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This chapter addresses the following FDA-approved medications for the treatment of major depressive disorder available for use in the United States including bupropion, mirtazapine, trazodone, vortioxetine, and vilazodone. These medications do not belong to one of the previously featured classes of antidepressants discussed in the preceding chapters. Each medication featured in this chapter has a unique structure and properties that target diverse receptors in the central nervous system. These diverse targets are distinct from other classes of medications used to treat major depressive disorder. This chapter will provide an overview of each medication's indication for use, history of development, pharmacology, metabolism, dosing recommendations, onset of action, use in special populations, safety and tolerability, adverse effects, potential interactions with additional medications, and data regarding possible overdose with available treatments.Bupropion was initially developed for its combined effects on the norepinephrine and dopamine neurotransmitters. Currently, bupropion is the only antidepressant on the market in the United States with no appreciable activity on serotonin concentrations in the central nervous system. Bupropion is extensively metabolized in humans into three active metabolites including hydroxybupropion, threohydrobupropion, and erythrohydrobuproprion each with substantial antidepressant activity. The most serious side effect of bupropion is the development of seizures, so the dose must be gradually titrated to a maximum dose of 450 mg per day of the immediate-release formulation and 400 mg per day of the sustained-release formulation. Additional adverse effects include agitation, dry mouth, insomnia, headaches, migraines, nausea, vomiting, constipation, and tremor. The onset of action of bupropion is 2 weeks with full efficacy attained at 4 weeks of treatment. Bupropion produced similar depression remission rates when compared to SSRIs with a median time to relapse of 44 weeks. Bupropion has additionally been approved for smoking cessation and may have a combined role in treating nicotine cravings and depression.Mirtazapine has a unique method of action by enhancing norepinephrine and serotonin neurotransmission by blocking the alpha-2 presynaptic adrenoceptors resulting in increased release of serotonin at the nerve terminals. Mirtazapine additionally binds to the 5-HT<sub2</sub, 5-HT<sub3</sub, and H<sub1</sub receptors resulting in increased sedation, which is the most common side effect. Additional side effects include increased appetite and weight gain, dizziness, and transient elevations in cholesterol levels and liver function tests. Mirtazapine is unlike any other antidepressant in that it also has a hormonal effect that reduces cortisol levels within the body. Patients on mirtazapine showed significant improvement in symptoms of major depressive disorder within the first 1-2 weeks of treatment with long-term studies at 40 weeks showing continued improvements in response rates in addition to lower relapse rates. Mirtazapine has an antagonistic effect at the central presynaptic 5-HT<sub2</sub receptors and alpha-2 adrenergic inhibitory autoreceptors and heteroreceptors resulting in increased norepinephrine release with an indirect release of serotonin due to increased noradrenergic input to the raphe nucleus. Mirtazapine has an effective dose range from 15 to 45 mg once daily with a long half-life preventing dose adjustments more often than every 1-2 weeks.Trazadone is a 5-HT<sub2A</sub and 5-HT<sub2C</sub receptor antagonist and selective serotonin reuptake inhibitor. While trazodone has only been FDA approved for use in the treatment of major depressive disorder, it has been used off label for numerous conditions including insomnia, anxiety, dementia, Alzheimer's disease, substance abuse, schizophrenia, bulimia, and fibromyalgia. The most common adverse reaction is drowsiness, followed by dizziness, dry mouth, and nervousness. In the United States, trazadone is the second most commonly prescribed agent used to treat insomnia. The hypnotic action of this medication at lower doses is attributed primarily to the antagonism of the 5-HT<sub2A</sub receptors, H<sub1</sub receptors, and alpha-1 adrenergic receptors. The most active metabolite is m-chlorophenylpiperazine produced by the CYP<sub3A4</sub enzyme, which is a more profound inhibitor of serotonin reuptake as compared to the parent molecule of trazadone. The maximum outpatient dose should not exceed 400 mg per day in divided doses, but in hospitalized patients, the dose may be increased to a maximum dose of 600 mg daily in divided doses while the patient is being actively monitored for side effects. One third of inpatients and one half of outpatients had a significant therapeutic response to trazadone by the end of the first week with the remainder of patients responding in 2-4 weeks of therapy.Vortioxetine is a novel antidepressant classified by the World Health Organization as a N06AX antidepressant that was derived from studies targeting the combination of direct serotonin transporter inhibition and 5-HT<sub1A</sub receptor modulation leading to rapid desensitization of the somatodendritic 5-HT<sub1A</sub autoreceptors and activation of the postsynaptic 5-HT<sub1A</sub receptors. This medication is an antagonist at 5-HT<sub3</sub, 5-HT<sub1D</sub, and 5-HT<sub7</sub receptors, an agonist at 5-HT<sub1A</sub receptors, and a partial agonist at 5-HT<sub1B</sub receptors. Blockade of the 5-HT<sub3</sub receptor was noted to produce increased levels of serotonin, dopamine, norepinephrine, acetylcholine, and histamine in the prefrontal cortex and hippocampus, which are known to be associated with the development of depression. The most common adverse effect is nausea followed by sexual dysfunction, constipation, and vomiting. The maximum dose of vortioxetine is 20 mg daily with improvement in symptoms of depression noted at 2 weeks with a full therapeutic effect observed at 4-6 weeks.Vilazodone is a selective serotonin reuptake inhibitor and 5-HT<sub1A</sub receptor partial agonist. This medication works by enhancing serotonergic activity in the central nervous system through selective inhibition of serotonin reuptake with no significant effects noted on norepinephrine or dopamine uptake. Vilazodone additionally binds with high affinity to the 5-HT<sub1A</sub receptors as a partial agonist resulting in faster onset of action, greater efficacy, and better tolerability with reduced sexual side effects when compared to other SSRIs. The most common adverse effects were diarrhea, nausea, vomiting, and insomnia. Additional reported adverse effects included dizziness, dry mouth, fatigue, abnormal dreams, decreased libido, arthralgias, and palpitations which were self-limited with resolution in 4-5 days after starting the medication. The recommended therapeutic dose of vilazodone is 40 mg daily with improvement noted in depressive symptoms within 1 week of initiating therapy with increased remission rates noted at 6 weeks of therapy.The medications featured in this chapter do not fall within the major categories of antidepressant classes but add additional unique mechanisms for the treatment of major depressive disorder. Each medication targets different receptors in the central nervous system involved in the development of depression. Resolution of depressive symptoms and response rates of these medications are similar to SSRIs with reduced side effects that can often lead to discontinuation of therapy. Use of these unique medications allows clinicians to target specific symptoms and comorbidities often associated with depression resulting in improved symptom resolution and long-term maintenance of remission.

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To assess the clinical and cost-effectiveness of adjuvant carmustine wafers (BCNU-W) and also of adjuvant and concomitant temozolomide (TMZ), compared with surgery with radiotherapy. Electronic databases were searched up to August 2005. Included trials were critically appraised for key elements of internal and external validity. Relevant data were extracted and a narrative synthesis of the evidence produced. Where possible, data on absolute survival at a fixed time point were meta-analysed using a random effects model. A Markov (state transition) model was developed to assess the cost-utility of the two interventions. The model compared BCNU-W or TMZ separately with current standard treatment with surgery and radiotherapy. The simulated cohort had a mean age of 55 years and was modelled over 5 years. Two randomised controlled trials (RCTs) (n = 32, n = 240) and two observational studies of BCNU-W compared with placebo wafers as adjuvant therapy to surgery and radiotherapy for newly diagnosed high-grade glioma were identified. All the studies were in adults and provided data on 193 patients who had received BCNU-W. The RCT findings excluded under 65-year-olds and those with a Karnofsky Performance Status of less than 60. The largest multi-centre RCT suggested a possible survival advantage with BCNU-W among a cohort of patients with grade III and IV tumours, adding a median of 2.3 months [95% confidence interval (CI) -0.5 to 5.1]. However, analysis using per-protocol, unstratified methods shows this difference to be not statistically significant (HR 0.77, 95% CI 0.57 to 1.03, p = 0.08). Long-term follow-up suggests a significant survival advantage using unstratified analysis. No difference in progression-free survival (PFS) was demonstrated. Subgroup analysis of those with grade IV tumours also showed no significant survival advantage with BCNU-W [hazard ratio (HR) 0.82, 95% CI 0.55 to 1.11, p = 0.20, unstratified analysis]. It is estimated that the cost of surgery and radiotherapy, with follow-up, treatment of adverse effects and end of life care is around 17,000 pounds per patient. Treatment with BCNU-W adds an additional 6600 pounds. Across the modelled cohort of 1000 patients, use of BCNU-W costs an additional 6.6 million pounds and confers an additional 122 quality-adjusted life-years (QALYs). On average, that is 6600 pounds per patient for 0.122 QALYs (6.3 quality-adjusted life-weeks). The base-case incremental cost-effectiveness ratio (ICER) is 54,500 pounds/QALY. In probabilistic sensitivity analyses, BCNU-W was not cost-effective in 89% of the simulations assuming a willingness to pay threshold of 30,000 pounds/QALY. In 15% of simulations, BCNU-W was dominated (i.e. did more harm than good, conferring fewer QALYs at greater cost). The cost-effectiveness acceptability curve (CEAC) suggests that it is very unlikely to be the most cost-effective option at normal levels of willingness to pay (11% probability at 30,000 pounds/QALY), only becoming likely to be the most cost-effective option at much higher levels of willingness to pay (50% probability at 55,000 pounds/QALY). Two RCTs (n = 130, n = 573) and two observational studies were included, giving evidence for 429 adult patients receiving TMZ. Currently, TMZ is licensed for use in those with newly diagnosed grade IV gliomas only. The RCTs excluded those with lower performance status and, in the larger RCT, those older than 70 years. TMZ provides a small but statistically significant median survival benefit of 2.5 months (95% CI 2.0 to 3.8), giving an HR of 0.63 (95% CI 0.52 to 0.75, p &lt; 0.001). At 2 years, 26.5% of patients treated with TMZ were alive compared with 10.4% of those in the control arm. Median PFS is also enhanced with TMZ, giving a median 1.9 months' advantage (95% CI 1.4 to 2.7, p &lt; 0.001). No analysis of the subgroup of patients with confirmed grade IV tumours was undertaken. Subgroup analysis of patients by O6-methylguanine-DNA methyltransferase (MGMT) activity showed a significant treatment advantage for those with reduced MGMT activity but not for those with normal activity, although this analysis was based on a selected sample of patients and the test used has proved difficult to replicate. A median gain of 6.4 (95% CI 4.4 to 9.5) more life-months is seen with TMZ among those with reduced MGMT, giving an HR of 0.51 (p &lt; 0.007). PFS is increased by a median of 4.4 months (95% CI 1.2 to 6.3), giving an HR of 0.48 (p = 0.001). The model shows a cost per patient for being treated with surgery, radiotherapy and including adverse effects of treatment and end of life care of around 17,000 pounds per patient. TMZ in the adjuvant and concomitant phase adds an additional cost of around 7800 pounds. Across the modelled cohort of 1000 patients, use of TMZ costs an additional 7.8 million pounds and confers an additional 217 QALYs. For the average patient this is 7800 pounds for an additional 0.217 QALYs (11 quality-adjusted life-weeks). The base-case ICER is 36,000 pounds/QALY. Probabilistic sensitivity analyses shows that TMZ was not cost-effective in 77% of the simulations. The CEAC suggests that there is a 23% chance that TMZ is the most cost-effective option at a willingness to pay level of 30,000 pounds/QALY, rising to be more cost-effective than no TMZ at slightly higher levels (50% probability at 35,000 pounds/QALY). BCNU-W has not been proven to confer a significant advantage in survival for patients with grade III tumours when treated with the drug, compared with placebo. There does not appear to be a survival advantage for patients with grade IV tumours. No increase in PFS has been shown. Limited evidence suggests a small but significant advantage in both overall survival and PFS with TMZ among a mixed population with grade IV and grade III (7-8%) tumours. However, it remains unclear whether this is true in grade IV tumours alone. On the basis of best available evidence, the authors consider that neither BCNU-W nor TMZ is likely to be considered cost-effective by NHS decision-makers. However, data for the model were drawn from limited evidence of variable quality. Tumour type is clearly important in assessing patient prognosis with different treatments. Grade IV tumours are commonest and appear to have least chance of response. There were too few grade III tumours included to carry out a formal assessment, but they appear to respond better and drive results for both drugs. Future use of genetic and biomarkers may help identify subtypes which will respond, but current licensing indications do not specify these. Further research is suggested into the effectiveness of these drugs, and also into areas such as genetic markers, chemotherapy regimens, patient and carer quality of life, and patient views on survival advantages vs treatment disadvantages.

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The aim of the work described here was to improve our understanding of beta-cell function (BCF) and beta-cell mass (BCM) and their relationship in vivo using the minipig as a model for some of the aspects of human type 2 diabetes (T2DM). More specifically, the aim was to evaluate the following questions: How is BCF, especially high frequency pulsatile insulin secretion, affected by a primary reduction in BCM or by primary obesity or a combination of the two in the minipig? Can evaluation of BCF in vivo be used as a surrogate measure to predict BCM in minipigs over a range of BCM and body weight? We first developed a minipig model of reduced BCM and mild diabetes using administration of a combination of streptozotocin (STZ) and nicotinamide (NIA) as a tool to study effects of a primary reduction of BCM on BCF. The model was characterized using a mixed-meal oral glucose tolerance test and intravenous stimulation with glucose and arginine as well as by histology of the pancreas after euthanasia. It was shown that stable, moderate diabetes can be induced and that the model is characterized by fasting and postprandial hyperglycemia, reduced insulin secretion and reduced BCM. Several defects in insulin secretion are well documented in human T2DM; however, the role in the pathogenesis and the possible clinical relevance of high frequency (rapid) pulsatile insulin secretion is still debated. We therefore investigated this phenomenon in normal minipigs and found easily detectable pulses in peripheral vein plasma samples that were shown to be correlated with pulses found in portal vein plasma. Furthermore, the rapid kinetics of insulin in the minipig strongly facilitates pulse detection. These characteristics make the minipig particularly suitable for studying the occurrence of disturbed pulsatility in relation to T2DM. Disturbances of rapid pulsatile insulin secretion have been reported to be a very early event in the development of T2DM and include disorderliness of pulses and reduced ability to entrain pulses with glucose. However, the role of reduced BCM and/or obesity in the development of these defects in humans is unknown. Therefore, the investigations were extended to include lean NIA/STZ minipigs where it was shown that a primary reduction of BCM leads to reduced insulin pulse mass but does not change periodicity of the pulses or the ability of glucose to entrain pulses. In contrast, obesity was found to be associated with reduced pulsatile insulin secretion and improved orderliness of glucose entrained pulses in the minipig. Furthermore obesity was associated with pancreatic lipid accumulation and increased beta-cell volume, although BCM relative to body weight was not changed. Finally, a combination of obesity and reduced BCM resulted in severely disturbed insulin secretion and severe morphological changes. Thus, results from NIA/STZ minipigs suggest that not all of the defects of rapid pulsatile insulin secretion seen in human T2DM can be explained by a primary reduction of BCM mass or up to 2 weeks of mild hyperglycemia. Furthermore, based on the results from obese minipigs, obesity in itself induces small defects in rapid pulsatile insulin secretion and the combination of obesity and reduced BCM leads to further deterioration of BCF. Another major characteristic of human diabetes is thought to be reduction of BCM and the ability to follow this parameter over time would greatly improve our understanding of disease progression and allow evaluation of pharmacological methods to increase BCM. BCM cannot, at present, be measured in vivo in humans. We therefore set out to further validate data from smaller studies in lean non-human primates and minipigs showing a correlation between measures of BCF in vivo and BCM. In a large study in lean minipigs with a range of BCM, we found that a strong stimulation of insulin secretion with a combination of glucose and arginine resulted in the best correlation to BCM, as determined using stereology. A similar relationship was also shown in a group of both lean and obese animals, thereby supporting the application of similar methods to estimate BCM in humans over a range of body weights. Since changes in rapid pulsatile insulin secretion are detectable early in the development of diabetes and in obesity, we hypothesized that this parameter could also be highly correlated to BCM as it has been shown in smaller studies in lean minipigs. However, rapid pulsatile insulin secretion did not show a better correlation to BCM than combined stimulation with glucose and arginine, and thus analysis of pulses does not provide a better surrogate marker for BCM in the minipig. To evaluate the weaker correlation of glucose stimulation compared to combined glucose and arginine stimulation in vivo with BCM, we further investigated BCF in lean, beta-cell reduced minipigs by studying BCF in vitro after isolation and perfusion of their pancreases to investigate the ability of the remaining beta-cells to compensate for the loss of BCM by increasing insulin secretion per BCM. The perfused pancreas was chosen in order to allow direct measurement of the insulin secretion without the effects of peripheral tissues. During the perfusion, it was shown that the remaining beta-cells were indeed able to compensate for the loss of BCM to a large extent in response to stimulation with glucose and glucagon-like peptide-1 but not in response to arginine. This shows that the type of stimulus applied is important for the ability to compensate for reduced BCM from the remaining population of beta-cells, and further supports the use of combined stimulation with glucose and arginine for estimation of BCM in vivo. In conclusion, an animal model of reduced BCM and mild diabetes has been developed and characterized. The model has been used to evaluate effects of a primary reduction of BCM, showing a reduced rapid insulin pulse mass but normal periodicity and entrainability of the pulses, whereas obesity was associated with reduced rapid pulsatile insulin secretion. Thus, based on these data, the disturbed rapid pulsatile insulin secretion seen in T2DM humans may not directly be explained by the reduced BCM in diabetes, whereas obesity may be related to the reduced pulsatility. Furthermore, the model has been used to establish a correlation between extensive stimulation of insulin secretion in vivo and BCM obtained by stereology in both lean and obese animals. The ability to estimate BCM based on in vivo experiments in the minipig would allow longitudinal studies on changes in this parameter over time in the intact animal and support application of similar methods in humans. Such methods could be useful for the diagnosis and the measurement of the effectiveness of treatment of diabetes in humans in the future.

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The primary objective is to demonstrate that, in patients with PCR-confirmed SARS-CoV-2 resulting in Acute Respiratory Distress Syndrome (ARDS), administration of 120mg/kg of body weight of intravenous Prolastin®(plasma-purified alpha-1 antitrypsin) reduces circulating plasma levels of interleukin-6 (IL-6). Secondary objectives are to determine the effects of intravenous Prolastin® on important clinical outcomes including the incidence of adverse events (AEs) and serious adverse events (SAEs). Phase 2, randomised, double-blind, placebo-controlled, pilot trial. The study will be conducted in Intensive Care Units in hospitals across Ireland. Patients with a laboratory-confirmed diagnosis of SARS-CoV-2-infection, moderate to severe ARDS (meeting Berlin criteria for a diagnosis of ARDS with a PaO<sub2</sub/FiO<sub2</sub ratio &lt;200 mmHg), &gt;18 years of age and requiring invasive or non-invasive mechanical ventilation. All individuals meeting any of the following exclusion criteria at baseline or during screening will be excluded from study participation: more than 96 hours has elapsed from onset of ARDS; age &lt; 18 years; known to be pregnant or breastfeeding; participation in a clinical trial of an investigational medicinal product (other than antibiotics or antivirals) within 30 days; major trauma in the prior 5 days; presence of any active malignancy (other than nonmelanoma skin cancer) which required treatment within the last year; WHO Class III or IV pulmonary hypertension; pulmonary embolism prior to hospital admission within past 3 months; currently receiving extracorporeal life support (ECLS); chronic kidney disease receiving dialysis; severe chronic liver disease with Child-Pugh score &gt; 12; DNAR (Do Not Attempt Resuscitation) order in place; treatment withdrawal imminent within 24 hours; Prisoners; non-English speaking patients or those who do not adequately understand verbal or written information unless an interpreter is available; IgA deficiency. Intervention: Either a once weekly intravenous infusion of Prolastin® at 120mg/kg of body weight for 4 weeks or a single dose of Prolastin® at 120mg/kg of body weight intravenously followed by once weekly intravenous infusion of an equal volume of 0.9% sodium chloride for a further 3 weeks. Comparator (placebo): An equal volume of 0.9% sodium chloride intravenously once per week for four weeks. The primary effectiveness outcome measure is the change in plasma concentration of IL-6 at 7 days as measured by ELISA. Secondary outcomes include: safety and tolerability of Prolastin® in the respective groups (as defined by the number of SAEs and AEs); PaO<sub2</sub/FiO<sub2</sub ratio; respiratory compliance; sequential organ failure assessment (SOFA) score; mortality; time on ventilator in days; plasma concentration of alpha-1 antitrypsin (AAT) as measured by nephelometry; plasma concentrations of interleukin-1β (IL-1β), interleukin-8 (IL-8), interleukin-10 (IL-10), soluble TNF receptor 1 (sTNFR1, a surrogate marker for TNF-α) as measured by ELISA; development of shock; acute kidney injury; need for renal replacement therapy; clinical relapse, as defined by the need for readmission to the ICU or a marked decline in PaO<sub2</sub/FiO<sub2</sub or development of shock or mortality following a period of sustained clinical improvement; secondary bacterial pneumonia as defined by the combination of radiographic findings and sputum/airway secretion microscopy and culture. Following informed consent/assent patients will be randomised. The randomisation lists will be prepared by the study statistician and given to the unblinded trial personnel. However, the statistician will not be exposed to how the planned treatment will be allocated to the treatment codes. Randomisation will be conducted in a 1:1:1 ratio, stratified by site and age. The investigator, treating physician, other members of the site research team and patients will be blinded to treatment allocation. The clinical trial pharmacy personnel and research nurses will be unblinded to facilitate intervention and placebo preparation. The unblinded individuals will keep the treatment information confidential. The infusion bag will be masked at the time of preparation and will be administered via a masked infusion set to maintain blinding. A total of 36 patients will be recruited and randomised in a 1:1:1 ratio to each of the trial arms. In March 2020, version 1.0 of the trial protocol was submitted to the local research ethics committee (REC), Health Research Consent Declaration Committee (HRCDC) and the Health Products regulatory Authority (HPRA). REC approval was granted on April 1<supst</sup 2020, HPRA approval was granted on April 24<supth</sup 2020 and the HRCDC provided a conditional declaration on April 17<supth</sup 2020. In July 2020 a substantial amendment (version 2.0) was submitted to the REC, HRCDC and HPRA. Protocol changes in this amendment included: the addition of trial sites; extending the duration of the trial to 12 months from 3 months; removal of inclusion criteria requiring the need for vasopressors; amendment of randomisation schedule to stratify by age only and not BMI and sex; correction of grammatical error in relation to infusion duration; to allow for inclusion of subjects who may have been enrolled in a clinical trial involving either antibiotics or anti-virals in the past 30 days; to allow for inclusion of subjects who may be currently enrolled in a clinical trial involving either antibiotics or anti-virals; to remove the need for exclusion based on alpha-1 antitrypsin phenotype; removal of mandatory isoelectric focusing of plasma to confirm Pi*MM status at screening; removal of need for mandatory echocardiogram at screening; amendment on procedures around plasma analysis to reflect that this will be conducted at the central site laboratory (as trial is multi-site and no longer single site); wording amended to reflect that interim analysis of cytokine levels taken at 7 days may be conducted. HRCDC approved version 2.0 on September 14th 2020, and HPRA approved on October 22nd 2020. REC approved the substantial amendment on November 23<suprd</sup. In November 2020, version 3.0 of the trial protocol was submitted to the REC and HPRA. The rationale for this amendment was to allow for patients with moderate to severe ARDS from SARS-CoV-2 with non-invasive ventilation. HPRA approved this amendment on December 1st 2020 and the REC approved the amendment on December 8th 2020. Patient recruitment commenced in April 2020 and the last patient will be recruited to the trial in April 2021. The last visit of the last patient is anticipated to occur in April 2021. At time of writing, patient recruitment is now complete, however follow-up patient visits and data collection are ongoing. EudraCT 2020-001391-15 (Registered 31 Mar 2020). The full protocol (version 3.0 23.11.2020) is attached as an additional file accessible from the Trials website (Additional file 1). In the interest in 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. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

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The kinetics of development of micrometastases, and especially of small numbers of metastases (oligometastases), was explored by using simple assumptions to develop concepts that may be useful for framing future research. The conclusions depend on the assumptions and hence must be considered speculative. It is assumed that beyond a threshold size for initiation of metastatic spread, which varies widely from tumor to tumor, the rate at which a primary tumor sheds new metastases increases exponentially, in parallel with its exponential growth. This increasing rate of release of new metastatic clonogens from the primary tumor is accompanied by a similar exponential growth of each of the micrometastases newly established at a secondary site. This creates a log-log linear relationship between the volume distribution of metastases and number of metastases, there being one largest metastasis followed by an exponentially expanding number of logarithmically smaller micrometastases. For example, if the micrometastases and the primary tumor grew at the same rate for 6 doublings after initiation of the first metastasis, then the primary tumor would have increased its volume by a factor of 64 (2(6)) and would be shedding metastatic clonogens at 64 times the initial rate. The first metastasis would undergo 6 doublings and contain 64 cells; the succeeding 2 metastases, released as the primary doubled in volume, would undergo 5 doublings and each would contain 32 cells; and so forth down to the 64 most recently developed single-cell metastases. However, the growth rate of metastases is expected to be faster than that of the primary tumor so that the rate of increase in volume of the micrometastases would be faster than the rate of increase in their numbers (through release of new metastases from the primary). Thus, although the log-log linear relationship is maintained, the slope of the volume frequency curve is changed; if the micrometastases grew 5 times faster than the primary, the slope would change by a factor of 5. Removal of the primary tumor as a source of new metastases truncates the expansion in numbers of metastases without affecting the growth rate of existing micrometastases, with the result that the volume-frequency relationship is maintained but the whole curve is shifted to larger volumes as micrometastases grow toward clinical detectability. The development of an oligometastatic distribution requires that the exponential expansion in the number of new metastases be stopped by eliminating the primary tumor soon after the first metastasis is shed. A cell destined to become part of an oligometastatic distribution had just been newly deposited at its metastatic site at the time the primary tumor was removed and must undergo about 30 doublings to become clinically detectable as an overt metastasis (2(30) or 10(9) cells). Thus, the time interval between removal of the primary and subsequent appearance of oligometastases will be toward the upper end of a distribution of "metastasis-free" intervals for its particular class of tumor. The actual time to appearance of a solitary metastasis, or of oligometastases, in any particular patient will depend on the growth rate of the metastases in that individual but will always require about 30 volume doublings. An apparently solitary metastasis appearing synchronously with the primary tumor is unlikely to be solitary because, to do so, it would have to have undergone about 30 doublings without further release of metastatic clonogens from the primary that is, in our model, within 1 doubling in volume of the primary tumor. For the same reason, a synchronous or early appearing oligometastatic distribution is unlikely, but if it were to exist, there would be a steep gradient between the volumes of largest and smallest metastases because the growth rate of the micrometastases to produce synchronous metastases, without having further metastases shed from the primary, would have to be fast (up to 30x) relative to the growth rate of the primary. Conversely, a steep gradient in volumes of successive echelons of metastases reflects fast growth of metastases relative to the primary and favors the possibility of an oligometastatic distribution. This ratio of growth rates of metastases to primary is defined by the slope of the log-log curve for the volume-frequency distribution of metastases, which, in clinical practice, is difficult to determine over a wide range and is, by definition, essentially impossible for oligometastases. However, the volume-frequency relationship, measured over a wide range, is the same as the ratio of the volume of the largest to second-largest metastases in an oligometastatic situation. For example, if the metastasis doubled 5 times faster than the primary, the largest metastasis would be larger by 5 doublings than its closest follower(s), that is, by a factor of 2(5) or 32, equivalent to a 3.2-fold difference in diameter if the metastases were spherical. Alternatively, if an initially solitary and measurable metastasis is subsequently joined by measurable followers, the number of volume doublings separating successive echelons in the series can be determined directly, and the larger the difference (measured in doublings), the greater the probability that there will be a limited, oligometastatic condition (ie, in clinical terms, subsequent metastases will stop appearing after the large leader metastasis and a short succession of followers have been removed at 1 or more operations). In summary, the probability of there being an oligometastatic distribution is increased as the interval between removal of the primary tumor and appearance of metastases lengthens. It is also more likely the faster the metastases are growing relative to the growth rate of the primary tumor before its removal. Effective systemic cytotoxic treatment (eg, chemotherapy, hormonal manipulation, biological agents) given in the perioperative period, or concomitantly with radiation therapy for the primary tumor, would truncate the volume-frequency distribution toward an oligometastatic one by eliminating the smallest, most recently formed "tail-ender" metastases. That process, which only occurs at the threshold volume of the primary at which metastases are first initiated, would not be influenced by whether surgery or radiation therapy was chosen to treat the primary tumor, regardless of the overall duration of radiation therapy. Chemotherapy adjuvant to surgery is not usually indicated in the curative treatment of solitary or oligometastases because they represent a truncated distribution with few or no stragglers. If subclinical stragglers exist, they would usually be relatively large and, even though subclinical, too large to be cured by chemotherapy. Exceptions would be early rapidly growing oligometastases, especially from a slowly growing primary, or solitary metastases from an unknown primary where second echelon metastases, if they exist, may still be small. Otherwise chemotherapy could be postponed and used for palliative growth restraint of unusually large and/or numerous stragglers.

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In recent years, Asia has experienced rapid economic growth and a deteriorating environment caused by the increasing use of fossil fuels. Although the deleterious effects of air pollution from fossil-fuel combustion have been demonstrated in many Western nations, few comparable studies have been conducted in Asia. Time-series studies of daily mortality in Asian cities can contribute important new information to the existing body of knowledge about air pollution and health. Not only can these studies verify important health effects of air pollution in local regions in Asia, they can also help determine the relevance of existing air pollution studies to mortality and morbidity for policymaking and environmental controls. In addition, the studies can help identify factors that might modify associations between air pollution and health effects in various populations and environmental conditions. Collaborative multicity studies in Asia-especially when designed, conducted, and analyzed using a common protocol-will provide more robust air pollution effect estimates for the region as well as relevant, supportable estimates of local adverse health effects needed by environmental and public-health policymakers. The Public Health and Air Pollution in Asia (PAPA*) project, sponsored by the Health Effects Institute, consisted of four studies designed to assess the effects of air pollution on mortality in four large Asian cities, namely Bangkok, in Thailand, and Hong Kong, Shanghai, and Wuhan, in China. In the PAPA project, a Common Protocol was developed based on methods developed and tested in NMMAPS, APHEA, and time-series studies in the literature to help ensure that the four studies could be compared with each other and with previous studies by following an established protocol. The Common Protocol (found at the end of this volume) is a set of prescriptive instructions developed for the studies and used by the investigators in each city. It is flexible enough to allow for adjustments in methods to optimize the fit of health-effects models to each city's data set. It provides the basis for generating reproducible results in each city and for meta-estimates from combined data. By establishing a common methodology, factors that might influence the differences in results from previous studies can more easily be explored. Administrative support was provided to ensure that the highest quality data were used in the analysis. It is anticipated that the PAPA results will contribute to the international scientific discussion of how to conduct and interpret time-series studies of air pollution and will stimulate the development of high-quality routine systems for recording daily deaths and hospital admissions for time-series analysis. Mortality data were retrieved from routine databases with underlying causes of death coded using the World Health Organization (WHO) International Classification of Diseases, 9th revision or 10th revision (ICD-9, ICD-10). Air quality measurements included nitrogen dioxide (NO2), sulfur dioxide (SO2), particulate matter with aerodynamic diameter &lt; or = 10 microm (PM10), and ozone (O3) and were obtained from several fixed-site air monitoring stations that were located throughout the metropolitan areas of the four cities and that met the standards of procedures for quality assurance and quality control carried out by local government units in each city. Using the Common Protocol, an optimized core model was established for each city to assess the effects of each of the four air pollutants on daily mortality using generalized linear modeling with adjustments for time trend, seasonality, and other time-varying covariates by means of a natural-spline smoothing function. The models were adjusted to suit local situations by correcting for influenza activity, autocorrelation, and special weather conditions. Researchers in Hong Kong, for example, used influenza activity based on frequency of respiratory mortality; researchers in Hong Kong and Shanghai used autoregressive terms for daily outcomes at lag days; and researchers in Wuhan used additional smoothing for periods with extreme weather conditions. For mortality due to all natural (nonaccidental) causes at all ages, the effects of air pollutants per 10-microg/m3 increase in concentration was found to be higher in Bangkok than in the three Chinese cities, with the exception of the effect of NO2 in Wuhan. The magnitude of the effects for cardiovascular and respiratory mortality were generally higher than for all natural mortality at all ages. In addition, the effects associated with PM10 and O3 in all natural, cardiovascular; and respiratory mortality were found to be higher in Bangkok than in the three Chinese cities. The explanation for these three findings might be related to consistently higher daily mean temperatures in Bangkok, variations in average time spent outdoors by the susceptible populations, and the fact that less air conditioning is available and used in Bangkok than in the other cities. However, when pollutant concentrations were incorporated into the excess risk estimates through the use of interquartile range (IQR), the excess risk was more comparable across the four cities. We found that the increases in effects among older age groups were greater in Bangkok than in the other three cities. After excluding data on extremely high concentrations of PM10 in Bangkok, the effect estimate associated with PM10 concentrations decreased in Bangkok (suggesting a convex relationship between risk and PM10, where risk levels off at high concentrations) instead of increasing, as it did in the other cities. This leveling off of effect estimates at high concentrations might be related to differences in vulnerability and exposure of the population to air pollution as well as to the sources of the air pollutant. IMPLICATIONS OF THE STUDY: The PAPA project is the first coordinated Asian multicity air pollution study ever published; this signifies the beginning of an era of cooperation and collaboration in Asia, with the development of a common protocol for coordination, data management, and analysis. The results of the study demonstrated that air pollution in Asia is a significant public health burden, especially given the high concentrations of pollutants and high-density populations in major cities. When compared with the effect estimates reported in the research literature of North America and Western Europe, the study's effect estimates for PM10 were generally similar and the effect estimates for gaseous pollutants were relatively higher. In Bangkok, however, a tropical city where total exposures to outdoor pollution might be higher than in most other cities, the observed effects were greater than those reported in the previous (i.e., Western) studies. In general, the results suggested that, even though social and environmental conditions across Asia might vary, it is still generally appropriate to apply to Asia the effect estimates for other health outcomes from previous studies in the West. The results also strongly support the adoption of the global air quality guidelines recently announced by WHO.

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<bObjective:</b To explore the transcriptional regulation mechanism of transforming growth factor β(1) (TGF-β(1)) on Meox1 and its effect on cell migration of adult human dermal fibroblasts (HDF-a). <bMethods:</b (1) HDF-a cells were cultured in RPMI 1640 complete medium (hereinafter referred to as routinely cultured). The cells were divided into TGF-β(1) stimulation group and blank control group. The cells in TGF-β(1) stimulation group were stimulated with 10 μL TGF-β(1) in the mass concentration of 1 mg/μL, while the cells in blank control group were stimulated with the equal volume of phosphate buffer solution. After 72 hours in culture, partial cells in both groups were collected for transcriptome sequencing. The genes with differential expression ratio greater than or equal to 2 and <iP</i&lt;0.01 between the two groups were selected to perform enrichment analysis and analysis of metabolic pathways of the Kyoto Gene and Genome Encyclopedia with, and the expression value of Meox1 per million transcripts (TPM) was recorded (<in</i=3). Partial cells from the two groups were used to detect the Meox1 mRNA expression by real-time fluorescent quantitative reverse transcription polymerase chain reaction (RT-PCR) (<in</i=3). (2) Cultured HDF-a cells in the logarithmic growth phase (the same growth phase of cells below) were divided into empty plasmid group, Smad2 overexpression (OE) group, Smad3 OE group, and Smad4 OE group, which were transfected respectively with 2 μg empty pcDNA3.1 plasmid and pcDNA3.1 plasmids separately carrying Smad2, Smad3, and Smad4 for 6 hours, and then were routinely cultured for 48 hours. The Meox1 mRNA expression in the transfected cells of each group was detected by real-time fluorescent quantitative RT-PCR (<in</i=3). (3) HDF-a cells were routinely cultured and grouped the same as in experiment (1). After 72 hours in culture, the enrichment of Smad2, Smad3, and Smad4 protein on the Meox1 promoter in the cells of each group was detected by chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR) (<in</i=3). (4) HDF-a cells were routinely cultured and divided into negative interference group, small interference RNA (siRNA)-Smad2 group, siRNA-Smad3 group, siRNA-Smad4 group, empty plasmid group, Smad2 OE group, Smad3 OE group, and Smad4 OE group, which were transfected respectively with 50 μmol/L random siRNA, siRNA-Smad2, siRNA-Smad3, siRNA-Smad4, 2 μg empty pcDNA3.1 plasmid and pcDNA3.1 plasmids separately carrying Smad2, Smad3, and Smad4 for 6 hours and then routinely cultured for 48 hours. The enrichment of Smad2, Smad3, and Smad4 protein on the Meox1 promoter in the cells of corresponding group was detected by ChIP-qPCR (<in</i=3). (5) Two batches of HDF-a cells were cultured and divided into negative interference group, siRNA-Meox1 group, empty plasmid group, and Meox1 OE group, which were transfected respectively with 50 μmol/L random siRNA, siRNA-Meox1, 2 μg empty pcDNA3.1 plasmid and pcDNA3.1 plasmid carrying Meox1 for 6 hours and then routinely cultured for 24 hours. One batch of cells were subjected to scratch test with the scratch width being observed 24 hours after scratching and compared with the initial width for scratch wound healing; the other batch of cells were subjected to Transwell assay, in which the migrated cells were counted after being routinely cultured for 24 hours (<in</i=3). (6) From January 2018 to June 2019, 3 hypertrophic scar patients (2 males and 1 female, aged 35-56 years) were admitted to the First Affiliated Hospital of Army Medical University (the Third Military Medical University) 8-12 months after burns. The scar tissue and normal skin tissue along the scar margin resected during surgery were taken, and immunohistochemical staining was performed to observe the distribution of Meox1 protein expression. Data were statistically analyzed with one-way analysis of variance and independent sample <it</i test. <bResults:</b (1) After 72 hours in culture, a total of 843 genes were obviously differentially expressed between the two groups, being related to tissue repair, cell migration, inflammatory cell chemotaxis induction process and potential signaling pathways such as tumor necrosis factor, interleukin 17, extracellular matrix receptor. The TPM value of Meox1 in the cells of blank control group was 45.9±1.9, which was significantly lower than 163.1±29.5 of TGF-β(1) stimulation group (<it</i=6.88, <iP</i&lt;0.01) with RNA-sequencing. After 72 hours in culture, the Meox1 mRNA expression levels in the cells of blank control group was 1.00±0.21, which was significantly lower than 11.00±3.61 of TGF-β(1) stimulation group (<it</i=4.79, <iP</i&lt;0.01). (2) After 48 hours in culture, the Meox1 mRNA expression levels in the cells of Smad2 OE group, Smad3 OE group, and Smad4 OE group were 198.70±11.02, 35.47±4.30, 20.27±2.50, respectively, which were significantly higher than 1.03±0.19 of empty plasmid group (<it</i=31.07, 13.80, 13.12, <iP</i&lt;0.01). (3) After 72 hours in culture, the enrichment of Smad2, Smad3, and Smad4 protein on the promoter of Meox1 in the cells of TGF-β(1) stimulation group was significantly higher than that of blank control group respectively (<it</i=12.99, 41.47, 29.10, <iP</i&lt;0.01). (4) After 48 hours in culture, the enrichment of Smad2 protein on the promoter of Meox1 in the cells of negative interference group was (0.200 000±0.030 000)%, significantly higher than (0.000 770±0.000 013)% of siRNA-Smad2 group (<it</i=11.67, <iP</i&lt;0.01); the enrichment of Smad2 protein on the promoter of Meox1 in the cells of empty plasmid group was (0.200 000±0.040 000)%, significantly lower than (0.700 000±0.090 000)% of Smad2 OE group (<it</i=8.85, <iP</i&lt;0.01). The enrichment of Smad3 protein on the promoter of Meox1 in the cells of negative interference group was (0.500 0±0.041 3)%, significantly higher than (0.006 0±0.001 3)% of siRNA-Smad3 group (<it</i=17.79, <iP</i&lt;0.01); the enrichment of Smad3 protein on the promoter of Meox1 in the cells of empty plasmid group was (0.470 0±0.080 0)%, which was significantly lower than (1.100 0±0.070 0)% of Smad3 OE group (<it</i=9.93, <iP</i&lt;0.01). The enrichment of Smad4 protein on the promoter of Meox1 in the cells of negative interference group was similar to that of siRNA-Smad4 group (<it</i=2.11, <iP</i&gt;0.05); the enrichment of Smad4 protein on the promoter of Meox1 in the cells of empty plasmid group was similar to that of Smad4 OE group (<it</i=0.60, <iP</i&gt;0.05). (5) Twenty-four hours after scratching, the scratch healing width of cells in siRNA-Meox1 group was narrower than that of negative interference group, while that of Meox1 OE group was wider than that of empty plasmid group. After 24 hours in culture, the number of migration cells in negative interference group was significantly higher than that in siRNA-Meox1 group (<it</i=9.12, <iP</i&lt;0.01), and that in empty plasmid group was significantly lower than that in Meox1 OE group (<it</i=8.99, <iP</i&lt;0.01). (6) The expression of Meox1 protein in the scar tissue was significantly higher than that in normal skin of patients with hypertrophic scars. <bConclusions:</b TGF-β(1) transcriptionally regulates Meox1 expression via Smad2/3 in HDF-a cells, thus promoting cell migration.

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Evaluation by means of citation patterns can be successful only insofar as published papers and their bibliographies reflect scientific activity and nothing else. Such an innocent descrip tion is becoming less and less tenable. The present scientific explosion gave rise to more than a proportional pub lication explosion, which not only re flects the scientific explosion but has its own dynamics and vicious circles. Publication of results is probably the main means of accomplishing the al most impossible task of accounting for time and money spent on research. Inevitably, this puts a premium on quantity at the expense of quality, and, as with any other type of inflation, the problem worsens: the more papers are written, the less they count for and the greater is the pressure to publish more. What makes matters worse is the fact that the sheer volume of the"litera ture" makes it increasingly difficult to separate what is worthwhile from the rest. Critical reviews have become somewhat of a rarity, and editorial judgment is usually relegated to ref erees, who are contemporaries and, per haps, competitors of the authors-a situation which has its own undesirable implications (11, 18). It requires little imagination to discover other vicious circles, all arising from distortion of the primary reasons for publishing the results of scientific inquiry. There are, it is true, signs of ad justment to this crisis, partly due to some easing of the pressure to pub lish at all costs, and partly due to the readers' changing attitudes toward the flood of publications. An increasing amount of research is now being car ried out in the form of collective proj ects in large institutions where publica tion is no longer the standard method of accounting for individual work. At the same time there is apparent an in creasing tendency for scientific journals to polarize into the relatively few leading ones which carry important informa tion and the many subsidiary journals which serve as vehicles for interim lo cal accounting and, in a way, sub stitute for detailed intradepartmental re ports. This division is a result not of some arbitrary decree but of normal competition between journals, as a re sult of which, however, the strong usual ly get stronger and the weak get weaker. Were it not for these changes and also for a striking improvement in abstracting, indexing, and alerting serv ices, most research workers would have found long ago that, even in their own specialized fields, new information is accumulating faster than it can be sorted out. These developments can pro vide only a temporary reprieve, so long as there remains a strong incentive to publish the greatest possible number of papers. A new scale of values based on citations is by no means infallible or, in many cases, even fair, but at least it provides an alternative to the existing one, which is at the root of the crisis. It might, of course, be asked whether wide acceptance of such new stand ards would not lead to deliberate abuses. A little reflection shows that the system is less open to manipula tion than might appear. First, the ref erees are expected to see to it that the submitted papers cite work which is pertinent to the subject. An increased awareness of the usefulness of citation indexing as a tool for retrieval and evaluation will make this aspect of refereeing more important, and what now passes for minor carelessness or discourtesy could easily come to be regarded as serious malpractice. Sec ond, as noted above, careful selection of references is in the author's own interest, because it helps him to reach his readers. There is, therefore, some room for hope that healthy feedback in the system will tend to keep it viable. At the basis of this hope lies the supposition that, in the long run, only good work can ensure recognition. As Martyn (2) has pointed out, as an information-retrieval method, cita tion indexing is rather "noisy." The word noisy may apply even more to the problem of evaluation. Whereas in information retrieval much of the unwanted information can be filtered out by suitable search strategy (2, 6), this is not so easy to do for the pur pose of evaluation, because a simple descendence relationship between papers is still an ideal far removed from actuality (7). The situation would be much better if we could at will exclude all citations which do not indi cate real indebtedness. A scheme of citation relationship indicators, first men tioned by Garfield (12) and elaborated by Lipetz (17), would be a help, but, even if it were technically feasible, to provide such indicators would greatly add to the production costs of the Index. Another possible way to minimize the effects of "noise" is to increase the size of the samples on which the reckon ing is based. Now that research has be come a rather popular occupation, it seems that a kind of public vote may have to be accepted as a factor in evaluation. Since this is the case, there is something to be said for extending the "franchise" to minimize acciden tal effects. An index which attempted to process all scientific publications would be several times the size of the present Index, and, what is more, it would not necessarily be an improve ment as a tool for information retrieval because most of the significant work is already concentrated in the present Index. Whether this attempt will ever be considered worthwhile remains pri marily a matter of policy and eco nomics. In the meantime there is an urgent need for more experience with the existing services. It is not the purpose of this article to advocate evaluation of scientific work by some kind of public opinion poll; its purpose is to recognize a pos sible trend in this direction. Any judg ment by public acclaim is subject to obvious fallacies, but we must not be carried away by the analogy to the Stock Exchange or to electoral prac tices. The fact that, in this case, the "public" consists of authors whose con tributions are generally linked creates quite a new pattern of organization. In this discussion some of the aspects of this pattern have been explored through analogy to idealized genetic or mechani cal network models, but the very uniqueness of the system, with its many self-organizing ramifications, makes it a new field which deserves close study, since these developments may have pro found effects on the future of scientific communication.

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Current tuberculosis (TB) problems are reflections of Japanese society. Living or dying alone among the elderly, difficulty in finding jobs or withdrawal into themselves among the youths are features of modem society. The future needs for TB care were discussed on specific topics of TB among the elderly, foreigners and the homeless. Presenters showed the importance of the patient-centered care in collaboration with public health and welfare services. Both patients and staffs will see others shining, as they touch each other in the deep part of human existence. A diabetic ex-TB patient talked his experience in his treatment. His window of mind was gradually opened from inside with the continuous support in DOTS by the staff of the public health center. To accumulate these experiences of a heartwarming atmosphere will have the effective power on establishment of social supporting systems. This symposium can be a step towards humanized society or a new horizon of public health which can answer to another need of inner cry of a sick people particularly among the socially disadvantaged who are the victims of the weakness of society. 1. Current situation and issues of elderly tuberculosis patients: Eriko SHIGETO (NHO Higashihiroshima Medical Center). By the analysis of 102 tuberculosis patients of 70 years old and above who were registered at Hiroshima Prefectural Health Center in 2009, 41 patients had severe complications such as diabetes mellitus, renal insufficiency, malignancy or cerebrovascular disorder. Their prognosis was rather poor and the ADL tended to be worsened during hospitalization. Though 16 of the 34 deaths were caused with non-tuberculosis diseases, the ratio of the tuberculosis deaths was higher (4/17) among the patients living alone. Sufficient care of the elderly for early diagnosis, care system to treat various complications and patient support are required. 2. Provision of medical interpreters to help foreigners with tuberculosis in Tokyo: Takashi SAWADA (Services for Health in Asian &amp; African Regions (SHARE)). In 2006, Tokyo Metropolitan Government started to dispatch interpreters for foreigners to strengthen DOTS program. Collaboration with NGOs made it possible to train 37 volunteer interpreters, and to provide services in 13 languages, as of 2010. In Japan, the treatment defaulter rate among non-Japanese tuberculosis patients had been remarkably high. But with having the assistance of interpreters, the treatment completion rate has become higher than 80%. It is recommended to expand a similar system to other part of Japan, as the proportion of foreigners among total tuberculosis cases keeps on increasing nationwide. 3. Tuberculosis problems in Japan from the view point of homelessness-through the activities of a NPO supporting the homeless in collaboration with a public health center: Sadako KANAZAWA (Volunteer, NPO Medical Care Team of Shinjuku Renraku-Kai). It has been 20 years since the issue of homelessness emerged in Japanese society. The people with a history of both tuberculosis and experience of homelessness tend to show a poor prognosis. Our team has played an active role, working with Shinjuku Public Health Center for conducting a screening for tuberculosis every year. It seems that the screening service itself does not make a fundamental solution for homeless people with tuberculosis. Developing a more basic system of 'from street to apartment' is more essential. We believe that understanding the importance of the system is most essential to the people who are involved in health and medical care. 4. What we have learned from DOTS--Toward care by cuddling the patient's mind: Kazuyo ARIMA (PHN, Osaka City Public Health Center). Osaka City has achieved the goals of DOTS set up by the City's TB Control Guidelines since 2001 such as 80% DOTS implementation rate, halving the defaulter rate and incidence rate. It was shown by analysis that the treatment success depends on 'patient's awareness of the disease', 'appropriate DOTS method for each patient', 'existence of side effects', or 'the relationship between treatment supporters'. Through working for the patients whose treatment management was difficult, we have learned that our attitude towards the patients is a most important first step to build a good relationship and mutual trust with the patients, and DOT is an important tool. For treatment supporters,'the patient-centered care', 'care by staying close to the patients' or 'cuddling the patient' s mind' is most necessary to lead the patients to cure. 5. Patient's view: Through DOTS, my life has been renewed: Kuniyoshi MAEDA (Himawari no kai; Ex-homeless TB patients self-help group). It is an unforgettable memory that I was hospitalized due to TB back in 2009. I was seriously ill with also diabetes mellitus. Because I had lost everything due to my friend's cheating, I could not trust anyone before the TB treatment. But I learned how to think of others through the daily communication with doctors, nurses, other staff at the hospital, and Public Health Center. They encouraged me every day and I came to desire to answer to their expectations. Public health nurses taught me that building the reliable relationship is so essential for humans, and I may not have realized this importance if I had not been treated for TB, or treated outside Shinjuku. I would rather say that I was lucky to have got TB, as I have become able to trust other people through DOTS TB care. DOTS is not only for medication, but also general health care and counseling. I hope that as many as poor people, especially homeless can have a similar experience by knowing more about TB and using a health service. I would like to cooperate with TB services if I can be useful. health: Toshio TAKATORIGE (Graduate School of Safety Science, Kansai University). Tuberculosis was ever the biggest health problem in Japan. Ministry of Health and Welfare and Public Health Centers were founded to push forward tuberculosis control. Local governments, companies and people had to follow the national tuberculosis control program uniformly without exception. Currently a new stream of tuberculosis control has been started by DOTS strategy. The aim of DOTS has made all patients take medicine regardless of their social conditions until cure. Every patient is snuggled up and supported whether he is homeless, criminal or a foreigner. The patients also participate in the program actively. The DOTS may be a new public health movement. The strong public health infrastructure is necessary to maintain tuberculosis control towards the low incidence situation. The role of the local government should be more important. This symposium has also shown that the tuberculosis services must be patients-centered and supported by the people, addressing a new horizon of public health in Japan through tuberculosis control.

