). Tanorexia as a term was more widely known among cosmetology students, which may illustrate that although students knew about the addictive properties of tanning, they were sure that this did not apply to them. Many studies showed that increased knowledge did not translate into safer tanning habits (13,14). Our study agrees with those findings. Our study demonstrated that medical and cosmetology student knowledge about sunbeds and risk of UV radiation is deficient. However, cosmetology students demonstrated better knowledge than medical students. Future cosmetologists may be better information providers about sun risk and its prevention. On the other hand, students of the cosmetology faculty tended to tan more often and longer and engage in more risky behavior despite being aware of the hazards of tanning. They may be more likely to develop skin cancers in the future.

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Marfan syndrome (MFS) is a systemic disorder of connective tissue with autosomal dominant inheritance. The diagnosis of MFS is based on the identification of a combination of clinical manifestations in the ocular, musculoskeletal, and cardiovascular organ systems defined in the Ghent Nosology (De Paepe et al, 1996). Confirmation of the diagnosis in an individual requires the presence of major clinical manifestations in at least two organ systems associated with involvement of a third organ system. In relatives of an affected proband, major involvement of one organ system and involvement of a second organ system confirms the diagnosis. Major clinical criteria are very specific for MFS and include a combination of (4 out of 8) skeletal manifestations, ectopia lentis, dural ectasia and dilatation or dissection of the ascending aorta. The prevalence of- and the guidelines for the assessment of each of these major criteria are well established. Minor clinical criteria are less typical, but their importance in the diagnostic process should not be underestimated. Unfortunately, figures on the prevalence as well as practical guidelines for the assessment of most minor criteria are lacking, especially for those involving the cardiovascular system. The major cardiovascular manifestation in MFS is a progressive dilatation of the ascending aorta, leading to aortic aneurysm formation and eventually to fatal aortic rupture or dissection. Aortic dissection in early adult life is the leading cause of death in MFS. Early diagnosis of individuals at risk of the disease is extremely important as timely treatment of cardiovascular complications has greatly improved life expectancy in MFS. Despite progress in medical and surgical treatment of aortic aneurysms, MFS continues to be associated with significant morbidity and mortality. This may be related to inadequate diagnosis or treatment, but also to the occurrence of cardiovascular problems in ageing MFS patients that were unrecognised until now, such as left ventricular (LV) dysfunction.This thesis is focused on the study of cardiovascular manifestations of MFS which localize beyond the aortic root and on the presently unknown relationship between the severity of the cardiovascular phenotype and the genotype. In the first part, we have studied the prevalence and diagnostic value of the following cardiovascular manifestations of MFS: mitral valve prolapse (MVP) and calcification of the mitral valve annulus, dilatation of the main pulmonary artery (MPA) and dilatation or dissection of the descending aorta. We found a significantly higher prevalence of MVP in MFS patients compared to normal controls, indicating that this feature is useful in the diagnostic evaluation of the condition. In contrast, calcification of the mitral valve annulus appears to be very uncommon, difficult to quantify and therefore not useful in the diagnosis of MFS. We also studied the dimension of the MPA in a series of MFS patients and defined a cut-of value that can be used in the diagnostic evaluation of adult MFS patients. In addition, we showed that diameters of the aorta measured at different levels beyond the aortic root are increased in MFS patients compared to controls. Unfortunately, there was too much overlap with the values obtained in the normal control population to provide cut-off values for the descending aorta. Based on these findings, we developed practical guidelines for the cardiovascular evaluation of patients referred for MFS. In the second part, we studied LV function in MFS patients free of valvular heart disease using a combination of echocardiography (both conventional echocardiography and tissue Doppler imaging) and Magnetic Resonance Imaging. We could demonstrate that MFS patients present a combination of systolic and diastolic dysfunction that is not related to valvular heart disease. This may be attributed to a primary contractile dysfunction of the myocardium and is likely related to the underlying alterations in the elastic features of the myocardium, resulting from the microfibrillar defect. This observation is important in the development of new therapeutic strategies for MFS. Affected individuals may benefit from a treatment with agents that support myocardial function such as angiotensin converting enzyme--inhibitors or angiotensin II type-1 receptor blockers. Furthermore, since MFS patients survive longer thanks to improved medical and surgical treatments, LV dysfunction may become an important issue in the follow-up of these patients. In the third part, we have studied aspects of local and global wave reflection in the aorta of MFS patients. Early return of reflected waves boosts systolic pressure and presents an extra load for the heart and the central vessels. As such, these wave reflections are regarded as one of the important determinants of central blood pressure and can contribute to the development of aortic dilatation in MFS. However, we were unable to demonstrate clear differences in both local and global parameters of wave reflection between MFS patients and normal controls. This could be explained by the fact that increased length of the aorta on the one hand and increased aortic stiffness on the other hand counterbalance each other in MFS patients without yielding any net effect on wave reflection. In the last part of this thesis, we investigated the correlation between the severity of the cardiovascular phenotype in MFS and the type of FBN1 mutation. First, we investigated the correlation between parameters of aortic stiffness (distensibility and pulse wave velocity measured by Magnetic Resonance Imaging) and the type of FBN1 mutation (missense or in-frame deletions/insertions versus nonsense or out-of-frame deletions/insertions). We could not demonstrate any significant differences between these different mutation types, indicating that the FBN1 genotype is not the sole determinant of aortic stiffness. Second, we provided a detailed description of clinical findings in three unrelated MFS families in which an FBN1 mutation was identified and which demonstrate striking intrafamilial phenotypic variability as another illustration of the absence of genotype/phenotype correlations in MFS. This study also illustrated several important issues in MFS. First, repeated clinical examination of suspected patients can be necessary in order to establish a correct and final diagnosis. Second, extensive family history taking and clinical examination of first degree relatives can be highly contributory to the diagnosis. Third, patients with an 'atypical' MFS phenotype may show substantial clinical overlap with other connective tissue disorders such as Weill-Marchesani syndrome or Ehlers-Danlos syndrome and represent a diagnostic challenge. We demonstrated that additional mutational analysis of the FBN1 gene can be a valuable aid to the diagnosis and help to outline medical management options in these challenging cases. In conclusion, we have refined diagnostic guidelines for the assessment of minor cardiovascular manifestations in MFS, shown that LV dysfunction is part of the cardiovascular spectrum and should be followed in the management of MFS patients, and demonstrated that aortic wave reflection is not elevated in MFS. In this work, we also investigated genotype/phenotype correlations, illustrated the marked (intrafamilial) variability in phenotypic expression of the condition, and the value of molecular testing in the diagnosis of MFS. Overall, this thesis nicely illustrates that close interaction and collaboration between cardiology and genetics is an added value to the study of disease pathogenesis of MFS and aortic aneurysms in general.

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Although Risser stages are visible on the same radiograph of the spine, Risser staging is criticized for its insensitivity in estimating the remaining growth potential and its weak correlation with curve progression in patients with adolescent idiopathic scoliosis. Risser staging is frequently accompanied by other skeletal maturity indices to increase its precision for assessing pubertal growth. However, it remains unknown whether there is any discrepancy between various maturity parameters and the extent of this discrepancy when these indices are used concurrently to assess pubertal growth landmarks, which are important for the timing of brace initiation and weaning. (1) What is the chronologic order of skeletal maturity grades based on the growth rate and curve progression rate in patients with adolescent idiopathic scoliosis? (2) What are the discrepancies among the grades of each maturity index for indicating the peak growth and start of the growth plateau, and how do these indices correspond to each other? (3) What is the effectiveness of Risser staging, Sanders staging, and the distal radius and ulna classification in assessing peak growth and the beginning of the growth plateau? Between 2014 and 2017, a total of 13,536 patients diagnosed with adolescent idiopathic scoliosis were treated at our tertiary clinic. Of those, 3864 patients with a radiograph of the left hand and wrist and a posteroanterior radiograph of the spine at the same visits including initial presentation were considered potentially eligible for this study. Minimum follow-up was defined as 6 months from the first visit, and the follow-up duration was defined as 2 years since initial consultation. In all, 48% (1867 of 3864) of patients were eligible, of which 26% (485 of 1867) were excluded because they were prescribed bracing at the first consultation. These patients visited the subsequent clinics wearing the brace, which might have affected body height measurement. Six percent (117 of 1867) of eligible patients were also excluded as their major coronal Cobb angle reached the surgical threshold of 50° and had undergone surgery before skeletal maturity. Another 21% (387 of 1867) of patients were lost before minimum follow-up or had incomplete data, leaving 47% (878) for analysis. These 878 patients with 1139 skeletal maturity assessments were studied; 74% (648 of 878) were girls. Standing body height was measured in a standardized manner by a wall-mounted stadiometer. Several surgeons measured curve magnitude as per routine clinical consultation, skeletal maturity was measured according to the distal radius and ulna classification, and two raters measured Risser and Sanders stages. Reliability tests were performed with satisfaction. Data were collected for the included patients at multiple points when skeletal maturity was assessed, and only up to when brace wear started for those who eventually had bracing. The growth rate and curve progression rate were calculated by the change of body height and major coronal Cobb angle over the number of months elapsed between the initial visit and next follow-up. At each skeletal maturity grading, we examined the growth rate (in centimeters per month) and curve progression rate (in degrees per month) since the skeletal maturity assessment, as well as the mean age at which this maturity grading occurred. Each patient was then individually assessed for whether he or she was experiencing peak growth and the beginning of growth plateau at each timepoint by comparing the calculated growth rate with the previously defined peak growth rate of ≥ 0.7 cm per month and the beginning of growth plateau rate of ≤ 0.15 cm per month in this adolescent idiopathic scoliosis population. Among the timepoints at which the peak growth and the beginning of growth plateau occurred, the median maturity grade of each maturity index was identified as the benchmark grade for comparison between indices. We used the McNemar test to investigate whether pubertal growth landmarks were identified by specific maturity grades concurrently. We assessed the effectiveness of these skeletal maturity indices by the difference in proportions (%) between two benchmark grades in indicating peak growth and the growth plateau. For girls, the chronological order of maturity grades that indicated peak growth was the radius grade, ulna grade, Sanders stage, and Risser stage. Curve progression peaked between the age of 11.6 and 12.1 years at a similar timing by all maturity indices for girls but was inconsistent for boys. For both sexes, radius (R) grade 6, ulna (U) grade 5, Sanders stage (SS) 3, and Risser stage 0+ were the median grades for peak growth, whereas Risser stage 4, R8/9, U7/8, and SS6/7 indicated the beginning of the growth plateau. The largest discrepancy between maturity indices was represented by Risser stage 0+, which corresponded to six grades of the Sanders staging system (SS2 to SS7) and to R6 in only 41% (62 of 152) of girls in the whole cohort. Despite Risser stage 0+ corresponding to the wide range of Sanders and distal radius and ulna grades, none of the R6, U5, SS3, and Risser stage 0+ was found more effective than another grade in indicating the peak growth in girls. R6 most effectively indicated the peak growth in boys, and Risser stage 0+ was the least effective. For the beginning of the growth plateau in girls, SS6/7 was the most effective indicator, followed by U7/8. Risser stage 4 was the least effective because it indicated 29% (95% CI 21% to 36%; p &lt; 0.001) fewer patients who reached the beginning of the growth plateau than did those with R8/9. Risser stage 4 also indicated 36% (95% CI 28% to 43%; p &lt; 0.001) fewer patients who reached the beginning of the growth plateau than those indicated by U7/8, and it identified 39% fewer patients than SS6/7 (95% CI 32% to 47%; p &lt; 0.001). For boys, similarly, R8/9, U7/8, and SS6/7 were all more effective than Risser stage 4 in identifying when the growth plateau began. Risser stage 0+ corresponds to a wide range of Sanders and distal radius and ulna grades. Risser stage 0+ is least effective in indicating the peak growth in boys, and Risser stage 4 is the least effective maturity grade for indicating when the growth plateau starts in both sexes. The concurrent use of R6 and SS3 can be useful for detecting the peak growth, and SS6/7 in conjunction with U7/8 is most effective in indicating the beginning of the growth plateau. Using a combination of specific grades of Sanders staging and the distal radius and ulna classification can indicate pubertal growth landmarks with reduced risk of underestimating or overestimating skeletal maturity. These findings may aid in refining clinical decision-making of brace initiation and weaning at a more precise timing. Among Risser stage 0, the appearance of R6, U5, and SS3 provide the most effective assessment of peak growth that can indicate the most effective bracing period within which curve progression occurs. For initiation of the growth plateau, Risser 4 is not useful, and SS6/7, R8/9 and U7/8 should be used instead. Level III, diagnostic study.

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Ovarian cancer is the seventh most common cancer among women and a leading cause of death from gynaecological malignancies. Epithelial ovarian cancer is the most common type, accounting for around 90% of all ovarian cancers. This specific type of ovarian cancer starts in the surface layer covering the ovary or lining of the fallopian tube. Surgery is performed either before chemotherapy (upfront or primary debulking surgery (PDS)) or in the middle of a course of treatment with chemotherapy (neoadjuvant chemotherapy (NACT) and interval debulking surgery (IDS)), with the aim of removing all visible tumour and achieving no macroscopic residual disease (NMRD). The aim of this review is to investigate the prognostic impact of size of residual disease nodules (RD) in women who received upfront or interval cytoreductive surgery for advanced (stage III and IV) epithelial ovarian cancer (EOC). To assess the prognostic impact of residual disease after primary surgery on survival outcomes for advanced (stage III and IV) epithelial ovarian cancer. In separate analyses, primary surgery included both upfront primary debulking surgery (PDS) followed by adjuvant chemotherapy and neoadjuvant chemotherapy followed by interval debulking surgery (IDS). Each residual disease threshold is considered as a separate prognostic factor. We searched CENTRAL (2021, Issue 8), MEDLINE via Ovid (to 30 August 2021) and Embase via Ovid (to 30 August 2021). We included survival data from studies of at least 100 women with advanced EOC after primary surgery. Residual disease was assessed as a prognostic factor in multivariate prognostic models. We excluded studies that reported fewer than 100 women, women with concurrent malignancies or studies that only reported unadjusted results. Women were included into two distinct groups: those who received PDS followed by platinum-based chemotherapy and those who received IDS, analysed separately. We included studies that reported all RD thresholds after surgery, but the main thresholds of interest were microscopic RD (labelled NMRD), RD 0.1 cm to 1 cm (small-volume residual disease (SVRD)) and RD &gt; 1 cm (large-volume residual disease (LVRD)). Two review authors independently abstracted data and assessed risk of bias. Where possible, we synthesised the data in meta-analysis. To assess the adequacy of adjustment factors used in multivariate Cox models, we used the 'adjustment for other prognostic factors' and 'statistical analysis and reporting' domains of the quality in prognosis studies (QUIPS) tool. We also made judgements about the certainty of the evidence for each outcome in the main comparisons, using GRADE. We examined differences between FIGO stages III and IV for different thresholds of RD after primary surgery. We considered factors such as age, grade, length of follow-up, type and experience of surgeon, and type of surgery in the interpretation of any heterogeneity. We also performed sensitivity analyses that distinguished between studies that included NMRD in RD categories of &lt; 1 cm and those that did not. This was applicable to comparisons involving RD &lt; 1 cm with the exception of RD &lt; 1 cm versus NMRD. We evaluated women undergoing PDS and IDS in separate analyses. We found 46 studies reporting multivariate prognostic analyses, including RD as a prognostic factor, which met our inclusion criteria: 22,376 women who underwent PDS and 3697 who underwent IDS, all with varying levels of RD. While we identified a range of different RD thresholds, we mainly report on comparisons that are the focus of a key area of clinical uncertainty (involving NMRD, SVRD and LVRD). The comparison involving any visible disease (RD &gt; 0 cm) and NMRD was also important. SVRD versus NMRD in a PDS setting In PDS studies, most showed an increased risk of death in all RD groups when those with macroscopic RD (MRD) were compared to NMRD. Women who had SVRD after PDS had more than twice the risk of death compared to women with NMRD (hazard ratio (HR) 2.03, 95% confidence interval (CI) 1.80 to 2.29; I<sup2</sup = 50%; 17 studies; 9404 participants; moderate-certainty). The analysis of progression-free survival found that women who had SVRD after PDS had nearly twice the risk of death compared to women with NMRD (HR 1.88, 95% CI 1.63 to 2.16; I<sup2</sup = 63%; 10 studies; 6596 participants; moderate-certainty). LVRD versus SVRD in a PDS setting When we compared LVRD versus SVRD following surgery, the estimates were attenuated compared to NMRD comparisons. All analyses showed an overall survival benefit in women who had RD &lt; 1 cm after surgery (HR 1.22, 95% CI 1.13 to 1.32; I<sup2</sup = 0%; 5 studies; 6000 participants; moderate-certainty). The results were robust to analyses of progression-free survival. SVRD and LVRD versus NMRD in an IDS setting The one study that defined the categories as NMRD, SVRD and LVRD showed that women who had SVRD and LVRD after IDS had more than twice the risk of death compared to women who had NMRD (HR 2.09, 95% CI 1.20 to 3.66; 310 participants; I<sup2</sup = 56%, and HR 2.23, 95% CI 1.49 to 3.34; 343 participants; I<sup2</sup = 35%; very low-certainty, for SVRD versus NMRD and LVRD versus NMRD, respectively). LVRD versus SVRD + NMRD in an IDS setting Meta-analysis found that women who had LVRD had a greater risk of death and disease progression compared to women who had either SVRD or NMRD (HR 1.60, 95% CI 1.21 to 2.11; 6 studies; 1572 participants; I<sup2</sup = 58% for overall survival and HR 1.76, 95% CI 1.23 to 2.52; 1145 participants; I<sup2</sup = 60% for progression-free survival; very low-certainty). However, this result is biased as in all but one study it was not possible to distinguish NMRD within the &lt; 1 cm thresholds. Only one study separated NMRD from SVRD; all others included NMRD in the SVRD group, which may create bias when comparing with LVRD, making interpretation challenging. MRD versus NMRD in an IDS setting Women who had any amount of MRD after IDS had more than twice the risk of death compared to women with NMRD (HR 2.11, 95% CI 1.35 to 3.29, I<sup2</sup = 81%; 906 participants; very low-certainty). In a PDS setting, there is moderate-certainty evidence that the amount of RD after primary surgery is a prognostic factor for overall and progression-free survival in women with advanced ovarian cancer. We separated our analysis into three distinct categories for the survival outcome including NMRD, SVRD and LVRD. After IDS, there may be only two categories required, although this is based on very low-certainty evidence, as all but one study included NMRD in the SVRD category. The one study that separated NMRD from SVRD showed no improved survival outcome in the SVRD category, compared to LVRD. Further low-certainty evidence also supported restricting to two categories, where women who had any amount of MRD after IDS had a significantly greater risk of death compared to women with NMRD. Therefore, the evidence presented in this review cannot conclude that using three categories applies in an IDS setting (very low-certainty evidence), as was supported for PDS (which has convincing moderate-certainty evidence).

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The guidance in this report is for evaluation and treatment of patients with complications from smallpox vaccination in the preoutbreak setting. Information is also included related to reporting adverse events and seeking specialized consultation and therapies for these events. The frequencies of smallpox vaccine-associated adverse events were identified in studies of the 1960s. Because of the unknown prevalence of risk factors among today's population, precise predictions of adverse reaction rates after smallpox vaccination are unavailable. The majority of adverse events are minor, but the less-frequent serious adverse reactions require immediate evaluation for diagnosis and treatment. Agents for treatment of certain vaccine-associated severe adverse reactions are vaccinia immune globulin (VIG), the first-line therapy, and cidofovir, the second-line therapy. These agents will be available under Investigational New Drug (IND) protocols from CDC and the U.S. Department of Defense (DoD). Smallpox vaccination in the preoutbreak setting is contraindicated for persons who have the following conditions or have a close contact with the following conditions: 1) a history of atopic dermatitis (commonly referred to as eczema), irrespective of disease severity or activity; 2) active acute, chronic, or exfoliative skin conditions that disrupt the epidermis; 3) pregnant women or women who desire to become pregnant in the 28 days after vaccination; and 4) persons who are immunocompromised as a result of human immunodeficiency virus or acquired immunodeficiency syndrome, autoimmune conditions, cancer, radiation treatment, immunosuppressive medications, or other immunodeficiencies. Additional contraindications that apply only to vaccination candidates but do not include their close contacts are persons with smallpox vaccine-component allergies, women who are breastfeeding, those taking topical ocular steroid medications, those with moderate-to-severe intercurrent illness, and persons aged &lt; 18 years. In addition, history of Darier disease is a contraindication in a potential vaccinee and a contraindication if a household contact has active disease. In the event of a smallpox outbreak, outbreak-specific guidance will be disseminated by CDC regarding populations to be vaccinated and specific contraindications to vaccination. Vaccinia can be transmitted from a vaccinee's unhealed vaccination site to other persons by close contact and can lead to the same adverse events as in the vaccinee. To avoid transmission of vaccinia virus (found in the smallpox vaccine) from vaccinees to their close contacts, vaccinees should wash their hands with warm soapy water or hand rubs containing &gt; or = 60% alcohol immediately after they touch their vaccination site or change their vaccination site bandages. Used bandages should be placed in sealed plastic bags and can be disposed of in household trash. Smallpox vaccine adverse reactions are diagnosed on the basis of clinical examination and history, and certain reactions can be managed by observation and supportive care. Adverse reactions that are usually self-limited include fever, headache, fatigue, myalgia, chills, local skin reactions, nonspecific rashes, erythema multiforme, lymphadenopathy, and pain at the vaccination site. Other reactions are most often diagnosed through a complete history and physical and might require additional therapies (e.g., VIG, a first-line therapy and cidofovir, a second-line therapy). Adverse reactions that might require further evaluation or therapy include inadvertent inoculation, generalized vaccinia (GV), eczema vaccinatum (EV), progressive vaccinia (PV), postvaccinial central nervous system disease, and fetal vaccinia. Inadvertent inoculation occurs when vaccinia virus is transferred from a vaccination site to a second location on the vaccinee or to a close contact. Usually, this condition is self-limited and no additional care is needed. Inoculations of the eye and eyelid require evaluation by an ophthalmologist and might require therapy with topical antiviral or antibacterial medications, VIG, or topical steroids. GV is characterized by a disseminated maculopapular or vesicular rash, frequently on an erythematous base, which usually occurs 6-9 days after first-time vaccination. This condition is usually self-limited and benign, although treatment with VIG might be required when the patient is systemically ill or found to have an underlying immunocompromising condition. Infection-control precautions should be used to prevent secondary transmission and nosocomial infection. EV occurs among persons with a history of atopic dermatitis (eczema), irrespective of disease severity or activity, and is a localized or generalized papular, vesicular, or pustular rash, which can occur anywhere on the body, with a predilection for areas of previous atopic dermatitis lesions. Patients with EV are often systemically ill and usually require VIG. Infection-control precautions should be used to prevent secondary transmission and nosocomial infection. PV is a rare, severe, and often fatal complication among persons with immunodeficiencies, characterized by painless progressive necrosis at the vaccination site with or without metastases to distant sites (e.g., skin, bones, and other viscera). This disease carries a high mortality rate, and management of PV should include aggressive therapy with VIG, intensive monitoring, and tertiary-level supportive care. Anecdotal experience suggests that, despite treatment with VIG, persons with cell-mediated immune deficits have a poorer prognosis than those with humoral deficits. Infection-control precautions should be used to prevent secondary transmission and nosocomial infection. Central nervous system disease, which includes postvaccinial encephalopathy (PVE) and postvaccinial encephalomyelitis (or encephalitis) (PVEM), occur after smallpox vaccination. PVE is most common among infants aged &lt; 12 months. Clinical symptoms of central nervous system disease indicate cerebral or cerebellar dysfunction with headache, fever, vomiting, altered mental status, lethargy, seizures, and coma. PVE and PVEM are not believed to be a result of replicating vaccinia virus and are diagnoses of exclusion. Although no specific therapy exists for PVE or PVEM, supportive care, anticonvulsants, and intensive care might be required. Fetal vaccinia, resulting from vaccinial transmission from mother to fetus, is a rare, but serious, complication of smallpox vaccination during pregnancy or shortly before conception. It is manifested by skin lesions and organ involvement, and often results in fetal or neonatal death. No known reliable intrauterine diagnostic test is available to confirm fetal infection. Given the rarity of congenital vaccinia among live-born infants, vaccination during pregnancy should not ordinarily be a reason to consider termination of pregnancy. No known indication exists for routine, prophylactic use of VIG in an unintentionally vaccinated pregnant woman; however, VIG should not be withheld if a pregnant woman develops a condition where VIG is needed. Other less-common adverse events after smallpox vaccination have been reported to occur in temporal association with smallpox vaccination, but causality has not been established. Prophylactic treatment with VIG is not recommended for persons or close contacts with contraindications to smallpox vaccination who are inadvertently inoculated or exposed. These persons should be followed closely for early recognition of adverse reactions that might develop, and clinicians are encouraged to enroll these persons in the CDC registry by calling the Clinician Information Line at 877-554-4625. To request clinical consultation and IND therapies for vaccinia-related adverse reactions for civilians, contact your state health department or CDC's Clinician Information Line (877-554-4625). Clinical evaluation tools are available at http.//www.bt.cdc.gov/agent/smallpox/vaccination/clineval. Clinical specimen-collection guidance is available at http://www.bt.cdc.gov/agent/smallpox/vaccination/vaccinia-specimen-collection.asp. Physicians at military medical facilities can request VIG or cidofovir by calling the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) at 301-619-2257 or 888-USA-RIID.

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Estragole is a natural organic compound that is used as an additive, flavoring agent, or fragrance in a variety of food, cleaning, and cosmetic products; as an herbal medicine; as an antimicrobial agent against acid-tolerant food microflora; and to produce synthetic anise oil. Estragole was nominated for toxicity testing by the National Institute of Environmental Health Sciences to characterize its toxicity when administered by gavage to F344/N rats and B6C3F1 mice and to determine how similar its effects might be to those of the structurally related compound, methyleugenol. Male and female F344/N rats and B6C3F1 mice were given estragole (greater than 99% pure) in corn oil by gavage for 3 months. Genetic toxicology studies were conducted in Salmonella typhimurium and mouse peripheral blood erythrocytes. Core and special study (rats only) groups of 10 male and 10 female rats and mice were administered 37.5, 75, 150, 300, or 600 mg estragole/kg body weight in corn oil by gavage, 5 days per week. The core study groups were given estragole for 3 months and the special study groups for 30 days. All core study rats survived the 3-month exposure period. Mean body weights of the 300 and 600 mg/kg groups were 73% to 92%, respectively, of those of the vehicle control groups. A staining pattern on the ventral surface anterior to the genitalia beginning at week 9 in the 300 and 600 mg/kg groups was attributed to residue of estragole or metabolites in the urine. Alterations in the erythron related to estragole administration occurred in male and female rats; male rats demonstrated a stronger response. The changes in the erythron were characterized as a microcytic, normochromic, nonresponsive anemia. There were decreases in serum iron concentration in the 300 mg/kg females and 600 mg/kg males and females. The average percent saturation of total iron binding capacity was decreased in the 600 mg/kg males and females. Dose-related increases in platelet counts occurred in most of the dosed groups of rats; the effect appeared to be stronger in males. The increase could be consistent with a reactive thrombocytosis. Increases in the serum alanine aminotransferase and sorbitol dehydrogenase activities suggested a hepatocellular effect (increased leakage) and were consistent with the morphological liver changes observed. There were dose-related increases in serum bile salt concentration in most treated male rats at all time points; females were less affected. Absolute and relative liver weights were significantly increased in 300 and 600 mg/kg males and in 75 mg/kg or greater females. Relative kidney weights were significantly increased in all dosed groups of male rats and in female rats given 75 mg/kg or greater. Absolute and relative testis weights of 300 and 600 mg/kg males were significantly decreased. Two 600 mg/kg male rats had multiple cholangiocarcinomas in the liver and a third had an hepatocellular adenoma. All 600 mg/kg males exhibited cholangiofibrosis. All 75 mg/kg or greater males and all 150 mg/kg or greater females had hepatocellular hypertrophy. Incidences of bile duct hyperplasia, oval cell hyperplasia, and chronic periportal inflammation were significantly increased in all dosed groups. Incidences of basophilic and mixed cell foci were significantly increased in 150 mg/kg or greater males and females. Incidences of eosinophilic focus were significantly increased in 300 and 600 mg/kg males and 600 mg/kg females. Incidences of cellular infiltration of the periportal region by histiocytes increased significantly in all dosed groups of males and in 150 mg/kg or greater females. Incidences of bone marrow hyperplasia were significantly increased in 75, 300, and 600 mg/kg male rats. Incidences of renal tubule papillary mineralization were significantly increased in 300 mg/kg males and females and 600 mg/kg males. Incidences of cortical renal tubule pigmentation were significantly increased in 150 mg/kg or greater males, and the incidence of renal tubule regeneration was significantly increased in 600 mg/kg females. Incidences of degeneration of the olfactory epithelium in the nose were significantly increased in 300 and 600 mg/kg rats. Incidences of hypertrophied chromophobe cells in the pars distalis of the pituitary gland were significantly increased in 300 and 600 mg/kg males. Cytoplasmic alteration of the submandibular salivary gland occurred in all 75 mg/kg or greater rats. Incidences of atrophy of the gastric glands in the stomach were significantly increased in 150 mg/kg or greater rats. Bilateral degeneration of the germinal epithelium in the testes and bilateral hypospermia of the epididymis occurred in all 300 and 600 mg/kg males. In the special study, serum gastrin concentration and stomach pH were significantly increased in rats exposed to 600 mg/kg for 30 days. Gastric gland atrophy was significantly increased in the stomach of 300 and 600 mg/kg rats. Hepatic 7-pentoxyresorufin-O-deethylase activity was significantly increased in all exposed groups except 37.5 mg/kg females, and the increases were generally dose related. In the mouse core study, a 600 mg/kg male died during week 9, and all 600 mg/kg female mice died during week 1; the female deaths were attributed to liver necrosis caused by estragole exposure. Mean body weights of 300 and 600 mg/kg males and 75 mg/kg or greater females were 79% to 89% those of the vehicle control groups. Liver weights were generally increased in 75 mg/kg or greater males and in 300 mg/kg females. Relative thymus weights were significantly increased in all dosed groups of female mice. The incidences of hepatocellular hypertrophy and hepatocellular degeneration were significantly increased in 300 and 600 mg/kg male mice and 150 and 300 mg/kg female mice. Incidences of oval cell hyperplasia were significantly increased in 300 and 600 mg/kg males and in 75 mg/kg or greater females. Liver necrosis occurred in all 600 mg/kg female mice, along with a significant increase in the incidence of diffuse fatty change. In addition, 600 mg/kg females exhibited significant increases in the incidences of degeneration of the gastric glands of the glandular stomach, as well as squamous hyperplasia, mineralization, and ulcer in the forestomach. Degeneration of the olfactory epithelium in the nose occurred in all 300 and 600 mg/kg mice. Estragole was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 when tested in the presence or absence of exogenous metabolic activation enzymes. No increases in the frequencies of micronucleated normochromatic erythrocytes were observed in peripheral blood samples from male and female mice in the 3-month study. Under the conditions of these 3-month studies, estragole showed carcinogenic activity based on the occurrence of two cholangiocarcinomas and one hepatocellular adenoma in the liver of three of 10 male F344/N rats in the high dose group. Because rats and mice were exposed for only 3 months, these studies do not access the full carcinogenic potential of estragole. Nonneoplastic effects were observed in the liver, glandular stomach, nose, kidney, and salivary gland of male and female rats and in the testes, epididymides, and pituitary gland of male rats. Nonneoplastic effects were also observed in the liver and nose of male and female mice and in the stomach of female mice.

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The progressive shifts in the legal and social contexts, along with major changes in information seeking habits with the development of the Internet, have placed patients' information at the core of medical practice. This has to be applied to the psychiatric fields as well, and to questions about how schizophrenic patients are being told their diagnosis nowadays in France. This paper is a national and international literature review about schizophrenia diagnosis disclosure practices, from 1972 to 2014, using French and English languages and various psychology and medical databases. The used key words were "diagnosis", "disclosure", "communication", "breaking bad news", "information", "schizophrenia" and "psychosis". Proportions of diagnosis announcement: our results show that the proportion of psychiatrists delivering schizophrenia diagnosis to their patients varies between countries. Although we must acknowledge that the questionnaires and samples are diverse, we have found that psychiatrists are in general less prone to deliver diagnosis information in France (from 13,5% to 39% given the studies), Germany (28%), Italy (30%), and Japan (30%), than in Anglo-Saxon countries. Thus, 70% of the psychiatrists in North America and 56% in Australia claim that they disclose their diagnosis to schizophrenic patients. In the United-Kingdom, a study targeting psychotic patients themselves has shown that 47% of them had been told their diagnosis by their doctor. Even in the countries where the proportion of diagnosis disclosure is the highest, there remains a substantial difference with other mental illnesses such as affective or anxiety disorders, which are almost always labeled as such in the information communicated to the patient (90% in North America). Diagnostic information about schizophrenia continues therefore to appear problematic for health professionals, which can seem a paradox given the recent social and legal evolutions, the therapeutic progress, the proved benefits of disclosure on compliance and therapeutic alliance, and the fact that numerous studies have shown that a majority of patients already know their diagnosis having discovered it on the Internet or by reading their treatments' notice. Reasons alleged for not disclosing diagnosis: the reasons alleged by psychiatrists for not disclosing diagnosis are various, including fear of aggravating the stigma and the emotional state of the patient, fear of giving a wrong diagnosis, fear of suicidal behavior, risk of misunderstanding, low level of patient's insight, absence of therapeutic advantage, or absence of request from the patient. Evolution of the French position about diagnosis disclosure: The publication of the relatively large study of Baylé et al. in 1999, as well as the patients' rights evolutions, has led to a debate among psychiatrists about the reasons alleged in France for not disclosing diagnosis. Among other explanations, it appeared that the theoretical reference of the psychiatrist plays a role, a psychoanalytic practice leading to increased reluctance in breaking the bad news. Thus, the psychiatrist's view of the disease, in terms of etiology and prognosis, is important as the diagnosis could become accusing if the psychiatrist believes the family environment played a role, or harmful if he has a pessimistic conception of prognosis. The question of stigma: among other reasons alleged by psychiatrists for not announcing the diagnosis, the fear of causing an increased stigma is frequently reported by professionals. In France, stigma about schizophrenia is high, not only among the general population but also among health practitioners. Even if the context has evolved during the past 30 years and the therapeutic efficiency has improved, French representations of schizophrenia remain often tinted with catastrophism and should be modified. Benefits of diagnosis disclosure: however, the benefits of disclosing diagnosis have been constantly proved in France as in other environments. Several studies have shown that patients knowing their diagnosis were likely to develop a better compliance and a stronger therapeutic alliance with their doctor. No aggravation of symptoms, suicidal risk or anxiety has been linked to the diagnosis disclosure. On the contrary, the relief of being able to put some words on symptoms, better recognize them and anticipate them, and be part of a group of patients sharing the same symptomatology has been described by patients. Furthermore, disclosing a schizophrenia diagnosis can be essential to the psychotherapeutic project, in the sense that it places the patient into an active role towards the disease and the care plan. Last but not least, the relatives can benefit from the disclosure as well and build a partnership with health professionals about medical care. Existing recommendations: in the French context, apart from individual recommendations produced by a few authors in the literature, there are no official specific recommendations about how to disclose a difficult diagnosis in the psychiatric field; only recommendations concerning severe chronic somatic disease are available. The complexity of the schizophrenia diagnosis disclosure has led some researchers - especially in North America and Australia - to adapt and use in the context of schizophrenia protocols, recommendations and even communication skills training programs that have been developed in oncology or in the field of severe chronic somatic disease. For the situation to evolve in France, tools able to measure patients' consent - including consent to hear the bad news - ability could be used. The question of how much information and what kind of information the patients really wish should therefore be explored in deep. Also, we have seen that schizophrenia representations should be modified in the general public understanding as well as in the professional environment. Families should be more included in the reflection about diagnosis announcement, as psycho-education programs have shown their efficiency and usefulness for both patients and relatives. Finally, in order to overcome some of the difficulties related to breaking the bad news about a schizophrenia diagnosis, developing the existing Anglo-Saxon models and recommendations in France, where only very few protocols exist, could allow a positive evolution in clinical practice and help to set a therapeutic and partnering approach of diagnosis disclosure. However, in order to better understand the situation in France regarding schizophrenia diagnosis disclosure, the present state of clinical practice still remains to be analyzed precisely, as the last study on a relatively large sample was made only in 1999. Thus, the obvious limits of our study lie in the fact that most available surveys in France are not recent enough to have taken into account legal and social evolutions. Also, the studies that we used for this paper use different methodologies, in the majority focus solely on health professionals, and they are not representative enough in terms of size or sample to inform about the present state of the practice. As a conclusion, having stressed the lack of recent data about schizophrenia diagnosis disclosure in France, we suggest a new study using validated tools on a representative sample and taking into account both perceptions of psychiatrist and patient. As has been the case for other severe pathologies, we also suggest that a consensus conference take place on the subject of schizophrenia diagnostic information in order to elaborate guidelines to support this difficult disclosure.

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Parabens is the name given to a group of p-hydroxybenzoic acid (PHBA) esters used in over 22,000 cosmetics as preservatives at concentrations up to 0.8% (mixtures of parabens) or up to 0.4% (single paraben). The group includes Methylparaben, Ethylparaben, Propylparaben, Isopropylparaben, Butylparaben, Isobutylparaben, and Benzylparaben. Industry estimates of the daily use of cosmetic products that may contain parabens were 17.76 g for adults and 378 mg for infants. Parabens in cosmetic formulations applied to skin penetrate the stratum corneum in inverse relation to the ester chain length. Carboxylesterases hydrolyze parabens in the skin. Parabens do not accumulate in the body. Serum concentrations of parabens, even after intravenous administration, quickly decline and remain low. Acute toxicity studies in animals indicate that parabens are not significantly toxic by various routes of administration. Subchronic and chronic oral studies indicate that parabens are practically nontoxic. Numerous genotoxicity studies, including Ames testing, dominant lethal assay, host-mediated assay, and cytogenic assays, indicate that the Parabens are generally nonmutagenic, although Ethylparaben and Methylparaben did increase chromosomal aberrations in a Chinese Hamster ovary cell assay. Ethylparaben, Propylparaben, and Butylparaben in the diet produced cell proliferation in the forestomach of rats, with the activity directly related to chain length of the alkyl chain, but Isobutylparaben and Butylparaben were noncarcinogenic in a mouse chronic feeding study. Methylparaben was noncarcinogenic when injected subcutaneously in mice or rats, or when administered intravaginally in rats, and was not cocarcinogenic when injected subcutaneously in mice. Propylparaben was noncarcinogenic in a study of transplacental carcinogenesis. Methylparaben was nonteratogenic in rabbits, rats, mice, and hamsters, and Ethylparaben was nonteratogenic in rats. Parabens, even at levels that produce maternal toxicity, do not produce fetal anomalies in animal studies. Parabens have been extensively studied to evaluate male reproductive toxicity. In one in vitro study, sperm were not viabile at concentrations as low as 6 mg/ml Methylparaben, 8 mg/ml Ethylparaben, 3 mg/ml Propylparaben, or 1 mg/ml Butylparaben, but an in vivo study of 0.1% or 1.0% Methylparaben or Ethylparaben in the diet of mice reported no spermatotoxic effects. Propylparaben did affect sperm counts at all levels from 0.01% to 1.0%. Epididymis and seminal vesicle weight decreases were reported in rats given a 1% oral Butylparaben dose; and decreased sperm number and motile activity in F(1) offspring of rats maternally exposed to 100 mg/kg day(- 1) were reported. Decreased sperm numbers and activity were reported in F(1) offspring of female rats given Butylparaben (in DMSO) by subcutaneous injection at 100 or 200 mg/kg day(- 1), but there were no abnormalities in the reproductive organs. Methylparaben was studied using rats at levels in the diet up to an estimated mean dose of 1141.1 mg/kg day(- 1) with no adverse testicular effects. Butylparaben was studied using rats at levels in the diet up to an estimated mean dose of 1087.6 mg/kg day(- 1) in a repeat of the study noted above, but using a larger number of animals and a staging analysis of testicular effects-no adverse reproductive effects were found. Butylparaben does bind to estrogen receptors in isolated rat uteri, but with an affinity orders of magnitude less than natural estradiol. Relative binding (diethylstilbesterol binding affinity set at 100) to the human estrogen receptors alpha and beta increases as a function of chain length from not detectable for Methylparaben to 0.267 +/- 0.027 for human estrogen receptor alpha and 0.340 +/- 0.031 for human estrogen receptor beta for Isobutylparaben. In a study of androgen receptor binding, Propylparaben exhibited weak competitive binding, but Methylparaben had no binding effect at all. PHBA at 5 mg/kg day(-1) subcutaneously (s.c.) was reported to produce an estrogenic response in one uterotrophic assay using mice, but there was no response in another study using rats (s.c. up to 5 mg/kg day(- 1)) and mice (s.c. up to 100 mg/kg day(- 1)) and in a study using rats (s.c. up to 100 mg/kg day(- 1)). Methylparaben failed to produce any effect in uterotrophic assays in two laboratories, but did produce an effect in other studies from another laboratory. The potency of Methylparaben was at least 1000x less when compared to natural estradiol. The same pattern was reported for Ethylparaben, Propylparaben, and Butylparaben when potency was compared to natural estradiol. In two studies, Isobutylparaben did produce an estrogenic response in the uterotrophic assay, but the potency was at least 240,000x less than estradiol. In one study, Benzylparaben produced an estrogenic response in the uterotrophic assay, but the potency was at least 330,000x less than estradiol. Estrogenic activity of parabens and PHBA was increased in human breast cancer cells in vitro, but the increases were around 4 orders of magnitude less than that produced by estradiol. Parabens are practically nonirritating and nonsensitizing in the population with normal skin. Paraben sensitization has occurred and continues to be reported in the case literature, but principally when exposure involves damaged or broken skin. Even when patients with chronic dermatitis are patch-tested to a parabens mix, parabens generally induce sensitization in less than 4% of such individuals. Many patients sensitized to paraben-containing medications can wear cosmetics containing these ingredients with no adverse effects. Clinical patch testing data available over the past 20 years demonstrate no significant change in the overall portion of dermatitis patients that test positive for parabens. As reviewed by the Cosmetic Ingredient Review (CIR) Expert Panel, the available acute, subchronic, and chronic toxicity tests, using a range of exposure routes, demonstrate a low order of parabens' toxicity at concentrations that would be used in cosmetics. Parabens are rarely irritating or sensitizing to normal human skin at concentrations used in cosmetics. Although parabens do penetrate the stratum corneum, metabolism of parabens takes place within viable skin, which is likely to result in only 1% unmetabolized parabens available for absorption into the body. The Expert Panel did consider data in the category of endocrine disruption, including male reproductive toxicity and various estrogenic activity studies. The CIR Expert Panel compared exposures to parabens resulting from use of cosmetic products to a no observed adverse effect level (NOAEL) of 1000 mg/kg day(- 1) based on the most statistically powerful and well-conducted study of the effects of Butylparabens on the male reproductive system. The CIR Expert Panel considered exposures to cosmetic products containing a single parabens preservative (use level of 0.4%) separately from products containing multiple parabens (use level of 0.8%) and infant exposures separately from adult exposures in determining margins of safety (MOS). The MOS for infants ranged from approximately 6000 for single paraben products to approximately 3000 for multiple paraben products. The MOS for adults ranged from 1690 for single paraben products to 840 for multiple paraben products. The Expert Panel considers that these MOS determinations are conservative and likely represent an overestimate of the possibility of an adverse effect (e.g., use concentrations may be lower, penetration may be less) and support the safety of cosmetic products in which parabens preservatives are used.