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Trichloroethylene (TCE) is an industrial solvent used for vapor degreasing and cold cleaning of fabricated metal parts. TCE has also been used as a carrier solvent for the active ingredients of insecticides and fungicides, as a solvent for waxes, fats, resins, and oils, as an anesthetic for medical and dental use, and as an extractant for spice oleoresins and for caffeine from coffee. Trichloroethylene may be found in printing inks, varnishes, adhesives, paints, lacquers, spot removers, rug cleaners, disinfectants, and cosmetic cleansing fluids. TCE may also be used as a chain terminator in polyvinyl chloride production and as an intermediate in the production of pentachloroethane. Trichloroethylene is no longer used with food, drugs, or cosmetics. NTP Carcinogenesis studies of epichlorohydrin-free trichloroethylene were conducted by administering the test chemical in corn oil by gavage to groups of 50 male and 50 female F344/N rats and B6C3F1 mice. Dosage levels were 500 and 1,000 mg/kg for rats and 1,000 mg/kg for mice. Trichloroethylene was administered five times per week for 103 weeks, and surviving animals were killed between weeks 103 and 107. Groups of 50 rats and 50 mice of each sex received corn oil by gavage on the same schedule and served as vehicle controls. Groups of 50 male and 50 female rats were used as untreated controls. The dosage levels selected for the 2-year study were based on the results of the 13-week studies. Groups of 10 male and 10 female rats received TCE by gavage at doses of 125 to 2,000 mg/kg (males) and 62.5 to 1,000 mg/kg (females) for 13 weeks. Groups of 10 male and 10 female mice received gavage doses of 375 to 6,000 mg/kg of TCE for 13 weeks. Survival, body weight gains, and previous experience with TCE were used to select doses for the 2-year study. All rats survived the 13-week study, but males receiving 2,000 mg/kg exhibited a 24% difference in final body weight. At the 1,000 mg/kg dose, final body weights for males (-3%) and for females (-2%) were similar to those of controls. The doses selected for the 2-year study in rats were 500 and 1,000 mg/kg for both sexes. The initial doses used in the earlier bioassay in Osborne-Mendel rats were 549 and 1,097 mg/kg for both sexes. A total of 8/10 male mice and 10/10 female mice receiving doses of TCE as high as 1,500 mg/kg survived the 13-week experimental period. The single dosage level selected for the 2-year study in mice was 1,000 mg/kg for both sexes. This dose was less than the high dose used in the earlier bioassay in B6C3F1 mice (2,339 mg/kg for males and 1,739 for females) and was similar to the previous low doses (1,169 mg/kg for males and 869 for females). In the 2-year study, the survival of both low and high dose male rats and dosed male mice was less (P&lt;/=0.005) than that of the vehicle controls. Mean body weights of dosed rats of each sex were lower than those of the vehicle controls, and after week 65, the decrements in body weight gains were dose related. The mean body weight of dosed male mice was lower than that of the vehicle controls throughout the study, while those of the dosed and vehicle control female mice were comparable. Cytomegaly (toxic nephrosis) of the kidney was observed in 96/98 male and in 97/97 female rats given TCE, with none being found in male or female vehicle control rats. This lesion was more severe in males, particularly in the high dose group. Cytomegaly was observed in 45/50 male mice and in 48/49 female mice administered TCE, and in none of the vehicle controls. Renal tubular cell adenocarcinomas were found in the three high dose male rats; these neoplasms were observed in those male rats killed at the end of the study (0/33, 0/20, and 3/16, 19%). The incidence in the high dose male rats at the end of the study was greater (P&lt;0.05) than that in the controls. Renal tubular cell adenocarcinomas are considered uncommon occurrences in F344/N rats, with 3/748 (0.4%) being observed in historical vehicle gavage controls. Additional renal tumors in dosed male rats included one transitional cell carcats included one transitional cell carcinoma of the renal pelvis and two tubular cell adenomas in low dose animals and one carcinoma of the renal pelvis in a high dose animal. No renal neoplasms were found in vehicle control rats; one untreated control male rat had a transitional cell papilloma of the renal pelvis. In female rats, one tubular cell adenocarcinoma was found in the high dose group. An increased incidence (P&amp;lt;0.05, life table) of peritoneal mesotheliomas was detected in low dose male rats (control, 1/50; low dose, 5/50; high dose, 1/49). Mesotheliomas have been diagnosed in 16/752 (2.1&amp;percnt;) historical vehicle control male F344/N rats, and the increased incidence in the present study may have been related to the administration of TCE. The results in male F344/N rats were considered equivocal for detecting a carcinogenic response because both groups receiving TCE showed significantly reduced survival compared to vehicle controls (35/50, 70&amp;percnt;, 20/50, 40&amp;percnt;; 16/50, 32&amp;percnt;) and because 20&amp;percnt; of the animals in the high dose group were killed accidently by gavage error. Negative trends were observed for chromophobe adenomas of the pituitary gland and for endometrial stomal polyps in female rats. These decreases were not considered to be related to the administration of TCE. The administration of TCE to mice caused increased incidences of hepatocellular carcinoma in males (control, 8/48; dosed, 31/50; P&amp;lt;0.001) and in females (control, 2/48; dosed, 13/49; P&amp;lt;0.005). Hepatocellular carcinomas metastasized to the lungs in five dosed male mice and one control male mouse, and none were observed in females. The incidence of hepatocellular adenomas was increased in male mice (control, 7/48; dosed 14/50) and in female mice (control, 4/48; dosed, 16/49; P&amp;lt;0.05). Under the conditions of these studies, epichlorohydrin-free trichloroethylene caused renal tubular-cell neoplasms in male F344/N rats, produced toxic nephrosis in both sexes, and shortened the survival time of males. This experiment in male F344/N rats was considered to be inadequate to evaluate the presence or absence of a carcinogenic response to trichloroethylene. For female F344/N rats receiving trichloroethylene, containing no epichlorohydrin, there was no evidence of carcinogenicity. Trichloroethylene (without epichlorohydrin) was carcinogenic for B6C3F1 mice, causing increased incidences of hepatocellular carcinomas in males and females and of hepatocellular adenomas in females. Levels of Evidence of Carcinogenicity: Male Rats: Inadequate Study Female Rats: Negative Male Mice: Positive Female Mice: Positive Synonym: TCE

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The primary objective of this document is to clarify the indications for pelvic examination. Physicians, including gynaecologists, obstetricians, family physicians, and emergency physicians; nurses, including registered nurses and nurse practitioners; midwives, including midwives in clinical practice and midwifery trainees; medical trainees, including medical students, residents, and fellows; and all other health care providers who care for women. This publication provides evidence and expert-based recommendations for pelvic examination in adult women (18 years and older) both with and without gynaecologic symptoms. This publication clarifies indications for pelvic examination in the context of recently published national task force statements on the utility of pelvic examination. We aim to ensure that women who have clinical indications for examination receive proper clinical investigation with minimal delays to diagnosis of treatable disease. For this committee opinion, relevant studies were identified in PubMed and Medline using the following terms, either alone or in combination, with the search limited to English-language materials and human subjects and no publication date cut-off: pelvic examination, bimanual examination, speculum examination, rectovaginal examination, ovarian cancer screening, asymptomatic women, periodic health examination. The search was performed in May and June 2018. Relevant evidence was selected for inclusion in the following order: meta-analyses, systematic reviews, guidelines and national task force statements, randomized controlled trials, prospective cohort studies, observational studies, non-systematic reviews, case series, and reports. Additional articles were identified by cross-referencing the identified publications. A formal systematic review was not conducted for all topics discussed due to the paucity of evidence and number of different subtopics discussed. The total number of publications included in this review was 66. The content and recommendations were drafted and agreed upon by the principal authors. The Boards of the Society of Gynecologic Oncology of Canada (GOC), the College of Family Physicians of Canada (CFPC), and the Society of Obstetricians and Gynaecologists of Canada (SOGC) approved the final draft for publication after review by their respective representative committees. The quality of evidence was rated using the criteria described in the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology framework (Tables 1 and 2). The Summary of Findings is available upon request. This committee opinion should benefit all women with and without gynaecologic symptoms who present to gynaecologists and primary care practitioners. It will help guide practitioners in identifying indications for pelvic examination to reduce unnecessary examination with related potential harm while also increasing indicated examination to reduce delays in diagnosis of treatable gynaecologic conditions. This SOGC Committee Opinion will be automatically reviewed 5 years after publication to determine if all or part of the committee opinion should be updated. However, this review may be performed earlier if new high-impact research is published in the interim. 1. National and international statements and guidelines on pelvic examination should not be interpreted to suggest that the pelvic examination is irrelevant or noncontributory to physical assessment or that the pelvic examination in symptomatic women should be omitted. 2. Pelvic examination may include visual inspection, speculum examination, bimanual examination, single digit examination, and/or rectovaginal examination depending on the indication for examination. 3. No study published to date has adequately evaluated any component of the pelvic examination as a screening method for any type of malignant gynaecologic disease, except for the speculum examination for cervical cancer cytology screening. As such, any universal recommendations for or against pelvic examinations for other indications can only be made based on expert opinion and low-quality evidence. 4. In asymptomatic women at average risk for cervical cancer, cervical cytology screening reduces both the incidence of, and mortality from, cervical cancer by detecting pre-invasive, treatable lesions. 5. In asymptomatic women at average risk of malignancy, a visual and bimanual examination at the time of obtaining cervical cytology samples may add value to this screening manoeuvre: Women might not raise certain gynaecologic concerns until the time of pelvic examination; the examination provides an opportunity for patient education and practitioner skill maintenance; and, although inadequately studied to date, there may be positive effects on ovarian and vulvar malignancy that require further investigation. These potential benefits should be weighed against potential harms like patient discomfort and false positives/negatives that may result in inappropriate reassurance or unnecessary investigations/interventions. Symptomatic Women. 1) Any woman with gynaecologic complaints including, but not limited to, vulvar complaints, vaginal discharge, abnormal premenopausal bleeding, postmenopausal bleeding, infertility, pelvic organ prolapse symptoms, urinary incontinence, new and unexplained gastrointestinal symptoms (abdominal pain, increased abdominal size/bloating, and difficulty eating/early satiety), pelvic pain, or dyspareunia should undergo appropriate components of the pelvic examination to identify benign or malignant disease (strong, low). 2) Health care providers may consider discussing the risks and benefits of performing a baseline pelvic examination including visual and bimanual examination prior to prescribing hormonal replacement therapy/menopausal hormonal treatment (weak, very low). Asymptomatic Women. 3) Health care practitioners should perform cervical cytology cancer screening in accordance with provincial/territorial guidelines (strong, strong). 4) There is insufficient evidence to guide recommendations on screening pelvic examination for noncervical gynaecologic malignancy or any benign gynaecologic disease in healthy, asymptomatic women with average risk of malignancy. However, health care practitioners may consider performing a screening pelvic examination including visual, speculum, and bimanual examinations in concert with cervical cytology sampling intervals as recommended by provincial/territorial guidelines. This practice may identify clinically important benign or malignant disease not recognized or reported by the patient (weak, very low). 5) In women over age 70 who no longer require screening with cervical cytology, health care practitioners should consider continuing periodic screening of asymptomatic women for vulvar disease with inspection of the vulva, perineum, and anus to identify benign or malignant disease unrecognized by this population. There is insufficient evidence to guide recommendations on frequency of this examination (weak, low). 6) Women with a personal history of gynaecologic malignancy, a genetic diagnosis that increases gynaecologic malignancy risk, or a history of in utero diethylstilbestrol exposure may benefit from more frequent screening pelvic examinations to identify early primary, recurrent, or metastatic malignancy in the absence of symptoms. Because there is inadequate evidence to define these screening intervals, they should be in accordance with provincial/territorial guidelines and expert opinion (weak, very low). 7. Non-invasive and self-collection screening options for chlamydia and gonorrhea are acceptable in asymptomatic women, but pelvic examination, including visual inspection, speculum examination, and bimanual examination, is required in the presence of symptoms to rule out pelvic inflammatory disease or tubo-ovarian abscess (strong, low). 8) No pelvic examination is required prior to prescription of hormonal contraception in a healthy woman with no gynaecologic symptoms (strong, low).

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Dear Editor, Adamantiades-Behçet's disease (ABD) is an inflammatory disease classified as vasculitis, which was originally diagnosed in patients with aphthous stomatitis, genital ulcerations, and ocular manifestations. However, any organ or system may be involved, particularly the central and peripheral nervous systems, joints, as well as the gastrointestinal tract. The etiology of ABD is still not fully understood, but some evidence indicates that an autoimmune process could be triggered by an infectious or environmental agent specific for the geographic region (1). Although BD can occur worldwide, it is most prevalent in the region along the ancient commercial route called the "Silk Road". In Italy, studies on the precise prevalence of ABD are lacking (2). As there are no specific diagnostic laboratory tests or histopathologic findings which confirm the preliminary diagnosis, the final diagnosis should be based on clinical criteria (3). Skin and mucosae are the target organs of this disease, and therefore their involvement has been considered in the numerous diagnostic criteria developed over the years (4). The first most important and popular criteria were created in 1990 by the International Study Group (ISG) (5). Because of their low sensitivity, the new International Criteria for Behçet's Disease (ICBD) were established, and were presented at the International Conference of Behçet's Disease in Lisbon in 2006 (6,7). In 2014, the International Team for the Revision of the International Criteria for BD submitted new criteria assigning 2 points to ocular lesions, oral aphthosis, and genital aphthosis, and 1 point to skin lesions, central nervous system involvement, and vascular manifestations. The pathergy test, when used, was assigned 1 point. A patient scoring ≥4 points is classified as having BD (8). We performed a single center, case-control study on a cohort of patients of Friuli Venezia Giulia, enrolled from January 2010 to September 2015 in the Dermatology Unit of the University of Trieste. The aim was to analyze the clinical features and compare the sensitivity, specificity, and accuracy of the three diagnostic criteria for ABD presented above in patients born in this particular region which is located at the very start of the "Silk Route". We enrolled 153 consecutive patients (74 cases and 79 controls) in the study. The characteristics and clinical features of patients and controls are summarized in Table 1. The most common diagnoses in the control group were recurrent oral aphtosis, lichen planus, mucous-membrane pemphigoid, and lupus erythematosus. The inclusion criterion was the presence of at least one principal clinical feature of ABD (oral aphtosis, genital aphtosis, skin lesions, ocular involvement) properly recorded in clinical records. Patient recruitment was done in a consecutive manner. Exclusion criteria were incomplete clinical records and absence of follow-up data. The diagnosis of ABD was established by expert dermatologists, without the use of any particular diagnostic criterion. For ABD, diagnosis agreement among dermatologists was required. The study was conducted according to the Declaration of Helsinki protocols. Possible associations between categorical variables were detected by the use of Fisher's exact test or Pearson χ2 test, depending on the sample size. Logistic regression was performed in order to identify which symptoms are of higher impact in the diagnosis of ABD. A comparison in terms of sensitivity, specificity, and accuracy among the three diagnostic criteria (ISG 1990, ITR 2006, and ITR 2014) was performed. The receiver operator characteristic (ROC) curve was obtained for each diagnostic criterion. Data were produced with a 95% confidence interval; P values &lt;0.05 were considered statistically significant. Statistical analysis was done using Stata SE12 software (Stata Corporation, Tx, USA). According to our data, patients with ABD had a significantly lower age at diagnosis compared with controls (P=0.0001); this was confirmed for both men (P=0.0006) and women (P=0.004). The presence of oral aphtosis was not necessarily pathognomonic of ABD (P=0.005) as it was found in 97.3% of patients with ABD and in 83.5% of controls. Genital aphtosis was directly associated with ABD diagnosis (P&lt;0.001), as it was present in 79.7% of patients with ABD, but in only 8.9% of controls. Furthermore, even skin manifestations and ocular lesions were observed at different rates in patients with ABD and controls (P&lt;0.001 and P=0.003, respectively). The presence of pseudofolliculitis was significantly more frequent in patients than in controls (P&lt;0.001), whereas erythema nodosum and skin aphtosis did not differ considerably between ABD and controls. Joint manifestations were as common in patients with ABD as in controls (P=0.6): arthralgia and arthritis alone do not indicate a diagnosis of ABD. Neurological symptoms as well as vascular involvement, if present, can be suggestive of ABD, but their absence does not exclude an ABD diagnosis (P=0.06 and P=0.04). Positive pathergy tests and positive HLA B51 tests were significantly more frequent in patients than in controls (P=0.007 and P=0.009, respectively), although if negative they did not exclude a diagnosis of ABD. Logistic regression showed that genital aphtosis (odds ratio (OR)=12948, P&lt;0.001), neurological manifestations (OR=819.263, P=0.001), vascular manifestations (OR=240.2573, P=0.001), cutaneous manifestations (OR=104.5625, P=0.002), oral aphtosis (OR=145.3229, P=0.004), and younger age at diagnosis (OR=0.8950334, P=0.000) were associated with ABD diagnosis (Table 2). There was no single pathognomonic symptom of ABD. We found that the ITR criteria -both from 2006 and 2014 - had a higher sensitivity (98.7% and 100%, respectively), specificity (94.9% and 97.9%, respectively), and accuracy (96.7% and 98.7%, respectively) compared with the ISG 1990 criterion, which scored 66% sensitivity, 100% specificity, and 83.7% accuracy. Area Under Roc Curve (AUC) was significantly different between ISG 1990 and ITR 2006 and between ISG 1990 and ITR 2014 (Figure 1). Even though no statistically significant difference was found between the ITR 2014 and ITR 2006 criteria, the former had a better performance according to our records. The clinical features reported in our retrospective case-control study are comparable to data found in the literature from European and international reports. A recent study (8) found a similar organ involvement percentage to our study, although we found a higher prevalence of HLA B51 positive patients and a lower percentage of ocular manifestations in our records. The results of the logistic regression performed based on our records indicate genital aphtosis, oral aphtosis, ocular involvement, neurological signs, and vascular features are more strongly linked to the diagnosis of ABD. According to our data, the presence of oral aphtosis is not paramount for the diagnosis of ABD, which fits well with the intent of the ITR 2006 and 2014 diagnostic criteria. The new ITR 2014 criteria added neurological signs to the diagnostic symptoms of ABD, emphasizing the importance of a multidisciplinary approach to patients suspected to have ABD.

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<bObjective:</b To observe the effects of basic fibroblast growth factor (bFGF), hepatocyte growth factor (HGF), and vascular endothelial growth factor C (VEGF-C) on the differentiation of bone marrow mesenchymal stem cells (BMSCs) into lymphatic endothelial cells (LECs). <bMethods:</b The third to the fifth passage of BMSCs of rats were collected for the following experiments. (1) BMSCs of rats were collected and divided into negative control group, CD90 group, CD44 group, and CD34 group according to the random number table (the same grouping method below), with 3 samples in each group. Phosphate buffer of 5 μL was added to cells in negative control group, and cells in the other 3 groups were added with 5 μL corresponding antibodies respectively. The positive expression of cell surface antigen was detected by flow cytometer. (2) BMSCs of rats in 3 batches were collected and divided into blank control group, VEGF-C group, HGF group, bFGF group, VEGF-C+ HGF group, VEGF-C+ bFGF group, HGF+ bFGF group, and VEGF-C+ HGF+ bFGF group, with 3 samples in each group. Cells in blank control group were added with 2 mL complete medium, cells in VEGF-C group were added with 2 mL complete medium and 10 μL VEGF-C of 10 μg/mL, cells in HGF group were added with 2 mL complete medium and 16 μL HGF of 10 μg/mL, and cells in bFGF group were added with 2 mL complete medium and 20 μL bFGF of 1 μg/mL. Cells in VEGF-C+ HGF group, VEGF-C+ bFGF group, HGF+ bFGF group, and VEGF-C+ HGF+ bFGF group were added with 2 mL complete medium and induction factors with corresponding concentration and volume as above. On 10 d of culture, the morphology of the cells was observed by the inverted phase contrast microscope, and the protein and mRNA expressions of lymphatic vessel endothelial hyaluronic acid receptor 1 (LYVE-1), VEGF receptor 3 (VEGFR3), and integrin α9 were detected by Western blotting and real-time fluorescent quantitative reverse transcription polymerase chain reaction respectively. (3) BMSCs of rats were collected and divided into blank control group, HGF+ VEGF-C+ bFGF group, bFGF+ VEGF-C+ HGF group, and VEGF-C+ HGF+ bFGF group, with 3 samples in each group. Cells in blank control group were added with 2 mL complete medium. Cells in HGF+ VEGF-C+ bFGF group were added with 2 mL complete medium, 16 μL HGF of 10 μg/mL, and 10 μL VEGF-C of 10 μg/mL, after 6 hours, 20 μL bFGF of 1 μg/mL was added. Cells in bFGF+ VEGF-C+ HGF group were added with 2 mL complete medium, 20 μL bFGF of 1 μg/mL, and 10 μL VEGF-C of 10 μg/mL, after 6 hours, 16 μL HGF of 10 μg/mL was added. Cells in VEGF-C+ HGF+ bFGF group were simultaneously added with 2 mL complete medium and the same concentration and volume of three inducing factors as above. In addition, BMSCs of rats in another 2 batches were collected and grouped, and they were dealt with the same methods as above except that the interval time of 6 hours in HGF+ VEGF-C+ bFGF group and bFGF+ VEGF-C+ HGF group was adjusted to 12 and 24 hours. On 10 d of culture, protein expressions of LYVE-1, VEGFR3, and integrin α9 were detected by Western blotting. Data were processed with analysis of variance of factorial design, one-way analysis of variance, and least significant difference <it</i test, and Bonferroni correction. <bResults:</b (1) The positive expression rates of surface antigen of cells in negative control group, CD90 group, CD44 group, and CD34 group were 0.39%, 99.84%, 99.90%, and 0.57%, respectively. (2) On 10 d of culture, cells in blank control group, HGF group, bFGF group, and HGF+ bFGF group presented long fusiform, while cells in the other groups presented polygonal shape. (3) On 10 d of culture, there were no protein expressions of LYVE-1, VEGFR3, and integrin α9 in cells of blank control group, HGF group, bFGF group, and HGF+ bFGF group. On 10 d of culture, protein expressions of LYVE-1, VEGFR3, and integrin α9 in cells of VEGF-C+ HGF+ bFGF group were significantly higher than those in VEGF-C group (<it</i=24.21, 11.04, 15.43, <iP</i&lt;0.01), VEGF-C+ HGF group (<it</i=10.81, 9.93, 10.20, <iP</i&lt;0.01), and VEGF-C+ bFGF group (<it</i=11.67, 6.32, 19.00, <iP</i&lt;0.01). Protein expressions of LYVE-1 in cells of VEGF-C+ HGF group and VEGF-C+ bFGF group were significantly higher than the protein expression in VEGF-C group (<it</i=8.69, 15.20, <iP</i&lt;0.01). Protein expression of VEGFR3 in cells of VEGF-C+ bFGF group was obviously higher than the protein expressions in VEGF-C group and VEGF-C+ HGF group (<it</i=8.67, 7.21, <iP</i&lt;0.01). Protein expression of integrin α9 in cells of VEGF-C+ HGF group was obviously higher than the protein expressions in VEGF-C group and VEGF-C+ bFGF group (<it</i=8.80, 8.83, <iP</i&lt;0.01). (4) On 10 d of culture, there were no mRNA expressions of LYVE-1, VEGFR3, and integrin α9 in cells of blank control group, HGF group, bFGF group, and HGF+ bFGF group. On 10 d of culture, mRNA expressions of LYVE-1 and VEGFR3 in cells of VEGF-C group were significantly lower than those in VEGF-C+ bFGF group and VEGF-C+ HGF+ bFGF group (<it</i(LYVE-1)=6.22, 18.01, <it</i(VEGFR3)=8.49, 15.34, <iP</i&lt;0.01), and mRNA expression of integrin α9 were significantly lower than that in VEGF-C+ HGF group and VEGF-C+ HGF+ bFGF group (<it</i=13.24, 9.65, <iP</i&lt;0.01). The mRNA expressions of LYVE-1, VEGFR3, and integrin α9 in cells of VEGF-C+ HGF+ bFGF group were obviously higher than those in VEGF-C+ HGF group and VEGF-C+ bFGF group (<it</i=13.92, 11.95, 13.72, 5.27, 5.64, 9.10, <iP</i&lt;0.01). Compared with those of VEGF-C+ bFGF group, the mRNA expression of VEGFR3 of cells in VEGF-C+ HGF group was significantly lower (<it</i=6.91, <iP</i&lt;0.01), while the mRNA expression of integrin α9 of cells in VEGF-C+ HGF group was significantly higher (<it</i=11.69, <iP</i&lt;0.01). (5) On 10 d of culture at interval time of 6, 12, 24 h, there were no protein expressions of LYVE-1, VEGFR3, or integrin α9 in cells of blank control group. On 10 d of culture at interval time of 6, 12, 24 h, the protein expressions of LYVE-1, VEGFR3, and integrin α9 in cells of HGF+ VEGF-C+ bFGF group, bFGF+ VEGF-C+ HGF group, and VEGF-C+ HGF+ bFGF group were close (<iF</i(6 h)=2.25, 2.47, 2.19, <iF</i(12 h)=2.93, 1.47, 3.25, <iF</i(24 h)=0.28, 0.20, 1.01, <iP</i&gt;0.05). <bConclusions:</b VEGF-C is a necessary factor for inducing BMSCs to differentiate into LECs. HGF and bFGF may promote the differentiation by up-regulating the expressions of integrin α9 and VEGFR3 respectively. But the induction effects of the two factors may be independent. The combination of VEGF-C, HGF, and bFGF have the best effects of promoting differentiation.

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PRIMARY OBJECTIVE: To determine whether chemoprophylaxis with hydroxychloroquine versus placebo increases time to contracting coronavirus disease 2019 (COVID-19) in frontline healthcare workers. 1) To determine whether chemoprophylaxis with daily versus weekly dosing of hydroxychloroquine increases time to contracting COVID-19 disease in frontline healthcare workers. 2) To compare the number of COVID-19 cases between each trial arm on the basis of positive tests (as per current clinical testing methods and/or serology) 3) To compare the percentage of COVID-19 positive individuals with current testing methods versus serologically-proven COVID-19 in each trial arm 4) To compare COVID-19 disease severity in each trial arm 5) To compare recovery time from COVID-19 infection in each trial arm EXPLORATORY OBJECTIVES: 1) To determine compliance (as measured by trough pharmacokinetic hydroxychloroquine levels) on COVID-19 positive tests 2) To determine if genetic factors determine susceptibility to COVID-19 disease or response to treatment 3) To determine if blood group determines susceptibility to COVID-19 disease 4) To compare serum biomarkers of COVID-19 disease in each arm TRIAL DESIGN: Double-blind, multi-centre, 2-arm (3:3:2 ratio) randomised placebo-controlled trial PARTICIPANTS: National Health Service (NHS) workers who have direct patient contact delivering care to patients with COVID-19. Participants in the trial will be recruited from a number of NHS hospitals directly caring for patients with COVID-19. To be included in the trial the participant MUST: 1) Have given written informed consent to participate 2) Be aged 18 years to 70 years 3) Not previously have been diagnosed with COVID-19 4) Work in a high-risk secondary or tertiary healthcare setting (hospitals accepting COVID-19 patients) with direct patient-facing care EXCLUSION CRITERIA: The presence of any of the following will mean participants are ineligible: 1) Known COVID-19 positive test at baseline (if available) 2) Symptomatic for possible COVID-19 at baseline 3) Known hypersensitivity reaction to hydroxychloroquine, chloroquine or 4-aminoquinolines 4) Known retinal disease 5) Known porphyria 6) Known chronic kidney disease (CKD; eGFR&lt;30ml/min) 7) Known epilepsy 8) Known heart failure or conduction problems 9) Known significant liver disease (Gilbert's syndrome is permitted) 10) Known glucose-6-phosphate dehydrogenase (G6PD) deficiency 11) Currently taking any of the following contraindicated medications: Digoxin, Chloroquine, Halofantrine, Amiodarone, Moxifloxacin, Cyclosporin, Mefloquine, Praziquantel, Ciprofloxacin, Clarithromycin, Prochlorperazine, Fluconazole 12) Currently taking hydroxychloroquine or having a clinical indication for taking hydroxychloroquine 13) Currently breastfeeding 14) Unable to be followed-up during the trial 15) Current or future involvement in the active treatment phase of other interventional research studies (excluding observational/non-interventional studies) before study follow-up visit 16) Not able to use or have access to a modern phone device/web-based technology 17) Any other clinical reason which may preclude entry in the opinion of the investigator INTERVENTION AND COMPARATOR: Interventions being evaluated are: A) Daily hydroxychloroquine or B) Weekly hydroxychloroquine or C) Placebo The maximum treatment period is approximately 13 weeks per participant. Hydroxychloroquine-identical matched placebo tablets will ensure that all participants are taking the same number and dosing regimen of tablets across the three trial arms. There is no variation in the dose of hydroxychloroquine by weight. The dosing regimen for the three arms of the study (A, B, C) are described in further detail below. Arm A: Active Hydroxychloroquine (- daily dosing and placebo-matched hydroxychloroquine - weekly dosing). Form: Tablets Route: Oral. Dose and Frequency: Active hydroxychloroquine: Days 1-2: Loading phase - 400mg (2 x 200mg tablets) taken twice a day for 2 days Days 3 onwards: Maintenance Phase - 200mg (1 x 200mg tablet) taken once daily, every day for 90 days (~3 months) Matched Placebo hydroxychloroquine: Days 3 onwards: Maintenance Phase - 2 tablets taken once a week on the same day each week (every 7<supth</sup day) for 90 days (~3 months) Arm B: Active Hydroxychloroquine (- weekly dosing and placebo matched hydroxychloroquine - daily dosing.) Form: Tablets Route: Oral. Dose and Frequency: Active hydroxychloroquine: Days 1-2: Loading Phase - 400mg (2 x 200mg tablets) taken twice daily for 2 days Days 3 onwards: Maintenance Phase - 400mg (2 x 200mg tablets) taken once a week on the same day each week (every 7<supth</sup day) for 90 days (~3 months) Matched Placebo hydroxychloroquine: Days 3 onwards: Maintenance Phase - 1 tablet taken once daily for 90 days (~3 months) Arm C: Matched placebo Hydroxychloroquine (- daily dosing and matched placebo hydroxychloroquine - weekly dosing.) Form: Table. Route: Oral. Frequency: Matched placebo hydroxychloroquine - daily dosing: Days 1-2: Loading Phase - 2 tablets taken twice daily for 2 days Days 3 onwards: Maintenance Phase - 1 tablet taken once daily for 90 days (~3 months) Matched placebo hydroxychloroquine - weekly dosing: Days 3 onwards: Maintenance Phase - 2 tablets taken once a week on the same day each week (every 7th day) for 90 days (~3 months) A schematic of the dosing schedule can be found in the full study protocol (Additional File 1). Time to diagnosis of positive COVID-19 disease (defined by record of date of symptoms onset and confirmed by laboratory test) RANDOMISATION: Participants will be randomised to either hydroxychloroquine dosed daily with weekly placebo, HCQ dosed weekly with daily placebo, or placebo dosed daily and weekly. Randomisation will be in a 3:3:2 ratio [hydroxychloroquine-(daily), hydroxychloroquine-(weekly), placebo], using stratified block randomisation. Random block sizes will be used, and stratification will be by study site. Participants and trial investigators consenting participants, delivering trial assessments and procedures will be blinded to intervention. A sufficient number of participants will be enrolled so that approximately 1000 participants in total will have data suitable for the primary statistical analysis. It is anticipated that approximately 1,200 participants will need to be enrolled in total, to allow for a 20% dropout over the period of the trial. This would result in approximately 450:450:300 participants randomised to hydroxychloroquine daily, hydroxychloroquine weekly+daily matched placebo or matched-placebo daily and weekly. V 1.0, 7<supth</sup April 2020 EU Clinical Trials Register EudraCT Number: 2020-001331-26 Date of registration: 14<supth</sup April 2020 Trial registered before first participant enrolment. Trial site is Cambridge University Hospitals NHS Foundation Trust. Recruitment started on 11<supth</sup May 2020. It is anticipated that the trial will run for 12 months. The recruitment end date cannot yet be accurately predicted. The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest 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. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

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Announcement of schizophrenia diagnostic to the patients is a topical issue in France. The evolution in clinical practices, a better efficiency in therapeutic procedures and the fundamental right of the patient to obtain information have initialised the discussion of its interest. Spontaneous claim for information from the patient is rarely observed although awareness troubles might be reported at the instauration of the mental disorder or during its evolution. Methodological studies concerning the diagnostic announcement are limited. Except the Bayle studies recently published, only a few publications are available in France about the knowledge of their pathology and their need to be clearly informed. French scientific literature deals generally about medico-legal aspects of this information and consisted of survey about diagnostic announcement. International literature is more abundant and presents positive and negative aspects of the announcement. An information procedure of schizophrenia announcement to the patient has been developed in our hospitalisation unit of psychiatry. This procedure has taken place on the basis of the literature data, our specificity and our clinical experiences. For some Anglo-American psychiatrists who have proceeded to semi-structured interview in order to announce the diagnostic, information to the patients might improve the clinical relationship. Thus, compliance to the treatment is significantly increased. The ability of the patient to recognise the symptoms of the disease and to accept their consequences and the treatments is associated to a better social prognosis, daily activities and response to the treatment. The announcement impact justifies the prescription of neuroleptics, treatment that is notoriously perceived as prejudicial by the patients themselves or more commonly in the basic population. To obtain compliance to the treatment, a satisfactory acceptance of the mental disorder is required. Compliance is based on satisfactory information in order to gain the cooperation of the patient and its relative (10). Atkinson has classified four main types of arguments, the ethical principle to be informed, talk to explain and give sense to the symptoms, reduce the feeling of guilt perceived by the patient and his relative and enhance the collaboration between the patient and the nursing staff. According to Ferreri and Bayle studies French psychiatrists reluctance to announce schizophrenia diagnostic are the following: lack of request or of interrogations asked by the patient about their disease, diagnostic and prognosis uncertainty and irreversibility of the disease, complexity of the pathology and its origin which hinder an accessible explanation, cognitive disorders frequently observed with schizophrenic patients which may be associated with difficulties of understanding information, destabilization of the patient-nursing staff relationship and social stigmatisation risks. Other arguments like reluctance to give a "label" to the disease, too abstract diagnostic, a negative social vision and the possibility of discouragement for the relative are classically retrieved in French literature. In fact, divulgation of the term schizophrenia involves a panel of negative representations and is hindered by the confusion in the social imagination of such a term related with lost of control, quintessence of madness, dangerous behaviour possibilities, evil and incurability. Some psychiatrists do not transmit information arguing that significant obstruction of the future may be consecutive to the information. They prefer to use vague terms more socially acceptable like "nervous breakdown or depression, atypical or emotional disorder, dissociative troubles...". Information to the patient about his mental disorder is more frequent in psychiatry for affective, anxious and additive troubles than for schizophrenia. Our procedure of diagnostic announcement has been elaborated after preliminary discussion with the medical and nursing staff. Diagnostic of schizophrenia announcement has been presented by weighing the pros and cons according to the intemational literature. It clearly appeared that benefits for the patients prevail on the drawbacks. Nevertheless, inclusion and clinical supervision have to be carefully precised in particular to verify the ability to receive information. Short term objectives: deliver progressively information to the patient about his disease by means of an active and educational process with hope and optimism using a accessible language (explanation of each terms used with the intention of being well understood); quantify the impact of diagnostic announcement on the schizophrenic patient using clinical rating scales during a period of one month (clinical interview at day 1, day 7 and day 28). Mid term objectives: improve the global supervision and autonomy of schizophrenic by means of a therapeutic project helping the patient to become an active partner in the monitoring of his mental disorder; enhance a psycho-educational program after the procedure of announcement in order to optimise the observance of his treatment, increase his quality of life and answer to the requests of his relative; 45 patients (age 29.3 +/- 8.8 years old) have been included to be informed on their diagnostic since the elaboration of this procedure during a time period of 24 months. Time interval between the beginning of their pathology and the delivering of this information was 4.7 years. Most of them (56%) presented a paranoid type of schizophrenia. In most of the cases, the patients did not know their diagnostic or declared suffering from a diagnostic, which was erroneous; 80% of the 45 patients have complied with the procedure until its end. On more than 24 of following after the instauration of the diagnostic announcement procedure, these patients ha ve presented satisfactory observance to the medical supervision (medical consultation and drug intake); 60% of the patients were regularly present to their medical appointment. The number of patients included (45 patients) appears small compared to the time interval of the study (24 months) but was significant according to the great changes in our clinical approach. Thus, this procedure was not systematically applied, in particular the patients who did not want to be informed on their disease. Is it clinically relevant or not to announce diagnostic of schizophrenia to the patient? This issue remains questioned according to the few studies published at the present time, any consensus has been clearly presented on formal indications or contra-indications. If on an ethical side, this information appears logical, the medical and nursing staff should require special care. Special care must be taken before delivering information to the patients; each situation must be evaluated in order not to comply with an ideology of total and inadequate information, which could have serious consequences. Nevertheless, it appeared clearly that information must be given to stabilized patients with satisfactory insight. Moreover, psychotherapeutic projects become easier because patients awareness and understanding towards pathological symptoms are greatly improved. Partnership between patient and medical staff is the key of this dynamic and psycho-educative procedure, which opens new horizons in our therapeutic prospect.

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One of the most continually vexing problems in society is the variability with which citizens support endeavors that are designed to help a great number of people. In this article, we examine the twin roles of cooperative and antagonistic behavior in this variability. We find that each plays an important role, though their contributions are, understandably, at odds. It is this opposition that produces seeming unpredictability in citizen response to collective need. In fact, we suggest that careful consideration of the research allows one to often predict when efforts to provide a collectively beneficial good will succeed and when they will fail. To understand the dynamics of participation in response to collective need, it is necessary to distinguish between the primary types of need situations. A public good is an entity that relies in whole or in part on contributions to be provided. Examples of public goods are charities and public broadcasting. Public goods require that citizens experience a short-term loss (of their contribution) in order to realize a long-term gain (of the good). However, because everyone can use the good once it is provided, there is also an incentive to not contribute, let others give, and then take advantage of their efforts. This state of affairs introduces a conflict between doing what is best for oneself and what is best for the group. In a public goods situation, cooperation and antagonism impact how one resolves this conflict. The other major type of need situation is a common-pool resource problem. Here, a good is fully provided at the outset, and citizens may sample from it. The resource is usually, but not necessarily, partially replenished. Examples of replenished resources are drinking water and trees; examples of resources that are functionally not replenished are oil and minerals. Common-pool resources allow citizens to experience a short-term gain (by getting what they want in the early life of the resource) but also present the possibility of a long-term loss (if the resource dries up). As with public goods, there is thus a conflict between, on the one hand, acting in one's best interest and taking as much as one wants all the time and, on the other, acting for the good of the group, which requires taking a lesser amount so that the replenishment rate can keep up with the rate of use. As with public goods, both cooperation and antagonism affect this decision. With these situations in mind, we can now dig deeply into the dynamics of both cooperation and antagonism. Cooperation is one of the most heavily studied aspects of human behavior, yet despite this attention, there is much that is not understood about it, including its fundamental base. There are a number of different perspectives on the base. Interdependence theory argues that cooperation is driven by how one interprets the subjective value of the outcomes that will result from various combinations of behaviors. A person who sees a potential result of "50 to you, 50 to me" as "We both would do well" is more likely to cooperate than the person who sees it as "I would not outgain the other person." Self-control theory suggests that cooperation is a function of how well a person can resist the impulse to benefit now and delay gratification. Evolutionary theory takes many forms but revolves around the extent to which cooperation is adaptive. Finally, the appropriateness framework takes a cognitive approach and assumes that cooperation is determined by a combination of social-cognitive (interpretation of self and the situation) and decision-heuristic factors. We propose that it is possible to integrate across these approaches and understand cooperation as a behavior that is influenced by all of these factors as well as other dynamics, such as cultural mores and personality traits. Antagonism, as it relates to the collective welfare, is a phenomenon with a lesser history but one that is clearly influential. A number of facets of antagonism are relevant. Power, and its abuse, is a major factor, and a specific application to collective goods is the notion of a "gatekeeper," or a person who can completely determine whether a public good exists or a common-pool resource can be used. Gatekeepers tend to demand ample compensation from others in order for the good or resource to go forward. If this demand is resisted, as it often is, the end result is that the good is not provided or the resource not accessed. Another facet is the desire to see an out-group be harmed. Sometimes, this motivation is so strong that people will deny themselves a good outcome in order to see the harm occur. Why someone would want to see an out-group be harmed is debatable, but it may be attributable to a desire to be seen as a winner, or it may be a strategy designed to produce a net benefit for one's in-group. Emotions also play a role, with people tending to assume that out-group members have just basic emotions such as happiness and sadness and not secondary emotions such as guilt and shame. Because out-group members are emotionally simple, it is seen as acceptable to treat them badly. Complicating matters even further is that antagonism can sometimes be seen against in-group members who deviate, in either direction, from the group norm and against individuals who are behaving in a clearly selfless manner, like volunteers. A number of approaches have been proposed to the resolution of public goods problems. Structural solutions act to alter the basic dynamic of the dilemma by means of interventions such as rewards for cooperation, punishment for noncooperation, and selection of a single group member to chart a course of action for everyone. Third-party solutions involve the bringing in of an external agent to help determine how group members should behave. These agents may be more passive and merely suggest solutions, or they may be more active and dictate how decisions will be made, what decision will be made, or both. Finally, psychological solutions involve changing how people view the situation. We finish by discussing how policy makers can improve the chances of a publicly valuable good being supported. We particularly emphasize creation of a felt connection with future generations; clear demonstration of immediate and concrete consequences as a result of failure to provide the good; instillation of a sense of community; and isolation of the good from other, related issues. We also take up the general problem of distrust of those who establish policy and discuss some methods for helping minimize distrust.

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To describe the needs and evidence-based practice specific to care of the pregnant adolescent in Canada, including special populations. Healthy pregnancies for adolescent women in Canada, with culturally sensitive and age-appropriate care to ensure the best possible outcomes for these young women and their infants and young families, and to reduce repeat pregnancy rates. Published literature was retrieved through searches of PubMed and The Cochrane Library on May 23, 2012 using appropriate controlled vocabulary (e.g., Pregnancy in Adolescence) and key words (e.g., pregnancy, teen, youth). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. Results were limited to English or French language materials published in or after 1990. Searches were updated on a regular basis and incorporated in the guideline to July 6, 2013. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, national and international medical specialty societies, and clinical practice guideline collections. 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). BENEFITS/HARMS/COSTS: These guidelines are designed to help practitioners caring for adolescent women during pregnancy in Canada and allow them to take the best care of these young women in a manner appropriate for their age, cultural backgrounds, and risk profiles. 1. Health care providers should adapt their prenatal care for adolescents and offer multidisciplinary care that is easily accessible to the adolescent early in the pregnancy, recognizing that adolescents often present to care later than their adult counterparts. A model that provides an opportunity to address all of these needs at one site may be the preferred model of care for pregnant adolescents. (II-1A) 2. Health care providers should be sensitive to the unique developmental needs of adolescents through all stages of pregnancy and during intrapartum and postpartum care. (III-B) 3. Adolescents have high-risk pregnancies and should be managed accordingly within programs that have the capacity to manage their care. The unique physical risks of adolescent pregnancy should be recognized and the care provided must address these. (II-1A) 4. Fathers and partners should be included as much as possible in pregnancy care and prenatal/infant care education. (III-B) 5. A first-trimester ultrasound is recommended not only for the usual reasons for properly dating the pregnancy, but also for assessing the increased risks of preterm birth. (I-A) 6. Counselling about all available pregnancy outcome options (abortion, adoption, and parenting) should be provided to any adolescent with a confirmed intrauterine gestation. (III-A) 7. Testing for sexually transmitted infections (STI) (II-2A) and bacterial vaginosis (III-B) should be performed routinely upon presentation for pregnancy care and again in the third trimester; STI testing should also be performed postpartum and when needed symptomatically. a. Because pregnant adolescents are inherently at increased risk for preterm labour, preterm birth, and preterm pre-labour rupture of membranes, screening and management of bacterial vaginosis is recommended. (III-B) b. After treatment for a positive test, a test of cure is needed 3 to 4 weeks after completion of treatment. Refer partner for screening and treatment. Take the opportunity to discuss condom use. (III-A) 8. Routine and repeated screening for alcohol use, substance abuse, and violence in pregnancy is recommended because of their increased rates in this population. (II-2A) 9. Routine and repeated screening for and treatment of mood disorders in pregnancy is recommended because of their increased rates in this population. The Edinburgh Postnatal Depression Scale administered in each trimester and postpartum, and more frequently if deemed necessary, is one option for such screening. (II-2A) 10. Pregnant adolescents should have a nutritional assessment, vitamins and food supplementation if needed, and access to a strategy to reduce anemia and low birth weight and to optimize weight gain in pregnancy. (II-2A) 11. Conflicting evidence supports and refutes differences in gestational hypertension in the adolescent population; therefore, the care usual for adult populations is supported for pregnant adolescents at this time. (II-2A) 12. Practitioners should consult gestational diabetes mellitus (GDM) guidelines. In theory, testing all patients is appropriate, although rates of GDM are generally lower in adolescent populations. Practitioners should be aware, however, that certain ethnic groups including Aboriginal populations are at high risk of GDM. (II-2A) 13. An ultrasound anatomical assessment at 16 to 20 weeks is recommended because of increased rates of congenital anomalies in this population. (II-2A) 14. As in other populations at risk of intrauterine growth restriction (IUGR) and low birth weight, an ultrasound to assess fetal well-being and estimated fetal weight at 32 to 34 weeks gestational age is suggested to screen for IUGR. (III-A) 15. Visits in the second or third trimester should be more frequent to address the increased risk of preterm labour and preterm birth and to assess fetal well-being. All caregivers should be aware of the signs and symptoms of preterm labour and should educate their patients to recognize them. (III-A) 16. It should be recognized that adolescents have improved vaginal delivery rates and a concomitantly lower Caesarean section rate than their adult counterparts. (II-2A) As with antenatal care, peripartum care in hospital should be multidisciplinary, involving social care, support for breastfeeding and lactation, and the involvement of children's aid services when warranted. (III-B) 17. Postpartum care should include a focus on contraceptive methods, especially long-acting reversible contraception methods, as a means to decrease the high rates of repeat pregnancy in this population; discussion of contraception should begin before delivery. (III-A) 18. Breastfeeding should be recommended and sufficient support given to this population at high risk for discontinuation. (II-2A) 19. Postpartum care programs should be available to support adolescent parents and their children, to improve the mothers' knowledge of parenting, to increase breastfeeding rates, to screen for and manage postpartum depression, to increase birth intervals, and to decrease repeated unintended pregnancy rates. (III-B) 20. Adolescent women in rural, remote, northern, and Aboriginal communities should be supported to give birth as close to home as possible. (II-2A) 21. Adolescent pregnant women who need to be evacuated from a remote community should be able to have a family member or other person accompany them to provide support and encouragement. (II-2A) 22. Culturally safe prenatal care including emotional, educational, and clinical support to assist adolescent parents in leading healthier lives should be available, especially in northern and Aboriginal communities. (II-3A) 23. Cultural beliefs around miscarriage and pregnancy issues, and special considerations in the handling of fetal remains, placental tissue, and the umbilical cord, must be respected. (III).

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Due to its accessible position and tissue heterogeneity, the eye is ideally suited for studying the lymphatic system. As early as the 19th century, questions about the origin and function of this system were discussed. For example, whether Schlemm's canal, which is of particular importance in the pathogenesis of glaucoma, is a lymphatic vessel, or does this vascular system begin with finger-shaped protuberances? Despite the discovery of lymphatic endothelial molecules and the use of molecular imaging technologies, these questions are still discussed controversially today. Leber demonstrated in 1873 with a solution consisting of two dyes of different particle size that only the smaller particles from the anterior chamber of the eye filled the episcleral and conjunctival veins around the corneal margin. He believed to have proven - to be read in the historical review of our article - that the Canalis Schlemmii in humans is a venous circular vessel and not a lymphatic vessel. In our own investigations, we reduced the rather contradictory and complex question of whether there are lymphatic vessels in the eye to the question of whether there are drainage connections between the different sections of the eye and the lymphatic system or not. With different radioactive tracers and combined with unilateral ligation of cervical lymph vessels, we observed outflow from the subconjunctival and retrobulbar space, from the anterior chamber and the vitreous body. The rate of discharge of the radioactive tracer was determined by the radiopharmaceutical and injection site. In analogy to the lymphatic drainage of the head we found a segmental drainage of lymphatic substances on the eye. Vitreous humour and retrobulbar space were drained by lymphatic vessels, predominantly to the deep cervical lymph nodes, while anterior chamber and subconjunctival space drains predominated over the superficial cervical lymph nodes. Eyeball tattoos - as loved by some fan communities - should therefore cause a coloured staining of the superficial cervical lymph nodes. The boundary of the drained segments would be in the area of the eyeball's equator. According to the textbooks, the lymph is actively removed from finger-shaped initial segments via pre-collectors and collectors with properly functioning intraluminal valves and smooth muscle cells in the vessels' media. In patients with spontaneous conjunctival bleeding, however, we observed phenomena in the conjunctival lymph vessels, which ca not be explained with old familiar ideas. At nozzle-shaped vessel constrictions separation of blood components occurred. The erythrocytes formed partially a so-called fluidic "resting bulk layer". Parallel vessel parts caused a retrograde filling of already emptied segments. These observations led our experimental investigations. In the literature, there are different scanning electron microscopy (SEM) images of lymphatic endothelial surfaces; nevertheless they are unassigned to a particular vessel segment. In the conjunctiva, we studied the question whether there is a dependence between vessel diameter and the surface characteristics of endothelial cells (after unfolding by lymphography). A constantly applied photo-mathematical procedure for all specimens allowed determining the size of the cross sections. The specimens were randomized into seven groups with diameters of 0.1-1.0mm and above and examined by SEM. In the smallest vessels (diameter=0.11mm), the impressions of the occasionally occurring nuclei in the lumen were clearly impressive. With increasing diameter, these impressions were lost and the individual endothelial nuclei could no longer be identified. Rather, one recognized only wall-like structures. In vessels of intermediate diameter (0.3-0.4mm), structures could be seen on the surface similar to reticular fibres. With increasing diameters, their prominent character weakened. In the group with diameters above 0.5mm, wavy surface structures were shown. Finally, in vessels of diameters over 1.0mm, a uniform, flat surface was observed. Regardless of the collection site of the specimens, we found certain surface characteristics related to the vessels' calibre. In further investigations by means of interstitial dye lymphography, we were able to demonstrate in the conjunctiva that under increasing injection pressure, additional vessels stained from finger-shaped processes. At least in the conjunctiva, the existence of so-called "blind-ending initial segments" seems doubtful (despite the fact that initial segments or "initial lymphatics" would begin in periphery, not end). Rather, these are likely to be temporary filling states. SEM investigations were carried out on the internal structure of these dome-shaped vessel parts by means of a specially developed preparation technique. Despite numerous variants in the lymphographic design of the blind bags - in the form of finger, balloon, dome, piston, pyramidal, double-humped and spearhead-like endings - slot-shaped, lip-shaped and saw blade-like structures were repeatedly found, similar to a zipper. These findings suggest preformed connections to the next segment and may control lymphatic flow. To clarify the retrograde fluid movements, we examined the lymph vessels' valves or those structures that were previously interpreted as valves. The different structures found could be subdivided into three groups. The lack of common bicuspid structures provides an explanation for retrograde fluid movement. That nevertheless a directional flow is possible, is explained by the flow model developed by Gerhart Liebau. Conjunctival lymphatics show intraluminal structures by double contrast injection, which we divided into four groups due to anatomical differences: An accurate statement about the occurrence of certain intraluminal vascular structures in certain vascular calibres was possible only conditionally. However, complex and extended structures (group d) were found almost exclusively in larger vessel calibres (diameter&gt;0.9mm). The structures are reminiscent of published findings in the "collector channel orifices of Schlemm's canal". They should play an important role in the regulation of the intraocular pressure, or the balance between production and outflow of the aqueous humour. The influence of such structures on the function of the lymphatic vessels is not yet known. As an approach models could be used, which for instance are applied in the water industry for the drainage, the degradation of introduced substances, or the detention pond. The latter serves for the retention and purification of drainage water (storage, treatment and reuse of drainage water). Dead zones, barriers, short-circuit currents and swirling are further hydraulic terms. Can intraluminal vascular structures, for example, affect the lymphatic flow and thus the mechano-sensitivity of lymphatic endothelial cells? Whatever interpretation model we use, the warning of the Swiss anatomist His from 1862 is still true today that all theories about the formation and movement of lymph should be based on precise anatomical basics. This review article therefore tries to make a contribution therefore. Despite knowing of lymphatic endothelial molecules, despite the discovery of the role of lymphangiogenic growth factors in diseases and the use of molecular imaging technologies, we still know too little about the anatomy and function of the lymphatic system.

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Moldy core is a fungal disease of apple fruits that is characterized by mycelial growth in the seed locules and is sometimes accompanied by penetration of the immediate surrounding flesh. The disease can go undetected until the fruit is cut open, as no external symptoms appear on the fruit. Alternaria, Aspergillus, Cladosporium, Coniothyrium, Epicoccum, Phoma and Stemphylium are some of the common pathogens associated with moldy core (Serdani et al. 2002; Gao et al. 2013; McLeod 2014). The disease is more common in apple cultivars with an open calyx, where spores may initiate infections during the growing season or at the post-harvest storage stage (Spotts et al. 1988). In 2018, a shipment of 'Sweet Tango' apples from New Zealand to Scotian Gold Co-operative Ltd., Nova Scotia, Canada, was found to be affected by moldy core. Moderate to severe moldy core symptoms were observed when 10 apples were cut open (Figure S1). In comparison, 'Sweet Tango' apples grown in Nova Scotia showed no moldy core symptoms when 10 random fruits were cut open. Small pieces of the diseased fruit tissue from the core region were surface-disinfected for 1 min in 1% NaOCl, rinsed three times with sterilized water and placed onto potato dextrose agar (PDA) dishes. The PDA dishes were incubated in dark at 22 oC and single spore isolation was carried out to fresh PDA dishes. These isolate produced colonies of regular shape, tan black with prominent white gray margin and gray colour conidia (Figure S2 AB). The colonies turn dark black after 3 weeks of growth on PDA. Mycelia were septate and conidia were oval or obclavate or club-shaped with a tapering end with 4-6 longitudinal and transverse septa (Figure S2 C-D). The size of conidia ranges from 12.5-20 x 8.7-12.5 µM on 20 days old PDA dishes. Based on the size and shape of conidia and other morphological characteristics the isolated fungi were identical to Alternaria spp. (Simmons 2007). To assess the identity of the isolated pathogen species by multi-locus sequence analysis, genomic DNA was extracted from the pure cultures of two isolates (5.8 and 8) using the E.Z.N.A. SP Fungal DNA Kit (Omega Bio-Tek). The glyceraldehyde-3-phosphate dehydrogenase (GAPDH), major allergen (Alt a 1), OPA10-2, the internal transcribed spacer (ITS) region of ribosomal DNA and the translation elongation factor 1-α (TEF1-α) region from two Alternaria spp. isolates (5.8 and 8) were amplified and sequenced using primers gpd1/2 (Berbee et al. 1999), A21F/A21R (Gabriel 2015), OPA10-2/ OPA10-2L (Andrew et al. 2009), ITS1/ITS4 (White et al. 1990) and EF1-up /EF1-low (O'Donnell et al. 1998) respectively. The resulting sequences of both isolates were deposited in the NCBI GenBank (GAPDH; MW411052, MW411053, Alt a 1; MW411050, MW411051, OPA10-2; MW415762, MW415763, ITS; MK140445, MT225559, TEF1-α; MT305773 and MT305774 ). Sequences of GAPDH, Alt a 1, OPA-10-2, ITS and TEF1-α genes of both isolates were identical to each other and showed 100 %, 100 %, 99.21 %, 100% and 100% identity to A. arborescens S. (AY278810.1, AY563303.1, KP124712.1, KY965831.1, KY965831.1) respectively. Identity with reference strain CBS 102605 confirms that both of the isolated strains 5.8 and 8 are A. arborescens. The pathogenicity of the two A. arborescens isolates were confirmed by artificially inoculating healthy 'Sweet Tango' fruit by dispensing the conidial suspension directly on the seed locule. Briefly, surface-disinfected fruits were air-dried for 5 min and then peeled using a sterilized knife and cut transversally. Each half of the fruit was inoculated with 100 µl of conidial suspensions (∼1 × 104 conidia/ml) in potato dextrose broth (PDB) and incubated at 22 °C in a humid chamber for 7-10 days, or until symptoms with visible mycelial growth were observed. The control fruits were treated with 100 µl of sterilized PDB. Both A. arborescens isolates produced visible moldy core symptoms on the inoculated 'Sweet Tango' fruits, whereas no symptoms were observed on the control fruits (Figure S1). The experiment was repeated three times with at least three replicates with similar results. A. arborescens was successfully re-isolated from the artificially-inoculated fruits to complete Koch's postulates. To our knowledge, this is the first report of Alternaria arborescens causing moldy core disease in 'Sweet Tango' apples from New Zealand. Acknowledgments We thank Eric Bevis for his help in sample preparation for DNA sequencing, Willy Renderos for pathogenicity assay. We also thank Joan Hebb (Scotian Gold Cooperative Ltd.,) for providing the apple sample for this study. This research was made possible through financial support from Agriculture and Agri-Food Canada. The authors(s) declare no conflict of interest. Literature Cited Andrew M., Peever T.L., Pryor B.M. An expanded multilocus phylogeny does not resolve species among the small-spored Alternaria species complex. 2009. Mycologia. 101:95-109. Berbee, M. L. et al. 1999. Cochliobolus phylogenetics and the origin of known, highly virulent pathogens, inferred from ITS and glyceraldehyde-3-phosphate dehydrogenase gene sequences Mycologia. 91:964. Gabriel, M.F. I. Postigo, A. Gutiérrez-Rodríguez, E. Suñén, C.T. Tomaz, J. Martínez 2015. Development of a PCR-based tool for detecting immunologically relevant Alt a 1 and Alt a 1 homologue coding sequences. Medical Mycology. 53 (6):636-642. Gao, L. L., Zhang, Q., Sun, X. Y., Jiang, L., Zhang, R., Sun, G. Y., Zha, Y. L., and Biggs, A. R. 2013. Etiology of moldy core, core browning, and core rot of Fuji apple in China. Plant Dis. 97:510-516. Kerry, O'Donnell, H.C. Kistler, E. Cigelnik, R.C. Ploetz. 1998. Multiple evolutionary origins of the fungus causing Panama disease of banana: concordant evidence from nuclear and mitochondrial gene genealogies. PNAS. 95: 2044-2049. McLeod, A. 2014. Moldy core and core rots. Pages 40-41 in: Compendium of Apple and Pear Diseases and Pests, 2nd ed. T. B. Sutton, H. S. Aldwinckle, A. M. Agnello, and J. F. Walgenbach, eds. American Phytopathological Society, St Paul, MN. Serdani, M., Kang, J. C., Peever, T. L., Andersen, B., and Crous, P. W. 2002. Characterization of Alternaria species groups associated with core rot of apples in South Africa. Mycol. Res. 106:561-569. Simmons, E. G. 2007. Alternaria: an identification manual. CBS Biodiversity Series. 6:780 pp. Spotts, R. A., Holmes, R. J., and Washington, W. S. 1988. Factors affecting wet core rot of apples. Australas. Plant Pathol. 17:53-57. White, T. J., Bruns, T., Lee, S., and Taylor, J. 1990. Amplification and direct sequencing of fungal ribosomal RNA genes for phylogenetics. Pages 315-322 in: PCR Protocols: A Guide to Methods and Applications. M. A. Innis, D. H. Gelfand, J. J. Sninsky, and T. J. White, eds. San Diego, CA: Academic Press. Woudenberg, J. H. C., et al. 2015. Alternaria section Alternaria: Species, formae speciales or pathotypes. Stud. Mycol. 82:1-21.

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Malaria was once one of the most common diseases in Uzbekistan. There were massive epidemics with high mortality rates, wherein 140,000 to 700,000 cases of malaria were recorded. Following large-scale malaria control measures, the disease was eradicated in Uzbekistan in 1961 and the epidemiological situation is still favorable. The natural and climatic conditions that prevail in the Republic of Uzbekistan mean that the country is very susceptible to malaria. There are large water areas varying in type and origin, which provide a habitat for a number of epidemiologically dangerous species of malaria-transmitting mosquitoes in a single area. These are Anopheles maculipennis, An. pulcherrimus and An. superpictus. The prevailing temperatures promote rapid growth of vector mosquitoes and parasites and the malaria transmission season is over 5 months long. Seven malaria-transmitting mosquito species have been recently recorded in the Republic. DDT resistance has been so far noted in Anopheles maculipennis, An. hyrcanus and An. bifurcatus. An. superpictus is sensitive to all insecticides used in clinical practice (organophosphorus and organochlorine compounds, HOS, carbamates, pyrethroids). The most dangerous areas for transmitting malaria by importation are the flood plains of the country's main rivers, such as Syrdarya, Amudarya, Chirchik, Surkhana, etc., and rice-growing areas (an area of about 150,000 ha was under rice cultivation in 1999). The Republic is still very subjected to large-scale importations of malaria particularly in the towns and areas along the border with Tajikistan. There has been recently an increase in the incidence of infections imported into the Republic: 27 cases in 1995, 51 in 1996, 52 in 1997, 74 in 1998, and 78 in 1999. Eight regions of Uzbekistan border Tajikistan, their population is over 5.6 million people. In addition, close family ties between the populations of the frontier towns and regions further increase the risk for malaria to be imported and passed on. Noteworthy is the Surkhandaryin region that accounted for 60% of the cases recorded in 1999. The number of towns and villages where malaria occurs for the first time increased (49 and 46 cases in 1999 and 1998, respectively). The number of cases imported into rural areas also increased (70 (83%) cases in 1999 versus 48 (65%) cases in 1998); due to the large populations of malaria mosquitoes, there is a real danger that the disease may spread. In 1999, most cases of malaria were imported from Tajikistan (65 cases or 76% of all cases). There was a case from each of the following countries: Afghanistan, Pakistan, and Kazakhstan and 5 cases from Azerbaijan and Kyrgyzstan. The recorded cases included slighly more men than women (54% vs 46%). There were 10 infected children under 14 years, which was 23.5% of all notified cases. Analyzing various populations showed that 67.1% of the patients visited their relatives in malaria-endemic countries (mostly Tajikistan) and 25.8% migrated from Tajikistan. All the detected cases were confirmed by laboratory tests. As in the past, most cases were tertian (P. vivax) malaria (n = 82 or 96.4% of all cases). Tropical (P. falciparum) malaria was confirmed in 3 (3.5%) cases. These cases had been imported from Tajikistan into the Surkhandaryin region. Seventy seven (91%) cases were detected in the epidemical season. Of them 58 (68.2%) cases were detected during a malaria transmission season. Seven cases who contacted the patients with imported malaria and were infected were recorded in 1999. They included 4 and 3 cases in the Surkhandaryin and Kashkadaryin Regions, respectively. In 1999, there was a decline in the number of malaria patients who needed health care and in the diagnosed malaria cases in therapeutical and prophylactic institutions. Throughout the country, 34 (40%) of the 85 detected cases presented within 3 days of malaria outbreak (68.9% in 1998). Malaria was immediate diagnosed in 43.5% of cases (64.9% in 1998). The remaining cases were diagnosed as having acute respiratory viral infections, tropical and parasitic diseases, viral hepatitis, or influenza. Early diagnosis of malaria was made in 60% of cases (77% in 1998). Three cases of imported tertian malaria were recorded in the Tashkent Region in the first quarter of 2000. They were imported from Tajikistan into rural areas and the patients had been infected during the 1999 season. Epidemiological surveillance of malaria in Uzbekistan is regularly carried out by the general network of health facilities and by the departments of parasitology of state epidemiological surveillance centers in collaboration with medical administrative departments, the Ministry of Agriculture and Fisheries, the L.M. Isayev Research Institute of Medical Parasitology, and other agencies. Active links are maintained with WHO under the Roll Back Malaria programme. Great emphasis is laid on medical staff training at all levels. During the 1999 epidemiological survey, 672,536 laboratory tests were performed on blood samples from suspected malaria patients and individuals who had visited malaria-endemic countries, 55% of them suffering from fever. A total area of 17 million m2 of dwelling and nondwelling buildings 20 ha of water areas were treated against mosquitoes and the larvivorous fish Gambusia was put into the water areas occupying 6,500 ha. In all cases of malaria, the focus of infection was epidemiologically surveyed and required epidemic preventive measures were implemented. All malaria patients received a full course of radical therapy and recovered completely. The epidemiological surveillance system for malaria is affected by staff shortages at the parasitology departments of state epidemiological surveillance centers and by shortages of microscopes, reagents, sterilizing equipment, insecticides, etc. There are still difficulties in obtaining supplies of primaquine although a small stock is locally available as due to WHO humanitarian assistance. The Epidemiological Malaria Surveillance Programme for the Republic of Uzbekistan for 2000-2004, intended to strengthen the epidemic control capacity of health care facilities, Ministry of Health, is under adoption. The following activities are scheduled for 2000: to plan malaria control activities, including the zoning of the country by the risk of malaria transmission in accordance with republic-leveled directives, instructions, and methodology and WHO recommendations: adjustments to these plans to be made as necessary; to fill vacant posts in the parasitology departments of state epidemiological surveillance centers; to procure stocks of antimalarial drugs, reagents, insecticides, sterilizing equipment, etc., to be paid for from epidemiological service resources; to include malaria issues into certifying tests for physicians, as appropriate for the posts to be occupied and their level of qualifications; to publish posters, brochures, and leaflets about malaria prevention before the malaria transmission season for health education; to hold seminars and meetings for health workers on the etiology of malaria, its clinical features, diagnosis, treatment, and prevention.

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Although the practice of western medicine in Ethiopia dates back to the time of King Libne Dengel (1520-1535), organized and sustainable modern medical practice started after the battle of Adwa (1896). To review hospitals construction, medical doctors production and attrition, and to suggest alternative medical doctors retention mechanisms in the public sector and production scale up options. In this article, 100 years Ethiopian modern medical history is revised from old and recent medical chronicles. Until December 2006 primary data was collected from 87 public hospitals. Much emphasis is given to medical doctors profile (1906-2006), hospitals profile (1906-2005), medical doctors to population and hospitals ratio (1965-2006), Ethiopian public medical schools 42 years attainment (1964-2006), annual attrition rate (1984-2006), organizational structure of medical faculties &amp; university hospitals, medical doctors remuneration by the Ministry of Health (MOH), Ministry of Education (MOE), NGOs and private health institutions. This article also addresses the way forward from physician training and retention perspectives, multiple alternate mechanisms to increase physicians' motivation to work in government institutions and reveres the loss. Medical doctors production scale up option is also given much emphasis. Most data are presented using line and bar graphs. Literature review showed that the first three hospitals were constructed in 1896 (Russian hospital), 1903 (Harar Ras Mekonnen hospital) and 1906 (Menelik II hospital). In 2005, 139 hospitals (87 public and 52 others) were reported. Remarkable hospital construction was done between 1935 and 1948, and recently between 1995 and 2005; however, in the latter case, private hospitals construction took the lions share. By the time MOH was established (1948), 110 Ethiopian and expatriate medical doctors were working, mainly in the capital, and 46 hospitals constructed. Physician number increment was very slow till 1980 at which time it started to get doubled every five years and reached peak (1658 medical doctors of all type) in 1989 in the public sector. As there was sharp increment in physician number, on the contrary, there was sharp decline in the last 15 years (1990-2006) to nadir 638 doctors in 2006 in the public sector. The last 25 years of Ethiopian modern medical history, in reference to physician number, forms a triangle with the lower and upper base 1980 and 2006, respectively. Since MOH of Ethiopia started registering health professionals with qualifications in 1987, 5743 (76.5% Ethiopian and 23.5% expatriate) medical doctors were registered for the first time. Out of these, 3717 were general practitioners. The three prestigious medical schools (Addis Ababa, Gondar, Jimma) were established in 1964, 1978 and 1984, respectively. Since establishment till 2006, about 3728 medical doctors were graduated with MD degree from the three medical schools. Addis Ababa university medical faculty alone graduated 1890 general practitioners (1964-2006) and 862 clinical specialists (1979-2006). In the 23 years period (1984-2006), the highest and lowest physician to population ratios in the public sector were found to be in 1989 (1:28,000) and 2006 (1:118,000), respectively. In 2006, the physician to population ratio in Amhara, Oromia and SNNPR regional states was computed to be 1:280,000, 1:220,000, and 1:230,000, respectively. The physician deficit analysis in the last 23 years in relation to the WHO standard for developing countries (1:10,000) revealed the lowest record at the national and regional states in the last 12-years. Average physician to hospital ratio in five regional states in December 2006 was 3.6 (Tigray), 4.3 (Amhara), 6.1 (Oromia) and 5.3 (SNNPR). As the December 2006 direct interview with 76 public hospitals outside Addis Ababa showed, there was no specialist in 36 hospitals and no doctor at all in 3 hospitals. Seven public hospitals located in big regional states' town took the lions share of medical doctors. In short, in December 2006, 80.3% of regional hospitals were equipped with 0-2 specialists of one kind, and in 48.7% there were 0-3 General practitioners. Highest medical doctors annual attrition rates (20%-54.3%) were found in 1991-1992, 1998, 2002-2006. In general, in 20 years period (1987-2006), 73.2% of Ethiopian medical doctors left the public sector mainly due to attractive remuneration in overseas countries and local NGOs/private sectors. The number of postgraduate programme in Addis Ababa, Jimma and Gondar medical schools in December 2006 was 22, 12 and 3, respectively. The total number of fully employed academic staff of the medical schools in declining order was Addis Ababa 181, Gondar 118, Jimma 71, Hawassa 63 and Mekele 52: those with second degree and above being 97.2%, 35.6%, 90.1%, 55.6% and 15.4%, respectively. Currently (2006), there are about 416 clinical residents in 3 medical schools. High annual attrition rate, fast population growth, governmental and nongovernmental health institution expansion, low production and increased postgraduate enrollment in the last 3-4 years contributed for extremely low physician-to-population ratio in Ethiopia. Although the Ethiopian government and private sector worked and achieved much on health infrastructure construction and midlevel health professionals training, it does not appear that medical doctors retention mechanisms are sorted out so far. As a result, even despite salary equivalent top up payments in some regions, more than 80% of public hospitals outside Addis Ababa were found ill-equipped with the most important human element--physicians. This implies that the push factors may not invariably correlate with remuneration. It is high time that the government discusses the possible solutions among health professional associations/societies and other health stakeholders, and apply concrete medical doctors retention mechanisms before the public medical schools and hospitals dry off doctors. Among actions to be undertaken from the current Ethiopian perspective: providing land plot for physicians for residential house construction, giving priority to physicians in providing low cost houses, low interest or interest free loan for residential house construction and automobile procurement, allowing duty free automobile procurement, improving the fully employed academic staff taxation system, approving the different remuneration options proposed, adopting the other countries experience of dual employment to academic staff working in teaching hospitals, modifying the academic rank promotion based on year of training, for university hospitals either establishing hospital organizational structure in the Ministry of Education or letting them be under MOH, establishing joint appointment (mutual beneficiary) agreement between medical schools and local hospitals, directing donors and stakeholders to work on the line of reducing internal and external medical doctors brain drain, making independent MOH and higher institutions from Civil Service Agency are proposed as short term solutions. Retention as a strategy &amp; production as a programme, medical doctors production scale up options are proposed as a long term solution to achieve physician to population ratio of 1:15,000. and 1:8,000 by the year 2015 and 2020, respectively.

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The objective of this review is to identify and appraise existing evidence regarding the effectiveness of interventions designed to enhance staff-family relationships for people with dementia living in residential aged care facilities.More specifically, the objectives are to identify the effectiveness of constructive communication, cooperation programs, and practices or strategies to enhance family-staff relationships. The effectiveness of these interventions will be measured by comparing the intervention to no intervention, comparing one intervention with another, or comparing pre- and post-interventions.Specifically the review question is: What are the most effective interventions for improving communication and cooperation to enhance family-staff relationships in residential aged care facilities? In our aging world, dementia is prevalent and is a serious health concern affecting approximately 35.6 million people worldwide. This figure is expected to increase two-fold by 2030 and three-fold by 2050. Although younger-onset dementia is increasingly recognized, dementia is most commonly a disease that affects the elderly. Among those aged 65 to 85, the prevalence of dementia increases exponentially, and doubles with every five-year increase in age.Dementia is defined as a syndrome, commonly chronic or progressive in nature, and caused by a range of brain disorders that affect memory, thinking and the ability to perform activities of daily living. While the rate of progression and manifestation of decline differs, all cases of dementia share a similar trajectory of decline. The progressive decline in cognitive functions and ultimately physical function that these people face affects not only the person with the disease but also their family caregivers and health care staff.The manifestation of dementia presents unique and extreme challenges for the family caregiver. Generally it causes great physical, emotional and social strain because the caregiving process is long in duration, unfamiliar, unpredictable and ambiguous. In the later stages of dementia, many family caregivers relocate their relative to a residential aged care facility, most often when the burden of care outweighs the means of the caregiver. This is especially likely when the person with dementia ages, and has lower cognitive function increased limitations in activities in daily living and poorer self-related health. As a result, approximately 50% of all persons aged 65 years or over admitted into residential aged care facilities have dementia.The relocation of a relative into a residential aged care facility can be complex and distressing for family caregivers. While relocation alleviates many issues for the family caregiver, it does not consequently reduce their stress. The stress experienced by the family caregivers who remain involved post-relocation often continues and may even worsen. This is because family caregivers are uncertain about how to transition from a direct caregiving role to a more indirect, supportive interpersonal role, and may be provided with little support from care staff in this regard. Although family caregivers experience a new form of stress post-relocation, family involvement in residential aged care settings has been shown to be beneficial to residents with dementia, their families and care staff.Family involvement is widely acknowledged to provide the resident physical and emotional healing, optimal well-being, and the sustainment of quality of life. Family caregivers benefit from improved satisfaction with the facility and experiences of care, and greater well-being. Care staff benefit from enhanced job satisfaction and greater motivation to remain in their job. The key to these positive outcomes is effective communication and strong relationships between care staff and family caregivers.Effective communication between care staff and family caregivers is crucial for residents with dementia. This is because residents with cognitive impairment may have difficulties articulating their needs, concerns and preferences effectively. Family caregivers rely on staff for information about their relative's behavior in the residential aged care facility; however they themselves have in-depth information about the resident's physical, psychosocial and emotional histories that are necessary for developing individualized care support plans. Family involvement can support care staff in reducing residents' behavioral symptoms by assisting to identify social and emotional needs, or unmet medical needs. Ineffective communication from family caregivers in conveying information to care staff may be disruptive in the caregiving process, and may lead to disagreement regarding respective roles and approaches to caring for the resident. Consequently, family caregivers may withhold information that may support care staff and improve care. They may also be concerned about negative repercussions for the resident.Care staff and family caregivers generally have differing needs and expectations. Care staff are usually in the position where they have to manage a relationship with the family, which is based on multiple roles. Perceptions of family caregivers by care staff include seeing them as colleagues, subordinates, or people who themselves may be in need of nursing care. These different perceptions lead to role ambiguity and result in separate approaches to the caregiving process.Cohen et al. suggest in their study that family involvement can benefit people with dementia in residential aged care settings, their family carers and staff; however further research is required. The relationship between care staff and family caregivers is often challenging due to problems with communication, role ambiguity of both care staff and family carers, and differing approaches to caring for the resident. These problems highlight the need for interventions to constructively enhance the quality of family-staff relationships. For example, one intervention called Partners and Caregiving has been reported as being designed to increase cooperation and effective communication between staff and family. In this study, staff and family members were randomly subjected to treatment and control conditions. The treatment group received parallel training sessions on communication and conflict resolution techniques, followed by a joint meeting with the facility administrators. The results of the study demonstrated improved outcomes in the form of improved attitudes of staff and family members towards each other, less conflict between family and staff, and fewer intentions of staff to quit. Further research is vital in order to identify effective family-staff intervention studies that can provide directions for implementation in residential aged care facilities. Furthermore, it is equally important to identify interventions that are ineffective, so as to provide insights into potential pitfalls to avoid in order to improve staff and family members' relationships and the provision of care to people living with dementia in the future.Previous systematic reviews have focused on factors associated with constructive family-staff relationships in caring for older adults in the institutional setting and the family's involvement in decision making for people with dementia in residential aged care facilites. This review will however specifically investigate interventions for improving communication and cooperation that promote effective family-staff relationships when caring for people with dementia living in residential aged care facilities.

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Congenital anomalies (CAs) represent one of the main cause of foetal death, infant mortality and morbidity, and long-term disability. CAs have been object of systematic registration activity for a long-time in many geographical areas in Europe and worldwide. CAs are often associated with disabilities of different types and severity, including the developed Countries worldwide. According to the World Health Organization (WHO), each year approximately 3,2 million of children worldwide are born with a CA and approximately 300,000 newborns with a diagnosis of birth defect die within the first 28 days of life. In Europe, CAs are the leading cause of perinatal mortality: the European Surveillance of Congenital Anomalies (EUROC AT) network estimated a perinatal mortality associated with CAs of 9.2 per 10,000 births in 2008-2012. In Italy, the Ministry of Health estimates that, on the average of 500,000 births each year, about 25,000 present at least one CA. Moreover, approximately 25% of infant mortality is due to CAs and about 50% of infant mortality is attributable to perinatal morbidity, almost always of prenatal origin. Regarding long-term survival, a recent population study conducted between 1985 and 2003 in the UK estimated a 20.5-year survival of 85.5% of children born with at least one CA. According to the Centre for Disease Control and Prevention, approximately 3.3% of live births in the United States have a severe birth defect. Since CAs represent a significant public health issue, an effective primary prevention strategy should be a priority for public policies and healthcare system. Regarding aetiology, although in many cases the cause is still unknown, it has been hypothesized that CAs may be developed during the first trimester of pregnancy as a result of hereditary polygenic defects or of a gene-environment interaction. The aetiology is predominantly multifactorial, caused by complex interactions between genes and environment, which modify the normal embryo-foetal development, especially during the organogenesis phase. In particular, environmental factors (e.g., chemical toxicants, infection agents, maternal disease, and exogenous factors) can have preconceptional mutagenic action, postconceptional teratogenic effects, periconceptional endocrine disruption or epigenetic action. Regarding genetic causes, there are genetic chromosomal aberrations or dysgeneses. Furthermore, socioeconomic factors affect reproductive health by differentiating the exposure to the other risk factors as well as the access to prevention measures. In recent years, the importance of the environment as a major factor of reproductive risk has been highlighted. An individual may be exposed to pollutants present in the workplace and the population may be exposed to multiple sources of environmental contamination of water, soil, and air matrices. Pregnant women and the developing foetus are particularly sensitive to the effects of environmental exposure. The aim of the present working paper is to produce an updated review of the epidemiological evidence on the risk of CAs associated with environmental exposures, socioeconomic, and main individual risk factors, such as cigarette smoking and alcohol consumption, according to the approach proposed by Pirastu et al. 2010 in the framework of the SENTIERI Project (the Italian Epidemiological Study of Residents in National Priority Contaminated Sites). Literature search was carried out in PubMed, following the SENTIERI project criteria to evaluate evidence, by selecting articles in English or Italian language published from 2011 to 2016 regarding human studies. For this review, descriptive and analytical epidemiological studies (cohort, case-control, cross-sectional, and ecological), systematic reviews, and metanalyses reporting association estimates between the outcome and at least one of the risk factors were selected. As in Pirastu et al., the sources of environmental exposure have been classified into four macrocategories: industries, mines, landfills, and incinerators. The sources of individual exposure considered were: active and passive cigarette smoking, alcohol consumption, socioeconomic status (SES), occupational and environmental exposures related to air pollutants from vehicular traffic only. The obtained results were assessed according to the evaluation criteria on the epidemiological evidence related to the association between the outcome and exposures predefined and published by the SENTIERI working group (WG). For the evidence assessment, the SENTIERI WG criteria favoured firstly primary sources and quantitative metanalyses, secondly, consistency among sources. The evaluation of the epidemiological evidence for the association between outcome and the exposure has been classified into three categories: sufficient (S), limited (L), inadequate (I). Industries: during the period under review, six single studies evaluating the association between industrial sites exposure and the risk of CAs were found. The epidemiological evidence of association between outcome and exposure has been considered limited. Mines: from the bibliographic research, three single studies investigating possible cause-effect relationship between maternal residential proximity to mines and the risk of CAs have been collected providing inadequate epidemiological evidence. Landfills: during the period under review, one systematic review and one literature review evaluating the causal associations between maternal residential proximity to landfills and CAs were identified. The epidemiological evidence is limited and concerns almost exclusively sites containing industrial or hazardous waste. Incinerators: a systematic review has been selected; it concludes that the evidence for the association between maternal residential proximity to incinerators and CAs are inadequate. Cigarette smoking: the literature search identified eight systematic reviews with metanalysis, five multicentre studies, and ten single studies assessing the causal association between maternal and/or paternal exposure to smoking and the risk of CAs in the offspring providing sufficient evidence for a causal association between maternal exposure to cigarette smoke and the risk of congenital heart defects, oro-facial clefts, neural tube defects, and gastrointestinal malformations. Alcohol: three systematic reviews with metanalysis, two metanalyses, one multicentre study, and four single studies were collected for the period under review. The acquired literature has provided limited epidemiological evidence for associations between alcohol consumption and CAs in the nervous system, particularly for anencephaly and spina bifida. Socioeconomic status: the evidence of an association with socioeconomic factors was inadequate due to an insufficient number of studies selected during the period under consideration. Occupational exposure: the literature search collected one metanalysis, eight multicentre studies, and five single studies. The epidemiological evidence for associations between paternal occupational exposure to solvents and neural tube defects and between maternal pesticide exposure and gold-facial clefts were judged limited. Air pollution: two systematic reviews with metanalyses, two multicentre studies, and nine single studies were selected by literature search; the epidemiological evidence for a causal association between air pollutants exposure and the risk of CAs is still to be considered limited. For future epidemiological studies, a better exposure assessment, using in particular more accurate spatial measurements or models, a standardized case definition, a larger sample and more accurate control of the recognized or presumed confounding variables are needed.

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<bObjective:</b To explore the effects and mechanism of interleukin-17 (IL-17)-modified mouse bone marrow mesenchymal stem cells (BMSCs) on the allogeneic skin transplantation in mice. <bMethods:</b (1) The femur, tibia, and humerus were isolated from five BALB/c mice (all female, aged 4 to 8 weeks, the same gender and age below) after sacrifice. BMSCs were isolated, purified, and cultured by whole bone marrow density gradient centrifugation combined with adherent separation method. The third passage of cells was used for morphological observation and identification of adipogenic and osteogenic differentiation. The fourth passage of cells was used for identification of the expression of stem cell surface markers. The third to sixth passages of BMSCs were pretreated with mouse recombinant IL-17 at a final mass concentration of 50 ng/mL for 5 days, and then were harvested for morphological observation. After being labeled with carbocyanine fluorescent dye (CM-Dil), IL-17-pretreated BMSCs and IL-17-unpretreated BMSCs were obtained for morphological observation and the labeling rates were calculated. (2) Forty-five C57BL/6J mice were divided into phosphate buffer solution (PBS) control group (<in</i=13), BMSCs alone group (<in</i=16), and BMSCs+ IL-17 group (<in</i=16) according to the random number table. One day before the skin transplantation of mice, 0.1 mL BMSCs (5×10(6) cells/mL) without CM-Dil labeling were injected to the 13 mice in BMSCs alone group through the tail vein, and 0.1 mL BMSCs (5×10(6) cells/mL) labeled with CM-Dil were injected to the other 3 mice in BMSCs alone group through the tail vein. IL-17-pretreated BMSCs (5×10(6) cells/mL) without CM-Dil labeling in the volume of 0.1 mL were injected to the 13 mice in BMSCs+ IL-17 group through the tail vein, and 0.1 mL IL-17-pretreated BMSCs (5×10(6) cells/mL) labeled with CM-Dil were injected to the other 3 mice in BMSCs+ IL-17 group through the tail vein. PBS in the volume of 0.1 mL was injected to the 13 mice in PBS control group through the tail vein. Forty-five BALB/c mice were used as donors, and forty-five treated C57BL/6J mice in the 3 groups were used as recipients to establish a back-to-back full-thickness skin transplantation model. On the 2nd day after transplantation, the same number of corresponding cells and the equal amount of PBS were injected to the recipient mice of each group again. On the 7th day after transplantation, three mice injected with CM-Dil-labeled BMSCs in BMSCs alone group and three mice injected with CM-Dil-labeled IL-17-pretreated BMSCs in BMSCs+ IL-17 group were sacrificed by cervical dislocation to track the CM-Dil-labeled BMSCs by fluorescence microscope, which was counted. After the dressing removal on the 6th day post transplantation, 7 mice were selected respectively from 13 mice in BMSCs alone group injected with BMSCs without CM-Dil-labeling, 13 mice in BMSCs+ IL-17 group injected with IL-17-pretreated BMSCs without CM-Dil-labeling, and 13 mice in PBS control group, respectively, to record the skin graft survival time. On the 8th day post transplantation, three of the remaining six mice in the three groups were taken for general observation of the grafted skin, serum levels of interferon-γ, IL-10, and transforming growth factor β (TGF-β) by enzyme-linked immunosorbent assay method, the percentage of CD4(+) CD25(+) forkhead/winged helix transcription factor p3 (Foxp3)(+) regulatory T cells (Tregs) in spleen by flow cytometer, and the histopathological observation of the grafted skin by hematoxylin eosin staining. The rest three mice in each group were also taken for histopathological observation as above on the 14th day post transplantation. Data were statistically analysed with independent sample <it</i test, one-way analysis of variance, and least significant difference test. <bResults:</b (1) There were no significant differences in the morphology and size between IL-17-pretreated BMSCs and IL-17-unpretreated BMSCs on culture day 5. (2) After CM-Dil labeling, BMSCs and IL-17-pretreated BMSCs grew well, and the labeling rate was almost 100%. (3) On the 7th day post transplantation, there were 6.2±2.6 CM-Dil-labeled BMSCs per 100 fold visual field in the skin and adjacent subcutaneous tissue of mice in BMSCs alone group, which were significantly fewer than the 15.0±5.3 CM-Dil-labeled IL-17-pretreated BMSCs per 100 fold visual field in BMSCs+ IL-17 group (<it</i=-2.962, <iP</i&lt;0.05). (4) The skin graft survival time of mice in BMSCs alone group and BMSCs+ IL-17 group was (13.3±1.2) and (17.0±1.5) days respectively, significantly longer than (8.7±0.8) days in PBS control group (<iP</i&lt;0.01), and the skin graft survival time of mice in BMSCs+ IL-17 group was significantly longer than that in BMSCs alone group (<iP</i&lt;0.01). (5) On the 8th day post transplantation, most of the skin grafts of mice in PBS control group was black, scabby, and necrotic. Most of the skin grafts of mice in BMSCs alone group survived well, while all the skin grafts of mice in BMSCs+ IL-17 group survived well. (6) On the 8th day post transplantation, compared with those of PBS control group, the serum levels of IL-10 and TGF-β of mice in BMSCs alone group and BMSCs+ IL-17 group were significantly higher (<iP</i&lt;0.01), and the serum level of interferon-γ was significantly lower (<iP</i&lt;0.01). Compared with those of BMSCs alone group, the serum levels of IL-10 and TGF-β of mice in BMSCs+ IL-17 group were significantly higher (<iP</i&lt;0.01), and the serum level of interferon-γ was significantly lower (<iP</i&lt;0.01). (7) On the 8th day post transplantation, the percentages of CD4(+) CD25(+) Foxp3(+) Treg in spleen of mice in BMSCs alone group and BMSCs+ IL-17 group were significantly higher than the percentage of PBS control group (<iP</i&lt;0.01), and the percentage of CD4(+) CD25(+) Foxp3(+) Treg in spleen of mice in BMSCs+ IL-17 group was significantly higher than that of BMSCs alone group (<iP</i&lt;0.01). (8) On the 8th day post transplantation, infiltration of a large number of inflammatory cells and necrosis of epidermis and dermis were found in the skin grafts of mice in PBS control group; focal infiltration of inflammatory cells and slight epidermal degeneration were found in the skin grafts of mice in BMSCs alone group; the skin appendages of the skin grafts of mice in BMSCs+ IL-17 group survived well with angiogenesis. On the 14th day post transplantation, the skin grafts of mice in BMSCs alone group showed extensive infiltration of inflammatory cells, severe epidermal degeneration and focal necrosis; the skin grafts of mice in BMSCs+ IL-17 group showed focal infiltration of inflammatory cells and slight epidermal degeneration; the skin grafts of mice in PBS control group were completely necrotic. <bConclusions:</b IL-17 can reduce the immune rejection in allogeneic skin grafting and prolong the survival time of mouse skin grafts by improving mice BMSCs' capabilities to induce immune tolerance and enhancing the homing ability of BMSCs.

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<bObjective:</b To investigate the effects and molecular mechanism of exogenous L-carnitine on hepatic pyroptosis mediated by excessive endoplasmic reticulum stress in severely scald rats. <bMethods:</b The experimental research method was adopted. According to the random number table (the same group method below), fifteen female Sprague Dawley rats aged 6-8 weeks were divided into sham-injury group, scald alone group, and scald+carnitine group (with 5 rats in each group), and full-thickness scald of 30% total body surface area were made on the back of rats in scald alone group and scald+carnitine group, and rats in scald+carnitine group were additionally given intraperitoneal injection of L-carnitine. At post injury hour (PIH) 72, The levels of aspartate aminotransferase (AST) and alanine dehydrogenase (ALT) of biochemical indicators of liver injury were detected by automatic biochemical analyzer with the sample number of 5. At PIH 72, liver tissue damage was detected by hematoxylin-eosin staining. At PIH 72, The mRNA levels of nucleotide-binding oligomerization domain-containing protein-like receptor family pyrin domain containing 3 (NLRP3), cysteine aspartic acid specific protease 1 (caspase-1), gasderminD (GSDMD), and interleukin 1β(IL-1β) in liver tissue as pyroptosis-related markers and glucose regulatory protein 78 (GRP78) and CCAAT/enhancer binding protein homologous protein (CHOP) in liver tissue as endoplasmic reticulum stress-related markers were detected by real-time fluorescence quantitative reverse transcription polymerase chain reaction (RT-qPCR). Protein expression levels of GRP78, CHOP, NLRP3, caspase-1, caspase-1/p20, GSDMD-N, and cleaved IL-1β in liver tissue were detected by Western blotting, and the sample numbers were all 5. HepG2 cells as human liver cancer cells were divided into dimethyl sulfoxide (DMSO) group, 0.1 μmol/L tunicamycin (TM) group, 0.2 μmol/L TM group, 0.4 μmol/L TM group, and 0.8 μmol/L TM group and were treated accordingly. After 24 h of culture, cell viability was detected by cell counting kit 8, and the intervention concentration of TM was screened, and the sample number was 5. HepG2 cells were divided into DMSO group, TM alone group, and TM+carnitine group, and treated accordingly. After 24 h of culture, the protein expression levels of GRP78, CHOP, NLRP3, caspase-1, caspase-1/p20, GSDMD-N, and cleaved IL-1β in cells were detected by Western blotting, and the sample numbers were all 3. Data were statistically analyzed with one-way analysis of variance and least significant difference-<it</i test. <bResults:</b At PIH 72, the AST and ALT levels of serum in scald alone group were (640±22) and (157±8) U/L, which were significantly higher than (106±13) and (42±6) U/L in sham-injury group, respectively, with <it</i values of -46.78 and -25.98, respectively, <iP</i&lt;0.01. The AST and ALT levels of serum in scald+carnitine group were (519±50) and (121±10) U/L, which were significantly lower than those in scald alone group, respectively, with <it</i values of 4.93 and 6.06, respectively, <iP</i&lt;0.01. At PIH 72, the morphology of liver tissue of rats in sham-injury group were basically normal with no obvious inflammatory cell infiltration; compared with those in sham-injury group, the liver tissue of rats in scald alone group showed a large number of inflammatory cell infiltration and disturbed cell arrangement; compared with that in scald alone group, the liver tissue of rats in scald+carnitine group showed a small amount of inflammatory cell infiltration. At PIH 72, the mRNA expression on levels of NLRP3, caspase-1, GSDMD, and IL-1β in liver tissue of rats in scald alone group were significantly higher than those in sham-injury group (with <it</i values of 34.42, 41.93, 30.17, and 15.68, respectively, <iP</i&lt;0.01); the mRNA levels of NLRP3, caspase-1, GSDMD, and IL-1β in liver tissue of rats in scald+carnitine group were significantly lower than those in scald alone group (with <it</i values of 34.40, 37.20, 19.95, and 7.88, respectively, <iP</i&lt;0.01). At PIH 72, the protein expression levels of NLRP3, caspase-1, caspase-1/p20, GSDMD-N, and cleaved IL-1β in liver tissue of rats in scald alone group were significantly higher than those in sham-injury group (with <it</i values of 12.28, 26.92, 5.20, 10.02, and 24.78, respectively, <iP</i&lt;0.01); compared with those in scald alone group, the protein expression levels of NLRP3, caspase-1, caspase-1/p20, GSDMD-N, and cleaved IL-1β in liver tissue of rats in scald+carnitine group were significantly decreased (with <it</i values of 10.99, 27.96, 12.69, 8.96, and 12.27, respectively, <iP</i&lt;0.01). At PIH 72, the mRNA levels of GRP78 and CHOP in liver tissue of rats in scald alone group were significantly higher than those in sham-injury group (with <it</i values of 21.00 and 16.52, respectively, <iP</i&lt;0.01), and the mRNA levels of GRP78 and CHOP in liver tissue of rats in scald+carnitine group were significantly lower than those in scald alone group (with <it</i values of 8.92 and 8.21, respectively, <iP</i&lt;0.01); the protein expression levels of GRP78 and CHOP in liver tissue of rats in scald alone group were significantly higher than those in sham-injury group (with <it</i values of 22.50 and 14.29, respectively, <iP</i&lt;0.01), and the protein expression levels of GRP78 and CHOP in liver tissue of rats in scald+carnitine group were significantly lower than those in scald alone group (with <it</i values of 14.29 and 5.33 respectively, <iP</i&lt;0.01). After 24 h of culture, the cell survival rates of 0.1 μmol/L TM group, 0.2 μmol/L TM group, 0.4 μmol/L TM group, and 0.8 μmol/L TM group were significantly decreased than that in DMSO group (with <it</i values of 4.90, 9.35, 18.64, and 25.09, respectively, <iP</i&lt;0.01). Then 0.8 μmol/L was selected as the intervention concentration of TM. After 24 h of culture, compared with that in DMSO group, the protein expression levels of GRP78 and CHOP in cells in TM alone group were significantly increased (with <it</i values of 10.48 and 17.67, respectively, <iP</i&lt;0.01), and the protein expression levels of GRP78 and CHOP in TM+carnitine group were significantly lower than those in TM alone group (with <it</i values of 8.08 and 13.23, respectively, <iP</i&lt;0.05 or <iP</i&lt;0.01). After 24 h of culture, compared with those in DMSO group, the protein expression levels of NLRP3 and GSDMD-N in cells in TM alone group were significantly increased (with <it</i values of 13.44 and 27.51, respectively, <iP</i&lt;0.01), but the protein expression levels of caspase-1, caspase-1/p20, and cleaved IL-1β in cells were not significantly changed (<iP</i&gt;0.05); compared with that in TM alone group, the protein expression levels of NLRP3 and GSDMD-N in cells in TM+carnitine group were significantly decreased (with <it</i values of 20.49 and 21.95, respectively, <iP</i&lt;0.01), but the protein expression levels of caspase-1, caspase-1/p20, and cleaved IL-1β in cells were not significantly changed (<iP</i&gt;0.05). <bConclusions:</b In severely scald rats, exogenous L-carnitine may play a protective role against liver injury by inhibiting the pathways related to excessive endoplasmic reticulum stress-mediated pyroptosis.

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<bObjective:</b To investigate the effects and mechanism of exosomes from hepatocyte growth factor (HGF)-modified human adipose mesenchymal stem cells (ADSCs) on full-thickness skin defect wounds in diabetic mice. <bMethods:</b The experimental study method was adopted. Discarded adipose tissue of 3 healthy females (10-25 years old) who underwent abdominal surgery in the Department of Plastic Surgery of First Affiliated Hospital of Air Force Medical University from February to May 2021 was collected, and primary ADSCs were obtained by collagenase digestion method and cultured for 7 days. Cell morphology was observed by inverted phase contrast microscope. The ADSCs of third passage were transfected with HGF lentivirus and cultured for 5 days, and then the fluorescence of cells was observed by imaging system and the transfection rate was calculated. The exosomes of ADSCs of the third to sixth passages and the HGF transfected ADSCs of the third to sixth passages were extracted by density gradient centrifugation, respectively, and named, ADSC exosomes and HGF-ADSC exosomes. The microscopic morphology of exosomes was observed by transmission electron microscopy, and the positive expressions of CD9, CD63, and CD81 of exosomes were detected by flow cytometry, respectively. Twenty-four 6-week-old male Kunming mice were selected to make the diabetic models, and full-thickness skin defect wounds were made on the backs of mice. According to the random number table method, the mice were divided into phosphate buffer solution (PBS) group, HGF alone group, ADSC exosome alone group, and HGF-ADSC exosome group, with 6 mice in each group, and treated accordingly. On post injury day (PID) 3, 7, 10, and 14, the wounds were observed and the wound healing rate was calculated; the blood flow intensity of wound base was detected by Doppler flowmeter and the ratio of relative blood flow intensity on PID 10 was calculated. On PID 10, the number of Ki67 positive cells in wounds was detected by immunofluorescence method, and the number of new-vascularity of CD31 positive staining and tubular neovascularization in the wounds was detected by immunohistochemistry method; the protein expressions of protein endothelial nitric oxide synthase (eNOS), phosphatidylinositol 3-kinase (PI3K), phosphorylated PI3K (p-PI3K), protein kinase B (Akt) and phosphorylated Akt (p-Akt) in wounds were detected by Western blotting, and the ratios of p-PI3K to PI3K and p-Akt to Akt were calculated. On PID 14, the defect length and collagen regeneration of wound skin tissue were detected by hematoxylin and eosin staining and Masson staining, respectively, and the collagen volume fraction (CVF) was calculated. The number of samples is 3 in all cases. Data were statistically analyzed with repeated measurement analysis of variance, one-way analysis of variance, and Tukey test. <bResults:</b After 7 days of culture, the primary ADSCs were spindle shaped and arranged in vortex shape after dense growth. After 5 days of culture, HGF transfected ADSCs of the third passage carried green fluorescence, and the transfection rate was 85%. The ADSC exosomes and HGF-ADSC exosomes were similar in microscopic morphology, showing vesicular structures with an average particle size of 103 nm and 98 nm respectively, and both were CD9, CD63, and CD81 positive. On PID 3, the wounds of mice in the 4 groups were all red and swollen, with a small amount of exudate. On PID 7, the wounds of HGF-ADSC exosome group were gradually reduced, while the wounds of the other three groups were not significantly reduced. On PID 10, the wounds in the 4 groups were all reduced and scabbed. On PID 14, the wounds in HGF-ADSC exosome group were basically healed, while the residual wounds were found in the other three groups. On PID 3, the healing rates of wounds in the four groups were similar (<iP</i&gt;0.05); On PID 7 and 10, the wound healing rates in HGF-ADSC exosome group were significantly higher than those in PBS group, HGF alone group, and ADSC exosome alone group, respectively (with <iq</i values of 13.11, 13.11, 11.89, 12.85, 11.28, and 7.74, respectively, all <iP</i&lt;0.01); on PID 14, the wound healing rate in HGF-ADSC exosome group was significantly higher than that in PBS group, HGF alone group, and ADSC exosome alone group (with <iq</i values of 15.50, 11.64, and 6.36, respectively, all <iP</i&lt;0.01). On PID 3, there was no obvious blood supply in wound base of mice in the 4 groups. On PID 7, microvessels began to form in the wound base of HGF-ADSC exosome group, while the wound base of the other three groups was only congested at the wound edge. On PID 10, microvessel formation in wound base was observed in the other 3 groups except in PBS group, which had no obvious blood supply. On PID 14, the blood flow intensity of wound base in HGF-ADSC exosome group was stronger than that in the other 3 groups, and the distribution was uniform. On PID 10, the ratio of wound base relative blood flow intensity in HGF-ADSC exosome group was significantly higher than that in PBS group, HGF alone group, and ADSC exosome alone group (with <iq</i values of 23.73, 19.32, and 9.48, respectively, all <iP</i&lt;0.01); The numbers of Ki67-positive cells and new-vascularity of wounds in HGF-ADSC exosome group were significantly higher than those in PBS group, HGF alone group, and ADSC exosome alone group, respectively (with <iq</i values of 19.58, 18.20, 11.04, 20.68, 13.79, and 8.12, respectively, <iP</i&lt;0.01). On PID 10, the protein expression level of eNOS of wounds in HGF-ADSC exosome group was higher than that in PBS group, HGF alone group, and ADSC exosome alone group (with <iq</i values of 53.23, 42.54, and 26.54, respectively, all <iP</i&lt;0.01); the ratio of p-PI3K to PI3K and the ratio of p-Akt to Akt of wounds in HGF-ADSC exosome group were significantly higher than those in PBS group, HGF alone group, and ADSC exosome alone group, respectively (with <iq</i values of 16.11, 11.78, 6.08, 65.54, 31.63, and 37.86, respectively, <iP</i&lt;0.01). On PID 14, the length of skin tissue defect in the wounds of HGF-ADSC exosome group was shorter than that in PBS group, HGF alone group, and ADSC exosome alone group (with <iq</i values of 20.51, 18.50, and 11.99, respectively, all <iP</i&lt;0.01); the CVF of wounds in HGF-ADSC exosome group was significantly higher than that in PBS group, HGF alone group and ADSC exosome alone group (with <iq</i values of 31.31, 28.52, and 12.35, respectively, all <iP</i&lt;0.01). <bConclusions:</b Human HGF-ADSC exosomes can significantly promote wound healing in diabetic mice by increasing neovascularization in wound tissue, and the mechanism may be related to the increased expression of eNOS in wounds by activating PI3K/Akt signaling pathway.

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Toxicology and carcinogenesis studies of d-limonene, a naturally occurring monoterpene found in many volatile oils, especially in citrus oils, were conducted because of its widespread use as a flavor and fragrance additive for food and household cleaning products and its increasing use as an industrial solvent. The d-limonene used in these studies was more than 99% pure and was administered in corn oil by gavage. Short-term studies were conducted in F344/N rats and B6C3F1 mice to identify toxic effects and affected sites and to help establish doses for the 2-year studies. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse L5178Y cells, and Chinese hamster ovary (CHO) cells. The doses selected for the 16-day studies ranged from 413 to 6,600 mg/kg for both rats and mice; deaths and reduction in body weight gain occurred at the two highest doses. No compound-related clinical signs or histopathologic lesions were observed in any of the surviving dose groups. In the 13-week studies, doses of d-limonene ranged from 150 to 2,400 mg/kg for rats and from 125 to 2,000 mg/kg for mice. Deaths occurred in the high dose group of each species and sex. Greater than 10% reductions in body weight gain were observed in the two highest dose groups of male rats and male mice and the high dose female rats. Rough hair coats and decreased activity were observed at the two highest doses in both rats and mice. There were no chemical-related histopathologic lesions in female rats or in mice of either sex. A compound-related increased severity of nephropathy was observed in the kidney of male rats. This lesion was characterized by degeneration of epithelial cells in the convoluted tubules, granular casts in the outer stripe of the outer medulla, and epithelial regeneration. These lesions have been described as reasonably characteristic of the hyaline droplet nephropathy that is associated with an accumulation of liver-generated a2u-globulin in the cytoplasm of tubular epithelial cells. Two-year studies of d-limonene were conducted by administering 0, 75, or 150 mg/kg d-limonene in corn oil by gavage to groups of 50 F344/N male rats, 5 days per week for 103 weeks; groups of 50 female F344/N rats were administered 0, 300, or 600 mg/kg. These doses were selected based on compound-related, potentially life-threatening kidney lesions observed in males at 300 mg/kg and higher and on the large number of deaths of female rats at 2,400 mg/kg. Groups of 50 male B6C3F1 mice were administered 0, 250, or 500 mg/kg according to the same schedule; groups of 50 female B6C3F1 mice were administered 0, 500, or 1,000 mg/kg. These doses were selected based on the deaths observed for both male and female mice at 2,000 mg/kg during the 13-week studies and the body weight depression in male mice at 1,000 mg/kg and higher. Mean body weights of rats dosed with d-limonene were similar to those of vehicle controls throughout the studies. Survival of the high dose female rats after week 39 and of the vehicle control male rats after week 81 was significantly reduced (survival at week 104-- male: vehicle control, 29/50; low dose, 33/50; high dose, 40/50; female: 42/50; 40/50; 26/50). Mean body weights of dosed and vehicle control male mice were similar throughout the studies. Mean body weights of high dose female mice were notably lower than those of the vehicle controls after week 28. Survival of the low dose group of male mice was significantly lower than that of vehicle controls at the end of the study (33/50; 24/50; 39/50). No difference in survival was observed between vehicle control and dosed female mice (43/50; 44/50; 43/50). In the 2-year studies, the kidney was confirmed as the primary target organ for chemically related lesions. No lesions were observed in female rats. For males, the nonneoplastic lesions included exacerbation of the age-related nephropathy, linear deposits of mineral in the renal medulla and papilla, and focal hyperplasia of the transitional epithelium overlying the renal papilla. Uncommon tubular cell adenomas and adenocarc and adenocarcinomas of the kidney also occurred in dosed male rats, and this effect was supported by a dose-related increased incidence of tubular cell hyperplasia, as shown in the table below. INCIDENCES OF MALE RATS WITH RENAL LESIONS IN THE TWO-YEAR GAVAGE STUDY OF d-LIMONENE Site/Lesion Vehicle Control 75 mg/kg 150 mg/kg Renal papilla Mineralization 7/50 43/50 48/50 Epithelial hyperplasia 0/50 35/50 43/50 Kidney Tubular cell hyperplasia 0/50 4/50 7/50 Tubular cell adenoma 0/50 4/50 8/50 Tubular cell adenocarcinoma 0/50 4/50 3/50 In subsequent 21-day studies, male and female F344/N rats were administered d-limonene at doses ranging from 75 to 1,200 mg/kg. Microscopic examination of the kidney sections from these rats indicated a compound-related increase in intracytoplasmic granules in the proximal convoluted tubules of dosed male rats but not of female rats. The granules were shown to contain a2u-globulin by an immunohistochemical strain. a2u-Globulin was shown to be increased in kidney homogenates from dosed male rats by an ELISA test. In mice, no chemically related increases in neoplasms were observed. The incidence of neoplasms of the anterior pituitary gland in high dose female mice was lower than that in vehicle controls (adenomas or carcinomas, combined:vehicle control, 12/49; high dose, 2/48). Cells with an abnormal number of nuclei (8/49; 32/50) and cytomegaly (23/49; 38/50) were observed in the liver of high dose male mice. Genetic Toxicology: d-Limonene was not mutagenic in four strains of S. typhimurium (TA98, TA100, TA1535, or TA1537), did not significantly increase the number of trifluorothymidine (Tft)-resistant cells in the mouse L5178Y/TK&amp;plusmn; assay, and did not induce chromosomal aberrations or sister chromatid exchanges (SCEs) in cultured CHO cells. All assays were conducted in the presence and absence of exogenous metabolic activation. Conclusions: Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenic activity of d-limonene for male F344/N rats, as shown by increased incidences of tubular cell hyperplasia, adenomas, and adenocarcinomas of the kidney. There was no evidence of carcinogenic activity of d-limonene for female F344/N rats that received 300 or 600 mg/kg. There was no evidence of carcinogenic activity of d-limonene for male B6C3F1 mice that received 250 or 500 mg/kg. There was no evidence of carcinogenic activity of d-limonene for female B6C3F1 mice that received 500 or 1,000 mg/kg. An increased severity of spontaneous nephropathy, increased incidences of linear mineralization of the renal medulla and papilla, and hyperplasia of the transitional epithelium of the renal papilla were present in dosed male rats. Synonyms: cyclohexene; 4-isopropenyl-1-methyl; 1-methyl-4-(1-methylethenyl)cyclohexene; p-mentha-1,8-diene; carvene; cinene; cajeputene

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Sexually transmitted infections (STI) are common in developing countries. The World Health Organisation (WHO) estimates that in 1999, 340 million new cases of syphilis, gonorrhoea, chlamydial infection and trichomoniasis occurred. Human immunodeficiency virus (HIV) infection is also common in developing countries. UNAIDS estimates that over 95% of the 40 million people infected with HIV by December 1999 live in developing countries (UNAIDS 2003). The STI and HIV epidemics are interdependent. Similar behaviours, such as frequent unprotected intercourse with different partners, place people at high risk of both infections, and there is clear evidence that conventional STIs increase the likelihood of HIV transmission. Several studies have demonstrated a strong association between both ulcerative and non-ulcerative STIs and HIV infection (Cameron 1989, Laga 1993). There is biological evidence, too, that the presence of an STI increases shedding of HIV, and that STI treatment reduces HIV shedding (Cohen 1997, Robinson 1997). Therefore, STI control may have the potential to contribute substantially to HIV prevention. To determine the impact of population-based STI interventions on the frequency of HIV infection, frequency of STIs and quality of STI management. The following electronic databases were searched for relevant randomised trials or reviews:1) MEDLINE for the years 1966 to 2003 using the search terms "sexually transmitted diseases" and "human immunodeficiency virus infection"2) The Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effectiveness and the Cochrane Clinical Trials Register, in the most recent issue of the Cochrane Library3) The specialist registry of trials maintained by the Cochrane Infectious Diseases Group.4) EMBASE The abstracts of relevant conferences were searched, and reference lists of all review articles and primary studies were scanned. Finally, authors of included trials and other experts in the field were contacted as appropriate. Randomised controlled trials in which the unit of randomisation is either a community or a treatment facility. Studies where individuals are randomised were excluded. Two reviewers independently applied the inclusion criteria to potential studies, with any disagreements resolved by discussion. Trials were examined for completeness of reporting. The methodological quality of each trial was assessed by the same two reviewers, with details recorded of randomisation method, blinding, use of intention-to-treat analysis and the number of patients lost to follow-up, using standard guidelines of the Cochrane Infectious Diseases Group. Five trials were included. Frequency of HIV infection: In Rakai, after 3 rounds of treatment of all community members for STIs, the rate ratio of incident HIV infection was 0.97 (95%CI 0.81 to 1.16), indicating no effect of the intervention. In Mwanza, the incidence of HIV infection in the intervention groups (strengthened syndromic management of STIs in primary care clinics) was 1.2% compared with 1.9% in the control groups (OR=0.58, 95% CI 0.42-0.70), corresponding to a 38% reduction (95%CI 15% to 55%) in HIV incidence in the intervention group. In the newest trial by Kamali et al, the rate ratio of behavioral intervention &amp; STI management compared to control on HIV incidence was 1.00 (0.63-1.58, p=.98). These are consistent with Rakai data showing no effect of intervention. Frequency of STIs: In both Mwanza and Rakai, there was no significant reduction in gonorrhoea, chlamydia, urethritis, or reported STI symptoms among intervention communities. The prevalence ratio of syphilis between intervention and control groups in Rakai was 0.8 (95%CI 0.71-0.89), of trichmoniasis was 0.59 (0.38-0.91), and of bacterial vaginosis was 0.87 (0.74-1.02). In Mwanza, the prevalence of serologically diagnosed syphilis in the intervention community was 5% compared with 7% in the control community at the end of the trial (adjusted re7% in the control community at the end of the trial (adjusted relative risk 0.71 (95%CI 0.54-0.93). In Kamali et al, there was a significant decrease in gonorrhoea and active syphilis cases. Rate ratio for gonorrhoea was 0.29(0.12-0.71, p=0.016), active syphilis was 0.53(0.33-0.84,p=0.016). There was a trend towards significance with intervention on the use of condoms with the last casual partner; the rate ratio was 1.27(1.02-1.56,p=0.036). Quality of treatment: In Lima, following training of pharmacy assistants in STI syndromic management, symptoms were recognised as being due to an STI in 65% of standardised simulated patients (SSPs) visiting intervention and 60% of SSPs visiting control pharmacies (p=0.35). Medication was offered without referral to a doctor in most cases (83% intervention and 78% control, p=0.61). Of those SSPs offered medication, only 1.4% that visited intervention pharmacies and only 0.7% of those that visited control pharmacies (p=0.57) were offered a recommended regimen. Similarly in only 15% and 16% of SSP visits respectively was any recommended drug offered. However, education and counseling were more likely to be given to SSPs visiting intervention pharmacies (40% vs 27%, p=0.01). No SSPs were given partner cards or condoms. In Hlabisa, following the intervention targeting primary care clinic nurses (strengthened STI syndromic management and provision of STI syndrome packets containing recommended drugs, condom, partner cards and patient information leaflets), SSPs were more likely to be given recommended drugs in intervention clinics (83% vs 12%, p&lt;0.005) and more likely to be correctly case managed [given correct drugs, partner cards and condoms] (88% vs 50%, p&lt;0.005). There were no significant differences in the proportions adequately counseled (68% vs 46%, p=0.06), experiencing good staff attitude (84% vs 58%, p=0.07), and being consulted in privacy (92% vs 86%, p=0.4). There was no strong evidence of any impact on treatment-seeking behaviour, utilisation of services, or sexual behaviour in any of the four trials. There is limited evidence from randomised controlled trials for STI control as an effective HIV prevention strategy. Improved STI treatment services have been shown to reduce HIV incidence in an environment characterised by an emerging HIV epidemic (low and slowly rising prevalence), where STI treatment services are poor and where STIs are highly prevalent. There is no evidence for substantial benefit from treatment of all community members. The addition of the Kamali trial to the existing evidence supports the data from the Rakai trial of no effect. There are, however, other compelling reasons why STI treatment services should be strengthened, and the available evidence suggests that when an intervention is accepted it can substantially improve quality of services provided. The Kamali trial shows an increase in the use of condoms, a marker for improved risk behaviors. Further community-based randomised controlled trials that test a range of alternative STI control strategies are needed in a variety of different settings. Such trials should aim to measure a range of factors that include health seeking behaviour and quality of treatment, as well as HIV, STI and other biological endpoints.