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Transient tachypnoea of the newborn (TTN) is characterised by tachypnoea and signs of respiratory distress. It is caused by delayed clearance of lung fluid at birth. TTN typically appears within the first two hours of life in term and late preterm newborns. Although it is usually a self-limited condition, admission to a neonatal unit is frequently required for monitoring, the provision of respiratory support, and drugs administration. These interventions might reduce respiratory distress during TTN and enhance the clearance of lung liquid. The goals are reducing the effort required to breathe, improving respiratory distress, and potentially shortening the duration of tachypnoea. However, these interventions might be associated with harm in the infant. The aim of this overview was to evaluate the benefits and harms of different interventions used in the management of TTN. We searched the Cochrane Database of Systematic Reviews on 14 July 2021 for ongoing and published Cochrane Reviews on the management of TTN in term (&gt; 37 weeks' gestation) or late preterm (34 to 36 weeks' gestation) infants. We included all published Cochrane Reviews assessing the following categories of interventions administered within the first 48 hours of life: beta-agonists (e.g. salbutamol and epinephrine), corticosteroids, diuretics, fluid restriction, and non-invasive respiratory support. The reviews compared the above-mentioned interventions to placebo, no treatment, or other interventions for the management of TTN. The primary outcomes of this overview were duration of tachypnoea and the need for mechanical ventilation. Two overview authors independently checked the eligibility of the reviews retrieved by the search and extracted data from the included reviews using a predefined data extraction form. Any disagreements were resolved by discussion with a third overview author. Two overview authors independently assessed the methodological quality of the included reviews using the AMSTAR 2 (A MeaSurement Tool to Assess systematic Reviews) tool. We used the GRADE approach to assess the certainty of evidence for effects of interventions for TTN management. As all of the included reviews reported summary of findings tables, we extracted the information already available and re-graded the certainty of evidence of the two primary outcomes to ensure a homogeneous assessment. We provided a narrative summary of the methods and results of each of the included reviews and summarised this information using tables and figures. We included six Cochrane Reviews, corresponding to 1134 infants enrolled in 18 trials, on the management of TTN in term and late preterm infants, assessing salbutamol (seven trials), epinephrine (one trial), budesonide (one trial), diuretics (two trials), fluid restriction (four trials), and non-invasive respiratory support (three trials). The quality of the included reviews was high, with all of them fulfilling the critical domains of the AMSTAR 2. The certainty of the evidence was very low for the primary outcomes, due to the imprecision of the estimates (few, small included studies) and unclear or high risk of bias. Salbutamol may reduce the duration of tachypnoea compared to placebo (mean difference (MD) -16.83 hours, 95% confidence interval (CI) -22.42 to -11.23, 2 studies, 120 infants, low certainty evidence). We did not identify any review that compared epinephrine or corticosteroids to placebo and reported on the duration of tachypnoea. However, one review reported on "trend of normalisation of respiratory rate", a similar outcome, and found no differences between epinephrine and placebo (effect size not reported). The evidence is very uncertain regarding the effect of diuretics compared to placebo (MD -1.28 hours, 95% CI -13.0 to 10.45, 2 studies, 100 infants, very low certainty evidence). We did not identify any review that compared fluid restriction to standard fluid rates and reported on the duration of tachypnoea. The evidence is very uncertain regarding the effect of continuous positive airway pressure (CPAP) compared to free-flow oxygen therapy (MD -21.1 hours, 95% CI -22.9 to -19.3, 1 study, 64 infants, very low certainty evidence); the effect of nasal high-frequency (oscillation) ventilation (NHFV) compared to CPAP (MD -4.53 hours, 95% CI -5.64 to -3.42, 1 study, 40 infants, very low certainty evidence); and the effect of nasal intermittent positive pressure ventilation (NIPPV) compared to CPAP on duration of tachypnoea (MD 4.30 hours, 95% CI -19.14 to 27.74, 1 study, 40 infants, very low certainty evidence). Regarding the need for mechanical ventilation, the evidence is very uncertain for the effect of salbutamol compared to placebo (risk ratio (RR) 0.60, 95% CI 0.13 to 2.86, risk difference (RD) 10 fewer, 95% CI 50 fewer to 30 more per 1000, 3 studies, 254 infants, very low certainty evidence); the effect of epinephrine compared to placebo (RR 0.67, 95% CI 0.08 to 5.88, RD 70 fewer, 95% CI 460 fewer to 320 more per 1000, 1 study, 20 infants, very low certainty evidence); and the effect of corticosteroids compared to placebo (RR 0.52, 95% CI 0.05 to 5.38, RD 40 fewer, 95% CI 170 fewer to 90 more per 1000, 1 study, 49 infants, very low certainty evidence). We did not identify a review that compared diuretics to placebo and reported on the need for mechanical ventilation. The evidence is very uncertain regarding the effect of fluid restriction compared to standard fluid administration (RR 0.73, 95% CI 0.24 to 2.23, RD 20 fewer, 95% CI 70 fewer to 40 more per 1000, 3 studies, 242 infants, very low certainty evidence); the effect of CPAP compared to free-flow oxygen (RR 0.30, 95% CI 0.01 to 6.99, RD 30 fewer, 95% CI 120 fewer to 50 more per 1000, 1 study, 64 infants, very low certainty evidence); the effect of NIPPV compared to CPAP (RR 4.00, 95% CI 0.49 to 32.72, RD 150 more, 95% CI 50 fewer to 350 more per 1000, 1 study, 40 infants, very low certainty evidence); and the effect of NHFV versus CPAP (effect not estimable, 1 study, 40 infants, very low certainty evidence). Regarding our secondary outcomes, duration of hospital stay was the only outcome reported in all of the included reviews. One trial on fluid restriction reported a lower duration of hospitalisation in the restricted-fluids group, but with very low certainty of evidence. The evidence was very uncertain for the effects on secondary outcomes for the other five reviews. Data on potential harms were scarce, as all of the trials were underpowered to detect possible increases in adverse events such as pneumothorax, arrhythmias, and electrolyte imbalances. No adverse effects were reported for salbutamol; however, this medication is known to carry a risk of tachycardia, tremor, and hypokalaemia in other settings. This overview summarises the evidence from six Cochrane Reviews of randomised trials regarding the effects of postnatal interventions in the management of TTN. Salbutamol may reduce the duration of tachypnoea slightly. We are uncertain as to whether salbutamol reduces the need for mechanical ventilation. We are uncertain whether epinephrine, corticosteroids, diuretics, fluid restriction, or non-invasive respiratory support reduces the duration of tachypnoea and the need for mechanical ventilation, due to the extremely limited evidence available. Data on harms were lacking.

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Oblimersen is an antisense oligonucleotide developed by Genta for systemic use as an injection. It comprises a phosphorothioate backbone linking 18 modified DNA bases. Oblimersen targets the first six codons of Bcl-2 mRNA to form a DNA/RNA complex. The duplex is subsequently recognised as a foreign message and is cleaved enzymatically, thereby destroying the Bcl-2 message. The Bcl-2 protein, which is a potent inhibitor of apoptosis, is overexpressed in many cancers, including follicular lymphomas, breast, colon and prostate cancers, and intermediate-/high-grade lymphomas. By reducing the amount of Bcl-2 protein in cancer cells, oblimersen may enhance the effectiveness of conventional anticancer treatments. Genta has reported results from randomised phase III trials of oblimersen in four different indications: malignant melanoma, chronic lymphocytic leukaemia (CLL), multiple myeloma and acute myleoid leukaemia (AML). A negative opinion has been issued for the company's MAA for the product in the treatment of malignant melanoma in the EU; the EMEA has indicated an additional confirmatory trial is needed in this indication for approval. An NDA for CLL was deemed non-approvable by the US FDA; the company is appealing this decision. The phase III trials in multiple myeloma and AML did not meet their primary endpoints. Phase I and II trials are also underway or have been completed for a range of other cancer types. Genta and sanofi-aventis (formerly Aventis) entered into a collaboration agreement in 2002; however, this agreement was terminated by sanofi-aventis in May 2005. Genta became solely responsible for all costs relating to oblimersen at this time. Genta expanded its Cooperative Research and Development Agreement (CRADA) with the National Cancer Institute in November 2001. The expanded collaboration was to investigate the use of oblimersen in combination with standard anticancer therapy in a broad range of cancers. This expansion occurred following the Gensynergy project, which showed that oblimersen was synergistic with other anticancer therapies. Genta signed a 5-year manufacturing agreement with Avecia Ltd in December 2002 to supply it with oblimersen. Genta's NDA was submitted to the FDA in December 2005 and accepted for review in March 2006. The application was based on data from a phase I/II trial (NCT00021749) of oblimersen alone in approximately 40 patients and a phase III study (NCT00024440) of 241 patients who received fludarabine and cyclo-phosphamide with or without oblimersen. Genta received a Special Protocol Assessment (SPA) from the FDA in October 2006 for a randomised, pivotal, clinical trial of oblimersen in CLL. The trial will be conducted in patients who have not received prior chemotherapy and who would be randomised to receive fludarabine and rituximab with or without oblimersen. This trial has not yet begun.Fast-track status was given to oblimersen for CLL in June 2003 by the FDA. Oblimersen previously obtained orphan drug status in the US and EU for CLL in September 2001. Genta previously submitted the MAA under the centralised licensing procedure and Spain and France were assigned as rapporteur and co-rapporteur countries, respectively. It was supported by an extended 24-month follow-up of patients from a phase III study (NCT00016263) of oblimersen plus dacarbazine. The EMEA validated the MAA for review in January 2006. Genta received a number of scientific questions from the EMEA in June 2006, which the company responded to. Genta intends to file a formal complaint and a request for correction of information with the FDA under the Federal Data Quality Act. The complaint is related to a key statistical analysis of the company's data for oblimersen in the treatment of melanoma used by the FDA at the Oncology Drug Advisory Committee (ODAC) in May 2004. Genta believes that analysis sought to discredit the finding that treatment with oblimersen significantly increased progression-free survival; ODAC previously agreed this endpoint would support full approval in the absence of a survival improvement in patients with advanced melanoma.A rolling NDA submission was submitted to the FDA in the third quarter of 2003; however, Genta and Aventis withdrew the NDA after the application failed to gain marketing approval from the FDA's Oncology Drug Advisory Committee (ODAC). In May 2004, ODAC voted that phase III trial results did not provide substantial evidence of effectiveness to outweigh toxicity of oblimersen treatment in patients with metastatic melanoma. Genta has the option to resubmit this application. The FDA gave oblimersen orphan drug status for malignant melanoma in August 2000. In October 1999, fast-track status was given to oblimersen by the FDA for malignant melanoma when used in combination with dacarbazine. In addition, oblimersen received orphan drug status for malignant melanoma in Australia in October 2006.A phase III study (NCT00016263) of oblimersen in combination with dacarbazine was conducted in patients with malignant melanoma. The combination treatment did not significantly increase overall survival time, but did significantly increase progression-free survival time, compared with dacarbazine treatment alone. The phase III trial enrolled 771 patients at 140 sites in 12 different countries. Patients were randomly assigned to receive dacarbazine alone or in combination with oblimersen. The primary endpoint of this trial was to compare the overall survival between the two treatment arms. Secondary endpoints included comparative analyses of progression-free survival and tumour response. Genta will conduct another phase III study of oblimersen in patients with advanced melanoma. The trial is designed to provide additional safety and efficacy evidence of the drug, in combination with dacarbazine, in patients who have not previously received chemotherapy. Approximately 300 patients are expected to be enrolled in the trial, which is planned to begin during mid-2007, at sites throughout Europe, Australia, and North and South America. Genta is conducting a phase I clinical trial (NCT00409383) to evaluate the combination of oblimersen, ABI 007, and temozolomide in chemotherapy-naive patients with advanced melanoma. This trial was initiated in November 2006 and is the first follow-on study to Genta's phase III trial of oblimersen plus dacarbazine. Oblimersen received orphan drug status in the US and EU for multiple myeloma in September 2001. In addition, fast-track designation was given to oblimersen by the FDA in the same month.A phase I/II clinical study (NCT00062244) of oblimersen was conducted by the NCI in patients with Waldenstrom's macroglobulinaemia, a disease that is similar to multiple myeloma. The study results indicated that oblimersen may be a useful treatment in this group of patients (all had high levels of Bcl-2 expression). In June 2003, Genta and Aventis announced the presentation of clinical data from a phase II trial of oblimersen in combination with docetaxel injection concentrate for patients with advanced HRPC. Researchers reported that these findings validated progression into phase III trials. Genta has licensed eight US patents relating to oblimersen and its backbone chemistry and these expire between 2008 and 2015. Genta has two pending US patent applications that relate to oblimersen. Corresponding patent applications have been filed in Canada, Europe and Japan. Genta owns three US patents relating to methods of using oblimersen that will expire in 2020, and also has approximately 45 corresponding foreign patent applications.

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People with cancer experience a variety of symptoms as a result of their disease and the therapies involved in its management. Inadequate symptom management has implications for patient outcomes including functioning, psychological well-being, and quality of life (QoL). Attempts to reduce the incidence and severity of cancer symptoms have involved the development and testing of psycho-educational interventions to enhance patients' symptom self-management. With the trend for care to be provided nearer patients' homes, telephone-delivered psycho-educational interventions have evolved to provide support for the management of a range of cancer symptoms. Early indications suggest that these can reduce symptom severity and distress through enhanced symptom self-management. To assess the effectiveness of telephone-delivered interventions for reducing symptoms associated with cancer and its treatment. To determine which symptoms are most responsive to telephone interventions. To determine whether certain configurations (e.g. with/without additional support such as face-to-face, printed or electronic resources) and duration/frequency of intervention calls mediate observed cancer symptom outcome effects. We searched the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 1); MEDLINE via OVID (1946 to January 2019); Embase via OVID (1980 to January 2019); (CINAHL) via Athens (1982 to January 2019); British Nursing Index (1984 to January 2019); and PsycINFO (1989 to January 2019). We searched conference proceedings to identify published abstracts, as well as SIGLE and trial registers for unpublished studies. We searched the reference lists of all included articles for additional relevant studies. Finally, we handsearched the following journals: Cancer, Journal of Clinical Oncology, Psycho-oncology, Cancer Practice, Cancer Nursing, Oncology Nursing Forum, Journal of Pain and Symptom Management, and Palliative Medicine. We restricted our search to publications published in English. We included randomised controlled trials (RCTs) and quasi-RCTs that compared one or more telephone interventions with one other, or with other types of interventions (e.g. a face-to-face intervention) and/or usual care, with the stated aim of addressing any physical or psychological symptoms of cancer and its treatment, which recruited adults (over 18 years) with a clinical diagnosis of cancer, regardless of tumour type, stage of cancer, type of treatment, and time of recruitment (e.g. before, during, or after treatment). We used Cochrane methods for trial selection, data extraction and analysis. When possible, anxiety, depressive symptoms, fatigue, emotional distress, pain, uncertainty, sexually-related and lung cancer symptoms as well as secondary outcomes are reported as standardised mean differences (SMDs) with 95% confidence intervals (CIs), and we presented a descriptive synthesis of study findings. We reported on findings according to symptoms addressed and intervention types (e.g. telephone only, telephone combined with other elements). As many studies included small samples, and because baseline scores for study outcomes often varied for intervention and control groups, we used change scores and associated standard deviations. The certainty of the evidence for each outcome was interpreted using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Thirty-two studies were eligible for inclusion; most had moderate risk of bias,often related to blinding. Collectively, researchers recruited 6250 people and studied interventions in people with a variety of cancer types and across the disease trajectory, although many participants had breast cancer or early-stage cancer and/or were starting treatment. Studies measured symptoms of anxiety, depression, emotional distress, uncertainty, fatigue, and pain, as well as sexually-related symptoms and general symptom intensity and/or distress. Interventions were primarily delivered by nurses (n = 24), most of whom (n = 16) had a background in oncology, research, or psychiatry. Ten interventions were delivered solely by telephone; the rest combined telephone with additional elements (i.e. face-to-face consultations and digital/online/printed resources). The number of calls delivered ranged from 1 to 18; most interventions provided three or four calls. Twenty-one studies provided evidence on effectiveness of telephone-delivered interventions and the majority appeared to reduce symptoms of depression compared to control. Nine studies contributed quantitative change scores (CSs) and associated standard deviation results (or these could be calculated). Likewise, many telephone interventions appeared effective when compared to control in reducing anxiety (16 studies; 5 contributed quantitative CS results); fatigue (9 studies; 6 contributed to quantitative CS results); and emotional distress (7 studies; 5 contributed quantitative CS results). Due to significant clinical heterogeneity with regards to interventions introduced, study participants recruited, and outcomes measured, meta-analysis was not conducted. For other symptoms (uncertainty, pain, sexually-related symptoms, dyspnoea, and general symptom experience), evidence was limited; similarly meta-analysis was not possible, and results from individual studies were largely conflicting, making conclusions about their management through telephone-delivered interventions difficult to draw. Heterogeneity was considerable across all trials for all outcomes. Overall, the certainty of evidence was very low for all outcomes in the review. Outcomes were all downgraded due to concerns about overall risk of bias profiles being frequently unclear, uncertainty in effect estimates and due to some inconsistencies in results and general heterogeneity. Unsubstantiated evidence suggests that telephone interventions in some capacity may have a place in symptom management for adults with cancer. However, in the absence of reliable and homogeneous evidence, caution is needed in interpreting the narrative synthesis. Further, there were no clear patterns across studies regarding which forms of interventions (telephone alone versus augmented with other elements) are most effective. It is impossible to conclude with any certainty which forms of telephone intervention are most effective in managing the range of cancer-related symptoms that people with cancer experience. Telephone interventions provide a convenient way of supporting self-management of cancer-related symptoms for adults with cancer. These interventions are becoming more important with the shift of care closer to patients' homes, the need for resource/cost containment, and the potential for voluntary sector providers to deliver healthcare interventions. Some evidence supports the use of telephone-delivered interventions for symptom management for adults with cancer; most evidence relates to four commonly experienced symptoms - depression, anxiety, emotional distress, and fatigue. Some telephone-delivered interventions were augmented by combining them with face-to-face meetings and provision of printed or digital materials. Review authors were unable to determine whether telephone alone or in combination with other elements provides optimal reduction in symptoms; it appears most likely that this will vary by symptom. It is noteworthy that, despite the potential for telephone interventions to deliver cost savings, none of the studies reviewed included any form of health economic evaluation. Further robust and adequately reported trials are needed across all cancer-related symptoms, as the certainty of evidence generated in studies within this review was very low, and reporting was of variable quality. Researchers must strive to reduce variability between studies in the future. Studies in this review are characterised by clinical and methodological diversity; the level of this diversity hindered comparison across studies. At the very least, efforts should be made to standardise outcome measures. Finally, studies were compromised by inclusion of small samples, inadequate concealment of group allocation, lack of observer blinding, and short length of follow-up. Consequently, conclusions related to symptoms most amenable to management by telephone-delivered interventions are tentative.

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This report is a supplement to an earlier evidence report, Telemedicine for the Medicare Population, which was intended to help policymakers weigh the evidence relevant to coverage of telemedicine services under Medicare. That report focused on telemedicine programs and clinical settings that had been used with or were likely to be applied to Medicare beneficiaries. While we prepared that report, it became apparent that there are also telemedicine studies among non-Medicare beneficiaries--e.g., children and pregnant women--that could inform policymakers and provide more comprehensive evidence of the state of the science regarding telemedicine applications. In addition, the first evidence report only partially included a class of telemedicine applications (called self-monitoring/testing telemedicine) in which the beneficiary used a home computer or modern-driven telephone system to either report information or access information and support from Internet resources and indirectly interact with a clinician. Self-monitoring/testing applications in the first report required direct interaction with a clinician. The goal of this report is to systematically review the evidence in the clinical areas of pediatric and obstetric telemedicine as well as home-based telemedicine where there is indirect involvement of the health care professional. (In this report, we will refer to the latter as clinician-indirect home telemedicine.) Specifically, the report summarizes scientific evidence on the diagnostic accuracy, access, clinical outcomes, satisfaction, and cost-effectiveness of services provided by telemedicine technologies for these patient groups. It also identifies gaps in the evidence and makes recommendations for evaluating telemedicine services for these populations in the future. The evidence is clustered according to three categories of telemedicine service defined in our original report: store-and-forward, self-monitoring/testing, and clinician-interactive services. The three clinical practice areas reviewed in this report are defined as follows. The term pediatric applies to any telemedicine study in which the sample consisted wholly or partially of persons aged 18 or younger, including studies with neonatal samples. The term obstetric applies to any telemedicine study in which the sample consisted entirely of women seeking pregnancy-related care. The term clinician-indirect home telemedicine applies to home-based telemedicine (called self-monitoring/testing in our original report) where a telemedicine application used in the home has only indirect involvement by the health care professional. Interactive home telemedicine was applied in this report to all patient populations. The key questions that served as a guide for reviewing the literature in the evaluation of pediatric, obstetric, and clinician-indirect home telemedicine applications were derived by consensus among the evidence-review team based on the analytic framework established for the original evidence report. For the current report, the questions were applied to studies in all three practice areas as a whole group within each of the three categories of telemedicine services: store-and-forward; self-monitoring/testing; and clinician-interactive. The specific key questions were: 1. Does telemedicine result in comparable diagnosis and appropriateness of recommendations for management? 2. Does the availability of telemedicine provide comparable access to care? 3. Does telemedicine result in comparable health outcomes? 4. Does telemedicine result in comparable patient or clinician satisfaction with care? 5. Does telemedicine result in comparable costs of care and/or cost-effectiveness? We searched for peer-reviewed literature using several bibliographic databases. In addition, we conducted hand searches of leading telemedicine journals and identified key papers from the reference lists of journal articles. For our original evidence report on telemedicine for the Medicare population, we designed a search to find any publications about telemedicine and used it to search the MEDLINE, CINAHL, and HealthSTAR databases for all years the databases were available. Through this process, we captured studies of pediatric, obstetric, and clinician-indirect home telemedicine; however, they were excluded from the original report since they were outside its scope. For this supplemental report, we reviewed our original search results and identified studies relevant to this report. We identified additional studies from the reference lists of included papers and from hand searching two peer-reviewed telemedicine publications, the Journal of Telemedicine and Telecare and Telemedicine Journal. We critically appraised the included studies for each study area and key question and discussed the strengths and limitations of the most important studies at weekly meetings of the research team. We also developed recommendations for research to address telemedicine knowledge gaps. To match these gaps with the capabilities of specific research methods, we classified the telemedicine services according to the type of evidence that would be needed to determine whether the specific goals of covering such services had been met. We emphasized the relationship between the type and level of evidence found in the systematic review of effectiveness and the types of studies that might be funded to address the gaps in knowledge in this growing field of research. We identified a total of 28 eligible studies. In the new clinical areas, we found few studies in store-and-forward telemedicine. There is some evidence of comparable diagnosis and management decisions made using store-and-forward telemedicine from the areas of pediatric dental screening, pediatric ophthalmology, and neonatalogy. In self-monitoring/testing telemedicine for the areas of pediatrics, obstetrics, and clinician-indirect home telemedicine, there is evidence that access to care can be improved when patients and families have the opportunity to receive telehealth care at home rather than in-person care in a clinic or hospital. Access is particularly enhanced when the telehealth system enables timely communication between patients or families and care providers that allows self-management and necessary adjustments that may prevent hospitalization. There is some evidence that this form of telemedicine improves health outcomes, but the study sample sizes are usually small, and even when they are not, the treatment effects are small. There is also some evidence for the efficacy of clinician-interactive telemedicine, but the studies do not clearly define which technologies provide benefit or cost-efficiency. Some promising areas for diagnosis include emergency medicine, psychiatry, and cardiology. Most of the studies measuring access to care provide evidence that it is improved. Although none of these studies were randomized controlled trials, they provide some evidence of access improvement over prior conditions. Clinician-interactive telemedicine was the only area for which any cost studies were found. The three cost studies did not adequately demonstrate that telemedicine reduces costs of care (except comparing only selected costs). No study addressed cost-effectiveness. This supplemental report covering the areas of pediatrics, obstetrics, and indirect-clinician home telemedicine echoes the findings of our initial report for the Medicare domain, which is that while the use of telemedicine is small but growing, the evidence for its efficacy is incomplete. Many of the studies are small and/or methodologically limited, so it cannot be determined whether telemedicine is efficacious. Future studies should focus on the use of telemedicine in conditions where burden of illness and/or barriers to access for care are significant. Use of recent innovations in the design of randomized controlled trials for emerging technologies would lead to higher quality studies. Journals publishing telemedicine evaluation studies must set high standards for methodologic quality so that evidence reports need not rely on studies with marginal methodologies.

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2-Chloronitrobenzene and 4-chloronitrobenzene are oily yellow solids that are used primarily as chemical intermediates in the production of dyes, lumber preservatives, drugs, and photographic chemicals. Although these chemicals are solids at room temperature, the vapor pressures of these chemicals are sufficiently high to result in significant inhalation exposure. Toxicity studies of 2-chloronitrobenzene and 4-chloronitrobenzene were performed by exposing male and female F344/N rats and B6C3F1 mice to the chemicals by whole-body inhalation 6 hours per day, 5 days per week, for 2 weeks or 13 weeks. Animals were evaluated for histopathology, clinical chemistry (rats), hematology (rats), and reproductive system effects. In separate studies, the dermal absorption of the chemicals was compared, and the absorption, distribution, metabolism, and excretion were partially characterized following oral administration to male F344/N rats. 2-Chloronitrobenzene and 4-chloronitrobenzene were also administered orally to CD-1(R) Swiss mice for evaluation of reproductive and developmental toxicity. Genetic effects were evaluated in Salmonella typhimurium, in Chinese hamster ovary cells, and in Drosophila melanogaster. The highest exposure concentrations used in the 2 week and 13 week studies were limited by technical factors in vapor generation to 18 ppm (115.2 mg/m(3)) for 2-chloronitrobenzene and 24 ppm (153.6 mg/m(3)) for 4-chloronitrobenzene. Other concentrations were 0, 1.1, 2.3, 4.5, and 9 ppm (0, 7, 14.7, 28.8, and 57.6 mg/m(3)) for 2-chloronitrobenzene and 0, 1.5, 3, 6, and 12 ppm (0, 9.6, 19.2, 38.4, and 76.8 mg/m(3)) for 4-chloronitrobenzene. In 2-week studies with 2-chloronitrobenzene, all rats survived to the end of the study. One of five male mice exposed to 18 ppm died, but weight gains of exposed rats and mice were not affected. Exposed rats and mice had concentration-related increases in liver weights, and spleen weights were increased in rats and mice exposed to 18 ppm. Histopathologic findings in rats were limited to hemosiderin deposition in the liver and spleen at the highest exposure concentration. Exposed mice, primarily those in the 18 ppm groups, had coagulative necrosis, hepatocytomegaly, and granulomatous inflammation in the liver. Splenic changes including increased hematopoietic cell proliferation and hemosiderin deposition occurred at concentrations as low as 4.5 ppm. In 13-week studies with 2-chloronitrobenzene, all rats survived to the end of the study; 2 of 10 male mice exposed to 18 ppm died. Body weight gains of exposed rats and mice were similar to or somewhat higher than those of the respective controls. Methemoglobinemia occurred in rats and resulted in a normocytic, normochromic anemia that became responsive by the end of the study. Exposed rats and mice had increased liver weights, but these increases were not as great as those seen in the 2-week studies. Spleen weights were increased in exposed rats. Histopathologic changes in rats included increased basophilia of centrilobular hepatocytes, pigmentation and regeneration of the proximal convoluted tubules of the kidney, and hyperplasia of the nasal cavity respiratory epithelium. In mice, hepatocellular necrosis, cytomegaly, mineralization, and chronic inflammation occurred in the liver, primarily in mice in the 18 ppm group, and hematopoietic activity in the spleen was increased. In 2-week studies with 4-chloronitrobenzene, all rats and mice survived to the end of the studies. Body weight gains of exposed rats were similar to those of the controls; body weight gains of exposed mice were greater than those of the controls. Liver and spleen weights were increased in exposed rats and mice. In rats, histopathologic changes in the liver were limited to an increase in hemosiderin pigment in Kupffer cells. The spleens of exposed rats were congested and had increased hematopoietic activity and hemosiderin deposition. Kidneys of exposed male rats had lesions consistent with hyaline droplet nephropathy. The proximal convoluted tubules of exposed female rats c contained hemosiderin. Microscopic changes in exposed mice primarily involved increased hematopoietic activity in the spleen and hemosiderin pigmentation in the spleen, liver, and proximal convoluted tubules in the kidney. In 13-week studies with 4-chloronitrobenzene, there were no deaths that were clearly related to exposure to 4-chloronitrobenzene. Body weight gains of exposed rats and mice were either equal to or greater than those of the controls. A more severe methemoglobinemia developed in rats exposed to 4-chloronitrobenzene than occurred in rats exposed to 2-chloronitrobenzene, and this methemoglobinemia resulted in a responsive macrocytic, hyperchromic anemia. Spleen weights were markedly greater in exposed rats and mice than in controls. In exposed rats, lesions in the spleen, liver, and kidney were similar to those described for the 2-week study. Additionally, increased hematopoietic cell proliferation in bone marrow, histiocytic hyperplasia in mediastinal lymph nodes, testicular atrophy, and chronic inflammation of the harderian gland occurred in exposed rats. In exposed mice, microscopic changes in the spleen and liver were similar to those noted in the 2-week study. Additional lesions included increased hematopoiesis and hemosiderin deposition in the bone marrow of exposed males and females and squamous cell hyperplasia of the forestomach epithelium in female mice. In reproductive system assessments, there was evidence of decreased spermatogenesis in rats exposed to either 2- or 4-chloronitrobenzene. In mice, effects were limited to a decrease in sperm motility in males exposed to 2-chloronitrobenzene and an increase in estrous cycle length in females exposed to 4-chloronitrobenzene. In continuous breeding studies, a progressive decrease in fertility was noted in CD-1&amp;reg; Swiss mice receiving 4-chloronitrobenzene by oral gavage; fertility was not affected in mice administered 2-chloronitrobenzene by oral gavage. Percutaneous absorption of [14C]-2-chloronitrobenzene and [14C]-4-chloronitrobenzene was demonstrated in rats. For doses ranging from 0.65 to 65 mg/kg of either chemical, 33&amp;percnt; to 40&amp;percnt; of 2-chloronitrobenzene and 51&amp;percnt; to 62&amp;percnt; of 4-chloronitrobenzene were absorbed under nonocclusive conditions. Oral absorption was somewhat higher than dermal absorption for both chemicals, and metabolism was complicated, with over 20 unidentified metabolites isolated from urine of rats given either 2- or 4-chloronitrobenzene. 2-Chloronitrobenzene and 4-chloronitrobenzene were mutagenic in Salmonella typhimurium with S9 activation. In addition, both compounds induced sister chromatid exchanges and chromosomal aberrations in Chinese hamster ovary cells; requirements for S9 activation varied among testing laboratories. Neither compound induced sex-linked recessive lethal mutations in germ cells of male Drosophila melanogaster treated as adults or as larvae. In summary, inhalation exposure of rats and mice to 2- or 4-chloronitrobenzene resulted in methemoglobin formation and oxidative damage to red blood cells, leading to a regenerative anemia and a recognized spectrum of tissue damage and changes secondary to erythrocyte injury. In addition, numerous other lesions that were considered primary toxic effects occurred following exposure. These included renal hyaline droplet accumulation and testicular atrophy in male rats exposed to 4-chloronitrobenzene and hyperplasia of the respiratory epithelium in rats exposed to 2-chloronitrobenzene. A no-observed-adverse-effect-level (NOAEL) for rats was not achieved, as increases in methemoglobin and histopathologic changes occurred at exposure concentrations as low as 1.1 ppm for 2-chloronitrobenzene and 1.5 ppm for 4-chloronitrobenzene in the 13-week studies. The NOAEL for histopathologic injury in mice was 4.5 ppm for 2-chloronitrobenzene and 6 ppm for 4-chloronitrobenzene. 2-Chloronitrobenzene Synonyms: o-Cloronitrobenzene; 2-chloro-1-nitrobenzene; ONCB. 4-chloronitrobenzene Synonyms: p-Chloronitrobenzene; 4-chloro-1-nitrobenzene; PNCB.

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Glycidol is a viscous liquid that is used as a stabilizer in the manufacture of vinyl polymers, as an additive for oil and synthetic hydraulic fluids, and as a diluent in some epoxy resins. NTP Toxicology and Carcinogenesis studies were conducted by administering glycidol (94% pure, containing 1.2% 3-methoxy-1,2-propanediol, 0.4% 3-chloro-1,2-propanediol, 2.8% diglycidyl ether, and 1.1% 2,6-dimethanol-1,4-dioxane) in water by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Chinese hamster ovary (CHO) cells, Drosophila melanogaster, and the bone marrow of male B6C3F1 mice. Sixteen-Day Studies: Glycidol doses for groups of five rats or five mice of each sex ranged from 37.5 to 600 mg/kg; vehicle controls received distilled water. All rats that received 600 mg/kg died between days 3 and 13. Edema and degeneration of the epididymal stroma, atrophy of the testis, and granulomatous inflammation of the epididymis occurred in males that received 300 mg/kg. All mice that received 600 mg/kg and two males and two females that received 300 mg/kg died by day 4 of the studies. Focal demyelination in the medulla and thalamus of the brain occurred in all female mice that received 300 mg/kg. Thirteen-Week Studies: Doses for groups of 10 rats ranged from 25 to 400 mg/kg, and doses for groups of 10 mice ranged from 19 to 300 mg/kg; vehicle controls received distilled water. All rats that received 400 mg/kg died by week 2; three males and one female that received 200 mg/kg died during weeks 11-12. Final mean body weights of male rats that received 50, 100, or 200 mg/kg were 96%-85% that of vehicle controls; final mean body weights of female rats receiving the same doses were 95%-89% that of vehicle controls. Sperm count and sperm motility were reduced in male rats that received 100 or 200 mg/kg. Necrosis of the cerebellum, demyelineation in the medulla of the brain, tubular degeneration and/or necrosis of the kidney, lymphoid necrosis of the thymus, and testicular atrophy and/or degeneration occurred in rats that received 400 mg/kg. All mice that received 300 mg/kg died by week 2; deaths of mice that received 150 mg/kg occurred during weeks 4-8 for males and weeks 1-5 for females. Mean body weights of chemically exposed mice surviving to the end of the studies were generally 90%-94% those of vehicle controls. Sperm count and sperm motility were reduced in dosed male mice. Compound-related histopathologic lesions included demyelination of the brain in males and females that received 150 or 300 mg/kg, testicular atrophy in males at all doses, and renal tubular cell degeneration in male mice that received 300 mg/kg. Based on reduced survival, reduced weight gain, and histopathologic lesions in the brain and kidney in rats that received 200 or 400 mg/kg and on reduced survival and histopathologic lesions of the brain in mice that received 150 or 300 mg/kg, doses selected for the 2-year studies of glycidol were 37.5 and 75 mg/kg for rats and 25 and 50 mg/kg for mice. Body Weights and Survival in the Two-Year Studies: Mean body weights of chemically exposed male rats generally ranged from 80% to 94% of those of vehicle controls, and mean body weights of chemically exposed female rats were from 90% to 97% those of vehicle controls. Mean body weights of chemically exposed male mice were similar to those of vehicle controls; mean body weights of chemically exposed female mice were 79%-95% of those of vehicle controls. Virtually all male and female rats that received glycidol died or were killed in a moribund condition as a result of the early induction of neoplastic disease (final survival--male: vehicle control, 16/50; low dose, 0/50; high dose, 0/50; female: 28/50; 4/50; 0/50). Survival of vehicle control male rats was lower than that usually observed; however, specific causes of deaths could not be determined. The survival of male mice and low dose female mice was similar to that of vehicle controls; survival of female mice that resurvival of male mice and low dose female mice was similar to that of vehicle controls; survival of female mice that received 50 mg/kg was lower than that of vehicle controls after week 101 (final survival--male: 33/50; 25/50; 27/50; female: 29/50; 27/50; 17/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Chemical-related nonneoplastic lesions in both rats and mice included hyperkeratosis and epithelial dysplasia of the forestomach. Fibrosis of the spleen was also present in rats of each sex, and cysts of the preputial gland and kidney were present in male mice. Exposure to glycidol induced dose-related increases in the incidences of neoplasms in numerous tissues in both rats and mice (see summary table on page 5 of the Technical Report). In male rats, mesotheliomas arising in the tunica vaginalis and frequently metastasizing to the peritoneum were considered the major cause of early death. Early deaths in female rats were associated with the presence of mammary gland neoplasms. Genetic Toxicology: Glycidol was mutagenic in a variety of in vitro and in vivo short-term tests. Mutagenic activity was observed in S. typhimurium strains TA97, TA98, TA100, TA1535, and TA1537 exposed to glycidol with and without exogenous metabolic activation. Glycidol was positive in the absence of exogenous metabolic activation in the mouse lymphoma assay for induction of trifluorothymidine resistance in L5178Y/TK cells; it was not tested with activation. In cytogenetic tests with CHO cells, glycidol induced both sister chromatid exchanges and chromosomal aberrations in the presence and absence of exogenous metabolic activation. Glycidol induced sex-linked recessive lethal mutations and reciprocal translocations in the germ cells of male D. melanogaster exposed by feeding. The incidence of micronucleated polychromatic erythrocytes was increased in the bone marrow of male B6C3F1 mice administered glycidol by intraperitoneal injection. Conclusions: Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenic activity of glycidol for male F344/N rats, based on increased incidences of mesotheliomas of the tunica vaginalis; fibroadenomas of the mammary gland; gliomas of the brain; and neoplasms of the forestomach, intestine, skin, Zymbal gland, and thyroid gland. There was clear evidence of carcinogenic activity for female F344/N rats, based on increased incidences of fibroadenomas and adenocarcinomas of the mammary gland; gliomas of the brain; neoplasms of the oral mucosa, forestomach, clitoral gland, and thyroid gland; and leukemia. There was clear evidence of carcinogenic activity for male B6C3F1 mice based on increased incidences of neoplasms of the harderian gland, forestomach, skin, liver, and lung. There was clear evidence of carcinogenic activity for female B6C3F1 mice, based on increased incidences of neoplasms of the harderian gland, mammary gland, uterus, subcutaneous tissue, and skin. Other neoplasms that may have been related to the administration of glycidol were fibrosarcomas of the glandular stomach in female rats and carcinomas of the urinary bladder and sarcomas of the epididymis in male mice. Synonym: 2,3-epoxy-1-propanol

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The Japan-China Joint Medical Workshop on Drug Discoveries and Therapeutics 2008 (JCMWDDT 2008) was held from September 29 to October 1, 2008 at The University of Tokyo, Tokyo, Japan. JCMWDDT is an international workshop that is mainly organized by Asian editorial members of Drug Discoveries &amp; Therapeutics (&lt;a href="http://www.ddtjournal.com/home" class="blue"&gt;http://www.ddtjournal.com/home&lt;/a&gt;) for the purpose of promoting research exchanges in the field of drug discovery and therapeutic. This year's JCMWDDT is the second workshop and focused particularly on novel development and technological innovation of anti-influenza agents. The workshop began with an announcement by the Japanese Co-chairperson, Dr. Sekimizu (Department of Microbiology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Japan; Editorin- Chief of Drug Discoveries &amp; Therapeutics, DDT) followed by a speech by the Chinese Co-chairperson, Dr. Wenfang Xu (School of Pharmaceutical Sciences, Shandong University, Shandong, China; Editor in China Office of DDT), with additional speeches by Dr. Norio Matsuki (The University of Tokyo, Japan; Editor of DDT) and Dr. Guanhua Du (Chinese Academy of Medical Science, China; Editor of DDT). Fifty-nine titles were presented in 6 specialized sessions (Research Advances in Drug Discoveries and Therapeutics, Drug Synthesis/Clinical Therapeutics, Medicinal Chemistry/Natural Products, Anti-influenza Drugs, Anti-infection/antiviral Drugs, Biochemistry/Molecular Biology /Pharmacology) and a poster session (Drug Discov Ther 2008; 2, Suppl; available at &lt;a href="http://www.ddtjournal.com/Announce/index.htm" class="blue"&gt;http://www.ddtjournal.com/Announce/index.htm&lt;/a&gt;). An annual outbreak of avian influenza in Asian countries including China and Japan has sparked fears that the virus will mutate and then cause an epidemic in humans. Therefore, Asian researchers need to work together to control this infection. This year's JCMWDDT helped provide an opportunity to reiterate the crucial role of medicinal chemistry in conquering influenza and created an environment for cooperative research in Asian countries. (reported on October 1st, with grateful thanks to all participants) &lt;b&gt;Main program&lt;/b&gt; &lt;b&gt;Session I. Research Advances in Drug Discoveries and Therapeutics&lt;/b&gt; ● Design, synthesis and preliminary activity assay of influenza virus neuraminidase inhibitors by Wenfang Xu (Shandong University, China) ● Infection disease models with silkworms to evaluate the therapeutic effects of drug candidates by Kazuhisa Sekimizu (The University of Tokyo, Japan) ● Japan's governmental approaches to facilitate drug development process by Makoto Shimoaraiso (Ministry of Foreign Affairs of Japan, Japan) ● Effective detection of the epidermal growth factor receptor mutation by the peptide nucleic acid-locked nucleic acid PCR Clamp by Sakuo Hoshi (The University of Tokyo Hospital, Japan) ● Design and synthesis of p53-MDM2 binding inhibitors by Yongzhou Hu (Zhejiang University, China) &lt;b&gt;Session II. Drug Synthesis/Clinical Therapeutics&lt;/b&gt; ● Pharmacogenomics-based clinical studies using a novel fully-automated genotyping system by Setsuo Hasegawa (Sekino Clinical Pharmacology Clinic, Japan) ● Synthesis and biological evaluation of pentacyclic triterpenes as anti-tumor agents by Hongbin Sun (China Pharmaceutical University, China) ● Drug discovery and therapeutics using silkworm as experimental animal by Yasuyuki Ogata (The University of Tokyo, Japan) ● Novel selective estrogen recetpor modulators (SERMs) with unusual structure and biological activities by Haibing Zhou (Wuhan University, China) &lt;b&gt;Session III. Medicinal Chemistry/Natural Products&lt;/b&gt; ● Synthesis and properties of isonucleosides incorporated oligonucleotides by Zhenjun Yang (Peking University, China) ● Isolation of antiviral compounds from plant resources using silkworm bioassay by Yutaka Orihara (The University of Tokyo, Japan) ● Synthesis and structural modifcation of tasiamide and the effect of these modifications on in vitro anticancer activity by Yingxia Li (Ocean University of China, China) ● Spirohexalines A and B, novel undecaprenyl pyrophosphate inhibitors produced by Penicillium sp. FKI-3368 by Junji Inokoshi (Kitasato University, Japan) ● Nosokomycins, novel anti-MRSA antibiotics, produced by Streptomyces sp. K04-0144 by OR. Uchida (Kitasato University, Japan) ● In vivo screening for antimicrobial activity of Thai Herbal Medicines using silkworm model by Santad Chanprapaph (Chulalongkorn University, Thailand) ● Novel electrochemical sensor of nitric oxide for screening anti-aging Traditional Chinese Medicine by Zilin Chen (Wuhan University, China) ● Polysacchride from green tea purified by silkworm muscle contraction assay induces innate immunity by increasing the expression of various inflammatory cytokine mRNA in human leukocytes by Saphala Dhital (The University of Tokyo, Japan) &lt;b&gt;Session IV. Anti-influenza Drugs&lt;/b&gt; ● Structure-activity relationship of flavonoids as influenza virus neuraminidase inhibitors and their in vitro anti-viral activities by Guanhua Du (Chinese Academy of Medical Sciences and Peking Union Medical College, China) ● Mechanisms and consequences of phagocytosis of influenza virus-infected cells by Yoshinobu Nakanishi (Kanazawa University, Japan) ● Nuclear export inhibitors; a possible target for novel anti-influenza viral drugs by Ken Watanabe (Nagasaki University, Japan) ● Catalytic asymmetric synthesis of oseltamivir phosphate directing toward its stable worldwide supply by Motomu Kanai (The University of Tokyo, Japan) ● Clinical effects of probiotic bifidobacterium in the prevention of influenza virus infections and allergic diseases by Jin-zhong Xiao (Morinaga Milk Industry Co., Ltd., Japan) ● Production of anti-influenza PR8-scFv using a phage display by Normaiza Zamri (Tokai University, Japan) &lt;b&gt;Session V. Anti-infection/Antiviral Drugs&lt;/b&gt; ● Emerging infectious diseases and anti-viral drugs: Urgent need to develop effective drugs which cause less resistant virus by Nobuyuki Kobayashi (Nagasaki University, Japan) ● Design, synthesis and antiviral evaluation of novel heterocyclic compounds as HIV-1 NNRTIs by Xinyong Liu (Shandong University, China) ● Antiviral drug screening from microbial products by Eisaku Tsujii (Astellas Pharma Inc., Japan) ● Viral factors that determine the natural course of chronic hepatitis B viral infection by Hiroshi Yotsuyanagi (The University of Tokyo, Japan) ● Effect of andrographolide derivatives having α-glucosidase inhibition, on HBsAg, HBeAg secretion in HepG2 2.2.15 cells by Hongmin Liu (Zhengzhou University, China) ● Current and future antiviral therapy for influenza by Hideki Asanuma (Tokai University, Japan) ● Establishment of an HIV-based pseudotyping system as a safe model for screening inhibitors on bird flu H5N1 entry by Ying Guo (Peking Union Medical Collegee Chinese Academy of Medical Sciences, China) ● Strategy of discovery for novel antibiotics using silkworm infection model by Hiroshi Hamamoto (The University of Tokyo, Japan) ● Potent neuraminidase inhibitors and anti-inflammatory substances from Chaenomeles speciosa by Li Zhang (Chinese Academy of Medical Sciences and Peking Union Medical College, China) ● High-throughput screening assay for hepatitis C virus helicase inhibitors using fluorescence-quenching phenomenon by Hidenori Tani (Waseda University and National Institute of Advanced Industrial Science and Technology, Japan) &lt;b&gt;Session VI. Biochemistry/Molecular Biology/Pharmacology&lt;/b&gt; ● A novel conjugate of low-molecular-weight heparin and Cu,Zn-superoxide dismutase: Study on its mechanism in preventing brain reperfusion injury after ischemia in gerbils by Fengshan Wang (Shandong University, China) ● A novel gene fudoh in SCCmec region regulates the colony spreading ability and virulence in Staphylococcus aureus by Chikara Kaito (The University of Tokyo, Japan) ● Water soluble fluorescent boronic acid sensors for tumor cell-surface saccharide by Hao Fang (Shandong Unviersity, China) ● Molecular characterization of the biosynthetic enzyme for the biotechnological production of tetrahydrocannabinol, the active constituent of marijuana by Futoshi Taura (Kyushu University, Japan) ● Galloyl cyclic-imide derivative CH1104I inhibits tumor invasion via suppressing matrix metalloproteinase activity by Xianjun Qu (Shandong University, China) ● Neuroprotection by inhibition of GAPDH-MAO B mediated cell death induced by ethanol by Xiao-Ming Ou (University of Mississippi Medical Center, USA).