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The objective of this review is to assess the effectiveness of selective thoracic fusion as a form of treatment in adolescent idiopathic scoliosis (AIS). This will be compared with all other forms of operative management for major structural thoracic curves. Scoliosis is defined as a lateral curvature of the spine of at least 10 degrees, as measured by the Cobb angle. It can be categorized into three broad categories - neuromuscular, congenital and idiopathic. Of these categories, idiopathic is by far the most common, and is a diagnosis of exclusion. Idiopathic scoliosis can then be further broken down into categories based on age of onset. Of these, AIS (children presenting at 10 years of age or older) accounts for 80-85% of cases.Scoliosis curves have a proven complex deformity, consisting of a three-dimensional deformity involving the coronal, sagittal and rotational planes. Each curve (of which there may be many in one patient) can be described with an apex (the vertebra with the greatest lateral distance from the centre of the spine) and the two vertebrae at the end of the curve (named the end vertebrae). The Cobb angle, measured by the intersection of parallel lines from the endplates of the superior and inferior end vertebrae, is the standard way of quantifying the magnitude of scoliosis curves.Major or primary curves are the largest abnormal curves as classified by the Cobb angle. These curves are almost always structural. In addition, secondary or tertiary curves are described as structural if the Cobb angle cannot be reduced to under 25 degrees, on side bending radiographs. Due to the permanent nature of physiological and morphological change of the vertebral bodies and ligaments, structural curves will usually progress as the patient matures, usually at 1 degree per year after maturity. Non-structural curves usually do not progress as the patient matures; instead they are hypothesized to be a product of the body's instinctive nature to provide truncal balance.For many years spinal surgeons have been debating whether a more rigid and straighter spine or a mobile and less straight spine provides better outcomes. The treatment for AIS can include both an operative and non-operative approach. However when the Cobb angle is above 40, the likelihood of curve progression is high and surgical treatment is warranted.Although technology has advanced, the primary goals for operative management have remained constant. The primary goals of surgical treatment in AIS should be to optimize coronal and sagittal correction and avoid further curve progression. This involves not only correction of the major primary curve but also any minor (secondary) curves, while maintaining adequate thoracic kyphosis and lumbar lordosis. Ideally, a balance should be struck between fusing the lowest number of mobile segments and properly correcting the existing deformity. This is where selective spinal fusion has a role to play.The premise of selective thoracic fusion is that after fixation of the primary thoracic curve, there is spontaneous coronal correction of the unfused lumbar curve. Thus the thoracic curve can be exclusively fused to allow for a more mobile lumbar spine. This has been described in studies since the 1950s. However since then, results have varied greatly in the extent of spontaneous lumbar correction. Studies have shown that the degree of spontaneous correction of the lumbar spine is somewhat close to the correction of the thoracic curve; however the extent of optimal correction that can be achieved is uncertain.The alternative to selective thoracic infusion involves complete fusion of both the primary thoracic and secondary lumbar curve in a consecutive series. This can be done via either an anterior or a posterior approach. Complete fusion gives better correction of both curves. It also diminishes the risk of coronal decompensation, adding on phenomenon, junctional kyphosis and eventual revision surgery. However this needs to be calculated against the risk of sagittal decompensation, increased risk of lumbar degeneration and chronic back pain, all of which seem to be more prevalent in patients with fusion of both curves.Another goal of surgical intervention is the need to avoid complications. Examples of complications of selective spinal fusion include: junctional kyphosis, coronal imbalance, adding-on and revision surgery. Junctional kyphosis is described as kyphosis of over 10 degrees more than pre-operative measurements. This is measured by the angle between the inferior end plate of the highest instrumented vertebrae and the superior end plate of the vertebra two levels higher. Coronal imbalance is when the distance between the C7 plumb line and the central sacral vertical line is greater than 2 centimeters. The adding-on phenomenon is described as progression or extension of the primary curve after fusion.In 2001, Lenke et al reported a classification for AIS that has been able to identify those patients who may benefit from a selective spinal fusion (1C, 2C, 5C). A three-tiered approach is used with the Lenke classification system involving curve type, lumbar modifier and sagittal modifier. Firstly the curves of the spinal column (proximal thoracic, main thoracic and thoracolumbar/lumbar) are classified as structural or non-structural before a lumbar modifier (A, B, C) based on the distance from the central sacral vertical line and the lumbar apical vertebra is applied. Further classification is then undertaken measuring the kyphosis of the thoracic curve T5-T12 (-, N, +).Lenke proposed that a selective thoracic fusion could be undertaken when the primary curve is structural and the compensatory lumbar curve is non-structural and that additionally certain radiological criteria were met such as the Cobb angle magnitude, apical vertebral translation and rotation. These are all objective markers that can be accurately measured on plain radiographs, with good inter-and intra-observer reliability.However all surgeons do not routinely accept these treatment guidelines. It has been reported that only approximately 49-67% of experienced surgeons are performing a selective thoracic fusion in Lenke 1C curves. This may be due to the fear of complications (of which the rates are relatively unknown) and well as misunderstanding of how much correction can be achieved by the un-fused compensatory lumbar curve. A search of PubMed, the Cochrane Library, PROSPERO and the JBI Databases of Systematic Reviews and Implementation Reports found no current systematic review assessing the effectiveness of selective thoracic fusion compared to other approaches. As such, the aim of this review is to evaluate and critically appraise available evidence on selective thoracic fusion in order to provide a suitable estimate of the radiological and functional outcomes of this type of surgical intervention as well as the approximate complication rate in order to give patients correct information prior to their providing their informed consent.

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Multiple sclerosis (MS) is the most common neurological cause of disability in young adults. Off-label rituximab for MS is used in most countries surveyed by the International Federation of MS, including high-income countries where on-label disease-modifying treatments (DMTs) are available.  OBJECTIVES: To assess beneficial and adverse effects of rituximab as 'first choice' and as 'switching' for adults with MS. We searched CENTRAL, MEDLINE, Embase, CINAHL, and trial registers for completed and ongoing studies on 31 January 2021. We included randomised controlled trials (RCTs) and controlled non-randomised studies of interventions (NRSIs) comparing rituximab with placebo or another DMT for adults with MS. We followed standard Cochrane methodology. We used the Cochrane Collaboration's tool for assessing risk of bias. We rated the certainty of evidence using GRADE for: disability worsening, relapse, serious adverse events (SAEs), health-related quality of life (HRQoL), common infections, cancer, and mortality. We conducted separate analyses for rituximab as 'first choice' or as 'switching', relapsing or progressive MS, comparison versus placebo or another DMT, and RCTs or NRSIs. We included 15 studies (5 RCTs, 10 NRSIs) with 16,429 participants of whom 13,143 were relapsing MS and 3286 progressive MS. The studies were one to two years long and compared rituximab as 'first choice' with placebo (1 RCT) or other DMTs (1 NRSI), rituximab as 'switching' against placebo (2 RCTs) or other DMTs (2 RCTs, 9 NRSIs). The studies were conducted worldwide; most originated from high-income countries, six from the Swedish MS register. Pharmaceutical companies funded two studies. We identified 14 ongoing studies. Rituximab as 'first choice' for relapsing MS Rituximab versus placebo: no studies met eligibility criteria for this comparison. Rituximab versus other DMTs: one NRSI compared rituximab with interferon beta or glatiramer acetate, dimethyl fumarate, natalizumab, or fingolimod in active relapsing MS at 24 months' follow-up. Rituximab likely results in a large reduction in relapses compared with interferon beta or glatiramer acetate (hazard ratio (HR) 0.14, 95% confidence interval (CI) 0.05 to 0.39; 335 participants; moderate-certainty evidence). Rituximab may reduce relapses compared with dimethyl fumarate (HR 0.29, 95% CI 0.08 to 1.00; 206 participants; low-certainty evidence) and natalizumab (HR 0.24, 95% CI 0.06 to 1.00; 170 participants; low-certainty evidence). It may make little or no difference on relapse compared with fingolimod (HR 0.26, 95% CI 0.04 to 1.69; 137 participants; very low-certainty evidence). The study reported no deaths over 24 months. The study did not measure disability worsening, SAEs, HRQoL, and common infections. Rituximab as 'first choice' for progressive MS One RCT compared rituximab with placebo in primary progressive MS at 24 months' follow-up. Rituximab likely results in little to no difference in the number of participants who have disability worsening compared with placebo (odds ratio (OR) 0.71, 95% CI 0.45 to 1.11; 439 participants; moderate-certainty evidence). Rituximab may result in little to no difference in recurrence of relapses (OR 0.60, 95% CI 0.18 to 1.99; 439 participants; low-certainty evidence), SAEs (OR 1.25, 95% CI 0.71 to 2.20; 439 participants; low-certainty evidence), common infections (OR 1.14, 95% CI 0.75 to 1.73; 439 participants; low-certainty evidence), cancer (OR 0.50, 95% CI 0.07 to 3.59; 439 participants; low-certainty evidence), and mortality (OR 0.25, 95% CI 0.02 to 2.77; 439 participants; low-certainty evidence). The study did not measure HRQoL. Rituximab versus other DMTs: no studies met eligibility criteria for this comparison. Rituximab as 'switching' for relapsing MS  One RCT compared rituximab with placebo in relapsing MS at 12 months' follow-up. Rituximab may decrease recurrence of relapses compared with placebo (OR 0.38, 95% CI 0.16 to 0.93; 104 participants; low-certainty evidence). The data did not confirm or exclude a beneficial or detrimental effect of rituximab relative to placebo on SAEs (OR 0.90, 95% CI 0.28 to 2.92; 104 participants; very low-certainty evidence), common infections (OR 0.91, 95% CI 0.37 to 2.24; 104 participants; very low-certainty evidence), cancer (OR 1.55, 95% CI 0.06 to 39.15; 104 participants; very low-certainty evidence), and mortality (OR 1.55, 95% CI 0.06 to 39.15; 104 participants; very low-certainty evidence). The study did not measure disability worsening and HRQoL.  Five NRSIs compared rituximab with other DMTs in relapsing MS at 24 months' follow-up. The data did not confirm or exclude a beneficial or detrimental effect of rituximab relative to interferon beta or glatiramer acetate on disability worsening (HR 0.86, 95% CI 0.52 to 1.42; 1 NRSI, 853 participants; very low-certainty evidence). Rituximab likely results in a large reduction in relapses compared with interferon beta or glatiramer acetate (HR 0.18, 95% CI 0.07 to 0.49; 1 NRSI, 1383 participants; moderate-certainty evidence); and fingolimod (HR 0.08, 95% CI 0.02 to 0.32; 1 NRSI, 256 participants; moderate-certainty evidence). The data did not confirm or exclude a beneficial or detrimental effect of rituximab relative to natalizumab on relapses (HR 1.0, 95% CI 0.2 to 5.0; 1 NRSI, 153 participants; very low-certainty evidence). Rituximab likely increases slightly common infections compared with interferon beta or glatiramer acetate (OR 1.71, 95% CI 1.11 to 2.62; 1 NRSI, 5477 participants; moderate-certainty evidence); and compared with natalizumab (OR 1.58, 95% CI 1.08 to 2.32; 2 NRSIs, 5001 participants; moderate-certainty evidence). Rituximab may increase slightly common infections compared with fingolimod (OR 1.26, 95% CI 0.90 to 1.77; 3 NRSIs, 5187 participants; low-certainty evidence). It may make little or no difference compared with ocrelizumab (OR 0.02, 95% CI 0.00 to 0.40; 1 NRSI, 472 participants; very low-certainty evidence). The data did not confirm or exclude a beneficial or detrimental effect of rituximab on mortality compared with fingolimod (OR 5.59, 95% CI 0.22 to 139.89; 1 NRSI, 136 participants; very low-certainty evidence) and natalizumab (OR 6.66, 95% CI 0.27 to 166.58; 1 NRSI, 153 participants; very low-certainty evidence). The included studies did not measure SAEs, HRQoL, and cancer. For preventing relapses in relapsing MS, rituximab as 'first choice' and as 'switching' may compare favourably with a wide range of approved DMTs. A protective effect of rituximab against disability worsening is uncertain. There is limited information to determine the effect of rituximab for progressive MS.  The evidence is uncertain about the effect of rituximab on SAEs. They are relatively rare in people with MS, thus difficult to study, and they were not well reported in studies. There is an increased risk of common infections with rituximab, but absolute risk is small.  Rituximab is widely used as off-label treatment in people with MS; however, randomised evidence is weak. In the absence of randomised evidence, remaining uncertainties on beneficial and adverse effects of rituximab for MS might be clarified by making real-world data available.

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Cancer chemotherapy celebrated its fiftieth anniversary last year. It was in 1945 that wartime research on the nitrogen mustards, which uncovered their potential use in the treatment of leukaemias and other cancers, was first made public. Fifty years later, more than sixty drugs have been registered in the USA for the treatment of cancer, but there are still lessons to be learnt. One problem, paradoxically, is that many anticancer agents produce a response in several different classes of the disease. This means that once a new agent has been shown to be effective in one cancer, much effort is devoted to further investigations of the same drug in various combinations for different disorders. While this approach has led to advances in the treatment of many childhood cancers and some rare diseases, a plethora of studies on metastatic colon cancer, for example, has yielded little benefit. 5-fluorouracil continues to be used in trials, yet there is no evidence for an increase in survival. The lesson to be learnt is that many common cancers are not adequately treated by present-day chemotherapy, and most trials of this sort are a waste of time. Significant increases in survival will only occur if the selectivity of present-day anticancer agents can be increased or new classes of more selective agents can be discovered. There are two fundamental problems in drug development: a lack of suitable laboratory tests and the difficulty of conducting early clinical trials. Firstly, no existing laboratory method can accurately predict which chemical will be effective against a particular class of human cancer. At best, tests can demonstrate a general 'anticancer' property. This is well exemplified by the discovery of cisplatin. The fact that cisplatin caused regression in a number of transplanted rodent tumours created no great excitement amongst chemotherapists. It was only later when it was tested clinically against ovarian cancer that results were sufficiently positive to encourage others to investigate. Only then was it discovered that metastatic teratoma was extraordinarily sensitive to the drug. This finding was made as a result of phase II trials and no laboratory model could have predicted it. The lesson to be learnt is that new drugs should be tested extensively in phase II trials before they are discarded. The second problem concerns early clinical trials. Because new drugs can only be tested against advanced and usually heavily pretreated disease, it is unlikely that dramatic responses will occur. The methods used to detect responses in solid tumours and metastases are crude, and it is likely that many useful drugs are missed. New techniques are needed to detect small but important responses. In addition to these technical problems, clinical trials are expensive and the time required for preclinical pharmacology and toxicology is lengthy. In the early days, drugs could enter clinical trials after fairly simple toxicological studies. The thalidomide disaster in the 1960s, however, led to the setting up of regulatory bodies to scrutinize drugs before clinical trials. This proved detrimental for cancer drug development because a series of fairly long-term tests is now required. These must be carried out in both rodents and one other species, usually the dog. This approach was probably a good thing for most medicines where a large margin of safety is required between the therapeutic dose and the dose which causes side effects, but was inappropriate for anticancer agents which are tested at the maximum possible dose which gives manageable side effects. These new regulations meant that the cost of one clinical trial after the 1970s was equivalent to the cost of ten before that time. Solutions to these problems are available, although to put them into practice would require the cooperation of government regulatory authorities, the pharmaceutical industry and other organisations such as the US National Cancer Institute (NCI), the UK Cancer Research Campaign (CRC) and the European Organisation for Research and Treatment of Cancer (EORTC). Firstly, it is important to switch from clinical trials of analogues and combinations of standard drugs to trials of new classes of anticancer agents. Further, an international effort should be launched whereby these new agents can be rapidly tested in phase II trials against common solid cancers using new techniques to detect small but significant tumour responses. Lead chemicals discovered in this way could then be taken back to the laboratory for further development. There is no shortage of new drugs which act by mechanisms quite different from present-day agents, and new approaches can greatly increase the amount of cytotoxic agents delivered to solid tumours. As long ago as 1980, the CRC introduced protocols which enabled early clinical trials to be carried out rapidly and with minimal cost. These procedures used short-term tests only in rodents to determine a safe starting dose. The test can be completed within six months and around fifty clinical trials using this protocol have been successfully carried out in collaboration with the EORTC. Despite this, the American Food and Drug Administration (FDA), regulatory authorities in many other countries and many drug companies still insist on using a second animal species before a phase I clinical trial is permitted instead of using the money spent to develop several agents with minimal toxicology testing. The EORTC and CRC also plan to introduce positron emission tomographic scanning into early clinical trials as a highly sensitive method of measuring tumour response. Cancer mortality has changed little over the past forty years, mainly because of our failure to develop curative chemotherapy for the common solid cancers. The way forward is to carry out extensive phase I and II clinical trials of the many new types of anticancer agent that have become available as a result of increased knowledge about cancer cells and how they differ from normal tissues. In order to do this, the regulatory authorities must recognize that minimal toxicology protocols are adequate, and drug companies must be persuaded to give more emphasis to the search for new chemotherapeutic agents. A coordinated effort to achieve these aims would be a wonderful way to mark the fiftieth anniversary of modern chemotherapy. Unfortunately the regulatory authorities find it less risky to stick with extensive safety testing rather than to use shortcuts, however well-validated clinically. Many but not all drug companies, mindful of profits, prefer the easy way out and concentrate on analogues, while most clinicians opt for trials of combinations of known agents, being aware that they are worth a publication or two. Reprinted with permission from Helix, Volume V, Issue 1, 1996, pp. 20-21.

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Spinal muscular atrophy (SMA) is common. The prevalence of SMA in southern Chinese is 1 in 53,000. The clinical course is variable. The traditional classification of SMA includes age of onset, age of death, achievement of motor milestones, and ambulatory status as criteria. There was a lack of inclusion of the best lifetime functional status of any child with SMA. With the advances in medical care, the life expectancy and ambulatory status of patients with SMA have improved. The objective of this study was to assess the survival pattern, ambulatory status, and functional status of children with SMA. Patients with SMA were recruited from the neuromuscular clinic of the Duchess of Kent Children's Hospital, which is a university-affiliated hospital, and the Families of SMA in Hong Kong. By September 2002, 102 SMA cases had been registered in the Duchess of Kent Children's Hospital neuromuscular clinic and Families of SMA registry, and 83 patients were analyzed. Among them, 39 were recruited for the administration of Functional Independence Measure for Children (WeeFIM), an assessment tool for functional status that has been previously validated by us for Chinese children. The diagnosis of SMA was made from clinical history, serum muscle enzyme, electromyography, muscle biopsy, and, recently, by molecular studies. In Hong Kong, molecular tests of the survivor motor neuron gene was available since 1995. A total of 36 in our cohort of 83 patients had the diagnosis confirmed with molecular analyses. We adopted the classification of SMA from previous studies in which the criteria were based on the International SMA consortium (1992) with modifications according to the 59th European Neuromuscular Center International Workshops. As only SMA patients with childhood onset were studied, we did not include any type IV patients in our study. Parents were interviewed and records were reviewed for demographic and clinical data, including age of onset, gender, family history, motor milestones, disease progression, loss of motor function, and involvement of respiratory or bulbar muscles. We define the age of disease onset as the age in which the first abnormalities were obvious from the medical records or from the descriptions of the parents about the first signs of weakness, eg, age of achievement of certain motor milestones or loss of functions. For the ambulatory status, we define "being ambulatory" as having the ability to walk for 100 meters, either with assistance such as calipers or walkers or without assistance. Actuarial survival curves were obtained by using the Kaplan-Meier method for calculating survival probabilities and probabilities of remaining ambulatory. The parents or the chief caregivers were interviewed for functional status using WeeFIM at the last registered date in September 2002. The WeeFIM consists of 3 domains: 1) self-care, 2) mobility, and 3) cognition. The self-care domain consists of 8 items, namely eating, grooming, bathing, dressing (upper body), dressing (lower body), toileting, and bladder and bowel management. The mobility domain consists of 5 items: transfer from chair or wheelchair, transfer to toilet, transfer to tub or shower, walking/wheelchair/crawling distance, and moving up and down stairs. The cognition domain assesses comprehension, expression, social interaction, problem solving, and memory. A scoring scale from 1 to 7 was used (1 = total assistance, 2 = maximal assistance, 3 = moderate assistance, 4 = minimal contact assistance, 5 = supervision, 6 = modified independence, and 7 = complete independence). The maximum total WeeFIM score is 126, and the maximum score for self-care, mobility, and cognition are 56, 35, and 35, respectively. For type I SMA (n = 22), the survival probabilities at 1, 2, 4, 10, and 20 years were 50%, 40%, 30%, 30%, and 30%, respectively. For type II SMA (n = 26), the survival probabilities at 1, 2, 4, 10, and 20 years were 100%, 100%, 100%, 92%, and 92%, respectively. Sixteen of the SMA I patients and 4 of the SMA II patients died of cardiorespiratory failure. The 5 surviving SMA I patients all were ventilator dependent. All SMA III patients were surviving at the time of study. The probability of remaining ambulatory at 2, 4, 10, and 20 years after onset was 100%, 100%, 81%, and 50% for type IIIa (age of onset &lt;3 years) and 100%, 100%, 84%, and 68% for type IIIb (age of onset between 3 and 30 years), respectively. The interval between disease onset and inability to walk was 15.0 +/- 10.9 years (mean +/- standard deviation) and 21.2 +/- 11.7 years for patients with SMA IIIa and IIIb, respectively. Only 39 patients participated in the WeeFIM interview as 20 had already died at the time of study and 24 refused participation. No difference could be found in the age of onset, gender, or types of SMA between those who participated (n = 39) and those who did not (n = 24). The mean total WeeFIM quotients were 24% for SMA type 1, 57% for SMA type 11, 75% for SMA type IIIa, and 78% for SMA type IIIb. For the self-care domain, 100% SMA type I and 73% SMA type II patients required assistance, whereas 55% and 63% of SMA types IIIa and IIIb patients achieved functional independence. Bathing and dressing (upper and lower body) were items with which most SMA children required help or supervision. For the mobility domain, assistance was needed in &gt;90% of SMA types I, II, and IIIa and in 63% of SMA type IIIb patients. Stair management was the major obstacle for independence in achieving mobility for all types of SMA. For the cognition domain, performance was the best among the 3 domains, and 60% of SMA type II, 78% of SMA type IIIa, and 90% of SMA type IIIb patients achieved functional independence. However, except for SMA type IIIb, a significant proportion of patients still need assistance or supervision in the area of problem solving. Statistically significant differences were found in the WeeFIM scores between type I and type II and between type IIIa and IIIb patients. However, no significant difference could be observed between type II and type IIIa SMA patients in the overall WeeFIM scores or performance in any of the 3 domains. We found that there was improvement in survival in SMA patients as compared with other studies. Assistance or supervision was needed for the majority of SMA patients for both mobility and self-care domains. With improvement in survival as a result of medical advances, assessment of the most current or the best-ever functional status at a designated age might be an important criterion for classification of SMA.

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The Harms technique of stabilizing C1-C2 by fixation with polyaxial screws and rods is a further option for atlantoaxial fixation from the dorsal approach. Harms and Melcher published this method in 2001, but the operation had first been performed by Harms in August 1997. The aim of this study is to evaluate the first results and try to assign the Harms C1-C2 fixation an appropriate standing in the in broad range of options for stabilization of the atlantoaxial complex. Between December 2002 and January 2004 we carried out the Harms fixation of C1-C2 on 22 patients admitted to the Department of Spine Surgery, Motol University Hospital, 2nd Medical Faculty in Prague. Out of these, 18 patients were included in this study, 10 men and 8 women between 23 and 84 years of age (average, 55.4 years) followed-up longer than 6 months. In 14 patients we used the Harms technique as a permanent fixation of C1-C2 in order to achieve atlantoaxial arthrodesis and, in four patients, we applied it only for a period of 4 to 6 months without the use of bone grafts or their substitutions. We employed the permanent fixation to treat the following conditions: fracture of the atlas in three patients, type IIA comminuted fracture of the dens base in three patients, fracture of C2 categorized as "other" in two patients, atlantoaxial vertical instability in one patient with rheumatoid arthritis, malunion of the fractured dens in one patient, and complicated trauma to C1-C2 in four patients. The temporary fixation was used for type III displaced fractures of the dens in two and fixed atlantoaxial rotatory dislocations also in two cases. Only one patient showed signs of Frankel C neurological deficit on admission, the rest were without neurological findings. All screws were inserted under an image intensifier always in lateral projection. First we retracted the greater occipital nerve in a caudal direction towards C2 with a fine raspatory and, using an awl, marked the entry point in the C1 lateral mass; a pilot hole, reaching through the anterior cortical bone, was made with a 2.5 mm drill. It followed a straight or slightly convergent trajectory in an anterior-posterior direction and parallel to the plane of the C1 posterior arch in the sagittal direction. Individual anatomical variations in the atlantoaxial complex of every patient were respected. The hole was tapped through the entire vertebral body, with the exception of osteoporous bone in which only the posterior cortical bone was treated with a screw tap. At this stage profuse bleeding usually arose from dissection around the epidural venous plexus along the C1-C2 joint. This was effectively controlled by a quick insertion of a screw and compression of the venous plexus with the screw head. To control bleeding by bipolar electrocautery is difficult and is always associated with a risk of nerve injury. Screws 3.5 mm thick, with polyaxial heads, were inserted bicortically into the lateral mass of C1. Subsequently, the intervertebral C2-C3 joint was localized and its medial border in the spinal canal was palpated. The entry point for placement of a C2 pedicle screw was marked with an awl at the point of intersection at a distance of 2 mm from the medial border and 5 mm from the caudal border of the C2 articular process. Under an X-ray intensifier in lateral projection, a hole was drilled approximately parallel to the screws inserted in C1, i. e., at an angle of 20 to 30 degrees cranially, up to and through the anterior cortical bone. In the transversal plane, the screws were situated in a convergent direction at an angle of 20 to 25 degrees. After all screws had been inserted, we reduced the antlantoaxial complex in the correct anatomical position by manipulating the patient's head or by directly adjusting the screws. Connecting 3.0-mm rods were then applied and fastened by cap nuts or inner nuts according to the instrumentation used. Operative time ranged from 35 to 155 min, with an average of 81 min. Intra-operative blood loss ranged from 50 to 1500 ml, with an average of 560 ml. The X-ray intensifier was used for a period of 0.4 to 2.6 min, with an average of 0.9 min. A total of 36 screws were inserted in the atlas; their length ranged from 16 to 34 mm (average, 30.6 mm). All screws were positioned correctly in the C1 lateral mass; two screws did not reach up to the anterior cortical bone and one protruded over it, but without causing clinical problems. Thirty-six screws were inserted in the axis. Their length ranged from 28 to 36 mm (average, 31.7) mm). Twenty-seven screws were correctly applied through the isthmus into the C2 anterior cortical bone, three were too short to reach it and five were placed too close to the vertebral artery canal. Of these, two protruded into the artery canal, but without clinical consequences. One screw inserted too medially passed into the spinal canal, but this also was without clinical response. Of the 36 screws inserted in C2, three (8.3 %) were malpositioned. Bony fusion at C1-C2 was the goal of this operation in 14 patients. At 6 weeks post-operatively, it was achieved in two patients, at 12 weeks in 12 patients and at 6 months in all 14 patients. The C1-C2 segment was stable at 12 weeks in all 18 treated patients. Four patients reported restriction of motion in rotation by 10 to 25 % after removal of the instrumentation. Operative time, longer at the beginning than with the Magerl technique, gradually shortened to between 45 and 60 min. Similar trends were seen when intra-operative blood loss and X-ray exposure were evaluated. Using the Harms and Melcher procedure we saved the greater suboccipital nerve. In contrast to these authors, however, we did not resect the atlantoaxial joint. Solid fusion was achieved in all our patients. Of the total of 72 screws inserted, only three (4.2 %) were assessed as malpositioned; however, when related to the 36 screws inserted in C2, this was 8.3 %, which indicates that insertion of screws in C2 was more difficult. We did not observe any clinical consequences in any of these cases. The Harms fixation of C1-C2 is a very effective technique for stabilizing the atlantoaxial complex. It enables us to provide temporary fixation without damage to atlantoaxial joints and to reduce the vertebrae after the screws and rods had been inserted, which is unique. These advantages compensate for a higher cost of the implant.

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Improving quality of care in many countries is one of the priorities of health systems. At the same time one of the most important methods of improving quality of care is the widespread use of methods and principles of evidence-based medicine (EBM) [1]. The implementation of EBM in public health practice provides for the optimization of quality of care in terms of safety, efficacy and cost, one way of which is the use of clinical guidelines. Clinical guidelines developed with the use of EBM, provide an opportunity to use the latest and accurate information to optimize or neutralize impact on physician decision-making of subjective factors such as intuition, expertise, opinion of respected colleagues, recommendations of popular manuals and handbooks, etc. To assess and analyze the developed clinical guidelines (CG) and protocols (CP) in the Kyrgyz Republic in the period from 2008 to 2014 and evaluate their implementation in practical healthcare. Retrospective analysis of the developed clinical guidelines and protocols according to the approved methodology, interviewing leaders, questioning doctors and patients for their implementation. All participants gave informed consent for voluntary participation in the study. Within the framework of the National Program "Manas Taalimi" "Strategy for development of evidence-based medicine in the Kyrgyz Republic for 2006-2010" (MOH Order №490 from 09.04.06) was developed and approved for use. Its main purpose was to create a sustainable system of development, deployment and monitoring of the CG and CP and further promotion of EBM into practical health care, education and science. As a result, a number of documents ("Expert Council for assessing the quality of clinical guidelines/protocols", "AGREE instrument to assess the methodological content of clinical guidelines" [2], "The methodology of development and adaptation of clinical guidelines based on evidence-based medicine") were approved by the Order of the Ministry of Health from 31.12.2008 №704.This methodology was based on the international guideline SIGN-50 [3], as part of the strategy, it was decided to adapt clinical guidelines of the advanced countries of the world to the organizational characteristics of health care in the Kyrgyz Republic. According to the adopted methodology, the development of clinical guidelines should include the following steps: choose a theme, create a multidisciplinary group to conduct a search of existing clinical guidelines and assess their quality, if necessary, conduct an additional search of evidence, make recommendations and draw up the text of clinical guidelines, conduct peer review and consultations, approve clinical guidelines in the pilot, approve the clinical management of the Ministry of Health, publish and distribute, put into practice, monitor the effectiveness of implementation, provide for the revision and updating of clinical guidelines as new credible information appears. In the future, these CGs will be considered as a basis for the development of the CP in accordance with the possibilities of health care organizations of the country. Figuratively speaking, the CG answers the question - "What can be done in an ideal situation? ', And CP -" What should be done in a country?".The Ministry of Health over the period 2008-2014 years approved 41 CGs and 118 CPs for common diseases. It should be noted that only 31.7% of them were represented by the corresponding CGs. Among the approved CPs only 15.3% were based on the corresponding CGs. All of the CGs and CPs (100%) identified experts who prepared the documents and to whom they are addressed. The search strategy information was available only in 24.3% of cases, and only 18.1% used the criteria for selection of international guidelines, which were found in the CGs. 100% of the CGs and CPs indicated no conflict of interest of their developers, but it should be noted that 89% of the CG and CP were developed with the financial assistance of donor organizations supporting the Kyrgyz health reform. The degree of evidence of the recommendations was presented in 100% of the documents, but grading scales were different: in one CG manual grading was used with 3 levels of evidence (A, B, C), in the other - 4 levels (A, B, C, D ), and in the third - tier 5-6 (I, II, III, IV, V), which is not the approved methodology, which was based on gradation - A, B, C, D. In the process of approval of CGs and CPs, 100% did not specify points of methodological quality evaluation.To assess the implementation of approved CG in the practice (training, availability of the CG and CP for each doctor, informing patients about the CG and CP, monitoring use) we interviewed the leaders of health care organizations (20), surveyed 200 doctors and 100 patients. Only 10% of leaders said that they participated in the training on the CG and CP. 5% of them confirmed that every doctor had the corresponding copies of CGs and CPs, 100% of the leaders conduct internal audits on the use of the CG and CP, in 95% of cases the developed CGs and CPs do not take into account local health systems conditions (drugs, equipments etc.). 100% of respondents followed the CGs and CPs, as penalties were introduces by the Ministry of Health, Health Insurance Fund for violation of these recommendations. 25% of respondents reported improved clinical outcomes. To the question "How to improve the practice of medicine with the use of CGs and CPs?" 100% of the managers answered that they needed trainings: trainings for physicians, trainings for the developers of these documents. The survey of doctors showed that only 5% of them were trained in the use of CGs and CPs, 100% of them had the copies of CGs and CPs, 100% of doctors answered that the CGs and CPs not always were suitable for their practice. Questioning patients revealed the following: 100% of them never heard of the CGs and CPs, 2% of patients noted some improvement in healthcare delivery, and 20% of patients were referred to private laboratories for diagnostic tests, and 100% of the patients-respondents bought their drugs for their own pocket money. It is very important to ensure equal opportunities in access to medical interventions designed accordingly to the CGs and CPs at all health facilities that will prevent discrimination, depending on territorial distribution, administrative subordination, and other factors in the provision of health care. Implementation of CG and CP recommendations depends not only on the level of health care, knowledge and judgment of a clinician, but also on affordability of a particular diagnostic or therapeutic technologies for a patient. Cases when effective services are not unaffordable for patients should be considered from ethical perspective.

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Motion sickness is a syndrome that occurs as a result of passive body movement in response to actual motion, or the illusion of motion when exposed to virtual and moving visual environments. The most common symptoms are nausea and vomiting. Antihistamines have been used in the management of motion sickness for decades, however studies have shown conflicting results regarding their efficacy. To assess the effectiveness of antihistamines in the prevention and treatment of motion sickness in adults and children. The Cochrane ENT Information Specialist searched the Cochrane ENT Register; Central Register of Controlled Trials; Ovid MEDLINE; Ovid Embase; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 7 December 2021. Randomised controlled trials (RCTs) in susceptible adults and children in whom motion sickness was induced under natural conditions such as air, sea and land transportation. We also included studies in which motion sickness was induced under experimental conditions (analysed separately). Antihistamines were included regardless of class, route or dosage and compared to no treatment, placebo or any other pharmacological or non-pharmacological interventions. We used standard Cochrane methods. Our primary outcomes were 1) the proportion of susceptible participants who did not experience any motion sickness symptoms; 2) the proportion of susceptible participants who experienced a reduction or resolution of existing symptoms. Secondary outcomes were 1) physiological measures (heart rate, core temperature and gastric tachyarrhythmia (electrogastrography)) and 2) adverse effects (sedation, impaired cognition, blurred vision). We used GRADE to assess the certainty of the evidence for each outcome. We included nine RCTs (658 participants). Studies were conducted across seven countries, with an overall age range of 16 to 55 years. Motion sickness was induced naturally in six studies and experimentally in four studies (rotating chair). All the naturally induced studies only evaluated first-generation antihistamines (cinnarizine and dimenhydrinate). Risk of bias across the studies varied, with mostly low risk for random sequence generation and allocation concealment, and mostly high risk for selective reporting. Only the experimentally induced studies measured physiological parameters and only the naturally induced studies evaluated adverse effects. There were no studies that clearly assessed the paediatric population. Antihistamines versus placebo or no treatment Antihistamines are probably more effective than placebo at preventing motion sickness symptoms under natural conditions (symptoms prevented: 25% placebo; 40% antihistamines) (risk ratio (RR) 1.81, 95% confidence interval (CI) 1.23 to 2.66; 3 studies; 240 participants) (moderate-certainty). The evidence is very uncertain about the effect of antihistamines on preventing motion sickness under experimental conditions (standardised mean difference (SMD) 0.32, 95% CI -0.18 to 0.83; 2 studies; 62 participants) (very low-certainty). No studies reported results on the resolution of existing motion sickness symptoms. Antihistamines may result in little or no difference in gastric tachyarrhythmia under experimental conditions (mean difference (MD) -2.2, 95% CI -11.71 to 7.31; 1 study; 42 participants) (low-certainty). No studies reported results for any other physiological measures. When compared to placebo, antihistamines may be more likely to cause sedation (sedation: 44% placebo; 66% antihistamines) (RR 1.51, 95% CI 1.12 to 2.02; 2 studies; 190 participants) (low-certainty); they may result in little or no difference in blurred vision (blurred vision: 12.5% placebo; 14% antihistamines) (RR 1.14, 95% CI 0.53 to 2.48; 2 studies; 190 participants) (low-certainty); and they may result in little or no difference in terms of impaired cognition (impaired cognition: 33% placebo; 29% antihistamines) (RR 0.89, 95% CI 0.58 to 1.38; 2 studies; 190 participants) (low-certainty). Antihistamines versus scopolamine The evidence is very uncertain about the effect of antihistamines on preventing motion sickness under natural conditions when compared to scopolamine (symptoms prevented: 81% scopolamine; 71% antihistamines) (RR 0.89, 95% CI 0.68 to 1.16; 2 studies; 71 participants) (very low-certainty). No studies were performed under experimental conditions. No studies reported results on the resolution of existing motion sickness symptoms. The evidence is very uncertain about the effect of antihistamines on heart rate under natural conditions (narrative report, 1 study; 20 participants; "No difference in pulse frequency"; very low-certainty). No studies reported results for any other physiological measures. When compared to scopolamine, the evidence is very uncertain about the effect of antihistamines on sedation (sedation: 21% scopolamine; 30% antihistamines) (RR 0.82, 95% CI 0.07 to 9.25; 2 studies; 90 participants) (very low-certainty) and on blurred vision (narrative report: not a significant difference; 1 study; 51 participants; very low-certainty). No studies evaluated impaired cognition. Antihistamines versus antiemetics Antihistamines may result in little or no difference in the prevention of motion sickness under experimental conditions (MD -0.20, 95% CI -10.91 to 10.51; 1 study; 42 participants) (low-certainty). The evidence is of low certainty due to imprecision as the sample size is small and the confidence interval crosses the line of no effect. No studies assessed the effects of antihistamines versus antiemetics under natural conditions. No studies reported results on the resolution of existing motion sickness symptoms. Antihistamines may result in little or no difference in gastric tachyarrhythmia (MD 4.56, 95% CI -3.49 to 12.61; 1 study; 42 participants) (low-certainty). No studies reported results for any other physiological measures. No studies evaluated sedation, impaired cognition or blurred vision. One study reported physiological data for this outcome, evaluating gastric tachyarrhythmia specifically. Antihistamines may result in little or no difference in gastric tachyarrhythmia (MD 4.56, 95% CI -3.49 to 12.61; 1 study; 42 participants; low-certainty evidence). This evidence is of low certainty due to imprecision as the sample size is small and the confidence interval crosses the line of no effect. Antihistamines versus acupuncture The evidence is very uncertain about the effects of antihistamines on the prevention of motion sickness under experimental conditions when compared to acupuncture (RR 1.32, 95% CI 1.12 to 1.57; 1 study; 100 participants) (very low-certainty). This study did not assess the prevention of motion sickness under natural conditions, nor the resolution of existing motion sickness symptoms. There was no study performed under natural conditions. Physiological measures and adverse effects were not reported. There is probably a reduction in the risk of developing motion sickness symptoms under naturally occurring conditions of motion when using first-generation antihistamines, in motion sickness-susceptible adults, compared to placebo. Antihistamines may be more likely to cause sedation when compared to placebo. No studies evaluated the treatment of existing motion sickness, and there are few data on the effect of antihistamines in children. The evidence for all other outcomes and comparisons (versus scopolamine, antiemetics and acupuncture) was of low or very low certainty and we are therefore uncertain about these effects of antihistamines.

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p,pN-Dichlorodiphenyl sulfone is used as a starting material in the production of polysulfones and polyethersulfones and as a component in reactive dyes in the textile industry; it is also a by-product of pesticide production. p,pN-Dichlorodiphenyl sulfone was nominated for study by the National Cancer Institute because of its history of high production and use, the prospect of increased production and use, and the absence of adequate toxicity testing. Male and female F344/N rats and B6C3F1 mice were exposed top,pN-dichlorodiphenyl sulfone (greater than 99% pure)in feed for 14 weeks or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium,cultured Chinese hamster ovary cells, and mouse bone marrow. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were fed diets containing 0, 30, 100, 300, 1,000, or 3,000 ppm p,pN-dichlorodiphenyl sulfone (equivalent to average daily doses of approximately 2, 6, 19, 65, or 200 mgp,pN-dichlorodiphenyl sulfone/kg body weight) for 14 weeks. All rats survived until the end of the study. Mean body weights of groups exposed to 300 ppm or greater were significantly less than those of the controls. Liver weights of groups exposed to 100 ppm or greater and kidney weights of 1,000 and 3,000 ppm male rats were significantly greater than those of the controls. Centrilobular hepatocyte hypertrophy of the liver was observed in most male rats exposed to 100 ppm or greater and in all female rats exposed to 300 ppm or greater, and the severities were increased in 300 ppm males and 1,000 and 3,000 ppm males and females. The incidences of nephropathy in 1,000 and 3,000 ppm female rats were significantly increased. Dose-related increases in severity of nephropathy were observed in male rats. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were fed diets containing 0, 30, 100, 300, 1,000, or 3,000 ppm p,pN-dichlorodiphenyl sulfone (equivalent to average daily doses of approximately 3.5, 15, 50, 165,or 480 mg/kg) for 14 weeks. All mice survived until the end of the study. Mean body weights of groups exposed to 300 ppm or greater were significantly less than those of the controls. Liver weights of groups exposed to 300 ppm or greater were significantly increased. Centrilobular hypertrophy of the liver was observed in most males exposed to 100 ppm or greater and in all females exposed to 1,000 or 3,000 ppm, and the severities generally increased with increasing exposure concentration. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were fed diets containing 0, 10 (males), 30, 100, or 300 (females) ppm p,pN-dichlorodiphenyl sulfone for 105 weeks. Dietary concentrations of 10, 30, and 100 ppm resulted in average daily doses of approximately 0.5, 1.5, and 5.0 mg/kg to males. Dietary concentrations of 30, 100,and 300 ppm resulted in average daily doses of approximately 1.6, 5.4, and 17 mg/kg to females. Additional groups of 10 male and 10 female rats were fed the same p,pN-dichlorodiphenyl sulfone-containing diets for 18 months and bled for plasma determinations of p,pN-dichlorodiphenyl sulfone at approximately 2 weeks and 3, 12, and 18 months. Survival of all exposed groups of male and female rats was similar to that of the control groups. Mean body weights of 30 and 100 ppm males were generally less than those of the controls during the latter part of the study, and mean body weights of 100 and 300 ppm female rats were less from weeks 30 and 18,respectively. Feed consumption by the exposed groups was similar to that by the controls throughout the study. The incidences of centrilobular hepatocyte hypertrophy in 100 ppm male and 100 and 300 ppm female rats were significantly greater than those in the controls. The incidences of bile duct hyperplasia and centrilobular degeneration were also significantly increased in 100 and 300 ppm females. No neoplasms were related to chemical exposure. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were fed diets containing 0, 30, 100, or 300 ppm p,pN-dichlorodiphenyl sulfone for 105 to 106 weeks. Dietary concentrations of 30, 100, and 300 ppm delivered average daily doses of approximately 4, 13, and 40 mg/kg to males and approximately 3, 10, and 33 mg/kg to females. Additional groups of 10 male and 10 female mice were fed the same p,pN-dichlorodiphenyl sulfone-containing diets for up to 12 months;three mice in each group were bled for plasma determinations of p,pN-dichloro-diphenyl sulfone at approximately 2 weeks or 3 or 12 months. Survival of all exposed groups of male and female mice was similar to that of the control groups. Mean body weights of 300 ppm mice were less than those of the controls throughout most of the study. Feed consumption by the exposed groups was similar to that by the controls throughout the study. The incidences of centrilobular hepatocyte hypertrophy in all exposed groups of male mice and in 100 and 300 ppm females were significantly greater than those in the controls. The incidence of eosinophilic foci in 300 ppm females was significantly increased. No neoplasms were related to chemical exposure. PHARMACOKINETICS OF p,pN-DICHLORODIPHENYL SULFONE: p,pN-Dichlorodiphenyl sulfone is rapidly absorbed from the gut and metabolized by a saturable process. Although some p,pN-dichlorodiphenyl sulfone is eliminated unchanged in feces and urine, most of the elimination is via metabolism. Mathematical modeling of the toxicokinetics supports the view that p,pN-dichlorodiphenyl sulfone induces enzymes involved in its metabolism. p,pN-Dichlorodiphenyl sulfone was not mutagenic in any of several strains of Salmonella typhimurium, with or without metabolic activation enzymes (S9). Results of the sister chromatid exchange test in cultured Chinese hamster ovary cells were judged to be negative in the presence of S9 and equivocal in the absence of S9, but no induction of chromosomal aberrations was noted, with or without S9. In contrast to the in vitro results, positive results were obtained in an acute in vivo mouse bone marrow micronucleus assay with p,pN-dichlorodiphenyl sulfone administered by intraperitoneal injection three times over a dose range of 200 to 800 mg/kg. Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity* of p,pN-dichlorodiphenyl sulfone in male F344/N rats exposed to 10, 30, or 100 ppm or in female F344/N rats exposed to 30, 100, or 300 ppm. There was no evidence of carcinogenic activity of p,pN-dichlorodiphenyl sulfone in male or female B6C3F1 mice exposed to 30,100, or 300 ppm. Exposure to p,pN-dichlorodiphenyl sulfone for 2 years caused increased incidences of nonneoplastic lesions of the liver in male and female rats and mice.

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Part 1: Technical and methodological issues. Contrast echocardiography is based on the use of gas microbubbles. The size, gas composition and shell structure of the microbubbles modify their stability, resistance to pressure and scattering behavior. A proposed classification of contrast agents is based on the modalities of production of microbubbles (galenic or industrial); the industrial agents are divided into three generations depending on their characteristics. Following venous administration, the industrial microbubbles behave as intravascular free-flowing tracers and this is fundamental for their use in perfusion studies. When insonated at a low acoustic pressure, microbubbles show a linear behavior and can be used for signal amplification. At intermediate acoustic pressures microbubbles resonate and produce a harmonic signal that is detectable by new scanners. Higher acoustic pressures cause microbubble disruption with emission of a transient acoustic signal. The available contrast agents behave differently in an ultrasound field. Part 2: Safety of contrast echocardiography. Galenic contrast agents were tested in many studies for intracoronary and intravenous injection and no clinically relevant side effects were detected. The intravenous injection of industrial contrast agents is safe in all conditions, even in acute coronary syndromes. The interaction between ultrasound and microbubbles produces energy with potential effects on tissue for inertial cavitation and acoustic current production. These effects seem particularly interesting for the therapeutic applications of contrast echocardiography, but they do not appear to have clinically relevant effects. Part 3: Experimental studies. Experimental studies in contrast echocardiography are designed to induce, in animal models, acute myocardial infarction and coronary artery stenosis and to evaluate the differences in blood flow. The risk area and infarct area are well visualized with serial contrast agent infusion. No-reflow after coronary occlusion is a well-known phenomenon and is detectable at contrast echocardiography. Different degrees of induced coronary stenosis cause differences in the regional flow rate. The results of contrast echocardiographic studies are comparable with those of other invasive flow measurements. Caution must be used to transfer the knowledge acquired from animal studies to the clinical arena, owing to both methodological and anatomical differences. Part 4: Enhancement of Doppler signal and coronary flow study. The anterior descending coronary artery flow is detectable in almost all patients, and the posterior descending coronary artery in about 70%. The coronary flow reserve can be measured by injection of a vasodilator agent (dipyridamole or preferably adenosine) with a success rate of almost 100 % for the anterior descending but only 50 % for the posterior descending coronary artery. Data from transthoracic studies are comparable with those of Doppler flow wire. The fields of application presently include the evaluation of acute myocardial infarction, the short- and long-term results of percutaneous coronary interventions and coronary grafts, and the study of the microcirculation in several clinical conditions where the coronary flow reserve may be reduced, such as in syndrome X, hypertension, hypercholesterolemia or diabetes. Part 5: Endocardial border enhancement. Opacification of the left ventricle is the main indication to contrast echocardiography that, in this setting, is principally used to improve endocardial border delineation. This allows accurate evaluation of left ventricular volumes and function, increasing the role of echocardiography for the quantitative study of the left ventricle. Other indications for left ventricular opacification are the identification of intraventricular thrombosis, non-compaction of the left ventricle and heart rupture. In this respect, industrial second-generation contrast agents are more useful. The most appropriate patients for contrast echocardiography are those with a poor or suboptimal acoustic window, in whom a predictable diagnostic and prognostic usefulness of the procedure is expected. If appropriately used, contrast echocardiography is a cost-effective technique, although lack of reimbursement presently limits its use. Part 6: Use of contrast agents during stress echocardiography. Contrast agents during stress echocardiography may be used to improve the diagnostic accuracy of the test and to study myocardial perfusion. The diagnosis of ischemia in stress echo relies on the operator's visual assessment of changes in contractility during stress. Contrast agents must be considered an important tool that improve image quality especially in patients with an intermediate or poor acoustic window and their use has been reported to be cost-effective in the few studies designed to this end. The evaluation of myocardial perfusion during stress is certainly one of the most important goals of contrast echocardiography. Preliminary data are interesting but there is still a number of methodological problems that currently hamper clinical application. Part 7: Myocardial perfusion. Echocardiography has the potential of visualizing microbubbles in the microcirculation by detecting stimulated acoustic emission, produced by high-energy applied ultrasound, or by detecting the harmonic signal produced by resonance of the microbubbles in a low-energy ultrasound field. In the first case images are triggered at increasing end-systolic intervals (intermittent imaging), whereas in the second case entire cardiac cycles are analyzed (real-time imaging). Continuous infusion is the preferred method of maintaining a large and constant microbubble concentration inside the microcirculation. Analysis of the perfusion signal may be made in the qualitative, semi-quantitative or quantitative mode. Quantitative analysis is based on the construction of videointensity-time curves to study the refilling phase after complete microbubble destruction. There are not enough data in the literature showing the additional role of quantitative analysis for clinical purposes. Thus, at present, quantitative softwares should be considered as research tools. Conversely, there is a general consensus based on experimental and clinical studies on the use of myocardial contrast echo in patients with acute myocardial infarction by means of qualitative or semi-quantitative analysis. Important information on the infarct area extension, on the efficacy of reperfusion therapy, on the presence and extension of the no-reflow phenomenon and on the extent of residual tissue viability may be derived from the routine use of myocardial contrast echo. The reference technique still remains myocardial scintigraphy even though many theoretical problems are being discussed. Part 8: Implementing ultrasound contrast in the echocardiography laboratory. Contrast echocardiography should be considered an extension of the existing echocardiographic examination. Standard laboratory equipment is sufficient to run a contrast echocardiography program. However, cultural and technological upgrading is mandatory to obtain good results in contrast echocardiography. Intravenous infusion is easier during stress echocardiography than during rest study, because the time and cost for the venous line are comprised. In this setting, the cost-effectiveness for the addition of contrast agent is optimal, but patient selection is a critical point. The economic issue (contrast agent and personnel costs, and time needed) of contrast echocardiography determines the fact that without adequate reimbursement there is no incentive to perform the procedure.

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Despite the dramatic pertussis decrease since the licensure of whole-cell pertussis (diphtheria-tetanus toxoids-pertussis [DTP]) vaccines in the middle 1940s, pertussis remains endemic in the United States and can cause illness among persons at any age; &gt;11000 pertussis cases were reported in 2003. Since July 1996, in addition to 2 DTP vaccines already in use, 5 acellular pertussis (diphtheria-tetanus toxoids-acellular pertussis [DTaP]) vaccines were licensed for use among infants; 3 DTaP vaccines were distributed widely during the study period. Because of the availability of 3 DTaP and 2 DTP vaccines and the likelihood of the vaccines being used interchangeably to vaccinate children with the recommended 5-dose schedule, measuring the effectiveness of the pertussis vaccines was a high priority. To measure the pertussis vaccine effectiveness (VE) among US children 6 to 59 months of age. We conducted a case-control study in the Cincinnati, Ohio, metropolitan area, Colorado, Idaho, and Minnesota. Confirmed pertussis cases among children 6 to 59 months of age at the time of disease onset, with onset in 1998-2001, were included. For each case subject, 5 control children were matched from birth certificate records, according to the date of birth and residence. A standardized questionnaire was used to obtain vaccination data from parents and providers. Parents/guardians were asked about demographic characteristics, child care attendance, the number of household members who stayed at the same home as the enrolled child for &gt; or =2 nights per week, and cough illness of &gt; or =2-week duration among these household members in the month before the case patient's cough onset. Pertussis vaccine doses among case children were counted as valid if they were received &gt; or =14 days before the cough onset date ("valid period"). The age of the case patient (in days) at the end of the valid period was determined, and doses of vaccine for the matched control subjects were counted as valid if they were received by that age. Conditional logistic regression models were used to estimate the matched odds ratios (ORs) for pertussis according to the number of pertussis vaccine doses. The VE was calculated with the following formula: (1 - OR) x 100. Because the pertussis antigen components or amounts differed according to vaccine, the VE of 3 or 4 doses of DTP and/or DTaP was estimated according to the recorded vaccine manufacturer and vaccine type. All enrolled children (184 case subjects and 893 control subjects) had their vaccine history verified. The proportions of children who received 0, 1 or 2, 3, and &gt; or =4 pertussis (DTP and/or DTaP) vaccine doses among case subjects were 26%, 14%, 26%, and 34% and among control subjects were 2%, 8%, 33%, and 57%, respectively. Compared with 0 doses, the unadjusted VE estimate for 1 or 2 pertussis doses was 83.6% (95% confidence interval [CI]: 61.1-93.1%), that for 3 doses was 95.6% (95% CI: 89.7-98.0%), and for &gt; or =4 doses was 97.7% (95% CI: 94.7-99.0%). Among children who received 4 pertussis vaccinations, the risk of pertussis was slightly higher among those who received only 1 type of vaccine (either 4 DTP doses or 4 DTaP doses), compared with those who received a combination of DTP for doses 1 to 3 and DTaP for dose 4 (OR: 2.4; 95% CI: 1.1-5.2). Among children who received 3 or 4 DTaP vaccine doses, the risk of pertussis was slightly higher among those who received a DTaP vaccine with 4 pertussis antigen components (a vaccine no longer available), compared with those who received the DTaP vaccine with 2 pertussis antigen components (OR: 2.5; 95% CI: 1.1-5.8). Among children who received 4 doses, the risk of pertussis was 2.7 times higher for children who received dose 4 early (age of &lt; or =13 months), compared with children who received dose 4 at an older age (age of &gt; or =14 months) (95% CI: 1.1-6.8). For children 6 to 23 months of age, features of household structure were significant risk factors for pertussis. In a multivariate model, compared with living with an older parent (&gt; or =25 years of age), not living with an "other" household member (a relative other than a parent or sibling or a nonrelated person), and not living with a sibling 6 to 11 years of age, the risk of pertussis for children 6 to 23 months of age was 6.8 times higher if they lived with a young parent (&lt; or =24 years of age) (95% CI: 3.1-15.0), 2.5 times higher if they lived with an "other" household member (95% CI: 1.2-5.4), and 2.2 times higher if they lived with a sibling 6 to 11 years of age (95% CI: 1.2-4.3). Adjusting for these risk factors did not change the VE. Compared with control children, case children were significantly more likely to live with a household member (representing all age groups and relationships) who reported a recent cough illness with duration of &gt; or =2 weeks (87 [52%] of 168 case subjects, compared with 79 [8%] of 860 control subjects). Any combination of &gt; or =3 DTP/DTaP vaccine doses for children 6 to 59 months of age was highly protective against pertussis. However, there were differences according to vaccine type (DTaP or DTP) and DTaP manufacturer. Among children who received 4 pertussis vaccine doses, a combination of 3 DTP doses followed by 1 DTaP dose had a slightly higher VE than other combinations; among children who received 3 or 4 DTaP vaccine doses, 1 DTaP vaccine performed less well. The finding that pertussis dose 4 was more effective when given to children at &gt; or =14 months of age might be confounded if health care providers were more likely to vaccinate children at 12 months of age because of a perceived risk of undervaccination and if these same children were also at higher risk for pertussis. Household members of any age group and relationship could have been the source of pertussis, and household structure was associated with risk for pertussis for children 6 to 23 months of age. In contrast to control children in the study, 26% of case children had never been vaccinated against pertussis. Unvaccinated children are at risk for pertussis and, in a community with other unvaccinated children, can lead to community-wide pertussis outbreaks. Parents need to be educated about the morbidity and mortality risks associated with Bordetella pertussis infection, and they need to be encouraged to vaccinate their children against pertussis on time and with the recommended number of vaccine doses for optimal protection.