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The objective of this systematic review is to synthesize the best available evidence on the impact of pre-injury anticoagulation therapy in the older adult patient who experiences a traumatic brain injury. Trauma in the elderly remains one of the most challenging problems for healthcare providers in the 21 century. The most recent United States (U.S.) census estimates that by the year 2020 more than 52 million Americans will be age 65 years or older, and one million of those will live to be over 100 years of age. In the older adult population, classified as age 65 years or greater, the two leading causes of injury were reported as motor vehicle crashes (MVC) and falls. We have become increasingly aware of the unique physiologic changes in this population that make them more susceptible to succumb to traumatic injuries than their younger counterparts. This is especially true in the anticoagulated patient with a traumatic brain injury.Traumatic brain injury (TBI) is defined as an injury occurring when an external force traumatizes the brain. It may also be known as an intracranial or head injury. TBI is classified depending on the mechanism of injury (blunt or penetrating), severity, and location of the assault. Damage to the brain, skull, and/or scalp transpires. TBI is the leading cause of death and disability in the U.S, and persons of all ages, races, ethnicities, and incomes are affected. In the past five to ten years, trauma services have recorded an increase in major trauma admissions of patients age 65 years and older. In review of the literature to date, it is recognized that outcomes following moderate to severe TBI in older adults are poor, with high rates of significant disability and mortality reported. A recent Australian study reported that 28% of older adults died in the hospital following a TBI and in Finland adults aged 75 years and older had the highest rates of TBI related hospitalizations and death. According to a systematic review of European studies, the overall incidence of hospitalized TBI patients was 235 incidents/per 100,000 individuals, with a mortality rate of 15.4 deaths/per 100,000 of the population.The association between medications that alter a patient's coagulation function and adverse trauma outcome continues to be an important area of interest and study. The percentage of Americans on anticoagulant and antiplatelet agents continues to increase with the long-term trend towards longer life expectancies. Older adults are prescribed anticoagulants and antiplatelet agents to prevent thromboembolic complications of artial fibrillation; prosthetic cardiac valves; cerebral, coronary, and peripheral vascular disease; as well as several other medical conditions. One of the most frequently prescribed anticoagulant medications is warfarin. The prevalence of warfarin use in the Unites States is unknown, but the Food and Drug Administration (FDA) estimates that more than 31 million prescriptions were written in 2004. Newer, more potent antiplatelet medications like clopidogrel (Plavix) pose an even greater risk for uncontrolled bleeding in trauma patients. The uncertainty regarding the impact on trauma outcomes is compounded by the variable response of patients to anticoagulant or antiplatelet medication for an associated comorbidity. Evidence suggests that outcomes for TBI are worse, and there may be delayed intracranial hemorrhage in this population of patients.According to a Western Australian study, trauma patients are theoretically at risk for prolonged major bleeding. Studies of traumatic intracranial hemorrhage (ICH) suggest that patients taking anticoagulants have two to six times greater mortality. Mina et al. noted that the trauma patient with preinjury anticoagulation such as warfarin or even aspirin who had an intracranial injury had a four to five fold higher risk of death than the non-anticoagulated patient. Franko et al. concluded that mortality of patients over age 70 was significantly higher than that of younger patients when taking preinjury anticoagulants. The concern about unfavourable outcomes in the anticoagulated older adult patient presenting with traumatic injury has led many healthcare systems to take action. Ivascu et al. looked at early identification in triage for at- risk patients, and implemented warfarin (coumadin) protocols to assist in promoting improved patient outcomes; however, her research did not demonstrate a positive impact. In an effort to find a relationship between preinjury anticoagulation and outcomes in the older adult trauma patient, the degree of anticoagulation rather than the anticoagulant itself was studied to assist with predicting the severity of the TBI. Pieracci et al. concluded that among older adult patients who have sustained a head injury, warfarin use with an admission International Normalized Ratio (INR) greater than or equal to two was associated with an increase severity of TBI, a trend toward an increased likelihood of intracranial hemorrhage (ICH), increased overall mortality, and increased mortality after ICH.The impact of trauma- related morbidity and mortality in the elderly population is significant. Older adult patients account for 25% of trauma related hospital costs, 25% of trauma-related deaths, have the highest age-specific rate of TBI, and have worse outcomes reported. Fortuna et al. concluded that preinjury anticoagulants and antiplatelet medications used by the older adult patient were not associated with increased mortality, but age was a significant predictor of mortality. Research by Wojcik et al., concluded that preinjury anticoagulation therapy did not adversely impact mortality or length of stay (LOS) outcomes in the head injured patients.The influence of anticoagulation on outcomes in the older adult patient with a head injury has been studied, and has resulted in significant debate. Chronic use of anticoagulants and antiplatelet medications in the management of many medical conditions has increased over the decades. As a consequence, older adults over the age of 65 are at risk for trauma related injuries. Concomitant risks include bleeding after traumatic injury.What is known nationally and internationally is our population is aging. With an aging population comes acute and chronic illness. Anticoagulant medication is frequently prescribed for health conditions to promote positive patient outcomes. We know the impact of anticoagulant and antiplatelet therapy may have detrimental effects; especially when an older adult experiences a traumatic brain injury. What we don't know about the impact of anticoagulant and antiplatelet therapy is how it effects the trauma patient, how to rapidly and successful reverse the detrimental outcomes, and how to prevent mortality in this specific age group. A systematic review of the literature will synthesize the data, identify gaps, and recommend on-going research related to the impact of untoward outcomes in the older adult, anticoagulated, trauma patient.Theoutcome to be studied is mortality prior to discharge from the healthcare system. The gaps in the literature, timeliness of research, and change in demographic data justifies a systematic review of the literature to assist in providing consensus to base practice change, policy advances, and protocol development to promote positive patient outcomesPrior to the commencement of the review, a search of the Cochrane Library of Systematic Reviews, Joanna Briggs Institute (JBI) Library of Systematic Reviews, and MEDLINE was performed. No systematic reviews of the proposed topic were located.

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Major depression is defined as a period of depression lasting at least 2 weeks characterized by depressed mood, most of the day, nearly every day, and/or markedly diminished interest or pleasure in all, or almost all, activities. Anxiety disorders encompass a broad range of disorders in which people experience feelings of fear and excessive worry that interfere with normal day-to-day functioning.Cognitive behavioural therapy (CBT) is a form of evidence-based psychotherapy used to treat major depression and anxiety disorders. Internet-delivered CBT (iCBT) is structured, goal-oriented CBT delivered via the internet. It may be guided, in which the patient communicates with a regulated health care professional, or unguided, in which the patient is not supported by a regulated health care professional. We conducted a health technology assessment, which included an evaluation of clinical benefit, value for money, and patient preferences and values related to the use of iCBT for the treatment of mild to moderate major depression or anxiety disorders. We performed a systematic review of the clinical and economic literature and conducted a grey literature search. We reported Grading of Recommendations Assessment, Development, and Evaluation (GRADE) ratings if sufficient information was provided. When other quality assessment tools were used by the systematic review authors in the included studies, these were reported. We assessed the risk of bias within the included reviews. We also developed decision-analytic models to compare the costs and benefits of unguided iCBT, guided iCBT, face-to-face CBT, and usual care over 1 year using a sequential approach. We further explored the lifetime and short-term cost-effectiveness of stepped-care models, including iCBT, compared with usual care. We calculated incremental cost-effectiveness ratios (ICERs) from the perspective of the Ontario Ministry of Health and Long-Term Care and estimated the 5-year budget impact of publicly funding iCBT for mild to moderate major depression or anxiety disorders in Ontario. To contextualize the potential value of iCBT as a treatment option for major depression or anxiety disorders, we spoke with people with these conditions. People who had undergone guided iCBT for mild to moderate major depression (standardized mean difference [SMD] = 0.83, 95% CI 0.59-1.07, GRADE moderate), generalized anxiety disorder (SMD = 0.84, 95% CI 0.45-1.23, GRADE low), panic disorder (small to very large effects, GRADE low), and social phobia (SMD = 0.85, 95% CI 0.66-1.05, GRADE moderate) showed a statistically significant improvement in symptoms compared with people on a waiting list. People who had undergone iCBT for panic disorder (SMD= 1.15, 95% CI: 0.94 to 1.37) and iCBT for social anxiety disorder (SMD=0.91, 95% CI: 0.74-1.07) showed a statistically significant improvement in symptoms compared with people on a waiting list. There was a statistically significant improvement in quality of life for people with generalized anxiety disorder who had undergone iCBT (SMD = 0.38, 95% CI 0.08-0.67) compared with people on a waiting list. The mean differences between people who had undergone iCBT compared with usual care at 3, 5, and 8 months were -4.3, -3.9, and -5.9, respectively. The negative mean difference at each follow-up showed an improvement in symptoms of depression for participants randomized to the iCBT group compared with usual care. People who had undergone guided iCBT showed no statistically significant improvement in symptoms of panic disorder compared with individual or group face-to-face CBT (d = 0.00, 95% CI -0.41 to 0.41, GRADE very low). Similarly, there was no statistically significant difference in symptoms of specific phobia in people who had undergone guided iCBT compared with brief therapist-led exposure (GRADE very low). There was a small statistically significant improvement in symptoms in favour of guided iCBT compared with group face-to-face CBT (d= 0.41, 95% CI 0.03-0.78, GRADE low) for social phobia. There was no statistically significant improvement in quality of life reported for people with panic disorder who had undergone iCBT compared with face-to-face CBT (SMD = -0.07, 95% CI -0.34 to 0.21).Guided iCBT was the optimal strategy in the reference case cost-utility analyses. For adults with mild to moderate major depression, guided iCBT was associated with increases in both quality-adjusted survival (0.04 quality-adjusted life-years [QALYs]) and cost ($1,257), yielding an ICER of $31,575 per QALY gained when compared with usual care. In adults with anxiety disorders, guided iCBT was also associated with increases in both quality-adjusted survival (0.03 QALYs) and cost ($1,395), yielding an ICER of $43,214 per QALY gained when compared with unguided iCBT. In this population, guided iCBT was associated with an ICER of $26,719 per QALY gained when compared with usual care. The probability of cost-effectiveness of guided iCBT for major depression and anxiety disorders, respectively, was 67% and 70% at willingness-to-pay of $100,000 per QALY gained. Guided iCBT delivered within stepped-care models appears to represent good value for money for the treatment of mild to moderate major depression and anxiety disorders.Assuming a 3% increase in access per year (from about 8,000 people in year 1 to about 32,000 people in year 5), the net budget impact of publicly funding guided iCBT for the treatment of mild to moderate major depression would range from about $10 million in year 1 to about $40 million in year 5. The corresponding net budget impact for the treatment of anxiety disorders would range from about $16 million in year 1 (about 13,000 people) to about $65 million in year 5 (about 52,000 people).People with depression or an anxiety disorder with whom we spoke reported that iCBT improves access for those who face challenges with face-to-face therapy because of costs, time, or the severity of their condition. They reported that iCBT provides better control over the pace, time, and location of therapy, as well as greater access to educational material. Some reported barriers to iCBT include the cost of therapy; the need for a computer and internet access, computer literacy, and the ability to understand complex written information. Language and disability barriers also exist. Reported limitations to iCBT include the ridigity of the program, the lack of face-to-face interactions with a therapist, technological difficulties, and the inability of an internet protocol to treat severe depression and some types of anxiety disorder. Compared with waiting list, guided iCBT is effective and likely results in symptom improvement in mild to moderate major depression and social phobia. Guided iCBT may improve the symptoms of generalized anxiety disorder and panic disorder compared with waiting list. However, we are uncertain about the effectiveness of iCBT compared with individual or group face-to-face CBT. Guided iCBT represents good value for money and could be offered for the short-term treatment of adults with mild to moderate major depression or anxiety disorders. Most people with mild to moderate depression or anxiety disorders with whom we spoke felt that, despite some perceived limitations, iCBT provides greater control over the time, pace, and location of therapy. It also improves access for people who could not otherwise access therapy because of cost, time, or the nature of their health condition.

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As this paper goes to press a complete review of the chemistry of the fertile egg will be appearing (19). The author, Mr. J. Needham, was kind enough to allow me to inspect his manuscript and thus avail myself of the comprehensive bibliography and discussion. It is surprising that no biochemists have estimated the changing water content of the egg during incubation. Many of the analyses reported in Needham's review were expressed in per cent of total weight or per cent of dry solid, and consequently are of questionable value, since these latter functions are themselves changing; the former due to water evaporation and the latter through the addition of shell constituents and the burning of oxidizable organic compounds. Moreover, there has been no statistical treatment of the results, and the reliability of the average, figures obtained has consequently been difficult to estimate. Tangl's work, quoted throughout this paper, except for its lack of statistical treatment is more enlightening. However, his concept of the so called "Energy of Embryogenesis" which he propounds, seems to me misleading and unwarranted. What Tangl measured was the amount and the caloric value of the solid material burned and thus the quantity of energy lost during the embryonic period. The latter is equivalent to the usual measurements of catabolism. In the case of the embryo it is not basal metabolism which is being estimated, since the conditions are not basal. The embryo is absorbing and assimilating nutriment all the while at a relatively rapid rate. The calorific value of the oxidized solid, which is in truth the amount of energy lost during a certain chosen interval, in Tangl's judgment stands for the energy of embryogenesis; i.e., the energy of development (growth + differentiation). We believe that this conception is erroneous. The two processes, anabolism and catabolism, occur together and undoubtedly have some relationship, but surely one is not a measure of the other. In a starving animal, and so probably in a starving embryo, there is a considerable amount of so called basal metabolism. Thus if the "Embryogenetic Energy" were measured under these conditions a figure would be obtained for which there was no growth to correspond, or in other words there would be a value for something which did not exist. It will be seen in our later communications that the changes with age of metabolic rate and growth rate do not coincide. The amount of catabolism under certain circumstances does not accelerate growth or anabolism, but seems rather to be a limiting factor. It is as if when the absorbed energy were constant an increase of catabolism would make inroads upon the amount of energy which otherwise would remain for storage (growth). If, as Pembrey's (20) experiments would tend to show, there is an increase of metabolism in the oldest embryos when the outside temperature is lowered, one would find at the end of incubation in such cases that there was a greater amount of so called "Energy of Development" but smaller embryo. It seems that the potential energy amassed as growth comes from that remaining after the needs of the body have been satisfied. The results of the experiments described in this paper have formed the basis for judgment in the selection of suitable standard conditions for the incubation of hen's eggs. Standardization was necessary so that in future experiments the more important environmental factors might be kept uniform within a certain appropriate range and therefore not be held accountable for deviations observed in the embryos. Henceforth in this series of papers the term "standard incubation conditions" will signify that (1) the temperature was constantly at 38.8 +/- 0.4 degrees C., (2) the humidity at 67.5 +/- 2.5 per cent, (3) there was a continuous flow of warm air into the incubator to provide the necessary circulation, and (4) the eggs were rolled once a day within the constant temperature room. The incubator, a double-walled copper cabinet, stands in a constant temperature room, the fluctuations of which are +/- 1.0 degrees C. The space between the walls of the incubator is filled with water which serves as a buffer to outer variations. It might be repeated that all the eggs are from White Leghorn hens, are incubated 2 days after laying, and that they are kept cold during the interval necessary for transportation. With the figures from our chemical analyses and metabolic rate experiments, it was possible to calculate values for the concentration of total solids, fat, and nitrogen throughout the incubation period. These data were necessary as a general chemical background for further work. The results of the calculations are obviously rough. Because of the great variability of the eggs a satisfactory degree of accuracy could not have been attained without a very large number of analyses supplemented by complete statistical treatment. The necessity for such a comprehensive study was not evident, and it is our belief that the approximations reached in this paper are sufficiently close to serve our present purposes. The chief facts that have been ascertained in this investigation are (1) Loss of water by the egg during incubation is a function of the atmospheric humidity in its immediate environment. More rapid circulation of air lowers the humidity around the egg and thus increases evaporation. Other facts influencing evaporation are (a) atmospheric temperature, (b) thickness and surface area of the shell, and (c) conditions within the egg, the most important of which, it is suggested, is the amount of heat produced by the embryo. The latter factor, in turn, depends upon its size and age, and a significant change does not become apparent until the last 3 or 4 days of incubation, that is to say, when the embryo is of sufficient mass to exert a measurable force. (2) The surface area of the eggs in sq. cm. may be approximately represented by the formula S = K W(2/3), where K = 5.07 +/- 0.10, and W = the weight of the whole egg in gm. (3) There is a loss of weight by the shell during incubation. This is most noticeable near the end of the cycle, when the loss seems to parallel in general the weight of the embryo. (4) There is also a loss of solid matter during incubation. Chemical analyses indicate that about 98 per cent of the material oxidized is fat. This conclusion is corroborative of previous work by Hasselbalch, Hasselbalch and Bohr, and Tangl. (5) Carbon dioxide may be measured with relative accuracy. When it is assumed that it is derived from the oxidation of fat, satisfactory corroboration of the chemical analyses is obtained. These experiments have furnished the data from which the values have been calculated for total solids, fats, and protein in the whole egg throughout incubation. The figures may be used later for comparison with the concentration of these substances within the embryo.

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University of Manitoba and Queens Joanna Briggs Collaboration for Patient Safety: a Collaborating Center of the Joanna Briggs Institute The overall objective of this systematic review is to synthesize the available evidence on the relationship between new knowledge (gained through educational interventions about substance use/abuse) and health care providers' attitudes (measured by well validated instruments such as the Drug and Drug Problems Perceptions Questionnaire [DDPPQ], the Short Alcohol and Alcohol Problems Perception Questionnaire [SAAPPQ], etc.) towards patients with substance-related presentations to emergency departments.The specific review question is: Among emergency department staff, does the acquisition of knowledge (on educational interventions about substance use) impact attitudes in relation to their therapeutic role towards patients with substance-related presentations? Substance-related emergency department (ED) visits are common worldwide. Estimates of cases with alcohol involvement presenting to the ED range from 6% to 45%. Research conducted in the UK and Australia suggests that presentations related to illicit drug use are common and have increased in recent years.In 2012, an estimated six million Canadians met the criteria for substance use disorder; alcohol was the most common substance of abuse followed by cannabis and other drugs. The relationship between substance use and physical injury is well documented. The risk of mortality is increased by the side effects of substances on users involved in accidents and trauma. Not surprisingly, substance-related ED visits have been on the rise. Although only 3 to 10% of overall visits are typically related to a primary entrance complaint of drug or alcohol use or abuse, studies estimate that up to 35% of ED visits may be directly or indirectly substance related. These reasons may range from injury resulting from accidents or violence to substance-related illnesses.Health care providers (i.e., typically medical and nursing staff) have often perceived substance using patients as a challenging group to manage and as adding to the workload of already busy staff. The challenges of providing care to this patient population may be attributed to: (1) the chaotic ED environment, (2) health care providers' lack of knowledge, experience or skill in identifying and addressing substance misuse, (3) health care providers' lack of support structures such as sufficient time, staff and resources in working with this population, (4) health care providers' negative attitudes towards this patient population, (5) unpleasant tasks (i.e. intoxicated patients who urinate on themselves) associated with care delivery to this patient population, (6) patients' aggressive or violent behavior, and (7) patients' lack of motivation to change.Health care providers' attitudes towards patients with substance use problems have been found to affect health care delivery. This is of concern given the research findings that suggest they generally hold negative attitudes towards this patient population. For instance, in their study of nurses' attitudes towards patients who use illicit drugs, Ford, Bammer and Becker found that only 15% of nurses gained satisfaction from caring for these patients and only 30% were motivated to care for this patient group. Researchers who have examined substance using patients' experiences accessing health care also point to the suboptimal attitudes of health care providers towards this patient population. In the Neale, Tompkins and Sheard study of the barriers encountered by injecting drug users when accessing health and social care services, injecting drug users reported that they were often treated poorly or differently from other patients (i.e. sent home prematurely, not given appropriate aftercare or discharge), and made them feel not worthy of receiving help. Although the evidence relating to health care providers' attitudes toward substance using patients comes primarily from studies conducted in mental health or primary care settings, researchers who have examined ED staff attitudes towards this patient population paint a similar picture. For instance, Camilli &amp; Martin's review of ED nurses' attitudes toward intoxicated and psychiatric patients suggests that nurses are often frustrated when it comes to these patients as they are time consuming and offer repeat business to the ED. An ethnographic study of care delivery in an ED also points to the negative attitudes of ED staff towards this patient group. Henderson, Stacey and Dohan found that ED providers had interactions with substance using patients that may be considered excluding, rejecting or de-valuing, that is, in observations and interviews, providers often spoke of this patient population as abusing the system, overusing system resources, and not caring about their own health care. Other negative attitudes of ED staff towards substance using patients found in the literature pertain to: (1) being reluctant to ask patients about substance use, (2) believing little can be done in EDs to help these patients, (2) feeling angry or professionally dissatisfied when treating this patient group, (4) lacking a sense of responsibility for referring to specialist treatment, and (5) believing patients lack motivation to change following interaction with medical staff.Although there is considerable evidence that indicates health care providers hold negative attitudes towards substance using patients, there are also some studies that have found positive attitudes towards this patient population. For instance, in their study of physician attitudes toward injecting drug users, Ding et al. found that seeing more injecting drug users was associated with more positive attitudes towards this patient population. Similarly, Kelleher &amp; Cotter's descriptive study of ED doctors' and nurses' knowledge and attitudes concerning substance use found that the ED doctors and nurses who participated in the study had positive attitudes with regards to working with substance using patients. In the majority of these studies, however, positive attitudes were reported when health care providers were professionals working in addiction services, had more experience caring for this patient population, or had more personal contact with substance using patients. But does knowledge about substance use impact attitudes towards patients with substance-related presentations?Providing education or experience-based exercises may impact positively on attitudes towards substance using patients. Brief educational interventions, typically, informational sessions, either didactic or online, about alcohol and other drugs and how to assess and work with individuals using them, have been shown to have a positive impact on students' attitudes, knowledge and confidence relating to substance use and substance users. Whether ED staff attitudes towards patients with substance-related presentations are similarly impacted by the knowledge acquired through educational interventions remains unknown. A full systematic review of the literature will answer this question. A systematic review that examines the impact of knowledge on attitudes of ED staff will inform the design of educational strategies with emergency department staff to improve attitudes towards this patient population.To confirm that no other systematic review has been published on this topic, a preliminary literature search was conducted. The following databases were searched and no current or planned review was found related to this topic: JBI Database of Systematic Reviews and Implementation Reports, Cochrane Database of Systematic Reviews, PROSPERO, CINAHL, PubMed, and Scopus. Grey literature was also searched; however, no systematic review addressing the impact of knowledge on attitudes of ED staff towards patients with substance-related presentations was located.

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On a global scale, pathogenic contamination of drinking water poses the most significant health risk to humans, and there have been countless numbers of disease outbreaks and poisonings throughout history resulting from exposure to untreated or poorly treated drinking water. However, significant risks to human health may also result from exposure to nonpathogenic, toxic contaminants that are often globally ubiquitous in waters from which drinking water is derived. With this latter point in mind, the objective of this commission paper is to discuss the primary sources of toxic contaminants in surface waters and groundwater, the pathways through which they move in aquatic environments, factors that affect their concentration and structure along the many transport flow paths, and the relative risks that these contaminants pose to human and environmental health. In assessing the relative risk of toxic contaminants in drinking water to humans, we have organized our discussion to follow the classical risk assessment paradigm, with emphasis placed on risk characterization. In doing so, we have focused predominantly on toxic contaminants that have had a demonstrated or potential effect on human health via exposure through drinking water. In the risk assessment process, understanding the sources and pathways for contaminants in the environment is a crucial step in addressing (and reducing) uncertainty associated with estimating the likelihood of exposure to contaminants in drinking water. More importantly, understanding the sources and pathways of contaminants strengthens our ability to quantify effects through accurate measurement and testing, or to predict the likelihood of effects based on empirical models. Understanding the sources, fate, and concentrations of chemicals in water, in conjunction with assessment of effects, not only forms the basis of risk characterization, but also provides critical information required to render decisions regarding regulatory initiatives, remediation, monitoring, and management. Our discussion is divided into two primary themes. First we discuss the major sources of contaminants from anthropogenic activities to aquatic surface and groundwater and the pathways along which these contaminants move to become incorporated into drinking water supplies. Second, we assess the health significance of the contaminants reported and identify uncertainties associated with exposures and potential effects. Loading of contaminants to surface waters, groundwater, sediments, and drinking water occurs via two primary routes: (1) point-source pollution and (2) non-point-source pollution. Point-source pollution originates from discrete sources whose inputs into aquatic systems can often be defined in a spatially explicit manner. Examples of point-source pollution include industrial effluents (pulp and paper mills, steel plants, food processing plants), municipal sewage treatment plants and combined sewage-storm-water overflows, resource extraction (mining), and land disposal sites (landfill sites, industrial impoundments). Non-point-source pollution, in contrast, originates from poorly defined, diffuse sources that typically occur over broad geographical scales. Examples of non-point-source pollution include agricultural runoff (pesticides, pathogens, and fertilizers), storm-water and urban runoff, and atmospheric deposition (wet and dry deposition of persistent organic pollutants such as polychlorinated biphenyls [PCBs] and mercury). Within each source, we identify the most important contaminants that have either been demonstrated to pose significant risks to human health and/or aquatic ecosystem integrity, or which are suspected of posing such risks. Examples include nutrients, metals, pesticides, persistent organic pollutants (POPs), chlorination by-products, and pharmaceuticals. Due to the significant number of toxic contaminants in the environment, we have necessarily restricted our discussion to those chemicals that pose risks to human health via exposure through drinking water. A comprehensive and judicious consideration of the full range of contaminants that occur in surface waters, sediments, and drinking water would be a large undertaking and clearly beyond the scope of this article. However, where available, we have provided references to relevant literature to assist the reader in undertaking a detailed investigation of their own. The information collected on specific chemicals within major contaminant classes was used to determine their relative risk using the hazard quotient (HQ) approach. Hazard quotients are the most widely used method of assessing risk in which the exposure concentration of a stressor, either measured or estimated, is compared to an effect concentration (e.g., no-observed-effect concentration or NOEC). A key goal of this assessment was to develop a perspective on the relative risks associated with toxic contaminants that occur in drinking water. Data used in this assessment were collected from literature sources and from the Drinking Water Surveillance Program (DWSP) of Ontario. For many common contaminants, there was insufficient environmental exposure (concentration) information in Ontario drinking water and groundwater. Hence, our assessment was limited to specific compounds within major contaminant classes including metals, disinfection by-products, pesticides, and nitrates. For each contaminant, the HQ was estimated by expressing the maximum concentration recorded in drinking water as a function of the water quality guideline for that compound. There are limitations to using the hazard quotient approach of risk characterization. For example, HQs frequently make use of worst-case data and are thus designed to be protective of almost all possible situations that may occur. However, reduction of the probability of a type II error (false negative) through the use of very conservative application factors and assumptions can lead to the implementation of expensive measures of mitigation for stressors that may pose little threat to humans or the environment. It is important to realize that our goal was not to conduct a comprehensive, in-depth assessment of risk for each chemical; more comprehensive assessments of managing risks associated with drinking water are addressed in a separate issue paper by Krewski et al. (2001a). Rather, our goal was to provide the reader with an indication of the relative risk of major contaminant classes as a basis for understanding the risks associated with the myriad forms of toxic pollutants in aquatic systems and drinking water. For most compounds, the estimated HQs were &lt; 1. This indicates that there is little risk associated with exposure from drinking water to the compounds tested. There were some exceptions. For example, nitrates were found to commonly yield HQ values well above 1 in- many rural areas. Further, lead, total trihalomethanes, and trichloroacetic acid yielded HQs &gt; 1 in some treated distribution waters (water distributed to households). These latter compounds were further assessed using a probabilistic approach; these assessments indicated that the maximum allowable concentrations (MAC) or interim MACs for the respective compounds were exceeded &lt;5% of the time. In other words, the probability of finding these compounds in drinking water at levels that pose risk to humans through ingestion of drinking water is low. Our review has been carried out in accordance with the conventional principles of risk assessment. Application of the risk assessment paradigm requires rigorous data on both exposure and toxicity in order to adequately characterize potential risks of contaminants to human health and ecological integrity. Weakness rendered by poor data, or lack of data, in either the exposure or effects stages of the risk assessment process significantly reduces the confidence that can be placed in the overall risk assessment. (ABSTRACT TRUNCATED)

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Evolutionary idea is the core of the modern biology. Due to this, phylogenetics dealing with historical reconstructions in biology takes a priority position among biological disciplines. The second half of the 20th century witnessed growth of a great interest to phylogenetic reconstructions at macrotaxonomic level which replaced microevolutionary studies dominating during the 30s-60s. This meant shift from population thinking to phylogenetic one but it was not revival of the classical phylogenetics; rather, a new approach emerged that was baptized The New Phylogenetics. It arose as a result of merging of three disciplines which were developing independently during 60s-70s, namely cladistics, numerical phyletics, and molecular phylogenetics (now basically genophyletics). Thus, the new phylogenetics could be defined as a branch of evolutionary biology aimed at elaboration of "parsimonious" cladistic hypotheses by means of numerical methods on the basis of mostly molecular data. Classical phylogenetics, as a historical predecessor of the new one, emerged on the basis of the naturphilosophical worldview which included a superorganismal idea of biota. Accordingly to that view, historical development (the phylogeny) was thought an analogy of individual one (the ontogeny) so its most basical features were progressive parallel developments of "parts" (taxa), supplemented with Darwinian concept of monophyly. Two predominating traditions were diverged within classical phylogenetics according to a particular interpretation of relation between these concepts. One of them (Cope, Severtzow) belittled monophyly and paid most attention to progressive parallel developments of morphological traits. Such an attitude turned this kind of phylogenetics to be rather the semogenetics dealing primarily with evolution of structures and not of taxa. Another tradition (Haeckel) considered both monophyletic and parallel origins of taxa jointly: in the middle of 20th century it was split into phylistics (Rasnitsyn's term; close to Simpsonian evolutionary taxonomy) belonging rather to the classical realm, and Hennigian cladistics that pays attention to origin of monophyletic taxa exclusively. In early of the 20th century, microevolutionary doctrine became predominating in evolutionary studies. Its core is the population thinking accompanied by the phenetic one based on equation of kinship to overall similarity. They were connected to positivist philosophy and hence were characterized by reductionism at both ontological and epistemological levels. It led to fall of classical phylogenetics but created the prerequisites for the new phylogenetics which also appeared to be full of reductionism. The new rise of phylogenetic (rather than tree) thinking during the last third of the 20th century was caused by lost of explanatory power of population one and by development of the new worldview and new epistemological premises. That new worldview is based on the synergetic (Prigoginian) model of development of non-equilibrium systems: evolution of the biota, a part of which is phylogeny, is considered as such a development. At epistemological level, the principal premise appeared to be fall of positivism which was replaced by post-positivism argumentation schemes. Input of cladistics into new phylogenetics is twofold. On the one hand, it reduced phylogeny to cladistic history lacking any adaptivist interpretation and presuming minimal evolution model. From this it followed reduction of kinship relation to sister-group relation lacking any reference to real time scale and to ancestor-descendant relation. On the other hand, cladistics elaborated methodology of phylogenetic reconstructions based on the synapomorphy principle, the outgroup concept became its part. The both inputs served as premises of incorporation of both numerical techniques and molecular data into phylogenetic reconstruction. Numerical phyletics provided the new phylogenetics with easily manipulated algorithms of cladogram construing and thus made phylogenetic reconstructions operational and repetitive. The above phenetic formula "kinship = similarity" appeared to be a keystone for development of the genophyletics. Within numerical phyletics, a lot of computer programs were elaborated which allow to manipulate with evolutionary scenario during phylogenetic reconstructions. They make it possible to reconstruct both clado- and semogeneses based on the same formalized methods. Multiplicity of numerical approaches indicates that, just as in the case of numerical phenetics, choice of adequate method(s) should be based on biologically sound theory. The main input of genophyletics (= molecular phylogenetics) into the new phylogenetics was due to completely new factology which makes it possible to compare directly such far distant taxa as prokaryotes and higher eukaryotes. Genophyletics is based on the theory of neutral evolution borrowed from microevolutionary theory and on the molecular clock hypothesis which is now considered largely inadequate. The future developments of genophyletics will be aimed at clarification of such fundamental (and "classical" by origin) problems as application of character and homology concepts to molecular structures. The new phylogenetics itself is differentiated into several schools caused basically by diversity of various approaches existing within each of its "roots". Cladistics makes new phylogenetics splitted into evolutionary and parsimonious ontological viewpoints. Numerical phyletics divides it into statistical and (again) parsimonious methodologies. Molecular phylogenetics is opposite by its factological basis to morphological one. The new phylogenetics has significance impact onto the "newest" systematics. From one side, it gives ontological status back to macrotaxa they have lost due to "new" systematics based on population thinking. From another side, it rejects some basical principles of classical phylogenetic (originally Linnean) taxonomy such as recognitions of fixed taxonomic ranks designated by respective terms and definition of taxic names not by the diagnostic characters but by reference to the ancestor. The latter makes the PhyloCode overburdened ideologically and the "newest" systematics self-controversial, as concept of ancestor has been acknowledged non-operational from the very beginning of cladistics. Relation between classical and new phylogenetics is twofold. At the one hand, general phylogenetic hypothesis (in its classical sense) can be treated as a combination of cladogenetic and semogenetic reconstructions. Such a consideration is bound to pay close attention to the uncertainty relation principle which, in case of the phylogenetics, means that the general phylogenetic hypothesis cannot be more certain than any of initial cladogenetic or semogenetic hypotheses. From this standpoint, the new phylogenetics makes it possible to reconstruct phylogeny following epistemological principle "from simple to complex". It elaborates a kind of null hypotheses about evolutionary history which are more easy to test as compared to classical hypotheses. Afterward, such hypotheses are possible to be completed toward the classical, more content-wise ones by adding anagenetic information to the cladogenetic one. At another hand, reconstructions elaborated within the new phylogenetics could be considered as specific null hypotheses about both clado- and semogeneses. They are to be tested subsequently by mean of various models, including those borrowed from "classical" morphology. The future development of the new phylogenetics is supposed to be connected with getting out of plethora of reductionism inherited by it from population thinking and specification of object domain of the phylogenetics. As the latter is a part of an evolutionary theory, its future developments will be adjusted with the latter. Lately predominating neodarwinism is now being replaced by the epigenetic evolutionary theory to which phylistics (one of the modern versions of classical phylogenetics) seems to be more correspondent.

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To study the expression levels of annexin A1 (ANXA1), GATA-3, and T-bet in T lymphocytes of peripheral blood in burned mice with sepsis at early stage, and to analyze their immune regulatory mechanisms. Seven-hundred and eighty male mice of clean grade were divided into sham injury group (n=60, sham injured on the back by immersing in 37 ℃ warm water for 10 s), burn group (n=240, inflicted with 20% TBSA deep partial- thickness burn on the back by immersing in 100 ℃ hot water for 10 s), sepsis group (n=240, intraperitoneally injected with 6 mg/kg lipopolysaccharide), and burn+ sepsis group (n=240) according to the random number table. Mice of burn+ sepsis group were treated as that in burn group at first, and then they were treated as that in sepsis group. (1) Immediately after injury, six mice in sham injury group were selected to collect lymphocyte suspension of peripheral blood (1 tube each mouse) according to the random number table. According to the random number table, 6 mice of each of the other three groups were respectively selected at post injury hour (PIH) 12, 24, 48, and 72 for the collection of lymphocyte suspension from peripheral blood (1 tube each mouse). Each tube of cell suspension was equally divided into two parts. Fluorescein isothiocyanate (FITC)-labeled human anti-mouse CD4 monoclonal antibody and phycoerythrin (PE)-labeled human anti-mouse interferon-γ monoclonal antibody were added to one part of cell suspension to mark helper T lymphocyte 1 (Th1). FITC-labeled human anti-mouse CD4 monoclonal antibody and PE-labeled human anti-mouse interleukin-4 (IL-4) monoclonal antibody were added to the other part of cell suspension to mark Th2. The percentages of Th1 and Th2 were determined with flow cytometer, and the ratio of Th1 to Th2 was calculated. (2) According to the random number table, 18 mice in sham injury group were selected immediately after injury for the collection of lymphocyte suspension of peripheral blood (1 tube each mouse), and 18 mice of each of the other 3 groups were respectively selected at PIH 12, 24, 48, and 72 to collect the lymphocyte suspension of peripheral blood (1 tube each mouse). The mRNA expression levels of ANXA1, GATA-3, and T-bet were determined by real-time fluorescent quantitative reverse transcription-PCR. (3) Immediately after injury, 36 mice in sham injury group were selected to collect lymphocyte suspension of peripheral blood (1 tube each mouse) according to the random number table, and then 36 tubes of cell suspension were divided into 6 batches (6 tubes each batch). Each one of 6 kinds of antibody combinations: antibodies for labeling Th1 and Th2 in combination with PE-anthocyanin 7 labeled human anti-mouse ANXA1 monoclonal antibody, PE-anthocyanin 7 labeled human anti-mouse GATA-3 monoclonal antibody, and PE-anthocyanin 7 labeled human anti-mouse T-bet monoclonal antibody was added to 1 tube of cell suspension at each batch. According to the random number table, 36 mice of each of the other 3 groups were respectively selected at PIH 12, 24, 48, and 72 for the collection of lymphocyte suspension of peripheral blood (1 tube each mouse), and then 36 tubes of cell suspension at each time point were divided into 6 batches for marking with 3 kinds of surface markers of Th1 and Th2 (6 tubes each batch). Each one of above-mentioned 6 kinds of antibodies was added to 1 tube of cell suspension at each time point for each batch. The percentages of ANXA1, GATA-3, and T-bet positive cells in Th1 and Th2 were determined with flow cytometer. Data were processed with one-way analysis of variance, analysis of variance of factorial design, and SNK test. The relationship between the percentages of ANXA1 positive cell and the percentages of GATA-3 positive cell in Th1 and Th2, and mRNA expression level of ANXA1 and mRNA expression level of GATA-3 in lymphocytes were assessed by linear correlation analysis. (1) Compared with those in sham injury group immediately after injury, the percentages of Th1 and Th2 and the ratio of Th1 to Th2 of mice in burn group were significantly decreased from PIH 24 on, with P values below 0.05; the percentages of Th1 and Th2 and the ratios of Th1 to Th2 of mice in sepsis group and burn+ sepsis group were significantly decreased from PIH 12 on, with P values below 0.05. (2) Compared with those in sham injury group immediately after injury, the mRNA expression levels of ANXA1 and GATA-3 in lymphocyte of mice in burn group were significantly decreased from PIH 24 on, with P values below 0.05; the mRNA expression level of T-bet was significantly decreased at PIH 24 but significantly increased at PIH 48 and 72, with P values below 0.05. Compared with those in sham injury group immediately after injury, the mRNA expression levels of ANXA1 and GATA-3 in lymphocytes of mice in sepsis group were significantly decreased from PIH 12 on, and the mRNA expression level of T-bet was increased significantly from PIH 12 on, with P values below 0.05; the mRNA expression levels of ANXA1, GATA-3, and T-bet in lymphocytes of mice in burn+ sepsis group were significantly decreased from PIH 12 on, with P values below 0.05, reaching the nadir at PIH 72 (0.50±0.04, 0.45±0.03, 0.21±0.05, respectively). (3) A significant positive correlation was observed between ANXA1 mRNA expression level and GATA-3 mRNA expression level in lymphocytes of peripheral blood (r=0.862, P&lt;0.05). (4) Compared with those in sham injury group immediately after injury, the percentages of ANXA1 and GATA-3 positive cellsin Th1 and Th2 of mice in burn group were significantly lowered from PIH 24 on, and the percentage of T-bet positive cells was significantly decreased at PIH 24, but it was increased from PIH 48 on, with P values below 0.05. The percentages of ANXA1 and GATA-3 positive cells in Th1 and Th2 of mice in sepsis group were continuously decreased from PIH 12 on, which were lower at most time points than those in sham injury group immediately after injury, with P values below 0.05. The percentages of T-bet positive cells in Th1 and Th2 of mice in sepsis group were significantly increased since PIH 12 as compared with those in sham injury group immediately after injury, with P values below 0.05. The percentages of ANXA1, GATA-3, and T-bet positive cells in Th1 and Th2 of mice in burn+ sepsis group were continuously lowered from PIH 12, with significantly statistical differences at most time points as compared with those in sham injury group immediately after injury, with P values below 0.05. (5) The percentages of GATA-3 positive cells in Th1 and Th2 were significantly positively correlated with those of ANXA1 (with r values respectively 0.747 and 0.787, P values below 0.05). The expression levels of ANXA1, GATA-3, and T-bet were continuously lowered in burned mice with sepsis, and it may play an important role in Th1/Th2 balance switching to Th2 bias and immunosuppressive process.

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<bObjective:</b To explore the effects of hypoxia inducible factor-1α (HIF-1α) on P311 and its influence on the migration of murine epidermal stem cells (ESCs) under hypoxia in vitro. <bMethods:</b Two kinds of murine ESCs were isolated and obtained from 15 neonatal wild-type C57BL/6J mice and 5 congeneric source P311 gene knock-out mice, respectively. The first passage of cells were used in the following experiments after morphologic observation and detection of expression of cell surface markers CD71 and CD49f with flow cytometer. (1) After cell scratch assay, according to the random number table (the same dividing method below), ESCs of P311 gene knock-out mice were divided into normoxia group (cells were cultured with complete medium in normoxic carbon dioxide incubator, and the subsequent normoxic treatments were the same) and hypoxia group (cells were cultured in hypoxic carbon dioxide incubator containing 1% oxygen, and the subsequent hypoxic treatments were the same), with 12 inserts in each group. ESCs of wild-type mice were divided into normoxia group, pure hypoxia group, dimethyl sulfoxide (DMSO) control group (2 μL DMSO solvent was added for 1 h of normoxia treatment before hypoxia treatment), HIF-1α inhibitor group (cells were treated with 11 μmol/L HIF-1 inhibitor of 2 μL under normoxia condition for 1 h before hypoxia treatment), HIF-1α stabilizer group (the cells were treated with 2 μmol/L FG-4592 of 2 μL under normoxia condition for 1 h before hypoxia treatment), with 12 inserts in each group. Three inserts of each time point in each group were adopted respectively to measure the residual width of scratch under inverted phase contrast microscope at post scratch hour (PSH) 0 (immediately), 12, 24, and 48. (2) After hypoxia treatment, the protein level of HIF-1α in ESCs of wild-type mice was detected by Western blotting at post hypoxia hour (PHH) 0, 12, 24, and 48. (3) ESCs of wild-type mice were divided into pure hypoxia group, DMSO control group, HIF-1α inhibitor group, and HIF-1α stabilizer group as that of experiment (1) with the same treatment. The mRNA expression of P311 and expression of P311 in ESCs were determined by real-time fluorescent quantitative reverse transcription polymerase chain reaction and immunocytochemical staining, respectively, at PHH 0 (immediately), 12, 24, and 48 (with sample numbers of 12). (4) The second passage of human embryonic kidney 293 (HEK-293) cells were divided into empty vector hypoxia group (cells were cultured under hypoxia condition after being transfected with empty vector plasmid), P311 normoxia group (cells were cultured under normoxia condition after being transfected with P311 reporter gene plasmid), P311 hypoxia group (cells were cultured under hypoxia condition after being transfected with P311 reporter gene plasmid), P311 hypoxia+ HIF-1α inhibitor group (cells which were incubated with HIF-1α inhibitor were cultured under hypoxia condition after being transfected with P311 reporter gene plasmid). The luciferase activity was detected at post culture hour (PCH) 0 and 12, respectively, and then the P311 transcriptional regulatory binding site of HIF-1α and the promoter sequence of P311 were predicted and searched by bioinformatics methods. Data were processed with factorial design variance analysis, one-way analysis of variance, LSD test and Bonferroni correction. <bResults:</b (1) The results of ESCs. The cells showed cobblestone-like pattern and different clonal morphology due to the different cell proliferation potential. The proportion of CD71(-)CD49f(+) cells accounted for about 85%. The identification results indicated that the cells showed strong stem cell properties and high purity. Compared with those in cells of normoxia group of P311 gene knock-out mice, the residual widths of scratch of cells in pure hypoxia group were smaller at PSH 12 and 24 (with <iP</i values below 0.05), and those in hypoxia group, normoxia group of wild-type mice, DMSO control group, HIF-1α inhibitor group, and HIF-1α stabilizer group were smaller at PSH 12 (with <iP</i values below 0.05). Compared with those in cells of normoxia group of wild-type mice, the residual widths of scratch of cells in hypoxia group, pure hypoxia group, and DMSO control group were smaller at PSH 12 and 24 (with <iP</i values below 0.05), and the residual width of scratch of cells in HIF-1α stabilizer group was smaller at PSH 12 (<iP</i&lt;0.05). Compared with those of cells in pure hypoxia group, the residual widths of scratch of cells in hypoxia group were wider at PSH 12 and 24 (with <iP</i values below 0.05), and the residual width of scratch of cells in HIF-1α inhibitor group was wider at PSH 12 (<iP</i&lt;0.05), and those of cells in HIF-1α stabilizer group were smaller at PSH 12 and 24 (with <iP</i values below 0.05). There was no obvious difference in the width of scratch in cells among the 7 groups (<iF</i=19.02, <iP</i&gt;0.05). The protein levels of HIF-1α in ESCs of wild-type mice at PHH 0, 12, 24, and 48 were respectively 1.02±0.05, 2.56±0.09, 1.60±0.17, and 1.17±0.03. Compared with that at PHH 0, the protein level of HIF-1α at PHH 12 was significantly enhanced (<iP</i&lt;0.01). It began to decline at PHH 24 but was still higher than that at PHH 0 (<iP</i&lt;0.05), and the protein level of HIF-1α at PHH 48 was close to the normoxia level (<iP</i&gt;0.05). Compared with those of cells in pure hypoxia group, the mRNA expressions of P311 of cells in HIF-1α inhibitor group were significantly decreased at each time point (with <iP</i values below 0.05), and those in HIF-1α stabilizer group were significantly increased at PHH 12 and 24 (with <iP</i values below 0.05). Compared with those of cells in HIF-1α inhibitor group, the mRNA expressions of P311 of cells in DMSO control group and HIF-1α stabilizer group were significantly increased at PHH 0, 12, and 24 (with <iP</i values below 0.05). Compared with those of cells in pure hypoxia group, the expressions of P311 of cells in HIF-1α inhibitor group were significantly decreased at each time point (with <iP</i values below 0.05), while those in HIF-1α stabilizer group were significantly increased at PHH 12 and 24 (with <iP</i values below 0.05). Compared with those of cells in HIF-1α inhibitor group, the expressions of P311 of cells in DMSO control group and HIF-1α stabilizer group were significantly increased at PHH 12 and 24 (with <iP</i values below 0.05). (2) The results of HEK-293 cells. At PCH 0, there was no significant difference in the luciferase activity among cells of empty vector hypoxia group, P311 normoxia group, P311 hypoxia group, and P311 hypoxia+ HIF-1α inhibitor group (<iF</i=13.33, <iP</i&gt;0.05). At PCH 12, the luciferase activity of cells in P311 hypoxia group was higher than that in empty vector hypoxia group (<iP</i&lt;0.01). The luciferase activity of cells in hypoxia group was higher than that in P311 normoxia group (<iP</i&lt;0.05), while that of cells in P311 hypoxia+ HIF-1α inhibitor group was lower than that in P311 hypoxia group (<iP</i&lt;0.01). <bConclusions:</b HIF-1α may increase the migration of murine ESCs through inducing the expression of P311 at the early stage of hypoxia.

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Melanoma has one of the fastest rising incidence rates of any cancer. It accounts for a small percentage of skin cancer cases but is responsible for the majority of skin cancer deaths. Although history-taking and visual inspection of a suspicious lesion by a clinician are usually the first in a series of 'tests' to diagnose skin cancer, dermoscopy has become an important tool to assist diagnosis by specialist clinicians and is increasingly used in primary care settings. Dermoscopy is a magnification technique using visible light that allows more detailed examination of the skin compared to examination by the naked eye alone. Establishing the additive value of dermoscopy over and above visual inspection alone across a range of observers and settings is critical to understanding its contribution for the diagnosis of melanoma and to future understanding of the potential role of the growing number of other high-resolution image analysis techniques. To determine the diagnostic accuracy of dermoscopy alone, or when added to visual inspection of a skin lesion, for the detection of cutaneous invasive melanoma and atypical intraepidermal melanocytic variants in adults. We separated studies according to whether the diagnosis was recorded face-to-face (in-person), or based on remote (image-based), assessment. We undertook a comprehensive search of the following databases from inception up to August 2016: CENTRAL; MEDLINE; Embase; CINAHL; CPCI; Zetoc; Science Citation Index; US National Institutes of Health Ongoing Trials Register; NIHR Clinical Research Network Portfolio Database; and the World Health Organization International Clinical Trials Registry Platform. We studied reference lists and published systematic review articles. Studies of any design that evaluated dermoscopy in adults with lesions suspicious for melanoma, compared with a reference standard of either histological confirmation or clinical follow-up. Data on the accuracy of visual inspection, to allow comparisons of tests, was included only if reported in the included studies of dermoscopy. Two review authors independently extracted all data using a standardised data extraction and quality assessment form (based on QUADAS-2). We contacted authors of included studies where information related to the target condition or diagnostic threshold were missing. We estimated accuracy using hierarchical summary receiver operating characteristic (SROC),methods. Analysis of studies allowing direct comparison between tests was undertaken. To facilitate interpretation of results, we computed values of sensitivity at the point on the SROC curve with 80% fixed specificity and values of specificity with 80% fixed sensitivity. We investigated the impact of in-person test interpretation; use of a purposely developed algorithm to assist diagnosis; observer expertise; and dermoscopy training. We included a total of 104 study publications reporting on 103 study cohorts with 42,788 lesions (including 5700 cases), providing 354 datasets for dermoscopy. The risk of bias was mainly low for the index test and reference standard domains and mainly high or unclear for participant selection and participant flow. Concerns regarding the applicability of study findings were largely scored as 'high' concern in three of four domains assessed. Selective participant recruitment, lack of reproducibility of diagnostic thresholds and lack of detail on observer expertise were particularly problematic.The accuracy of dermoscopy for the detection of invasive melanoma or atypical intraepidermal melanocytic variants was reported in 86 datasets; 26 for evaluations conducted in person (dermoscopy added to visual inspection), and 60 for image-based evaluations (diagnosis based on interpretation of dermoscopic images). Analyses of studies by prior testing revealed no obvious effect on accuracy; analyses were hampered by the lack of studies in primary care, lack of relevant information and the restricted inclusion of lesions selected for biopsy or excision. Accuracy was higher for in-person diagnosis compared to image-based evaluations (relative diagnostic odds ratio (RDOR) 4.6, 95% confidence interval (CI) 2.4 to 9.0; P &lt; 0.001).We compared accuracy for (a), in-person evaluations of dermoscopy (26 evaluations; 23,169 lesions and 1664 melanomas),versus visual inspection alone (13 evaluations; 6740 lesions and 459 melanomas), and for (b), image-based evaluations of dermoscopy (60 evaluations; 13,475 lesions and 2851 melanomas),versus image-based visual inspection (11 evaluations; 1740 lesions and 305 melanomas). For both comparisons, meta-analysis found dermoscopy to be more accurate than visual inspection alone, with RDORs of (a), 4.7 (95% CI 3.0 to 7.5; P &lt; 0.001), and (b), 5.6 (95% CI 3.7 to 8.5; P &lt; 0.001). For a), the predicted difference in sensitivity at a fixed specificity of 80% was 16% (95% CI 8% to 23%; 92% for dermoscopy + visual inspection versus 76% for visual inspection), and predicted difference in specificity at a fixed sensitivity of 80% was 20% (95% CI 7% to 33%; 95% for dermoscopy + visual inspection versus 75% for visual inspection). For b) the predicted differences in sensitivity was 34% (95% CI 24% to 46%; 81% for dermoscopy versus 47% for visual inspection), at a fixed specificity of 80%, and predicted difference in specificity was 40% (95% CI 27% to 57%; 82% for dermoscopy versus 42% for visual inspection), at a fixed sensitivity of 80%.Using the median prevalence of disease in each set of studies ((a), 12% for in-person and (b), 24% for image-based), for a hypothetical population of 1000 lesions, an increase in sensitivity of (a), 16% (in-person), and (b), 34% (image-based), from using dermoscopy at a fixed specificity of 80% equates to a reduction in the number of melanomas missed of (a), 19 and (b), 81 with (a), 176 and (b), 152 false positive results. An increase in specificity of (a), 20% (in-person), and (b), 40% (image-based), at a fixed sensitivity of 80% equates to a reduction in the number of unnecessary excisions from using dermoscopy of (a), 176 and (b), 304 with (a), 24 and (b), 48 melanomas missed.The use of a named or published algorithm to assist dermoscopy interpretation (as opposed to no reported algorithm or reported use of pattern analysis), had no significant impact on accuracy either for in-person (RDOR 1.4, 95% CI 0.34 to 5.6; P = 0.17), or image-based (RDOR 1.4, 95% CI 0.60 to 3.3; P = 0.22), evaluations. This result was supported by subgroup analysis according to algorithm used. We observed higher accuracy for observers reported as having high experience and for those classed as 'expert consultants' in comparison to those considered to have less experience in dermoscopy, particularly for image-based evaluations. Evidence for the effect of dermoscopy training on test accuracy was very limited but suggested associated improvements in sensitivity. Despite the observed limitations in the evidence base, dermoscopy is a valuable tool to support the visual inspection of a suspicious skin lesion for the detection of melanoma and atypical intraepidermal melanocytic variants, particularly in referred populations and in the hands of experienced users. Data to support its use in primary care are limited, however, it may assist in triaging suspicious lesions for urgent referral when employed by suitably trained clinicians. Formal algorithms may be of most use for dermoscopy training purposes and for less expert observers, however reliable data comparing approaches using dermoscopy in person are lacking.

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Hypertonic-hyperoncotic solutions are used for the improvement of micro- and macrocirculation in various types of shock. In pediatric intensive care medicine, controlled, randomized studies with hypertonic-hyperoncotic solutions are lacking. Hypertonic-hyperoncotic solutions may improve cardiac function in children. The primary objective of this controlled, randomized, blinded study was to evaluate the hemodynamic effects and safety of hypertonic-hyperoncotic solution infusions in children shortly after open-heart surgery for congenital cardiac disease. The secondary objective was to determine whether the administration of hypertonic-hyperoncotic solutions could be a potential and effective therapeutic option for preventing a probable capillary leakage syndrome that frequently occurs in children after open-heart surgery. The children were randomly assigned to 2 groups of 25. The hypertonic-hyperoncotic solution group received Poly-(O-2)-hydroxyethyl-starch 60.0 g, with molecular weight of 200 kDa, Na+ 1232 mmol/L and osmolality of 2464 mOsmol/L (7.2% sodium chloride with 6% hydroxyethyl-starch 200 kDa). The isotonic saline solution group received isotonic saline solution (0.9% sodium chloride). Atrial and ventricular septal defects were corrected using a homograft patch. Monitoring consisted of an arterial, a central venous, and a thermodilution catheter (PULSIOCATH). Cardiac index, extravascular lung water index, stroke volume index, mean arterial blood pressure, and systemic vascular resistance index were measured (Pulse Contour Cardiac Output technique). Immediately after surgery, patients were loaded either with hypertonic-hyperoncotic solution or with isotonic saline solution (4 mL/kg). Blood samples (sodium concentration, osmolality, thrombocyte count, fibrinogen, and arterial blood gases) were drawn directly before; immediately after; 15 minutes after; and, 1, 4, 12, and 24 hours after the end of volume loading. Hemodynamic parameters were registered at the same time. The total amount of dobutamine required was documented, as well as the 24- and 48-hour fluid balances. In the hypertonic-hyperoncotic solution group, cardiac index was 3.6 +/- 0.26 L/min per m2 before volume administration and increased to 5.96 +/- 0.27 after the administration of the study solution (64%). Fifteen and 60 minutes after administration, the cardiac index remained significantly elevated (5.55 +/- 0.29 L/min per m2 and 4.65 +/- 0.18 L/min per m2, respectively) and returned to preadministration values after 4 hours. In the isotonic saline solution group, the cardiac index did not change during the entire observation period (3.39 +/- 0.21 before and 3.65 +/- 0.23 L/min per m2 after isotonic saline solution). The systemic vascular resistance index decreased in the hypertonic-hyperoncotic solution group after administration from 1396 +/- 112 to 868 +/- 63 dyn/sec per cm(-5)/m2. The decrease of systemic vascular resistance index in the hypertonic-hyperoncotic solution group was transiently significant within 60 minutes after administration but stayed lower than before volume load (999 +/- 70 dyn/sec per cm-(5)/m2). In the isotonic saline solution group, we found no statistically relevant change in systemic vascular resistance index. Stroke volume index significantly increased after hypertonic-hyperoncotic solution infusion (53.9 +/- 3.0 mL/m2 directly after, 48.8 +/- 2.46 mL/m2 15 minutes after, and 41.4 +/- 2.2 mL/m2 60 minutes after) when compared with stroke volume index before administration (32.4 +/- 2.6 mL/m2). In the hypertonic-hyperoncotic solution group, an increase in mean arterial blood pressure remained transiently significant within 60 minutes after administration when compared with the isotonic saline solution group, in which the mean arterial blood pressure remained unchanged. Both central venous pressure and heart rate were unchanged during the whole time of observation in both groups. In the hypertonic-hyperoncotic solution group, extravascular lung water index decreased from 10.6 +/- 1.2 to 5.6 +/- 1.2 mL/kg and remained significantly decreased 15 minutes after (6.5 +/- 1.2 mL/kg) when compared with before volume administration. In the isotonic saline solution group, extravascular lung water index increased from 12.3 +/- 1.1 mL/kg to 18.1 +/- 1.7 mL/kg directly after administration and remained elevated for 60 minutes after volume loading (15.6 +/- 1.5 mL/kg). In all patients, no hypoxia (Pa(O2)&lt;60 mm Hg) or hypercapnia (Pa(CO2) &gt;60 mm Hg) was observed. Arterial blood gas analysis showed pH and base excess within physiologic range, and this did not change throughout the whole period of observation. After infusion of hypertonic-hyperoncotic solution, sodium concentration increased from 139.2 +/- 0.7 to 147.5 +/- 0.7 mmol/L. The maximum sodium concentration was 153 mmol/L, measured immediately after hypertonic-hyperoncotic solution in 1 patient. The total amount of fluid infused was similar in both groups. The postoperative need for infused dobutamine in the patients in the hypertonic-hyperoncotic solution group was decreased compared with the isotonic saline solution group (46.9 +/- 8.8 microg/kg vs 308.2 +/- 46.6 microg/kg). No patient presented with severe bleeding. Short- and long-term cardiac and neurologic outcome was not reduced and all patients left the hospital in a clinically sufficient state. This study demonstrates a profound increase of cardiac index after the administration of hypertonic-hyperoncotic solution in children after uncomplicated open-heart surgery, suggesting a positive inotropic effect. The total amount of catecholamine was lower, assuming that hypertonic-hyperoncotic solution reduces the need for positive inotropic support. The observed positive cardiac effect of hypertonic-hyperoncotic solution may even be intensified by the decreased afterload (decreased systemic vascular resistance index). According to the Frank-Starling relation, an effective tool in the treatment of low cardiac output are an elevated preload while afterload is diminished. Therefore, we postulate that hypertonic-hyperoncotic solution may be helpful in preventing or attenuating low cardiac output failure in childhood. Capillary leakage syndrome also is a frequent problem after cardiopulmonary bypass. For quantification of edema formation, extravascular lung water index measurement is a useful tool. Using this approach, we provided evidence that the infusion of hypertonic-hyperoncotic solution is transiently able to reduce extravascular lung water index. This reduction was transient but might prevent the triggering of a clinically relevant capillary leakage syndrome. This is in line with in vitro studies demonstrating that hypertonic-hyperoncotic solution improves microcirculation by reducing vascular permeability. The single administration of hypertonic-hyperoncotic solution infusion was safe, and no adverse effects, such as hemostatic disturbances, were observed. A single infusion of hypertonic-hyperoncotic saline solution after cardiac surgery is safe despite the hypertonicity and the colloid component of the hypertonic-hyperoncotic saline solution. In children after cardiopulmonary bypass surgery, the administration of hypertonic-hyperoncotic saline solution increased cardiac index by elevating stroke volume index in combination with a lowered systemic vascular resistance index. Extravascular lung water index transiently decreased, suggesting that hypertonic-hyperoncotic saline solution effectively counteracts the capillary leakage that often occurs after cardiac surgery in children. Additional investigations might elucidate whether the temporary effects of hypertonic-hyperoncotic saline solution are beneficial in the treatment of severe capillary leakage after complicated cardiac surgery. It has to be shown that hypertonic-hyperoncotic saline solution is a long-lasting, effective treatment strategy for low cardiac output failure in children that is caused by sepsis, multiorgan failure, and endothelial edema. We have provided evidence to pediatric intensive care clinicians that the single administration of hypertonic-hyperoncotic saline solution might be a useful and safe treatment in the amelioration of contractility, inotropy, and the possible treatment of early-onset capillary leakage.

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It would, of course, be incorrect to attempt to draw conclusions as to the dangers and the chances of success of suture of cardiac wounds in man from the results obtained by animal experimentation. Animals are placed in very unfavorable conditions after the operation. They are very restless and cannot be kept quiet. Ideal cleanliness is impossible and the animals may infect their wound by rubbing the external wound against the dirt on the floor of their cage. From the animal mortality in these investigations no rigid inferences applicable to human beings can therefore be made. Some conclusions of importance can, however, be drawn. Above all, my experiments seem to show that the mammalian heart will bear a much greater amount of manipulation than has hitherto been suspected. Very large wounds of the heart can heal and the healing process occurs in a manner entirely analogous to that in other muscular tissues. Even an extensive suture of the heart-wall of rabbits and dogs, although we know that thereby a large number of muscle fibres are destroyed and replaced by connective tissue, does not interfere with the function of the cardiac muscle as a whole. Can some of the results in the above recorded experiments be, with some restrictions of course, applied to the human heart? I think that this question must be answered in the affirmative. If we compare the knowledge we possess of wounds of the heart in man, with that obtained from animal experiments, and find that they agree in all essential particulars, then we are justified in reasoning by analogy that suture of wounds of the heart in man will give results similar to those obtained in the animal. In the last few decades, the advances made in all the branches of medicine-especially in pathology, bacteriology and surgery-have been due to a great extent to the generalization of the results of animal experimentation. To the careful and critical investigator, the results obtained in the animal experiment have always been of the greatest value in indicating to him the possibility of results to be obtained by similar procedures in the human body. From the study of wounds of the heart in man, and from the results obtained in my experiments, this conclusion seems therefore justified: wounds of the heart in man, when all other means have been tried and found wanting, can and ought to be closed by suture. The application itself of the suture is devoid of the one great danger that was feared in the past, i. e. of sudden arrest of the heart during the manipulations incident upon the application of the sutures. The number of sutures should be as small as possible so as to limit the amount of connective tissue which will be formed; for all the muscle fibres that are compressed by the sutures eventually atrophy and are replaced by new-formed connective tissue. It is probable that this connective tissue will not lead to degenerative changes in the heart-muscle. On the post-mortem table, fibrous plaques are often found in the otherwise normal human heart. In a number of the muscles of the body fibrous bands-tendinous intersections as they are called-are normally found. In the large number of microscopic sections of the heart-muscle that I have examined, I could find no evidence of pathological changes in the muscle fibres some distance from the scar. For similar reasons the suture should always be an interrupted one. We have shown that there are dangers and disadvantages in the continuous suture both on theoretical grounds and in practical use. The sutures should be passed through as little of the heart substance as possible; if they penetrate the epicardium and a small part of the thickness of the heart-muscle it will generally be sufficient. When the heart's action is not too rapid, each suture should be tied during a diastolic relaxation of the part under treatment. On this point we have not yet any experience in man. Cappelen, in his patient, tied the sutures during systole. Rehn tied them in his case during diastole. Only time and further experience will show how much importance is to be attached to this point. All that can be said, in the present state of our knowledge, is, that on theoretical grounds and from animal experimentation, it must be considered safest to tie the sutures during diastole. On first sight, it might appear difficult to apply sutures to an organ in such constant motion as is the heart. In practice, however, the difficulties have been proven not to be so great as might appear. The heart may be grasped with a forceps and the needle and suture easily passed. It is no more difficult to pass and tie a suture in a large dog than in a small rabbit. Hence we should infer that the difficulties of this procedure in the human heart, are not so great, a fact that has been borne out by the experience of those surgeons who have reported cases of heart-suture in man. The cases will always be few in which this extreme method of treatment-for so we must style it-is necessary. Indeed, of the patients that come under the care of the surgeon, there are some who will recover from even large heart wounds without any local treatment at all. Cases have been recently reported by Conner, Brugnoli, Hamilton and others, where after wounds as large as three centimetres, the haemorrhage ceased spontaneously and the patients recovered. One cannot say, therefore, that wounds larger than a certain size must always be sutured. Each case must be carefully considered by itself. When we examine the nine cases of suture of the human heart in man (see pages 487 to 490) we cannot but hope for considerable success from this new method of surgical procedure. Of the nine cases, four recovered entirely, and four died of complications referable to other organs-quite an encouraging record in a few cases. Finally, I may be permitted to summarize these conclusions as follows: 1. Suture of a wound of the heart as a final resort is an operation worthy of consideration in some cases and often justifiable. 2. Suture of wounds of the heart in animals, and also in man, is devoid of the danger of sudden arrest of the heart, due to the manipulation of the heart incident to the procedure, unless Kronecker's coördination centre be injured. 3. The suture should be an interrupted one of silk, applied in most cases so that the epicardium and superficial layers of the myocardium should be the only ones penetrated, and tied, when possible, during diastole. 4. No stated indications can be given as to the cases that are operable or the time when the operation should be done. Each case must be considered by itself for symptoms which would justify operative interference.

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Hydroxychloroquine has shown to have antiviral activity in vitro against coronaviruses, specifically SARS-CoV-2. It is believed to block virus infection by increasing endosomal pH required for virus cell fusion and glycosylation of viral surface proteins. In addition to its antiviral activity, hydroxychloroquine has an immune-modulating activity that may synergistically enhance its antiviral effect in vivo, making it a potentially promising drug for the prevention and the cure of SARS-CoV-19. However, randomized controlled trials are needed to assess whether it can be used safely to treat COVID-19 patients or to prevent infection. The main objective of the present study is to evaluate the efficacy of hydroxychloroquine for (I) the prevention of COVID-19 or related symptoms in SARS-CoV-2-exposed subjects, such as as household members/contacts of COVID-19 patients and (II) the treatment of early-phase asymptomatic or paucisymptomatic COVID-19 patients. This is a controlled, open label, cluster-randomized, superiority trial with parallel group design. Subjects will be randomized either to receive hydroxychloroquine or to observation (2:1). SARS-CoV-2-exposed subjects, including household members and/or contacts of COVID-19 patients and healthcare professionals (Group 1) or patients with COVID-19 (positive PCR test on a rhinopharyngeal or oropharyngeal swab for SARS-CoV-2), asymptomatic or paucisymptomatic in home situations who are not undergoing treatment with any anti COVID-19 medication (Group 2), will be enrolled. Paucisymptomatic patients are defined as patients with a low number of mild symptoms. All subjects must be aged ≥18 years, male or female, must be willing and able to give informed consent and must not have any contraindications to take hydroxychloroquine (intolerance or previous toxicity for hydroxychloroquine/chloroquine, bradycardia or reduction in heart rhythm with arrhythmia, ischemic heart disease, retinopathy, congestive heart failure with use of diuretics, favism or glucose-6-phosphate dehydrogenase (G6PD) deficiency, diabetes type 1, major comorbidities such as advanced chronic kidney disease or dialysis therapy, known history of ventricular arrhythmia, any oncologic/hematologic malignancy, severe neurological and mental illness, current use of medications with known significant drug-drug interactions, and known prolonged QT syndrome or current use of drugs with known QT prolongation). The study is monocentric and will be conducted at Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS. Subjects will be enrolled from a large epidemic region (North-Central Italy). The Public Health Departments of several Italian regions will collaborate by identifying potentially eligible subjects. The participants will be randomized (2:1 randomization) to receive either hydroxychloroquine (Arm A) or to Observation (Arm B). Hydroxychloroquine will be administered with the following schedule: Group1: A loading dose hydroxychloroquine 400 mg twice daily on day 1, followed by a weekly dose of hydroxychloroquine 200 mg twice daily on days 8, 15 and 22, for a total of one month of treatment. Group 2: A loading dose hydroxychloroquine 400 mg twice daily on day 1 followed by 200 mg twice daily for a total of 5-7 days. The comparator in this trial is observation given that currently neither treatment is administered to asymptomatic or paucisymptomatic subjects, nor prophylaxis is available for contacts. Hydroxychloroquine will be shipped to subjects within 24 hours of randomization. Given the extraordinary nature of the COVID-19 pandemic, only telephonic interviews will be carried out and electronic Patient Reported Outcomes (ePRO) completed. During treatment, each subject will be contacted every other day for the first week and weekly thereafter (Group 2) or weekly (Group 1) by a study physician to assess early onset of any COVID-19 symptom or any adverse reaction to hydroxychloroquine and to check subject compliance. Furthermore, all subjects will receive periodic ePROs which may be completed through smartphone or tablets to record drug self-administration and onset of any symptom or adverse event. All subjects will be followed up for a total of 6 months by periodic telephonic interviews and ePROs. The primary endpoint/outcome measure for this trial is: for Group 1, the proportion of subjects who become symptomatic and/or swab-positive in each arm within one month of randomization; for Group 2, the proportion of subjects who become swab-negative in each arm within 14 days of randomization. All household members and/or contacts of each COVID-19 index case, and the COVID-19 patient himself/herself, fulfilling all inclusion criteria will be grouped into a single cluster and this cluster will be randomized (2:1) to either arm A or arm B. Information on each subject will be recorded in specific data records. Randomization lists will be stratified according to the following factors regarding COVID-19 index cases: 1. COVID-19 risk level on the basis of province of residence (high vs. low/intermediate); 2. Index case is a healthcare professional (yes vs.no) 3. Index case with COVID-19 treatment (yes vs. no) An independent statistician not otherwise involved in the trial will generate the allocation sequence, and COVID-19 response teams will be unaware of the allocation of clusters. Randomization will be performed through an interactive web-based electronic data-capturing database. An Independent Data Monitoring Committee has been established. This study is open label. For Group 1, a sample size of about 2000 SARS-CoV-2-exposed subjects such as household members and/or contacts of COVID-19 patients will take part in the study. Assuming around 1.5-2.0 asymptomatic household members and/or contacts for each COVID-19 patient, we expect to identify approximately 1000-1300 COVID-19 index cases to be randomized. An interim analysis on efficacy is planned using standard alpha-spending function. For Group 2, sufficient power for primary objective (negative swab within 14 days of randomization) will be reached given a sample size of 300 asymptomatic or paucisymptomatic COVID-19 subjects in home situations not treated for COVID-19 (25%-30% of about 1000-1300 expected index cases). Since up to date reduced evidence about COVID-19 infection epidemiology, the continuous update of diagnostic and therapeutic approaches, the sample size estimation could be updated after a one third of population will be recruited and eventually modified according to a substantial protocol amendment. An interim analysis at 100 enrolled COVID-19 patients is planned. We have planned a Generalized Estimating Equation analysis, which is more efficient than a cluster level analysis, to take advantage of subject-specific covariates. The above reported sample size analysis is therefore to be considered conservative. The current version of the PROTECT trial protocol is 'Final version, 15 April 2020'. The study started on 9<supth</sup May 2020. The first patient was enrolled on 14<supth</sup May 2020. Recruitment is expected to last through September 2020. The PROTECT trial is registered in the EudraCT database (no. 2020-001501-24) and in ClinicalTrials.gov ( NCT04363827 ), date of registration 24 April 2020. The full PROTECT protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interests of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol (Protocol final version, 15<supth</sup April 2020). The study protocol has been reported in accordance with Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

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Cardiovascular disease (CVD) is the leading cause of death in the United States, and substantial research has linked ambient air pollution to elevated rates of CVD etiology and events. Much of this research identified increased effects of air pollution in lower socioeconomic position (SEP) communities, where pollution exposures are also often higher. The complex spatial confounding between air pollution and SEP makes it very challenging, however, to disentangle the impacts of these very different exposure types and to accurately assess their interactions. The specific causal components (i.e., specific social stressors) underlying this SEP-related susceptibility remain unknown, because there are myriad pathways through which poverty and/or lower-SEP conditions may influence pollution susceptibility - including diet, smoking, coexposures in the home and occupational environments, health behaviors, and healthcare access. Growing evidence suggests that a substantial portion of SEP-related susceptibility may be due to chronic psychosocial stress - given the known wide-ranging impacts of chronic stress on immune, endocrine, and metabolic function - and to a higher prevalence of unpredictable chronic stressors in many lower-SEP communities, including violence, job insecurity, and housing instability. As such, elucidating susceptibility to pollution in the etiology of CVD, and in the risk of CVD events, has been identified as a research priority. This interplay among social and environmental conditions may be particularly relevant for CVD, because pollution and chronic stress both impact inflammation, metabolic function, oxidative stress, hypertension, atherosclerosis, and other processes relevant to CVD etiology. Because pollution exposures are often spatially patterned by SEP, disentangling their effects - and quantifying any interplay - is especially challenging. Doing so, however, would help to improve our ability to identify and characterize susceptible populations and to improve our understanding of how community stressors may alter responses to multiple air pollutants. More clearly characterizing susceptible populations will improve our ability to design and target interventions more effectively (and cost-effectively) and may reveal greater benefits of pollution reduction in susceptible communities, strengthening cost-benefit and accountability analyses, ultimately reducing the disproportionate burden of CVD and reducing health disparities. In the current study, we aimed to quantify combined effects of multiple pollutants and stressor exposures on CVD events, using a number of unique datasets we have compiled and verified, including the following. 1. Poverty metrics, violent crime rates, a composite socioeconomic deprivation index (SDI), an index of racial and economic segregation, noise disturbance metrics, and three composite spatial factors produced from a factor analysis of 27 community stressors. All indicators have citywide coverage and were verified against individual reports of stress and stressor exposure, in citywide focus groups and surveys. 2. Spatial surfaces for multiple pollutants from the New York City (NYC) Community Air Survey (NYCCAS), which monitored multiple pollutants year-round at 150 sites and used land use regression (LUR) modeling to estimate fine-scale (100-m) intra-urban spatial variance in fine particles (PM<sub2.5</sub), nitrogen dioxide (NO<sub2</sub), sulfur dioxide (SO<sub2</sub), and ozone (O<sub3</sub). 3. Daily data and time-trends derived from all U.S. Environmental Protection Agency (EPA) Air Quality System (AQS) monitors in NYC for 2005-2011, which we combined with NYCCAS surfaces to create residence- and day-specific spatiotemporal exposure estimates. 4. Complete data on in- and out-patient unscheduled CVD events presented in NYC hospitals for 2005-2011 (n = 1,113,185) from the New York State (NYS) Department of Health's Statewide Planning and Research Cooperative System (SPARCS). In the study, we quantified relationships between multiple pollutant exposures and both community CVD event rates and individual risk of CVD events in NYC and tested whether pollution-CVD associations varied by community SEP and social stressor exposures. We hypothesized (1) that greater chronic community-level SEP, stressor, and pollution exposures would be associated with higher community CVD rates; (2) that spatiotemporal variations in multiple pollutants would be associated with excess risk of CVD events; and (3) that pollution-CVD associations would be stronger in communities of lower SEP or higher stressor exposures. To first understand the separate and combined associations with CVD for both stressors and pollutants measured at the same spatial and temporal scale of resolution, we used ecological cross-sectional models to examine spatial relationships between multiple chronic pollutant and stressor exposures and age-adjusted community CVD rates. Using census-tract-level annual averages (n = 2,167), we compared associations with CVD rates for multiple pollutant concentrations and social stressors. We found that associations with community CVD rates were consistently stronger for social stressors than for pollutants, in terms of both magnitude and significance. We note, however, that this result may be driven by the relatively greater variation (on a proportional basis) for stressors than for pollutants in NYC. We also tested effect modification of pollutant-CVD associations by each social stressor and found evidence of stronger associations for NO<sub2</sub, PM<sub2.5</sub, and wintertime SO<sub2</sub with CVD rates, particularly across quintiles of increasing community violence or assault rates (P trend &lt; 0.0001). To examine individual-level associations between spatiotemporal exposures to multiple pollutants and the risk of CVD events, across multiple lag days, we examined the combined effects of multiple pollutant exposures, using spatiotemporal (day- and residence-specific) pollution exposure estimates and hospital data on individual CVD events in case-crossover models, which inherently adjust for nontime-varying individual confounders (e.g., sex and race) and comorbidities. We found consistent significant relationships only for <isame-day</i pollutant exposures and the risk of CVD events, suggesting very acute impacts of pollution on CVD risk. Associations with CVD were positive for NO<sub2</sub, PM<sub2.5</sub, and SO<sub2</sub, as hypothesized, and we found inverse associations for O<sub3</sub (a secondary pollutant chemically decreased ["scavenged"] by fresh emissions that, in NYC, displays spatial and temporal patterns opposite those of NO<sub2</sub). Finally, to test effect modification by chronic community social stressors on the relationships between spatiotemporal pollution measures and the risk of CVD events, we used individual-level case-crossover models, adding interaction terms with categorical versions of each social stressor. We found that associations between NO<sub2</sub and the risk of CVD events were significantly elevated only in communities with the highest exposures to social stressors (i.e., in the highest quintiles of poverty, socioeconomic deprivation, violence, or assault). The largest positive associations for PM<sub2.5</sub and winter SO<sub2</sub were generally found in the highest-stressor communities but were not significant in any quintile. We again found inverse associations for O<sub3</sub, which were likewise stronger for individuals living in communities with greater stressor exposures. In ecological models, we found stronger relationships with community CVD rates for social stressors than for pollutant exposures. In case-crossover analyses, higher exposures to NO<sub2</sub, PM<sub2.5</sub, and SO<sub2</sub were associated with greater excess risk of CVD events but only on the case day (there were no consistent significant lagged-day effects). In effect-modification analyses at both the community and individual level, we found evidence of stronger pollution-CVD associations in communities with higher stressor exposures. Given substantial spatial confounding across multiple social stressors, further research is needed to disentangle these effects in order to identify the predominant social stressors driving this observed differential susceptibility.

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Near-road ambient air pollution concentrations that are affected by vehicle emissions are typically characterized by substantial spatial variability with respect to distance from the roadway and temporal variability based on the time of day, day of week, and season. The goal of this work is to identify variables that explain either temporal or spatial variability based on case studies for a freeway site and an urban intersection site. The key hypothesis is that dispersion modeling of near-road pollutant concentrations could be improved by adding estimates or indices for site-specific explanatory variables, particularly related to traffic. Based on case studies for a freeway site and an urban intersection site, the specific aims of this project are to (1) develop and test regression models that explain variability in traffic-related air pollutant (TRAP) ambient concentration at two near-roadway locations; (2) develop and test refined proxies for land use, traffic, emissions and dispersion; and (3) prioritize inputs according to their ability to explain variability in ambient concentrations to help focus efforts for future data collection and model development. The key pollutants that are the key focus of this work include nitrogen oxides (NO<subx</sub), carbon monoxide (CO), black carbon (BC), fine particulate matter (PM<sub2.5</sub; PM ≤ 2.5 μm in aerodynamic diameter), ultrafine particles (UFPs; PM ≤ 0.1 μm in aerodynamic diameter), and ozone (O<sub3</sub). NO<subx</sub, CO, and BC are tracers of vehicle emissions and dispersion. PM<sub2.5</sub is influenced by vehicle table emissions and regional sources. UFPs are sensitive to primary vehicle emissions. Secondary particles can form near roadways and on regional scales, influencing both PM<sub2.5</sub and UFP concentrations. O<sub3</sub concentrations are influenced by interaction with NO<subx</sub near the roadway. Nitrogen dioxide (NO<sub2</sub), CO, PM<sub2.5</sub, and O<sub3</sub are regulated under the National Ambient Air Quality Standards (NAAQS) because of demonstrated health effects. BC and UFPs are of concern for their potential health effects. Therefore, these pollutants are the focus of this work. The methodological approach includes case studies for which variables are identified and assesses their ability to explain either temporal or spatial variability in pollutant ambient concentrations. The case studies include one freeway location and one urban intersection. The case studies address (1) temporal variability at a fixed monitor 10 meters from a freeway; (2) downwind concentrations perpendicular to the same location; (3) variability in 24-hour average pollutant concentrations at five sites near an urban intersection; and (4) spatiotemporal variability along a walking path near that same intersection. The study boundary encompasses key factors in the continuum from vehicle emissions to near-road exposure concentrations. These factors include land use, transportation infrastructure and traffic control, vehicle mix, vehicle (traffic) flow, on-road emissions, meteorology, transport and evolution (transformation) of primary emissions, and production of secondary pollutants, and their resulting impact on measured concentrations in the near-road environment. We conducted field measurements of land use, traffic, vehicle emissions, and near-road ambient concentrations in the vicinity of two newly installed fixed-site monitors. One is a monitoring station jointly operated by the U.S. Environmental Protection Agency (U.S. EPA) and the North Carolina Department of Environmental Quality (NC DEQ) on I-40 between Airport Boulevard and I-540 in Wake County, North Carolina. The other is a fixed-site monitor for measuring PM<sub2.5</sub at the North Carolina Central University (NCCU) campus on E. Lawson Street in Durham, North Carolina. We refer to these two locations as the freeway site and the urban site, respectively. We developed statistical models for the freeway and urban sites. We quantified land use metrics at each site, such as distances to the nearest bus stop. For the freeway site, we quantified lane-by-lane total vehicle count, heavy vehicle (HV) count, and several vehicle-activity indices that account for distance from each lane to the roadside monitor. For the urban site, we quantified vehicle counts for all 12 turning movements through the intersection. At each site, we measured microscale vehicle tailpipe emissions using a portable emission measurement system. At the freeway site, we measured the spatial gradient of NO<subx</sub, BC, UFPs, and PM, quantified particle size distributions at selected distances from the roadway and assessed partitioning of particles as a function of evolving volatility. We also quantified fleet-average emission factors for several pollutants. At the urban site, we measured daily average concentrations of nitric oxide (NO), NO<subx</sub, O<sub3</sub, and PM<sub2.5</sub at five sites surrounding the intersection of interest; we also measured high resolution (1-second to 10-second averages) concentrations of O<sub3</sub, PM<sub2.5</sub, and UFPs along a pedestrian transect. At both sites, the Research LINE-source (R-LINE) dispersion model was applied to predict concentration gradients based on the physical dispersion of pollution. Statistical models were developed for each site for selected pollutants. With variables for local wind direction, heavy-vehicle index, temperature, and day type, the multiple coefficient of determination (R<sup2</sup) was 0.61 for hourly NO<subx</sub concentrations at the freeway site. An interaction effect of the dispersion model and a real-time traffic index contributed only 24% of the response variance for NO<subx</sub at the freeway site. Local wind direction, measured near the road, was typically more important than wind direction measured some distance away, and vehicle-activity metrics directly related to actual real-time traffic were important. At the urban site, variability in pollutant concentrations measured for a pedestrian walk-along route was explained primarily by real-time traffic metrics, meteorology, time of day, season, and real-world vehicle tailpipe emissions, depending on the pollutant. The regression models explained most of the variance in measured concentrations for BC, PM, UFPs, NO, and NO<subx</sub at the freeway site and for UFPs and O<sub3</sub at the urban site pedestrian transect. Among the set of candidate explanatory variables, typically only a few were needed to explain most of the variability in observed ambient concentrations. At the freeway site, the concentration gradients perpendicular to the road were influenced by dilution, season, time of day, and whether the pollutant underwent chemical or physical transformations. The explanatory variables that were useful in explaining temporal variability in measured ambient concentrations, as well as spatial variability at the urban site, were typically localized real-time traffic-volume indices and local wind direction. However, the specific set of useful explanatory variables was site, context (e.g., next to road, quadrants around an intersection, pedestrian transects), and pollutant specific. Among the most novel of the indicators, variability in real-time measured tailpipe exhaust emissions was found to help explain variability in pedestrian transect UFP concentrations. UFP particle counts were very sensitive to real-time traffic indicators at both the freeway and urban sites. Localized site-specific data on traffic and meteorology contributed to explaining variability in ambient concentrations. HV traffic influenced near-road air quality at the freeway site more so than at the urban site. The statistical models typically explained most of the observed variability but were relatively simple. The results here are site-specific and not generalizable, but they are illustrative that near-road air quality can be highly sensitive to localized real-time indicators of traffic and meteorology.

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p-Nitrotoluene is used to synthesize agricultural and rubber chemicals, azo and sulfur dyes, and dyes for cotton, wool, silk, leather, and paper. p-Nitrotoluene was nominated by the National Institute for Occupational Safety and Health and the NTP for study based on its considerable human exposure as well as the absence of long-term studies of its carcinogenicity in rodents. Male and female F344/N rats and B6C3F1 mice were exposed to p-nitrotoluene (greater than 99% pure) in feed for 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, L5178Y mouse lymphoma cells, cultured Chinese hamster ovary cells, and rat and mouse bone marrow cells. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were fed diets containing 0, 1,250, 2,500, or 5,000 ppm p-nitrotoluene (equivalent to average daily doses of approximately 55, 110, or 240 mg p-nitrotoluene/kg body weight to males and 60, 125, or 265 mg/kg to females) for 105 or 106 weeks. Survival, Body Weights, and Feed Consumption: Survival of all exposed groups of rats was similar to that of the control groups. Mean body weights of 5,000 ppm male and 2,500 and 5,000 ppm female rats were less than those of the controls during most of the study; mean body weights of 1,250 ppm females were less during the second year of the study. Feed consumption by 5,000 ppm females was less than that by the controls during year 2 of the study. Biomarkers of Exposure: Two urinary metabolites were followed during the study as biomarkers of exposure. The ratios of p-nitrobenzoic acid to creatinine and of p-acetamidobenzoic acid to creatinine determined at 2 weeks and at 3, 12, and 18 months were linearly related to exposure concentration in males and females. Pathology Findings: The incidence of clitoral gland adenoma or carcinoma (combined) was significantly greater in 2,500 ppm females than that in the controls and exceeded the historical control ranges. The incidence of clitoral gland neoplasms was not increased in 5,000 ppm females, possibly because of the lower body weights in this group. The incidences of subcutaneous fibroma and of subcutaneous fibroma or fibrosarcoma (combined) in 2,500 ppm male rats were significantly increased and exceeded the historical control ranges. The incidences of several nonneoplastic kidney lesions were significantly increased in exposed groups of rats, and the severities of these lesions generally increased with increasing exposure concentration. In the spleen, incidences of hematopoietic cell proliferation and pigmentation were significantly increased in the 2,500 and 5,000 ppm groups. Significantly increased incidences of various types of altered cell foci in the liver of males and females were associated with exposure. Incidences of germinal epithelial atrophy of the testis in 5,000 ppm males and endometrial cystic hyperplasia of the uterus in 2,500 and 5,000 ppm females were significantly increased. The incidences of mononuclear cell leukemia were significantly decreased in all exposed groups except 1,250 ppm females. The incidence of interstitial cell adenoma of the testis in 5,000 ppm males was significantly decreased. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were fed diets containing 0, 1,250, 2,500, or 5,000 ppm p-nitrotoluene (equivalent to average daily doses of approximately 170, 345, or 690 mg/kg to males and 155, 315, or 660 mg/kg to females) for 105 or 106 weeks. Survival, Body Weights, and Feed Consumption: Survival of all exposed groups of male and female mice was similar to that of the control groups. Mean body weights of 5,000 ppm males and females were less than those of the control groups during most of the study. Mean body weights of 2,500 ppm males were less than those of the controls after week 92. Feed consumption by all exposed groups of mice was similar to that by the control groups. Pathology Findings: The incidence of alveolar/bronchiolar adenoma or carcinoma (combined) was significantly greater in 5,000 ppm male mice than in the controls, as was the incidence of alveolar epithelial hyperplasia in this group. The incidences of alveolar epithelial bronchiolization were significantly increased in all exposed groups of males and females. p-Nitrotoluene was not mutagenic in any of several strains of S. typhimurium, with or without metabolic activation enzymes (S9). A positive response to p-nitrotoluene was observed in the L5178Y mouse lymphoma cell assay in trials with S9. Significantly increased sister chromatid exchange frequencies were observed in cultured Chinese hamster ovary cells treated with p-nitrotoluene with and without S9. Chromosomal aberrations were also induced in Chinese hamster ovary cells treated with p-nitrotoluene in the presence of S9; no increased aberrations were seen without S9. p-Nitrotoluene did not induce a significant reproducible increase in the frequency of micronuclei in bone marrow polychromatic erythrocytes of male rats or male mice when administered by intraperitoneal injection. Under the conditions of these 2-year feed studies there was equivocal evidence of carcinogenic activity* of p-nitrotoluene in male F344/N rats based on increased incidences of subcutaneous skin neoplasms. There was some evidence of carcinogenic activity of p-nitrotoluene in female F344/N rats based on increased incidences of clitoral gland neoplasms. There was equivocal evidence those of the control groups during most of the study. Mean body weights of 2,500 ppm males were less than those of the controls after week 92. Feed consumption by all exposed groups of mice was similar to that by the control groups. Pathology Findings: The incidence of alveolar/bronchiolar adenoma or carcinoma (combined) was significantly greater in 5,000 ppm male mice than in the controls, as was the incidence of alveolar epithelial hyperplasia in this group. The incidences of alveolar epithelial bronchiolization were significantly increased in all exposed groups of males and females. p-Nitrotoluene was not mutagenic in any of several strains of S. typhimurium, with or without metabolic activation enzymes (S9). A positive response to p-nitrotoluene was observed in the L5178Y mouse lymphoma cell assay in trials with S9. Significantly increased sister chromatid exchange frequencies were observed in cultured Chinese hamster ovary cells treated with p-nitrotoluene with and without S9. Chromosomal aberrations were also induced in Chinese hamster ovary cells treated with p-nitrotoluene in the presence of S9; no increased aberrations were seen without S9. p-Nitrotoluene did not induce a significant reproducible increase in the frequency of micronuclei in bone marrow polychromatic erythrocytes of male rats or male mice when administered by intraperitoneal injection. Under the conditions of these 2-year feed studies there was equivocal evidence of carcinogenic activity of p-nitrotoluene in male F344/N rats based on increased incidences of subcutaneous skin neoplasms. There was some evidence of carcinogenic activity of p-nitrotoluene in female F344/N rats based on increased incidences of clitoral gland neoplasms. There was equivocal evidence in male and female rats, testis in male rats, and lung in male and female mice. Decreased incidences of mononuclear cell leukemia in male and female rats and testicular interstitial cell adenoma in male rats were attributed to exposure to p-nitrotoluene.