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SUMMARY OF CONSENSUS: 1. The use of opioids in cancer pain: The criteria for selecting analgesics for pain treatment in the elderly include, but are not limited to, overall efficacy, overall side-effect profile, onset of action, drug interactions, abuse potential, and practical issues, such as cost and availability of the drug, as well as the severity and type of pain (nociceptive, acute/chronic, etc.). At any given time, the order of choice in the decision-making process can change. This consensus is based on evidence-based literature (extended data are not included and chronic, extended-release opioids are not covered). There are various driving factors relating to prescribing medication, including availability of the compound and cost, which may, at times, be the main driving factor. The transdermal formulation of buprenorphine is available in most European countries, particularly those with high opioid usage, with the exception of France; however, the availability of the sublingual formulation of buprenorphine in Europe is limited, as it is marketed in only a few countries, including Germany and Belgium. The opioid patch is experimental at present in U.S.A. and the sublingual formulation has dispensing restrictions, therefore, its use is limited. It is evident that the population pyramid is upturned. Globally, there is going to be an older population that needs to be cared for in the future. This older population has expectations in life, in that a retiree is no longer an individual who decreases their lifestyle activities. The "baby-boomers" in their 60s and 70s are "baby zoomers"; they want to have a functional active lifestyle. They are willing to make trade-offs regarding treatment choices and understand that they may experience pain, providing that can have increased quality of life and functionality. Therefore, comorbidities--including cancer and noncancer pain, osteoarthritis, rheumatoid arthritis, and postherpetic neuralgia--and patient functional status need to be taken carefully into account when addressing pain in the elderly. World Health Organization step III opioids are the mainstay of pain treatment for cancer patients and morphine has been the most commonly used for decades. In general, high level evidence data (Ib or IIb) exist, although many studies have included only few patients. Based on these studies, all opioids are considered effective in cancer pain management (although parts of cancer pain are not or only partially opioid sensitive), but no well-designed specific studies in the elderly cancer patient are available. Of the 2 opioids that are available in transdermal formulation--fentanyl and buprenorphine--fentanyl is the most investigated, but based on the published data both seem to be effective, with low toxicity and good tolerability profiles, especially at low doses. 2. The use of opioids in noncancer-related pain: Evidence is growing that opioids are efficacious in noncancer pain (treatment data mostly level Ib or IIb), but need individual dose titration and consideration of the respective tolerability profiles. Again no specific studies in the elderly have been performed, but it can be concluded that opioids have shown efficacy in noncancer pain, which is often due to diseases typical for an elderly population. When it is not clear which drugs and which regimes are superior in terms of maintaining analgesic efficacy, the appropriate drug should be chosen based on safety and tolerability considerations. Evidence-based medicine, which has been incorporated into best clinical practice guidelines, should serve as a foundation for the decision-making processes in patient care; however, in practice, the art of medicine is realized when we individualize care to the patient. This strikes a balance between the evidence-based medicine and anecdotal experience. Factual recommendations and expert opinion both have a value when applying guidelines in clinical practice. 3. The use of opioids in neuropathic pain: The role of opioids in neuropathic pain has been under debate in the past but is nowadays more and more accepted; however, higher opioid doses are often needed for neuropathic pain than for nociceptive pain. Most of the treatment data are level II or III, and suggest that incorporation of opioids earlier on might be beneficial. Buprenorphine shows a distinct benefit in improving neuropathic pain symptoms, which is considered a result of its specific pharmacological profile. 4. The use of opioids in elderly patients with impaired hepatic and renal function: Functional impairment of excretory organs is common in the elderly, especially with respect to renal function. For all opioids except buprenorphine, half-life of the active drug and metabolites is increased in the elderly and in patients with renal dysfunction. It is, therefore, recommended that--except for buprenorphine--doses be reduced, a longer time interval be used between doses, and creatinine clearance be monitored. Thus, buprenorphine appears to be the top-line choice for opioid treatment in the elderly. 5. Opioids and respiratory depression: Respiratory depression is a significant threat for opioid-treated patients with underlying pulmonary condition or receiving concomitant central nervous system (CNS) drugs associated with hypoventilation. Not all opioids show equal effects on respiratory depression: buprenorphine is the only opioid demonstrating a ceiling for respiratory depression when used without other CNS depressants. The different features of opioids regarding respiratory effects should be considered when treating patients at risk for respiratory problems, therefore careful dosing must be maintained. 6. Opioids and immunosuppression: Age is related to a gradual decline in the immune system: immunosenescence, which is associated with increased morbidity and mortality from infectious diseases, autoimmune diseases, and cancer, and decreased efficacy of immunotherapy, such as vaccination. The clinical relevance of the immunosuppressant effects of opioids in the elderly is not fully understood, and pain itself may also cause immunosuppression. Providing adequate analgesia can be achieved without significant adverse events, opioids with minimal immunosuppressive characteristics should be used in the elderly. The immunosuppressive effects of most opioids are poorly described and this is one of the problems in assessing true effect of the opioid spectrum, but there is some indication that higher doses of opioids correlate with increased immunosuppressant effects. Taking into consideration all the very limited available evidence from preclinical and clinical work, buprenorphine can be recommended, while morphine and fentanyl cannot. 7. Safety and tolerability profile of opioids: The adverse event profile varies greatly between opioids. As the consequences of adverse events in the elderly can be serious, agents should be used that have a good tolerability profile (especially regarding CNS and gastrointestinal effects) and that are as safe as possible in overdose especially regarding effects on respiration. Slow dose titration helps to reduce the incidence of typical initial adverse events such as nausea and vomiting. Sustained release preparations, including transdermal formulations, increase patient compliance.

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Wy-14,643 was selected for inclusion in a series of studies on peroxisome proliferators because it is known to produce considerable peroxisome proliferation and hepatocarcinogenicity in rats. Male Sprague-Dawley rats were exposed to Wy-14,643 (greater than 98% pure) in feed for up to 3 months; male B6C3F1 mice and male Syrian hamsters were exposed to Wy-14,643 in feed for 2 weeks or up to 3 months. Animals were evaluated for clinical pathology, plasma concentrations of Wy-14,643, reproductive system effects, cell proliferation and peroxisomal enzyme analyses, and histopathology. Single and multiple-dose toxicokinetic studies of Wy-14,643 were conducted in additional groups of male Sprague-Dawley and Wistar Furth rats, B6C3F1 mice, and Syrian hamsters. Genetic toxicology studies were conducted in vivo in Tg.AC mouse peripheral blood erythrocytes. In the 2-week studies, groups of five mice were fed diets containing 0, 10, 50, 100, 500, or 1,000 ppm Wy-14,643 (equivalent to average daily doses of approximately 2 to 184 mg Wy-14,643/kg body weight). Groups of five hamsters were fed diets containing 0, 10, 100, 500, 1,000, or 5,000 ppm Wy-14,643 (equivalent to average daily doses of approximately 1 to 550 mg/kg). All animals survived to the end of the studies. The mean body weight gain of 500 ppm mice was significantly less than that of the controls; hamsters exposed to 100 ppm or greater lost weight during the study. Feed consumption by 500 ppm mice was greater than that by the controls. Liver weights of all exposed groups of mice and hamsters were generally significantly increased. In the 2-week studies, an increase in peroxisomal enzyme activity occurred in 10 ppm mice; increases in peroxisomal $-oxidation, carnitine acetyltransferase, catalase, and acyl CoA oxidase occurred in all exposed mice compared to controls. Significantly increased BrdU-labeled hepatocyte percentages occurred in 100 and 1,000 ppm mice and 500 and 5,000 ppm hamsters; peroxisomal $-oxidation of lipids was increased in all exposed groups of mice and hamsters. Gross lesions in the 2-week studies included liver foci in one 500 ppm mouse and one 1,000 ppm hamster and enlarged livers in one hamster in each of the 100 and 500 ppm groups and two 5,000 ppm hamsters. All 500 and 1,000 ppm mice had hepatocyte hypertrophy of the liver, and 1,000 ppm mice also had widespread individual cell necrosis. Minimal to mild multifocal vacuolation of the liver occurred in hamsters exposed to 500 ppm or greater. In the 3-month core studies, groups of 10 male rats, mice, or hamsters were fed diets containing 0, 5, 10, 50, 100, or 500 ppm Wy-14,643 (equivalent to average daily doses of approximately 0.3 to 34 mg/kg for rats, 0.9 to 135 mg/kg for mice, and 0.4 to 42 mg/kg for hamsters). Groups of 15 male rats, mice, or hamsters designated for special studies received the same concentrations of Wy-14,643 for up to 13 weeks. Groups of six male rats, 36 male mice, or 12 male hamsters designated for plasma concentration studies were fed diets containing 50, 100, or 500 ppm Wy-14,643 for up to 9 weeks. All core study animals survived to the end of the studies. Mean body weights were significantly decreased in all exposed groups except the 5 ppm groups and 10 ppm mice; hamsters in the 100 and 500 ppm groups lost weight during the study. Feed consumption by exposed rats and mice was generally similar to that by the controls; during week 14, hamsters exposed to 50 ppm or greater consumed slightly less feed than did the controls. The only clinical finding of toxicity was thinness of two 50 ppm and five 500 ppm hamsters. At all time points, the liver weights of exposed groups of core and special study rats, mice, and hamsters were generally significantly greater than those of the controls. Testis weights were significantly decreased in 500 ppm hamsters on day 34, in hamsters exposed to 5 ppm or greater at week 13 (special study), and in 100 and 500 ppm core study hamsters at the end of the study. In the sperm motility evaluation, the cauda epididymis weight of 500 ppm rats, epididymis weights of 100 and 500 ppm rats and mice, and the testis weight of 500 ppm mice were significantly less than those of the controls. For hamsters, cauda epididymis, epididymis, and testis weights; spermatid heads per testis; and spermatid counts were significantly decreased in all exposed groups evaluated for sperm motility. Epididymal spermatozoal motility and concentration in the 100 and 500 ppm groups and spermatid heads per gram testis in the 500 ppm group were also significantly decreased. Serum concentrations of estradiol were significantly decreased in all exposed groups of hamsters, and concentrations of testosterone and luteinizing hormone were decreased in groups exposed to 50 ppm or greater. At necropsy in the 3-month studies, liver foci were observed in three special study mice, including one 100 ppm mouse and one 500 ppm mouse on day 34 and one 100 ppm mouse at week 13. Liver discoloration and small testes were noted in 500 ppm hamsters on day 34, and hamsters exposed to 50 ppm or greater had enlarged livers and/or small testes at week 13 (special study) and at 3 months (core study). The incidences of cytoplasmic alteration in the liver were significantly increased in all exposed core groups of rats, mice, and hamsters; the severity of this lesion increased with increasing exposure concentration. The incidences of mitotic alteration of the liver in mice exposed to 50 ppm or greater and of liver pigmentation and oval cell hyperplasia in 500 ppm mice were significantly increased. Minimal regeneration of the corticomedullary junction of the renal tubule occurred in all exposed groups of rats. Significantly increased incidences of atrophy of the prostate gland, seminal vesicle, and testis occurred in 100 and 500 ppm hamsters. Degenerative myopathy of skeletal muscle was observed in the lumbar area and thigh of rats, mice, and hamsters and the lower leg of mice, primarily at 500 ppm. Following single-dose gavage exposure to Wy-14,643, plasma concentrations were generally higher in mice than in rats, which in turn were higher than those in hamsters. This pattern of plasma concentrations was usually attributed to high bioavailability in mice, medium bioavailability in rats, and low bioavailabilty in hamsters following an oral exposure to Wy-14,643. No increase in the frequency of micronucleated normochromatic erythrocytes was observed in the peripheral blood of male or female Tg.AC mice exposed to Wy-14,643 in feed or via dermal application for 6 months. Synonyms: [4-Chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid.

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Worldwide, many countries have adopted colorectal cancer (CRC) screening programmes, often based on faecal occult blood tests (FOBTs). CRC screening aims to detect advanced neoplasia (AN), which is defined as CRC or advanced adenomas. FOBTs fall into two categories based on detection technique and the detected blood component: qualitative guaiac-based FOBTs (gFOBTs) and faecal immunochemical tests (FITs), which can be qualitative and quantitative. Screening with gFOBTs reduces CRC-related mortality. To compare the diagnostic test accuracy of gFOBT and FIT screening for detecting advanced colorectal neoplasia in average-risk individuals. We searched CENTRAL, MEDLINE, Embase, BIOSIS Citation Index, Science Citation Index Expanded, and Google Scholar. We searched the reference lists and PubMed-related articles of included studies to identify additional studies. We included prospective and retrospective studies that provided the number of true positives, false positives, false negatives, and true negatives for gFOBTs, FITs, or both, with colonoscopy as reference standard. We excluded case-control studies. We included studies in which all participants underwent both index test and reference standard ("reference standard: all"), and studies in which only participants with a positive index test underwent the reference standard while participants with a negative test were followed for at least one year for development of interval carcinomas ("reference standard: positive"). The target population consisted of asymptomatic, average-risk individuals undergoing CRC screening. The target conditions were CRC and advanced neoplasia (advanced adenomas and CRC combined). Two review authors independently screened and selected studies for inclusion. In case of disagreement, a third review author made the final decision. We used the Rutter and Gatsonis hierarchical summary receiver operating characteristic model to explore differences between tests and identify potential sources of heterogeneity, and the bivariate hierarchical model to estimate sensitivity and specificity at common thresholds: 10 µg haemoglobin (Hb)/g faeces and 20 µg Hb/g faeces. We performed indirect comparisons of the accuracy of the two tests and direct comparisons when both index tests were evaluated in the same population. We ran the initial search on 25 June 2019, which yielded 63 studies for inclusion. We ran a top-up search on 14 September 2021, which yielded one potentially eligible study, currently awaiting classification. We included a total of 33 "reference standard: all" published articles involving 104,640 participants. Six studies evaluated only gFOBTs, 23 studies evaluated only FITs, and four studies included both gFOBTs and FITs. The cut-off for positivity of FITs varied between 2.4 μg and 50 µg Hb/g faeces. For each Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 domain, we assessed risk of bias as high in less than 20% of studies. The summary curve showed that FITs had a higher discriminative ability than gFOBTs for AN (P &lt; 0.001) and CRC (P = 0.004). For the detection of AN, the summary sensitivity of gFOBTs was 15% (95% confidence interval (CI) 12% to 20%), which was significantly lower than FITs at both 10 μg and 20 μg Hb/g cut-offs with summary sensitivities of 33% (95% CI 27% to 40%; P &lt; 0.001) and 26% (95% CI 21% to 31%, P = 0.002), respectively. Results were simulated in a hypothetical cohort of 10,000 screening participants with 1% CRC prevalence and 10% AN prevalence. Out of 1000 participants with AN, gFOBTs missed 850, while FITs missed 670 (10 μg Hb/g cut-off) and 740 (20 μg Hb/g cut-off). No significant differences in summary specificity for AN detection were found between gFOBTs (94%; 95% CI 92% to 96%), and FITs at 10 μg Hb/g cut-off (93%; 95% CI 90% to 95%) and at 20 μg Hb/g cut-off (97%; 95% CI 95% to 98%). So, among 9000 participants without AN, 540 were offered (unnecessary) colonoscopy with gFOBTs compared to 630 (10 μg Hb/g) and 270 (20 μg Hb/g) with FITs. Similarly, for the detection of CRC, the summary sensitivity of gFOBTs, 39% (95% CI 25% to 55%), was significantly lower than FITs at 10 μg and 20 μg Hb/g cut-offs: 76% (95% CI 57% to 88%: P = 0.001) and 65% (95% CI 46% to 80%; P = 0.035), respectively. So, out of 100 participants with CRC, gFOBTs missed 61, and FITs missed 24 (10 μg Hb/g) and 35 (20 μg Hb/g). No significant differences in summary specificity for CRC were found between gFOBTs (94%; 95% CI 91% to 96%), and FITs at the 10 μg Hb/g cut-off (94%; 95% CI 87% to 97%) and 20 μg Hb/g cut-off (96%; 95% CI 91% to 98%). So, out of 9900 participants without CRC, 594 were offered (unnecessary) colonoscopy with gFOBTs versus 594 (10 μg Hb/g) and 396 (20 μg Hb/g) with FITs. In five studies that compared FITs and gFOBTs in the same population, FITs showed a higher discriminative ability for AN than gFOBTs (P = 0.003). We included a total of 30 "reference standard: positive" studies involving 3,664,934 participants. Of these, eight were gFOBT-only studies, 18 were FIT-only studies, and four studies combined both gFOBTs and FITs. The cut-off for positivity of FITs varied between 5 µg to 250 µg Hb/g faeces. For each QUADAS-2 domain, we assessed risk of bias as high in less than 20% of studies. The summary curve showed that FITs had a higher discriminative ability for detecting CRC than gFOBTs (P &lt; 0.001). The summary sensitivity for CRC of gFOBTs, 59% (95% CI 55% to 64%), was significantly lower than FITs at the 10 μg Hb/g cut-off, 89% (95% CI 80% to 95%; P &lt; 0.001) and the 20 μg Hb/g cut-off, 89% (95% CI 85% to 92%; P &lt; 0.001). So, in the hypothetical cohort with 100 participants with CRC, gFOBTs missed 41, while FITs missed 11 (10 μg Hb/g) and 11 (20 μg Hb/g). The summary specificity of gFOBTs was 98% (95% CI 98% to 99%), which was higher than FITs at both 10 μg and 20 μg Hb/g cut-offs: 94% (95% CI 92% to 95%; P &lt; 0.001) and 95% (95% CI 94% to 96%; P &lt; 0.001), respectively. So, out of 9900 participants without CRC, 198 were offered (unnecessary) colonoscopy with gFOBTs compared to 594 (10 μg Hb/g) and 495 (20 μg Hb/g) with FITs. At a specificity of 90% and 95%, FITs had a higher sensitivity than gFOBTs. FITs are superior to gFOBTs in detecting AN and CRC in average-risk individuals. Specificity of both tests was similar in "reference standard: all" studies, whereas specificity was significantly higher for gFOBTs than FITs in "reference standard: positive" studies. However, at pre-specified specificities, the sensitivity of FITs was significantly higher than gFOBTs.

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We distinguish two types of predations: the predation of matter-energy equals the food chain, and the informative predation is the capture of the information brought by the sexual partners. The cell or parent consumes energy and matter to grow, multiply and produce offspring. A fixed amount of resources is divided by the number of organisms, so individual growth and numerical multiplication are limited by depletion resources of the environment. Inversely, fertilization does not destroy information, but instead produces news. The information is multiplied by the number of partners and children, since each fertilization gives rise to a new genome following a combinatorial process that continues without exhaustion. The egg does not swallow the sperm to feed, but exchange good food for quality information. With the discovery of sex, that is, 1.5 Ga ago, life added soft predation to hard predation, i.e. information production within each species to matter-energy flow between species. Replicative and informative structures are subject to two competing biological constraints: replicative fidelity promotes proliferation, but limits adaptive evolution. On the contrary, the offspring of a couple obviously cannot be a copy of both partners, they are a new production, a re-production. Sexual recombination allows the exponential enrichment of the genetic diversity, thus promoting indefinite adaptive and evolutionary capacities. Evolutionary history illustrates this: the bacteria proliferate but have remained at the first purely nutritive stage in which most of the sensory functions, mobility, defense, and feeding have experienced almost no significant novelty in three billion years. Another world appeared with the sexual management of information. Sexual reproduction actually combines two functions: multiplicative by "vertical transfer" and informative by "horizontal transfer". This distinction is very common: polypus - medusa alternations, parasite multiplication cycles, the lytochal and deuterotochal parthenogenesis of aphids, and the innumerable para- and pseudo-sexual strategies of plants opportunistically combine the two modes of asexual replication and sexual combination. However, for the majority of animals and multicellular plants that produce many gametes, numerical proliferation by descendants and informative diversity by sexuality are mutually implicated, for example in the seed. The true discovery of eukaryotes may not be the "true nucleus", as their name implies, but an orderly informative function. The field of recombinations circumscribes a class of partners genetically compatible with each other, each simultaneously prey and predator of the DNA of the other. The mythical Maxwell demon capable of tracing entropy by sorting molecules according to their state does exist: each mate is the other's Maxwell's demon. While a sexless bacterium is simply divided into two cells, two sexual parents work together to produce a single offspring a time. Added to this are the burdens involved in meiosis and crossing-over, cellular diploidy, and mating. Sex produces an information gain that is paid for by a cost of energy-material, and this barter must be fair to survive. The domains of sexual intercourse are very diverse: uniparental reproduction, alternation of asexual proliferation and sexual information, self-fertilization, endogamy, exogamy, panmixis, diffuse or structured polymorphism, fertile or sterile hybridization, horizontal transfers. Each species is a recombination field between two domains, cloning and hybridization. Multiplicative descent and informative fertilization are organically distinct, but selectively associated: the information produced by the parents' sexuality favors the predation of matter-energy and therefore the proliferation of offspring, and this proliferation in turn favors the sexed producers of information. The equation specific to each species is: enough energy to proliferate, enough information to diversify. Alternatively, two other reproductive modes obtain or transmit less information at lower cost: not enough recombinations=repetitive clonal proliferation, and too many recombinations=disordered hybridization. But these marginal modes have poor prospects, as the model of the species is successfully attractive. Better discriminate to better inform. In bacteria, the exchanged and incorporated DNA segments are directly identified by the parity of the complementary strands, which determines simultaneously the similarity, the offspring, and the pairing. In eukaryotes, on the contrary, somatic growth and germinal information are segregated. During speciation, adaptive information is compacted, delocalized, codified and published to inform the species about its own state: the prezygotic relationship governs viable mating. Under the effect of sexual selection, the runaway and the reinforcement of the characters related to courtship testifies to their identifying function, which explains the paradox of the singularity and luxuriance of the sexual hypertrophies. The speciation discretizes a balanced recombination field and validates the informative relations. The species is without degree. Mates of a species recognize each other quickly and well because the logic of coding disengages from the ecological game of adaptations. The system of mate recognition has a function of cohesion and its regularity allows the adaptations of the less regular being, it is neither elitist nor normative, it is subjected neither to a level of aptitudes, nor to sexual performances, but permissive; it protects the variability and polymorphism. Two mutually irreducible relationships triggered the debate between the taxonomists who support the phyletic definition of the species by the descendance, and the proponents of the definition by interfertility. Such a taxonomic disagreement is not insurmountable, but the issue is deeper than taxonomic concepts, because these concepts relate to two different modes of evolution. According to the phyletic model, each species is a lineage passively isolated by external circumstances; on the contrary, in the sexual model each species is actively produced by an internal process of adjustment between replicative costs and informative gains. Each species develops a solution of the equation that matches material-energy expenditures with informative gains. A species concept based on a lasting relationship between these two quantities or on the limits of certain values or their equilibrium is therefore legitimate. It is this equilibrium that all couples resolve, without our formulation being as clearly as biology desires and as physics demands. Energy expenditures and informative gains in sexuality are almost impossible to measure, yet observation and experience allow an approximate ranking of the energy/information ratio. For example, endogamy is more economical, but less diversifying than exogamy, polymorphism increases information, the reinforcement of sexual isolation limits the rate of unproductive fertilization, between neighboring species hybridization allows certain genetic contributions, etc. A closed species evolves naturally towards another just as closed. On the contrary, the artificial transfer of DNA opens the species. The natural boundaries that isolate the species are easily trespassed as energy costs and constraints of sexual recognition are easily controlled; and the perspectives of manipulations are visible, whereas natural selection never anticipates and thus works blindly. Informative, artificially directed predation stimulates the evolution of species.

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<bObjective:</b To study the clinical effect of nano-fat mixed granule fat transplantation in the treatment of cicatricial facial depression and atrophy, and to explore the related experimental mechanism. <bMethods:</b (1) From January 2012 to April 2018, 105 patients conforming to the inclusion criteria, with cicatricial facial depression and atrophy deformity who needed facial fat transplantation, were admitted to our unit. Their medical records were analyzed retrospectively. According to the patients' wishes, 54 patients (12 males and 42 females) aged 10-59 years received traditional transplantation of pure autologous granule fat collected from abdomen/thigh and were included in simple transplantation group, while the other 51 patients (14 males and 37 females) aged 7-63 years received transplantation of autologous nano-fat mixed granule fat collected from abdomen/thigh and were included in mixed transplantation group. The treatment satisfaction of patients 3 and 6 months after operation was assessed by the facial fullness, symmetry, scar, and complications using self-made scales and photo data before and after operation. Six months after operation, the patients were assessed whether they needed to undergo a second operation, and the rate of second operation was calculated. During the second operation, the fat of patients transplanted in the first operation was collected, and the morphology of adipocytes and microangiogenesis was observed under a scanning electron microscope. (2) Adipose-derived stem cells (ADSCs) were isolated and cultured from abdominal fat of a 4-week-old male Sprague-Dawley (SD) rat. The 5th passage of cells were selected to observe cell morphology after cultured for 14 days, observe expression of vimentin and cytokeratin-18 by immunofluorescence method, identify osteogenic and adipogenic differentiation, and detect rates of CD29 and CD44 positive cells by flow cytometer (<in</i=3). Eighteen 4-week-old male SD rats were divided into ADSCs transplantation group, simple scar group, and blank control group according to the random number table, with 6 rats in each group. Rats in ADSCs transplantation group and simple scar group were subcutaneously injected with 1 mL bleomycin which was dissolved in phosphate buffered saline (PBS) with a mass concentration of 1 mg/mL at the back to establish scar models. After 3 hours, rats in ADSCs transplantation group were injected with 1×10(6) ADSCs suspended in 0.1 mL PBS at the same injection site, while rats in simple scar group were injected with 0.1 mL PBS. Rats in blank control group were injected with the same doses of PBS in the same place at the same two time points mentioned above. After continuous injection for 28 days in each group, the full-thickness skin tissue of the injected area of all rats was collected to observe the collagen fibers by Masson staining and expressions of α-smooth muscle actin (α-SMA) and transforming growth factor β(1) (TGF-β(1)) by immunohistochemistry, and the positive cells were counted. Data were processed with Mann-Whitney <iU</i test, <iχ</i(2) test, one-way analysis of variance, and least significant difference test. <bResults:</b (1) Compared with the preoperative condition, the facial fullness and symmetry of patients in simple transplantation group were better in 3 months after operation, with scar color closer to the surrounding skin, and the filling volume of patients in this group decreased in 6 months after operation as compared with that in 3 months after operation. In mixed transplantation group, the facial fullness and symmetry of patients were better in 3 and 6 months after operation as compared with the preoperative condition, with scar color and texture closer to the surrounding skin, and the filling volume in 6 months after operation was not obviously reduced as compared with that in 3 months after operation. Fat liquefaction and subcutaneous nodule formation occurred respectively in 1 patient in simple transplantation group within 3 months after operation. The treatment satisfaction of patients in mixed transplantation group was significantly higher than that in simple transplantation group in 3 and 6 months after operation (<iZ</i=-2.566, -3.084, <iP</i&lt;0.05 or <iP</i&lt;0.01). Six months after operation, the second operation rate of patients in mixed transplantation group was 7.84% (4/51), which was significantly lower than 22.22% (12/54) in simple transplantation group (<iχ</i(2)=4.199, <iP</i&lt;0.05). At the second operation, compared with those of simple transplantation group, the cells of fat transplanted in the first operation of patients in mixed transplantation group were more plump, without collapse or dryness, and the cells were closely arranged, with smaller gap; the tubular and the cord-like microvascular structure on the cell surface were more abundant, and the cell gap was full of network-like microvascular structure that grew into the adipose tissue. (2) The fifth passage of cells isolated and cultured from rat fat grew adherently to the wall, with long fusiform or spindle shape, showing shoal-of-fish-like growth. Vimentin and cytokeratin-18 were highly expressed in the cells. Cells showed osteogenic and adipogenic differentiation ability by induction. The positive expression rates of CD29 and CD44 were higher than 90.00%. The cells were identified as ADSCs. After 28 days of injection, the collagen fibers in the dermis of skin tissue at the injection area of rats in blank control group were finely arranged. In simple scar group, a large amount of collagen was deposited in the dermis of skin tissue at the injection area of rats, the fiber bundles were thick and loosely unevenly arranged, and a large number of inflammatory infiltration and scattered muscle fibers were observed. In ADSCs transplantation group, the collagen fibers in the dermis of skin tissue at the injection area of rats were thicker than those of blank control group, with still neat arrangement, and a small amount of scattered muscle fiber and inflammatory infiltration was observed. After 28 days of injection, the expression of α-SMA in ADSCs transplantation group was mainly in microvessels in the dermis of skin tissue at the injected area of rats, and the number of α-SMA and TGF-β(1) positive cells was (49±12) and (63±10) cells per 20-fold field of view, respectively, which was similar to (35±16) and (44±17) cells per 20-fold field of view of blank control group (<iP</i&gt;0.05), all significantly less than (135±13) and (121±23) cells per 20-fold field of view of simple scar group (<iP</i&lt;0.05). <bConclusions:</b Compared with those of autologous simple granule fat transplantation, autologous nano-fat mixed granule fat transplantation has better filling fullness in the treatment of patients with scar facial depression and atrophy. The filling effect lasts longer, and the improvement of scar texture is more obvious. As showed in the rat scar model experiment, the mechanism may be that ADSCs inhibit the expressions of α-SMA and TGF-β(1), thus inhibiting the formation of scar.

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Oral administration of 8-methoxypsoralen followed by exposure to longwave ultraviolet light (primarily ultraviolet A, 320-400 nm) is used in the treatment of vitiligo and psoriasis. 8-Methoxypsoralen also occurs naturally in a variety of vegetables. Toxicology and carcinogenesis studies of 8-methoxypsoralen without ultraviolet A were conducted by administering USP-grade 8-methoxypsoralen (99% pure) in corn oil by gavage to groups of F344/N rats once or for 16 days, 13 weeks, or 2 years. In vitro genetic toxicology tests were performed with bacteria and mammalian cells. Single-Administration, Sixteen-Day, and Thirteen-Week Studies: In the single-administration studies, the chemical was administered at doses of 0 and 63-1,000 mg/kg. Four of five male rats and 5/5 female rats that received 1,000 mg/kg 8-methoxypsoralen died within 2 days. In the 16-day studies, the chemical was administered at doses of 0 and 50-800 mg/kg. All rats receiving 800 mg/kg died within 5 days, and one male and one female at 400 mg/kg and one female at 200 mg/kg also died before the end of the studies. The final mean body weights of animals at 200 or 400 mg/kg were 14% or 30% lower than those of vehicle controls. No compound-related effects were observed at necropsy. In the 13-week studies, the chemical was administered at doses of 0 and 25-400 mg/kg. Six of 10 male rats and 8/10 female rats that received 400 mg/kg died before the end of the studies. The final mean body weight of male rats that received 100, 200, or 400 mg/kg was 12%, 22%, or 45% lower than that of vehicle controls. The final mean body weight of female rats that received 200 or 400 mg/kg was 15% or 35% lower than that of vehicle controls. The liver weight to body weight ratios for all dosed groups of rats except the lowest (25 mg/kg) were greater than those for vehicle controls. Compound-related effects included fatty change in the liver in males and females and atrophy of the testis, seminal vesicles, and prostate. Based on these results, 2-year studies were conducted by administering 0, 37.5 or 75 mg/kg 8-methoxypsoralen in corn oil by gavage, 5 days per week for 103 weeks, to groups of 50 F344/N rats of each sex. Body Weight and Survival in the Two-Year Studies: The mean body weights of dosed male rats were generally 3%-14% lower than those of vehicle controls, and the mean body weights of high dose female rats were 5%-17% lower. The survival of both the low and the high dose groups of male rats was lower than that of the vehicle controls (male: vehicle control, 30/50; low dose, 16/50; high dose, 16/50; female: 39/50; 33/50; 36/50), likely because of kidney toxicity and neoplasia. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Mineralization of the renal papilla was observed in high dose male rats (vehicle control, 0/50; low dose, 0/50; high dose, 31/49). The severity of nephropathy was increased in dosed male rats. Focal hyperplasia of renal tubular cells was observed in dosed male rats (0/50; 8/50; 8/49). The incidences of tubular cell adenomas (1/50; 11/50; 8/49), adenocarcinomas (0/50; 1/50; 3/49), and adenomas or adenocarcinomas (combined) (1/50; 12/50; 11/49) were increased in dosed male rats. Hyperplasia of the parathyroid glands (2/49; 22/47; 18/48) and fibrous osteodystrophy (2/50; 10/50; 12/49) in male rats were secondary to chronic nephropathy. The incidences of carcinomas or squamous cell carcinomas (combined) of the Zymbal gland were increased in dosed male rats (1/50; 7/50; 4/49). The mean historical incidence for carcinomas or squamous cell carcinomas (combined) in corn oil vehicle control male F344/N rats is 0.8% (16/1,949); the highest incidence in any one group is 4% (2/49). Fibromas of the subcutaneous tissue in male rats occurred with a positive trend (1/50; 5/50; 7/49). An additional high dose male had a sarcoma. The mean historical incidence of fibromas or fibrosarcomas (combined) of subcutaneous tissue in corn oil vehicle control male F344/N rats is 9% (171/1,949). Alveolar/bronchiolar adenomas occurred with a positive trend in male rats (4ts is 9&amp;percnt; (171/1,949). Alveolar/bronchiolar adenomas occurred with a positive trend in male rats (4/50; 9/50; 9/49). The mean historical incidence of alveolar/bronchiolar neoplasms in corn oil vehicle control male F344/N rats is 3&amp;percnt; (68/1,944); the highest incidence is 10&amp;percnt; (5/50). Chronic inflammation, ulcers, and epithelial hyperplasia of the forestomach were observed at increased incidences in dosed male rats (chronic inflammation: 1/50; 6/50; 5/49; ulcers: 5/50; 13/50; 11/49; epithelial hyperplasia: 4/50; 19/50; 20/49). Squamous cell papillomas were observed in two low dose male rats. Squamous cell papillomas were observed in the palate or tongue of one low dose and three high dose female rats; none were observed in vehicle controls. These papillomas were not considered to be related to chemical administration. Diffuse hypertrophy of the thyroid gland was observed at increased incidences in dosed male rats (2/50; 31/50; 39/49). Genetic Toxicology: 8-Methoxypsoralen was mutagenic in Salmonella typhimurium strain TA104 in the presence and absence of activation and in strains TA98, TA100, and TA102 when tests were conducted with exogenous metabolic activation; 8-methoxypsoralen was not mutagenic with or without activation in strain TA1535. Treatment with 8-methoxypsoralen induced both sister chromatid exchanges (SCEs) and chromosomal aberrations in Chinese hamster ovary (CHO) cells in the absence of exogenous metabolic activation; in the presence of activation, in the presence of activation, induction of SCEs occurred, but no significant increases in chromosomal aberrations was observed. Audit: The data, documents, and pathology materials from the 2-year studies of 8-methoxypsoralen have been audited at the NTP Archives. The audit findings show that the conduct of the studies is documented adequately and support the data and results given in this Technical Report. Conclusions: Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenic activity of 8-methoxypsoralen (without ultraviolet radiation) for male F344/N rats, as shown by increased incidences of tubular cell hyperplasia, adenomas, and adenocarcinomas of the kidney and carcinomas of the Zymbal gland. Subcutaneous tissue fibromas and alveolar/bronchiolar adenomas of the lung in male F344/N rats may have been related to chemical administration. Dose-related nonneoplastic lesions in male F344/N rats included increased severity of nephropathy and mineralization of the kidney and forestomach lesions. There was no evidence of carcinogenic activity of 8-methoxypsoralen for female F344/N rats given the chemical at 37.5 or 75 mg/kg per day for 2 years. Synonyms: 9-methoxy-7H-furo[3,2-g]benzopyran-7-one; 6-hydroxy-7-methoxy-5-benzofuranacrylic acid d-lactone; 8-MP; 8-MOP; 8-methoxy-(furano-3',2':6,7-coumarin); 8-methoxy-4',5':6,7-furocoumarin; 9-methoxypsoralen; 8-methoxypsoralene; methoxsalen; oxypsoralen Trade Names: Ammoidin; Meladinin (VAN); Meladinine; Meladoxen; Meloxine; Methoxa-Dome; Mopsoralen; Oxsoralen; Soloxsalen; Trioxun; Xanthotoxin; Xanthotoxine

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Perfectionism is a dimension which has been studied very little as a separate entity. It is not even considered as a nosological factor. No classification of the medical sciences underlines its importance other than to speak of a personality trait, of an aspect, or of a parameter. Nevertheless, perfectionism is related to multiple disorders such as depression (18, 20, 36), suicide (8, 16, 55), nutritional problems (11, 28), anxiety (3), obsessive-compulsive personality disorder (53), social phobia (2), as well as insomnia (46). Certain authors stress the possible role of perfectionism in the development or the persistence of a substantial number of these disorders (7, 22, 38). Given these facts, it is all the easier to understand the interest shown by clinicians and researchers in the subject. Better detection and evaluation of its impact on behaviour is important in putting therapies in place (6, 53). Relationships between perfectionism and fear of failure have been approached (21, 51, 54). Correlations between perfectionism and high levels of state and trait anxiety have been demonstrated (23). The evaluation of perfectionism has been dealt with very little. Some questionnaires devote a sub-category to it, such as the Eating Disorder Inventory and the Irrational Beliefs Test. However, recently, it has been recognized that perfectionism is a multidimensional construct. Two Multidimensional Perfectionism Scales have been developed and investigated in relative isolation. Frost, Marten, Lahart and Rosenblate defined perfectionism as the setting of excessively high standards for performance associated with critical self-evaluation. Six dimensions are described: concern over making mistakes, high personal standards, parental expectations, parental criticism, doubt about quality of performance and organization. Internal consistency and validity have been established (25, 26). Hewitt and Flett (30, 31, 33, 35) have developed another approach where three dimensions of perfectionism are described: SOP (Self Oriented Perfectionism) related to high standards and self criticism, SPP (Socially Prescribed Perfectionism) related to the need of approval from others and fear of negative evaluation, OOP (Other-Oriented Perfectionism) reflecting a tendency to set high expectations for others and to evaluate them in a demanding way; this component is related, especially for males, to self-esteem, hostility and authoritarianism. Validity and internal consistency have been established too (30, 31, 35). The Frost and al's Multidimensional Perfectionism Scale and the Hewitt and Flett's scales are closely associated, except concerning the OOP. Because this component could provide new information, we have chosen the second scale, referring to the French translation and validation of Labrecque (45). EMP is the French name of MPS; it is a self-report questionnaire of 45 questions, in fact three subscales of 15 items rated on a 7-point Likert-type scale. MPS was administered to 617 first year students at the university of Liège (table II). Differences are considered according to gender and experience of failure i.e. the fact of repeating an academic year. We realized a component analysis with promax rotation. Among the different possibilities offered by the scree-test the choice of a 4 factor solution stresses the original structure: SOP (14 items), SPP (12 items), OOP (9 items) and anti OOP (10 items); the last one is additional but allows for respecting semantics and saturation of the items. The first aim of confirming validity and internal consistency is satisfactory. In other respects the multidimensional structure of the concept leads to consideration of a positive, adaptive perfectionism and a more negative perfectionism, facilitating psychopathology (59, 60, 61). So it seems interesting to compare the different components of MPS in order to find an eventual sex-failure effect. The evaluation of perfectionism is obvious, considering it as a personality trait, but it can be used also in taking into account stress and its impact, for instance that of academic performance (29, 37, 39, 58). Conferring on MPS more pertinence in gender differentiation and failure evaluation is an other goal of this research. Through the particular choice of statistical results, sex and sex-failure effects can be demonstrated: a MANOVA underlines sex effect (lambda de Wilks = 0.96, p = 0.001) and sex-failure effect (lambda de Wilks = 0.98, p = 0.05). Structure of MPS is different in four groups (FE: women with failure, FnE: women without failure, ME: men with failure, MnE: men without failure). ANOVA show differences of MPS3, MPS1 and MPS2. Far more promising is the use of LISREL method allowing for the construction of a coherent model of relationships between some dimensions of MPS and Test-Anxiety, approached here with THEE (test d'habileté aux études et à leur évaluation) French abbreviated version (49) of TASTE (Test for Ability to Study and Evaluation). In fact according to the literature of fear of failure, girls score higher on anxiety and procrastination but less on self-confidence. The structural model shows different pathways, more especially between SPP (socially prescribed perfectionism), T2 (sense of incompetence) and T1 (anxiety). SOP (self oriented perfectionism) and SPP (socially prescribed perfectionism) by girls are very much correlated; it seems that they are more subjected to society and its exigencies of studying but consequently they are more at risk of anxiety and a sense of incompetence. SOP (self oriented perfectionism) by boys functions more indiscriminately of SPP (socially prescribed perfectionism) and is negatively correlated with self-incompetence; boys are more self-confident but they usually procrastinate more probably because failure expectancies would be particularly harmful for their self-esteem; consequently, failure should be related to something else than their own capacity; this may be an explanation of the high rate of male dropouts and failure in the first year at the university of Liège; also a factor explaining the female domination at the university. In the same way the first choice of studies is moving towards shorter and less difficult orientation (46). In case of failure the model is very similar according to gender: SOP (self oriented perfectionism) and T1 (anxiety) are directly connected; SOP and SPP are in this case better correlated by boys but the path between SPP, sense of incompetence and anxiety is less significant than in girls. In conclusion, providing some modifications according to semantics, the choice of a four factor solution allows for confirmation of the original structure of MPS and for internal consistency. The different components of MPS vary according to gender: SOP and more OOP discriminate men and women; SPP allows for differentiating women with failure. A structural model enhances the role of perfectionism in the cognitive and behavioural contexts; for instance it clarifies its action on fear of failure and success rates according to gender.

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Uptake of human papillomavirus (HPV) vaccine remains low in many countries, although the bivalent and quadrivalent HPV vaccines given as a three-dose schedule are effective in the prevention of precancerous lesions of the cervix in women. Simpler immunisation schedules, such as those with fewer doses, might reduce barriers to vaccination, as may programmes that include males. To evaluate the efficacy, immunogenicity, and harms of different dose schedules and different types of HPV vaccines in females and males. We conducted electronic searches on 27 September 2018 in Ovid MEDLINE, the Cochrane Central Register of Controlled Trials (CENTRAL) (in the Cochrane Library), and Ovid Embase. We also searched the WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov (both 27 September 2018), vaccine manufacturer websites, and checked reference lists from an index of HPV studies and other relevant systematic reviews. We included randomised controlled trials (RCTs) with no language restriction. We considered studies if they enrolled HIV-negative males or females aged 9 to 26 years, or HIV-positive males or females of any age. We used methods recommended by Cochrane. We use the term 'control' to refer to comparator products containing an adjuvant or active vaccine and 'placebo' to refer to products that contain no adjuvant or active vaccine. Most primary outcomes in this review were clinical outcomes. However, for comparisons comparing dose schedules, the included RCTs were designed to measure antibody responses (i.e. immunogenicity) as the primary outcome, rather than clinical outcomes, since it is unethical to collect cervical samples from girls under 16 years of age. We analysed immunogenicity outcomes (i.e. geometric mean titres) with ratios of means, clinical outcomes (e.g. cancer and intraepithelial neoplasia) with risk ratios or rate ratios and, for serious adverse events and deaths, we calculated odds ratios. We rated the certainty of evidence with GRADE. We included 20 RCTs with 31,940 participants. The length of follow-up in the included studies ranged from seven months to five years. Two doses versus three doses of HPV vaccine in 9- to 15-year-old females Antibody responses after two-dose and three-dose HPV vaccine schedules were similar after up to five years of follow-up (4 RCTs, moderate- to high-certainty evidence). No RCTs collected clinical outcome data. Evidence about serious adverse events in studies comparing dose schedules was of very low-certainty owing to imprecision and indirectness (three doses 35/1159; two doses 36/1158; 4 RCTs). One death was reported in the three-dose group (1/898) and none in the two-dose group (0/899) (low-certainty evidence). Interval between doses of HPV vaccine in 9- to 14-year-old females and males Antibody responses were stronger with a longer interval (6 or 12 months) between the first two doses of HPV vaccine than a shorter interval (2 or 6 months) at up to three years of follow-up (4 RCTs, moderate- to high-certainty evidence). No RCTs collected data about clinical outcomes. Evidence about serious adverse events in studies comparing intervals was of very low-certainty, owing to imprecision and indirectness. No deaths were reported in any of the studies (0/1898, 3 RCTs, low-certainty evidence). HPV vaccination of 10- to 26-year-old males In one RCT there was moderate-certainty evidence that quadrivalent HPV vaccine, compared with control, reduced the incidence of external genital lesions (control 36 per 3081 person-years; quadrivalent 6 per 3173 person-years; rate ratio 0.16, 95% CI 0.07 to 0.38; 6254 person-years) and anogenital warts (control 28 per 2814 person-years; quadrivalent 3 per 2831 person-years; rate ratio 0.11, 95% CI 0.03 to 0.38; 5645 person-years). The quadrivalent vaccine resulted in more injection-site adverse events, such as pain or redness, than control (537 versus 601 per 1000; risk ratio (RR) 1.12, 95% CI 1.06 to 1.18, 3895 participants, high-certainty evidence). There was very low-certainty evidence from two RCTs about serious adverse events with quadrivalent vaccine (control 12/2588; quadrivalent 8/2574), and about deaths (control 11/2591; quadrivalent 3/2582), owing to imprecision and indirectness. Nonavalent versus quadrivalent vaccine in 9- to 26-year-old females and males Three RCTs were included; one in females aged 9- to 15-years (n = 600), one in females aged 16- to 26-years (n = 14,215), and one in males aged 16- to 26-years (n = 500). The RCT in 16- to 26-year-old females reported clinical outcomes. There was little to no difference in the incidence of the combined outcome of high-grade cervical epithelial neoplasia, adenocarcinoma in situ, or cervical cancer between the HPV vaccines (quadrivalent 325/6882, nonavalent 326/6871; OR 1.00, 95% CI 0.85 to 1.16; 13,753 participants; high-certainty evidence). The other two RCTs did not collect data about clinical outcomes. There were slightly more local adverse events with the nonavalent vaccine (905 per 1000) than the quadrivalent vaccine (846 per 1000) (RR 1.07, 95% CI 1.05 to 1.08; 3 RCTs, 15,863 participants; high-certainty evidence). Comparative evidence about serious adverse events in the three RCTs (nonavalent 243/8234, quadrivalent 192/7629; OR 0.60, 95% CI 0.14 to 2.61) was of low certainty, owing to imprecision and indirectness. HPV vaccination for people living with HIV Seven RCTs reported on HPV vaccines in people with HIV, with two small trials that collected data about clinical outcomes. Antibody responses were higher following vaccination with either bivalent or quadrivalent HPV vaccine than with control, and these responses could be demonstrated to have been maintained for up to 24 months in children living with HIV (low-certainty evidence). The evidence about clinical outcomes and harms for HPV vaccines in people with HIV is very uncertain (low- to very low-certainty evidence), owing to imprecision and indirectness. The immunogenicity of two-dose and three-dose HPV vaccine schedules, measured using antibody responses in young females, is comparable. The quadrivalent vaccine probably reduces external genital lesions and anogenital warts in males compared with control. The nonavalent and quadrivalent vaccines offer similar protection against a combined outcome of cervical, vaginal, and vulval precancer lesions or cancer. In people living with HIV, both the bivalent and quadrivalent HPV vaccines result in high antibody responses. For all comparisons of alternative HPV vaccine schedules, the certainty of the body of evidence about serious adverse events reported during the study periods was low or very low, either because the number of events was low, or the evidence was indirect, or both. Post-marketing surveillance is needed to continue monitoring harms that might be associated with HPV vaccines in the population, and this evidence will be incorporated in future updates of this review. Long-term observational studies are needed to determine the effectiveness of reduced-dose schedules against HPV-related cancer endpoints, and whether adopting these schedules improves vaccine coverage rates.

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Parkinson's disease (PD) can lead to sexual dysfunction. Yet, studies have shown that neurologists do not often discuss possible sexual health consequences with their patients. Thus, in this study, we investigated the communication on sexual health between healthcare workers and PD patients in Flanders, Belgium. Through an online survey, PD patients were contacted. Sexual dysfunction was measured with the Arizona Sexual Experience Scale (ASEX), stage of PD with the Hoehn and Yahr scale, and self-made questions on the communication between healthcare workers and PD patients. In total, 100 PD patients responded, of which 23% had possible sexual dysfunction. Of these respondents, 60% had never received any information about possible sexual health consequences. More than half (58%) of the patients felt their neurologist should provide information on possible sexual health consequences, though only 14% had ever received information from their neurologist. Male respondents expressed a greater need for information than female respondents (p = .049), although no difference between both groups in receiving information was found (p = .294). In addition, low to middle educated people generally received more information than higher educated people (p = .018).. The more severe the disease is, as measured by the Hoehn and Yahr scale, the more information a patient receives (p = .012). The most frequently mentioned barriers in discussing sexual health are a lack of initiative by the neurologist (41%) and awkwardness to discuss sexuality (41%). This study showed that PD patients expect information from neurologists on possible sexual health consequences, but seldom receive information. More attention should be given to training neurologists in discussing sexual health. Table 1 Characteristics of the sample (N = 100) N % Gender  Male 59 59  Female 41 41 Education level  Lower 4 4  Middle 42 42  Higher 54 54 Relationship status  No partner 10 10  Partner 90 90 Stage of Parkinson (Hoehn &amp; Yahr scale)  Stage 0 3 3  Stage 1 36 36  Stage 1.5 12 12  Stage 2 9 9  Stage 2.5 6 6  Stage 3 21 21  Stage 4 9 9  Stage 5 4 4 Time since diagnosis  Less than 1 years ago 10 10  1-2 years 13 13  2-5 years 32 32  5-10 years 29 29  Longer than 20 years 13 13  10-15 years 2 2  15-20 years 1 1 Received information on sexual health consequences from…  Treating neurologist 14 14  GP 9 9  Geriater 0 0  Nurses 2 2  Psychotherapist 3 3  Sexuologist 1 1  Kinesitherapist 2 2  Other 4 4 Who do you think should provide you information on sexual health consequences  Treating neurologist 58 58  GP 43 43  Geriater 3 3  Nurses 6 6  Psychotherapist 23 23  Sexuologist 17 17  Kinesitherapist 3 3  Other 2 2 How would you like to receive information on possible sexual health consequences?  Brochure 38 38  Online (e.g. website) 38 38  Posters in waiting room 3 3  Personal conversation with healthcare worker 51 51  Other 1 1 From what moment do you think possible sexual health consequences of Parkinson's disease should be discussed?  From the moment of diagnosis 52 52  From moment patient indicates he/she experiences problems 33 33  From moment that the neurologist feels it should be discussed 9 9  Should not be discussed 6 6 Need for information on possible sexual health consequences  No need 31 31  A little need 19 19  Some need 21 21  Need 24 24  A lot of need 5 5 How often has healthcare personnel given you information on sexual health consequences  Never 60 60  Seldom 25 25  Sometimes 12 12  Regularly 3 3  At every consultation 0 0 ASEX  No possible sexual dysfunction 77 77  Possible Sexual dysfunction (score equal to or higher than 19) 23 23 How important are sexual activities for you?  Not important 20 20  Slightly important 33 33  Somewhat important 22 22  Important 18 18  Very important 7 7 I avoid sexual contact because of my disease  Agree completely 8 8  Agree 16 16  Agree somewhat 30 30  Disagree 28 28  Completely disagree 18 18 I feel unsatisfied with my sex life due to my disease  Agree completely 16 16  Agree 22 22  Agree somewhat 32 32  Disagree 20 20  Completely disagree 10 10 Mean Standard deviation Age 66.97 8.88 ASEX 16.02 4.53 Table 2 Associations of ASEX, need for information, receiving information ASEX p Need for information p Receiving information p Gender  Male 16.08 0.948 55.31 0.049 48.69 0.294  Female 16.11 44.13 43.38 Education level  Low-middle 15.83 0.068 53.26 0.356 53.41 0.018  High 16.20 48.06 41.49 Need for information and receiving information scores are mean ranks due to non-parametric tests ASEX scores are means Table 3 Correlations between variables ASEX Age Need for information Receiving information Hoehn and Yahr Importance of sex life Avoiding sex Unsatisfied with sex life ASEX -  - 0.04 0.27* 0.07  - 0.09  - 0.12  - 0.10  - 0.23* Age -  - 0.20 0.10 0.41***  - 0.28**  - 0.16 0.08 Need for information - 0.14  - 0.11 0.38***  - 0.13  - 0.46*** Receiving information - 0.22*  - 0.03  - 0.08  - 0.08 Hoehn and Yahr -  - 0.17  - 0.32**  - 0.17 Importance of sex life - 0.24*  - 0.07 Avoiding sex - 0.48*** Unsatisfied with sex life - <sup*</supp &lt; .05 <sup**</supp &lt; .01 <sup***</supp &lt; .001 Table 4 Regression analyses B (S.E.) Exp(B) P Pseudo R<sup2</sup Nagelkerke Pseudo R<sup2</sup Cox &amp; Snell Need for information 0.013 0.19 0.14  Gender  - 1.23 (0.48) 0.29 0.010  Education level  - 0.62 (0.43) 0.54 0.149  Hoehn and Yahr 0.01 (0.11) 1.01 0.925  ASEX 0.10 (0.06) 1.11 0.060 Receiving information 0.047 0.14 0.11  Gender  - 0.53 (0.45) 0.59 0.232  Education level  - 0.61 (0.41) 0.54 0.137  Hoehn and Yahr 0.29 (0.14) 1.33 0.012  ASEX 0.01 (0.05) 1.01 0.788 Table 5 Barriers to discuss sexual health % (that agree with statements) I do not feel comfortable to discuss sexuality with my neurologist 33 I wait until the neurologist begins discussing it 41 My neurologist is either too young or too old 11 My neurologist is of the other gender 26 Reasons that have to do with my faith or attitude towards sexuality 12 I do not have the feeling there is a solution for these problems (with sexual health) 31 My Parkinson related symptoms overshadow my possible sexual health problems 39 It feels awkward to discuss sexual acts like masturbation or discuss buying of sexual aiding tools 41 My family/partner/friends are present during consultation 37 Reasons that have to do with my sexual orientation 11.