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NTP Toxicology and Carcinogenesis studies of rhodamine 6G were conducted because of potential human exposure related to its use as a dye for natural and synthetic fibers and as a research chemical. These studies were conducted by administering rhodamine 6G (greater than 95% pure) in feed to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse L5178Y lymphoma cells, and Chinese hamster ovary (CHO) cells. Fourteen-Day and Thirteen-Week Studies: In the 14-day studies (0, 310, 620, 1,250, 2,500, or 5,000 ppm), all five male and five female rats that received 5,000 ppm and 1/5 male rats that received 2,500 ppm died before the end of the studies; all mice lived to the end of the study. The final mean body weights of rats that received 2,500 ppm were lower than the initial weights. The final mean body weights of mice that received 2,500 or 5,000 ppm were 8% or 18% lower than that of controls for males and 2% or 8% lower for females. In the 13-week studies, all rats lived to the end of the studies (dietary concentrations of 0 or 120-2,000 ppm). The final mean body weights of rats that received 500, 1,000 or 2,000 ppm were 12%, 13%, or 32% lower than that of controls for males and 4%, 8%, or 20% lower for females. Feed consumption by rats that received 2,000 ppm was somewhat lower than that by controls. Bone marrow atrophy was observed at increased incidences and severity in dosed rats. In the 13-week study (0 or 500-8,000 ppm), 1/10 male mice that received the highest concentration died before the end of the studies. The final mean body weights of mice that received 8,000 ppm were lower than the initial mean body weights. The final mean body weights of male mice that received 4,000 ppm and of female mice that received 2,000 or 4,000 ppm were 13%-19% lower than those of controls. Feed consumption was not related to dose. Minimal-to-moderate cytoplasmic vacuolization of hepatocytes was seen in 8/10 male mice that received 8,000 ppm. Based on these results, dietary concentrations selected for the 2-year studies were 0, 120, or 250 ppm rhodamine 6G for rats, 0, 1,000, or 2,000 ppm for male mice, and 0, 500, 1,000 ppm for female mice. Body Weight and Survival in the Two-Year Studies: Mean body weights of dosed rats were similar to those of controls throughout the studies. The average daily feed consumption by dosed rats was within 5% that by controls for all dosed groups. The average amount of rhodamine 6G consumed per day was approximately 5 mg/kg for low dose rats and 10 or 12 mg/kg for high dose male or female rats. Mean body weights of high dose male and dosed female mice were generally 5%-14% lower than those of controls. The average daily feed consumption by dosed mice was within 5% that by controls for all dosed groups. The average amount of rhodamine 6G consumed per day was approximately 210 or 440 mg/kg for low dose or high dose male mice and 125 or 250 mg/kg for low dose or high dose female mice. No significant differences in survival were observed between any groups of rats or mice (male rats: control, 22/50; low dose, 21/50; high dose, 27/50; female rats: 29/50; 30/50; 30/50; male mice: 36/50; 32/50; 38/50; female mice: 39/50; 35/50; 36/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: No chemically related nonneoplastic lesions in male or female rats and no chemically related neoplastic or nonneoplastic lesions in male or female mice were observed in these studies. The incidences of keratoacanthomas of the skin was increased in high dose male rats (control, 1/50; low dose, 2/50; high dose, 8/50). The historical incidence of keratoacanthomas in untreated control male F344/N rats is 31/1,936 (1.6%; range, 0/50-7/49). Both fur and skin of rats in the dosed groups apparently were exposed to feed dust containing rhodamine 6G; the intensity of staining was proportional to the concentration of rhodamine 6G in feed. Because of the variable background incidence of keratoacanthomas in F344/N rats, the incideentration of rhodamine 6G in feed. Because of the variable background incidence of keratoacanthomas in F344/N rats, the incidence of keratoacanthomas cannot be conclusively related to exposure to rhodamine 6G. The incidences of pheochromocytomas (3/50; 3/50; 8/50) or malignant pheochromocytomas (combined: 3/50; 3/50; 10/50) of the adrenal gland were increased in high dose female rats. The historical incidence of adrenal medullary neoplasms in untreated control F344/N female rats is 99/1,968 (5&amp;percnt;; range, 0/50-8/50). This marginal increase may be related to the administration of rhodamine 6G. Genetic Toxicology: Rhodamine 6G was not mutagenic in S. typhimurium strains TA98, TA100, TA1535, or TA1537 when tested with and without exogenous metabolic activation (S9). Rhodamine 6G gave a positive response in the absence of S9 in the mouse lymphoma assay for induction of trifluorothymidine (Tft) resistance in L5178Y cells; in the presence of S9, rhodamine 6G was negative. Rhodamine 6G induced sister chromatid exchanges (SCEs) and chromosomal aberrations in cultured CHO cells in the presence, but not the absence, of S9. Conclusions: Under the conditions of these 2-year feed studies, there was equivocal evidence of carcinogenic activity for male F344/N rats administered rhodamine 6G, as indicated by a marginally increased incidence of integumentary keratoacanthomas. There was equivocal evidence of carcinogenic activity for female F344/N rats administered rhodamine 6G, as indicated by a marginal increase in pheochromocytomas or malignant pheochromocytomas (combined) of the adrenal gland. There was no evidence of carcinogenic activity for male B6C3F1 mice administered 1,000 or 2,000 ppm rhodamine 6G in the diet. There was no evidence of carcinogenic activity for female B6C3F1 mice administered 500 or 1,000 ppm rhodamine 6G in the diet. There were no significant nonneoplastic lesions attributed to rhodamine 6G administration to male or female rats or male or female mice. Male and female rats might have been able to tolerate a higher concentration of rhodamine 6G in the feed. Synonym: 2-[6-(ethylamino)-3-(ethylimino)2,7-dimethyl-3H-xanthen-9-yl] benzoic acid ethyl ester, monohydrochloride Common Names: Basic Red 1; Basic Rhodamine Yellow; Basic Rhodaminic Yellow; Calcozine Red 6G; Calcozine Rhodamine 6GX; C.I. Basic Red 1, Monohydrochloride; Elcozine Rhodamine 6GDN; Eljon Pink Toner; Fanal Pink GFK; Fanal Red 25532; Flexo Red 482; Heliostable Brilliant Pink B extra; Mitsui Rhodamine 6GCP; Nyco Liquid Red GF; Rhodamine 69DN Extra; Rhodamine F4G; Rhodamine F5G; Rhodamine F5G chloride; Rhodamine 6GB; Rhodamine 6GBN; Rhodamine 6GCP; Rhodamine 6GD; Rhodamine 4GD; Rhodamine GDN; Rhodamine 5GDN; Rhodamine 6 GDN; Rhodamine GDN Extra; Rhodamine 6GEx ethyl ester; Rhodamine 6G Extra; Rhodamine 6G Extra Base; Rhodamine 4GH; Rhodamine 6GH; Rhodamine 5GL; Rhodamine 6G lake; Rhodamine 6GX; Rhodamine J; Rhodamine 6JH; Rhodamine 7JH; Rhodamine Lake Red 6G; Rhodamine Y 20-7425; Rhodamine Zh; Rhodamine 6ZH-DN; Silosuper Pink B; Valley Fast Red 1308

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To examine the clinical effectiveness and cost-effectiveness of intravenous formulations of topotecan monotherapy, pegylated liposomal doxorubicin hydorocholoride (PLDH) monotherapy and paclitaxel used alone or in combination with a platinum-based compound for the second-line or subsequent treatment of advanced ovarian cancer. Electronic databases covering publication years 2000-4. Company submissions. Seventeen databases were searched for randomised controlled trials (RCTs) and systematic reviews for the clinical effectiveness of PLDH, topotecan and paclitaxel and economic evaluations of the cost-effectiveness of PLDH, topotecan and paclitaxel. Selected studies were quality assessed and data extracted, as were the three company submissions. A new model was developed to assess the costs of the alternative treatments, the differential mean survival duration and the impact of health-related quality of life. Monte-Carlo simulation was used to reflect uncertainty in the cost-effectiveness results. Nine RCTs were identified. In five of these trials, both the comparators were used within their licensed indications. Of these five, three included participants with both platinum-resistant and platinum-sensitive advanced ovarian cancer, and a further two only included participants with platinum-sensitive disease. The comparators that were assessed in the three trials that included both subtypes of participants were PLDH versus topotecan, topotecan versus paclitaxel and PLDH versus paclitaxel. In the further two trials that included participants with the subtype of platinum-sensitive disease, the comparators that were assessed were single-agent paclitaxel versus a combination of cyclophosphamide, doxorubicin and cisplatin (CAP) and paclitaxel plus platinum-based chemotherapy versus conventional platinum-based therapy alone. A further four trials were identified and included in the review in which one of the comparators in the trial was used outside its licensed indication. The comparators assessed in these trials were oxaliplatin versus paclitaxel, paclitaxel given weekly versus every 3 weeks, paclitaxel at two different dose levels and oral versus intravenous topotecan. Four studies met the inclusion criteria for the cost-effectiveness review. The review of the economic evidence from the literature and industry submissions identified a number of significant limitations in existing studies assessing the cost-effectiveness of PLDH, topotecan and paclitaxel. Analysis 1 assessed the cost-effectiveness of PLDH, topotecan and paclitaxel administered as monotherapies. Sensitivity analysis was undertaken to explore the impact of patient heterogeneity (e.g. platinum-sensitive and platinum-resistant/refractory patients), the inclusion of additional trial data and alternative assumptions regarding treatment and monitoring costs. In the base-case results for Analysis 1, paclitaxel monotherapy emerged as the cheapest treatment. When the incremental cost-effectiveness ratios (ICERs) were estimated, topotecan was dominated by PLDH. Hence the options considered in the estimation of the ICERs were paclitaxel and PLDH. The ICER for PLDH compared with paclitaxel was pound 7033 per quality-adjusted life-year (QALY) in the overall patient population (comprising platinum-sensitive, -refractory and -resistant patients). The ICER was more favourable in the platinum-sensitive group ( pound 5777 per QALY) and less favourable in the platinum-refractory/resistant group ( pound 9555 per QALY). The cost-effectiveness results for the base-case analysis were sensitive to the inclusion of additional trial data. Incorporating the results of the additional trial data resulted in less favourable estimates for the ICER for PLDH versus paclitaxel compared with the base-case results. The ICER of PLDH compared with paclitaxel was pound 20,620 per QALY in the overall patient population, pound 16,183 per QALY in the platinum-sensitive population and pound 26,867 per QALY in the platinum-resistant and -refractory population. The results from Analysis 2 explored the cost-effectiveness of the full range of treatment comparators for platinum-sensitive patients. The treatment options considered in this model comprised PLDH, topotecan, paclitaxel-monotherapy, CAP, paclitaxel/platinum combination therapy and platinum monotherapy. Owing to the less robust approaches that were employed to synthesise the available evidence and the heterogeneity between the different trials, the reliability of these results should be interpreted with some caution. Topotecan, paclitaxel monotherapy and PLDH were all dominated by platinum monotherapy (i.e. higher costs and lower QALYs). After excluding these alternatives, the treatments that remained under consideration were platinum monotherapy, CAP and paclitaxel-platinum combination therapy. Of these three alternatives, platinum monotherapy was the least costly and least effective. The ICER for CAP compared with platinum monotherapy was pound 16,421 per QALY. The ICER for paclitaxel-platinum combination therapy compared with CAP was pound 20,950 per QALY. For participants with platinum-resistant disease there was a low probability of response to treatment with PLDH, topotecan or paclitaxel. Furthermore, there was little difference between the three comparators in relation to overall survival. The comparators did, however, differ considerably in their toxicity profiles. Given the low survival times and response rates, it appears that the maintenance of quality of life and the control of symptoms and toxicity are paramount in this patient group. As the three comparators differed significantly in terms of their toxicity profiles, patient and physician choice is also an important element that should be addressed when decisions are made regarding second-line therapy. It can also be suggested that this group of patients may benefit from being included in further clinical trials of new drugs. For participants with platinum-sensitive disease there was a considerable range of median survival times observed across the trials. The most favourable survival times and response rates were observed for paclitaxel and platinum combination therapy. This suggests that treatment with combination therapy may be more beneficial than treatment with a single-agent chemotherapeutic regimen. In terms of single-agent compounds, the evidence suggests that PLDH is more effective than topotecan. Evidence from a further trial that compared PLDH and paclitaxel suggests that there is no significant difference between these two comparators in this trial. The three comparators did, however, differ significantly in terms of their toxicity profiles across the trials. Although treatment with PLDH may therefore be more beneficial than that with topotecan, patient and physician choice as to the potential toxicities associated with each of the comparators and the patient's ability and willingness to tolerate these are of importance. Assuming the NHS is willing to pay up to pound 20,000-40,000 per additional QALY, PLDH appears to be cost-effective compared with topotecan and paclitaxel monotherapy, in terms of the overall patient population and the main subgroups considered. The cost-effectiveness results for the base-case analysis were sensitive to the inclusion of additional trial data. Incorporating the results of additional trial data gave less favourable estimates for the ICER for PLDH versus paclitaxel monotherapy, compared with the base-case results. Although the ICER of PLDH compared with paclitaxel monotherapy was less favourable, PLDH was still cost-effective compared with topotecan and paclitaxel monotherapy. For platinum-sensitive patients, the combination of paclitaxel and platinum appears to be cost-effective. On the strength of the evidence reviewed here, it can be suggested that participants with platinum-resistant disease may benefit from being included in further clinical trials of new drugs. To assess the effectiveness of combination therapy against a single-agent non-platinum-based compound, it can be suggested that a trial that compared paclitaxel in combination with a platinum-based therapy versus single-agent PLDH would be a reasonable option.

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To compare the clinical effectiveness and cost-effectiveness of treating upper limb spasticity due to stroke with botulinum toxin type A plus an upper limb therapy programme with the upper limb therapy programme alone. A multicentre open-label parallel-group randomised controlled trial and economic evaluation. Twelve stroke services in the north of England, UK. Three hundred and thirty-three adults with upper limb spasticity at the shoulder, elbow, wrist or hand and reduced upper limb function due to stroke more than 1 month previously. The intervention group received botulinum toxin type A injection(s) plus a 4-week programme of upper limb therapy. The control group received the upper limb therapy programme alone. Participants were clinically reassessed at 3, 6 and 9 months to determine the need for repeat botulinum toxin type A injection(s) and/or therapy. The primary outcome was upper limb function 1 month after study entry measured by the Action Research Arm Test (ARAT). A successful outcome was defined as: (1) a change of three or more points on the ARAT scale for a participant whose baseline ARAT score was between 0 and 3, (2) a change of six or more points on the ARAT scale for a participant whose baseline ARAT score was between 4 and 51, or (3) a final ARAT score of 57 for a participant whose baseline ARAT score was 52-56. Outcome assessments were undertaken at 1, 3 and 12 months by an assessor who was blinded to the study group allocation. Upper limb impairment and activity limitation were assessed by: Modified Ashworth Scale; Motricity Index; grip strength; ARAT; Nine-Hole Peg Test; upper limb basic functional activity questions and the Barthel Activities of Daily Living (ADL) Index. Stroke-related quality of life/participation restriction was measured using the Stroke Impact Scale, European Quality of Life-5 Dimensions (EQ-5D) and the Oxford Handicap Scale. Upper limb pain was assessed using numerical rating scales. Participant-selected upper limb goal achievement (1 month only) was measured using the Canadian Occupational Performance Measure. Adverse events were compared. Health-care and social services resource use was compared during the first 3 months postrandomisation. EQ-5D data were used to calculate the quality-adjusted life-years (QALYs) associated with intervention and control treatments, and the incremental cost per QALY gained of botulinum toxin type A plus therapy compared with therapy alone was estimated. The sensitivity of the base-case results to alternative assumptions was investigated, and cost-effectiveness acceptability curves, which summarise the evidence of botulinum toxin type A plus therapy being cost-effective for a range of societal willingness to pay for a QALY values, are presented. Randomisation groups were well matched at baseline. There was no significant difference between the groups for the primary outcome of improved arm function at 1 month. This was achieved by 30/154 (19.5%) in the control group and 42/167 (25.1%) in the intervention group (p = 0.232). The relative risk of having a 'successful treatment' in the intervention group compared with the control group was 1.3 [95% confidence interval (CI) 0.9 to 2.0]. No significant differences in improved arm function were seen at 3 or 12 months. In terms of secondary outcomes, muscle tone/spasticity at the elbow was decreased in the intervention group compared with the control group at 1 month. The median change in the Modified Ashworth Scale was - 1 in the intervention group compared with zero in the control group (p &lt; 0.001). No difference in spasticity was seen at 3 or 12 months. Participants treated with botulinum toxin type A showed improvement in upper limb muscle strength at 3 months. The mean change in strength from baseline (upper limb component of the Motricity Index) was 3.5 (95% CI 0.1 to 6.8) points greater in the intervention group compared with the control group. No differences were seen at 1 or 12 months. Participants in the intervention group were more likely to be able to undertake specific basic functional activities, e.g. dress a sleeve, clean the palm and open the hand for cutting fingernails. At 1 month, 109/144 (75.7%) of the intervention group and 79/125 (63.2%) of the control group had improved by at least one point on a five-point Likert scale for at least one of these tasks (p = 0.033). At 3 months the corresponding proportions were 102/142 (71.8%) of the intervention group and 71/122 (58.2%) of the control group (p = 0.027). Improvement was sustained at 12 months for opening the hand for cleaning the palm and opening the hand for cutting the nails but not for other activities. Pain rating improved by two points on a 10-point severity rating scale in the intervention group compared with zero points in the control group (p = 0.004) at 12 months, but no significant differences were seen at 1 or 3 months. There were a number of occasions when there were statistically significant differences in favour of the intervention group; however, these differences were small and of uncertain clinical relevance. These differences were: 3 months - upper limb function (change in ARAT score from baseline), pain (EQ-5D) and participation restriction (Oxford Handicap Scale); 12 months - anxiety/depression (EQ-5D) and participation restriction (Oxford Handicap Scale). No differences in grip strength, dexterity or the Barthel ADL Index were found at any time point. There were no differences between the groups for achievement of patient-selected goals. There was a higher incidence of general malaise/flu-like/cold symptoms in participants treated with botulinum toxin type A with a relative risk of 7.6 (95% CI 1.8 to 32.3). Only one serious adverse event (dysphagia) was potentially related to botulinum toxin type A. Time since stroke and severity of initial upper limb function were preplanned subgroup analyses. There was no significant difference in either subgroup for achievement of ARAT 'success' following treatment with botulinum toxin type A. The base-case incremental cost-effectiveness ratio was 93,500 pounds per QALY gained and estimation of the cost-effectiveness acceptability curve for botulinum toxin type A plus the upper limb therapy programme indicated that there was only a 0.36 probability of it being cost-effective at a threshold ceiling ratio of 20,000 pounds per QALY. The addition of botulinum toxin type A to an upper limb therapy programme to treat spasticity due to stroke did not enhance improvement in upper limb function when assessed by the prespecified primary outcome measure at 1 month. However, improvements were seen in muscle tone at 1 month, upper limb strength at 3 months, upper limb functional activities related to undertaking specific basic functional tasks at 1, 3 and 12 months, and upper limb pain at 12 months. Botulinum toxin was well tolerated and side effects were minor. The addition of botulinum toxin type A to an upper limb therapy programme for the treatment of upper limb spasticity due to stroke was not estimated to be cost-effective at levels of willingness to pay for a QALY set by NHS decision-makers. ISRCTN78533119; EudraCT 2004-002427-40; CTA 17136/0230/001.

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To observe the effects of San-huang-sheng-fu oil (S) on peripheral circulatory disorders and foot ulcers in diabetic rats and the relevant mechanisms. (1) Twenty-five Wistar rats were divided into non-diabetes (N), diabetes and sham treatment (DS), metformin (M), S, and combined treatment (CT) groups according to the random number table, with 5 rats in each group. Rats in group N were injected with sodium citrate buffer solution, while rats in the other 4 groups were injected with 10 mg/mL streptozotocin to induce diabetes. In post injection week (PIW) 3, feet of rats in all the 5 groups received an ice-cold stimulation to induce peripheral circulatory disorders. From PIW 9 to 12, rats in groups N and DS were gavaged with saline and applied with sesame oil on pelma of both hind limbs; rats in group M were gavaged with diluted M and applied with sesame oil on pelma of both hind limbs; rats in group S were gavaged with saline and applied with S on pelma of both hind limbs; rats in group CT were gavaged with diluted M and applied with S on pelma of both hind limbs. In PIW 9 before treatment (hereinafter referred to as before treatment) and post treatment week (PTW) 1, 2, and 3, plantar temperature and hot pain threshold of rats were detected by infrared thermometer and foot tester respectively. (2) Another 25 rats were divided and induced with diabetes (expect for group N) as above. In PIW 9, rats in the 5 groups were inflicted with foot ulcer in the left pelma of hind limb by steam and received the corresponding treatment. On post treatment day (PTD) 3, 7, 21, and 35, the general condition and area of wounds were observed and measured respectively. All the rats were sacrificed on PTD 35, and wound tissue was collected for histomorphological observation and determination of expressions of cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) using HE staining and immunohistochemical staining respectively. Data were processed with analysis of variance for repeated measurement, one-way analysis of variance, and Bonferroni post hoc test. (1) The experiment of peripheral circulatory disorders in diabetes. Compared with the plantar temperature of rats in group N, except for that in group CT in PTW 2 and groups M, S, and CT in PTW 3 (with t values from 0.258 to 2.647, P values above 0.05), the plantar temperature of rats with diabetes in the 4 groups at each time point was lowered significantly (with t values from 2.811 to 6.066, P values below 0.05). Compared with the plantar temperature of rats in group DS, except for that in group CT in PTW 2 and 3 significantly increased (with t values respectively 3.419 and 2.863, P values below 0.05), the plantar temperature of rats in groups M, S, and CT showed no significant difference at each time point (with t values from 0.128 to 1.654, P values above 0.05). The plantar hot pain threshold of rats was significantly decreased in group N than in the other 4 groups before treatment and group S in PTW 1 (with t values from 2.836 to 4.456, P values below 0.05). The plantar hot pain thresholds of rats in groups M, S, and CT were close to the hot pain threshold in group DS (with t values from 0.312 to 1.611, P values above 0.05). (2) The experiment of diabetic foot ulcers. Edema existed in all the wounds of rats on PTD 3. The wound areas of all the rats continued to increase with swelling and scar formation on PTD 7. On PTD 21, the scar of rats in groups N, S, and CT fell off; the wounds of rats in group DS were still swollen; scar of rats did not fall off with dark red in the skin around the wound in group M. On PTD 35, wounds of rats in groups N, S, and CT were nearly healed; while wounds of rats in groups DS and M were still swollen and the scar around the wound failed to fall off. On PTD 3 and 7, the wound areas of rats with diabetes in the 4 groups were close to those in group N (with t values from 0.111 to 1.476, P values above 0.05). On PTD 21, the wound area of rats in group DS was significantly larger than that in group N (t=5.502, P&lt;0.01), while the wound areas of rats with diabetes in the other 3 groups were close to the area in group N (with t values from 0.544 to 1.676, P values above 0.05). On PTD 21, the wound area of rats in group M was close to that in group DS (t=1.895, P&gt;0.05), while the wound areas of rats in groups S and CT were significantly smaller than the area in group DS (with t values respectively 5.809 and 3.426, P&lt;0.05 or P&lt;0.01). On PTD 35, the wound areas of rats in groups DS and M were significantly larger than the area in group N (with t values respectively 8.495 and 4.108, P values below 0.01), while the wound areas of rats in groups S and CT were close to the area in group N (with t values respectively 0.291 and 2.195, P values above 0.05). On PTD 35, the wound area of rats in group M was close to that in group DS (t=0.897, P&gt;0.05); while the wound areas of rats in groups S and CT were significantly smaller than the area in group DS (with t values respectively 6.923 and 6.583, P values below 0.01). On PTD 35, the structures of wound tissue were in better integrity with less inflammatory cells and more regularly arranged collagen fibers around the wounds of rats in groups N, S, and CT than in groups DS and M. On PTD 35, the expression levels of COX-2 and VEGF in the wounds of rats in group DS [respectively (222±89)% and (55±12)%] were close to those in group M [respectively (137±24)% and (94±36)%, with t values respectively 3.046 and 2.653, P values above 0.05]. On PTD 35, the expression level of COX-2 in the wounds of rats in group DS was significantly higher than the expression levels of COX-2 in groups N, S, and CT [respectively (100±35)%, (91±42)%, and (109±17)%, with t values from 4.039 to 4.653, P values below 0.01], while the expression level of VEGF in the wounds of rats in group DS was significantly lower than the expression levels of VEGF in groups N, S, and CT [respectively (100±28)%, (143±12)%, and (120±13)%, with t values from 3.363 to 5.905, P&lt;0.05 or P&lt;0.01]. S can improve the plantar temperature decrease and pain dysesthesia of rats caused by diabetic peripheral circulatory disorders. It also can promote wound healing of diabetic foot ulcers in rats with down-regulation of COX-2 and up-regulation of VEGF.

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There are few issues that generate as much confusion in diving medicine as the nomenclature of bubble-induced dysbaric disease. Prior to the late 1980s, the diagnosis 'decompression sickness' (DCS) was invoked for symptoms presumed to arise as a consequence of bubble formation from dissolved inert gas during or after decompression. These bubbles were known to form within tissues, and also to appear in the venous blood (presumably after forming in tissue capillaries). A second diagnosis, 'arterial gas embolism' (AGE) was invoked for symptoms presumed to arise when bubbles were introduced directly to the arterial circulation as a consequence of pulmonary barotrauma. This approach was predicated on an assumption that the underlying pathophysiology could usually be inferred from the nature and tempo of resulting symptoms. DCS was considered to exhibit a slower more progressive onset, symptoms were protean (including pain, rash, paraesthesias, subcutaneous swelling, and neurological symptoms), and the neurological manifestations were mainly attributable to spinal cord or inner ear involvement. In contrast, AGE was considered to exhibit a more precipitous onset (often immediately on surfacing), and the principal manifestation was stroke-like focal neurological impairment suggestive of cerebral involvement. In 1989 an association between a large persistent ('patent') foramen ovale (PFO) and serious neurological DCS was independently reported by two groups, and subsequently corroborated for neurological, inner ear, and cutaneous DCS by multiple studies. The assumed pathophysiological role of a PFO in this setting was to allow bubbles formed from inert gas in the venous blood to avoid removal in the pulmonary circulation and to enter the arterial circulation. These bubbles could then pass to the microcirculation of vulnerable target tissues where inward diffusion of supersaturated inert gas from the surrounding tissue could cause them to grow. This emergence of 'arterialisation' of venous bubbles as an important vector of harm in some forms of DCS resulted in a challenge to the use of traditional 'DCS/AGE' terminology. It was suggested that very early onset of cerebral symptoms after diving could be explained not only by arterial bubbles introduced by pulmonary barotrauma, but also by venous bubbles crossing a PFO into the arterial circulation. Moreover, once venous bubbles had entered the arterial circulation they were then technically 'arterial gas emboli'; thus creating confusion with arterial gas emboli from pulmonary barotrauma. To many commentators, it made little sense to use diagnostic labels (DCS and AGE) that implied a particular pathophysiology when the two disorders might be difficult to tell apart, and had mechanistic processes in common. An alternative approach derived at a UHMS workshop in 1991 was to shift from nomenclature that implied a particular pathophysiology, to a descriptive system that lumped both DCS and AGE together under the label "decompression illness" (DCI). Using this system, terms to describe the organ system(s) involved and the progression of symptoms were applied. For example, a diver with worsening upper arm pain after a dive could be suffering 'progressive musculoskeletal DCI'; and a diver who lost consciousness immediately on surfacing but regained consciousness minutes later would be considered to be suffering 'remitting cerebral DCI'. Classifying cases in this manner made considerable sense at a clinical level, particularly given that there was an emerging consensus that manifestations of DCS and AGE that potentially overlapped did not require different approaches to recompression treatment. This descriptive classification of bubble-induced dysbaric disease gained substantial traction in the community, though not always with a full appreciation by users of the intended nuances of its application. Indeed, it became increasingly common over time to see the terms DCS and DCI used interchangeably; for example, authors using the term DCI to specifically infer the consequences of bubble formation from dissolved gas. This highlights one of the shortcomings of the DCI terminology: it becomes confusing when discussing dysbaric disease at a theoretical or experimental level when the nature of the insult is known or there is a specific intent to discuss bubble formation either from dissolved gas or from pulmonary barotrauma. The potential for confusion between mechanisms and manifestations of DCS and AGE as one of the principle drivers for adopting the DCI terminology deserves further discussion. It is tempting to suggest that if venous bubbles cross a PFO into the arterial blood then any resulting symptoms should be considered a manifestation of 'AGE'. However, there seems little sense in re-naming the primary pathophysiological event (DCS caused by bubble formation from inert gas) just because the bubbles have distributed elsewhere; especially using a name that commonly infers a completely different primary event (bubble formation from pulmonary barotrauma). Moreover, there are grounds for suggesting that these two processes may not be as difficult to distinguish as previously believed. Venous inert gas bubbles are small, and of a similar size distribution to those used as bubble contrast during PFO testing. Decades of experience in testing thousands of divers (and other patients) for PFO using bubble-contrast echocardiograpy have shown that even when strongly positive (that is, large showers of bubbles enter the arterial circulation), symptoms of any sort are very rare. There are sporadic reports of evanescent visual or cerebral symptoms, but (to this author's knowledge) reports of the focal or multifocal cerebral infarctions that can be caused by large arterial bubbles introduced iatrogenically or by pulmonary barotrauma are lacking. One could argue that in the context of PFO testing the brain is not supersaturated with inert gas (which might cause small arterial bubbles to grow), but being such a 'fast tissue' nor is it likely to be after diving. Thus, while sustained showers of small inert gas bubbles crossing a PFO after diving appeal as a plausible cause of transient visual symptoms or dysexecutive syndromes after diving, they are less likely to be the cause of dramatic stroke-like events occurring early after surfacing. In the final edition of Bennett and Elliott it was suggested that one editorial approach to the terminology conundrum would be to utilise the traditional terminology (DCS and AGE) when referring specifically to the pathophysiology and manifestations of bubble formation from dissolved inert gas or pulmonary barotrauma respectively, and to utilise the descriptive (DCI) terminology in clinical discussions when a collective term is useful, or when discussing individual patients where there is either ambiguity about pathophysiology or no need to attempt a distinction. Diving and Hyperbaric Medicine recommends a similar approach. The journal is reluctant to attempt to generate or apply hard 'rules' in relation to terminology of bubble-induced dysbaric disease, but we strongly discourage use of the term 'arterial gas emboli(ism)' to characterise venous inert gas bubbles that cross a right-to-left shunt such as a PFO. The pathophysiological consequences of bubble formation from dissolved inert gas should be regarded as decompression sickness (DCS). There is an expectation that authors are cognisant of the above issues and attempt to adopt terminology that reflects these considerations and best suits the circumstances of their manuscript.

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Dear Editor, The 11th revision of the International Classification of Diseases and Related Health Problems (ICD-11), including the chapter on mental, behavioural and neurodevelopmental disorders, has been adopted unanimously by the 72nd World Health Assembly in Geneva on May 25, 2019. The endorsement of the new classification will not come into effect until January 1, 2022. Until that date, the Member States of the World Health Organization (WHO) will keep on using the ICD-10 for reporting data. The most significant innovations in the ICD-11 chapter, and the most important differences from the DSM-5, have been detailed elsewhere (Reed et al. 2019). Several issues debated in the process of development of the chapter - including the role of a dimensional component within a system that remains mainly based on categories, and the need for a further clinical characterization of the individual patient, in addition to the diagnosis, in order to guide the formulation of the prognosis and the management plan, have been also covered in the recent literature (Clark et al. 2017, Rebello et al. 2019, Fuss et al. 2019, Gureje et al. 2019, van Os et al. 2019, Fusar-Poli et al. 2019, Forbes et al. 2019, Gaebel et al. 2019, Patel 2019, Kotov et al. 2020, Maj et al. 2020, Sanislow et al. 2020). The training of professionals in the use of the ICD-11 chapter is now ongoing worldwide, under the coordination of a WHO International Advisory Group led by G.M. Reed. Educational courses have been conducted at the 18th and 19th World Congresses of Psychiatry (Mexico City, Mexico, September 27-30, 2018; and Lisbon, Portugal, August 21-24, 2019) (Giallonardo 2019, Pocai 2019, Perris 2020). A more comprehensive online 20-hr training course has been organized by the Naples WHO Collaborating Centre on Research and Training in Mental Health and the European Psychiatric Association from 9 to 30 April, 2021. The course has been coordinated by G.M. Reed and M. Maj, and has covered all the main sections of the ICD-11 chapter on mental disorders. W. Gaebel, M. Cloitre, M. Maj, C.S. Kogan, P. Monteleone, M. Swales, J.B. Saunders and N.A. Fineberg composed the Faculty. The live course has been attended by 120 psychiatrists, selected from almost 500 applicants, representing 78 different countries. A further group of 250 psychiatrists have had access to the course on demand. Two ICD-11 training sessions have been organized by the Psychiatric Association of Turkey within its 24th Clinical Education Symposium, held from 2 to 6 June 2021. One covered psychotic disorders and mood disorders, with the participation of W. Gaebel and M. Maj and the chairmanship of S. Vahip and C. Atbasoglu. The other dealt with trauma-related, fear-related and obsessive-compulsive disorders, with the participation of M. Cloitre and D.J. Stein and the chairmanship of R. Tukel and C. Kilic. Each session had more than 150 participants. An ICD-11 training event has been also organized by the UK Royal College of Psychiatrists from 25 to 26 May 2021. One further educational event is now going to be held by the World Psychiatric Association from 8 to 29 November 2021 (www.wpanet.org). A training course with exclusive access to the members of the WHO Global Clinical Practice Network (https://gcp.network) has been recently set up by the WHO Collaborating Centre on Mental Health at the Columbia University, in collaboration with the WHO Department of Mental Health and Substance Use. The course consists of 15 online training units, each focusing on a different disorder grouping and EDUCATIONAL ACTIVITIES RELATED TO THE ICD-11 CHAPTER ON MENTAL DISORDERS 292 Received: 13.09.2021, Accepted: 15.09.2021, Available Online Date: 30.11.2021 MD., University of Campania L. Vanvitelli, WHO Collaborating Centre for Research and Training in Mental Health, Naples, Italy. Dr. Vincenzo Giallonardo, e-mail: [email protected] https://doi.org/10.5080/u26898 taking from one to one and a half hours. Each unit provides a description of the relevant diagnostic grouping and the main innovations with respect to the ICD-10. Knowledge check questions are included to test the outcome of training. Participants have the opportunity to practice by applying diagnostic guidelines to clinical case examples. This training course is going to be available also in Spanish, and additional translations are planned. The WHO Global Clinical Practice Network now includes more than 16.000 clinicians from 159 countries (51% psychiatrists, 30% psychologists; 40% from Europe, 25% from Western Pacific, 24% from the Americas, 5% from Southeast Asia, 3% from Eastern Mediterranean, and 3% from Africa; 63% from high-income countries, 37% from middle- and low-income countries). The Network contributed significantly to the development of the ICD-11 chapter on mental disorders, in particular through its participation in the Internet field trials of the diagnostic system. It is now further serving as a catalyst for scientific and clinical research collaborations. All health professionals working in mental health or primary care are welcome to join the Network. Vincenzo GİALLONARDO REFERENCES Clark L, Cuthbert B, Lewis-Fernández R et al (2017). Three approaches to understanding and classifying mental disorder: ICD-11, DSM-5, and the National Institute of Mental Health's Research Domain Criteria (RDoC) Psychol Sci Public Interest 18:72-145. Forbes MK, Wright AGC, Markon KE et al (2019) The network approach to psychopathology: promise versus reality. World Psychiatry 18:272-3. Fusar-Poli P, Solmi M, Brondino N et al (2019) Transdiagnostic psychiatry: a systematic review. World Psychiatry 8:192-207. Fuss J, Lemay K, Stein DJ et al (2019) Public stakeholders' comments on ICD-11 chapters related to mental and sexual health. World Psychiatry 18:233-5. Giallonardo V (2019) ICD-11 sessions within the 18th World Congress of Psychiatry. World Psychiatry 18:115-6 Gaebel W, Reed GM, Jakob R (2019) Neurocognitive disorders in ICD-11: a new proposal and its outcome. World Psychiatry 18:232-3. Gureje O, Lewis-Fernandez R, Hall BJ et al (2019) Systematic inclusion of culture-related information in ICD-11. World Psychiatry 18:357-8. Kotov R, Jonas KG, Carpenter WT et al (2020) Validity and utility of Hierarchical Taxonomy of Psychopathology (HiTOP): I. Psychosis superspectrum. World Psychiatry 19:151-72. Maj M, Stein DJ, Parker G et al (2020) The clinical characterization of the adult patient with depression aimed at personalization of management. World Psychiatry 19:269-93. Patel V (2019) Reimagining outcomes requires reimagining mental health conditions. World Psychiatry 18:286-7. Perris F (2020) ICD-11 sessions at the 19th World Congress of Psychiatry. World Psychiatry 19:263-4. Pocai B (2019) The ICD-11 has been adopted by the World Health Assembly. World Psychiatry 18:371-2. Rebello TJ, Keeley JW, Kogan CS et al (2019) Anxiety and fear-related disorders in the ICD-11: results from a global case-controlled field study. Arch Med Res 50:490-501. Reed GM, First MB, Kogan CS et al (2019) Innovations and changes in the ICD-11 classification of mental, behavioural and neurodevelopmental disorders. World Psychiatry 18:3-19. Sanislow CA (2020) RDoC at 10: changing the discourse for psychopathology. World Psychiatry 19:311-2. van Os J, Guloksuz S, Vijn TW et al (2019) The evidence-based group-level symptom-reduction model as the organizing principle for mental health care: time for change? World Psychiatry 18:88-96.

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Once they have been generated, polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) and other persistent organic pollutants (POPs) can persist in soils and sediments and in waste repositories for periods extending from decades to centuries. In 1994, the US EPA concluded that contaminated sites and other reservoirs are likely to become the major source of contemporary pollution problems with these substances. With this in mind, this article is the first in a new series in ESPR under the title 'Case Studies on Dioxin and POP Contaminated Sites--Contemporary and Future Relevance and Challenges', which will address this important issue. The series will document various experiences from sites contaminated with PCDD/F and other POPs. This article provides an overview of the content of the articles comprising the series. In addition, it provides a review of the subject in its own right and identifies the key issues arising from dioxin/POP-contaminated sites. Additionally, it highlights the important conclusions that can be drawn from these examples. The key aim of this article and of the series as a whole is to provide a comprehensive overview of the types of PCDD/F contaminated sites that exist as a result of historical activities. It details the various processes whereby these sites became contaminated and attempts to evaluate their contemporary relevance as sources of PCDD/Fs and other POPs. It also details the various strategies used to assess these historical legacies of contamination and the concepts developed, or which are under development, to effect their remediation. Special sessions on 'Contaminated sites--Cases, remediation, risk and policy' were held at the DIOXIN conferences in 2006 and 2007, and this theme will be continued at DIOXIN 2008 to be held in Birmingham. Selected cases from the approximately 70 contributions made to these sessions, together with some additional invited case studies are outlined together with the key issues they raise. By evaluating these cases and adding details of experiences published in the current literature, an overview will be given of the different features and challenges of dioxin and POP-contaminated sites. This article provides a systematic categorisation of types of PCDD/F and POP-contaminated sites. These are categorised according to the chemical or manufacturing process, which generated the PCDD/Fs or POPs and also includes the use and disposal aspects of the product life cycle in question. The highest historical PCDD/F and dioxin-like polychlorinated biphenyl (PCB) contamination burdens have arisen as a result of the production of chlorine and of chlorinated organic chemicals. In particular, the production of chlorinated pesticides, PCBs and the related contaminated waste streams are identified being responsible for historical releases of toxic equivalents (TEQs) at a scale of many tonnes. Along with such releases, major PCDD/F contaminated sites have been created through the application or improper disposal of contaminated pesticides, PCBs and other organochlorine chemicals, as well through the recycling of wastes and their attempted destruction. In some extreme examples, PCDD/F contaminated sites have also resulted from thermal processes such as waste incinerators, secondary metal industries or from the recycling or deposition of specific waste (e.g. electronic waste or car shredder wastes), which often contain chlorinated or brominated organic chemicals. The examples of PCDD/F and dioxin-like PCB contamination of fish in European rivers or the impact of contaminated sites upon fishing grounds and upon other food resources demonstrate the relevance of these historical problems to current and future human generations. Many of the recent food contamination problems that have emerged in Europe and elsewhere demonstrate how PCDD/F and dioxin like PCBs from historical sources can directly contaminate human and animal feedstuffs and indeed highlight their considerable contemporary relevance in this respect. Accordingly, some key experiences and lessons learnt regarding the production, use, disposal and remediation of POPs from the contaminated sites are summarised. An important criterion for evaluating the significance and risks of PCDD/Fs and other POPs at contaminated sites is their present or future potential for mobility. This, in turn, determines to a large degree their propensity for off-site transport and environmental accessibility. The detailed evaluation of contaminated site cases reveals different site-specific factors, which influence the varied pathways through which poor water-soluble POPs can be mobilised. Co-contaminants with greater water solubility are also typically present at such sites. Hence, pumping of groundwater (pump and treat) is often required in addition to attempting to physically secure a site. At an increasing number of contaminated sites, securing measures are failing after relatively short time spans compared to the time horizon, which applies to persistent organic pollutant contamination. Due to the immense costs and challenges associated with remediation of contaminated sites 'monitored natural attenuation' is increasingly gaining purchase as a conceptual remediation approach. However, these concepts may well prove limited in their practical application to contaminated sites containing persistent organic pollutants and other key pollutants like heavy metals. It is inevitable, therefore, that dioxin/POP-contaminated sites will remain of contemporary and future relevance. They will continue to represent an environmental issue for future generations to address. The securing and/or remediation of dioxin/POP-contaminated sites is very costly, generally in the order of tens or hundreds of millions of dollars. Secured landfills and secured production sites need to be considered as constructions not made for 'eternity' but built for a finite time scale. Accordingly, they will need to be controlled, supervised and potentially repaired/renewed. Furthermore, the leachates and groundwater impacted by these sites will require ongoing monitoring and potential further remediation. These activities result in high maintenance costs, which are accrued for decades or centuries and should, therefore, be compared to the fully sustainable option of complete remediation. The contaminated site case studies highlight that, while extensive policies and established funds for remediation exist in most of the industrialised western countries, even these relatively well-regulated and wealthy countries face significant challenges in the implementation of a remediation strategy. This highlights the fact that ultimately only the prevention of contaminated sites represents a sustainable solution for the future and that the Polluter Pays Principle needs to be applied in a comprehensive way to current problems and those which may emerge in the future. With the continuing shift of industrial activities in developing and transition economies, which often have poor regulation (and weak self-regulation of industries), additional global challenges regarding POPs and other contaminated sites may be expected. In this respect, a comprehensive application of the "polluter pays principle" in these countries will also be a key to facilitate the clean-up of contaminated areas and the prevention of future contaminated sites. The threats and challenges of contaminated sites and the high costs of securing/remediating the problems highlight the need for a comprehensive approach based upon integrated pollution prevention and control. If applied to all polluting (and potentially polluting) industrial sectors around the globe, such an approach will prove to be both the cheapest and most sustainable way to underpin the development of industries in developing and transition economies.