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Pentachlorophenol has been used as an herbicide, algicide, defoliant, wood preservative, germicide, fungicide, and molluscicide. Pentachlorophenol was nominated by the National Cancer Institute for carcinogenicity testing based on its widespread use as a wood preservative, potential for entering the environment (pentachlorophenol residues have been found worldwide in soil, water, and air samples; in food products; and in human and animal tissues and body fluids), and likelihood of bioaccumulation in the environment (pentachlorophenol is persistent in soil, having a half-life of up to 5 years). Technical Report No. 349 contains the results of the 2-year studies of pentachlorophenol performed by the NTP with B6C3F1 mice. Male and female F344/N rats were exposed to pentachlorophenol (approximately 99% pure) in feed for 28 days or 2 years. Genetic toxicology studies were conducted in vitro in Salmonella typhimurium and cultured Chinese hamster ovary cells and in vivo in rat and mouse bone marrow cells. 28-DAY STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were given 0, 200, 400, 800, 1,600, or 3,200 ppm pentachlorophenol, equivalent to average daily doses of approximately 20, 40, 75, 150, or 270 mg pentachlorophenol/kg body weight to males and females in feed for 28 days. With the exception of one male and two females exposed to 3,200 ppm, all rats survived until the end of the study. The final mean body weights and body weight gains of male rats exposed to 1,600 or 3,200 ppm and female rats exposed to 400, 800, 1,600, or 3,200 ppm were significantly less than those of the controls; rats exposed to 3,200 ppm lost weight during the study. Feed consumption by 3,200 ppm males was less than that by the control group throughout the study. The absolute and relative liver weights of 400, 800, and 1,600 ppm males and all exposed groups of females were significantly greater than those of the controls. Compared to the control groups, the incidences of minimal to mild hepatocyte degeneration in males and females exposed to 400 ppm or greater and the incidences of centrilobular hepatocyte hypertrophy in the 3,200 ppm groups were increased. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were fed diets containing 200, 400, or 600 ppm pentachlorophenol (equivalent to average daily doses of approximately 10, 20, and 30 mg/kg) for 105 weeks. Stop-exposure groups of 60 male and 60 female rats received 1,000 ppm (equivalent to 60 mg/kg) in feed for 52 weeks, after which animals received undosed feed for the remainder of the 2-year study; 10 male and 10 female control and 1,000 ppm rats were evaluated at 7 months. Survival, Body Weights,and Feed Consumption: In the 2-year study, survival of 600 and 1,000 ppm males was greater than that of the controls. Mean body weights of 400 and 600 ppm males and females were generally less than those of controls. When exposure to pentachlorophenol was discontinued at week 52, mean body weights of 1,000 ppm males and females were 17%% and 22%% lower than those of the respective controls; however, by the end of week 87, the mean body weights were similar to those of the controls. Generally, feed consumption by exposed groups was similar to that by the controls. Pathology Findings: At 2 years, the incidence of malignant mesothelioma originating from the tunica vaginalis was significantly greater in 1,000 ppm males than in the controls, and the incidence exceeded the historical control range. Nasal squamous cell carcinomas were present in one control male, three 200 ppm males, one 400 ppm male, and five 1,000 ppm males at 2 years, and the incidence in 1,000 ppm males exceeded the historical control range. At the 7-month interim evaluation, the incidences of centrilobular hepatocyte hypertrophy in 1,000 ppm males and females and hepatocyte cytoplasmic vacuolization in 1,000 ppm males was significantly greater than those in the controls. At 2 years, the incidences of several nonneoplastic liver lesions including hepatodiaphragmatic nodules and hepatocyte cystic degeneration in all exposed ation in all exposed groups of males and basophilic foci in 1,000 ppm males were increased compared to the controls. GENETIC TOXICOLOGY: Pentachlorophenol (91.6%&amp;percnt; pure) was tested in Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537 at doses up to 30 &amp;mu;g/plate with and without induced rat or hamster liver S9; no significant increases in the number of revertant colonies were observed in any of the strain/activation combinations. When tested for cytogenetic effects in cultured Chinese hamster ovary cells, pentachlorophenol was weakly positive for induction of sister chromatid exchanges and chromosomal aberrations. In the sister chromatid exchange test, a weakly positive response was observed within a concentration range of 3 to 30 &amp;mu;g/mL in the absence of S9; with S9, no induction of sister chromatid exchanges was noted. In the chromosomal aberrations test, pentachlorophenol was negative without S9 but induced small but significant increases in the frequency of aberrant cells in the presence of S9 at doses of 80 and 100 &amp;mu;g/mL. In contrast to the positive in vitro results in the test for induction of chromosomal aberrations, no increase in the frequency of micronucleated erythrocytes was noted in bone marrow of male rats or mice administered pentachlorophenol by intraperitoneal injection three times at 24 hour intervals. The highest dose administered to rats (75 mg/kg) and mice (150 mg/kg) was lethal. CONCLUSIONS: Under the conditions of this 2-year feed study, there was no evidence of carcinogenic activity of pentachlorophenol in male or female F344/N rats fed diets containing 200, 400, or 600 ppm. There was some evidence of carcinogenic activity of pentachlorophenol in male F344/N rats given feed containing 1,000 ppm for 1 year followed by control feed for 1 year (stop-exposure study), based on increased incidences of mesothelioma and nasal squamous cell carcinoma. There was no evidence of carcinogenic activity of pentachlorophenol in female rats given feed containing 1,000 ppm for 1 year and maintained on control feed for 1 year. Stop-exposure males and females recovered from a transitory reduction in body weight gain by the end of the 2-year study, and males had increased survival compared to the controls. Synonyms: Chlorophen; PCP; penchlorol; penta; pentachlorofenol; pentachlorofenolo; 2,3,4,5,6-pentachlorophenol Trade names: Acutox; Chem-Penta; Chem-Tol; Cryptogil ol; Dowicide 7; Dowicide EC-7; Dow Pentachlorophenol DP-2 Antimicrobial; Durotox; EP 30; Fungifen; Fungol; Glazd Penta; Grundier Arbezol Lauxtol; Lauxtol A; Liroprem; Moosuran; Pentacon; Penta-Kil; Pentasol; Penwar; Peratox; Permacide; Permagard; Permasan; Permatox; Priltox; Permite; Santophen; Santophen 20; Sinituho; Term-i-Trol; Thompson's Wood Fix; Weedone; Witophen P

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There are two species of fresh water cetaceans surviving in the Yangtze River system in China: Baiji (Lipotes vexillifer) and Yangtze finless porpoise (Neophocaena phocaenoides asiaeorientalis). As a result of the expansion of human activities on the river, their distribution ranges appear to be decreasing and in the case of the Baiji, are even being restricted to several sections. The Baiji is the world's most critically endangered cetacean species with a population estimated at only a few tens of individuals. The Yangtze finless porpoise is the world's only freshwater-adapted population of the species, and it has been estimated that only around 1,000 individuals remain in the river system. In order to prevent the extinction of Baiji and a sharp decline in the abundance of the porpoise, in situ conservation (i.e. in the river) and two ex situ conservation (i.e. in semi-natural reserves and in captivity) strategies were proposed and have been implemented since the early 1990s. In view of both the severely endangered status of the animals and the severely degraded conditions of their habitats, the feasibility and actual status of these two strategies are raised for discussion. The threats faced by the cetaceans are mainly from the unfettered exploitation of the river's resources. In the past 20 years, five nature reserves have been established along the river. Imposing maximum prohibition of harmful and illegal fishing methods in the reserves might prolong the process of extinction of these cetaceans in the wild, but so far, the administrative measures taken in the reserves have not yet kept the abundance from sharply declining. As human use of the river and its resources is expected to intensify for many decades into the future, the ability of the river to continue to support these species is certainly undecided. Therefore, rescuing animals from the river and establishing viable breeding populations in seminatural reserves, in which the environment is similar to the main stream of the river, and in captivity, has to be considered urgently as the short-term goal of ex situ strategies. Since the abundance of porpoises is higher than that of the Baiji, we have first established breeding populations of them in the semi-natural reserves and in captivity. But, considering the extremely low density of Baiji in the river, an immediate range-wide Yangtze Baiji survey is an urgent need for locating and capturing sufficient Baiji for successfully establishing a breeding population of them in semi-natural reserves. Two semi-natural reserves (in Shishou, Hubei Province, and Tongling, Anhui Province) have been set up along the river in order to establish breeding populations of the Baiji and the porpoises. So far, several small groups of porpoises that were caught in the main stream of the river have successively been introduced into the semi-natural reserves. Under careful management, these animals in both of the semi-natural reserves not only survive, but can also reproduce naturally and successfully. At least one or three calves were born in each reserve each year. Additionally, a breeding group of porpoises is being established at the Baiji Dolphinarium at the Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan. There are presently four adults and one calf living in the Dolphinarium. The calf, born in July, 2005, is the first captive bred Yangtze Finless Porpoise in the world. In preparation for the range-wide Yangtze cetacean survey, a 9-day pilot expedition on the river near Wuhan was conducted in March, 2006, in order to develop methods for locating the Baiji. No Baiji were expected to be seen in such a short period but about 40 porpoise sightings were observed. Results of the pilot survey indicated that traditional visual and acoustical survey methods for cetaceans should be adapted to find the elusive Baiji in the river. Currently, the range-wide Yangtze cetacean survey is in preparation. The survey will cover over 1,700 km of the Yangtze River from Yichang to Shanghai, and is expected to provide detailed information on Baiji and porpoise numbers and distribution patterns in the river. Although the short-term goal of ex situ conservation is to rescue cetaceans from the river and to establish viable breeding populations in semi-natural reserves and in captivity, the long-term goal of releasing the animals back into the river when the threats have decreased and the natural environment has been improved, should not be neglected. Moreover, the in situ conservation efforts in the natural reserves, and even in the entire Yangtze River system, including the lakes, should not be ignored or abandoned at any time. The activities contributing to the conservation of the Baiji and the porpoise in the wild have the incidental effect of benefiting the entire Yangtze ecosystem and other rare threatened species. The dynamics of the groups of porpoises in semi-natural reserves should be monitored continually, in order to guide the establishment of breeding groups of Baiji in these semi-natural reserves in the near future. Under the existing severely degraded conditions of the Yangtze system, the sharply fall populations of Baiji and porpoises will not be suspended in the foreseeable future. Therefore, ex situ conservation should be emphasized, and the severely threatened Baiji in the river should be removed and translocated to semi-natural reserves for establishing viable breeding populations. The successful program of capturing, translocating and maintaining finless porpoises in the Shishou semi-natural reserve has demonstrated its adequacy as an ex situ environment for cetaceans. Following the successful pilot survey in the river, the immediate range-wide Yangtze cetacean survey is proposed and is in preparation. The range-wide survey is expected to ensure that any remaining Baiji can be found reliably and captured successfully after the survey. During the range-wide survey, not only the Baiji but also the porpoise as well as their habitats should be investigated based on visual and acoustical methods that adapted to the river and the animals. Meanwhile, the current risk levels to the Baiji and porpoises should be evaluated at each area where Baiji or porpoises can be reliably sighted. Any capture efforts should be targeted on the most threatened areas, or where there is maximum risk of injury or death. The immediate track of the Baiji should be carried out once a Baiji is sighted during the range-wide survey in order to obtain the movement route of the animals, which is crucial information for the successful capture operation. Additionally, the need to establish new semi-natural reserves for the porpoises should be placed on the agenda of local and central governments in the near future.

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In 2009, before passage of the 2010 Patient Protection and Affordable Care Act (ACA), approximately 20% of women aged 18-64 years had no health insurance coverage. In addition, many women experienced transitions in coverage around the time of pregnancy. Having no health insurance coverage or experiencing gaps or shifts in coverage can be a barrier to receiving preventive health services and treatment for health problems that could affect pregnancy and newborn health. With the passage of ACA, women who were previously uninsured or had insurance that provided inadequate coverage might have better access to health services and better coverage, including additional preventive services with no cost sharing. Because certain elements of ACA (e.g., no lifetime dollar limits, dependent coverage to age 26, and provision of preventive services without cost sharing) were implemented as early as September 2010, data from 2009 can be used as a baseline to measure the incremental impact of ACA on the continuity of health care coverage for women around the time of pregnancy. 2009. The Pregnancy Risk Assessment Monitoring System (PRAMS) is an ongoing state- and population-based surveillance system designed to monitor selected maternal behaviors and experiences that occur before, during, and shortly after pregnancy among women who deliver live-born infants in selected U.S. states and New York City, New York. PRAMS uses mixed-mode data collection, in which up to three self-administered surveys are mailed to a sample of mothers, and those who do not respond are contacted for telephone interviews. Self-reported survey data are linked to birth certificate data and weighted for sample design, nonresponse, and noncoverage. Annual PRAMS data sets are created and used to produce statewide estimates of preconception and perinatal health behaviors and experiences in selected states and New York City. This report summarizes data from 29 states that conducted PRAMS in 2009, before the passage of ACA, and achieved an overall weighted response rate of ≥65%. Data on the prevalence of health insurance coverage stability (stable coverage, unstable coverage, and uninsured) across three time periods (the month before pregnancy, during pregnancy, and at the time of delivery) are reported by state and selected maternal characteristics. Women with stable coverage had the same type of health insurance (private or Medicaid) for all three time periods. Women with unstable coverage experienced a change in health insurance coverage between any of the three time periods. This includes movement from having no insurance coverage to gaining coverage, movement from one type of coverage to another, and loss of coverage. Women in the uninsured group had no insurance coverage during any of the three time periods. Estimates for health insurance stability across the three time periods and estimates of coverage during each time period are presented by state. Patterns of movement between the different types of health insurance coverage among women with unstable coverage are described by state and selected maternal characteristics. In 2009, 30.1% of women who had a live birth experienced changes in health insurance coverage in the period between the month before pregnancy and the time of delivery, either because they lacked coverage at some point or because they moved between different types of coverage. Most women had stable coverage across the three time periods, reporting either private coverage (52.8%) or Medicaid coverage (16.1%) throughout. A small percentage of women (1.1%) reported having no health insurance coverage at any point. Overall, Medicaid coverage increased from 16.6% in the month before pregnancy to 43.9% at delivery. Private coverage decreased from 59.9% in the month before pregnancy to 54.6% at delivery. The percentage of women who were uninsured decreased from 23.4% in the month before pregnancy to 1.5% at the time of delivery. Among those who experienced changes in coverage, 74.4% reported having no insurance the month before pregnancy, 23.9% reported having private insurance, and 1.8% reported having Medicaid. Among those who started out uninsured before pregnancy, 70.2% reported Medicaid coverage, and 4.1% reported private coverage at the time of delivery. Among those who started out with private coverage, 21.3% reported Medicaid coverage at delivery, and 1.4% reported being uninsured. As a result of these transitions in health insurance coverage, 92.4% of all women who experienced a change in health insurance around the time of pregnancy reported Medicaid coverage at delivery. No women with unstable coverage who started out without insurance in the month before pregnancy reported being uninsured at the time of delivery. Women who reported unstable coverage were more likely to be young (aged &lt;35 years), be a minority (black, Hispanic, or American Indian/Alaska Native), have a high school education or less, be unmarried, have incomes ≤200% of the federal poverty level (FPL), or have an unintended pregnancy compared with women with stable private coverage. Compared with women with stable Medicaid coverage, women with unstable coverage were more likely to be Hispanic but less likely to be teenagers (aged ≤19 years), be black, have a high school education or less, have incomes ≤200% of the FPL, or have an unintended pregnancy. Women with unstable coverage were more likely than women in either stable coverage group (private or Medicaid) to report entering prenatal care after the first trimester. In 2009, nearly one third of women reported lacking health insurance or transitioning between types of health insurance coverage around the time of pregnancy. The majority of women who changed health insurance status obtained coverage for prenatal care, delivery, or both through Medicaid. Health insurance coverage during pregnancy can help facilitate access to health care and allow for the identification and treatment of health-related issues; however, prenatal coverage might be too late to prevent the consequences of preexisting conditions and preconception exposures that could affect maternal and infant health. Continuous access to health insurance and health care for women of reproductive age could improve maternal and infant health by providing the opportunity to manage or treat conditions that are present before and between pregnancies. PRAMS data can be used to identify patterns of health insurance coverage among women around the time of pregnancy. Removing barriers to obtaining health insurance for women who lack coverage, particularly before pregnancy, could improve the health of women and their infants. The findings in this report can be used by public health professionals, policy analysts, and others to monitor health insurance coverage for women around the time of pregnancy. In particular, 2009 state-specific data can serve as baseline information to assess and monitor changes in health insurance coverage since the passage of ACA.

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Direct health care costs of illness reflect the costs of medically necessary services and treatments paid for by public and private payers, including hospital-based care, outpatient physician consultations, prescription medications, diagnostic testing, complex continuing care, and home care. The costs of caring for persons with inflammatory bowel disease (IBD) have been rising well above inflation over the past fifteen years in Canada, largely due to the introduction and penetration of expensive biologic therapies. Changing paradigms of care toward frequent patient monitoring and achievement of stricter endpoints for disease control have also increased health services utilization and costs among IBD patients. While the frequency and costs of surgeries and hospitalizations have declined slightly in parallel with increased biologic use (due to better overall disease control), the direct medical costs of care for IBD patients are largely dominated by prescription drug costs. Introduction and penetration of biosimilar agents (at a markedly lower price point than the originator drugs) and increasing gastroenterologist involvement in the care of IBD patients may help to balance rising health care costs while improving health outcomes and quality of life for IBD patients. Ultimately, however, the predicted rise in the prevalence of IBD over the next decade, combined with increasing use of expensive biologic therapies, will likely dictate a continued rise in the direct costs of IBD patient care in Canada for years to come. In 2018, direct health care costs of IBD are estimated to be at least $1 billion Canadian dollars (CAD) and possibly higher than $2 billion CAD. 1. In Canada, the direct cost of caring for people living with IBD is estimated in 2018 to be close to $1.28 billion (roughly $4731 per person with IBD).2. The costs of caring for people living with IBD are dominated by prescription drugs, followed by hospitalization costs. There has been a shift away from hospitalizations and toward pharmaceuticals as the predominant driver of direct health care costs in IBD patients, due to the introduction and widespread use of expensive biologic therapies.3. The rates of hospitalizations and major abdominal surgeries have been declining in IBD patients in Canada over the past two decades, possibly due to penetration of biologic therapies and advances in patient management paradigms.4. Inflammatory bowel disease patients cared for by gastroenterologists have better outcomes, including lower risks of surgery and hospitalization. Canadians who live in rural and underserviced areas are less likely to receive gastroenterologist care, potentially due to care preferences or poorer access, which may result in poorer long-term outcomes.5. Introduction of biosimilar agents at a lower price point than originator biologic therapies, increased gastroenterologist care of IBD patients, and improvements in IBD care paradigms may balance overall treatment costs while improving health outcomes and quality of life for IBD patients. However, in the long-term, direct costs of care may continue to increase, dictated by a rising IBD prevalence and increasing use of biologic therapies. 1. The costs of health care for patients with IBD are more than double those without IBD.2. Prescription drug use accounts for 42% of total direct costs in IBD patients, and costs to treat IBD continue to rise due to increased use of existing biologic therapies and the introduction of several new biologic therapies in recent years.3. In Manitoba, the mean health care utilization and medication costs for persons with IBD in the year before beginning anti-TNF therapy was $10,206 and increased to $44,786 in the first year of therapy.4. Biosimilar agents to anti-TNF drugs are now entering the Canadian marketplace and may result in cost savings in patients using biologic agents to treat their IBD.5. Timely gastroenterologist care has been associated with reduced risks of requiring surgery and emergency care among ambulatory IBD patients and a reduced risk of death among hospitalized patients with ulcerative colitis.6. Inflammatory bowel disease care provided by gastroenterologists has increased over the past two decades. Even then, the average time from symptom onset to IBD diagnosis exceeds six months, and only one-third of IBD patients receive continuing care with a gastroenterologist during the first five years following diagnosis.7. Senior (age ≥65), rural-dwelling, and non-immigrant IBD patients have less frequent gastroenterologist care than other groups.8. About one in five adults with Crohn's disease and one in eight adults with ulcerative colitis are hospitalized in Ontario every year. Hospitalizations are most common during the first year following IBD diagnosis. Children with IBD (age &lt;18) have the highest rates of hospitalizations and hospital re-admissions.9. In Canada, 16% of patients hospitalized for Crohn's disease undergo an intestinal resection, and 11% of patients hospitalized for ulcerative colitis undergo a colectomy during their initial hospitalization. Rates of intestinal resection and colectomy are declining in Canada in persons with Crohn's disease and ulcerative colitis, respectively.10. In Ontario, one-third of adult-onset Crohn's disease patients undergo intestinal resection within ten years of diagnosis. Among Canadian children with Crohn's disease, approximately one in fifteen children will require intestinal surgery within the first year of diagnosis, and up to one-third will require surgery within ten years of diagnosis.11. In Ontario, the ten-year colectomy risk following ulcerative colitis diagnosis is 13.3% among young persons and adults and 18.5% among individuals with senior-onset ulcerative colitis. In children with ulcerative colitis, the risk of colectomy is 4.8% to 6% in the first year following diagnosis and increases to 15% to 17% by ten years. 1. Forecasting models are necessary to predict the rising costs attributable to biologics associated with increasing prevalence of IBD, more frequent use of these medications, and the introduction of newer agents.2. Research into ways to minimize the escalating costs associated with increasing use of biologic therapies to treat IBD (and other chronic diseases) is necessary to ensure sustainability of our publicly funded health care system. Biosimilars offer an opportunity to drive down the cost of biologic therapies, and future research should assess the uptake of biosimilars as new biosimilars are introduced into the marketplace.3. Cost-utility models and budget impact analyses that integrate changes in direct costs (i.e., reduced hospitalizations and increased pharmaceutical costs) with indirect cost savings from improved quality of life are necessary to inform policy decisions.4. Research into ways to reduce IBD hospitalizations further through targeted outpatient interventions is equally important for health system sustainability and to improve patient quality of life.5. Research into reasons for reduced gastroenterologist care among rural and underserviced IBD residents would allow targeted interventions to improve specialist care and thereby improve patient health outcomes and quality of life.

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Sulopenem (formerly known as CP-70,429, and CP-65,207 when a component of a racemic mixture with its R isomer) is an intravenous and oral penem that possesses in vitro activity against fluoroquinolone-resistant, extended spectrum β-lactamases (ESBL)-producing, multidrug-resistant (MDR) Enterobacterales. Sulopenem is being developed to treat patients with uncomplicated and complicated urinary tract infections (UTIs) as well as intra-abdominal infections. This review will focus mainly on its use in UTIs. The chemical structure of sulopenem shares properties of penicillins, cephalosporins, and carbapenems. Sulopenem is available as an oral prodrug formulation, sulopenem etzadroxil, which is hydrolyzed by intestinal esterases, resulting in active sulopenem. In early studies, the S isomer of CP-65,207, later developed as sulopenem, demonstrated greater absorption, higher drug concentrations in the urine, and increased stability against the renal enzyme dehydropeptidase-1 compared with the R isomer, which set the stage for its further development as a UTI antimicrobial. Sulopenem is active against both Gram-negative and Gram-positive microorganisms. Sulopenem's β-lactam ring alkylates the serine residues of penicillin-binding protein (PBP), which inhibits peptidoglycan cross-linking. Due to its ionization and low molecular weight, sulopenem passes through outer membrane proteins to reach PBPs of Gram-negative bacteria. While sulopenem activity is unaffected by many β-lactamases, resistance arises from alterations in PBPs (e.g., methicillin-resistant Staphylococcus aureus [MRSA]), expression of carbapenemases (e.g., carbapenemase-producing Enterobacterales and in Stenotrophomonas maltophilia), reduction in the expression of outer membrane proteins (e.g., some Klebsiella spp.), and the presence of efflux pumps (e.g., MexAB-OprM in Pseudomonas aeruginosa), or a combination of these mechanisms. In vitro studies have reported that sulopenem demonstrates greater activity than meropenem and ertapenem against Enterococcus faecalis, Listeria monocytogenes, methicillin-susceptible S. aureus (MSSA), and Staphylococcus epidermidis, as well as similar activity to carbapenems against Streptococcus agalactiae, Streptococcus pneumoniae, and Streptococcus pyogenes. With some exceptions, sulopenem activity against Gram-negative aerobes was less than ertapenem and meropenem but greater than imipenem. Sulopenem activity against Escherichia coli carrying ESBL, CTX-M, or Amp-C enzymes, or demonstrating MDR phenotypes, as well as against ESBL-producing Klebsiella pneumoniae, was nearly identical to ertapenem and meropenem and greater than imipenem. Sulopenem exhibited identical or slightly greater activity than imipenem against many Gram-positive and Gram-negative anaerobes, including Bacteroides fragilis. The pharmacokinetics of intravenous sulopenem appear similar to carbapenems such as imipenem-cilastatin, meropenem, and doripenem. In healthy subjects, reported volumes of distribution (V<subd</sub) ranged from 15.8 to 27.6 L, total drug clearances (CL<subT</sub) of 18.9-24.9 L/h, protein binding of approximately 10%, and elimination half-lives (t<sub½</sub) of 0.88-1.03 h. The estimated renal clearance (CL<subR</sub) of sulopenem is 8.0-10.6 L/h, with 35.5% ± 6.7% of a 1000 mg dose recovered unchanged in the urine. An ester prodrug, sulopenem etzadroxil, has been developed for oral administration. Initial investigations reported a variable oral bioavailability of 20-34% under fasted conditions, however subsequent work showed that bioavailability is significantly improved by administering sulopenem with food to increase its oral absorption or with probenecid to reduce its renal tubular secretion. Food consumption increases the area under the curve (AUC) of oral sulopenem (500 mg twice daily) by 23.6% when administered alone and 62% when administered with 500 mg of probenecid. Like carbapenems, sulopenem demonstrates bactericidal activity that is associated with the percentage of time that free concentrations exceed the MIC (%f T &gt; MIC). In animal models, bacteriostasis was associated with %f T &gt; MICs ranging from 8.6 to 17%, whereas 2-log<sub10</sub kill was seen at values ranging from 12 to 28%. No pharmacodynamic targets have been documented for suppression of resistance. Sulopenem concentrations in urine are variable, ranging from 21.8 to 420.0 mg/L (median 84.4 mg/L) in fasted subjects and 28.8 to 609.0 mg/L (median 87.3 mg/L) in those who were fed. Sulopenem has been compared with carbapenems and cephalosporins in guinea pig and murine systemic and lung infection animal models. Studied pathogens included Acinetobacter calcoaceticus, B. fragilis, Citrobacter freundii, Enterobacter cloacae, E. coli, K. pneumoniae, Proteus vulgaris, and Serratia marcescens. These studies reported that overall, sulopenem was non-inferior to carbapenems but appeared to be superior to cephalosporins. A phase III clinical trial (SURE-1) reported that sulopenem was not non-inferior to ciprofloxacin in women infected with fluoroquinolone-susceptible pathogens, due to a higher rate of asymptomatic bacteriuria in sulopenem-treated patients at the test-of-cure visit. However, the researchers reported superiority of sulopenem etzadroxil/probenecid over ciprofloxacin for the treatment of uncomplicated UTIs in women infected with fluoroquinolone/non-susceptible pathogens, and non-inferiority in all patients with a positive urine culture. A phase III clinical trial (SURE-2) compared intravenous sulopenem followed by oral sulopenem etzadroxil/probenecid with ertapenem in the treatment of complicated UTIs. No difference in overall success was noted at the end of therapy. However, intravenous sulopenem followed by oral sulopenem etzadroxil was not non-inferior to ertapenem followed by oral stepdown therapy in overall success at test-of-cure due to a higher rate of asymptomatic bacteriuria in the sulopenem arm. After a meeting with the US FDA, Iterum stated that they are currently evaluating the optimal design for an additional phase III uncomplicated UTI study to be conducted prior to the potential resubmission of the New Drug Application (NDA). It is unclear at this time whether Iterum intends to apply for EMA or Japanese regulatory approval. The safety and tolerability of sulopenem has been reported in various phase I pharmacokinetic studies and phase III clinical trials. Sulopenem (intravenous and oral) appears to be well tolerated in healthy subjects, with and without the coadministration of probenecid, with few serious drug-related treatment-emergent adverse events (TEAEs) reported to date. Reported TEAEs affecting ≥1% of patients were (from most to least common) diarrhea, nausea, headache, vomiting and dizziness. Discontinuation rates were low and were not different than comparator agents. Sulopenem administered orally and/or intravenously represents a potentially well tolerated and effective option for treating uncomplicated and complicated UTIs, especially in patients with documented or highly suspected antimicrobial pathogens to commonly used agents (e.g. fluoroquinolone-resistant E. coli), and in patients with documented microbiological or clinical failure or patients who demonstrate intolerance/adverse effects to first-line agents. This agent will likely be used orally in the outpatient setting, and intravenously followed by oral stepdown in the hospital setting. Sulopenem also allows for oral stepdown therapy in the hospital setting from intravenous non-sulopenem therapy. More clinical data are required to fully assess the clinical efficacy and safety of sulopenem, especially in patients with complicated UTIs caused by resistant pathogens such as ESBL-producing, Amp-C, MDR E. coli. Antimicrobial stewardship programs will need to create guidelines for when this oral and intravenous penem should be used.

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<bObjective:</b To explore the feasibility on the preparation of novel negative pressure materials for constructing new matrix of full-thickness skin defect wounds in rats. <bMethods:</b The experimental research method was applied. The microstructure of polyurethane foam dressing which was commonly used in negative pressure treatment was observed under scanning electron microscope, and its pore diameter was detected (<in</i=5). Polycaprolactone (PCL) and polybutylene succinate (PBS) were used respectively as raw materials for the preparation of PCL and PBS negative pressure materials by melt spinning technology, with the measured pore diameter of polyurethane foam dressing as the spinning spacing at the spinning rates of 15, 25, and 35 mm/s, respectively. The microstructures of the prepared negative pressure materials were observed under scanning electron microscope, and their fiber diameters were measured. The tensile strength and tensile modulus of the prepared negative pressure materials and polyurethane foam dressing were measured by tensile testing machine and composite testing machine, respectively (<in</i=5), to screen the spinning rate for subsequent preparation of negative pressure materials. Human skin fibroblasts (Fbs) in logarithmic growth phase were co-cultured with PCL negative pressure material and PBS negative pressure material prepared at the selected spinning rate, respectively. After 1, 4, and 7 day (s) of co-culture, the cell activity and adhesion in the materials was detected by living/dead cells detection kit, and the cell proliferation level in the materials was detected by cell counting kit 8 method (<in</i=5). A full-thickness skin defect wound was prepared on the back of 18 5-6 weeks old Sprague-Dawley rats (gender unlimited). Immediately after injury, the injured rats were divided into PCL+polyurethane group, PBS+polyurethane group, and polyurethane alone group according to the random number table (with 6 rats in each group). The wounds were covered with materials containing corresponding component and performed with continuous negative pressure suction at the negative pressure of -16.7 kPa. The wound tissue along with materials directly contacted to the wound (hereinafter referred to as wound specimens) were collected from 3 rats in each group after 7 and 14 days of negative pressure treatment (NPT), respectively. The growth of granulation tissue and the attachment of material to wound surface were observed after hematoxylin-eosin staining, the collagen fiber deposition was observed after Masson staining, and CD34 and interleukin-6 (IL-6) positive cells were detected and counted by immunohistochemical staining. Data were statistically analyzed with one-way analysis of variance, analysis of variance for factorial design, least significant difference-<it</i test, Kruskal-Wallis <iH</i test, Mann-Whitney <iU</i test, and Bonferroni correction. <bResults:</b The microstructure of polyurethane foam dressing was loose and porous, with the pore diameter of (815±182) μm. The spinning spacing for the subsequent negative pressure material was set as 800 μm. The microstructures of PBS negative pressure material and PCL negative pressure material were regular, with vertically interconnected layers and continuous fibers in even thickness, but the fibers of PBS negative pressure material were straighter than those of PCL negative pressure material. There was no obvious difference in the microstructure of negative pressure materials prepared from the same raw material at different spinning rates. The fiber diameters of PCL negative pressure materials prepared at three spinning rates were similar (<iP</i&gt;0.05). The fiber diameters of PBS negative pressure materials prepared at spinning rates of 25 mm/s and 35 mm/s were significantly smaller than the fiber diameter of PBS negative pressure material prepared at the spinning rate of 15 mm/s (with <it</i values of 4.99 and 6.40, respectively, <iP</i&lt;0.01). Both the tensile strength and tensile modulus of PCL negative pressure materials prepared at three spinning rates were similar (<iP</i&gt;0.05). The tensile strength of PBS negative pressure materials prepared at spinning rates of 15 mm/s and 25 mm/s was significantly lower than that of PBS negative pressure materials prepared at the spinning rate of 35 mm/s (with <it</i values of 9.20 and 8.92, respectively, <iP</i&lt;0.01), and the tensile modulus was significantly lower than that of PBS negative pressure materials prepared at the spinning rate of 35 mm/s (with <it</i values of 2.58 and 2.47, respectively, <iP</i&lt;0.05). Subsequently, PCL negative pressure material was prepared at the spinning rate of 35 mm/s, and PBS negative pressure material was prepared at the spinning rate of 15 mm/s. After 1, 4, and 7 day (s) of co-culture, the number of human skin Fbs that adhered to PCL negative pressure material and PBS negative pressure material increased with time, and there was no significant difference between the two materials. After 1 and 7 day (s) of co-culture, the proliferation levels of human skin Fbs between the two negative pressure materials were similar (<iP</i&gt;0.05). After being co-cultured for 4 days, the proliferation level of human skin Fbs in PBS negative pressure material was significantly higher than that in PCL negative pressure material (<it</i=6.37, <iP</i&lt;0.01). After 7 days of NPT, the materials were clearly identifiable and a small amount of collagen fibers were also observed in the wound specimens of rats in the three groups; a small amount of granulation tissue was observed in the wound specimens of rats in polyurethane alone group. After 14 days of NPT, a large number of granulation tissue and collagen fibers were observed in the wound specimens of rats in the three groups; the materials and wound tissue in the wound specimens of rats in PCL+polyurethane group could not be clearly distinguished. After 7 and 14 days of NPT, the collagen fibers in the wound specimens of rats in polyurethane alone group were denser than those in the other two groups. After 7 days of NPT, the number of CD34 positive cells in the wound specimens of rats in PBS+polyurethane group was 14.8±3.6 per 400 times visual field, which was significantly less than 27.8±9.1 in polyurethane alone group (<it</i=3.06, <iP</i&lt;0.05); the number of IL-6 positive cells was 60 (49, 72), which was significantly more than 44 (38, 50) in polyurethane alone group (<iZ</i=2.41, <iP</i&lt;0.05). After 14 days of NPT, the number of IL-6 positive cells in the wound specimens of rats in PBS+polyurethane group was 19 (12, 28) per 400 times visual field, which was significantly more than 3 (1, 10) in PCL+polyurethane group and 9 (2, 13) in polyurethane alone group (with <iZ</i values of 2.61 and 2.40, respectively, <iP</i&lt;0.05). <bConclusions:</b The prepared PCL negative pressure material and PBS negative pressure material have good biocompatibility, and can successfully construct the new matrix of full-thickness skin defect wounds in rats. PCL negative pressure material is better than PBS negative pressure material in general.

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Dimethylvinyl chloride is a clear colorless liquid, which, because of its volatility and flammability at room temperature, is a significant fire hazard. It has a boiling point of 68.1 degrees C (155 degrees F) and a density at 20 degrees C of 0.919 g/ml. Dimethylvinyl chloride is a byproduct in the production of 3-chloro-2-methylpropene by the chlorination of isobutene. It is not known to be produced in the United States for other than laboratory purposes. This chemical was nominated for toxicologic studies because of its reported presence in ambient air in the Baltimore area and was selected for toxicologic characterization because of its structural similarity to the known animal and human carcinogen, vinyl chloride monomer. Toxicology and carcinogenesis studies of dimethylvinyl chloride (96%-98% pure), a structural analog of vinyl chloride monomer, a known human carcinogen, by administered dimethylvinyl chloride in corn oil by gavage to groups of 50 male and 50 female F344/N rats and B6C3F1 mice at doses of 0, 100, or 200 mg/kg body weight 5 days per week for 102 or 103 weeks. The selection of these doses was based on results of 13-week studies, which included depression of body weight at doses of 500 mg/kg or above in rats as well as histopathologic changes intestinal epithelium, bone marrow, hepatocytes, and the testes at doses of 250 mg/kg and above; doses in mice were selected on the basis of histopathologic changes in lymphopoietic cells, liver, pancreatic islets, ovary, testis, and spleen, with changes being most prominent at doses of 500 mg/kg and above. In the 2-year studies, body weights of rats and mice given 100 mg/kg were comparable to those of the vehicle controls except for the last few weeks in mice when body weights were markedly lower than those for the vehicle controls. At 200 mg/kg, the mean body weights of rats and mice were progressively decreased relative to those of vehicle controls, with the significant departure from vehicle controls occurring somewhat earlier in males than in females. Survival of vehicle control rats and mice was comparable to historical values; however, survival of dosed male and female rats was significantly lower than that of vehicle controls, with the incidence of mortality being more severe at the high dose than at the low dose. There were no survivors in the high dose group of male rats after week 85 or in the high dose group of female rats after week 97. Survival was significantly lower among dosed male and female mice compared with vehicle controls. In the absence of toxicological findings that would explain the early deaths, it is assumed that the high incidence of tumors and chemical-related toxicity contributed to the decreased survival of dosed rats and mice. In rats, the severity and incidence of nonneoplastic lesions were minimal; these lesions included necrosis of the duodenum and epithelial hyperplasia at the sites of tumor formation--the nasal cavity, esophagus, and forestomach. In mice, the severity of nonneoplastic lesions was also minimal; the lesions included necrosis of the liver, bone marrow granulocytic hyperplasia, and inflammation of the nasal cavity (small number, females only.) Several types of neoplastic lesions occurred with significantly increased incidences in dosed animals as shown in the following table (see page 11 of Technical Report). Among rats, these lesions included malignant epithelial tumors of the nasal cavity and squamous cell tumors of the oral cavity, esophagus, and forestomach in males and females. The increased number of fibroadenomas of the mammary gland in female rats may have been related to dimethylvinyl chloride administration. The lack of a clear dose-response relationship for certain tumors in rats is considered to be related to the increased number of early deaths observed in the high dose groups. Among dosed mice, there were significantly increased incidences of squamous cell carcinomas of the forestomach (both sexes), squamous cell papillomas of the forestomach (males), and squamous cell carcinomas of the preputial gla preputial gland (males). The increased incidence of papillary adenomas of the harderian gland and alveolar/bronchiolar adenomas or carcinomas in female mice may have been related to administration of dimethylvinyl chloride. Limited metabolism studies of 14C-labeled dimethylvinyl chloride were conducted in male F344/N rats and B6C3F1 mice. Single doses of 150 mg/kg were administered to rats for 1, 2, or 4 consecutive days. About 25&amp;percnt; of the administered doses was exhaled as carbon dioxide; this amount was independent of the number of doses administered. Another 25&amp;percnt;-35&amp;percnt; of the administered dose was exhaled; 96&amp;percnt; of this parent was material. Approximately 35&amp;percnt; and 6&amp;percnt; were excreted in the urine and feces, respectively. The elimination half-life of radioactive label was 3-4 days for the liver and kidney, the two organs containing the greatest amounts of the administered dose. In mice, a much smaller fraction of the dose was exhaled and a larger proportion was excreted in urine compared with rats. Dimethylvinyl chloride was not mutagenic in four strains ofSalmonella typhimurium with or without metabolic activation, but it was mutagenic in the mouse lymphoma L5178Y/TK&amp;plusmn; assay in the absence of metabolic activation. Sister-chromatid exchanges were induced in Chinese hamster ovary cells with and without metabolic activation, but there was no increase in chromosomal aberrations. When fed to Drosophila, dimethylvinyl chloride induced significant increases in the frequencies of both sex-linked recessive lethal mutations and reciprocal translocations. Studies of the immunotoxicity of dimethylvinyl chloride were conducted in which female B6C3F1 mice received daily oral doses of 0, 50, 100, 200, or 400 mg dimethylvinyl chloride per kilogram body weight. Compound-related increases in susceptibility to bacterial infection and decreases in macrophage cytostasis were observed at all doses. At the highest dose, the decreased resistance to bacterial and viral challenge could be related to alterations in specific immune function. However, the increased mortality in rats and mice in the 2-year studies was not relatable to infectious processes. An audit of the experimental data was conducted for these2-year toxicology and carcinogenesis studies on dimethylvinyl chloride. No data discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenicity of dimethylvinyl chloride for both sexes of F344/N rats and B6C3F1 mice. This was based on increased incidences of neoplasms of the nasal cavity, oral cavity, esophagus, and forestomach of male and female F344/N rats. B6C3F1 mice showed increased incidences of squamous cell neoplasms of the forestomach in males and females and squamous cell carcinomas of the preputial gland in males. Synonym: 1-chloro-2-methylpropene

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Persistent infection with high-risk human papillomaviruses (hrHPV) types is causally linked with the development of cervical precancer and cancer. HPV types 16 and 18 cause approximately 70% of cervical cancers worldwide. To evaluate the harms and protection of prophylactic human papillomaviruses (HPV) vaccines against cervical precancer and HPV16/18 infection in adolescent girls and women. We searched MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL) and Embase (June 2017) for reports on effects from trials. We searched trial registries and company results' registers to identify unpublished data for mortality and serious adverse events. Randomised controlled trials comparing efficacy and safety in females offered HPV vaccines with placebo (vaccine adjuvants or another control vaccine). We used Cochrane methodology and GRADE to rate the certainty of evidence for protection against cervical precancer (cervical intraepithelial neoplasia grade 2 and above [CIN2+], CIN grade 3 and above [CIN3+], and adenocarcinoma-in-situ [AIS]), and for harms. We distinguished between the effects of vaccines by participants' baseline HPV DNA status. The outcomes were precancer associated with vaccine HPV types and precancer irrespective of HPV type. Results are presented as risks in control and vaccination groups and risk ratios (RR) with 95% confidence intervals in brackets. We included 26 trials (73,428 participants). Ten trials, with follow-up of 1.3 to 8 years, addressed protection against CIN/AIS. Vaccine safety was evaluated over a period of 6 months to 7 years in 23 studies. Studies were not large enough or of sufficient duration to evaluate cervical cancer outcomes. All but one of the trials was funded by the vaccine manufacturers. We judged most included trials to be at low risk of bias. Studies involved monovalent (N = 1), bivalent (N = 18), and quadrivalent vaccines (N = 7). Most women were under 26 years of age. Three trials recruited women aged 25 and over. We summarize the effects of vaccines in participants who had at least one immunisation.Efficacy endpoints by initial HPV DNA statushrHPV negativeHPV vaccines reduce CIN2+, CIN3+, AIS associated with HPV16/18 compared with placebo in adolescent girls and women aged 15 to 26. There is high-certainty evidence that vaccines lower CIN2+ from 164 to 2/10,000 (RR 0.01 (0 to 0.05)) and CIN3+ from 70 to 0/10,000 (RR 0.01 (0.00 to 0.10). There is moderate-certainty evidence that vaccines reduce the risk of AIS from 9 to 0/10,000 (RR 0.10 (0.01 to 0.82).HPV vaccines reduce the risk of any CIN2+ from 287 to 106/10,000 (RR 0.37 (0.25 to 0.55), high certainty) and probably reduce any AIS lesions from 10 to 0/10,000 (RR 0.1 (0.01 to 0.76), moderate certainty). The size of reduction in CIN3+ with vaccines differed between bivalent and quadrivalent vaccines (bivalent: RR 0.08 (0.03 to 0.23), high certainty; quadrivalent: RR 0.54 (0.36 to 0.82), moderate certainty). Data in older women were not available for this comparison.HPV16/18 negativeIn those aged 15 to 26 years, vaccines reduce CIN2+ associated with HPV16/18 from 113 to 6 /10,000 (RR 0.05 (0.03 to 0.10). In women 24 years or older the absolute and relative reduction in the risk of these lesions is smaller (from 45 to 14/10,000, (RR 0.30 (0.11 to 0.81), moderate certainty). HPV vaccines reduce the risk of CIN3+ and AIS associated with HPV16/18 in younger women (RR 0.05 (0.02 to 0.14), high certainty and RR 0.09 (0.01 to 0.72), moderate certainty, respectively). No trials in older women have measured these outcomes.Vaccines reduce any CIN2+ from 231 to 95/10,000, (RR 0.41 (0.32 to 0.52)) in younger women. No data are reported for more severe lesions.Regardless of HPV DNA statusIn younger women HPV vaccines reduce the risk of CIN2+ associated with HPV16/18 from 341 to 157/10,000 (RR 0.46 (0.37 to 0.57), high certainty). Similar reductions in risk were observed for CIN3+ associated with HPV16/18 (high certainty). The number of women with AIS associated with HPV16/18 is reduced from 14 to 5/10,000 with HPV vaccines (high certainty).HPV vaccines reduce any CIN2+ from 559 to 391/10,000 (RR 0.70 (0.58 to 0.85, high certainty) and any AIS from 17 to 5/10,000 (RR 0.32 (0.15 to 0.67), high certainty). The reduction in any CIN3+ differed by vaccine type (bivalent vaccine: RR 0.55 (0.43 to 0.71) and quadrivalent vaccine: RR 0.81 (0.69 to 0.96)).In women vaccinated at 24 to 45 years of age, there is moderate-certainty evidence that the risks of CIN2+ associated with HPV16/18 and any CIN2+ are similar between vaccinated and unvaccinated women (RR 0.74 (0.52 to 1.05) and RR 1.04 (0.83 to 1.30) respectively). No data are reported in this age group for CIN3+ or AIS.Adverse effectsThe risk of serious adverse events is similar between control and HPV vaccines in women of all ages (669 versus 656/10,000, RR 0.98 (0.92 to 1.05), high certainty). Mortality was 11/10,000 in control groups compared with 14/10,000 (9 to 22) with HPV vaccine (RR 1.29 [0.85 to 1.98]; low certainty). The number of deaths was low overall but there is a higher number of deaths in older women. No pattern in the cause or timing of death has been established.Pregnancy outcomesAmong those who became pregnant during the studies, we did not find an increased risk of miscarriage (1618 versus 1424/10,000, RR 0.88 (0.68 to 1.14), high certainty) or termination (931 versus 838/10,000 RR 0.90 (0.80 to 1.02), high certainty). The effects on congenital abnormalities and stillbirths are uncertain (RR 1.22 (0.88 to 1.69), moderate certainty and (RR 1.12 (0.68 to 1.83), moderate certainty, respectively). There is high-certainty evidence that HPV vaccines protect against cervical precancer in adolescent girls and young women aged 15 to 26. The effect is higher for lesions associated with HPV16/18 than for lesions irrespective of HPV type. The effect is greater in those who are negative for hrHPV or HPV16/18 DNA at enrolment than those unselected for HPV DNA status. There is moderate-certainty evidence that HPV vaccines reduce CIN2+ in older women who are HPV16/18 negative, but not when they are unselected by HPV DNA status.We did not find an increased risk of serious adverse effects. Although the number of deaths is low overall, there were more deaths among women older than 25 years who received the vaccine. The deaths reported in the studies have been judged not to be related to the vaccine. Increased risk of adverse pregnancy outcomes after HPV vaccination cannot be excluded, although the risk of miscarriage and termination are similar between trial arms. Long-term of follow-up is needed to monitor the impact on cervical cancer, occurrence of rare harms and pregnancy outcomes.

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Methotrexate is used routinely worldwide for the medical treatment of clinically stable women with a tubal ectopic pregnancy. This is despite the lack of robust evidence to show its superior effectiveness over expectant management. The aim of our multicenter randomized controlled trial was to compare success rates of methotrexate against placebo for the conservative treatment of tubal ectopic pregnancy. This study took place in two early-pregnancy units in the UK between August 2005 and June 2014. Inclusion criteria were clinically stable women with a conclusive ultrasound diagnosis of a tubal ectopic pregnancy, presenting with a low serum beta human chorionic gonadotropin (β-hCG) level of &lt; 1500 IU/L. Women were assigned randomly to a single systemic injection of either 50 mg/m<sup2</sup methotrexate or placebo. The primary outcome was a binary indicator for success of conservative management, defined as resolution of clinical symptoms and decline of serum β-hCG to &lt; 20 IU/L or a negative urine pregnancy test without the need for any additional medical intervention. An intention-to-treat analysis was followed. We recruited a total of 80 women, 42 of whom were assigned to methotrexate and 38 to placebo. The arms of the study were matched in terms of age, ethnicity, obstetric history, pregnancy characteristics and serum levels of β-hCG and progesterone. The rates of success were similar for the two study arms: 83% with methotrexate and 76% with placebo. On univariate analysis, this difference was not statistically significant (χ<sup2</sup (1 degree of freedom) = 0.53; P = 0.47). On multivariate logistic regression, the serum level of β-hCG was the only covariate found to be significantly associated with outcome. The odds of failure increased by 0.15% for each unit increase in β-hCG (odds ratio, 1.0015 (95% CI, 1.0002-1.003); P = 0.02). In 14 women presenting with serum β-hCG of 1000-1500 IU/L, the success rate was 33% in those managed expectantly compared with 62% in those receiving methotrexate. This difference was not statistically significant and a larger sample size would be needed to give sufficient power to detect a difference in the subgroup of women with higher β-hCG. In women with successful conservative treatment, there was no significant difference in median β-hCG resolution times between study arms (17.5 (interquartile range (IQR), 14-28.0) days (n = 30) in the methotrexate group vs 14 (IQR, 7-29.5) days (n = 25) in the placebo group; P = 0.73). The results of our study do not support the routine use of methotrexate for the treatment of clinically stable women diagnosed with tubal ectopic pregnancy presenting with low serum β-hCG (&lt; 1500 IU/L). Further work is required to identify a subgroup of women with tubal ectopic pregnancy and β-hCG ≥ 1500 IU/L in whom methotrexate may offer a safe and cost-effective alternative to surgery. Copyright © 2016 ISUOG. Published by John Wiley &amp; Sons Ltd. Comparación entre una sola dosis de metotrexate sistémico y la conducta expectante en el tratamiento de casos de embarazo ectópico tubárico: un ensayo aleatorio controlado con placebo RESUMEN OBJETIVO: El metotrexate se utiliza de modo rutinario en todo el mundo para el tratamiento de las mujeres clínicamente estables con un embarazo ectópico tubárico. Esto sucede a pesar de la falta de evidencia rigurosa que demuestre que su eficacia es superior a la conducta expectante. El objetivo de este ensayo controlado aleatorio multicéntrico fue comparar las tasas de éxito del metotrexate con las de un placebo para el tratamiento cauteloso del embarazo ectópico tubárico. MÉTODOS: Este estudio se llevó a cabo en dos clínicas de control de gestación temprana en el Reino Unido entre agosto de 2005 y junio de 2014. Los criterios de inclusión fueron mujeres clínicamente estables con un diagnóstico ecográfico concluyente de embarazo ectópico tubárico, las cuáles presentaban una concentración sérica baja de la β hormona coriónica gonadotrópica (β-hCG) inferior a 1500 UI/L. Las mujeres fueron asignadas aleatoriamente a una sola inyección sistémica de 50 mg/m2 de metotrexate o a placebo. El resultado primario fue un indicador binario del éxito del tratamiento conservador, definido como la resolución de los síntomas clínicos y la disminución en el suero de la β-hCG a &lt;20 UI/L o una prueba de embarazo negativa en orina sin la necesidad de ninguna intervención médica adicional. Se hizo un análisis por intención de tratar. Se reclutó un total de 80 mujeres; a 42 de ellas se les asignó el metotrexate y a 38 el placebo. Los grupos del estudio se realizaron en función de la edad, el origen étnico, los antecedentes obstétricos, las características del embarazo y los niveles séricos de la β-hCG y la progesterona. Las tasas de éxito fueron similares para los dos grupos de estudio: 83% con metotrexate y 76% con placebo. En el análisis univariante, esta diferencia no fue estadísticamente significativa (χ2 (1 grado de libertad) = 0,53; P = 0,47). En la regresión logística multivariante, el nivel sérico de la β-hCG fue la única covariable que se encontró significativamente asociada con el resultado. Las probabilidades de fracaso aumentaron en un 0,15% por cada unidad de aumento de la β-hCG (cociente de probabilidad 1,0015 (IC 95%, 1,0002-1,003); P = 0,02). La tasa de éxito en las 14 mujeres con un nivel sérico de la β-hCG de 1000-1500 UI/L fue del 33% en las tratadas con conducta expectante frente al 62% en las que recibieron metotrexate. Esta diferencia no fue estadísticamente significativa, por lo que se necesitaría un tamaño de muestra mayor, lo suficiente como para poder detectar diferencias en el subgrupo de mujeres con una β-hCG más elevada. En las mujeres en las que el tratamiento conservador tuvo éxito, no hubo una diferencia significativa en la mediana de los tiempos de resolución de la ß-hCG entre los grupos del estudio (17,5 (amplitud intercuartílica (IQR), 14-28,0) días (n = 30) en el grupo de metotrexate frente a 14 (IQR, 7-29.5) días (n = 25) en el grupo de placebo; P = 0,73). Los resultados de este estudio no apoyan el uso rutinario de metotrexate para el tratamiento de las mujeres clínicamente estables diagnosticadas con un embarazo ectópico tubárico que presenta un nivel sérico bajo la β-hCG (&lt;1500 UI/L). Serán necesarios estudios adicionales para identificar un subgrupo de mujeres con embarazo ectópico tubárico y β-hCG ≥1500 UI/L para quienes el metotrexate puede ofrecer una alternativa segura y rentable en comparación con la cirugía. : : ,,。。 : 2005820146,2。,,β(beta human chorionic gonadotropin,β-hCG)&lt;1500 IU/L。,(50 mg/m<sup2</sup )。,β-hCG&lt;20 IU/L,。。 : 80,42,38。2、、、β-hCG。2:83%,76%。,[χ<sup2</sup (1)=0.53;P=0.47]。logistic,β-hCG。β-hCG,0.15%[,1.0015(95% CI,1.0002~1.003);P=0.02]。14β-hCG1000~1500 IU/L,33%,62%。,β-hCG。,2β-hCG(P=0.73),17.5[(interquartile range,IQR),14~28.0](n=30),14 (IQR,7~29.5)(n=25)。 : 、、β-hCG(&lt;1500 IU/L)。,β-hCG&gt;1500 IU/L、。.

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Determination of the endogenous loss of fat (ELF) is used to adjust for the estimation of true total tract digestibility (TTTD) of fat in diets and ingredients. Any factor which affected ELF may further affect the digestibility of fat, including sources and concentrations of fat and fiber in the diet. There are some reports of determining the ELF using regression methods based on different levels of fat intake, while reports on effects of dietary fiber content and different fiber-rich ingredients in pig diets on ELF are very limited. Therefore, the objective of this study was to determine the effects of dietary fiber content and different fiber-rich ingredients on endogenous losses of fat and fatty acids at the end of ileum and throughout the entire intestinal tract in growing pigs. In Exp. 1, the effect of fiber content on endogenous loss of fat was determined using six growing pigs (Duroc × Landrace × Yorkshire; 27.6 ± 2.4 kg), fitted with a T-cannula at the end of ileum. The experimental design was a 6 × 6 complete Latin square design with six periods of feeding and six diets. The six experimental fat-free diets were formulated to include graded levels of neutral detergent fiber (NDF) (0, 40, 80, 120, 160 and 200 g/kg) and soybean hull (SH) was the only fiber source, providing 0, 75, 150, 225, 300 and 375 g/kg, respectively. Chromic oxide was included at 4 g/kg in all diets as an indigestible marker. In Exp. 2, six crossbred growing barrows (27.6 ± 1.6 kg) were used and the experimental design was the same as for Exp. 1. The six fat-free diets were formulated to include six common fiber-rich ingredients and the concentration of NDF was 100 g/kg. The six fiber-rich ingredients were defatted rice bran (DRB), sugar beet pulp (SBP), rice hull (RH), corn germ meal (CGM), SH and wheat bran (WB) and they were fed at represented 250, 270, 145, 250, 170 and 280 g/kg in the diet, respectively. In Exp. 1, the endogenous loss of fatty acids profile did not change as dietary NDF increased in growing pigs. The endogenous losses of fat, C16:0, C18:0, C18:1, C18:2, total unsaturated fatty acids (UFA) and total saturated fatty acids (SFA) in growing pigs at the end of ileum and throughout the entire intestinal tract increased linearly as NDF content of diets increased. The endogenous losses of fat, as well as C16:0 and C18:0 throughout the entire intestinal tract also increased quadratically as NDF content of diets increased. The ELF increased from 0.71 to 3.14 g/kg of dry matter intake (DMI) and 0.56 to 8.21 g /kg DMI at the end of ileum and throughout the entire intestinal tract in growing pigs, respectively. The ELF occurred in the hindgut except for the growing pigs fed 0 and 4% NDF in their diets. The endogenous losses of C16:0 and UFA occurred primarily in the upper regions of the gut and the greatest endogenous losses of C18:0 occurred in the hindgut. The endogenous losses of fat, individual SFA and total SFA throughout the entire intestinal tract were much greater than that at the end of ileum. However, the endogenous losses of individual UFA and total UFA were less throughout the intestinal tract than at the end of ileum. In Exp. 2, the endogenous losses of fat at the end of ileum were greater in growing pigs fed CGM or WB diets. The endogenous loss of fatty acids profile changed to a slight degree at the end of ileum that the endogenous loss of UFA (particularly C18:1 and C18:2) in growing pigs fed CGM or WB diets were greater (<iP</i &lt;  0.01) than that for the other four diets. The greatest (<iP</i &lt;  0.01) endogenous loss of SFA (particularly C18:0) was in growing pigs fed the RH diet. The endogenous losses of fat, C16:0, C18:0 and SFA over the entire intestinal tract were much greater in growing pigs fed CGM or WB diets, whereas the lowest values were in growing pigs fed DRB diet. The ELF at the end of ileum in growing pigs fed CGM or WB diets were 3.50 or 4.17 g/kg DMI, respectively, and the ELF over the entire intestinal tract was 7.23 or 7.38 g/kg DMI. The contribution in percentage of ELF in the upper gut was greater than that in the hindgut of growing pigs fed DRB and RH diets, while the ELF in the upper gut and hindgut were equal in growing pigs fed SBP, CGM and WB diets. On the whole, the endogenous losses of C18:1 and C18:2 throughout the entire intestinal tract in growing pigs fed the six fiber-rich ingredients diets were less than losses at the end of ileum, whereas the endogenous loss of fat, C16:0, C18:0 and SFA were greater throughout the intestinal tract than at the end of ileum. The profile of loss in endogenous fatty acids did not change as dietary NDF increased in growing pigs and the endogenous losses of fatty acids (C16:0, C18:0, C18:1 and C18:2) fat, UFA and SFA increased linearly as NDF content increased in the diets of pigs. The endogenous losses of fat or fatty acids at the end of ileum were greater in growing pigs fed RH, CGM or WB diets. The endogenous losses of fat, fatty acids (C16:0 and C18:0) and SFA were greater over the entire intestinal tract in pigs fed CGM or WB diet, while these values were the lowest in growing pigs fed the DRB diet. The contribution in percentage losses of fat in the upper gut were greater than in the hindgut of growing pigs fed DRB and RH diets, while the contribution of losses of fat in the upper gut and hindgut were equal in growing pigs fed SBP, CGM and WB diets. In addition, the endogenous loss of individual or total UFA was less over the entire intestinal tract of growing pigs fed fiber diets than that at the end of ileum, and the greatest endogenous losses of fat, individual or total SFA were over the entire intestinal tract. Therefore, differences in fiber content and the nature of fiber-rich ingredients in diets of pigs have different effects to the endogenous losses of fat or fatty acids. Considering the requirement of fat or fatty acids of pigs, careful attention must be paid that the endogenous losses of fat and fatty acids when fiber ingredients are used in diets of pigs.