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Since the first U.S. infant conceived with assisted reproductive technology (ART) was born in 1981, both the use of ART and the number of fertility clinics providing ART services have increased steadily in the United States. ART includes fertility treatments in which eggs or embryos are handled in the laboratory (i.e., in vitro fertilization [IVF] and related procedures). Women who undergo ART procedures are more likely than women who conceive naturally to deliver multiple-birth infants. Multiple births pose substantial risks to both mothers and infants, including obstetric complications, preterm delivery, and low birthweight infants. This report provides state-specific information for the United States (including Puerto Rico) on ART procedures performed in 2013 and compares infant outcomes that occurred in 2013 (resulting from ART procedures performed in 2012 and 2013) with outcomes for all infants born in the United States in 2013. 2013. In 1996, CDC began collecting data on ART procedures performed in fertility clinics in the United States as mandated by the Fertility Clinic Success Rate and Certification Act of 1992 (FCSRCA) (Public Law 102-493). Data are collected through the National ART Surveillance System (NASS), a web-based data collection system developed by CDC. This report includes data from 52 reporting areas (the 50 states, the District of Columbia [DC], and Puerto Rico). In 2013, a total of 160,521 ART procedures (range: 109 in Wyoming to 20,299 in California) with the intent to transfer at least one embryo were performed in 467 U.S. fertility clinics and were reported to CDC. These procedures resulted in 53,252 live-birth deliveries (range: 47 in Alaska to 6,979 in California) and 66,691 infants (range: 61 in Alaska to 8,649 in California). Nationally, the total number of ART procedures performed per million women of reproductive age (15-44 years), a proxy measure of the ART usage rate, was 2,521 (range: 352 in Puerto Rico to 7,688 in DC). ART use exceeded the national rate in 13 reporting areas (California, Connecticut, Delaware, Hawaii, Illinois, Maryland, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, Virginia, and DC). Nationally, among ART transfer procedures in patients using fresh embryos from their own eggs, the average number of embryos transferred increased with increasing age of the woman (1.8 among women aged &lt;35 years, 2.0 among women aged 35-37 years, and 2.5 among women aged &gt;37 years). Among women aged &lt;35 years, who typically are considered to be good candidates for elective single embryo transfer (eSET) procedures, the national eSET rate was 21.4% (range: 4.0% in Idaho to 77.5% in Delaware). In 2013, ART contributed to 1.6% of all infants born in the United States (range: 0.2% in Puerto Rico to 4.8% in Massachusetts) and 18.7% of all multiple-birth infants (range: 4.5% in Puerto Rico to 35.7% in Massachusetts), including 18.5% of all twin infants (range: 4.5% in Mississippi to 35.3% in Massachusetts) and 25.2% of all triplet and higher-order infants (range: 0% in several reporting areas to 51.5% in New Jersey). Multiple-birth deliveries were higher among infants conceived with ART (41.1%; range: 20.4% in Delaware to 61.6% in Wyoming) than among all infants born in the total birth population (only 3.5%; range: 1.8% in Puerto Rico to 4.5% in Massachusetts and New Jersey). Approximately 39% of ART-conceived infants were twin infants, and 2% were triplet and higher-order infants. ART-conceived twins accounted for approximately 95.4% of all ART-conceived infants born in multiple deliveries. Nationally, infants conceived with ART contributed to 5.8% of all low birthweight (&lt;2,500 grams) infants (range: 0.9% in Puerto Rico to 15.1% in Massachusetts). Among ART-conceived infants, 29.1% were low birthweight (range: 18.3% in Delaware to 42.6% in Louisiana), compared with 8.0% among all infants (range: 5.8% in Alaska to 11.5% in Mississippi). ART-conceived infants contributed to 4.6% of all preterm (&lt;37 weeks) infants (range: 0.6% in Puerto Rico to 13.3% in Massachusetts). Preterm birth rates were higher among infants conceived with ART (33.6%; range: 22.3% in DC to 50.7% in Louisiana) than among all infants born in the total birth population (11.4%; range: 8.8% in California to 16.6% in Mississippi). The percentage of ART-conceived infants who were low birthweight was 9.0% (range: 5.1% in Mississippi to 19.7% in Puerto Rico) among singletons and 56.3% (range: 48.3% in Maine to 72.4% in Puerto Rico) among twins; the corresponding percentages among all infants born were 6.3% for singletons (range: 4.6% in Alaska to 9.6% in Mississippi and Puerto Rico) and 55.3% for twins (range: 43.6% in Alaska to 65.6% in Mississippi). The percentage of ART-conceived infants who were preterm varied from 13.3% (range: 8.7% in Rhode Island to 26.9% in West Virginia) among singletons to 61.0% (range: 47.8% in DC to 78.8% in Oklahoma) among twins; the corresponding percentages among all infants were 10.1% for singletons (range: 6.8% in Vermont to 14.8% in Mississippi) and 56.6% for twins (range: 44.7% in New Hampshire to 68.9% in Louisiana). The percentage of infants conceived with ART varied considerably by reporting area. In most reporting areas, multiple births from ART contributed to a substantial proportion of all twins, triplets, and higher-order infants born, and the low birthweight and preterm infant birth rates were disproportionately higher among ART-conceived infants than among the overall birth population. Although women aged &lt;35 years are typically considered good candidates for eSET, on average two embryos were transferred per ART procedure with women in this group, increasing the overall multiple-birth rates in the United States. Compared with ART-conceived singletons, ART-conceived twins were approximately four-and-a-half times more likely to be born preterm, and approximately six times more likely to be born with low birthweight. Singleton infants conceived with ART had slightly higher rates of preterm delivery and low birthweight than all singleton infants born in the United States. ART use per population unit was geographically variable, with 13 reporting areas showing ART use above the national rate. Of the four states (Illinois, Massachusetts, New Jersey, and Rhode Island) with comprehensive statewide-mandated health insurance coverage for ART procedures (i.e., coverage for at least four cycles of IVF), two states (Massachusetts and New Jersey) had rates of ART use exceeding twice the national level. This type of mandated insurance has been associated with greater use of ART and likely accounts for some of the difference in per capita ART use observed among states. Reducing the number of embryos transferred per ART procedure and increasing use of eSET, when clinically appropriate (typically for women aged &lt;35 years), could help reduce multiple births, particularly ART-conceived twin infants, and related adverse consequences of ART. Because twins account for the majority of ART-conceived multiple births, improved patient education and counseling on the maternal and infant health risks of having twins is needed. Although ART contributes to high rates of multiple births, other factors not investigated in this report (e.g., delayed childbearing and non-ART fertility treatments) also contribute to multiple births and warrant further study.

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The results above reported lead to the conclusion that while in the degenerating cells chemical changes are taking place tending toward a diminution of the hexon bases as a whole, they affect the arginin especially. One may picture the process either as a partial or as a complete breaking down of certain proteid. material more or less rich in hexon bases, leaving behind. proteid matter poorer in bases. The meaning of these changes is, however, obscure, and with the limited number of known facts bearing upon the subject, it would seem idle even to attempt to formulate an hypothesis to explain them. Certain work of other investigators is, however, suggestive in this connection. Kossel and Dakin, for instance, as illustrated by their work upon the simple proteid body clupein, found that a partial destruction of the proteid molecule, involving the arginin group, is brought about by a ferment furnished by the animal organism. When subjected to the hydrolytic action of a mineral acid, clupein yields arginin in considerable abundance. But if the clupein is first acted upon by the ferment arginase found in the liver, and then subjected to acid hydrolysis, the yield of arginin is appreciably diminished. Among the cleavage products in the latter instance are the components of arginin, namely, omithin and urea. It would seem, therefore, as if the ferment had loosened the union between the omithin and urea in the arginin group, so that upon subsequent hydrolysis a diminution of arginin resulted. In the cases studied by me, it may be that the conditions were favorable for some such ferment action as that above described, and hence the relatively low yield of arginin. No attempt, however, was made to ascertain if omithin were present in the urine. Its presence there would seem not wholly unlikely when one considers the diminished power of oxidation of the phosphorus-poisoned cell, although Thompson has shown that arginin or omithin when administered to a healthy dog as food or by hypodermic injection is eliminated for the most part as urea, no ornithin being found. There might seem to be a conflict between this view and the results recently published by Wohlgemuth, but it must be borne in mind that the influences at work causing the breaking down of the proteid molecule are probably quite diverse in character. Wohlgemuth has recently shown for the first time that a diamino acid may actually find its way into the urine in phosphorus poisoning. He found arginin in the urine not only in rabbits poisoned with phosphorus but also in a patient suffering from phosphorus poisoning. On the other hand, he was unable to find lysin in the urine. This fact is of especial interest in view of the evidence set forth in this paper that the arginin base is lost to the proteid molecule more rapidly than the lysin base. The correspondence between the findings in the liver and in the urine is thus a close one. How much of the arginin liberated from the proteid molecule may find its way into the urine is of course uncertain. It seems reasonable to suppose that a portion of the base is acted upon by the arginase ferment in the manner already described. Of the seventeen to eighteen cleavage products of the proteid molecule thus far isolated, the hexon bases are among the most stable. One or more of these bases have been found in practically all proteid matter thus far investigated; in fact arginin is so uniformly present that Kossel has made the suggestion that it is the kernel of the proteid molecule. At all events, the question may be asked, whether, if the influences at work in the altered liver tissue were of a general character causing a diminution of the hexon bases, the monoamino acid groups would not suffer even a greater diminution; and since the pathological condition is undoubtedly associated with impaired oxidation, their presence should not be expected in the urine. As a matter of fact, Ignatowski found considerable quantities of monoamino acids in the urine of patients suffering from gout, pneumonia, and leukaemia, though under normal conditions no monoamino acids were found in the urine, indeed, not even after the subcutaneous injection of glycokoll. Furthermore, the loosening of the amino acids from the proteid molecule is suggested by the fact that Taylor found such acids in the liver of a patient who died from a hepatic disease of obscure etiology, but which he was inclined to attribute to chloroform poisoning. Taylor found not only leucin and tyrosin in the liver, but also arginin, a fact not without interest in view of the diminished arginin content found in the livers of the chloroformed dogs after acid hydrolysis. Moreover, the falling off of the hexon bases under the conditions studied seems quite in accordance with some results recently reported by Levene. He has shown that certain cleavage products obtained by the action of mineral acids upon self-digested pancreas, spleen, and liver, are much diminished when compared with the products obtained from the fresh glands. The lysin and arginin of the digested liver, for example, showed a diminution of over 50 per cent. It is now well established that in course of the process of aseptic autolysis, the proteids of the liver cell undergo decomposition into simpler substances, and Jacoby showed that during life autolysis may go on in portions of the liver in which the circulation has been hindered. But of greater significance still in this connection, is the observation made by Jacoby on the autolytic changes in the liver during phosphorus poisoning. He found that when the normal liver substance is permitted to autolyse the solution of the liver substance is a slow one. On the other hand, under similar conditions the liver of a phosphorus-poisoned animal undergoes rapid and almost complete solution. The difference in the behavior of the normal and damaged liver points to an increase of normal ferment action in the case of the poisoned organ. It thus seems reasonable to suppose that in phosphorus poisoning we have during life an exaggerated breaking down of the proteid molecule associated with an over-action of certain ferments, and among them probably arginase. The pathological process in the liver during life may, therefore, be thought of as proceeding in the same general direction as the process of post-morten autolytic decomposition. By means of further studies along lines indicated in this paper, it should be possible to gain a deeper insight into numerous pathological processes. The changes in amyloid degeneration are among those which promise to be better understood through the application of the new methods of chemical analysis. Moreover, it cannot be doubted that pharmacology as well as toxicology has much to gain from a study of what happens to the proteid molecule under the influence of poisons.

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EXECUTIVE SUMMARY: Objectives  The primary objective of this review was to determine, from the available evidence, the effectiveness of an antenatal and/or a post-natal program of pelvic floor muscle exercises (PFME) compared with usual care on preventing, reducing or resolving the incidence and severity of stress incontinence, urge incontinence or mixed stress and urge urinary incontinence following childbirth. Secondary objectives were included to examine the effectiveness of a PFME program on pelvic floor muscle strength and on encouraging adherence to an exercising program. TYPES OF STUDIES: Randomised controlled trials and non-randomised controlled trials were included in the review if, in relation to urinary incontinence, and/or adherence to a PFME program, and/or pelvic floor muscle strength, the following had been explored: • antenatal PFME compared with usual care; • post-natal PFME compared with usual care; • a PFME program compared with usual care. Usual care is commonly used to describe the care women normally receive from health professionals in the antenatal and/or post-natal period. In some cases usual care includes a standard information package given to all women attending the health service and in others it is advice about performing PFME. Participants included women who experienced a spontaneous onset of labour and who subsequently delivered at more than 20 weeks gestation either vaginally, both spontaneous and assisted, or by non-elective caesarean section. • women who delivered by elective caesarean section; • women experiencing post-partum overflow urinary incontinence. 1 Pelvic floor muscle exercises. 2 PFME instruction and a PFME program's components, such as educational materials, feedback (including biofeedback, e.g. information about strength of pelvic floor muscle contractions by various means) and number of PFME. • electrical stimulation of pelvic floor muscles; • vaginal cones; or • other adjunct therapies. In studies that included a subgroup treated with one of these interventions, the results of the subgroup were excluded from the review's analysis. Outcomes that were of interest: • non-occurrence of urinary incontinence following childbirth; • a change in the frequency, duration or severity (as appropriate) of urinary incontinence up to 12 months following childbirth. • a change in the strength of pelvic floor muscle contractions; • period of time PFME continued after initial instruction; • frequency of PFME undertaken; • women's awareness of the importance of PFME; • satisfaction with PFME instruction. Search strategy  All major electronic sources of information relevant to the topic (e.g. PubMed, CINAHL and the Cochrane Library) were searched to identify published and unpublished studies and previous work in the field. Printed journals were hand-searched and reference lists checked for potentially useful research. The review included any studies undertaken between 1981 and 2003. The search did not attempt to locate unpublished research before 1991. Assessment of quality  An independent Review Panel carried out quality assessment of studies. Two members of the panel, using quality assessment checklists developed for the review, reviewed each study. Disagreements between reviewers were resolved through discussion or a third reviewer examining a study. Data extraction and analysis  A data extraction tool was developed to extract data relating to participant characteristics, study methods, interventions and outcomes. Two reviewers independently extracted the required data. Randomised controlled trials included in the review were pooled in several meta-analyses using RevMan software program. Heterogeneity between studies was determined to ensure that they were sufficiently similar to allow for the pooling of their results. Non-randomised controlled trials were discussed in narrative comparisons. Results  Six randomised controlled trials met the inclusion criteria for the primary objective of the systematic review. The results of this review indicate that antenatal PFME and post-natal PFME are effective in resolving or reducing urinary incontinence following childbirth. There was insufficient evidence to conclude that PFME can prevent urinary incontinence in post-partum women. In most of these studies women were selected randomly and therefore included women without urinary incontinence and women with urinary incontinence. Two randomised controlled trials selected their sample on the criteria of existing post-partum urinary incontinence. A subgroup analysis of these studies showed that post-natal PFME also have a significant effect on reducing or resolving urinary incontinence in women with existing post-partum urinary incontinence. Seven randomised controlled trials and three non-randomised controlled trials met the inclusion criteria for the secondary objectives of the review. Findings of the studies included in the review suggest a PFME program will improve the frequency with which women perform PFME. Two studies found that women receiving the intervention (a PFME program) and who were performing PFME regularly in the month before data collection were significantly less likely to have any incontinence. The review's results support previous findings showing there is little evidence that a high-intensity PFME program is more effective than a low-intensity PFME regimen of exercising. No conclusions about the effectiveness of feedback to a woman about pelvic floor muscle strength, for example, perineometer measures, as part of a PFME program can be reached. The mixed results of this review mean that no conclusions can be reached about the effectiveness of a PFME program, antenatal or post-natal, on improving pelvic floor muscle strength. A number of studies reported a high percentage of women lost to follow-up and the data collected in most of the studies relied on self-reports relating to urinary incontinence and/or frequency of exercising. These factors may have affected the overall results of the review. However, wherever possible, tests for heterogeneity were carried out to determine if studies should be combined in meta-analyses and in other cases the results' limitations are acknowledged. Implications for practice  In terms of the effectiveness of PFME programs, the results of this review indicate that urinary incontinence following childbirth can be improved by performing PFME and that any form of a specific PFME program appears to improve exercising frequency. However, the value of individual components of PFME programs, such as take-home materials, reminder telephone calls and feedback of exercising effectiveness, is less clear. • Encourage women to undertake both antenatal and post-natal PFME (E1). • Pay particular attention to women with antenatal and post-natal urinary incontinence in providing advice and PFME instruction (E1). • To encourage adherence and continuation, PFME education programs should be multifaceted with a number of components, rather than only supplying an information booklet (E4). • Include PFME as a specific program in all antenatal and post-natal care, incorporating at least two individual instruction sessions into the program (E1). • Provide post-partum contact, particularly for those discharged early, either by telephone, electronic or home visits (E4). • Design pelvic floor muscle home exercise programs that are realistic given the demands on a mother and that can be incorporated into her daily routine in terms of number and frequency. Two or more training sessions per week are recommended (E4). • Health professionals working with women in the post-partum period should ask about symptoms of incontinence to ensure assistance is offered to those experiencing urinary incontinence (E4).

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Physical trauma affects 1 in 12 pregnant women and has a major impact on maternal mortality and morbidity and on pregnancy outcome. A multidisciplinary approach is warranted to optimize outcome for both the mother and her fetus. The aim of this document is to provide the obstetric care provider with an evidence-based systematic approach to the pregnant trauma patient. Significant health and economic outcomes considered in comparing alternative practices. Published literature was retrieved through searches of Medline, CINAHL, and The Cochrane Library from October 2007 to September 2013 using appropriate controlled vocabulary (e.g., pregnancy, Cesarean section, hypotension, domestic violence, shock) and key words (e.g., trauma, perimortem Cesarean, Kleihauer-Betke, supine hypotension, electrical shock). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies published in English between January 1968 and September 2013. Searches were updated on a regular basis and incorporated in the guideline to February 2014. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. The quality of evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1). This guideline is expected to facilitate optimal and uniform care for pregnancies complicated by trauma. Summary Statement Specific traumatic injuries At this time, there is insufficient evidence to support the practice of disabling air bags for pregnant women. (III) Recommendations Primary survey 1. Every female of reproductive age with significant injuries should be considered pregnant until proven otherwise by a definitive pregnancy test or ultrasound scan. (III-C) 2. A nasogastric tube should be inserted in a semiconscious or unconscious injured pregnant woman to prevent aspiration of acidic gastric content. (III-C) 3. Oxygen supplementation should be given to maintain maternal oxygen saturation &gt; 95% to ensure adequate fetal oxygenation. (II-1B) 4. If needed, a thoracostomy tube should be inserted in an injured pregnant woman 1 or 2 intercostal spaces higher than usual. (III-C) 5. Two large bore (14 to 16 gauge) intravenous lines should be placed in a seriously injured pregnant woman. (III-C) 6. Because of their adverse effect on uteroplacental perfusion, vasopressors in pregnant women should be used only for intractable hypotension that is unresponsive to fluid resuscitation. (II-3B) 7. After mid-pregnancy, the gravid uterus should be moved off the inferior vena cava to increase venous return and cardiac output in the acutely injured pregnant woman. This may be achieved by manual displacement of the uterus or left lateral tilt. Care should be taken to secure the spinal cord when using left lateral tilt. (II-1B) 8. To avoid rhesus D (Rh) alloimmunization in Rh-negative mothers, O-negative blood should be transfused when needed until cross-matched blood becomes available. (I-A) 9. The abdominal portion of military anti-shock trousers should not be inflated on a pregnant woman because this may reduce placental perfusion. (II-3B) Transfer to health care facility 10. Transfer or transport to a maternity facility (triage of a labour and delivery unit) is advocated when injuries are neither life- nor limb-threatening and the fetus is viable (≥ 23 weeks), and to the emergency room when the fetus is under 23 weeks' gestational age or considered to be non-viable. When the injury is major, the patient should be transferred or transported to the trauma unit or emergency room, regardless of gestational age. (III-B) 11. When the severity of injury is undetermined or when the gestational age is uncertain, the patient should be evaluated in the trauma unit or emergency room to rule out major injuries. (III-C) Evaluation of a pregnant trauma patient in the emergency room 12. In cases of major trauma, the assessment, stabilization, and care of the pregnant women is the first priority; then, if the fetus is viable (≥ 23 weeks), fetal heart rate auscultation and fetal monitoring can be initiated and an obstetrical consultation obtained as soon as feasible. (II-3B) 13. In pregnant women with a viable fetus (≥ 23 weeks) and suspected uterine contractions, placental abruption, or traumatic uterine rupture, urgent obstetrical consultation is recommended. (II-3B) 14. In cases of vaginal bleeding at or after 23 weeks, speculum or digital vaginal examination should be deferred until placenta previa is excluded by a prior or current ultrasound scan. (III-C) Adjunctive tests for maternal assessment 15. Radiographic studies indicated for maternal evaluation including abdominal computed tomography should not be deferred or delayed due to concerns regarding fetal exposure to radiation. (II-2B) 16. Use of gadolinium-based contrast agents can be considered when maternal benefit outweighs potential fetal risks. (III-C) 17. In addition to the routine blood tests, a pregnant trauma patient should have a coagulation panel including fibrinogen. (III-C) 18. Focused abdominal sonography for trauma should be considered for detection of intraperitoneal bleeding in pregnant trauma patients. (II-3B) 19. Abdominal computed tomography may be considered as an alternative to diagnostic peritoneal lavage or open lavage when intra-abdominal bleeding is suspected. (III-C) Fetal assessment 20. All pregnant trauma patients with a viable pregnancy (≥ 23 weeks) should undergo electronic fetal monitoring for at least 4 hours. (II-3B) 21. Pregnant trauma patients (≥ 23 weeks) with adverse factors including uterine tenderness, significant abdominal pain, vaginal bleeding, sustained contractions (&gt; 1/10 min), rupture of the membranes, atypical or abnormal fetal heart rate pattern, high risk mechanism of injury, or serum fibrinogen &lt; 200 mg/dL should be admitted for observation for 24 hours. (III-B) 22. Anti-D immunoglobulin should be given to all rhesus D-negative pregnant trauma patients. (III-B) 23. In Rh-negative pregnant trauma patients, quantification of maternal-fetal hemorrhage by tests such as Kleihauer-Betke should be done to determine the need for additional doses of anti-D immunoglobulin. (III-B) 24. An urgent obstetrical ultrasound scan should be undertaken when the gestational age is undetermined and need for delivery is anticipated. (III-C) 25. All pregnant trauma patients with a viable pregnancy who are admitted for fetal monitoring for greater than 4 hours should have an obstetrical ultrasound prior to discharge from hospital. (III-C) 26. Fetal well-being should be carefully documented in cases involving violence, especially for legal purposes. (III-C) Obstetrical complications of trauma 27. Management of suspected placental abruption should not be delayed pending confirmation by ultrasonography as ultrasound is not a sensitive tool for its diagnosis. (II-3D) Specific traumatic injuries 28. Tetanus vaccination is safe in pregnancy and should be given when indicated. (II-3B) 29. Every woman who sustains trauma should be questioned specifically about domestic or intimate partner violence. (II-3B) 30. During prenatal visits, the caregiver should emphasize the importance of wearing seatbelts properly at all times. (II-2B) Perimortem Caesarean section 31. A Caesarean section should be performed for viable pregnancies (≥ 23 weeks) no later than 4 minutes (when possible) following maternal cardiac arrest to aid with maternal resuscitation and fetal salvage. (III-B).

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In response to the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the impact of coronavirus disease 2019 (COVID-19), governments have implemented a variety of measures to control the spread of the virus and the associated disease. Among these, have been measures to control the pandemic in primary and secondary school settings. To assess the effectiveness of measures implemented in the school setting to safely reopen schools, or keep schools open, or both, during the COVID-19 pandemic, with particular focus on the different types of measures implemented in school settings and the outcomes used to measure their impacts on transmission-related outcomes, healthcare utilisation outcomes, other health outcomes as well as societal, economic, and ecological outcomes.  SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and the Educational Resources Information Center, as well as COVID-19-specific databases, including the Cochrane COVID-19 Study Register and the WHO COVID-19 Global literature on coronavirus disease (indexing preprints) on 9 December 2020. We conducted backward-citation searches with existing reviews. We considered experimental (i.e. randomised controlled trials; RCTs), quasi-experimental, observational and modelling studies assessing the effects of measures implemented in the school setting to safely reopen schools, or keep schools open, or both, during the COVID-19 pandemic. Outcome categories were (i) transmission-related outcomes (e.g. number or proportion of cases); (ii) healthcare utilisation outcomes (e.g. number or proportion of hospitalisations); (iii) other health outcomes (e.g. physical, social and mental health); and (iv) societal, economic and ecological outcomes (e.g. costs, human resources and education). We considered studies that included any population at risk of becoming infected with SARS-CoV-2 and/or developing COVID-19 disease including students, teachers, other school staff, or members of the wider community.  DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles, abstracts and full texts. One review author extracted data and critically appraised each study. One additional review author validated the extracted data. To critically appraise included studies, we used the ROBINS-I tool for quasi-experimental and observational studies, the QUADAS-2 tool for observational screening studies, and a bespoke tool for modelling studies. We synthesised findings narratively. Three review authors made an initial assessment of the certainty of evidence with GRADE, and several review authors discussed and agreed on the ratings. We included 38 unique studies in the analysis, comprising 33 modelling studies, three observational studies, one quasi-experimental and one experimental study with modelling components. Measures fell into four broad categories: (i) measures reducing the opportunity for contacts; (ii) measures making contacts safer; (iii) surveillance and response measures; and (iv) multicomponent measures. As comparators, we encountered the operation of schools with no measures in place, less intense measures in place, single versus multicomponent measures in place, or closure of schools. Across all intervention categories and all study designs, very low- to low-certainty evidence ratings limit our confidence in the findings. Concerns with the quality of modelling studies related to potentially inappropriate assumptions about the model structure and input parameters, and an inadequate assessment of model uncertainty. Concerns with risk of bias in observational studies related to deviations from intended interventions or missing data. Across all categories, few studies reported on implementation or described how measures were implemented. Where we describe effects as 'positive', the direction of the point estimate of the effect favours the intervention(s); 'negative' effects do not favour the intervention.  We found 23 modelling studies assessing measures reducing the opportunity for contacts (i.e. alternating attendance, reduced class size). Most of these studies assessed transmission and healthcare utilisation outcomes, and all of these studies showed a reduction in transmission (e.g. a reduction in the number or proportion of cases, reproduction number) and healthcare utilisation (i.e. fewer hospitalisations) and mixed or negative effects on societal, economic and ecological outcomes (i.e. fewer number of days spent in school). We identified 11 modelling studies and two observational studies assessing measures making contacts safer (i.e. mask wearing, cleaning, handwashing, ventilation). Five studies assessed the impact of combined measures to make contacts safer. They assessed transmission-related, healthcare utilisation, other health, and societal, economic and ecological outcomes. Most of these studies showed a reduction in transmission, and a reduction in hospitalisations; however, studies showed mixed or negative effects on societal, economic and ecological outcomes (i.e. fewer number of days spent in school). We identified 13 modelling studies and one observational study assessing surveillance and response measures, including testing and isolation, and symptomatic screening and isolation. Twelve studies focused on mass testing and isolation measures, while two looked specifically at symptom-based screening and isolation. Outcomes included transmission, healthcare utilisation, other health, and societal, economic and ecological outcomes. Most of these studies showed effects in favour of the intervention in terms of reductions in transmission and hospitalisations, however some showed mixed or negative effects on societal, economic and ecological outcomes (e.g. fewer number of days spent in school). We found three studies that reported outcomes relating to multicomponent measures, where it was not possible to disaggregate the effects of each individual intervention, including one modelling, one observational and one quasi-experimental study. These studies employed interventions, such as physical distancing, modification of school activities, testing, and exemption of high-risk students, using measures such as hand hygiene and mask wearing. Most of these studies showed a reduction in transmission, however some showed mixed or no effects.   As the majority of studies included in the review were modelling studies, there was a lack of empirical, real-world data, which meant that there were very little data on the actual implementation of interventions. Our review suggests that a broad range of measures implemented in the school setting can have positive impacts on the transmission of SARS-CoV-2, and on healthcare utilisation outcomes related to COVID-19. The certainty of the evidence for most intervention-outcome combinations is very low, and the true effects of these measures are likely to be substantially different from those reported here. Measures implemented in the school setting may limit the number or proportion of cases and deaths, and may delay the progression of the pandemic. However, they may also lead to negative unintended consequences, such as fewer days spent in school (beyond those intended by the intervention). Further, most studies assessed the effects of a combination of interventions, which could not be disentangled to estimate their specific effects. Studies assessing measures to reduce contacts and to make contacts safer consistently predicted positive effects on transmission and healthcare utilisation, but may reduce the number of days students spent at school. Studies assessing surveillance and response measures predicted reductions in hospitalisations and school days missed due to infection or quarantine, however, there was mixed evidence on resources needed for surveillance. Evidence on multicomponent measures was mixed, mostly due to comparators. The magnitude of effects depends on multiple factors. New studies published since the original search date might heavily influence the overall conclusions and interpretation of findings for this review.

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By day-90, the placenta secretes half of the circulating progesterone and 85% of the circulating estradiol-17beta [Weems YS, Vincent D, Tanaka Y, et al. Effects of prostaglandin F(2alpha) on sources of progesterone and pregnancy in intact, ovariectomized, and hysterectomized 90-100 day pregnant ewes. Prostaglandins 1992;43:203-22; Weems YS, Vincent DL, Nusser K, et al. Effects of prostaglandin F(2alpha) (PGF(2alpha)) on secretion of estradiol-17beta and cortisol in 90-100 day hysterectomized, intact, or ovariectomized pregnant ewes. Prostaglandins 1994;48:139-57]. Ovariectomy (OVX) or prostaglandin (PG) F(2alpha) (PGF(2alpha)) does not abort intact or OVX 90-day pregnant ewes and PGF(2alpha) regresses the corpus luteum, but does not affect placental progesterone secretion in vivo [Weems YS, Vincent D, Tanaka Y, et al. Effects of prostaglandin F(2alpha) on sources of progesterone and pregnancy in intact, ovariectomized, and hysterectomized 90-100 day pregnant ewes. Prostaglandins 1992;43:203-22]. Luteal progesterone secretion in vitro at day-90 of pregnancy in ewes is regulated by PGE(1)and/or PGE(2), not by ovine luteinizing hormone (LH; 3). Concentrations of PGE in uterine or ovarian venous plasma averaged 6 ng/ml at 90-100 days of pregnancy in ewes [Weems YS, Vincent DL, Tanaka Y, Nusser K, Ledgerwood KS, Weems CW. Effect of prostaglandin F(2alpha) on uterine or ovarian secretion of prostaglandins E and F(2alpha) (PGE; PGF(2alpha)) in vivo in 90-100 day hysterectomized, intact or ovariectomized pregnant ewes. Prostaglandins. 1993;46:277-96]. Ovine placental PGE secretion is regulated by LH up to day-50 and by pregnancy specific protein B (PSPB) after day-50 of pregnancy [Weems YS, Kim L, Humphreys V, Tsuda V, Weems CW. Effect of luteinizing hormone (LH), pregnancy specific protein B (PSPB), or arachidonic acid (AA) on ovine endometrium of the estrous cycle or placental secretion of prostaglandins E(2) (PGE(2)) and F(2alpha) (PGF(2alpha)), and progesterone in vitro. Prostaglandins Other Lipid Mediators 2003;71:55-73]. Indomethacin (INDO), a prostaglandin synthesis inhibitor [Lands WEM. The biosynthesis and metabolism of prostaglandins. Annu Rev Physiol 1979;41:633-46], lowers jugular venous progesterone [Bridges PJ, Weems YS, Kim L, et al. Effect of prostaglandin F(2alpha) (PGF(2alpha)), indomethacin, tamoxifen or estradiol-17beta on pregnancy, progesterone and pregnancy specific protein B (PSPB) secretion in 88-90 day pregnant ewes. Prostaglandins Other Lipid Mediators 1999;58:113-24] and inferior vena cava PGE of pregnant ewes with ovaries by half at day-90 [Bridges PJ, Weems YS, Kim L, LeaMaster BR, Vincent DL, Weems CW. Effect of prostaglandin F(2alpha) (PGF(2alpha)), indomethacin, tamoxifen or estradiol-17beta on prostaglandin E (PGE), PGF(2alpha) and estradiol-17beta secretion in 88-90 day pregnant sheep. Prostaglandins Other Lipid Mediators 1999;58:167-78]. In addition, treatment of 90 day ovine diced placental slices with androstenedione in vitro increased placental estradiol-17beta, but treatment with PGF(2alpha)in vitro did not decrease placental progesterone secretion, which indicates that ovine placenta progesterone secretion is resistant to the luteolytic action of PGF(2alpha) [Weems YS, Bridges PJ, LeaMaster BR, Sasser RG, Vincent DL, Weems CW. Secretion of progesterone, estradiol-17beta, prostaglandins (PG) E (PGE), F(2alpha) (PGF(2alpha)), and pregnancy specific protein B (PSPB) by day 90 intact or ovariectomized pregnant ewes. Prostaglandins Other Lipid Mediators 1999;58:139-48]. This also explains why ovine uterine secretion of decreased around day-50 [Weems YS, Kim L, Humphreys V, Tsuda V, Weems CW. Effect of luteinizing hormone (LH), pregnancy specific protein B (PSPB), or arachidonic acid (AA) on ovine endometrium of the estrous cycle or placental secretion of prostaglandins E(2) (PGE(2)) and F(2alpha) (PGF(2alpha)), and progesterone in vitro. Prostaglandins Other Lipid Mediators 2003;71:55-73], when placental estradiol-17beta secretion is increasing [Weems C, Weems Y, Vincent D. Maternal recognition of pregnancy and maintenance of gestation in sheep. In: Reproduction and animal breeding: advances and strategies. Enne G, Greppi G, Lauria A, editors, Elsevier Pub., Amsterdam 1995. p. 277-93]. Treatment of 90 day pregnant ewes with estradiol-17beta+ PGF(2alpha), but not either treatment alone, caused a linear increase in both estradiol-17beta and PGF(2alpha) and ewes were aborting [Bridges PJ, Weems YS, Kim L, Sasser RG, LeaMaster BR, Vincent DL, Weems CW. Effect of prostaglandin F(2alpha) (PGF(2alpha)), indomethacin, tamoxifen or estradiol-17beta on pregnancy, progesterone and pregnancy specific protein B (PSPB) secretion in 88-90 day pregnant ewes. Prostaglandins Other Lipid Mediators 1999;58:113-24; Bridges PJ, Weems YS, Kim L, LeaMaster BR, Vincent DL, Weems CW. Effect of prostaglandin F(2alpha) (PGF(2alpha)), indomethacin, tamoxifen or estradiol-17beta on prostaglandin E (PGE), PGF(2alpha) and estradiol-17beta secretion in 88-90 day pregnant sheep. Prostaglandins Other Lipid Mediators 1999;58:167-78]. Pregnant ewes OVX on day 83 of pregnancy and placental slices cultured in vitro secretes 2-3-fold more estradiol-17beta, PSPB, PGE, and progesterone than placental slices from 90 day intact pregnant ewes, but placental PGF(2alpha) secretion by placental slices from intact or OVX ewes did not change [Denamur R, Kann G, Short R V. How does the corpus luteum of the sheep know that there is an embryo in the uterus? In: Pierrepont G, editor. Endocrinology of pregnancy and parturition, vol. 2. Cardiff, Wales, UK: Alpha Omega Pub Co.; 1973. p. 4-38]. The objective of these experiments was to determine what regulates ovine placental progesterone and estradiol-17beta secretion at day-90 of pregnancy, since the hypophysis [Casida LE, Warwick J. The necessity of the corpus luteum for maintenance of pregnancy in the ewe. J Anim Sci 1945;4:34-9] or ovaries [Weems CW, Weems YS, Randel RD. Prostaglandins and reproduction in female farm animals. Vet J 2006;171:206-28] are not necessary after day-55 to maintain pregnancy. In Experiment 1, diced placental slices from day-90 intact or OVX pregnant ewes that were ovariectomized or laparotomized and ovaries were not removed on day 83 were collected on day-90 and incubated in vitro in M-199 with Vehicle, ovine luteinizing hormone (oLH), ovine follicle stimulating hormone (oFSH), ovine placental lactogen (oPL), PGE(l), PGE(2), PGD(2), PGI(2), insulin-like growth factor (IGF) 1 or 2 (IGF(l); IGF(2)), leukotriene C(4) (LTC(4)), platelet activating factor (PAF) 16 or 18 (PAF-16; PAF-18) at doses of 0, 1, 10, or 100ng/ml for 4h. In Experiment 2, placental slices from day-90 intact and OVX (intact or OVX laporotomized 7 days earlier) pregnant ewes were incubated in vitro with vehicle, INDO, Meclofenamate (MECLO), PGE(l), PGE(2), INDO+PGE(1), MECLO+PGE(l), INDO+PGE(2), or MECLO+PGE(2) for 4h. Media were analyzed for progesterone, estradiol-17beta, PGE, or PGF(2alpha) by RIA. Hormone data in media were analyzed in Experiment 1 by a 2x3x13 and in Experiment 2 by a 2x9 Factorial Design for ANOVA. In Experiment 1, placental progesterone, PGE, or estradiol-17beta secretion were increased (P&lt; or =0.05) two-fold by OVX. Progesterone was not increased (P&gt; or =0.05) by any treatment other than OVX and only FSH increased (P&lt; or =0.05) estradiol-17beta secretion by placental slices in both OVX and intact ewes 90-day pregnant ewes. In Experiment 2, INDO or MECLO decreased (P&lt; or =0.05) placental progesterone secretion by 88% but did not decrease (P&gt; or =0.05) placental estradiol-17beta secretion from intact or OVX ewes. PGE(l) or PGE(2) increased (P&lt; or =0.05) progesterone secretion only in ewes treated with INDO or MECLO. It is concluded that FSH probably regulates day-90 ovine placental estradiol-17beta secretion, while PGE(l) or PGE(2) regulates day-90 placental progesterone secretion.

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OBJECTIVE OF THE PROJECT: The introduction of the HPV test as a primary screening test will cause important changes in the screening system based on cytology. The purposes of this report are: to define the best screening policies with HPV-based screening on the basis of the resulting efficacy and of undesired effects; comparing them to cytology-based screening; to identify their best conditions of application; to evaluate economic cost, feasibility and impact on the organisation of services of such policy in the Italian situation. This report contains a section on efficacy and undesired effects based on a systematic review of literature conducted in strict coordination with the preparation of a supplement to the European Guidelines for quality assurance in cervical cancer screening. This chapter corresponds to a preliminary version of the chapter of the European Guidelines on primary screening with HPV. The sections on costs, impact on organisation, and social, ethical and legal impact reflect the Italian situation; they are based on a review of the available Italian data (including unpublished data, mainly from on-going pilot projects) and on a structured analysis of what will result if the proposed protocol is applied to the Italian situation. Efficacy and undesired effects. There is clear scientific evidence that a screening based on validated tests for the DNA of oncogenic HPV as primary test and applying an appropriate protocol is more effective than screening based on cytology in preventing invasive cancers of the uterine cervix. In addition, it entails a limited--if any--increase of the undesired effects both in terms of unneeded referral to diagnostic work-up and in terms of over-diagnosis and consequent overtreatment of spontaneously regressive lesions. The crucial elements of such protocol are the followings: HPV-positive women are not to be directly referred to colposcopy, but the use of triage systems is essential. The currently recommendable method is based on performing cytology in HPV positive women. If the result of this test is abnormal, the woman is immediately referred to colposcopy; if cytology is normal, the woman is invited to repeat a new HPV test after one year. In case such a test is still positive, the woman is referred to colposcopy; in case of negative result, the woman will be re-invited for a new screening round at the regular interval. In organised population-based screening programmes the interval after a negative primary HPV test should be at least 5 years. There is evidence that the 5-year cumulative risk of high-grade CIN after a negative HPV test is lower than the 3-year risk after a normal cytology. On the other hand, the probability of unneeded colposcopies and treatments would plausibly be relevant with 3-year intervals after a negative HPV test. HPV-based screening should not start before 30-35 years. There is evidence that below 30 years HPV-based screening leads to an increased overdiagnosis of CIN2 that would regress spontaneously, with consequent overtreatment. Some increase in overdiagnosis is plausible also between 30 and 34 years. Below such ages, cytological screening is the recommended test. Only tests for the DNA of oncogenic HPV, validated according to the European guidelines as for sensitivity and specificity for high-grade lesions, should be applied. There is no evidence that double testing with cytology and HPV is more protective than stand-alone HPV as primary test, although it entails a small and not relevant increase in sensitivity vs stand-alone HPV. On the contrary, there is evidence that double testing causes a substantial increase in referral to colposcopy and a decrease in its PPV. For this reason, if HPV is used as primary screening test, it is recommended not to add cytology in parallel. Cost and economic evaluation. It is estimated that, if the protocol described is applied, in the current Italian situation the overall costs of HPV-based screening are lower than those of conventional cytological screening applied at the current 3-year intervals, although the cost of each screening round is higher. Impact on organization. For reasons of quality and cost, both the interpretation of cytology and HPV testing require a centralisation. This need is particularly strong, in terms of costs, for HPV test execution. It is therefore recommended to perform the HPV test in a limited number of reference laboratories of large size. This also makes monitoring and evaluating the spontaneous activity easier. HPV-based screening entails problems of organisation related to the need of triage, to complex protocols and to reconversion of the activities of cytological interpretation. Social, ethical and legal impact. The communication of the result of the HPV test to women, particularly if positive, is a further crucial aspect in order to reduce not only the emotional impact, but also the possible risks that women are inappropriately managed or lost to follow-up. Great efforts must be put in the education of healthcare professionals, both directly involved in organised programmes or not, particularly private gynaecologists and general practitioners. In conclusion, the crucial requirement to introduce HPV-based screening programmes is the capacity to guarantee the application of appropriate screening protocols. If protocols do not respect the criteria described above they can cause relevant increase of undesired effects and costs compared to cytology-based screening. Therefore they should be avoided, except in studies able to provide clear evidence about human and economic costs. For this purpose, correct education and information both to healthcare professionals and to the population is needed. In the Italian situation, where organised screening and a relevant spontaneous activity coexist, their interaction is crucial. Actions directed to integrate them and to guarantee as more uniformity of interventions as possible are needed, in particular through the integration of registries and thorough monitoring and a progressive homogenization of protocols. In order to grant the safety of transition, it is needed that the HPV-based organised screening activities are strictly monitored and that the National Centre for Screening Monitoring (ONS) ensures coordination. Knowledge about HPV based screening is still rapidly evolving. It is possible that currently on-going researches suggest changes to the optimal protocols in the next few years, particularly as for the management of HPV positive women. In addition, studies on the validation of new assays were recently published and others are expected. It is suggested to exploit the organised screening activity to produce scientific evidence, in order to clarify the still uncertain aspects of optimal protocols. Different protocols in terms of screening intervals, age of application and management of HPV positive women should be studied in the frame of controlled implementation, through multicentre projects coordinated by ONS. Finally, it is suggested the creation of a National working group to promptly update the recommendations for screening and the list of assays to be considered as validated. On the bases of the results obtained in the first vaccinated cohorts reaching the screening age, for the future, it will be crucial to deliver specific recommendations to the population vaccinated against HPV during adolescence.

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<bObjective:</b To investigate the effects and mechanism of negative pressure microenvironment on the neogenesis of human umbilical vein endothelial cells (HUVECs). <bMethods:</b The experimental research methods were adopted. The third to the fifth passage of HUVECs in the logarithmic growth stage were used for the subsequent experiments. Three batches of cells were taken, with each batch of cells being divided into normal control group and negative pressure treatment alone group (both routinely cultured for 24 h), and 17-allylamino-17-demethoxy-geldanamycin (17-AAG) alone group and 17-AAG+negative pressure treatment group (both cultured with 17-AAG for 24 h). In addition, the intermittent negative pressure suction, with the negative pressure value of -5.33 kPa (suction for 30 s, pause for 10 s) was continuously applied for 8 h on cells in the two negative pressure treatment groups using an automatic three-dimensional cell gradient negative pressure loading device designed and developed by ourselves. After the treatment of the first batch of cells, the cell proliferation level was detected by cell counting kit 8 method at 0 (immediately), 24, 48, and 72 h of culture, with the number of samples being 6. After the treatment of the second batch of cells, the scratch experiment was performed. At 12 h after scratching, the cell migration was observed under an inverted phase contrast microscope and the cell migration rate was calculated, with the number of samples being 3. After the treatment of the third batch of cells, the tubule formation experiment was conducted. After 6 h of culture, the tubulogenesis was observed under an inverted phase contrast microscope and the total tubule length and the number of branch nodes of cells were calculated, with the number of samples being 3. The cells were taken and divided into normal control group, negative pressure treatment alone group, and 17-AAG+negative pressure treatment group. The cells were treated the same as in the previous corresponding group. After the treatment, Western blotting was used to detect the protein expressions of heat shock protein 90 (HSP90), caveolin 1, endothelial nitric oxide synthase (eNOS), and eNOS phosphorylation site 1177 in the cells, and the eNOS phosphorylation site 1177/eNOS ratio was calculated, with the number of samples being 3; co-immunoprecipitation (co-precipitating HSP90 and caveolin 1, caveolin 1 and eNOS) and Western blotting were used to detect the protein expressions of caveolin 1 and eNOS in the cells, with the number of samples being 3; the protein co-localization of HSP90 and caveolin 1 and that of caveolin 1 and eNOS in the cells was assessed by immunofluorescence double staining. The molecular docking prediction of caveolin 1 and eNOS was processed by HADDOCK 2.4 protein-protein docking program. Data were statistically analyzed with analysis of variance for factorial design, one-way analysis of variance, and least significant difference method. <bResults:</b Compared with that in normal control group, the cell proliferation level in 17-AAG alone group was significantly decreased at culture hour of 24, 48, and 72 after the treatment (<iP</i&lt;0.01), while the cell proliferation level in negative pressure treatment alone group was significantly increased at culture hour of 24, 48, and 72 after the treatment (<iP</i&lt;0.01). Compared with that in 17-AAG alone group, the cell proliferation level in 17-AAG+negative pressure treatment group was significantly increased at culture hour of 48 and 72 after the treatment (<iP</i&lt;0.05 or <iP</i&lt;0.01). Compared with that in negative pressure treatment alone group, the cell proliferation level in 17-AAG+negative pressure treatment group was significantly decreased at culture hour of 24, 48, and 72 after the treatment (<iP</i&lt;0.01). At 12 h after scratching, compared with (39.9±2.7)% in normal control group, the cell migration rate in 17-AAG alone group was significantly decreased ((10.7±2.7)%, <iP</i&lt;0.01), while the cell migration rate in negative pressure treatment alone group was significantly increased ((61.9±2.4)%, <iP</i&lt;0.01). Compared with those in 17-AAG alone group, the cell migration rate in 17-AAG+negative pressure treatment group was significantly increased ((37.7±3.7)%, <iP</i&lt;0.01). Compared with that in negative pressure treatment alone group, the cell migration rate in 17-AAG+negative pressure treatment group was significantly decreased (<iP</i&lt;0.01). At culture hour of 6 after the treatment, compared with those in normal control group, the total length of the tube formed by the cells in 17-AAG alone group was significantly shortened (<iP</i&lt;0.05) and the number of branch nodes was significantly reduced (<iP</i&lt;0.05), while the total length of the tube formed by the cells in negative pressure treatment alone group was significantly prolonged (<iP</i&lt;0.01) and the number of branch nodes was dramatically increased (<iP</i&lt;0.01). Compared with that in 17-AAG alone group, the number of branch nodes of the tube formed by the cells was significantly increased in 17-AAG+negative pressure treatment group (<iP</i&lt;0.05). Compared with those in negative pressure treatment alone group, the total length of the tube formed by the cells in 17-AAG+negative pressure treatment group was significantly shortened (<iP</i&lt;0.01) and the number of branch nodes was significantly reduced (<iP</i&lt;0.01). Western blotting detection showed that after treatment, the overall comparison of eNOS and caveolin 1 protein expressions among the three groups of cells showed no statistically significant differences (<iP</i&gt;0.05). The expression of HSP90 protein and the eNOS phosphorylation site 1177/eNOS ratio in the cells of negative pressure treatment alone group were significantly increased (<iP</i&lt;0.01) compared with those in normal control group. Compared with those in negative pressure treatment alone group, the HSP90 protein expression and the eNOS phosphorylation site 1177/eNOS ratio in the cells of 17-AAG+negative pressure treatment group were significantly decreased (<iP</i&lt;0.01). Co-immunoprecipitation and Western blotting detection after the treatment showed that compared with those in normal control group, the expression of caveolin 1 protein in the cells of negative pressure treatment alone group was significantly increased (<iP</i&lt;0.01), while the protein expression of eNOS was significantly decreased (<iP</i&lt;0.05). Compared with those in negative pressure treatment alone group, the expression of caveolin 1 protein in the cells of 17-AAG+negative pressure treatment group was significantly decreased (<iP</i&lt;0.01), while the protein expression of eNOS was significantly increased (<iP</i&lt;0.01). After the treatment, compared with those in normal control group, the co-localization of HSP90 and caveolin 1 protein in the cells of negative pressure treatment alone group was significantly increased, while the co-localization of caveolin 1 and eNOS protein was significantly decreased. Compared with those in negative pressure treatment alone group, the co-localization of HSP90 and caveolin 1 protein in the cells of 17-AAG+negative pressure treatment group was significantly decreased, while the co-localization of caveolin 1 and eNOS protein was significantly increased. Molecular docking prediction suggested that caveolin 1 interacted strongly with eNOS and inhibited the 1177 site phosphorylation of eNOS. <bConclusions:</b The negative pressure microenvironment may inhibit the binding of caveolin 1 to eNOS by promoting the binding of HSP90 to caveolin 1 in HUVECs, so as to relieve the inhibition of 1177 site phosphorylation of eNOS by caveolin 1, thereby promoting the proliferation, migration, and tubulogenesis of HUVECs, and ultimately promoting the neogenesis of HUVECs.

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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, 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. Polychlorinated biphenyls (PCBs) and their mixtures including 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 118 study was conducted as part of the dioxin TEF evaluation that included multiple 2-year rat bioassays to evaluate the relative chronic toxicity and carcinogenicity of DLCs, structurally related PCBs, and mixtures of these compounds. Female Harlan Sprague-Dawley rats were administered PCB 118 (at least 99% pure) in corn oil:acetone (99:1) by gavage for 14, 31, or 53 weeks or 2 years. 2-YEAR STUDY: Groups of 80 female rats were administered 100, 220, 460, 1,000, or 4,600 g PCB 118/kg body weight in corn oil:acetone (99:1) by gavage, 5 days per week, for up to 105 weeks; a group of 80 vehicle control female rats received the corn oil/acetone vehicle alone. Groups of 30 female rats received 10 or 30 g/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 4,600 g/kg PCB 118 in corn oil:acetone (99:1) by gavage for 30 weeks then the vehicle for the remainder of the study. Survival of all dosed groups of rats was similar to that of the vehicle control group. Mean body weights of 1,000 g/kg rats were 7% less than those of the vehicle controls after week 36, and those of the 4,600 g/kg core study and stop-exposure groups were 7% less than those of the vehicle controls after week 7. Following cessation of treatment, the body weight gain in the stop-exposure group was similar to that of the vehicle control group. In general, exposure to PCB 118 lead to dose-dependent decreases in the concentrations of serum total thyroxine (T4) and free T4 in all dosed groups. There were no effects on triiodothyronine or thyroid stimulating hormone levels in any dosed groups evaluated at the 14-, 31-, and 53-week interim evaluations. There were increases in hepatic cell proliferation in the 4,600 g/kg group at 14, 31, and 53 weeks. Administration of PCB 118 led to dose-dependent increases in CYP1A1-associated 7-ethoxyresorufin-O-deethylase, CYP1A2-associated acetanilide4-hydroxylase, and CYP2B-associated pentoxyresorufin-O-deethylase activities at the 14-, 31-, and 53-week interim evaluations. Analysis of PCB 118 concentrations in dosed groups showed dose- and duration of dosing-dependent increases in fat, liver, lung, and blood. The highest concentrations were seen in fat at 2 years with lower concentrations observed in the liver, lung, and blood. At the 53-week interim evaluation, three 4,600 g/kg rats had liver cholangiocarcinoma and one had hepatocellular adenoma. At 2 years, there were significant treatment-related increases in the incidences of cholangiocarcinoma and hepatocellular adenoma. Four incidences of hepatocholangioma occurred in the 4,600 g/kg core study group. 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, inflammation, oval cell hyperplasia, pigmentation, multinucleated hepatocyte, eosinophilic and mixed cell foci, diffuse fatty change, toxic hepatopathy, nodular hyperplasia, necrosis, bile duct hyperplasia and cyst, and cholangiofibrosis. The incidences of these lesions were often decreased in the 4,600 g/kg stop-exposure group compared to the 4,600 g/kg core study group. In the lung at 2 years, a significantly increased incidence of cystic keratinizing epithelioma occurred in the 4,600 g/kg core study group compared to the vehicle control group incidence. Incidences of bronchiolar metaplasia of the alveolar epithelium were significantly increased in the groups administered 460 g/kg or greater, and the incidence of squamous metaplasia was significantly increased in the 4,600 g/kg core study group. The incidence of carcinoma of the uterus in the 4,600 g/kg stop-exposure group was significantly greater than those in the vehicle control and 4,600 g/kg core study groups at 2 years. A marginal increase in squamous cell carcinoma occurred in the 220 g/kg group. At 2 years, there were marginally increased incidences of exocrine pancreatic adenoma or carcinoma in the 460, 1,000, and 4,600 g/kg core study groups. Numerous nonneoplastic effects were seen in other organs including: adrenal cortical atrophy and cytoplasmic vacuolization, pancreatic acinar cell cytoplasmic vacuolization and arterial chronic active inflammation, follicular cell hypertrophy of the thyroid gland, inflammation and respiratory epithelial hyperplasia of the nose, and kidney pigmentation. Under the conditions of this 2-year gavage study, there was clear evidence of carcinogenic activity of PCB 118 in female Harlan Sprague-Dawley rats based on increased incidences of neoplasms of the liver (cholangiocarcinoma, hepatocholangioma, and hepatocellular adenoma) and cystic keratinizing epithelioma of the lung. Occurrences of carcinoma in the uterus were considered to be related to the administration of PCB 118. Occurrences of squamous cell carcinoma of the uterus and acinar neoplasms of the pancreas may have been related to administration of PCB 118. Administration of PCB 118 caused increased incidences of nonneoplastic lesions in the liver, lung, adrenal cortex, pancreas, thyroid gland, nose, and kidney. Synonyms: 1,1'-Biphenyl, 2,3',4,4',5-pentachloro-(9CI); 1,1'-biphenyl, 2,3',4,4',5-pentachloro-; 2,3',4,4',5-pentachloro-1,1'-biphenyl; 2,4,5,3',4'-pentachlorobiphenyl; 3,4,2',4',5'-pentachlorobiphenyl; biphenyl, 2,3',4,4',5-pentachloro-; CB 118.

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The Tachinidae of the Afrotropical Region are catalogued and seven genera and eight species are newly described. There are 237 genera and 1126 species recognized, of which 101 genera and 1043 species are endemic to the region. The catalogue is based on examination of the primary literature comprising about 525 references as well as numerous name-bearing types and other specimens housed in collections. Taxa are arranged hierarchically and alphabetically under the categories of subfamily, tribe, genus, subgenus (where recognized), species, and rarely subspecies. Nomenclatural information is provided for all genus-group and species-group names, including lists of synonyms (mostly restricted to Afrotropical taxa) and name-bearing type data. Species distributions are recorded by country within the Afrotropical Region and by larger geographical divisions outside the region. Additional information is given in the form of notes, numbering about 300 in the catalogue section. Seven genera and eight species are described as new: Afrophylax Cerretti &amp; O'Hara with type species Sturmia aureiventris Villeneuve, 1910, gen. n. (Exoristinae, Eryciini); Austrosolieria Cerretti &amp; O'Hara with type species Austrosolieria londti Cerretti &amp; O'Hara, gen. n. and sp. n. (South Africa) and Austrosolieria freidbergi Cerretti &amp; O'Hara, sp. n. (Malawi) (Tachininae, Leskiini); Carceliathrix Cerretti &amp; O'Hara with type species Phorocera crassipalpis Villeneuve, 1938, gen. n. (Exoristinae, Eryciini); Filistea Cerretti &amp; O'Hara with type species Viviania aureofasciata Curran, 1927, gen. n. and Filistea verbekei Cerretti &amp; O'Hara, sp. n. (Cameroon, D.R. Congo, Uganda) (Exoristinae, Blondeliini); Mesnilotrix Cerretti &amp; O'Hara with type species Dexiotrix empiformis Mesnil, 1976, gen. n. (Dexiinae, Dexiini); Myxophryxe Cerretti &amp; O'Hara with type species Phorocera longirostris Villeneuve, 1938, gen. n., Myxophryxe murina Cerretti &amp; O'Hara, sp. n. (South Africa), Myxophryxe regalis Cerretti &amp; O'Hara, sp. n. (South Africa), and Myxophryxe satanas Cerretti &amp; O'Hara, sp. n. (South Africa) (Exoristinae, Goniini); and Stiremania Cerretti &amp; O'Hara with type species Stiremania karoo Cerretti &amp; O'Hara, gen. n. and sp. n. (South Africa), and Stiremania robusta Cerretti &amp; O'Hara, sp. n. (South Africa) (Exoristinae, Goniini). Paraclara Bezzi, 1908 is transferred from the Cylindromyiini to the Hermyini, comb. n. Sarrorhina Villeneuve, 1936 is transferred from the Minthoini to the Graphogastrini, comb. n. Three genera are newly recorded from the Afrotropical Region: Madremyia Townsend, 1916 (Eryciini); Paratrixa Brauer &amp; Bergenstamm, 1891 (Blondeliini); and Simoma Aldrich, 1926 (Goniini). Three genera previously recorded from the Afrotropical Region are no longer recognized from the region: Calozenillia Townsend, 1927 (Palaearctic, Oriental and Australasian regions); Eurysthaea Robineau-Desvoidy, 1863 (Palaearctic, Oriental and Australasian regions); and Trixa Meigen, 1824 (Palaearctic and Oriental regions). Two species are newly recorded from the Afrotropical Region: Amnonia carmelitana Kugler, 1971 (Ethiopia, Kenya); and Simoma grahami Aldrich, 1926 (Namibia). Three species previously recorded from the Afrotropical Region are no longer recognized from the region: Euthera peringueyi Bezzi, 1925 (Oriental Region); Hamaxia incongrua Walker, 1860 (Palaearctic, Oriental and Australasian regions); Leucostoma tetraptera (Meigen, 1824) (Palaearctic Region). New replacement names are proposed for five preoccupied names of Afrotropical species: Billaea rubida O'Hara &amp; Cerretti for Phorostoma rutilans Villeneuve, 1916, preoccupied in the genus Billaea Robineau-Desvoidy, 1830 by Musca rutilans Fabricius, 1781, nom. n.; Cylindromyia braueri O'Hara &amp; Cerretti for Ocyptera nigra Villeneuve, 1918, preoccupied in the genus Cylindromyia Meigen, 1803 by Glossidionophora nigra Bigot, 1885, nom. n.; Cylindromyia rufohumera O'Hara &amp; Cerretti for Ocyptera scapularis Villeneuve, 1944, preoccupied in the genus Cylindromyia Meigen, 1803 by Ocyptera scapularis Loew, 1845, nom. n.; Phytomyptera longiarista O'Hara &amp; Cerretti for Phytomyzoneura aristalis Villeneuve, 1936, preoccupied in the genus Phytomyptera Rondani, 1845 by Phasiostoma aristalis Townsend, 1915, nom. n.; and Siphona (Siphona) pretoriana O'Hara &amp; Cerretti for Siphona laticornis Curran, 1941, preoccupied in the genus Siphona Meigen, 1803 by Actia laticornis Malloch, 1930, nom. n. New type species fixations are made under the provisions of Article 70.3.2 of the ICZN Code for two genus-group names: Lydellina Villeneuve, 1916, type species newly fixed as Lydellina villeneuvei Townsend, 1933 (valid genus name); and Sericophoromyia Austen, 1909, type species newly fixed as Tachina quadrata Wiedemann, 1830 (synonym of Winthemia Robineau-Desvoidy, 1830). Lectotypes are designated for the following nine nominal species based on examination of one or more syntypes of each: Degeeria crocea Villeneuve, 1950; Degeeria semirufa Villeneuve, 1950; Erycia brunnescens Villeneuve, 1934; Exorista oculata Villeneuve, 1910; Kiniatilla tricincta Villeneuve, 1938; Myxarchiclops caffer Villeneuve, 1916; Ocyptera linearis Villeneuve, 1936; Peristasisea luteola Villeneuve, 1934; and Phorocera crassipalpis Villeneuve, 1938. The following four genus-group names that were previously treated as junior synonyms or subgenera are recognized as valid generic names: Bogosiella Villeneuve, 1923, status revived; Dyshypostena Villeneuve, 1939, status revived; Perlucidina Mesnil, 1952, status revived; and Thelymyiops Mesnil, 1950, status n. The following six species-group names that were previously treated as junior synonyms are recognized as valid species names: Besseria fossulata Bezzi, 1908, status revived; Degeeria cinctella Villeneuve, 1950, status revived (as Medina cinctella (Villeneuve)); Nemoraea miranda intacta Villeneuve, 1916, status revived (as Nemoraea intacta Villeneuve); Succingulum exiguum Villeneuve, 1935, status revived (as Trigonospila exigua (Villeneuve)); Wagneria rufitibia abbreviata Mesnil, 1950, status n. (as Periscepsia abbreviata (Mesnil)); and Wagneria rufitibia nudinerva Mesnil, 1950, status n. (as Periscepsia nudinerva (Mesnil)). The following 25 new or revived combinations are proposed: Afrophylax aureiventris (Villeneuve, 1910), comb. n.; Blepharella orbitalis (Curran, 1927), comb. n.; Bogosiella pomeroyi Villeneuve, 1923, comb. revived; Brachychaetoides violacea (Curran, 1927), comb. n.; Carceliathrix crassipalpis (Villeneuve, 1938), comb. n.; Charitella whitmorei (Cerretti, 2012), comb. n.; Dyshypostena edwardsi (van Emden, 1960), comb. n.; Dyshypostena tarsalis Villeneuve, 1939, comb. revived; Estheria buccata (van Emden, 1947), comb. n.; Estheria surda (Curran, 1933), comb. n.; Filistea aureofasciata (Curran, 1927), comb. n.; Madremyia setinervis (Mesnil, 1968), comb. n.; Mesnilotrix empiformis (Mesnil, 1976), comb. n.; Myxophryxe longirostris (Villeneuve, 1938), comb. n.; Nealsomyia chloronitens (Mesnil, 1977), comb. n.; Nealsomyia clausa (Curran, 1940), comb. n.; Nilea longicauda (Mesnil, 1970), comb. n.; Paratrixa aethiopica Mesnil, 1952, comb. revived; Paratrixa stammeri Mesnil, 1952, comb. revived; Perlucidina africana (Jaennicke, 1867), comb. n.; Perlucidina perlucida (Karsch, 1886), comb. revived; Prolophosia retroflexa (Villeneuve, 1944), comb. n.; Sturmia profana (Karsch, 1888), comb. n.; additionally, Ceromasia rufiventris Curran, 1927 is treated as an unplaced species of Goniini, comb. n. and Hemiwinthemia stuckenbergi Verbeke, 1973 is treated as an unplaced species of Leskiini, comb. n. New or revived generic and specific synonymies are proposed for the following nine names: Afrosturmia Curran, 1927 with Blepharella Macquart, 1851, syn. n.; Archiphania van Emden, 1945 with Catharosia Rondani, 1868, syn. revived; Besseria longicornis Zeegers, 2007 with Besseria fossulata Bezzi, 1908 (current name Besseria fossulata), syn. n.; Dexiomera Curran, 1933 with Estheria Robineau-Desvoidy, 1830, syn. n.; Hemiwinthemia francoisi Verbeke, 1973 with Nemoraea capensis Schiner, 1868 (current name Smidtia capensis), syn. n.; Kinangopana van Emden, 1960 with Dyshypostena Villeneuve, 1939, syn. n.; Metadrinomyia Shima, 1980 with Charitella Mesnil, 1957, syn. n.; Phorocera majestica Curran, 1940 with Phorocera longirostris Villeneuve, 1938 (current name Myxophryxe longirostris), syn. n.; and Podomyia discalis Curran, 1939 with Antistasea fimbriata Bischof, 1904 (current name Antistasea fimbriata), syn. n.

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<bObjective:</b To explore the effects and mechanism of rat epidermal stem cells (ESCs) that were treated with exogenous vascular endothelial growth factor (VEGF) on the healing of deep partial-thickness burn wounds in rats. <bMethods:</b ESCs were isolated and cultured from the trunk skin of a 3-month-old female Sprague-Dawley (SD) rat. The third passage of cultured cells in the logarithmic growth phase was used in experiments (1)-(3). (1) The cells were routinely cultured in keratinocytes-specified serum-free medium (K-SFM) (the same routine culture condition below). The morphology of cells cultured for 3 and 5 days was observed under the inverted optical microscope. (2) After 24 hours in routine culture, the expression of cell surface markers CD44, CD45, CD11b, and CD11c was detected by flow cytometer, with triplicate samples. (3) Four batches of cells were collected, and each batch was divided into VEGF group or blank control group according to the random number table. The cells in blank control group were routinely cultured, while the cells in VEGF group were cultured in K-SFM containing VEGF in the final mass concentration of 10 ng/mL. The protein expressions of cytokeratin 19 (CK19) and CK10 in cells cultured for 10 days were detected by Western blotting. The Nanog mRNA expression in cells cultured for 0 (immediately), 2, 4, 6, 8, and 10 day (s) was detected by real-time fluorescent quantitative reverse transcription polymerase chain reaction. The absorbance value was detected with cell counting kit-8 in cells cultured for 2, 4, 6, 8, and 10 days. The clone number of more than 50 cells was observed and counted under the optical microscope in cells cultured for 10 days, and the cell colony formation rate was calculated. Three samples at each time point was analysed. (4) Thirty-six 3-month-old SD rats (either male or female) were used for the study, and two deep partial-thickness burn wounds (10 mm in diameter) were created in each rat by pressing a 100 ℃ electric iron plate on symmetric dorsal side. According to the random number table, the injured rats were divided into VEGF+ ESCs group, ESCs alone group, and blank control group, with 12 rats and 24 wounds in each group. From 0 (immediately) to 2 day (s) after injury, 20 μL phosphate buffer solution (PBS) was injected into each wound in the three groups in one time, once a day, with the solution in VEGF+ ESCs group containing 0.8×10(6) cells/mL of ESCs treated by 10 ng/mL VEGF for 10 days, the solution in ESCs alone group containing 0.8×10(6) cells/mL of ESCs without any treatment, and the solution in blank control group being PBS only. On post first injection day (PFID) 0 (immediately), 3, 7, and 14, three rats from each group were taken respectively according to the random number table for wound healing assessment, and the wound healing rates on PFID 3, 7, and 14 were calculated. The mice at each time point were sacrificed with wound tissue harvested for histology, and the skin structure was observed by hematoxylin-eosin staining. Data were statistically analyzed with independent sample <it</i test, analysis of variance for factorial design, least significant difference test, and Bonferroni correction. <bResults:</b (1) By day 3 in culture, cells distributed in slowly-growing clusters. By day 5, the clusters were large and round, in which the cells mainly with large and round nuclei and little cytoplasm were observed. The above results were consistent with the morphological characteristics of ESCs. (2) The positive expression rate of CD44 was (94.3±1.2) %, and the expressions of CD45, CD11b, and CD11c were negative. The cells were confirmed as ESCs. (3) Compared with those of blank control group, the protein expression of CK19 in the cells of VEGF group was significantly increased after 10 days in culture (<it</i=3.756, <iP</i&lt;0.05), while the protein expression of CK10 was significantly decreased (<it</i=3.149, <iP</i&lt;0.05). Compared with those of blank control group, the Nanog mRNA expression in the cells cultured for 0 and 2 day (s) and absorbance values of the cells cultured for 2 and 4 day (s) were not significantly changed in VEGF group (<it</i=0.58, 0.77, 0.53, 3.02, <iP</i&gt;0.05), while the Nanog mRNA expression in the cells cultured for 4, 6, 8, and 10 days and absorbance values of the cells cultured for 6, 8, and 10 days were significantly increased in VEGF group (<it</i=6.34, 5.00, 5.58, 4.61, 5.65, 10.78, 15.51, <iP</i&lt;0.01). After 10 days in culture, the cell colony-forming rate in VEGF group was (56.4±1.3) %, significantly higher than (31.5±1.3) % of blank control group (<it</i=13.96, <iP</i&lt;0.01). (4) The burn wounds of rats in the three groups were confined to the superficial dermis of the skin on PFID 0. On PFID 3, normal skin tissue at wound margins slightly contracted in the rats of VEGF+ ESCs group, which was earlier than that in the other two groups. On PFID 7, the newly generated epidermis covered most parts of the rat wounds in VEGF+ ESCs group, and some of the epithelium crawled around the rat wounds in ESCs alone group, but no obvious epithelialization was observed in the rat wounds in blank control group. On PFID 14, the rat wounds in VEGF+ ESCs group were basically healed, while some parts of the rat wounds were unhealed in ESCs alone group, and most parts of the rat wounds were unhealed in blank control group. On PFID 3, the wound healing rates of rats in the three groups were similar (<iP</i&gt;0.05). On PFID 7 and 14, the wound healing rates of rats in ESCs alone group, respectively (26.0±2.0) % and (64.4±4.7) %, were obviously higher than (12.4±1.1) % and (29.1±3.3) % of blank control group (<iP</i&lt;0.01), all of which were obviously lower than (41.0±2.4) % and (91.3±3.5) % of VEGF+ ESCs group (<iP</i&lt;0.01). On PFID 3, infiltration of a large number of inflammatory cells were observed in the rat wounds in VEGF+ ESCs group, which was earlier than those in the other two groups. On PFID 7, a large number of endothelial cells were observed in the rat wounds in VEGF+ ESCs group, while proliferation of a few endothelial cells were observed in the rat wounds in ESCs alone group, and a large number of inflammatory cells infiltrated the rat wounds in blank control group. On PFID 14, the newly generated epidermal cells covered nearly all the rat wounds in VEGF+ ESCs group and most parts of the rat wounds in ESCs alone group, while a large number of endothelial cells were observed and the newly generated epidermal cells covered some parts of the rat wounds in blank control group. <bConclusions:</b ESCs of rats treated with exogenous VEGF can promote the healing of deep partial-thickness burn wounds in rats, which may be related to VEGF's roles in promoting the proliferation of ESCs and reducing its differentiation level, so as to maintain the potency of stem cells.

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1. Philippines: The development, expansion and maintenance of pilot area activities: Cristina B. Giango (Technical Division, Cebu Provincial Health Office, the Philippines) In 1994, the Department of Health developed the new NTP policies based on WHO recommendations and started a pilot project in Cebu Province in collaboration with the Japan International Cooperation Agency. To test its feasibility and effectiveness, the new NTP policies were pre-tested in one city and one Rural Health Unit. The test showed a high rate of three sputum collection (90%), high positive rate (10%), and high cure rate (80%). Before the new guidelines were introduced, the new policy was briefed, a baseline survey of the facility was conducted, equipment was provided, and intensive training was given. Recording/Reporting forms and procedures were also developed to ensure accurate reporting. Supervision, an important activity to ensure effective performance, was institutionalized. Laboratory services were strengthened, and a quality-control system was introduced in 1995 to ensure the quality of the laboratory services. With the implementation of DOTS strategy, barangay health workers were trained as treatment partners. In partnership with the private sector, the TB Diagnostic Committee was organized to deliberate and assess sputum negative but X-ray positive cases. The implementation of the new NTP guidelines in Cebe Province has reached a satisfactory level, the cure rate and positive rate have increased, and laboratory services have improved. Because of its successful implementation, the new NTP guidelines are now being used nationwide. 2. Nepal: The DOTS Strategy in the area with hard geographic situation: Dirgh Singh Bam (National Tuberculosis Center, Nepal) Three groups of factors characterize the population of Nepal: 1) Socio-cultural factors, e.g. migration, poverty, language; 2) Environmental factors, e.g. geography and climate; and 3) Political factors, prisoners and refugee populations. These factors pose particular problems for implementing DOTS in various ways. Socio-cultural and environmental factors are particularly important in Nepal, and several measures have been developed to overcome these difficulties. One is active community participation through the DOTS committee. The committee consists of a group of motivated people, including social workers, political leaders, health services providers, journalists, teachers, students, representatives of local organizations, medical schools and colleges, industries, private practitioners, and TB patients. One DOTS committee is formed in every treatment center. A key role of the DOTS committee is to identify local problems and their solutions. It increases public awareness about TB and DOTS; supports people with TB in the community by providing treatment observers and tracing late patients; and encourages cooperation among health institutions, health workers, NGOs, and political leaders. The case finding rate is now 69%, and nearly 95% of diagnosed TB cases are being treated under DOTS. The treatment success rate of new smear-positive cases is nearly 90%. Thus, DOTS increases the case finding and treatment success. 3. Cambodia: HIV/TB and the health sector reform: Tan Eang Mao (National Center for Tuberculosis and Leprosy Control, Cambodia) Cambodia is one of the 23 high burden countries of tuberculosis in the world. Moreover, HIV/AIDS has been spreading rapidly since 1990s, which is worsening the tuberculosis epidemics. To cope with the burden, Cambodia has started implementation of DOTS in 1994 and has expanded it to most of public hospitals across the country by 1998. NTP of Cambodia is now enjoying high cure rate of more than 90%. However, due to the constraints such as weak infrastructure and the poverty, it is proved that many of TB sufferers do not have access to the TB services, resulting in still low case detection rate. It is for this reason that the NTP has decided to expand DOTS to health center and community level based on the new health system. Its pilot program that has been carried out in collaboration with JICA and WHO since 1999 has achieved promising results with high detection and cure rates. All of the over 900 health centers across the country will be involved in DOTS strategy by 2005. In the fight against TB/HIV, National Center for TB Control is providing free TB screening for PLWH (people living with HIV/AIDS), and it is developing a comprehensive plan of TB/HIV care including home delivery DOT services. 4. China: The World Bank Project and the Prevalence Survey in China: Hong Jin DuanMu (National Tuberculosis Control Center, China) Since 1992, China has utilized a World Bank loan to implement TB control projects among 560 million people in 13 provinces. Free diagnosis and treatment services have been provided to all patients, and a fully supervised standard short-course chemotherapy was applied to all diagnosed tuberculosis patients. In 1999, more than 190,000 smear-positive cases, ten times the number in 1992, were detected, and the registration rate of new cases reached 30 per 100,000 population. From 1992 to 1999, a total of 1.40 million smear-positive TB patients were discovered. The cure rate of smear-positive TB patients has been improved to an overall cure rate of 93.6%. The cure rates for the new cases and re-treatment patients were 95.1% and 89.6%, respectively. The fourth nationwide random survey for the epidemiology of tuberculosis was conducted in 2000. The prevalence of active tuberculosis was 367/100,000, the prevalence of infectious tuberculosis was 160/100,000, and the prevalence of smear-positive tuberculosis was 122/100,000. The tuberculosis mortality was 9.8/100,000. 5. Vietnam: The road to reaching the Global Target: Le Ba Tung (Pham Ngoc Thach Tuberculosis and Lung Disease Center, Vietnam) TB control activities started in 1957 and were reorganized in 1986 with the technical assistance of IUATLD, KNCV and material assistance of Medical Committee Netherlands Vietnam (MCNV). The New National TB Control Program follows the main directives of WHO and IUATLD's procedures of case-finding, chemotherapy and management. Passive case-findings are based on sputum smear. Chemotherapy with priority for smear positive cases is 3SHZ/6S2H2 for new cases and 3HRE/6H2R2E2 for retreated cases, which is undertaken with directly observed therapy (DOT strategy) mainly at commune health posts. Since 1989, DOTS strategy with 2SHRZ/6HE for new cases and 2SHRZE/1HRZE/5H3R3E3 for retreated cases has gradually been introduced in districts and communes of every province. In 1995, the government established the National and Provincial TB Control Steering Committees and has provided incentives for detected smear positive cases and cured smear positive cases. The government has also started strengthening the program of managerial and supervisory capacity for TB staff and has promoted the cooperation of all associated organizations of TB control. The WHO global surveillance and monitoring project reports that in 2000 Vietnam reached the global target, i.e., 99.8% population covered by DOTS with 80% of expected new smear positive cases being detected and a high cure rate ranging from 85.3% in 1989 to 90.3% in 1999. A distinguishing aspect of TB control in Vietnam is the effective international partnerships combined with high political commitment of the government nationally and provincially as well as active participation of all organizations in the community.

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It has been estimated that 92 per cent of the total radiation emitted by radium in equilibrium with its subsequent products is given off in the form of alpha-rays. This, however, cannot be utilized when the source is enclosed in an ordinary container, because the alpha-rays are absorbed completely by even a small thickness of glass. About 3.2 per cent of the total radiation is emitted in the form of beta-rays, and 4.8 per cent as gamma radiation. The effects produced on the radiated mice of these experiments were due mainly to the beta-rays, which are easily absorbed by tissue. The gamma-rays, being only slightly absorbed by organic matter, probably contributed very little to the observed effects. It is interesting to correlate the different effects produced by the same dose of radiation. The mice which received a dose of 1.9 millicurie hours showed no local effects on the skin or hair. Neither females nor males were sterilized, and the time at which they opened their eyes or reached sexual maturity was not affected, as far as we could tell. The only difference noted between the radiated animals and the controls was in the body weight. This dose accelerated the growth of the young mice, that is, while initially of the same weight, soon after irradiation they became distinctly bigger than the controls, but finally the animals of each group had substantially the same average weight. That this variation in body weight should be accidental is unlikely, since it was observed also in the animals treated by a slightly larger dose (2.4 millicurie hours). The number of animals (seven) which showed this effect is too small to prove conclusively the accelerating effect of small doses of radiation on the body growth of mice. But considering that similar results have been. obtained by radiating plants and beetles, it is reasonable that the observed increase in weight might be attributed, at least in part, to the effects of radiation. Since this paper was first written Russ, Chambers, and Scott have shown that small doses of x-rays accelerate the body growth of rats. In view of this additional evidence there can be little doubt that the increase in weight observed in our experiments was due to the radiation. A dose of 2.4 millicurie hours applied over the backs of the animals produced no local skin effects, but it accelerated the growth of the mice as in the previous case. In addition it caused permanent sterilization of all the females. A similar result was obtained with 4.9 millicurie hours, except that the effect on the rate of growth was uncertain. A dose of 6.8 millicurie hours produced a definite but mild skin erythema and retarded the development of lanugo hair. But since in this instance the emanation was applied over the heads of the animals, the dose reaching the ovaries was not sufficient to cause sterilization, as already explained. No other definite effect was noted. In connection with the sterilization of the females it should be noted that a dose of radiation which produced no visible skin changes was sufficient to cause permanent sterility. On account of the greater distance of the ovaries from the source of radiation as compared with that of the skin directly below the tube, and the depth of tissue which the rays had to traverse to reach the ovaries, the amount of radiation acting on the latter was much smaller than the amount falling on the skin. The radiation emitted by the emanation tube is reduced to about 50 per cent of its initial value after traversing 1 mm. of tissue. Still, while the skin was not visibly affected, the mice were sterilized. This shows that the ovaries are influenced very easily by radiation of this type. We can estimate the amount of radiation reaching the ovaries which is sufficient to cause sterility to be less than 25 per cent of the amount necessary to produce visible skin changes in the mice. It should be noted also that whenever sterility of the female mice was induced, it was permanent. Furthermore, those mice which were not rendered sterile by radiation were, as far as the experiments enable us to say, as prolific as the controls. Remembering that a dose of 1.9 millicurie hours had no apparent effect on the ovaries, while a slightly larger dose, 2.4 millicurie hours, caused permanent sterility, it might be concluded that it is not possible to produce temporary sterility by radiation. We know, however, that temporary sterility can be produced, at least when the animals are radiated at a later stage in their development. The mice in our experiments were radiated for the first time soon after birth, and it is not improbable that under these conditions temporary sterility cannot be obtained. Large sublethal doses produced severe skin burns, retarded the body growth of the animals, but failed to sterilize the males. About one-third of the total skin area of the mice showed marked effects from the radiation. The animals were very sick for a time, and their growth was temporarily stunted. But nevertheless they recovered and finally became apparently normal except for the narrow hairless strip of skin which had been closest to the emanation tube. Only the females were rendered permanently sterile. The males did not show even temporary sterility when the doses of radiation were close to the lethal dose. While the testes of mammals are known to be very easily affected by radiation, still they are more resistant than the ovaries. In addition, in these experiments they were at a greater distance from the source of radiation than the ovaries, and they were better protected by the thicker layer of tissue in the path of the rays. The fact that no sublethal dose in these experiments sterilized the males shows that under the conditions of irradiation adopted the amount of radiation reaching the testes was not sufficient to affect them noticeably. If the source of radiation had been applied closer to the reproductive organs of the males, they would have been sterilized by millicurie hour doses much smaller than the lethal dose. Some of the radiated animals were killed with ether, and macroscopic and microscopic examinations of the reproductive organs were made. The ovaries of the sterile females were generally atrophied and colored yellow. The normal histological structure was altered. The characteristic findings were the destruction of the Graafian follicles, with absence of ovum cells. The testes and the epididymis of the radiated mice of the present experiment appeared macroscopically and histologically normal, with the presence of abundant spermatozoa. Owing to the method adopted for the irradiation of the mice, the testes were too far from the source of radiation, and too well protected by the intervening tissue to be definitely affected by the rays.

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Many studies have established associations between exposure to air pollution, or atmospheric particulate matter (PM), and adverse health effects. An increasing array of studies have suggested oxidative stress as a possible mechanism by which PM-induced health effects arise, and as a result, many chemical and cellular assays have been developed to study PM-induced oxidant production. Although significant progress has been made in recent years, there are still many gaps in this area of research that have not been addressed. Many prior studies have focused on the aerosol of primary origin (e.g., the aerosol emitted from combustion engines) although the aerosol formed from the oxidation of volatile species, secondary organic aerosol (SOA), has been shown to be the predominant type of aerosol even in urban areas. Current SOA health studies are limited in number, and as such, the health effects of SOA are poorly characterized. Also, there is a lack of perspective in terms of the relative toxicities of different SOA systems. Additionally, although chemical assays have identified some SOA constituents associated with adverse health endpoints, the applicability of these results to cellular responses has not been well established. The overall objective of this study was to better understand the oxidative properties of different types and components of PM mixtures (especially SOA) through systematic laboratory chamber experiments and ambient field studies. The study had four specific aims. 1 To develop a cellular assay optimized for measuring reactive oxygen and nitrogen species (ROS/RNS) production resulting from PM exposure and to identify a robust parameter that could represent ROS/RNS levels for comparison with different endpoints. 2 To identify ambient PM components associated with ROS/RNS production and evaluate whether results from chemical assays represented cellular responses in terms of ROS/RNS production. 3 To investigate and provide perspective on the relative toxicities of SOA formed from common biogenic and anthropogenic precursors under different conditions (e.g., humidity, nitrogen oxides [NO<subx</sub], and redox-active metals) and identify bulk aerosol properties associated with cellular responses. 4 To investigate the effects of photochemical aging on aerosol toxicity. Ambient PM samples were collected from urban and rural sites in the greater Atlanta area as part of the Southeastern Center for Air Pollution and Epidemiology (SCAPE) study between June 2012 and October 2013. The concentrations of water-soluble species (e.g., water-soluble organic carbon [WSOC], brown carbon [Br C], and metals) were characterized using a variety of instruments. Samples for this study were chosen to span the observed range of dithiothreitol (DTT) activities. Laboratory studies were conducted in the Georgia Tech Environmental Chamber (GTEC) facility in order to generate SOA under well-controlled photooxidation conditions. Precursors of biogenic origin (isoprene, α-pinene, and β-caryophyllene) and anthropogenic origin (pentadecane, m-xylene, and naphthalene) were oxidized under various formation conditions (dry vs. humid, NO<subx</sub, and ammonium sulfate vs. iron sulfate seed particles) to produce SOA of differing chemical composition and mass loading. For the naphthalene system, a series of experiments were conducted with different initial hydrocarbon concentrations to produce aerosols with various degree of oxidation. A suite of instruments was utilized to monitor gas- and particle-phase species. Bulk aerosol properties (e.g., O:C, H:C, and N:C ratios) were measured using a high-resolution time-of-flight aerosol mass spectrometer. Filter samples were collected for chemical oxidative potential and cellular measurements. For the naphthalene system, multiple filter samples were collected over the course of a single experiment to collect aerosols of different photochemical aging. For all filter samples, chemical oxidative potentials were determined for water-soluble extracts using a semiautomated DTT assay system. Murine alveolar macrophages and neonatal rat ventricular myocytes were also exposed to PM samples extracted in cell culture medium to investigate cellular responses. ROS/RNS production was detected using the intracellular ROS/RNS probe, carboxy-2',7'-dichlorodihydrofluorescein diacetate (carboxy-H<sub2</subDCFA), whereas cellular metabolic activity was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). Finally, cytokine production, that is, secreted levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), were measured post-exposure using an enzyme-linked immunosorbent assay (ELISA). To identify PM constituents associated with oxidative properties, linear regressions between oxidative properties (cellular responses or DTT activity) and aerosol composition (metals, elemental ratios, etc.) were evaluated using Pearson's correlation coefficient, where the significance was determined using multiple imputation and evaluated using a 95% confidence interval. We optimized several parameters for the ROS/RNS assay, including cell density (2 × 10<sup4</sup cells/well for macrophages and 3.33 × 10<sup4</sup cells/well for cardiomyocytes), probe concentration (10 µM), and sample incubation time (24 hours). Results from both ambient and laboratory-generated aerosols demonstrate that ROS/RNS production was highly dose-dependent and nonlinear with respect to PM dose. Of the dose-response metrics investigated in this study (maximum response, dose at which the response is 10% above the baseline [threshold], dose at which 50% of the response is attained [EC50], rate at which the maximum response is attained [Hill slope], and area under the dose-response curve [AUC]), we found that the AUC was the most robust parameter whose informativeness did not depend on dose range. A positive, significant correlation was observed between ROS/RNS production as represented by AUC and chemical oxidative potential as measured by DTT for ambient samples collected in summer. Conversely, a relatively constant AUC was observed for ambient samples collected in winter regardless of the corresponding DTT activity. We also identified several PM constituents (WSOC, BrC, iron, and titanium) that were significantly correlated with AUC for summer samples. The strong correlation between organic species and ROS/RNS production highlights a need to understand the contribution of organic aerosols to PM-induced health effects. No significant correlations were observed for other ROS/RNS metrics or PM constituents, and no spatial trends were observed. For laboratory-generated aerosol, precursor identity influenced oxidative potentials significantly, with isoprene and naphthalene SOA having the lowest and highest DTT activities, respectively. Both precursor identity and formation condition significantly influenced inflammatory responses induced by SOA exposure, and several response patterns were identified for SOA precursors whose photooxidation products share similar carbon-chain length and functionalities. The presence of iron sulfate seed particles did not have an apparent effect on oxidative potentials; however, a higher level of ROS/RNS production was observed for all SOA formed in the presence of iron sulfate compared with ammonium sulfate. We also identified a significant positive correlation between ROS/RNS production and average carbon oxidation state, a bulk aerosol property. It may therefore be possible to roughly estimate ROS/RNS production using this property, which is readily obtainable. This correlation may have significant implications as aerosols have an atmospheric lifetime of a week, during which average carbon oxidation state increases because of atmospheric photochemical aging. Our results suggest that aerosols might become more toxic as they age in the atmosphere. Finally, in the context of ambient samples, laboratory-generated SOA induced comparable or higher levels of ROS/RNS. Oxidative potentials for all laboratory SOA systems, with the exception of naphthalene (which was higher), were all comparable with oxidative potentials observed in ambient samples.

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Sonelokimab (also known as M1095) is a novel trivalent nanobody comprised of monovalent camelid-derived (ie, from the Camelidae family of mammals, such as camels, llamas, and alpacas) nanobodies specific to human interleukin (IL)-17A, IL-17F, and human serum albumin. Nanobodies are a novel class of proprietary therapeutic proteins based on single-domain, camelid, heavy-chain-only antibodies. We assessed the efficacy, safety, and tolerability of sonelokimab across four dosage regimens compared with placebo in patients with plaque-type psoriasis. Secukinumab served as an active control. This multicentre, randomised, placebo-controlled, phase 2b trial was done at 41 clinics and research sites in Bulgaria, Canada, Czech Republic, Germany, Hungary, Poland, and the USA. Participants (aged 18-75 years) with stable moderate to severe plaque-type psoriasis (defined as an Investigator's Global Assessment [IGA] score of ≥3, a body surface area involvement of ≥10%, and a Psoriasis Area and Severity Index score of ≥12) for more than 6 months before randomisation, who were candidates for systemic biological therapy were included. Participants previously treated with more than two biologics or any therapy targeting IL-17 were excluded. Randomisation was stratified by weight (≤90 kg or &gt;90 kg) and previous use of biologics. Investigators, participants, and vendors remained masked for the duration of the study, with the exception of each site's study drug administrator (who did not complete any other assessments in the study) and a study monitor who only assessed drug preparation, administration, and accountability. The study sponsor remained masked until all week 24 data were clean and locked. Participants were randomly assigned (1:1:1:1:1:1) using a centralised interactive response technology system to one of six parallel treatment groups: placebo group, sonelokimab 30 mg group, sonelokimab 60 mg group, sonelokimab 120 mg normal load group, sonelokimab 120 mg augmented load group, or secukinumab 300 mg group. All participants underwent a 4-week screening period, a 12-week placebo-controlled induction period, a 12-week dose maintenance or escalation period, and a 24-week response assessment or dose-holding period. During the placebo-controlled induction period (weeks 0-12), participants received either placebo (at weeks 0, 1, 2, 3, 4, 6, 8, and 10), sonelokimab 30 mg, 60 mg, or 120 mg normal load (at weeks 0, 2, 4, and 8), sonelokimab 120 mg augmented load (at weeks 0, 2, 4, 6, 8, and 10), or secukinumab 300 mg (at weeks 0, 1, 2, 3, 4, and 8), with placebo given at weeks 1, 3, 6, and 10 in the sonelokimab 30 mg, 60 mg, and 120 mg normal load groups, at weeks 1 and 3 in the sonelokimab 120 mg augmented load group, and at weeks 6 and 10 in the secukinumab 300 mg group. During the dose maintenance or escalation period (weeks 12-24), participants assigned to the placebo group received sonelokimab 120 mg (at weeks 12, 14, 16, and then every 4 weeks); those assigned to sonelokimab 30 mg or 60 mg groups with an IGA score of more than 1 were escalated to 120 mg and then every 4 weeks, and those with an IGA score of 1 or less stayed on the assigned dose at week 12 and then every 4 weeks; those assigned to the sonelokimab 120 mg groups received sonelokimab 120 mg at week 12 and then every 8 weeks (normal load group) or every 4 weeks (augmented load); and those assigned to the secukinumab 300 mg group received secukinumab 300 mg at week 12 and then every 4 weeks. During this period, placebo was given at week 14 in all groups, except in participants who initially received placebo, and at week 16 in the sonelokimab 120 mg normal load group. In the response assessment with dose-holding period (weeks 24-48), participants in the sonelokimab 30 mg or 60 mg groups who had dose escalation to 120 mg remained on the same regimen regardless of the IGA score at week 24. Participants in the secukinumab 300 mg group also remained on the same regimen regardless of IGA score at week 24. Participants in the sonelokimab 30 mg and 60 mg groups without dose escalation, and all participants in the two sonelokimab 120 mg groups (including placebo rollover patients) were eligible to stop the study drug at week 24. Those participants with an IGA score of 0 at week 24 received placebo; these participants resumed the previous dose of sonelokimab every 4 weeks when they had an IGA score of 1 or more (assessed every 4 weeks). Participants in these groups with an IGA score of 1 or more at week 24 continued on the same dosage. All study treatments were administered as subcutaneous injections. The final dose in all groups was given at week 44. The primary outcome was the proportion of participants in the sonelokimab groups with an IGA of clear or almost clear (score 0 or 1) at week 12 compared with the placebo group. The primary outcome and safety outcomes were assessed on an intention-to-treat basis. The study was not powered for formal comparisons between sonelokimab and secukinumab groups. This trial is registered with ClinicalTrials.gov, NCT03384745. Between Aug 15, 2018, and March 27, 2019, 383 patients were assessed for eligibility, 313 of whom were enrolled and randomly assigned to the placebo group (n=52), the sonelokimab 30 mg group (n=52), the sonelokimab 60 mg group (n=52), the sonelokimab 120 mg normal load group (n=53), the sonelokimab 120 mg augmented load group (n=51), or the secukinumab 300 mg group (n=53). Baseline characteristics of participants were similar among the groups. At week 12, none (0·0% [95% CI 0·0-6·8]) of the 52 participants in the placebo group had an IGA score of 0 or 1 versus 25 (48·1% [34·0-62·4], p&lt;0·0001) of 52 participants in the sonelokimab 30 mg group, 44 (84·6% [71·9-93·1], p&lt;0·0001) of 52 participants in the sonelokimab 60 mg group, 41 (77·4% [63·8-87·7], p&lt;0·0001) of 53 participants in the sonelokimab 120 mg normal load group, 45 (88·2% [76·1-95·6], p&lt;0·0001) of 51 participants in the sonelokimab 120 mg augmented load group, and 41 (77·4% [63·8-87·7], p&lt;0·0001) of 53 participants in the secukinumab 300 mg group. During the placebo-controlled induction period, 155 (49·5%) of 313 participants had one or more mostly mild to moderate adverse event; the most frequent adverse events in all participants on sonelokimab during weeks 0-12 were nasopharyngitis (28 [13·5%] of 208 participants), pruritus (14 [6·7%] participants), and upper respiratory tract infection (nine [4·3%] participants). One patient from all sonelokimab-containing groups had Crohn's disease that developed during weeks 12-52. Over 52 weeks, sonelokimab safety was similar to secukinumab, with the possible exception of manageable Candida infections (one [1·9%] of 53 participants in the secukinumab group had a Candida infection vs 19 [7·4%] of 257 participants in all sonelokimab-containing groups). Treatment with sonelokimab doses of 120 mg or less showed significant clinical benefit over placebo, with rapid onset of treatment effect, durable improvements, and an acceptable safety profile. Avillion.