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Ambient air pollution causes substantial morbidity and mortality in the United States and worldwide. To reduce this burden of adverse health effects, a broad array of strategies to reduce ambient air pollution has been developed and applied over past decades to achieve substantial reductions in ambient air pollution levels. This has been especially true in California, where the improvement of air quality has been a major focus for more than 50 years. Direct links between regulatory policies, changes in ambient pollutant concentrations, and improvements in public health have not been extensively documented. Data from the Children's Health Study (CHS), a multiyear study of children's respiratory health development, offered a unique opportunity to evaluate the effects of long-term reductions in air pollution on children's health. We assessed whether changes in ambient air quality and emissions were reflected in three important indices of children's respiratory health: lung-function growth, lung-function level, and bronchitic symptoms. To make the best use of available data, these analyses were performed across the longest chronological period and largest CHS population available for the respective lung-function or bronchitic symptoms data sets. During field study operations over the course of the CHS, children's health status was documented annually by testing lung-function performance and the completion of standardized questionnaires covering a broad range of respiratory symptoms. Air quality data for the periods of interest were obtained from community monitoring stations, which operated in collaboration with regional air monitoring networks over the 20-year study time frame. Over the 20-year sampling period, common protocols were applied to collect data across the three cohorts of children. Each cohort's data set was assessed to investigate the relationship between temporal changes in lung-function development, prevalence of bronchitic symptoms, and ambient air pollution concentrations during a similar, vulnerable adolescent growth period (age 11 to 15 years). Analyses were performed separately for particulate matter ≤10 µm in aerodynamic diameter (PM₁₀), particulate matter ≤2.5 µm in aerodynamic diameter (PM₂.₅), ozone (O₃), and nitrogen dioxide (NO₂). Emissions data and regulatory policies were collected from the staff of state and regional regulatory agencies, modeling estimates, and archived reports. Emissions in the regions of California studied during the 20-year period decreased by 54% for oxides of nitrogen (NOₓ), 65% for reactive organic gases (ROG), 21% for PM₂.₅, and 15% for PM₁₀. These reductions occurred despite a concurrent 22% increase in population and a 38% increase in motor vehicle miles driven during that time frame. Air quality improved over the same time frame, with reductions in NO₂ and PM₂.₅ in virtually all of the CHS communities. Annual average NO₂ decreased by about 53% (from ~41 to 19 ppb) in the highest NO₂-reporting community (Upland) and by about 28% (from ~10 to 7 ppb) in one of the lowest NO₂-reporting communities (Santa Maria). Reductions in annual average PM₂.₅ concentrations ranged from 54% (~33 to 15 µg/m³) in the community with the highest concentration (Mira Loma) to 13% (~9 to 8 µg/m³) in a community with one of the lowest concentrations (Santa Maria). Improvements in PM₁₀ and O₃ (measured during eight daytime hours, 10 AM to 6 PM) were most evident in the CHS communities that initially had the highest levels of PM and O₃. Trends in annual average NO₂, PM₂.₅, and PM₁₀ ambient air concentrations in the communities with higher-pollution levels were generally consistent with observed trends in NOₓ, ROG, PM₂.₅, and PM₁₀ emissions. Significant improvements in lung-function growth in progressive cohorts were observed as air quality improved over the study period. Improvements in four-year growth of both forced expiratory volume in the first second of exhalation (FEV<sub1</sub) and forced vital capacity (FVC) were associated with declining levels of NO₂ (<iP</i &lt; 0.0001), PM₂.₅ (<iP</i &lt; 0.01), and PM₁₀ (<iP</i &lt; 0.001). These associations persisted after adjustment for important potential confounders. Further, significant improvements in lung-function growth were observed in both boys and girls and among asthmatic and non-asthmatic children. Within-community decreases in O₃ exposure were not significantly associated with lung-function growth. The proportion of children with clinically low FEV<sub1</sub (defined as &lt;80% predicted) at age 15 declined significantly, from 7.9% to 3.6% across the study periods, respectively, as the air quality improved (<iP</i &lt; 0.005). We found little evidence to suggest that improvements in lung-function development were attributable to temporal confounding. Reductions in outdoor levels of NO₂, O₃, PM₁₀, and PM₂.₅ across the cohort years of participation were associated with significant reductions in the prevalence of bronchitic symptoms regardless of asthma status, but observed improvements were larger in children with asthma. Among asthmatic children, the reductions in prevalence of bronchitic symptoms at age 10 were 21% (<iP</i &lt; 0.01) for NO₂, 34% (<iP</i &lt; 0.01) for O₃, 39% (<iP</i &lt; 0.01) for PM₁₀, and 32% (<iP</i &lt; 0.01) for PM₂.₅ for reductions of 4.9 ppb, 3.6 ppb, 5.8 µg/m³, and 6.8 µg/m³, respectively. Similar reductions in prevalence of bronchitic symptoms were observed at age 15 among these same asthmatic children. As in the lung-function analyses, we found little evidence that temporal confounding accounted for the observed associations of symptoms reduction with air quality improvement. The large number and breadth of regulatory activities, as well as the prolonged phase-in periods of several policy approaches to reduce emissions, precluded the close temporal linkage of specific policies with specific changes in health status. However, the combination of policies addressing motor vehicle emissions - from on-board diagnostics to emission controls, from low-sulfur fuels to vehicle smog-check recertification, and from re-formulated gasoline to the various strategies contained within the San Pedro Bay Ports Clean Air Plan (especially the Clean Truck Program) - all contributed to an impressive and substantial reduction in emissions. These reductions collectively improved local and regional air quality, and improvements in local and regional air quality were associated with improvements in respiratory health. This study provides evidence that multiyear improvements in air quality and emissions, primarily driven through a broad array of science-based regulatory policy initiatives, have resulted in improved public health outcomes. Our study demonstrates that improvements in air quality, brought about by science-based regulatory actions, are associated with improved respiratory health in children. These respiratory health metrics include reductions in respiratory symptoms and improvements in lung-function development in a population widely accepted to be at risk and highly vulnerable to the effects of air pollution. Our research findings underscore the importance of sustained air regulatory efforts as an effective means of achieving improved respiratory health in communities and regions affected by airborne pollution.

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Legg-Calvé-Perthes disease (LCPD) is a childhood hip disease characterized by osteonecrosis of the femoral head. Because severe deformity of the femoral head can cause secondary osteoarthritis in adulthood, progressive collapse should be prevented in children with a necrotic epiphysis. The prognosis of patients with LCPD generally worsens as the age at disease onset increases, and the appropriate treatment for late-onset LCPD remains unclear. Based on the limited effect of nonoperative treatment using a nonweightbearing brace, flexion varus osteotomy (FVO) was introduced in 2010 as an initial treatment for late-onset LCPD in place of brace treatment, which we used in our institution before that time. We asked, (1) Which treatment, FVO or a nonweightbearing brace, is associated with a lower likelihood of progressive femoral head collapse in children whose diagnosis of LCPD was made at the age of ≥ 8 years and who were followed for a minimum of 3 years after their intervention? (2) What proportion of patients in the brace group had surgery despite the treatment, and what percentage of children in the FVO group had a second operation to remove hardware and/or additional operations? The initial treatment was applied in 181 patients with LCPD between 1995 and 2018 in our institution. Patients whose disease onset was at ≥ 8 years old (late-onset LCPD) with complete clinical and radiologic data were considered potentially eligible. In 2010, treatment for these patients changed from brace treatment to FVO for all patients. A total of 35% (42 of 121) of patients who were treated with a nonweightbearing brace between 1995 and 2009 and 40% (24 of 60) of patients who were treated with FVO between 2010 and 2018 were eligible. Among patients treated with a brace, 21% (nine of 42 patients) were excluded because of hospital transfer (three patients), short-term follow-up (three), the period from onset to the first visit was ≥ 7 months (two), and inability to use the brace because of mental incapacity (one patient). In patients treated with FVO, 12% (three of 24 patients) were excluded (two patients with a period from onset to the first visit ≥ 7 months and one with a comorbidity and multiple-epiphyseal dysplasia). Among the remaining patients, 79% (33 of 42 patients) were classified into the brace group and 88% (21 of 24 patients) were classified into the FVO group for analyses. There were no overlapping patients at the timepoint when the treatment strategy for late-onset LCPD changed. In the FVO group, subtrochanteric osteotomy with 35° to 40° of flexion and 15° to 20° of varus was performed using a locking compression plate for pediatric use. Patient demographics, radiographic parameters, and the assessment of femoral head deformity using the Stulberg classification were compared between the two groups. There was a greater proportion of boys than girls in both groups (brace: 88% and FVO: 86%), and there were no differences in the distribution of genders between the groups (p = 0.82). The right side was more frequently treated in the brace group, but there was no difference in laterality between the groups (brace: 58% right and FVO: 62% left; p = 0.16). There was no difference between groups in the median age at disease onset (9.0 years [range 8.0 to 12.5 years] in the brace group and 9.6 years [range 8.0 to 12.4 years] in the FVO group; p = 0.26). There was no difference between the groups in the period of treatment from onset (1.7 ± 1.9 months in the brace group and 1.5 ± 1.5 months in the FVO group; p = 0.73) or the follow-up period (6.7 ± 2.1 years in the brace group and 6.2 ± 2.1 years in the FVO group; p = 0.41). The LCPD stage at the first visit was assessed using the modified Waldenström classification. The intraobserver and interobserver values of the modified Waldenström classification, evaluated using kappa statistics, were excellent (kappa value 0.89 [95% CI 0.75 to 0.97]; p &lt; 0.01) and good (kappa value 0.65 [95% CI 0.43 to 0.87]; p &lt; 0.01). The radiographic degree of collapse at the maximum fragmentation stage was assessed using the lateral pillar classification. The intraobserver and interobserver reliabilities of the lateral pillar classification were excellent (kappa value 0.84 [95% CI 0.73 to 0.94]; p &lt; 0.01) and excellent (kappa value 0.83 [95% CI 0.71 to 0.94]; p &lt; 0.01). The degree of femoral head deformity at the most recent follow-up examination was compared between the groups in terms of the Stulberg classification, in which Classes I and II were classified as good and Classes III through V were classified as poor. The intraobserver and interobserver reliabilities of the Stulberg classification were good (kappa value 0.74 [95% CI 0.55 to 0.92]; p &lt; 0.01) and good (kappa value 0.69 [95% CI 0.50 to 0.89]; p &lt; 0.01). The evaluators were involved in the patients' clinical care as part of the treating team. Good radiographic results (Stulberg Class I or II) were obtained more frequently in the FVO group (76% [16 of 21 patients]) than in the brace group (36% [12 of 33 patients]), with an odds ratio of 5.6 (95% CI 1.7 to 18.5; p &lt; 0.01). In the brace group, a subsequent femoral varus osteotomy was performed in 18% (six of 33) of patients with progressive collapse and hinge abduction, and implant removal surgery was performed approximately 1 year after the first procedure. This traditional varus osteotomy was occasionally performed in patients who were considered for conversion from nonoperative treatment before 2009 because FVO had not yet been introduced. In the FVO group, all patients (n = 21) had a second procedure to remove the implant at a mean of 10.5 ± 1.2 months postoperatively. Additional procedures were performed in 24% (five of 21) of patients, including a second FVO for progressive collapse (one patient), guided growth for a limb length discrepancy (one patient), and flexion valgus osteotomy for coxa vara in patients with a limb length discrepancy (three patients). Our historical control study found that FVO may increase the possibility of obtaining good radiographic results (Stulberg Class I or II) compared with brace treatment for patients with late-onset LCPD, although surgical interventions after the first and second implant removal procedures may be indicated. Surgeons can consider FVO if they encounter patients with late-onset LCPD, which is a challenging condition. A larger study with long-term follow-up is needed to confirm the efficacy of FVO. Level III, therapeutic study.

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Following the intravenous injection of an overwhelming dose of pneumococci in normal animals there is a rapidly increasing bacteriemia which reaches its maximum with the death of the animal. Immunized animals, whether the immunity is active or passive, whether the animals have their leucocytes, or whether these have been destroyed by benzol, react differently. They have incommon the ability to cause the organisms to decrease rapidly in number, and, as far as could be determined by the methods used, to disappear absolutely in a very short time from the circulation. This may be called the immediate reaction. In actively and passively immunized normal rabbits the disappearance of the organisms from the blood is followed by their destruction in the body and the ultimate recovery of the animal. This same result occurs also in actively immunized rabbits deprived of their polymorphonuclear leucocytes by benzol. On the contrary, in passively immunized rabbits, deprived of their leucocytes in the same way, the immediate disappearance of the organisms from the circulation is followed, after a lapse of from six to twenty-four hours, by a recurrent, gradually increasing bacteriemia and the death of the animal. It is evident that the immediate reaction is no index of the ultimate result. This finding, that the result of the intravenous injection of an overwhelming dose of pneumococci in immunized animals may be divided into two stages, immediate and ultimate, has been utilized in the interpretation of the experiments that have been reported above. 1. Normal Rabbits.-In the normal rabbit the injection of a lethal dose of pneumococci is followed by the same immediate and ultimate response. The animal develops a rapidly progressing bacteriemia and dies. 2. Passively Immunised Normal Rabbits.-A diametrically opposed finding is obtained when the animals are passively immunized. Then following the intravenous injection of pneumococci the organisms rapidly disappear from the circulating blood and the animal recovers. The only apparent difference between these two groups of experiments is the introduction of a relatively small quantity of immune serum. Tentatively, therefore, it may be concluded that the immune serum is responsible both for the immediate and ultimate reaction in this case. 3. Passively Immunized Aplastic Rabbits.-A normal rabbit that has been previously benzolized, and in this way deprived of its myeloid elements, can not be successfully immunized. Here the immune serum injected even in excessive quantities is followed by the immediate reaction, but the ultimate result is entirely different, -the animal dies. It may be concluded, therefore, that the serum is the potent factor in bringing about the immediate disappearance of the organisms from the circulation. Furthermore, it is evident that the white blood cells of the myeloid tissue are necessary in order that passively immunized animals may recover following the introduction of a lethal dose of pneumococci. So far it seems that two elements are essential in the immunity process; i. e., immune bodies and white blood cells. Corroborative evidence of the importance of the white blood cell in this reaction is offered by the hyperleucocytosis which follows the injection of antigen in actively immunized animals (Gay). This hyperleucocytosis occurs in actively immunized rabbits injected with pneumococci, after the organisms have disappeared from the circulation. It occurs at about the same time that the septicemia recurs in passively immunized aplastic rabbits. 4. Actively Immunized Aplastic Rabbits.-The experiments with actively immunized aplastic rabbits complicate the conception of the part of the white blood cells in the immunity process. When actively immunized, benzolized animals are injected with a lethal dose of pneumococci, the immediate reaction occurs just as in the passively immunized aplastic animal. Available antibodies are present and cause the disappearance of the organisms from the circulation. The ultimate reaction differs from that in the passively immunized aplastic animal. The latter develops a recurrent bacteriemia and dies. The actively immunized aplastic animal recovers. It would seem that the white blood cell is no longer necessary in an animal that has been actively immunized, but that it must be present for the passive protection of the animal. The ultimate reaction in immunized rabbits seems to be dependent upon some action of the white blood cells. In the passively immunized animal this may occur at the time of, or following, the immediate reaction; and if it can not occur, owing to the absence of the white blood cells, the animal subsequently dies. In the actively immunized aplastic rabbit this action has apparently occurred at a previous time and is sufficiently developed to protect the animal even though the leucocytes have been destroyed. It may be assumed that the function of the white blood cell is exercised not directly, but perhaps indirectly, by some influence exerted on other body cells. This interrelation or interaction between the white blood cells and other cells in the body constitutes a third factor essential to the ultimate protection of the animal. Additional evidence of this action of the white blood cell is furnished by further experiments with actively immunized aplastic rabbits. Several immunized rabbits were benzolized and then injected with a lethal dose of pneumococci. The results were the same as those indicated above. The organisms disappeared rapidly from the circulation and the animals recovered. An interval of five days was allowed to elapse and the animals were injected again with the same amount of pneumococci. This time the reaction was different. The organisms disappeared rapidly from the circulation, but there was a recurrent bacteriemia and the animals died. In these animals the favorable ultimate result after the first inoculation of a lethal dose of pneumococci probably depended upon the presence of the immune bodies and the third factor mentioned above. After the subsequent inoculation of pneumococci the immediate reaction was followed by the recurrence of the bacteriemia and the death of the animals. It may, therefore, be inferred that the third factor present at the time of the first injection had been destroyed, and, owing to the absence of white blood cells at the time of the subsequent inoculation, it was not formed again. It may be concluded that there are at least three elements necessary in the immunization process: (l) immune bodies, (2) white blood cells, and (3)a third factor which is dependent for its existence upon the presence of white blood cells at the time of inoculation of the pneumococci. Furthermore, this third factor may be removed if the animal is inoculated at a time when it is aplastic.

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Milk thistle extracts have been used as medicinal herbs in the treatment of liver cirrhosis, chronic hepatitis (liver inflammation), and gallbladder disorders. Treatment claims also include lowering cholesterol levels; reducing insulin resistance; reducing the growth of cancer cells in breast, cervical, and prostate gland cancers; and antiviral activity. Other reported uses of milk thistle in folk medicine include as a treatment for malarial fever, bronchitis, gallstones, jaundice, peritonitis, uterine congestion, varicose veins, and as a milk production stimulant for nursing mothers. The roots soaked in water overnight are used in food, and the despined leaves are added to salads. Roasted milk thistle fruit has been used as a coffee substitute. Milk thistle extract was nominated for study by the National Institute of Environmental Health Sciences because it is one of the most widely used herbs in the United States. Male and female F344/N rats and B6C3F1 mice were exposed to an ethanol/water extract of milk thistle fruit (milk thistle extract) containing approximately 65% silymarin in feed for 3 months or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and Escherichia coli and mouse peripheral blood erythrocytes. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were fed diets containing 0, 3,125, 6,250, 12,500, 25,000, or 50,000 ppm milk thistle extract (equivalent to average daily doses of approximately 260, 525, 1,050, 2,180, or 4,500 mg milk thistle extract/kilogram body weight to males and 260, 510, 1,050, 2,150, or 4,550 mg/kg to females) for 14 weeks. All rats survived to the end of the study. Mean body weights of exposed groups were within 10% of those of the controls. Feed consumption by exposed and control groups was similar. The sperm motility in 12,500, 25,000, and 50,000 ppm males was decreased by 5%, 11%, and 9%, respectively, relative to that of the controls; the total number of spermatid heads per testis decreased by 11%, 21%, and 9% in 12,500, 25,000, and 50,000 ppm males. No significant differences in estrous cyclicity were observed between exposed and control groups of female rats. No exposure-related histopathologic lesions were observed. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female mice were fed diets containing 0, 3,125, 6,250, 12,500, 25,000, or 50,000 ppm milk thistle extract (equivalent to average daily doses of approximately 640, 1,340, 2,500, 5,280, or 11,620 mg/kg to males and 580, 1,180, 2,335, 4,800, or 9,680 mg/kg to females) for 14 weeks. All mice survived to the end of the study. Mean body weights and feed consumption of all exposed groups were similar to those of the controls. Absolute and relative thymus weights were significantly decreased in 25,000 and 50,000 ppm males. No significant differences were observed between exposed and control groups, for sperm parameters of male mice, for estrous cyclicity of female mice, or for reproductive organ weights of male or female mice, when mice were administered milk thistle extract in feed at 12,500, 25,000, or 50,000 ppm. No exposure-related histopathologic lesions were observed. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were fed diets containing 0, 12,500, 25,000, or 50,000 ppm milk thistle extract (equivalent to average daily doses of approximately 570, 1,180, or 2,520 mg/kg to males and 630, 1,300, or 2,750 mg/kg to females) for 105 to 106 weeks. Exposure to milk thistle extract had no effect on survival of male or female rats. Mean body weights of all exposed groups were similar to those of the controls throughout the study. Feed consumption by exposed groups of males and females was generally similar to that by the controls throughout the study. Significantly decreased incidences of mammary gland fibroadenoma, adenoma, or carcinoma (combined) occurred in females exposed to 25,000 or 50,000 ppm. Significantly increased incidences of clear cell and mixed cell focus of the liver occurred in 25,000 and 50,000 ppm females. The incidences of bile duct hyperplasia were significantly decreased in 50,000 ppm males and in all exposed groups of females, and the incidence of mixed inflammatory cell infiltration was significantly decreased in 50,000 ppm males. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were fed diets containing 0, 12,500, 25,000, or 50,000 ppm milk thistle extract (equivalent to average daily doses of approximately 1,610, 3,530, or 7,770 mg/kg to males and 1,500, 3,175, or 7,180 mg/kg to females) for 105 to 106 weeks. Exposure to milk thistle extract had no effect on survival of male or female mice. The mean body weights of the 25,000 ppm groups were less than those of controls after week 25; mean body weights of 50,000 ppm groups were less than those of controls after week 12. Feed consumption by exposed groups of males and females was generally similar to that by the controls throughout the study. Significantly decreased incidences of hepatocellular adenoma and hepatocellular carcinoma occurred in 50,000 ppm males, and decreased incidences of hepatocellular adenoma or carcinoma (combined) occurred in 25,000 and 50,000 ppm males. Five milk thistle extracts were tested independently in bacterial mutagenicity studies using a variety of S. typhimurium tester strains and one E. coli strain. Results were negative in three of the five studies, with and without exogenous metabolic activation. In two studies, milk thistle extract was mutagenic in S. typhimurium strain TA98 in the presence of exogenous metabolic activation enzymes. Silymarin, a major constituent of milk thistle extract, was positive in S. typhimurium strains TA98 and TA100, when testing occurred in the presence of exogenous metabolic activation enzymes. Silybin, another component of milk thistle extract, was negative in a S. typhimurium gene mutation assay, with and without liver S9 activation enzymes. Administration of milk thistle extract in feed for 3 months did not increase the frequencies of micronucleated normochromatic erythrocytes, an indication of chromosomal abnormalities, in the peripheral blood of male or female B6C3F1 mice. Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of milk thistle extract in male or female F344/N rats or B6C3F1 mice exposed to 12,500, 25,000, or 50,000 ppm. Exposure to milk thistle extract resulted in increased incidences of clear cell and mixed cell foci in the liver of female rats and decreases in body weights of exposed groups of male and female mice. Decreased incidences of mammary gland neoplasms occurred in exposed groups of female rats, and decreased incidences of hepatocellular neoplasms occurred in exposed groups of male mice.

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Salicylic Acid is an aromatic acid used in cosmetic formulations as a denaturant, hair-conditioning agent, and skin-conditioning agent--miscellaneous in a wide range of cosmetic products at concentrations ranging from 0.0008% to 3%. The Calcium, Magnesium, and MEA salts are preservatives, and Potassium Salicylate is a cosmetic biocide and preservative, not currently in use. Sodium Salicylate is used as a denaturant and preservative (0.09% to 2%). The TEA salt of Salicylic Acid is used as an ultraviolet (UV) light absorber (0.0001% to 0.75%). Several Salicylic Acid esters are used as skin conditioning agents--miscellaneous (Capryloyl, 0.1% to 1%; C12-15 Alkyl, no current use; Isocetyl, 3% to 5%; Isodecyl, no current use; and Tridecyl, no current use). Butyloctyl Salicylate (0.5% to 5%) and Hexyldodecyl Salicylate (no current use) are hair-conditioning agents and skin-conditioning agents--miscellaneous. Ethylhexyl Salicylate (formerly known as Octyl Salicylate) is used as a fragrance ingredient, sunscreen agent, and UV light absorber (0.001% to 8%), and Methyl Salicylate is used as a denaturant and flavoring agent (0.0001% to 0.6%). Myristyl Salicylate has no reported function. Isodecyl Salicylate is used in three formulations, but no concentration of use information was reported. Salicylates are absorbed percutaneously. Around 10% of applied salicylates can remain in the skin. Salicylic Acid is reported to enhance percutaneous penetration of some agents (e.g., vitamin A), but not others (e.g., hydrocortisone). Little acute toxicity (LD(50) in rats; &gt;2 g/kg) via a dermal exposure route is seen for Salicylic Acid, Methyl Salicylate, Tridecyl Salicylate, and Butyloctyl Salicylate. Short-term oral, inhalation, and parenteral exposures to salicylates sufficient to produce high blood concentrations are associated primarily with liver and kidney damage. Subchronic dermal exposures to undiluted Methyl Salicylate were associated with kidney damage. Chronic oral exposure to Methyl Salicylate produced bone lesions as a function of the level of exposure in 2-year rat studies; liver damage was seen in dogs exposed to 0.15 g/kg/day in one study; kidney and liver weight increases in another study at the same exposure; but no liver or kidney abnormalities in a study at 0.167 g/kg/day. Applications of Isodecyl, Tridecyl, and Butyloctyl Salicylate were not irritating to rabbit skin, whereas undiluted Ethylhexyl Salicylate produced minimal to mild irritation. Methyl Salicylate at a 1% concentration with a 70% ethanol vehicle were irritating, whereas a 6% concentration in polyethylene glycol produced little or no irritation. Isodecyl Salicylate, Methyl Salicylate, Ethylhexyl (Octyl) Salicylate, Tridecyl Salicylate, and Butyloctyl Salicylate were not ocular irritants. Although Salicylic Acid at a concentration of 20% in acetone was positive in the local lymph node assay, a concentration of 20% in acetone/olive oil was not. Methyl Salicylate was negative at concentrations up to 25% in this assay, independent of vehicle. Maximization tests of Methyl Salicylate, Ethylhexyl Salicylate, and Butyloctyl Salicylate produced no sensitization in guinea pigs. Neither Salicylic Acid nor Tridecyl Salicylate were photosensitizers. Salicylic Acid, produced when aspirin is rapidly hydrolyzed after absorption from the gut, was reported to be the causative agent in aspirin teratogenesis in animals. Dermal exposures to Methyl Salicylate, oral exposures to Salicylic Acid, Sodium Salicylate, and Methyl Salicylate, and parenteral exposures to Salicylic Acid, Sodium Salicylate, and Methyl Salicylate are all associated with reproductive and developmental toxicity as a function of blood levels reached as a result of exposure. An exposure assessment of a representative cosmetic product used on a daily basis estimated that the exposure from the cosmetic product would be only 20% of the level seen with ingestion of a "baby" aspirin (81 mg) on a daily basis. Studies of the genotoxic potential of Salicylic Acid, Sodium Salicylate, Isodecyl Salicylate, Methyl Salicylate, cosmetic product would be only 20% of the level seen with ingestion of a "baby" aspirin (81 mg) on a daily basis. Studies of the genotoxic potential of Salicylic Acid, Sodium Salicylate, Isodecyl Salicylate, Methyl Salicylate, Ethylhexyl (Octyl) Salicylate, Tridecyl Salicylate, and Butyloctyl Salicylate were generally negative. Methyl Salicylate, in a mouse skin-painting study, did not induce neoplasms. Likewise, Methyl Salicylate was negative in a mouse pulmonary tumor system. In clinical tests, Salicylic Acid (2%) produced minimal cumulative irritation and slight or no irritation(1.5%); TEA-Salicylate (8%) produced no irritation; Methyl Salicylate (&gt;12%) produced pain and erythema, a 1% aerosol produced erythema, but an 8% solution was not irritating; Ethylhexyl Salicylate (4%) and undiluted Tridecyl Salicylate produced no irritation. In atopic patients, Methyl Salicylate caused irritation as a function of concentration (no irritation at concentrations of 15% or less). In normal skin, Salicylic Acid, Methyl Salicylate, and Ethylhexyl (Octyl) Salicylate are not sensitizers. Salicylic Acid is not a photosensitizer, nor is it phototoxic. Salicylic Acid and Ethylhexyl Salicylate are low-level photoprotective agents. Salicylic Acid is well-documented to have keratolytic action on normal human skin. Because of the possible use of these ingredients as exfoliating agents, a concern exists that repeated use may effectively increase exposure of the dermis and epidermis to UV radiation. It was concluded that the prudent course of action would be to advise the cosmetics industry that there is a risk of increased UV radiation damage with the use of any exfoliant, including Salicylic Acid and the listed salicylates, and that steps need to be taken to formulate cosmetic products with these ingredients as exfoliating agents so as not to increase sun sensitivity, or when increased sun sensitivity would be expected, to include directions for the daily use of sun protection. The available data were not sufficient to establish a limit on concentration of these ingredients, or to identify the minimum pH of formulations containing these ingredients, such that no skin irritation would occur, but it was recognized that it is possible to formulate cosmetic products in a way such that significant irritation would not be likely, and it was concluded that the cosmetics industry should formulate products containing these ingredients so as to be nonirritating. Although simultaneous use of several products containing Salicylic Acid could produce exposures greater than would be seen with use of baby aspirin (an exposure generally considered to not present a reproductive or developmental toxicity risk), it was not considered likely that consumers would simultaneously use multiple cosmetic products containing Salicylic Acid. Based on the available information, the Cosmetic Ingredient Review Expert Panel reached the conclusion that these ingredients are safe as used when formulated to avoid skin irritation and when formulated to avoid increasing the skin's sun sensitivity, or, when increased sun sensitivity would be expected, directions for use include the daily use of sun protection.

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It is surprising to note the evolution of success rates in Belgian universities especially in the first Year. Men are less successful than women and the differences are escalating in an alarming way. Dropouts take the same direction and women now represent a majority of the students at the university. In a previous study, we assessed 616 students in the first Year at the university of Liège with Vasev, the English name of which was TASTE, a self report questionnaire constituted of 4 factors: anxiety, self confidence, procrastination and performance value; anxiety particularly concerned somatic expression of students before and during test evaluations; self confidence was a cognitive component close to self efficacy; procrastination was the behavioral component characterizing avoidance when students are confronted with the risk of failure; performance value referred to intrinsic and extrinsic motivations. French validation of TASTE led to an abbreviated version of 50 items (THEE) consisting of 5 factors, the four of TASTE and an additional one, very consistent, at first called depression because of its correlations with this dimension, then called sense of competence on account of its semantic content. Self-competence has been described in the literature of Achievement Motivation and corresponded to expectancy and ability beliefs in performance process which was also relevant to self-efficacy except the particularity of comparison with others, which was not included in the last construct. Self-competence has been considered as an important part of the Worry component of test anxiety. Some Authors didn't hesitate to view causality flowing from self-competence to test anxiety and have conceptualized the latter as a failure of the self where one's sense of competence has been undermined as a result of experienced failure. In our study, only that factor was equally scored in women and men whereas it was scored higher in failed students. In other respects anxiety and performance value were scored higher in women, self-confidence and procrastination higher in men. Because TASTE didn't discriminate the different components of motivation (performance value referred to intrinsic and extrinsic motivations without precise distinction) we decided to use the MPS (Multidimensional Perfectionism Scale) which gave the opportunity to distinguish SOP (Self Oriented Perfectionism) ie, the self-imposed unrealistic standards with inability to accept faults in order to know and master a subject, that corresponded to intrinsic motivation; SPP (Socially Prescribed Perfectionism) ie, the exaggerated expectancies of others which are subjectively believed as imposed and uncontrollable leading to anxiety, feelings of failure or helplessness, that corresponded to extrinsic motivation; POO (Perfectionism Oriented to Others) ie, the unrealistic demands expected from significant others, which especially characterized males. We assumed that women attached more importance to succeed and submitted more to society exigencies. That way extrinsic and intrinsic motivations were probably more combined unlike men who, dreading a loss of self esteem, tried to avoid failure responsibility in using self handicapping or aggressive behaviours, so separating motivation in an extrinsic part turned to performance value and an intrinsic one more concerned by self confidence and sense of competence with the result that the motivational balance was surely disrupted in case of high competition leading to failure or avoidance. In another previous study we established a structural model illustrating, according to gender, correlations between anxiety, sense of incompetence, self-oriented perfectionism and socially prescribed perfectionism. Self-oriented perfectionism was less correlated to socially prescribed perfectionism in boys than in girls; furthermore especially by those who had never failed, it was negatively correlated to sense of incompetence, thus leading to lower scores of anxiety while in girls, by contrast, such a correlation didn't exist, thus involving higher anxiety. That way, on the one hand, intrinsic and extrinsic motivations by female students complementarily operated on the sense of incompetence and consequently on anxiety, the emotional component of test anxiety; on the other hand, by male students, intrinsic motivation had a negative correlation with the sense of incompetence and a lower correlation with extrinsic motivation, thereby shedding some light on the problem of anxiety level differences according to gender. More, that observation corresponded well to the model of self-worth where test anxiety was understood as a manifestation of perceived incompetence and as a defensive way to ward off negative self-evaluation; that model suited particularly well to boys and explained their attempts to maintain self-worth when risking academic failure. The present research assumes that independence or combination of motivation components is also correlated to different expressions of aggressiveness: hostility corresponding to threat and characterizing more girls while physical aggression is corresponding to personal challenge, a more masculine attribution. If fighting against the sense of incompetence actually characterizes men and consequently shows too the competitive aspects of performance strong enough to mobilize intrinsic motivation, what would be expected regarding the notion of threat suspected to be predominant in girls? The idea of using a questionnaire discriminating the specific dimensions of aggressiveness in fact the Aggression Questionnaire should meet the following purposes: At first establish a French version of that aggression questionnaire, perform the factorial analyses and internal consistency, compare them with other previous samples, then differentiate gender in general and in failure versus success situations. Finally include the different components of aggressiveness in the first described model and build a new one liable to define in boys the explicit pathways between test anxiety, perfectionism and aggressiveness. Statistical analyses have confirmed, in a 3 factor solution, the presence of emotional (anger), cognitive (hostility) and behavioural (physical aggression) components. Internal consistency is satisfactory. It is demonstrated that physical aggression characterizes boys (F=12.04, p=0.0001) while hostility (F=5.22, p=0.0015) and anger (F=0.49, p=0.0001) characterizes girls; furthermore it is noted that physical aggression characterizes more failed students (F=13.43, p=0.0003). Four models (see figures 2, 3, 4, 5) have been established, at first focused on the distinction of correlations between motivation and cognitive and emotional components on the samples of boys (n=268) and girls (348), then developed on the samples of successful students, male (n=193) and female (n=271). They describe the differentiated action of intrinsic and extrinsic motivations on the different components of aggressiveness and test-anxiety according to gender and without experience of failure. The dynamic process of the organizational factors is different according to gender and psychopathology resulting from the combinations of behaviors, cognitions and emotions would be assumed, prioritizing physical aggression and psychopathy by boys, anxiety and depression by girls. Anyway more explanation about the evolution of success rates of boys and girls in Belgian universities is proposed.

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Reconstruction of defects after resection of malignant bone tumors with liquid nitrogen-sterilized recycled autografts is an alternative to bone allografts and endoprostheses in resource-constrained environments. Most studies reporting favorable outcomes with liquid nitrogen-sterilized autografts for bone reconstruction are geographically restricted to a few countries, and the technical challenges of routinely using liquid nitrogen intraoperatively, especially when using the pedicle freezing technique, has not been documented. (1) What are the technical challenges of liquid nitrogen sterilization of bone tumors for inexperienced surgeons? (2) What are the complications associated with the procedure? Between May 2017 and October 2019, 88 patients underwent limb salvage procedures for malignant bone tumors of the extremities at our institution. An endoprosthesis was used for reconstruction of the defect following resection in 45% (40 of 88) of these patients, mostly in adults (median age 21 years; range 9 to 68). In the remaining 55% (48 of 88) of patients undergoing biological reconstruction, liquid nitrogen-sterilized autograft was used in 90% (43 of 48), extracorporeal irradiation-sterilized autograft was used in 4% (2 of 48) and allograft was used in 6% (3 of 48). Of the 43 patients receiving liquid nitrogen-sterilized autograft, 5% (2 of 43) were excluded due to loss to follow-up and the remaining 95% (41 of 43) were included for the analysis. Liquid nitrogen-sterilized autograft was the preferred method of reconstruction at our institution during the study period, unless the patient had an indication for prosthesis reconstruction; extracorporeal irradiation-sterilized autograft was used due to resource constraints with liquid nitrogen and allograft was used when patients insisted.All surgical procedures were performed by the same team of trained orthopaedic oncology surgeons. The medical records of the included 41 patients were retrieved using an institutional database search in this retrospective study, and all were used to ascertain technical challenges associated with the operations as well as early (within 3 weeks of the index procedure) and late complications (those occurring 3 weeks or more after surgery). The technical challenges were defined as follows: the quantity of liquid nitrogen to be used; arranging, storing and handling of liquid nitrogen in the operating room, type and size of the container to be used for sterilization, the positioning of the container during pedicle freezing, level of fibular osteotomy for pedicle freezing of tibia, soft tissue protection, limb rotation during pedicle freezing, managing tourniquet time, and any other intraoperative factors with the use of liquid nitrogen for sterilizing the autograft. As our experience with the technique gradually grew, the answers to the above-mentioned factors were determined. Considering the removal of autograft as the endpoint of interest, survival of the autograft was determined by Kaplan-Meier analysis.The median (range) patient age was 14 years (2 to 49), and 54% (22 of 41) were males. Osteosarcoma was the most common diagnosis (68%, [28 of 41]) followed by Ewing's sarcoma (20%, [8 of 41]). On presentation, 27% of patients (11 of 41) had radiological evidence of pulmonary metastasis. Tumors were seen frequently around the knee (39% [16 of 41] proximal tibia and 22% [9 of 41] distal femur). Before resection 85% (35 of 41) underwent neoadjuvant chemotherapy. Sixty-six percent (27 of 41) underwent pedicle-freezing and the remaining 34% (14 of 41) underwent free-freezing of the tumor segment of the bone. The median (range) duration of surgery was 280 minutes (210 to 510). The patients were followed up for a median (range) duration of 21 months (5 to 30); two patients were lost to follow-up. With gradual experience using liquid nitrogen-sterilization over time at our institution, we determined that the following factors helped us in performing liquid nitrogen-sterilization more efficiently. For every operation 15 L to 20 L of unsterilized liquid nitrogen was arranged, 1 or 2 days before the procedure, and stored in industrial-grade cryocylinders in the operating complex. During the procedure, the operating surgeons wore additional plastic aprons under the surgical gowns, surgical goggles, and rubber boots. The staff managing the liquid nitrogen in the operating room wore thermal protective gloves. For most of the pedicle freezing procedures, we used a cylindrical stainless-steel container that was 30 cm in height and 15 cm in diameter, with a narrow opening. The container was kept on a separate moveable cart that was placed next to the operating table at a slightly lower level, and it was wrapped in multiple cotton rolls, plastic sheets, surgical sheets, and a crepe bandage. For pedicle freezing of the tibia, we performed the fibular osteotomy at least 5 cm away from the planned surgical margin, roughly around the axis of rotation of the limb. The soft tissue at the base of the delivered bone segment was dissected for at least 5 cm beyond the planned surgical margin of bone, and was protected with multiple layers of cotton rolls, plastic drapes, a single roll of Esmarch and crepe bandage. The tumor segment was externally rotated during pedicle freezing for all anatomic sites (proximal tibia, distal tibia, proximal humerus, and proximal femur). The tourniquet was inflated just before pedicle freezing to prevent tumor dissemination and not before the initial incision in all pedicle freezing procedures.Thirty-nine percent of patients (16 of 41) experienced complications associated with the procedures, and 15% (6 of 41) underwent revision surgery. Early complications (occurring within 3 weeks of the index procedure) were skin necrosis in four of 16 patients, intraoperative fracture in one of 16, superficial infection in one of 16, and neurapraxia in one of 16 patients. Late complications (occurring 3 weeks or more after surgery) were resorption of the recycled bone in four of 16 patients, nonunion of the osteotomy site in two of 12, delayed union of the osteotomy site in one of 16, collapse of the recycled bone in one of 16, and local recurrence in 1 of 16 patients. Kaplan-Meier survivorship free from removal of autograft at 2 years after surgery was 92% (95% confidence interval 89 to 96). Liquid nitrogen-sterilization is an alternative technique that requires some training and experience for the surgeon to become proficient in treating primary malignant bone tumors. Because it is widely available, it may be an option worth exploring in resource-constrained environments, where allografts and endoprostheses cannot be procured. The methods we developed to address the technical challenges will require more study and experience, but we believe these observations will aid others who may wish to use and evaluate liquid nitrogen sterilization of extremity bone sarcomas. Level IV, therapeutic study.

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The World Health Organization (WHO) has declared Tuberculosis (TB) a global emergency in 1993. Prevalence of TB and Human Immunodeficiency Virus (HIV) co-infection worldwide is 0.18% and about 8% TB cases have HIV infection. Effective chemotherapy has been available for treatment of TB for over 50 years now. In World Health Organization (WHO)-International Union Against Tuberculosis and Lung Disease (IUATLD) Working Group Global Anti-Tuberculosis Drug Resistance Surveillance (1994-1997), the incidence of MDR TB in Delhi was found to be 14%, of which primary multi-drug resistance was only 1.4%, indicating that most of MDR TB is acquired as a result of poor chemotherapy. Since TB is an infectious disease caused by Mycobacterium (M) tuberculosis the diagnosis of TB should (as far as possible) be by demonstration of M. tuberculosis on culture or acid-fast bacilli (AFB) on smear examination. The World Health Organization (WHO) has strongly recommended sputum smear examination as the preferred screening test and suggests examination of 3 deeply coughed out sputum samples - spot sample on day 1, overnight sample and a spot sample in the morning on day 2. Recently it has been shown that sputum smear positivity is greater than 90% where greater than 5 ml of sputum is used for smear diagnosis of pulmonary TB. Culture of M. tuberculosis is the gold standard for diagnosis of TB. Culture of mycobacteria is a much more sensitive test than smear examination and has been estimated to detect 10-100 viable mycobacteria per ml of sample and in case of active disease they are found to be 81% sensitive and 98.5% specific. Culture methods are also required for further drug sensitivity testing in cases of suspected drug resistant cases. Isoniazid and rifampicin resistance can be reliably measured; resistance to pyrazinamide, ethambutol, and streptomycin is more difficult due to limitations of technique. The therapeutic index for a given drug is low for certain second-line drugs such as ethionamide, cycloserine, viomycin and para amino salicylic acid (PAS) and it leads to misinterpretation of results due to failure to distinguish between sensitive and resistant strains. Misdiagnosis of MDR-TB due to laboratory related errors has been reported recently. Chemotherapy of TB consists of prevention of infection, also called primary chemoprophylaxis, when isoniazid 5 mg/kg is given to prevent infection in newborn infants of infectious mothers till mother is sputum smear positive (2-3months). Treatment of latent tuberculosis, also called secondary chemoprophylaxis, when isoniazid 5 mg/kg is given for 6 months to prevent disease in infected persons (asymptomatic MT positive individuals) and treatment of disease with Short Course Chemotherapy (SCC), as per WHO categories. Essential anti-tuberculosis (ATT) drugs Isoniazid (H), Rifampicin (R), Ethambutol (E), Pyrazinamide (Z) and Streptomycin (S) are the essential first line anti-tuberculosis drugs. Anti TB regimen consists of two phases: an initial intensive phase (IIP) and a continuation phase (CP). Best effective SCC for treatment of TB, for adults and children, for pregnant and lactating females, for cases associated with diabetes mellitus and HIV infection, for cases with pre-existing liver diseases (but normal liver functions) and mild renal failure is 2EHRZ, 4HR given daily or thrice weekly. Higher dose SCC intermittent therapy given in thrice weekly (2E3H3R3Z3, 4H3R3) has now been advocated by WHO and implemented by the Revised National TB Control Programme. DOTS, directly observed therapy short course, where the patient takes the drugs under the direct observation (DO) of a health worker to ensure regularity of consumption of drugs. Fixed dose combinations (FDCs) drugs consisting of two or three antituberculosis medications, provide a realistic and welcome alternative to DO that minimizes the opportunity for a patient to selectively take only a single medication. Pregnancy: All drugs, that is, rifampicin, isoniazid, ethambutol, and pyrazinamide can be used during pregnancy. Streptomycin is not given due to ototoxicity to the fetus. Prophylactic pyridoxine in the dose of 10mg/day is recommended along with ATT. Diabetes mellitus: The drug regimen is same as in nondiabetic. Strict control of blood glucose is mandatory. Also, doses of oral hypoglycemic agents may have to be increased due to interaction with Rifampicin. Prophylactic pyridoxine is indicated. Renal failure: Dosages may have to be adjusted according to the creatinine clearance especially for streptomycin, ethambutol and isoniazid. In acute renal failure, ethambutol should be given 8 hours before hemodialysis. In post renal transplant patients: Rifampicin-containing regimens are avoided as rifampicin causes increased clearance of cyclosporin. Pre-existing liver disease: In stable disease with normal liver enzymes, all anti-tuberculous drugs may be used but frequent monitoring of liver function tests is required. Treatment in unconscious patient (patients unable to swallow): If patients are fed by Ryle's tube or gastrostomy tube, usual doses and drugs may be powdered and administered avoiding feeds 2-3 hours before and after the dose. In cases where enterostomy has been performed or parenteral nutrition is being used, intramuscular streptomycin and isoniazid and intravenous quinolones may be used and switch to oral therapy once oral feed resume. Treatment of TB with HIV co-infection: In early stages the presentations of TB in TB-HIV co-infection is the same as HIV negative but in late stages extra-pulmonary and dissemination are common. The usual short course chemotherapy is indicated in HIV positive patients. The response is usually good but relapse is frequent. After initiating ATT or anti-retroviral therapy (ART) worsening of preexisting lesions or appearance of new lesions is seen, "paradoxical response" or "immune reconstitution phenomenon". Multidrug resistant TB can occur due to poor compliance to ATT due to behavioural pattern, increased incidence of side effects and malabsorption of drugs due to associated diarrhea. ART for HIV, containing protease inhibitors (PI) and non-nucleoside reverse transcriptase inhibitors (NNRTI) cannot be used along with R, as R induces metabolism of PI and reduces the efficacy. The various options are i) to postpone anti-retroviral therapy ii) to use no PI or NNRTI containing anti-retroviral combinations iii) to use certain PI/ and/or NNRTIs with modification in doses iv) Efavirenz (EFZ) or Saquinavir with Ritonavir, without the need to adjust the doses v) to use non R regimens e.g. 2SHEZ+10HE MANAGEMENT OF MDR TB: As far as possible treatment of MDR TB should be referred to specialized units with facilities for quality controlled DST and experienced in handling such cases. If such referrals are not possible, one must remember that while initiating or revising therapy for MDR-TB, drugs selection must rely on prior treatment history, results of susceptibility testing and an evaluation of the patient's adherence.

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The discriminative potentials of biogeography, vocalization, morphology, cytogenetics, hemoglobin, and molecular profiling of cytochrome b as taxonomic techniques for differentiating Brazilian tortoises were evaluated in this study. In Brazil, two species of tortoises are described, Chelonoidis carbonarius and Chelonoidis denticulatus. However, in the present study, some animals that were initially recognized based on morphological characters and coloring did not correspond to the typical pattern of C. carbonarius; these animals were classified as morphotypes 1 and 2. It was proposed that these morphotypes are differentiated species, and they should not be considered as a single taxonomic unit with C. carbonarius. Tortoises analyzed were provided by the National Institute for Amazonian Research (INPA); the Emilio Goeldi Museum, PA; municipal zoos in São José do Rio Preto, SP, and Araçatuba, SP; and the Reginaldo Uvo Leone breeding farm for Wild and Exotic Animals, Tabapuã, SP. Based on the data obtained using biogeographic evaluation of specimens in the literature, it was found that C. carbonarius is distributed in the Northeast Region of Brazil, and no animal of this pattern was observed in the investigated collections. On the other hand, C. denticulatus is found in all the states of the Legal Amazonia. In addition, isolated individual records of this species exist in the Atlantic Forest in Espírito Santo and Rio de Janeiro and in the Midwest Region composed of the states of Goiás, Mato Grosso, and Mato Grosso do Sul. In the Northeast Region, C. denticulatus occurs in the State of Bahia. Morphotype 1 has a wider geographical distribution than C. carbonarius, possibly because of several distribution reports associated with C. carbonarius, indicating erroneous association of morphotype 1 as a single taxonomic unit with C. carbonarius. Morphotype 2 is found only in the states of Pará, Maranhão, and Piauí. These biogeographic data indicate that the distribution of C. carbonarius can partially be explained by the fact that all the morphotypes are considered as a single taxonomic unit. Behavioral aspects such as intraspecific communication may be as reliable as morphological or molecular data for inferring evolutionary relationships. Analysis of the physical characteristics of vocalization [fundamental frequency (Hz), interval between notes (s), duration of each note (s), and number of notes from each vocalization] between C. carbonarius and morphotype 1 revealed statistically significant differences in the interval between notes (s) (P = 0.0000); duration of each note (s) (P = 0.0000); frequency of notes (Hz) (P = 0.0009); and number of notes (P = 0.0002). The results of preference experiments using sound stimulus were inconclusive with respect to species-specific vocalization preference; only females of C. carbonarius showed intraspecific vocalization preference, indicating possible reproductive isolation mechanisms. To explore the presence of sexual dimorphism and morphological differences between C. denticulatus, C. carbonarius, and morphotype 1, descriptive statistics to analyze the data obtained for the investigated measures were used. Two sets of analysis were conducted - the first for each group, to compare the sexes; and the second for each sex, to compare the groups. To examine the interspecific variation in size and shape, a correlation matrix inprincipal component analysis was used. Next, I used factor analysis to rank the features showing &gt;0.75 correlation in the differentiation between the sexes. The results were consistent with the hypothesis that morphotype 1 corresponds to a new species, because it differs from the species pattern in terms of morphology, coloring, and sexual dimorphism. The results of classical cytogenetic analysis - to differentiate C. denticulatus, C. carbonarius, and morphotype 1 - revealed no consistent data that would enable its use as a taxonomic parameter. Conventional Giemsa staining revealed a diploid chromosome number of 2n = 52 for all the evaluated groups. The patterns obtained using chromosomal banding techniques showed high similarity and low reproducibility. Moreover, the sensitivity and resolution were insufficient to enable differentiation between the three groups, implying the existence of conserved characteristics of the karyotype in Testudinidae. To establish a hemoglobin profile for C. denticulatus, C. carbonarius, and morphotype 1, and to visualize the hemoglobin fractions of each group, I conducted acid and alkaline electrophoreses. The results of high-performance liquid chromatography revealed percentage differences in the hemoglobin fractions. In addition, electrophoresis of the polypeptide chains under acid and alkaline pH conditions showed the globin composition of each fraction. The observed differences in the chromatographic profile between C. carbonarius and morphotype 1 with respect to C. denticulatus validated the technique as an additional method for elucidating taxonomic issues in Testudinidae. The similarities observed in the hemoglobin profiles of C. carbonarius and morphotype 1 suggest recent separation between these groups. Alignment of mitochondrial DNA cytochrome b fragments revealed a degree of homogeneity among the C. denticulatus samples and the sequences published in the literature, indicating low genetic variability of the mitochondrial DNA cytochrome b fragment for this species. In contrast, the sequences of the mitochondrial DNA cytochrome b fragments from C. carbonarius and morphotypes 1 and 2 differed from those available in the published literature databases, indicating a variable genetic structure. This may be because it does not consider taxonomic divisions within C. carbonarius. Phylogenetic analysis did not reveal an appropriate phylogenetic signal for differentiating C. carbonarius and morphotypes 1 and 2. However, this analysis did differentiate C. denticulatus, indicating that the separation of C. carbonarius and morphotypes 1 and 2 is more recent than the separation of C. denticulatus and C. carbonarius. Owing to the problems associated with the use of cytochrome b in phylogenetic analysis, the polytomy observed for C. carbonarius and morphotypes 1 and 2 does not exclude the hypothesis that these samples represent different species. It is possible that the inclusion of morphological, behavioral, and hemoglobin profile data in a mixed matrix with the molecular data would enable the separation of morphotypes 1 and 2 as monophyletic species. This analysis would require data regarding external groups, to facilitate a more robust phylogenetic analysis, thereby enabling greater taxonomic resolution. In view of the differences in the biogeographical pattern, vocalization, specific-sound preference, and morphology found in the present study, I propose that morphotype 1 should be considered a new species. Data regarding the conservation status of natural tortoise populations in Brazil should be reviewed, because of the intensive human pressure on this species. There are no private or public plans for the conservation or recovery of natural tortoise populations. Hence, it is very likely that these animals have a more endangered status than that reported in the literature.

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Type 2 diabetes mellitus (T2DM) is a heterogeneous disease. Currently, the typical clinical therapeutic pathway for the disease consists of the stepwise addition of antihyperglycemic preparations over time, followed lastly by insulin therapy when functional β-cell capacity is severely deteriorated. Recognizing the complexity of disease management, personalized (precision) medicine approaches may enable the physician to tailor diabetes treatment based on HbA1c levels, body mass index (BMI), efficacy, risk of hypoglycemia, risk of weight gain, age, safety, cost, and even genetic characteristics. Although insulin therapy has traditionally been recommended as the last option in the sequential treatment algorithm of T2DM, it is notable that several guidelines and consensus statements suggest consideration of insulin as part of a first-line regimen. In the American Association of Clinical Endocrinologists (AACE)/American College of Endocrinology (ACE) comprehensive T2DM 2017 management algorithm, insulin is recommended for T2DM patients presenting with symptoms and an HbA1c &gt;9.0%. In addition, the American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) consensus statement recommends initial insulin therapy as an option when HbA1c ≥9%, and definite consideration with HbA1c ≥10-12%, and mentions that it may be possible to taper off insulin once initial glucotoxicity is reversed and to consider transfer to other types of non-insulin therapies. Based on accumulating evidence, an expert group has endorsed the concept of short-term intensive insulin (STII) therapy as an option for some patients with T2DM at the time of diagnosis. Notably, the latest Israeli guidelines suggest considering immediate, sometimes short-term, insulin treatment for patients with HbA1c &gt;9% or with symptoms. It has been reported that nearly one-quarter (23%) of newly diagnosed T2DM patients in the US had an HbA1c ≥9.0% prior to initiation of treatment. For such patients, initiating insulin is difficult, although it has been almost 10 years since the ACE/AACE Diabetes Road Map suggested insulin therapy for treatment-naïve patients with high HbA1c. Lack of patient education resources in primary care and of provider knowledge as to approaches to insulin treatment (insulin initiation dosage, multiple daily injection or basal insulin supplement, insulin treatment duration) are major obstacles to selecting appropriately intensive but also timely therapy for newly diagnosed T2DM patients in clinical practice so as to minimize avoidable glycemic exposure. Treatment with STII early in the course of T2DM is of considerable interest. There is a wide range of evidence currently available supporting the use of STII therapy in newly diagnosed T2DM. For example, STII can quickly normalize glycemic control, improve β-cell function, restore first-phase insulin secretion, and even reduce glucagonemia in newly diagnosed T2DM, suggesting that it may provide unique capacity for modification of the natural process of diabetes. The largest and most robust clinical trial of STII therapy enrolled 382 newly diagnosed people with T2DM at nine centers in China and randomized them to either insulin (short-term continuous subcutaneous insulin infusion [CSII] or multiple daily injections [MDI]) or oral anti-hyperglycemic therapy. First-phase insulin secretion was increased in all three groups after 2 weeks of normoglycemia. Remission rates at 1 year were higher in the two insulin-treated groups (51.1% in the CSII group, 44.9% in the MDI group) than in the oral therapy group (26.7%). Furthermore, the increase in first-phase insulin response was maintained at 1 year in the two insulin-treated groups, but declined in the group allocated to oral medication (Fig. ). A beneficial effect of insulin therapy over oral anti-diabetic agents was also observed by Chen et al. [Figure: see text] A meta-analysis, including seven studies and 839 participants, further underscored the robustness of the evidence supporting STII therapy by showing that the proportion of patients in drug-free remission was 66.2% at 3 months, 58.9% at 6 months, 46.3% at 12 months, and 42.1% at 24 months. All but one study showed an improvement in β-cell function, as assessed by homeostatic model assessment of β-cell function (HOMA-B), and all but one study showed a decrease in insulin resistance, as assessed by homeostasis model assessment of insulin resistance (HOMA-IR). Therefore, STII has beneficial effects on both the fundamental pathophysiological mechanisms of T2DM (β-cell dysfunction and insulin resistance). Recent animal studies suggest a potential mechanism for such clinical benefits: β-cells dedifferentiate to endocrine progenitor-like cells during stress-induced hyperglycemia, and strictly normalizing blood glucose by insulin therapy could induce dedifferentiated cell redifferentiation to mature β-cells, and hence restoration of drug responsivity. In addition to its glucose-lowering activity, insulin may contribute to improved β-cell function by its antilipolytic, anti-inflammatory, and antiapoptotic effects. We recognized that not all newly diagnosed people with T2DM would experience improved β-cell function or achieve long-term remission following cessation of STII. It would be worthwhile to precisely identify the subpopulation more likely to benefit from this strategy. Previous studies have suggested that lower baseline fasting glucose, higher BMI, better early phase insulin secretion, and lower exogenous insulin requirements may be predictors of diabetes remission in newly diagnosed patients treated with STII therapy. A recent study demonstrated that a shorter duration of diabetes supplanted baseline HbA1c and β-cell function as an independent predictor of remission. In particular, diabetes duration &lt;2 years predicted sustained remission, suggesting that the key determinant of inducing persistent drug-free diabetes remission with STII is early intervention. Although reluctance to initiate insulin treatment in T2DM is well described, it is interesting to see that when introduced early in the course of the disease as a short-term treatment, STII resulted in significant improvement in patient-reported quality of life and treatment satisfaction, demonstrating the patient acceptability of early insulin therapy. In our clinical experience, patients often request insulin resumption after a trial has ended because of the good clinical outcomes and the recognition that such treatment is much easier and better tolerated than expected. The pros and cons of STII therapy for new-onset T2DM patients with HbA1c &gt;9%, based on current evidence and our understanding, are listed in Table . It is important that STII be considered an option at this early stage of the disease. Existing studies and clinical experience do indicate that this concept is very well received by patients and clinicians alike, especially when they realize that insulin only needs to be used for a few weeks, and that STII at that point in time does not necessarily require continuing long-term insulin therapy. Numerous public health, clinical efficacy and effectiveness, and cost-effectiveness questions need to be better understood before widespread adoption of this novel treatment regimen can be more endorsed. [Table: see text].