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<bObjective:</b To prepare the modified hyaluronic acid viscous hydrogel loaded with sliver particles and to explore the roles and mechanism of the hydrogel in healing of full-thickness skin defect wounds with bacterial colonization in mice. <bMethods:</b The experimental research method was adopted. Dopamine modified hyaluronic acid (HA-DA) and phenylboric acid modified hyaluronic acid (HA-PBA) were prepared, and their characteristic peaks were detected by Fourier-transform infrared spectroscopy. Different mass of acrylamides was added to HA-DA and HA-PBA to prepare the viscous hydrogel with mass fraction of acrylamide in 10%, 15%, and 20%. The gelation of the viscous hydrogel with mass fraction of acrylamide in 20% was observed in the state of tilt and inversion at 37 ℃, and the storage modulus and loss modulus of the above 3 kinds of viscous hydrogels were detected by rotational rheometer. The sliver-loaded viscous hydrogel was prepared by adding nano silver ions to the viscous hydrogel with mass fraction of acrylamide in 20%. The concentration of silver ions released by sliver-loaded viscous hydrogel was measured by inductively coupled plasma mass spectrometer, and the cumulative release rate of silver ion was calculated (<in</i=5). The mouse fibroblasts L929 were divided into phosphate buffered saline (PBS) group, viscous hydrogel group, and sliver-loaded viscous hydrogel group, which were dealt correspondingly, and the cell survival was detected by cell counting kit 8 method after 1, 2, and 3 d of culture (<in</i=5). Twenty-four male C57BL/6 mice aged 6-8 weeks were selected, and forty-eight full-thickness skin defect wounds were inflicted and inoculated with the mixture of <iEscherichia coli and Staphylococcus aureus</i in the back of the mice, with two wounds in each mouse. The wounds were divided into normal saline group, viscous hydrogel group, and sliver-loaded viscous hydrogel group, which were dealt correspondingly, with 16 wounds in each group, and two wounds in each mouse were divided into different groups. On post injury day (PID) 3, 7, 10, and 14, the wound healing was observed and the wound healing rate was calculated. On PID 3, the colony forming units of <iEscherichia coli and Staphylococcus aureus</i in wounds were observed and counted. On PID 14, the epithelized epidermal thickness and the optical density of collagen fiber in wounds were observed and analyzed after hematoxylin eosin staining and Masson staining, respectively. On PID 3, 7, and 10, the expressions of tumor necrosis factor α (TNF-α), transforming growth factor β<sub1</sub (TGF-β<sub1</sub), and vascular endothelial growth factor (VEGF) were detected by immunohistochemistry. The number of wounds in each index detecting at each time point was four. Data were statistically analyzed with analysis of variance for factorial design, one-way analysis of variance, and Bonferroni correction. <bResults:</b The characteristic peaks of HA-PBA were detected at the wave numbers of 1 369 and 1 425 cm<sup-1</sup, indicating that phenylboric acid had been successfully grafted on hyaluronic acid, and the characteristic peaks of HA-DA were detected at the wave numbers of 1 516 and 1 431 cm<sup-1</sup, indicating that dopamine had been successfully grafted on hyaluronic acid. The viscous hydrogel with mass fraction of acrylamide in 20% maintained the stable and no-flow condition of gelation in the state of tilt and inversion at 37 ℃. The storage modulus and loss modulus of the viscous hydrogel increased with the increase of acrylamide content, the storage modulus and loss modulus of the 3 kinds of viscous hydrogels had no obvious changes with the increase of the oscillation frequency or time, and the storage modulus of the 3 kinds of acrylamide hydrogels were greater than the loss modulus. The release of silver ion in the sliver-loaded viscous hydrogel lasted for 7 days, and the cumulative release rate of silver ion was up to 65%. After 1, 2, and 3 d of culture, the cell survival rates in sliver-loaded viscous hydrogel group were significantly lower than those in PBS group and viscous hydrogel group (<iP</i&lt;0.05 or <iP</i&lt;0.01), while after 1 d of culture, the cell survival rate in viscous hydrogel group was significantly lower than that in PBS group (<iP</i&lt;0.01). With extension of time after injury, the wounds of mice in the 3 groups shrank gradually. On PID 3, 7, 10, and 14, the wound healing rates in sliver-loaded viscous hydrogel group were (53.0±3.6)%, (75.3±6.9)%, (93.3±1.2)%, and (96.7±0.8)%, which were significantly higher than (21.8±6.4)%, (53.9±8.2)%, (72.0±7.8)%, and (92.5±0.4)% in normal saline group (<iP</i&lt;0.01). On PID 3 and 14, the wound healing rates in sliver-loaded viscous hydrogel group were significantly higher than (43.5±2.4)% and (94.1±1.5)% in viscous hydrogel group (<iP</i&lt;0.05). On PID 3 and 10, the wound healing rates in viscous hydrogel group were significantly higher than those in normal saline group (<iP</i&lt;0.01). On PID 3, the colony forming units of two bacteria in wound of sliver-loaded viscous hydrogel group were significantly less than those in normal saline group and viscous hydrogel group (<iP</i&lt;0.01), while the colony forming units of two bacteria in wound of viscous hydrogel group were significantly less than those in normal saline group (<iP</i&lt;0.05). On PID 14, the wounds were basically epithelialized and the epidermis was thicker, with collagen protein content being increased significantly and more orderly arranged collagen in sliver-loaded viscous hydrogel group compared with those in the other 2 groups. On PID 14, the epidermal thickness in wounds of sliver-loaded viscous hydrogel group was significantly increased compared with that in the other two groups (<iP</i&lt;0.05), and the optical density of collagen fiber was significantly increased compared with those in normal saline group (<iP</i&lt;0.05). On PID 3, the expressions of TGF-β<sub1</sub and VEGF in wounds of sliver-loaded viscous hydrogel group were significantly higher than those in normal saline group (<iP</i&lt;0.05 or <iP</i&lt;0.01), while the expression of VEGF in wounds of viscous hydrogel group was significantly higher than that in normal saline group (<iP</i&lt;0.01). On PID 7, the expression of TGF-β<sub1</sub in wounds of sliver-loaded viscous hydrogel group was significantly higher than that in the other 2 groups (<iP</i&lt;0.01), and the expression of VEGF was significantly higher than that in normal saline group (<iP</i&lt;0.01). On PID 10, the expression of TNF-α in wounds of sliver-loaded viscous hydrogel group was significantly lower than that in normal saline group (<iP</i&lt;0.05), the expressions of TGF-β<sub1</sub and VEGF in wounds of sliver-loaded viscous hydrogel group were significantly higher than those in normal saline group (<iP</i&lt;0.05 or <iP</i&lt;0.01), and the expression of VEGF in wounds of sliver-loaded viscous hydrogel group was significantly higher than that in viscous hydrogel group (<iP</i&lt;0.05). <bConclusions:</b The sliver-loaded viscous hydrogel prepared in this study has good stability and elasticity, which can continuously release silver ions and help to accelerate the healing of full-thickness defect wounds with bacterial colonization in mice. Besides, the sliver-loaded viscous hydrogel has low biological toxicity and can promote re-epithelialization, collagen deposition as well as angiogenesis of wounds, which may be related to the infiltration and regression of inflammatory cells.

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After Operation Desert Storm which took place in Iraq from August 1990 to July 1991 involving a coalition of 35 countries and a 700,000 strong contingent of mainly American men, some associations of war veterans, the media and researchers described a new diagnostic entity: the Gulf War Syndrome (GWS). GWS seems to be a new disorder which associates a litany of functional symptoms integrating the musculoskeletal, digestive, tegumentary and neurosensory systems. The symptoms presented do not allow a syndrome already known to be considered and the aetiology of the clinical picture remains unexplained, an increasing cause for concern resulting from the extent of the phenomenon and its media coverage. It quickly appears that there is no consensus amongst the scientific community concerning a nosographic description of GWS: where can all these functional complaints arise from? Different aetiopathogenic hypotheses have been studied by the American administration who is attempting to incriminate exposure to multiple risks such as vaccines and their adjuvants, organophosphorous compounds, pyridostigmine (given to the troops for the preventive treatment of the former), impoverished uranium, and the toxic emanations from oil well fires. But despite extremely in-depth scientific investigations, 10 years after the end of the war, no objective marker of physical suffering has been retained to account for the disorders presented. It would appear that the former soldiers are in even better objective health than the civil population whereas their subjective level of health remains low. Within this symptomatic population, some authors have begun to notice that the psychological disorders appear and persist associating: asthenia, fatigability, mood decline, sleep disorders, cognitive disorders and post-traumatic stress disorder (PTSD). Within the nosological framework, does GWS cause functional disorders or somatisation? Finally, 20 years after the end of the fighting, only PTSD has been causally attributed to military deployment. Certain functional symptoms of GWS occur during the latent phase of a future reexperiencing syndrome, latent phase which is the locus of nonspecific symptoms. The psychotraumatised subject does not express himself spontaneously and waits to be invited to do so: if the social context does not allow this expression, the suffering can remain lodged in a few parts of the body. How can the inexpressible part of the trauma be recounted, particularly if the social context does not allow it? For civil society, calling into question "the somatic word" of veterans is difficult: why were they sent to face these hardships? What could we learn from these soldiers we do not wish to listen to: the horror of the war, the aggressive impulse of men, and the confrontation with death? Another obstacle to this reflection is the reference to stress as a prevalent aetiopathogenic model of the psychological trauma. A model like this, considering that PTSD is a normal reaction to an abnormal situation, finally discredits the subject and society and disempowers them by freezing them in a passive status of victim. However, as GWS affects approximately a quarter of subjects deployed, it is not very likely that all these symptoms are caused by a psychotraumatic reaction. Many veterans suffering from GWS have themselves rejected the diagnosis of PTSD, arguing that they do not suffer repetition nightmares. What the veterans rightly tell us here is that the notions of stress and trauma cannot strictly be superimposed. A subject may have been intensely stressed without ever establishing traumatic flashbacks and likewise; a psychological trauma can be experienced without stress and without fear but in a moment of terror. This clarification is in line with the first criterion of the DSM-IV-TR which necessarily integrates the objective and subjective dimensions as determinants of PTSD. Yet, scientific studies relating to GWS are struggling to establish opposition or continuity links between the objective external exposure (smoke from petrol wells, impoverished uranium, biological agents, chemicals) and the share of inner emotion albeit reactive and characterised by a subjective stress. There were no lack of stress factors for the troops deployed: repeated alerts of chemical attacks, hostility of the environment with its sandstorms and venomous animals, climatic conditions making long hours of backup and static observation difficult, collecting bodies, lack of knowledge of the precise geography of their movements and uncertainty of the duration of the conflict. The military anti-nuclear-bacteriological-chemical uniform admittedly provided protective confinement, shutting out the hostile world from which the threat would come but, at the same time, this isolation increases the fear of a hypothetical risk whilst the internal perceptions are increased and can open the way to future somatisations. In a context like this, the somatic manifestations of anxiety (palpitations, sweating, paresthesia…) are willingly associated with somatised functional disorders to which can also be assigned over-interpretations of bodily feelings according to a hypochondriacal mechanism. The selective attention to somatic perceptions in the absence of mentalisations, the request for reassurance reiterated and the excessive use of the treatment system will be diagnostic indices of these symptoms caused by the stress. Rather than toxic exposure to such and such a substance, the non-specific syndrome called "Gulf War Syndrome" is the result of exposure to the eponymous operational theatre. But if the psychological and psychosomatic suffering occurring in veterans is immutable throughout history, the expression of these difficulties has specificities according to the past cultural, political and scientific context. In the example of GWS, the diffusion of the fear of a pathology resulting from chemical weapons has promoted this phenomenon. In the end, biochemical and biological weapons have not been used on a large scale but the mediatisation of this possibility has led to a deleterious… To spare the bother of a group psychological reflection, the scientific and political authorities chose to investigate the implication of environmental factors in the genesis of the disorder. At individual as well as social level, rather than accept a psychogenic origin, a common defence mechanism is to assign the suffering to an external cause. With the perspective of preventing the risk of diffusion of other unexplained syndromes, which could occur following future armed conflicts, new epidemiological diagnostic models must be defined. The media also has considerable responsibility for the diffusion of epidemic psychological reactions but at the same time, they can inform the population about certain individual or group psychopathological mechanisms. The GWS exists: it is not an "imaginary illness" but a serious public health issue which has led to tens of thousands of complaints and swallowed up millions of dollars. To reply to human suffering, a new nosographic entity can spread through society taking the epidemic expression of a somatised disorder via identification, imitation and suggestion mechanisms. This possibility questions not only mental health but also the sociology and politics. It is necessary to inform the leaders and the general population of the possibility of this type of mass reaction, which can take the shape of a highly contagious complex functional syndrome.

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To develop a Canadian consensus document on maternal screening for fetal aneuploidy (e.g., Down syndrome and trisomy 18) in singleton pregnancies. Pregnancy screening for fetal aneuploidy started in the mid 1960s, using maternal age as the screening test. New developments in maternal serum and ultrasound screening have made it possible to offer all pregnant patients a non-invasive screening test to assess their risk of having a fetus with aneuploidy to determine whether invasive prenatal diagnostic testing is necessary. This document reviews the options available for non-invasive screening and makes recommendations for Canadian patients and health care workers. To offer non-invasive screening for fetal aneuploidy (trisomy 13, 18, 21) to all pregnant women. Invasive prenatal diagnosis would be offered to women who screen above a set risk cut-off level on non-invasive screening or to pregnant women whose personal, obstetrical, or family history places them at increased risk. Currently available non-invasive screening options include maternal age combined with one of the following: (1) first trimester screening (nuchal translucency, maternal age, and maternal serum biochemical markers), (2) second trimester serum screening (maternal age and maternal serum biochemical markers), or (3) 2-step integrated screening, which includes first and second trimester serum screening with or without nuchal translucency (integrated prenatal screen, serum integrated prenatal screening, contingent, and sequential). These options are reviewed, and recommendations are made. Studies published between 1982 and 2009 were retrieved through searches of PubMed or Medline and CINAHL and the Cochrane Library, using appropriate controlled vocabulary and key words (aneuploidy, Down syndrome, trisomy, prenatal screening, genetic health risk, genetic health surveillance, prenatal diagnosis). Results were restricted to systematic reviews, randomized controlled trials, and relevant observational studies. There were no language restrictions. Searches were updated on a regular basis and incorporated in the guideline to August 2010. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. The previous Society of Obstetricians and Gynaecologists of Canada guidelines regarding prenatal screening were also reviewed in developing this clinical practice guideline. The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care. This guideline is intended to reduce the number of prenatal invasive procedures done when maternal age is the only indication. This will have the benefit of reducing the numbers of normal pregnancies lost because of complications of invasive procedures. Any screening test has an inherent false-positive rate, which may result in undue anxiety. It is not possible at this time to undertake a detailed cost-benefit analysis of the implementation of this guideline, since this would require health surveillance and research and health resources not presently available; however, these factors need to be evaluated in a prospective approach by provincial and territorial initiatives. RECOMMENDATIONS 1. All pregnant women in Canada, regardless of age, should be offered, through an informed counselling process, the option of a prenatal screening test for the most common clinically significant fetal aneuploidies in addition to a second trimester ultrasound for dating, assessment of fetal anatomy, and detection of multiples. (I-A) 2. Counselling must be non-directive and must respect a woman's right to accept or decline any or all of the testing or options offered at any point in the process. (III-A) 3. Maternal age alone is a poor minimum standard for prenatal screening for aneuploidy, and it should not be used a basis for recommending invasive testing when non-invasive prenatal screening for aneuploidy is available. (II-2A) 4. Invasive prenatal diagnosis for cytogenetic analysis should not be performed without multiple marker screening results except for women who are at increased risk of fetal aneuploidy (a) because of ultrasound findings, (b) because the pregnancy was conceived by in vitro fertilization with intracytoplasmic sperm injection, or (c) because the woman or her partner has a history of a previous child or fetus with a chromosomal abnormality or is a carrier of a chromosome rearrangement that increases the risk of having a fetus with a chromosomal abnormality. (II-2E) 5. At minimum, any prenatal screen offered to Canadian women who present for care in the first trimester should have a detection rate of 75% with no more than a 3% false-positive rate. The performance of the screen should be substantiated by annual audit. (III-B) 6. The minimum standard for women presenting in the second trimester should be a screen that has a detection rate of 75% with no more than a 5% false-positive rate. The performance of the screen should be substantiated by annual audit. (III-B) 7. First trimester nuchal translucency should be interpreted for risk assessment only when measured by sonographers or sonologists trained and accredited for this service and when there is ongoing quality assurance (II-2A), and it should not be offered as a screen without biochemical markers in singleton pregnancies. (I-E) 8. Evaluation of the fetal nasal bone in the first trimester should not be incorporated as a screen unless it is performed by sonographers or sonologists trained and accredited for this service and there is ongoing quality assurance. (II-2E) 9. For women who undertake first trimester screening, second trimester serum alpha fetoprotein screening and/or ultrasound examination is recommended to screen for open neural tube defects. (II-1A) 10. Timely referral and access is critical for women and should be facilitated to ensure women are able to undergo the type of screening test they have chosen as first trimester screening. The first steps of integrated screening (with or without nuchal translucency), contingent, or sequential screening are performed in an early and relatively narrow time window. (II-1A) 11. Ultrasound dating should be performed if menstrual or conception dating is unreliable. For any abnormal serum screen calculated on the basis of menstrual dating, an ultrasound should be done to confirm gestational age. (II-1A) 12. The presence or absence of soft markers or anomalies in the 18- to 20-week ultrasound can be used to modify the a priori risk of aneuploidy established by age or prior screening. (II-2B) 13. Information such as gestational dating, maternal weight, ethnicity, insulin-dependent diabetes mellitus, and use of assisted reproduction technologies should be provided to the laboratory to improve accuracy of testing. (II-2A) 14. Health care providers should be aware of the screening modalities available in their province or territory. (III-B) 15. A reliable system needs to be in place ensuring timely reporting of results. (III-C) 16. Screening programs should be implemented with resources that support audited screening and diagnostic laboratory services, ultrasound, genetic counselling services, patient and health care provider education, and high quality diagnostic testing, as well as resources for administration, annual clinical audit, and data management. In addition, there must be the flexibility and funding to adjust the program to new technology and protocols. (II-3B).

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The biological maturity status plays an important role in sports, since it influences the performance level and the talent selection in various types of sport. More mature athletes are favorably selected for regional and national squads. Therefore, the biological maturity status should be considered during the talent selection process. In this context, the relative age effect (RAE), which exists when the relative age quarter distribution of selected sports groups shows a biased distribution with an over-representation of athletes born in the first months after the specific cut-off-date for the competition categories, represents another problem in the talent development. From an ethical point of view, discrimination of young talented kids does exist: the relatively younger athletes have little to no chance of reaching the elite level, despite their talents and efforts. The causal mechanisms behind the RAE are still unclear and have to be assessed. In this context, the biological maturation seems to be a possible influential factor for the existence of a RAE in sport, which has to be examined. Several methods for estimating the biological maturity status exist; however, they are often expensive and not practicable. Consequently, the aim of the present study was to assess the concordance of a simple, yet accurate method of estimating biological maturation (prediction equation of age at peak height velocity, APHV) of Mirwald and co-workers, and the gold standard method of estimating skeletal age (SA, the x-ray of the left wrist). In total, 75 Austrian students (40♂, 35♀) aged 10 - 13 years, were examined. Thirty of the participants (17♂, 13♀) were students of a well-known Austrian ski boarding school, and 45 (23♂, 22♀) of a non-sportive secondary modern school of the same region. The participants included in the study had not experienced a rupture of the carpal bones of the left wrist. Parents and participants were informed of the study aims, requirements and risks before providing written informed consent. The study was performed according to the Declaration of Helsinki. The study was approved by the Board for Ethical Questions in Science (Nr.: 2/2014) and the Institutional Ethics Review Boards for Human Research. For the prediction equations, the body height, the body mass and the sitting height were examined 8. The actual CA at time of measurement, and the leg length as the difference between body height and sitting height were calculated. These parameters were used to predict MO as time before or after PHV for boys and girls using the prediction equations of Mirwald et al. 19. According to Malina and Koziel 8, the participants were classified as late, on time (average) or early maturing on the basis of their APHV relative to the sample mean and standard deviation separated by sex. Participants within plus/minus the standard deviation of the mean were considered on time; participants with APHV &gt; mean + standard deviation were classified late, while those with APHV &lt; mean - standard deviation were classified early. An expert in pediatric endocrinology evaluated the x-rays of the left-hand wrist with the Greulich-Pyle-Method for assessing SA, the most widely used method of determining SA 24. The difference between SA and CA were calculated (= difference SA-CA). Consistent with other studies, the participants were divided into three groups according to their maturity status: on time or average maturity status was a SA within ±1 year of CA, late maturating was a SA behind CA of more than 1 year, and early maturating was a SA in advance of CA of more than 1 year 5 19 25. The most accurate method used to compare two methods of measurement is the Bland-Altman plot and the 95 % limits of agreement 26 27 28. Bland-Altman plots of the difference between difference in APHV (from the literature mean) and difference SA-CA (y-axis) and the mean of difference in APHV and difference SA-CA (x-axis) were performed. Approximately 95 % of the points in the plot should lie within the limits; then the concordance between the two methods of measurement is given 28. Additionally, intraclass correlation coefficients (ICC(3,1); two-way-mixed, total agreement) were calculated between difference in APHV and difference SA-CA. Chi²-tests were used to assess the difference in the percentage of pupils classified as on time, early or late maturing between the classifications based on the SA and on APHV, respectively. The level of significance was set at p &lt; 0.05 and for highly significant at p &lt; 0.01. All of the calculations were performed using PASW Statistics V.21.0. Chi²-tests did not show any significant differences (p = 0.404) in the percentage of participants classified as on time, early or late maturing between the two classifications based on SA and on APHV, respectively, neither for the total sample, nor for the two groups ski racers and non-athletes. The Bland-Altman analysis showed that more than 95 % of the points in the plot lie within the limits; consequently, there is concordance between the two methods with regard to estimating biological maturation. The ICC(3,1) statistics showed a highly significant correlation: p = 0.002, ICC (95 % CI) = 0.48 (0.13 - 0.69). The prediction equations to determine APHV seem to be a valid method of assessing the biological maturity status of youths aged 10 - 13 years. The percentage of pupils classified as on time, early or late maturing did not differ significantly between the classifications based on the two methods. Also the Bland-Altman analysis proved the concordance between the two methods. The RAE could be influenced and strengthened by the biological age in sports in which advantages in maturity parameters are important. Athletes born early in the selection year, who are also at the same time advanced in maturity, might be advantaged in the selection process. However, since the prediction equations seem to be valid, this method can be used in the future in the talent selection process in order to not disadvantage late-maturing athletes, which in turn could result in the reduction of the occurrence of the RAE in various types of sports in the future. In talent selection processes the growth spurt and the implemented changes in proportions between core and the extremities are often not considered; although it was shown that during this period, athletes showed poor performances in physical fitness. Since physical fitness is an important criterion in talent selection processes, athletes who go through their individual peak growth spurt at the time of selection have disadvantages due to the diverse proportions. As a consequence, it seems important to know the athlete's APHV in order to consider the variations in physical performance caused by developmental changes. The prediction equations to determine APHV include the leg length and sitting height in order to consider the diverse proportions between core and extremities; hence, this method seems to be accurate and should be implemented in the talent selection process.

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Randomized controlled trials (RCTs) have recently compared intramuscular 17α-hydroxyprogesterone caproate (17-OHPC) with vaginal progesterone for reducing the risk of spontaneous preterm birth (SPTB) in singleton gestations with prior SPTB. The aim of this systematic review and meta-analysis was to evaluate the efficacy of vaginal progesterone compared with 17-OHPC in prevention of SPTB in singleton gestations with prior SPTB. Searches of electronic databases were performed to identify all RCTs of asymptomatic singleton gestations with prior SPTB that were randomized to prophylactic treatment with either vaginal progesterone (intervention group) or intramuscular 17-OHPC (comparison group). No restrictions for language or geographic location were applied. The primary outcome was SPTB &lt; 34 weeks. Secondary outcomes were SPTB &lt; 37 weeks, &lt; 32 weeks, &lt; 28 weeks and &lt; 24 weeks, maternal adverse drug reaction and neonatal outcomes. The summary measures were reported as relative risk (RR) with 95% CI. Risk of bias for each included study was assessed. Three RCTs (680 women) were included. The mean gestational age at randomization was about 16 weeks. Women were given progesterone until 36 weeks or delivery. Regarding vaginal progesterone, one study used 90 mg gel daily, one used 100 mg suppository daily and one used 200 mg suppository daily. All included RCTs used 250 mg intramuscular 17-OHPC weekly in the comparison group. Women who received vaginal progesterone had significantly lower rates of SPTB &lt; 34 weeks (17.5% vs 25.0%; RR, 0.71 (95% CI, 0.53-0.95); low quality of evidence) and &lt; 32 weeks (8.9% vs 14.5%; RR, 0.62 (95% CI, 0.40-0.94); low quality of evidence) compared with women who received 17-OHPC. There were no significant differences in the rates of SPTB &lt; 37 weeks, &lt; 28 weeks and &lt; 24 weeks. The rate of women who reported adverse drug reactions was significantly lower in the vaginal progesterone group compared with the 17-OHPC group (7.1% vs 13.2%; RR, 0.53 (95% CI, 0.31-0.91); very low quality of evidence). Regarding neonatal outcomes, vaginal progesterone was associated with a lower rate of neonatal intensive care unit admission compared with 17-OHPC (18.7% vs 23.5%; RR, 0.63 (95% CI, 0.47-0.83); low quality of evidence). For the comparison of 17-OHPC vs vaginal progesterone, the quality of evidence was downgraded for all outcomes by at least one degree due to imprecision (the optimal information size was not reached) and by at least one degree due to indirectness (different interventions). Daily vaginal progesterone (either suppository or gel) started at about 16 weeks' gestation is a reasonable, if not better, alternative to weekly 17-OHPC injection for prevention of SPTB in women with singleton gestations and prior SPTB. However, the quality level of the summary estimates was low or very low as assessed by GRADE, indicating that the true effect may be, or is likely to be, substantially different from the estimate of the effect. Copyright © 2016 ISUOG. Published by John Wiley &amp; Sons Ltd. COMPARACIÓN ENTRE LA PROGESTERONA VAGINAL Y EL 17Α-HIDROXIPROGESTERONA CAPROATO INTRAMUSCULAR PARA LA PREVENCIÓN DEL PARTO PRETÉRMINO ESPONTÁNEO RECURRENTE EN EMBARAZOS CON FETO ÚNICO: REVISIÓN SISTEMÁTICA Y METAANÁLISIS DE ENSAYOS CONTROLADOS ALEATORIOS: RESUMEN OBJETIVO: Recientemente se han realizado varios ensayos controlados aleatorios (ECA) que comparaban el caproato de 17α-hidroxiprogesterona (17-OHPC, por sus siglas en inglés) por vía intramuscular con la progesterona por vía vaginal para la reducción del riesgo de parto pretérmino espontáneo (PPTE) en embarazos con feto único de gestantes con historial de PPTE. El objetivo de esta revisión sistemática y metaanálisis fue evaluar la eficacia de la progesterona vaginal en comparación con la 17-OHPC en la prevención de embarazos con feto único de gestantes con historial de PPTE. MÉTODOS: Se realizaron búsquedas en bases de datos electrónicas para identificar todos los ECA con embarazos de feto único asintomáticos con historial de PPTE antes de ser asignados al azar a un tratamiento profiláctico, ya fuera con progesterona vaginal (grupo de intervención) o con 17-OHPC intramuscular (grupo de control). No se aplicaron restricciones respecto al idioma o la ubicación geográfica. El resultado primario fue PPTE &lt; 34 semanas. Los resultados secundarios fueron PPTE &lt;37 semanas, &lt; 32 semanas, &lt; 28 semanas y &lt; 24 semanas, la reacción materna adversa al fármaco y los resultados neonatales. Las medidas del resumen se reportaron como riesgo relativo (RR) con IC del 95%. Para cada estudio incluido se evaluó el riesgo de sesgo. Se incluyeron tres ECA (680 mujeres). La media de la edad gestacional en el momento de la aleatorización fue de 16 semanas. A las mujeres se les administró progesterona hasta la semana 36 o hasta el parto. Con respecto a la progesterona vaginal, un estudio utilizó gel de 90 mg diariamente, otro utilizó un supositorio diario de 100 mg y el otro utilizó un supositorio diario de 200 mg. Todos los ECA incluidos en el grupo de comparación utilizaron 250 mg semanales de 17-OHPC por vía intramuscular. Las mujeres que recibieron progesterona vaginal tuvieron tasas significativamente más bajas de PPTE &lt; 34 semanas (17,5% vs. 25,0%; RR 0,71 (IC 95%, 0,53-0,95); calidad de la evidencia baja) y &lt; 32 semanas (8,9% vs. 14,5%; RR 0,62 (IC 95%, 0,40-0,94); calidad de evidencia baja), en comparación con las mujeres que recibieron 17-OHPC. No hubo diferencias significativas en las tasas de PPTE &lt; 37 semanas, &lt; 28 semanas y &lt; 24 semanas. La tasa de mujeres que reportaron reacciones adversas a los medicamentos fue significativamente menor en el grupo de progesterona vaginal en comparación con el grupo de 17-OHPC (7,1% vs. 13,2%; RR 0,53 (IC 95%, 0,31-0,91); calidad de la evidencia muy baja). En cuanto a los resultados neonatales, la progesterona vaginal se asoció a una menor tasa de admisiones en la unidad neonatal de cuidados intensivos en comparación con la 17-OHPC (18,7% vs. 23,5%; RR 0,63 (IC 95%, 0,47-0,83); calidad de evidencia baja). Para la comparación del 17-OHPC con la progesterona vaginal se rebajó la calidad de las pruebas para todos los resultados en al menos un grado debido a imprecisiones (no se alcanzó el tamaño óptimo de la información) y en al menos un grado debido al carácter indirecto de los estudios (diferentes intervenciones). La progesterona vaginal administrada diariamente (ya fuera como supositorio o como gel) desde la semana 16 de gestación es una alternativa razonable, si no mejor, a una inyección semanal de 17-OHPC para la prevención de PPTE en mujeres con embarazos de feto único e historial de PPTE. Sin embargo, el nivel de calidad de las estimaciones del resumen fue bajo o muy bajo según lo evaluado por GRADE, lo que indica que el verdadero efecto puede ser, o es probable que sea, sustancialmente diferente de la estimación del efecto. 17Α-:META: : (randomized controlled trials,RCTs)(spontaneous preterm birth,SPTB)17α-(intramuscular 17α-hydroxyprogesterone caproate,17-OHPC)SPTB。metaSPTB17-OHPCSPTB。 : ,SPTBRCTs,RCTs()17-OHPC()。。34SPTB。37、32、2824SPTB,。(relative risk,RR)95%CI。。 : 3RCTs(680)。16。,36。,90 mg,100 mg,200 mg。,RCTs250 mg 17-OHPC。17-OHPC,34 [17.5%25.0%;RR,0.71(95% CI,0.53 ~ 0.95);]32[8.9%14.5%;RR,0.62(95% CI,0.40 ~ 0.94);]SPTB。37、2824SPTB。17-OHPC,[7.1%13.2%;RR,0.53(95% CI,0.31 ~ 0.91);]。,17-OHPC,[18.7%23.5%;RR,0.63(95% CI,0.47 ~ 0.83);]。17-OHPC,(),()。 : SPTBSPTB,16()17-OHPC,。,GRADE,,。.

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What is the association between ART conception and treatment parameters and the risk of birth defects? Compared to naturally conceived singleton infants, the risk of a major nonchromosomal defect among ART singletons conceived with autologous oocytes and fresh embryos without use of ICSI was increased by 18%, with increases of 42% and 30% for use of ICSI with and without male factor diagnosis, respectively. Prior studies have indicated that infertility and ART are associated with an increased risk of birth defects but have been limited by small sample size and inadequate statistical power, failure to differentiate results by plurality, differences in birth defect definitions and methods of ascertainment, lack of information on ART treatment parameters or study periods spanning decades resulting in a substantial historical bias as ART techniques have improved. This was a population-based cohort study linking ART cycles reported to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) from 1 January 2004 to 31 December 2015 that resulted in live births from 1 September 2004 to 31 December 2016 in Massachusetts and North Carolina and from 1 September 2004 to 31 December 2015 for Texas and New York: these were large and ethnically diverse States, with birth defect registries utilizing the same case definitions and data collected, and with high numbers of ART births annually. A 10:1 sample of non-ART births were chosen within the same time period as the ART birth. Naturally conceived ART siblings were identified through the mother's information. Non-ART children were classified as being born to women who conceived with ovulation induction (OI)/IUI when there was an indication of infertility treatment on the birth certificate, but the woman did not link to the SART CORS; all others were classified as being naturally conceived. The study population included 135 051 ART children (78 362 singletons and 56 689 twins), 23 647 naturally conceived ART siblings (22 301 singletons and 1346 twins) and 9396 children born to women treated with OI/IUI (6597 singletons and 2799 twins) and 1 067 922 naturally conceived children (1 037 757 singletons and 30 165 twins). All study children were linked to their respective State birth defect registries to identify major defects diagnosed within the first year of life. We classified children with major defects as either chromosomal (i.e. presence of a chromosomal defect with or without any other major defect) or nonchromosomal (i.e. presence of a major defect but having no chromosomal defect), or all major defects (chromosomal and nonchromosomal). Logistic regression models were used to generate adjusted odds ratios (AORs) and 95% CI to evaluate the risk of birth defects due to conception with ART (using autologous oocytes and fresh embryos), and with and without the use of ICSI in the absence or presence of male factor infertility, with naturally conceived children as the reference. Analyses within the ART group were stratified by combinations of oocyte source (autologous, donor) and embryo state (fresh, thawed), with births from autologous oocytes and fresh embryos as the reference. Analyses limited to fresh embryos were stratified by oocyte source (autologous, donor) and the use of ICSI. Triplets and higher-order multiples were excluded. A total of 21 998 singleton children (1.9%) and 3037 twin children (3.3%) had a major birth defect. Compared to naturally conceived children, ART singletons (conceived from autologous oocytes, fresh embryos without the use of ICSI) had increased risks of a major nonchromosomal birth defect (AOR 1.18, 95% 1.05, 1.32), cardiovascular defects (AOR 1.20, 95% CI 1.03, 1.40), and any birth defect (AOR 1.18, 95% CI 1.09, 1.27). Compared to naturally conceived children, ART singletons conceived (from autologous oocytes, fresh embryos) with the use of ICSI, the risks were increased for a major nonchromosomal birth defect (AOR 1.30, 95% CI 1.16, 1.45 without male factor diagnosis; AOR 1.42, 95% CI 1.28, 1.57 with male factor diagnosis); blastogenesis defects (AOR 1.49, 95% CI 1.08, 2.05 without male factor; AOR 1.56, 95% CI 1.17, 2.08 with male factor); cardiovascular defects (AOR 1.28, 95% CI 1.10,1.48 without male factor; AOR 1.45, 95% CI 1.27, 1.66 with male factor); in addition, the risk for musculoskeletal defects was increased (AOR 1.34, 95% CI 1.01, 1.78 without male factor) and the risk for genitourinary defects in male infants was increased (AOR 1.33, 95% CI 1.08, 1.65 with male factor). Comparisons within ART singleton births conceived from autologous oocytes and fresh embryos indicated that the use of ICSI was associated with increased risks of a major nonchromosomal birth defect (AOR 1.18, 95% CI 1.03, 1.35), blastogenesis defects (AOR 1.65, 95% CI 1.08, 2.51), gastrointestinal defects (AOR 2.21, 95% CI 1.28, 3.82) and any defect (AOR 1.11, 95% CI 1.01, 1.22). Compared to naturally conceived children, ART singleton siblings had increased risks of musculoskeletal defects (AOR 1.32, 95% CI 1.04, 1.67) and any defect (AOR 1.15, 95% CI 1.08, 1.23). ART twins (conceived with autologous oocytes, fresh embryos, without ICSI) were at increased risk of chromosomal defects (AOR 1.89, 95% CI 1.10, 3.24) and ART twin siblings were at increased risk of any defect (AOR 1.26, 95% CI 1.01, 1.57). The 18% increased risk of a major nonchromosomal birth defect in singleton infants conceived with ART without ICSI (∼36% of ART births), the 30% increased risk with ICSI without male factor (∼33% of ART births), and the 42% increased risk with ICSI and male factor (∼31% of ART births) translates into an estimated excess of 386 major birth defects among the 68 908 singleton children born by ART in 2017. In the SART CORS database, it was not possible to differentiate method of embryo freezing (slow freezing vs vitrification), and data on ICSI was only available in the fresh embryo ART group. In the OI/IUI group, it was not possible to differentiate type of non-ART treatment utilized, and in both the ART and OI/IUI groups, data were unavailable on duration of infertility. The use of ART is associated with increased risks of a major nonchromosomal birth defect, cardiovascular defect and any defect in singleton children, and chromosomal defects in twins; the use of ICSI further increases this risk, the most with male factor infertility. These findings support the judicious use of ICSI only when medically indicated. The relative contribution of ART treatment parameters versus the biology of the subfertile couple to this increased risk remains unclear and warrants further study. This project was supported by grant R01 HD084377 from the National Institute of Child Health and Human Development. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Child Health and Human Development, or the National Institutes of Health, nor any of the State Departments of Health which contributed data. E.W. is a contract vendor for SART; all other authors report no conflicts. N/A.

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<bObjective:</b To investigate the effects of hypoxia-pretreated rat adipose-derived mesenchymal stem cells (ADSCs) conditioned medium on wound healing of rats with full-thickness defects. <bMethods:</b (1) A 6-week-old male Sprague-Dawley rat was sacrificed by cervical dislocation, the bilateral inguinal adipose tissue was collected, the third generation ADSCs were isolated by collagenase digestion method, and the cells morphology was observed. The cells were harvested and divided into adipogenic induction group and osteogenic induction group according to the random number table (the same grouping method below), with 6 wells in each group. The cells in adipogenic induction group were cultured for 14 days to observe adipogenesis, and cells in osteogenic induction group were cultured for 28 days to observe osteogenesis. (2) The third generation ADSCs were collected and divided into normoxic group and hypoxic group. Cells in normoxic group was incubated in normal oxygen incubator with oxygen volume fraction of 21%, and cells in hypoxic group was incubated in low oxygen incubator with oxygen volume fraction of 2% respectively, with 3 samples in each group for each time point. Three samples in normoxic group on 3 h of culture and in hypoxic group on 3, 6, 12, 24, and 48 h of culture were collected for detecting the following indexes. The mRNA expressions of hypoxia inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and peroxisome proliferator-activated receptor γ (PPAR-γ) were detected by real time fluorescent quantitative reverse transcription polymerase chain reaction. The cell culture supernatant in the two groups was collected, centrifuged, and filtered to obtain normoxic conditioned medium (normo-CM ) and hypoxic conditioned medium (hypo-CM). Enzyme linked immunosorbent assay was used to detect content of VEGF, transforming growth factor β (TGF-β), epidermal growth factor (EGF), and insulin-like growth factor (IGF) in conditioned medium. (3) Twenty-seven male Sprague-Dawley rats aged 6-8 weeks were collected and divided into phosphate buffer solution (PBS) group, normo-CM group, and hypo-CM group, with 9 rats in each group. A circular full-thickness skin defect wound with diameter of 1 cm was made on the back of each rat, and the wounds of rats in PBS, normo-CM, and hypo-CM groups were respectively dropped with 50 μL PBS, normo-CM, and hypo-CM. On post injury day (PID) 0, 3, 5, 7, 9, and 11, the gross condition of wound was observed, wound area was measured, and the non-healing rate of wound was calculated. The wound tissue was collected for hematoxylin eosin staining to observe inflammatory reaction of wound on PID 3, 9, and 11 and re-epithelialization of wound on PID 9. Masson staining was used to observe the collagen deposition and analyze collagen volume fraction of wound on PID 11. Data were statistically analyzed with analysis of variance for repeated measurement, one-way analysis of variance, <it</i test, and Bonferroni correction. <bResults:</b (1) The isolated cells showed a fusiform, in adherent growth and close arrangement when in low fusion degree. On 14 d of culture, the red lipid droplets stained with oil red O were observed in cells in adipogenic induction group, and on 28 d of culture, the red nodules stained with alizarin red S were observed in cells in osteogenic induction group. The cells were identified as ADSCs. (2) Compared with that in normoxic group, the mRNA expression of HIF-1α was significantly increased at 12 and 24 h of culture (<it</i=5.43, 5.11, <iP</i&lt;0.05), the mRNA expression of VEGF was significantly increased at 6 and 12 h of culture (<it</i=3.29, 2.33, <iP</i&lt;0.05 or <iP</i&lt;0.01), the mRNA expression of bFGF was significantly increased at 12 h of culture (<it</i=12.59, <iP</i&lt;0.01) and significantly reduced at 48 h of culture (t=9.34, P&lt;0.01), and the mRNA expression of PPAR-γ was significantly reduced at 3, 12, and 24 h of culture in hypoxic group (<it</i=5.14, 6.56, 4.97, <iP</i&lt;0.05). (3) Compared with that in normoxic group, the VEGF content was significantly increased at 3, 6, 12, 24, and 48 h of culture (<it</i=5.74, 12.37, 14.80, 15.70, 34.63, <iP</i&lt;0.05 or <iP</i&lt;0.01), and the IGF content was significantly increased at 6, 12, 24, and 48 h of culture (<it</i=5.65, 8.06, 20.12, 22.99, <iP</i&lt;0.05 or <iP</i&lt;0.01), and the content of TGF-β and EGF showed no obvious change at 3, 6, 12, 24, and 48 h of culture in hypoxic group. (4) From PID 0 to 11, the wound of rats in the three groups shrank to varying degrees, with no obvious infection or exudate. On PID 11, the wound area of rats in PBS group was still large, which was larger than that in normo-CM group, and the wound area of rats in hypo-CM group was basically healed. On PID 0, 3, and 5, the non-healing rates of wound of rats in the three groups were similar. On PID 7, the non-healing rates of wound of rats in normo-CM and hypo-CM groups were significantly lower than that in PBS group (<it</i=10.26, 16.03, <iP</i&lt;0.05). On PID 9, the non-healing rate of wound of rats in hypo-CM group was significantly lower than that of PBS group and normo-CM group, respectively (<it</i=17.25, 6.89, <iP</i&lt;0.05 or <iP</i&lt;0.01), and the non-healing rate of wound of rats in normo-CM group was significantly lower than that in PBS group (<it</i=8.81, <iP</i&lt;0.05). On PID 11, the non-healing rate of wound of rats in hypo-CM group was (2.4±1.5)%, which was significantly lower than (20.0±5.0)% in PBS group and (7.7±1.7)% in normo-CM group (<it</i= 30.15, 84.80, <iP</i&lt;0.05). (5) On PID 3, the infiltration of inflammatory cells in the wound of rats in hypo-CM group was obviously more than those in the other two groups. On PID 9, the infiltration of inflammatory cells in the wound of rats in hypo-CM and normo-CM groups was obviously less than that in PBS group. On PID 11, the infiltration of inflammatory cells in the wound of rats in hypo-CM group was obviously less than those in PBS and normo-CM groups. On PID 9, the length of " epidermal migration tongue" on the wound of rats in hypo-CM group was longer than those of the other two groups, and the epidermis thickness was close to normal skin. On PID 11, compared with those in PBS and normo-CM groups, a large number of collagen deposits with dense structure, neat arrangement, and higher maturity were seen in the wound of rats in hypo-CM group. The wound collagen volume fraction of rats in PBS group was (22.90±1.25)%, which was significantly lower than (31.96±0.14)% in normo-CM group and (56.10±1.50)% in hypo-CM group (<it</i=12.48, 29.43, <iP</i&lt;0.05), and the wound collagen volume fraction of rats in normo-CM group was significantly lower than that in hypo-CM group (<it</i=27.73, <iP</i&lt;0.05). <bConclusions:</b Hypoxia-pretreated can significantly enhance paracrine effect of rat ADSCs. Hypoxia-pretreated rat ADSC conditioned medium can accelerate the healing of full-thickness skin defect wound in rats by regulating inflammatory cell infiltration, promoting re-epithelialization and collagen deposition in the wound.

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