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Passion fruit (Passiflora edulis Sims) is a widely cultivated dicotyledonous perennial plant with woody vines (Asande et al. 2020). In November 2020, leaf blight was observed on leaves of P. edulis (cultivar: 'Panama Red') newly planted in Wangyou, Huishui county, Guizhou province, China (25°82'57" N, 106°50'49" E). The leaf blight occurred on both young and old leaves, starting from the margins, and then extended to the entire leaves. The color of the affected tissue was brown with a yellow hallo in the early period, and then gradually turned to grey. The disease incidence was 60%-70% on a 0.08-ha field. Following isolation of the potential pathogen from 12 diseased leaves, nine isolates were obtained. The colonies were white with a regular round shape at the early stage and became black with fluffy hyphae after eight days on potato dextrose agar (PDA) medium, incubated at 25°C in the dark for 10 days. The single cell conidia were solitary, spherical or slightly ellipsoidal, black, shiny, smooth, aseptate, spherical, and 8.1-13.5 μm (n=50) in diameter. Conidiophores (5.2-9.9 × 4.4-7.2 μm) were mostly reduced to conidiogenous cells and aggregated in clusters on hyphae. Conidiogenous cells were hyaline to pale brown or black, globose to ampulliform or clavate. Morphological characteristics of the isolates matched the description of the genus Nigrospora Mei Wang &amp; L. Cai (Wang et al. 2017). For molecular identification, DNA was extracted, and PCRs were performed with primers ITS1/ITS4 for the ITS region (White et al. 1990), primers Bt2a/Bt2b for the β-tubulin gene (TUB) (Glass and Donaldson 1995), and primers EF1-728F/EF1-986R for the translation elongation factor 1-alpha gene (EF1-α) (Carbone and Kohn 1999). Representative sequences of the ITS region, EF1-α, and TUB sequences (from isolate WYR007) were deposited in GenBank (accession numbers: MW561355; MZ053463; MZ032030) and are included in the supplementary materials. BLAST analysis against sequences from previously published studies showed 99.58% (ITS region), 99.54% (EF1-α), and 99.45% (TUB) identity to Nigrospora sphaerica sequences (accession numbers: MN215808.1; MN864137.1; KY019606.1). In addition, homology was confirmed with a phylogenetic tree using concatenated sequences from ITS, EF1-α and TUB constructed with MEGA 7 for which the maximum likelihood method was used with 1,000 bootstrapping iterations. To complete Koch's postulates, conidia suspensions of isolate WYR007 (prepared from 1-month-old colonies in 0.05% Tween 20 buffer and adjusted to a concentration of 1 × 103 conidia/mL) were sprayed on 15 leaves (200 μL per leaf) of 5 one-year-old healthy P. edulis plants (cultivar: 'Panama Red'). The same number of leaves from control group plants was only treated with 0.05% Tween buffer. All plants were incubated at 26°C ± 2°C under a 16 h/8 h photoperiod and 70%-75% relative humidity (RH) after inoculation. After 14 days, symptomatic blight appeared on all inoculated leaves. In contrast, no symptoms appeared on leaves in the control group. The disease assays were repeated three times. Pure cultures were re-isolated from diseased leaves and confirmed to be N. sphaerica based on the morphological and molecular methods mentioned above (ITS region, the TUB, and the EF1-α sequences). To our knowledge, this study is the first report of N. sphaerica as a pathogen on P. edulis causing leaf blight. The identification of the pathogen could provide relevant background for its future management.s Sims) is a widely cultivated dicotyledonous perennial plant with woody vines (Asande et al. 2020). In November 2020, leaf blight was observed on leaves of P. edulis (cultivar: 'Panama Red') newly planted in Wangyou, Huishui county, Guizhou province, China (25°82'57" N, 106°50'49" E). The leaf blight occurred on both young and old leaves, starting from the margins, and then extended to the entire leaves. The color of the affected tissue was brown with a yellow hallo in the early period, and then gradually turned to grey. The disease incidence was 60%-70% on a 0.08-ha field. Following isolation of the potential pathogen from 12 diseased leaves, nine isolates were obtained. The colonies were white with a regular round shape at the early stage and became black with fluffy hyphae after eight days on potato dextrose agar (PDA) medium, incubated at 25°C in the dark for 10 days. The single cell conidia were solitary, spherical or slightly ellipsoidal, black, shiny, smooth, aseptate, spherical, and 8.1-13.5 μm (n=50) in diameter. Conidiophores (5.2-9.9 × 4.4-7.2 μm) were mostly reduced to conidiogenous cells and aggregated in clusters on hyphae. Conidiogenous cells were hyaline to pale brown or black, globose to ampulliform or clavate. Morphological characteristics of the isolates matched the description of the genus Nigrospora Mei Wang &amp; L. Cai (Wang et al. 2017). For molecular identification, DNA was extracted, and PCRs were performed with primers ITS1/ITS4 for the ITS region (White et al. 1990), primers Bt2a/Bt2b for the β-tubulin gene (TUB) (Glass and Donaldson 1995), and primers EF1-728F/EF1-986R for the translation elongation factor 1-alpha gene (EF1-α) (Carbone and Kohn 1999). Representative sequences of the ITS region, EF1-α, and TUB sequences (from isolate WYR007) were deposited in GenBank (accession numbers: MW561355; MZ053463; MZ032030) and are included in the supplementary materials. BLAST analysis against sequences from previously published studies showed 99.58% (ITS region), 99.54% (EF1-α), and 99.45% (TUB) identity to Nigrospora sphaerica sequences (accession numbers: MN215808.1; MN864137.1; KY019606.1). In addition, homology was confirmed with a phylogenetic tree using concatenated sequences from ITS, EF1-α and TUB constructed with MEGA 7 for which the maximum likelihood method was used with 1,000 bootstrapping iterations. To complete Koch's postulates, conidia suspensions of isolate WYR007 (prepared from 1-month-old colonies in 0.05% Tween 20 buffer and adjusted to a concentration of 1 × 103 conidia/mL) were sprayed on 15 leaves (200 μL per leaf) of 5 one-year-old healthy P. edulis plants (cultivar: 'Panama Red'). The same number of leaves from control group plants was only treated with 0.05% Tween buffer. All plants were incubated at 26°C ± 2°C under a 16 h/8 h photoperiod and 70%-75% relative humidity (RH) after inoculation. After 14 days, symptomatic blight appeared on all inoculated leaves. In contrast, no symptoms appeared on leaves in the control group. The disease assays were repeated three times. Pure cultures were re-isolated from diseased leaves and confirmed to be N. sphaerica based on the morphological and molecular methods mentioned above (ITS region, the TUB, and the EF1-α sequences). To our knowledge, this study is the first report of N. sphaerica as a pathogen on P. edulis causing leaf blight. The identification of the pathogen could provide relevant background for its future management.

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Accurate rapid diagnostic tests for SARS-CoV-2 infection would be a useful tool to help manage the COVID-19 pandemic. Testing strategies that use rapid antigen tests to detect current infection have the potential to increase access to testing, speed detection of infection, and inform clinical and public health management decisions to reduce transmission. This is the second update of this review, which was first published in 2020. To assess the diagnostic accuracy of rapid, point-of-care antigen tests for diagnosis of SARS-CoV-2 infection. We consider accuracy separately in symptomatic and asymptomatic population groups. Sources of heterogeneity investigated included setting and indication for testing, assay format, sample site, viral load, age, timing of test, and study design. We searched the COVID-19 Open Access Project living evidence database from the University of Bern (which includes daily updates from PubMed and Embase and preprints from medRxiv and bioRxiv) on 08 March 2021. We included independent evaluations from national reference laboratories, FIND and the Diagnostics Global Health website. We did not apply language restrictions. We included studies of people with either suspected SARS-CoV-2 infection, known SARS-CoV-2 infection or known absence of infection, or those who were being screened for infection. We included test accuracy studies of any design that evaluated commercially produced, rapid antigen tests. We included evaluations of single applications of a test (one test result reported per person) and evaluations of serial testing (repeated antigen testing over time). Reference standards for presence or absence of infection were any laboratory-based molecular test (primarily reverse transcription polymerase chain reaction (RT-PCR)) or pre-pandemic respiratory sample. We used standard screening procedures with three people. Two people independently carried out quality assessment (using the QUADAS-2 tool) and extracted study results. Other study characteristics were extracted by one review author and checked by a second. We present sensitivity and specificity with 95% confidence intervals (CIs) for each test, and pooled data using the bivariate model. We investigated heterogeneity by including indicator variables in the random-effects logistic regression models. We tabulated results by test manufacturer and compliance with manufacturer instructions for use and according to symptom status. We included 155 study cohorts (described in 166 study reports, with 24 as preprints). The main results relate to 152 evaluations of single test applications including 100,462 unique samples (16,822 with confirmed SARS-CoV-2). Studies were mainly conducted in Europe (101/152, 66%), and evaluated 49 different commercial antigen assays. Only 23 studies compared two or more brands of test. Risk of bias was high because of participant selection (40, 26%); interpretation of the index test (6, 4%); weaknesses in the reference standard for absence of infection (119, 78%); and participant flow and timing 41 (27%). Characteristics of participants (45, 30%) and index test delivery (47, 31%) differed from the way in which and in whom the test was intended to be used. Nearly all studies (91%) used a single RT-PCR result to define presence or absence of infection. The 152 studies of single test applications reported 228 evaluations of antigen tests. Estimates of sensitivity varied considerably between studies, with consistently high specificities. Average sensitivity was higher in symptomatic (73.0%, 95% CI 69.3% to 76.4%; 109 evaluations; 50,574 samples, 11,662 cases) compared to asymptomatic participants (54.7%, 95% CI 47.7% to 61.6%; 50 evaluations; 40,956 samples, 2641 cases). Average sensitivity was higher in the first week after symptom onset (80.9%, 95% CI 76.9% to 84.4%; 30 evaluations, 2408 cases) than in the second week of symptoms (53.8%, 95% CI 48.0% to 59.6%; 40 evaluations, 1119 cases). For those who were asymptomatic at the time of testing, sensitivity was higher when an epidemiological exposure to SARS-CoV-2 was suspected (64.3%, 95% CI 54.6% to 73.0%; 16 evaluations; 7677 samples, 703 cases) compared to where COVID-19 testing was reported to be widely available to anyone on presentation for testing (49.6%, 95% CI 42.1% to 57.1%; 26 evaluations; 31,904 samples, 1758 cases). Average specificity was similarly high for symptomatic (99.1%) or asymptomatic (99.7%) participants. We observed a steady decline in summary sensitivities as measures of sample viral load decreased. Sensitivity varied between brands. When tests were used according to manufacturer instructions, average sensitivities by brand ranged from 34.3% to 91.3% in symptomatic participants (20 assays with eligible data) and from 28.6% to 77.8% for asymptomatic participants (12 assays). For symptomatic participants, summary sensitivities for seven assays were 80% or more (meeting acceptable criteria set by the World Health Organization (WHO)). The WHO acceptable performance criterion of 97% specificity was met by 17 of 20 assays when tests were used according to manufacturer instructions, 12 of which demonstrated specificities above 99%. For asymptomatic participants the sensitivities of only two assays approached but did not meet WHO acceptable performance standards in one study each; specificities for asymptomatic participants were in a similar range to those observed for symptomatic people. At 5% prevalence using summary data in symptomatic people during the first week after symptom onset, the positive predictive value (PPV) of 89% means that 1 in 10 positive results will be a false positive, and around 1 in 5 cases will be missed. At 0.5% prevalence using summary data for asymptomatic people, where testing was widely available and where epidemiological exposure to COVID-19 was suspected, resulting PPVs would be 38% to 52%, meaning that between 2 in 5 and 1 in 2 positive results will be false positives, and between 1 in 2 and 1 in 3 cases will be missed. Antigen tests vary in sensitivity. In people with signs and symptoms of COVID-19, sensitivities are highest in the first week of illness when viral loads are higher. Assays that meet appropriate performance standards, such as those set by WHO, could replace laboratory-based RT-PCR when immediate decisions about patient care must be made, or where RT-PCR cannot be delivered in a timely manner. However, they are more suitable for use as triage to RT-PCR testing. The variable sensitivity of antigen tests means that people who test negative may still be infected. Many commercially available rapid antigen tests have not been evaluated in independent validation studies. Evidence for testing in asymptomatic cohorts has increased, however sensitivity is lower and there is a paucity of evidence for testing in different settings. Questions remain about the use of antigen test-based repeat testing strategies. Further research is needed to evaluate the effectiveness of screening programmes at reducing transmission of infection, whether mass screening or targeted approaches including schools, healthcare setting and traveller screening.

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From the foregoing description it is evident that when rabbits are inoculated intravenously with equal amounts of tubercle bacilli of bovine and human type respectively, they are subject to an immediate reaction in the form of an interstitial pulmonary exudation, which, being of equal severity and character does not serve to distinguish the type. There is an hyperplasia of the lymphoid tissue which is much more pronounced in the bovine series and which may distinguish this type. Opinion on this point may well be reserved until other typical cultures are examined for this response. The two types are sharply distinguished by the behavior of the tubercle bacillus and by the progression of tubercle formation. Tubercles are formed by both types and for about I week after inoculation they are not distinguishable. Progressively thereafter those formed as a response to the bovine bacillus become more numerous; they caseate and become conglomerate, finally coming to occupy the major part of the pulmonary tissue and its associated lymph nodes. With the human type the tubercles do not progress to caseation, do not become more numerous after their first well defined formation, and finally tend to disappear. The human type bacillus does not multiply considerably, if at all, and disappears early. The bovine bacillus suffers little or no restraint in growth and finally multiplies enormously. It seems clear that so far as histologic evidence goes the fundamental difference in the reaction of the rabbit to the two types of tubercle bacilli is referable to the ability of the animal to restrain the growth of the human type or to the prevalence of conditions which permit a most vigorous multiplication of the bovine type. The initial cellular responses seem to be qualitatively of the same order and their quantitative distinctions are for the most part developed coincidently with the manifest growth of the bovine type bacillus. If we undertake to state the observed results in the terminology of immunity we can say only that the histologic picture discloses a difference in the rate of bacillary multiplication which suggests that a difference in the physiologic requirements for growth of the two types of bacilli is satisfied or unsatisfied, in the respective cases, by the rabbit as host; or on the other hand, that there is a positive growth-restraining action exerted with efficiency against bacilli of the human type. It is evident that the present observations furnish no points of discrimination between these alternatives. There is, however, an occasional result of the injection of human type bacilli into rabbits (not seen in this series) which offers a suggestion. When animals so injected are allowed to live for 2 or 3 months, the lungs at autopsy not infrequently present a few nodules of large size, often 1 cm. in diameter, which are found to be well encapsulated, soft, caseous masses. These often contain large numbers of tubercle bacilli. Since we know nothing of the particular conditions which give rise to these rather exceptional formations it is impossible to draw general conclusions from them, but they do suggest that the rabbit is not lacking in the food materials required by the human type bacillus; and that if the more usual suppression of this type is due to failure of its essential nutritives, it is rather a question of the distribution within the animal than an absence which is responsible. The usual result would then appear to be due to a positive growth-restraining action exerted against the human type bacillus. Certain other points of interest in the histologic picture described are worthy of comment. The lymphocytes do not appear as active cells in any preponderant way in either series and they are much less in evidence in the immune case (human type) than in the non-immune (bovine type). This might suggest that the activity of this cell type is a response to infection rather than that it furnished an effective preexisting barrier against infection in this particular case. If the lymphocytes were the most important agents in the immune reaction, it might be expected that they would show an immediate sharp response in the human series. The large mononuclear type of cell is clearly most closely related physically to the tubercle bacillus within the body of the rabbit and this without distinction as to bacillary type. Foci of these cells are the loci of the disappearing bacilli of human type, and in either the active or necrotic state similar cell collections are the site of the most vigorous multiplication of the bovine bacilli. These cells undoubtedly stand in a central position in any picture which can be drawn of experimental tuberculosis in the rabbit and deserve as a consequence all of the very considerable attention they have received at the hands of numerous observers in recent years. It has been quite usual of late to consider that the whole of the essential reaction of the animal against tubercle bacilli is carried by the cells of the mononuclear series, either lymphocytes or large mononuclears according to the predilections of the observer. We cannot, however, entirely overlook the presence in very large numbers of polymorphonuclear leucocytes, both amphophilic and eosinophilic, in this experimental series. They are much less prominent in the animals injected with the killed culture and hence can hardly be neglected on the assumption that they are merely a part of a reaction to an indifferent foreign body They are in large measure a reaction to the living organism: whether a primary and direct or a secondary, indirect consequence of its presence we are unable to decide. These cells are not massed in any regular relationship to the well formed tubercles or to the clusters of mononuclear cells initiating tubercle formation. They are also very much less abundant in the very severe late lesions of the bovine type where enormous numbers of bacilli are enclosed in the tubercles. It seems possible that the polymorphonuclears are a response to the living free tubercle bacilli as contrasted with either the dead bacilli or the living bacilli segregated in mononuclear cell clusters or in tubercles. They would appear also to be related to something apart from the bacillus itself, either a diffusion or disintegration product, since phagocytosis of bacilli, or the presence of bacilli in close physical relation to polymorphonuclear leucocytes, is so infrequent in general as not to have been observed in this series of experiments.

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Strawberry (Fragaria x ananassa Duch.) is one of the most important fruit crops worldwide. With increasing cultivated area in the last decades, Brazil has become the largest strawberry producer in South America. Anthracnose caused by Colletotrichum spp. has been considered one of the most destructive diseases in Brazil. In May 2019, irregular and circular dark brown leaf spots sometimes associated with chlorosis and petiole necrosis were observed on strawberry plants (cv. Pircinque) organically cultivated in Santa Catarina state, Brazil (27°45'40"S, 49°59'06''W). The Colletotrichum isolate was obtained from leaf, and monosporic culture was grown on potato dextrose agar at 25°C and 12-h photoperiod under near ultraviolet light. Colonies at the age of 15 days showed upper surface color varying from white to orange and the reverse side grayish to orange. Conidia were hyaline, cylindrical with rounded ends, 13.9 to 9.2 × 4.2 to 6.7 µm ((x ) ̅= 11.3 × 5.2, n = 100). Perithecia were produced in vitro and their diameter ranged from 265.2 to 142.5 µm ((x ) ̅= 198.4). Asci were 47.3 to 39.9 × 5.2 to 7.2 µm ((x ) ̅= 42.8 × 5.9, n = 50), and ascospores 12.6 to 8.1 × 4.3 to 2.1 ((x ) ̅= 10.3 × 2.9, n = 100). To confirm pathogenicity, 90-day-old plants of strawberry (cv. Pircinque) were inoculated by spraying a suspension of 1×106 conidia/ml, incubated in a moist chamber in the dark for 48 h and then kept in a greenhouse for further 30 days. Plants sprayed with sterile distilled water served as control. Additionally, detached leaves were inoculated with six drops of 10 μl (1×106 conidia/ml) onto abaxial surface and incubated in a moist chamber at 25°C and 12 h photoperiod for 15 days. Inoculated plants exhibited first symptoms in both leaves and petioles at 15 days after inoculation (dai). On leaf, irregular and circular dark brown spots evolved to necrotic lesions and were frequently surrounded by chlorotic halos. In petioles, lesions were reddish-brown, elongated, and depressed. Typical anthracnose symptoms on fruits at 6 dai showed as circular, slightly sunken lesions that enlarged over time and produced an abundant orange mucilaginous mass of acervuli and conidia, and after 20 days, fruits became mummified. In the detached-leaf-assay, symptoms appeared at 7 dai, with presence of circular dark brown lesions measuring 1 to 15 mm and then evolved to necrosis. The same pathogen was consistently re-isolated from the inoculated leaves, petioles, and fruits, and confirmed by morphological characterization and molecular assays as described in this note. A representative isolate (MANE189) was molecularly identified using genomic regions of actin (ACT), β-tubulin (TUB2), calmodulin (CAL), glyceraldehyde-3-phosphate-dehydrogenase (GAPDH), glutamine synthetase (GS), and internal transcribed spacer (ITS). Nucleotide sequences exhibited 100% homology to the typical Colletotrichum karstii strains (CBS:127535, CBS:128500 and ML1792) and were deposited in GenBank database (MW396420, MW396430, MW396460, MW396440, MW396450, and MW331606). This species belongs to the C. boninense species complex (Damm et al. 2012) and was previoStrawberry (Fragaria x ananassa Duch.) is one of the most important fruit crops worldwide. With increasing cultivated area in the last decades, Brazil has become the largest strawberry producer in South America. Anthracnose caused by Colletotrichum spp. has been considered one of the most destructive diseases in Brazil. In May 2019, irregular and circular dark brown leaf spots sometimes associated with chlorosis and petiole necrosis were observed on strawberry plants (cv. Pircinque) organically cultivated in Santa Catarina state, Brazil (27°45'40"S, 49°59'06''W). The Colletotrichum isolate was obtained from leaf, and monosporic culture was grown on potato dextrose agar at 25°C and 12-h photoperiod under near ultraviolet light. Colonies at the age of 15 days showed upper surface color varying from white to orange and the reverse side grayish to orange. Conidia were hyaline, cylindrical with rounded ends, 13.9 to 9.2 × 4.2 to 6.7 µm ((x ) ̅= 11.3 × 5.2, n = 100). Perithecia were produced in vitro and their diameter ranged from 265.2 to 142.5 µm ((x ) ̅= 198.4). Asci were 47.3 to 39.9 × 5.2 to 7.2 µm ((x ) ̅= 42.8 × 5.9, n = 50), and ascospores 12.6 to 8.1 × 4.3 to 2.1 ((x ) ̅= 10.3 × 2.9, n = 100). To confirm pathogenicity, 90-day-old plants of strawberry (cv. Pircinque) were inoculated by spraying a suspension of 1×106 conidia/ml, incubated in a moist chamber in the dark for 48 h and then kept in a greenhouse for further 30 days. Plants sprayed with sterile distilled water served as control. Additionally, detached leaves were inoculated with six drops of 10 μl (1×106 conidia/ml) onto abaxial surface and incubated in a moist chamber at 25°C and 12 h photoperiod for 15 days. Inoculated plants exhibited first symptoms in both leaves and petioles at 15 days after inoculation (dai). On leaf, irregular and circular dark brown spots evolved to necrotic lesions and were frequently surrounded by chlorotic halos. In petioles, lesions were reddish-brown, elongated, and depressed. Typical anthracnose symptoms on fruits at 6 dai showed as circular, slightly sunken lesions that enlarged over time and produced an abundant orange mucilaginous mass of acervuli and conidia, and after 20 days, fruits became mummified. In the detached-leaf-assay, symptoms appeared at 7 dai, with presence of circular dark brown lesions measuring 1 to 15 mm and then evolved to necrosis. The same pathogen was consistently re-isolated from the inoculated leaves, petioles, and fruits, and confirmed by morphological characterization and molecular assays as described in this note. A representative isolate (MANE189) was molecularly identified using genomic regions of actin (ACT), β-tubulin (TUB2), calmodulin (CAL), glyceraldehyde-3-phosphate-dehydrogenase (GAPDH), glutamine synthetase (GS), and internal transcribed spacer (ITS). Nucleotide sequences exhibited 100% homology to the typical Colletotrichum karstii strains (CBS:127535, CBS:128500 and ML1792) and were deposited in GenBank database (MW396420, MW396430, MW396460, MW396440, MW396450, and MW331606). This species belongs to the C. boninense species complex (Damm et al. 2012) and was previously reported causing anthracnose on strawberry leaves in Taiwan (Chung et al. 2020). To our knowledge, this is the first report of C. karstii causing anthracnose on strawberry in Brazil. The accurate identification of the pathogen will assist in the disease management and resistance breeding. usly reported causing anthracnose on strawberry leaves in Taiwan (Chung et al. 2020). To our knowledge, this is the first report of C. karstii causing anthracnose on strawberry in Brazil. The accurate identification of the pathogen will assist in the disease management and resistance breeding.

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The coronavirus disease (COVID-19) pandemic has been impacting the whole society in every aspect of the daily life, comprising the sport field. Several restrictive strategies have been implemented by governments in an effort to stem the spread of the disease and salvage public health. Such efforts have severely constrained access to non-essential services, leading to the closure of non-essential points of gathering and business and the enforcement of rigorous social distancing and prolonged lockdowns, in addition to masking and stay-at-home mandates. However necessary, there is no denying that such extremely rigorous, and to most people unprecedented, measures have adversely affected the global economy and the daily lives of everyone of us, including professional and amateur athletes (1). The most important sport events were postponed or cancelled, including the 2020 Tokyo Olympic Games. But how was the phenomenon of performance-enhancing drug (PED) use impacted and how was the most concerning issue affecting the integrity of sport affected by the pandemic control restrictions? The World Anti-doping Agency (WADA) was established in 1999, whereas its code was implemented in 2004 in order to articulate and enforce doping control initiatives and provide educational strategies aimed at preventing PED use (2). Nonetheless, it is worth noting that the prevalence of PED use among athletes is mostly unchanged since the foundation of WADA. Unfortunately, the use of the performance-enhancing drugs is not limited to athletic performances, but it concerns other settings as well. Nowadays, several strategies for doping control are adopted such as education, deterrence, detection, enforcement and rule of law (3), but the most important anti-dissemination strategy is constituted by information campaigns, especially addressed to youngsters, meant to raise awareness as to the serious health risks involved in PED use. Currently, the primary drivers of anabolic androgenic steroids (ASA) use are 1) the determination to improve performances and prevail no matter what the cost may be; 2) the economic benefits, popularity and fame; 3) greater stamina and resistance. This public health issue has raised particular concerns due to the recent ASA market developments, which is somewhat similar to the illicit market of narcotic drugs. Moreover, it has to be considered that the higher stress and psychosocial condition related to pandemic social restrictions has fueled and exacerbated substance use disorders (4). The prevalence of doping in sport causes unfairness and damages the very fabric of our society, especially insofar as it involves children and young adults who look up to athletes as role models. In this concern, the impact of the COVD-19 pandemic may have led to substantial modifications in substance use patterns and an increased risk of substitution, adulteration, contamination, and dilution with a potentially harmful substance (5, 6). During the COVID-19 lockdown, WADA and stakeholders suspended or scaled down doping control programs, testing and other activities. As a consequence, athletes have seen the unexpected opportunity to misuse AAS without the possible risk of testing positive (7). This has been controversial, considering the measures taken by governments to flatten the pandemic curve in order to safeguard public health. Indeed, all the technologies implemented for teleworking, such as teaching students on-line, telehealth applications, prescriptions and referrals, and treating patients in hospitals/care homes via video links can also be applied to enhance and uphold sport integrity. Conversely, anti-doping testing for professional competitive athletes has increased, due to the lockdown raising suspicion about doping opportunities. The U.S. Anti-doping Agency has put in place novel measures to combat the lack of anti-doping testing during the pandemic: these include a "in-home self-test" that requires athletes to provide urine and small blood samples at home to be tested in the anti-doping laboratory, under supervision provided by video-conference (8). As such, reports from forensic science and toxicology laboratories are crucial for the early detection and response to such events. Furthermore, toxicology laboratories should assure their continue effort in providing new methods and technologies designed to tackle the consumption of illicit substances and to monitor the constantly changing illegal drug markets (9). The most recent WADA code revision has certainly brought about important progress in the ongoing fight against PED abuse. Indeed, it has introduced the possibility to store the samples for 10 years after the first analysis, maintaining the same legal value if re-tested and use for prosecution purposes (10). In that regard, the prospect of re-testing the same sample with newly developed analytical methods based on innovative technologies may represent a strong deterrent for doping users, since anti-doping research rapidly evolves (6), largely by implementing the same approaches used to fight new psychoactive substances (NPS) use (11,12). It is worth noting that the NPS phenomenon bears several similarities with doping, especially due to the constant emergence of new substances and methods aimed at circumventing current legal restrictions. In Italy, the National Antidoping Organization (NADO-Italia) is in charge of guaranteeing compliance with WADA rules and the transposition of the List of Prohibited Substances and Methods. However, the gap between elite athletes and amateur athletes is still broad and unaddressed, since non-professional sport competitions are not adequately overseen, and neither are the competing athletes . This difference may give rise to an important public health issue, on account of the adverse effects of uncontrolled doping agents consumption. In this concern, the Italian anti-doping law created the "Section of the Technical Health Committee for Supervision and Control on Doping and for Health Protection in Sport Activities", that carries out, among its other tasks, the following activities on amateur sport: 1) updating each year the list of banned substances and practices, adapting it to the WADA list; 2) determining cases, criteria and methodologies for anti-doping controls; 3) promoting research projects and information/training campaigns meant to protect health in sports and tackle doping (13). In conclusion, regarding the highly complex dynamics triggered by the pandemic, new and unexpected challenges have come to the fore in the ongoing fight against substance abuse in its every aspect, such as NPS (14), ASA consumption by amateur athletes, or other substance abuse settings, e.g. driving under the influence of psychotropic substances (15). The current Italian antidoping approach for amateur athletes seems to be a promising strategy to bridge the gap between professional sports and amateur sports. Moreover, youngsters should be thoroughly educated as to the threats posed by such substances, so that they can realize how profoundly and severely drug abuse can affect not only their sport career, but their health and well-being overall.

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Dear Editor, An 83-year-old woman developed yellow-brownish infiltrates, nodules, and tumors mimicking xanthomas, mostly involving the periorbital and chest area within three months (Figure 1). She had no abnormalities in serum cholesterol or triglycerides levels. A detailed laboratory analysis revealed the presence of mild monoclonal gammopathy with a presence of immunoglobulin G (IgG) kappa light chains; however, according to hematologist consultation, it did not require medical intervention. Imaging assessment and ultrasound examination did not show any specific involvement of internal organs. The skin biopsy demonstrated necrobiotic areas alternated with foci of xanthogranulomatous infiltration throughout the reticular dermis with extension into subcutaneous tissue. The granulomatous infiltrate was composed of epithelioid, foamy histiocytes in addition to conspicuous giant cells of the Touton type and foreign body type, as well as variable numbers of lymphocytes, plasma cells, and neutrophiles. Lipid vacuoles were seen within the foci of necrobiosis and xanthogranulomatous infiltration (Figure 2). Two months after first admission to our department, the first signs of necrosis within the lesions were noted, and massive necrosis of skin lesions occurred after the following 5 months (Figure 1). Based on the clinical manifestation and histological and laboratory findings, the diagnosis of necrobiotic xanthogranuloma (NXG) was established. In our patient, the extremely late onset of the disease, its very aggressive course, and the absence of malignant hematological disorder were remarkable. The general condition improved after local treatment and a low dose of prednisone. However, patient anamnesis revealed myocardial infarction in the past, congestive heart failure, and atrial fibrillation. Eventually, the patient died due to acute heart failure before alkylating agents could be administered; we consider the patient's death to have been unrelated to NXG. NXG is a rare, chronic granulomatous disorder which was first described in 1980 by Kossard and Winkelmann (1). Currently, less than one hundred fifty cases of this syndrome have been reported in the literature worldwide (2,3). The disease occurs during adulthood, slightly more frequently in women, and usually after the age of 60 years, although the youngest reported patient was 17 years old (3). The disease initially manifests as xanthoma-like eruptions of yellowish or red-orange papules and nodules that coalesce into indurated plaques (4). The size of the lesions typically increases over time or with the next recurrences. In comparison to hyperlipemic and normolipemic xanthomas, the lesions are firmer, more prominent, and more polymorphic (3) with superficial telangiectasias, sometimes erythematous and/or violaceous borders, and atrophy (5). Ulcerations of the lesions were observed in about 50% of patients and tended to be extensive and progressive (4). Skin lesions of NXG can occur anywhere on the body. However, about two-thirds of patients had periorbital involvement, particularly on the upper and/or lower eyelids or elsewhere on the face. The second most commonly affected site was the trunk, predominantly the chest (3-6). However, many skin lesions first appear on the trunk or extremities and subsequently involve the periorbital area (4). More than one body area was affected in about 90% of the published cases (3,4). In individual cases, the occurrence of NXG was noted within scars, after trauma, or in a previously X-ray irradiated area (5). Lesions may be asymptomatic; however, over half of patients asked reported various symptoms, predominantly itching but also burning, tenderness, and even pain (4,5). Periorbital skin lesions are often accompanied by ophthalmic manifestations, mainly scleritis, choroiditis, or conjunctivitis (3), and with complications such as blepharoptosis, restricted ocular motility, and proptosis (4,5). Extracutaneous lesions are most commonly seen in the respiratory tract, including the lungs and larynx, followed by the myocardium, oral cavity, skeletal muscles, kidneys, ovaries, intestine, and other sites (5,6). Extracutaneous involvement was reported in less than 20% of cases (3), but its frequency seems to have increased in recent years (5). Regarding laboratory abnormalities, the majority of patients with NXG (70% and up to 90% depending on the studied population) have a monoclonal gammopathy (more often IgG-kappa than IgG-lambda). Elevated erythrocyte sedimentation rate, anemia, leukopenia, low C1 and C4 levels, and cryoglobulinemia are also frequently present (3-6). Incisional biopsy is recommended to confirm the diagnosis of NXG, but correlations between the clinical presentation and specific histopathologic findings have been poorly characterized so far. The histopathology shows an inflammatory infiltrate composed of macrophages, foam cells, plasma cells, and other inflammatory cells as well as Touton and foreign body-type giant cells in the dermis and subcutaneous tissue. Necrobiosis is usually present, and nodular lymphoid aggregates are common. Cholesterol clefts or asteroid bodies are rare or absent. The epidermis may be atrophic or normal. Special stains are not helpful in establishing the diagnosis of NXG, but immunohistochemistry for CD68 is positive while it is always for CD1a and PS100 negative, like in non-X histiocytosis (4,5). In patients without a known myeloproliferative disorder, bone marrow biopsy may reveal atypical or increased plasma cells and, very rarely, true multiple myeloma (5). As mentioned above, NXG can be a manifestation of multiple myeloma. However, chronic lymphocyte leukemia, B-cell lymphoma, and other lymphoproliferative diseases have also been reported in patients with NXG (3). Remarkably, hematological disorders may emerge many years before or after the onset of skin lesions (even up to 11 years) (4). According to available literature data, the course of the disease is usually chronic and slowly progressive, and the prognosis is relatively good in the absence of co-occurrence of malignant hematological disorders ([5-7). Aside from hyperlipemic and normolipemic xanthomas, the differential diagnosis of NXG includes multifocal necrobiosis lipoidica, granuloma annulare, foreign-body granuloma, juvenile xanthogranuloma, rheumatoid nodules, and amyloidosis (4). In 5 cases from the literature, xanthoma and NXG were present at the same time (3). Despite several hypotheses, the etiopathogenesis of NXG remains unknown (3,4,8). For that reason and due to the rarity of the disease, the optimal therapy has not been not defined. Frequently, chlorambucil or melphalan have been used alone or in combination with prednisone (4). Treatment may result in remission of symptoms on the skin, but it does not provide a permanent cure (8). There are also single reports of the successful use of thalidomide, lenalidomide, cyclophosphamide, dexamethasone, interferon 2a and 2b, plasmapheresis and hydroxychloroquine, azathioprine, infliximab, and autologous bone marrow transplantation (3). Methotrexate seems to be ineffective (9). Local therapy, including local steroids, laser CO2, or radiotherapy, results in partial improvement (3,4). Skin lesions which relapsed or were unresponsive to treatment could be excised surgically and the defects resurfaced with skin grafts. [2].

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Determination of erythrocyte number and their indices and enzymatic activity of: glucose-6-phosphate dehydrogenase (G-6PD), superoxide dismutase (SOD), acetylcholinesterase (AchE), glutathione reductase (GR) and hexokinase (Hx) in peripheral blood erythrocytes of workers chronically exposed to mercury vapours during the production of chloride (the mercuric electrolysis method). The studied workers were equipment operators, electricians and electrolysis maintenance men at the chloride production department using the mercuric electrolysis method. The study involved 46 men, aged 21 to 56, (x = 39 +/- 10.4) exposed to mercury vapours for the period from 7 months to 32 years (x = 14.7+/-10.8), working in a three shift system, for 8 hours a day. Smokers constituted 50% of the studied group (23 men). Urine mercury concentrations of workers exposed to mercury vapours were in the range from 10 to 215 microg/dm3 (x = 81,4 +/- 72,9) and in blood in range 4 do 72 microg/dm3 (x=16.3 +/- 15,0). Controls were 46 men aged 20-54, (x=33.6 +/- 9.8), workers and voluntary blood donors, who never experienced occupational exposure to mercury vapours or other chemicals, and to physical agents. The percentage of smokers in the control group was 34.7% (16 men). Basic haematological determinations (hematocrit - Hct, Hb concentration, erythrocyte number in mm3 of blood, mean red cell hemoglobin concentration (MCHC), mean red cell volume (MCV) and enzymatic studies (activity of G-6PD, SOD, AchE, GR, Hx) in peripheral blood samples obtained from workers and controls were performed. Hematological parameters of the peripheral blood were determined using AVL 808 hematological counter, following the manufacturer's instructions. Activity of the studied enzymes was estimated by the spectrophotometric method described by Beutler, following the recommendations of the International Committee for Standardisation in Hematology. Values of Ht were higher in all the subgroups exposed to Hg workers (divided according to duration of exposure or urine mercury concentrations) in comparison to the control group. The erythrocyte number in mm3 of peripheral blood was also higher in the exposed workers group than in controls. MCHC in the total group exposed to mercury vapours was lower than in the controls. In the subgroup exposed to mercury vapours for &lt; 10 years, the value of this parameter was lower than in the control group; whereas in the subgroups separated in respect to mercury concentration in the urine, it was lower only in workers showing the highest urine concentration of this metal. In workers exposed to mercury vapours, MCV index values were lower than in the controls. In the subgroups of workers who smoked and those who did not smoke, they were also lower than in the controls; whereas in the group of the longest exposed workers from 21 to 35 years, it was found to be higher than in controls. The activity of G6PD was lower in the group of subjects occupationally exposed to mercury vapours than in the control group - 5.60 +/- 1.60 and 7.41 +/- 0.43 IU/gHb respectively. When comparing the subgroups of smokers and non-smokers with the controls, workers showed lower G6PD activity than in the matching control subgroups - 6.24 +/- 1.97 and 7.44 +/-0.22 IU/gHb in the subgroups of smokers and 4.97 +/- 0.72 and 7.38 +/- 0.18 IU/gHb in non-smokers respectively. Erythrocyte G6PD activity was lower in all studied groups separated in respect to exposure time - 5.54 +/- 1.75, 6.02 +/- 2.05 and 5.54 +/- 1.05 IU/gHb respectively. The same pattern of changes was observed in the subgroups separated in respect to mercury concentration in the urine compared to the controls. The lowest enzyme activity was found in the subgroups showing the highest mercury concentration in the urine wnen compared with the subgroup with the lowest urine concentration of this metal - 5.19 +/- 1.50 and 6.00 +/- 1.84 IU/gHb respectively SOD activity in the group of workers exposed to mercury was lower compared to the controls - 2289.97 +/- 122.31 and 2418.03 +/- 60.28 IU/gHb respectively. The smoking and non-smoking workers showed respective SOD activities on - 2305.43 +/- 102.75 and 2274.50 +/- 124.5 IU/gHb; whereas in the matching subgroup of controls - 2452.11 +/- 88.72 and 2382.09 +/- 91.22 IU/gHb, respectively. The activity of this enzyme in all investigated groups selected in respect to length of employment, revealed lower values when compared with the controls - 2271.20 +/- 115.23 in the group with under 10 years of exposure, 2335.11 +/-167.71 IU/gHb in those exposed for 11-20 years, and 2290.40 +/- 26.12 IU/gHb in the subgroup exposed for the longest period of time. Similar changes were observed in the activity of this enzyme in the subgroups separated in respect to mercury concentration in the urine when SOD activity was compared with the controls. The AchE activity was higher in the group exposed to mercury vapours compared to the controls and the respective values were - 50.22 +/- 14.44 and 36.87 +/- 2.92 IU/gHb. In the subgroups separated in respect to length of exposure, the activity of this enzyme was statistically significantly higher than in the control group. The GR activity levels were lower in the exposed group - 8.01 +/-2.54 IU/gHb, compared to the controls - 10.24 +/- 1.24 IU/gHb. In the subgroups of smokers and non-smokers, GR activity was lower, 8.48 +/- 2.37 and 7.54 +/- 2.68 IU/gHb, compared to smokers and non-smokers in the control group, 10.26 +/- 1.01 and 10.16 +/- 1.03 IU/gHb, respectively. The GR activity was also statistically significantly lower in all groups separated in respect to duration of exposure, with the values of 8.56 +/-2.39, 8.26 +/- 2.38, 7.06 +/- 2.75 IU/gHb, respectively in subject groups and 10.24 +/- 1.35 in the control group. Similar changes were noticed in the subgroup separated in respect to mercury concentration in the urine. The Hx activity was lower in the group exposed to mercury vapours - 1.08 +/-0.11. compared with the controls - 1.21 +/- 0.16 IU/gHb. The enzyme activity showed a similar pattern in the subgroups separated in respect to duration of exposure when they were compared with the control group. Exposure to mercury vapours present changes in the red blood cells, manifested by increased (when compared with the control group), number of erythrocytes in peripheral and decreased mean cell volume and mean cell hemoglobin concentration values, as well as changes in the metabolic processes occurring in the erythrocytes. In subjects exposed to mercury vapours some metabolic processes may be additionally modified by addiction to cigarette smoking.

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There is no doubt that postgraduate education and all "professional development activity" is in crisis, not only in our country but in all of Europe. The crisis is on one hand due to a lack of resources which has been evident for more than a decade, and on the other hand due to factors such as organization, culture, and education. Many of the chief medical disciplines such as internal medicine or general surgery, have been literally crushed and replaced by a myriad of subspecialties that have undermined the original unified character of the main disciplines 1. The teaching regulations in recent years have significantly limited students' opportunities to have direct, practical experience with surgery, which would allow them to develop their abilities and a true vocation , both crucial for a profession such as surgery which requires specific qualities and skills. Moreover the new regulations regarding admission to residency programs do not require candidates to make a definitive decision up front about what they want to specialize in, but rather leads them to accept any position among those still available after the candidates who are higher on the national rank-order list, get first pick of all specialties. General surgery is not among the specialties that are most popular in Italy and this appears to be true all over the world. It is therefore one of the few specialties that candidates with a low ranking are allowed to enter, even if they have no natural affinity for this discipline and no special desire to become a general surgeon. This is detrimental not only for healthcare as a whole and patients in particular, but for those doctors who would have selected surgery as their first choice , but cannot because they are too far down on the rank-order list. As a result a significant number of surgeons in training will leave during the five-year training period or after obtaining their diploma or will dedicate themselves to parasurgical activities or specific subspecialties, losing in a short time the broader skills of general surgery and emergency surgery. At the same time the universities has neither the organizational capacity, nor the resources to ensure that all these new subspecialties have the same degree of status and funding. Consequently, the training offered in each subspecialty is currently dependent not on an organic strategy but on factors such as problems with funding and administration, support from the medical industry, or, or even temporary appeal The crisis of training in emergency surgery is paradigmatic probably due to all of the above factors. The lack of foresight of the European institutions in charge has unfortunately had an completely negative influence on this discipline. While general surgery was imploding, the increase in the average age, the evolution of mechanization, the logistics of both work and pleasure, and the explosion of home automation, has dramatically increased the number of both trauma and non-trauma emergencies, increasing the need for professionals with specific cultural and technical skills. Coping with of surgical emergencies accounts for up to 50% of all surgical activity , but in Europe training in Emergency surgery, the only surgical discipline that still maintains the scientific, clinical, technical, and organizational knowledge and skills of general surgery, has been reduced to a bare minimum This affects morbidity and mortality rates, leading to a considerable increase in hospital costs 2. Our English colleagues put a spotlight on this problem some time ago, highlighting the professional and existential problems of surgeons who do not feel able to adequately manage any type of surgical emergency. They therefore demand on the one hand more effective technical training and on the other hand that emergency surgery be reserved only for specialists in the sector. But who will train them if residency programs in emergency surgery have been eliminated and have not been replaced, as they have, by training courses such as "Acute Care Surgery" Thanks to the attitude of national and continental institutions, the number and quality of training opportunities continues to decline Recently, the European Working Time Directive(EWTD) has been introduced, reducing by 50% the time that both tutors and residents could devote to professional activities (3), As a result, for some time now, public and private institutions, cultural and professional associations, trade union representatives, specialty organizations, scientific societies and whatever else, have been proposing and organizing events of all kinds: theoretical and practical courses, Masters programs, single-theme seminars, continuing medical education events, distance learning courses, Technical training live or on the simulator, Cadaver labs and so on, many of which have increased the financial burden on the individual doctor. The Royal College of Surgeons, calculated that the cost of completing the post-university requirements in surgery is today on average about £ 3360 (with a range of $2735 - 20780) compared to £2815 for internal medicine and £ 2215 for anesthesiology .This contributes significantly in increasing young doctors' loss of interest in this specialty. In particular, this applies to emergency surgery because of the poor quality of life , wage limitations, increased responsibilities, and legal disputes associated with this discipline4 . We feel that scientific societies must attempt to compensate for the deficits of institutional education by producing and supplying qualified products at a low price. In recent years various, chiefly Anglo-Saxon societies have proposed live courses on trauma surgery such as the ATOM and DSCT and practical theoretical courses on the first approach to patients requiring emergency care. AEMS has planned theoretical courses in emergency surgery aimed in particular at the acquisition of a European certificate of professional competence and qualification in emergency surgery and ESTES has done the same with regard to professional development in specific diagnostic and therapeutic emergency procedures 5. The Italian Society of Emergency Surgery and Trauma (SICUT), after having validated and proposed in Italy the best English-speaking products and having directly imported the DSCT, began its own production of residential events and dedicated education proposals addressed in particular to the young surgeons. The current symposium consists of a series of short presentations of the various training initiatives for the professional development of emergency surgical care staff that the SICUT has organized in the last few years . This is a series of educational and training events of different kinds, many of which are produced in partnership with other organizations, dedicated to surgeons willing to implement or renew their knowledge and technical skills.

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Darunavir is an oral nonpeptidic HIV-1 protease inhibitor (PI) that is used, together with a low boosting dose of ritonavir, as part of an antiretroviral therapy (ART) regimen in treatment-experienced and -naive patients with HIV-1 infection. Compared with early-generation PIs, boosted darunavir has a high genetic barrier to resistance and is active against multidrug-resistant HIV isolates. In clinical trials in treatment-experienced patients with HIV-1 infection receiving an optimized background regimen (OBR), twice-daily boosted darunavir was more effective than investigator-selected ritonavir-boosted control PIs (CPIs) or ritonavir-boosted lopinavir. In clinical trials in treatment-naive patients with HIV-1 infection receiving a fixed background regimen, once-daily boosted darunavir was noninferior to boosted lopinavir at 48 weeks and more effective than boosted lopinavir at 96weeks. Boosted darunavir was generally well tolerated in patients with HIV-1 infection in clinical trials. It was associated with a lower incidence of diarrhoea than CPIs or lopinavir in treatment-experienced or -naive patients, and fewer lipid abnormalities than lopinavir in treatment-naive patients. Thus, for the management of treatment-experienced or -naive patients with HIV-1 infection, a ritonavir-boosted darunavir-based ART regimen is a valuable treatment option. PHARMACOLOGICAL PROPERTIES: Darunavir is an oral nonpeptidic HIV-1 PI that selectively inhibits the cleavage of HIV gag and gag-pol polyproteins, thereby preventing viral maturation. Darunavir is highly potent against laboratory strains and clinical isolates of wild-type and multidrug-resistant HIV and has limited cytotoxicity. In an in vitro study in MT-2 cells, the potency of darunavir was greater than that of saquinavir, amprenavir, nelfinavir, indinavir, lopinavir and ritonavir. Darunavir binds with high affinity to HIV-1 protease, including multidrug-resistant proteases, and retains potency against multidrug-resistant HIV-1 strains. Although some potential may exist for cross-resistance with amprenavir, darunavir did not display cross-resistance with other PIs in vitro. In a 24-week analysis of pooled data from the POWER 1 and 2 studies in treatment-experienced patients, 11 protease mutations associated with a reduced response to boosted darunavir were identified (V11I, V32I, L33F, I47V, I50V, I54L/M, G73S, L76V, I84V and L89V). The presence of at least three darunavir resistance-associated mutations (prevalent in approximately 7-9% of treatment-experienced patients) together with a high number of protease resistance-associated mutations were required to confer darunavir resistance. In the 48-week analysis of treatment-experienced patients with virological failure in the the TITAN study, fewer in the boosted darunavir group than in the boosted lopinavir group developed additional mutations or lost susceptibility to PIs compared with baseline. In treatment-naive patients, no primary PI-resistance-associated mutations developed in patients with an available genotype at baseline and endpoint during 96 weeks of treatment with boosted darunavir or boosted lopinavir. Oral darunavir, boosted with low-dose ritonavir, is rapidly absorbed, generally reaching peak plasma concentrations within 2.5-4 hours. The bioavailability of oral darunavir is increased by about 30% when taken with food. Darunavir is primarily metabolized by the hepatic cytochrome P450 (CYP) enzymes, primarily CYP3A. The 'boosting' dose of ritonavir acts an an inhibitor of CYP3A, thereby increasing darunavir bioavailability. Drug interactions can result when darunavir is coadministered with other drugs that are inducers or inhibitors of, or act as substrates for, CYP3A. The mean elimination half-life of boosted darunavir is approximately 15 hours. THERAPEUTIC EFFICACY: In treatment-experienced patients with HIV-1 infection, the therapeutic efficacy of oral twice-daily darunavir 600 mg, boosted with ritonavir 100 mg, versus that of investigator selected boosted CPIs (POWER studies) or versus twice-daily boosted lopinavir (administered as a fixed dose combination of lopinavir/ritonavir 400/100 mg) [TITAN study] has been evaluated in phase IIb and III studies. All patients received concurrent treatment with an OBR. Significantly more patients receiving boosted darunavir achieved a viral load reduction from baseline of &gt;or=1 log(10) copies/mL (primary endpoint) than boosted CPI recipients at all timepoints, up to and including the final efficacy analysis at 144 weeks, in the combined analyses of POWER 1 and 2. The efficacy of boosted darunavir was noninferior to that of boosted lopinavir at 48 weeks, and was significantly better than boosted lopinavir at 48 and 96 weeks in the TITAN study, as determined by significantly more patients in the darunavir group than in the lopinavir group achieving a viral load of &lt;400 copies/mL (primary endpoint). In the ARTEMIS study in treatment-naive patients with HIV-1 infection receiving a fixed background regimen of tenofovir and emtricitabine, once-daily boosted darunavir 800 mg was noninferior to boosted lopinavir 800 mg/day at 48 weeks. At 96 weeks, boosted darunavir was found to be more effective than boosted lopinavir, as determined by significantly more patients in the darunavir group than in the lopinavir group achieving a confirmed plasma viral load of &lt;50 copies/mL (primary endpoint). Boosted darunavir was generally well tolerated in patients with HIV-1 infection in clinical trials, with most events being mild to moderate in severity. At 48-week analyses, the most common adverse events associated with once- or twice-daily boosted darunavir in treatment-experienced or -naive patients were diarrhoea, nausea, headache, upper respiratory tract infection and nasopharyngitis. The most common boosted darunavir-related grade 2-4 laboratory abnormalities in treatment-experienced patients included increased triglycerides and increased total cholesterol. Overall, boosted darunavir was associated with less diarrhoea than CPIs or boosted lopinavir in treatment-experienced and -naive patients, and a lower incidence of grade 2-4 elevations in triglycerides and total cholesterol than boosted lopinavir in treatment-naive patients. Treatment discontinuation because of adverse events occurred in 3% of boosted darunavir recipients and 7% of boosted lopinavir recipients during 48 weeks of therapy in treatment-naive patients. PHARMACOECONOMIC CONSIDERATIONS: Healthcare costs in the UK and US were estimated to be lower with boosted darunavir than with investigator-selected CPIs in treatment-experienced patients with HIV-1 infection in two 1-year cost analyses conducted from the perspective of a healthcare provider and using predicted costs based on CD4+ cell counts and clinical data from the POWER studies. The higher acquisition cost of boosted darunavir compared with CPIs was more than offset by the better efficacy of darunavir. In modelled cost-effectiveness analyses, boosted darunavir was predicted to be cost effective compared with other boosted CPIs in heavily pretreated adults from a healthcare payer perspective in Europe and from a societal perspective in the US. In a further model of a subgroup of patients with at least one primary International AIDS Society-USA PI mutation, boosted darunavir was predicted to be cost effective compared with boosted lopinavir from a healthcare payer perspective in Europe. The incremental costs per quality-adjusted life-year gained were within commonly accepted thresholds in all cost-effectiveness analyses.

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Major objective is the evaluation of the medical effectiveness of different therapeutical approaches and the cost effectiveness with relevance for Germany. This health technology assessment (HTA) evaluates systemically randomized controlled studies (RCT) on the therapy of atopic dermatitis which were published between 1999 and 2004. Further it includes some important clinical studies which have been published after 2004 and other updates the English HTA report by Hoare et al. [1]. Topical corticosteroids and topical calcineurin-inhibitors are the principal substances which are currently used for anti-inflammatory therapy in atopic dermatitis. These substances have shown a significant therapeutic efficacy in controlled studies. In newer controlled studies no difference was observable when corticosteroids were applied once or more than once daily onto the skin. Moreover, there is now one controlled study available which points to the fact that an interval therapy with a stronger topical corticosteroid over a limited time (some weeks) may lower the risk of recurrent flares of atopic dermatitis. Both topical calcineurin-inhibitors pimecrolimus and tacrolimus have shown a significant therapeutical efficacy in a number of placebo-controlled prospective studies. The wealth of data is high for these substances. Both substances have been shown to be efficient in infants, children and adult patients with atopic dermatitis. The importance of a so-called basic therapy with emollients which have to be adapted to the current status of skin is generally accepted in clinical practice. Controlled studies show the efficacy of "basic therapy" - although the level of evidence is quite low for this approach. The skin of patients with atopic dermatitis is colonized in the majority with Staphylococcus aureus, a gram-positive bacterium. Therefore, a therapeutical approach for the treatment of atopic dermatitis is the anti-bacterial or anti-septic treatment of the skin. Due to the lack of randomized controlled studies there is still not certain proof that antimicrobial or anti-septic treatment of non-infected eczematous skin is efficient for the treatment of atopic dermatitis. A reduction of Staphylococcus aureus is observable during an anti-inflammatory treatment of the skin with topical corticosteroids and/or the topical calcineurin-inhibitor tacrolimus. Antihistaminic drugs which are orally applied in atopic dermatitis may support the therapy of the itching skin disease. One controlled study showed a rapid reduction of itch during the use of a non-sedating antihistaminic drug. There are, however, no controlled studies which show the efficacy of antihistaminic drugs on the skin condition in atopic dermatitis. Dietetic restrictions should be applied only after a specific allergological diagnostic clarification. The "gold standard" is still a (blinded) oral provocation test which has to show an influence of a given food on the skin condition. There is sufficient evidence that there is no general dietetic approach which shows efficacy in atopic dermatitis. The treatment of patients with lactobacillae is still controversially discussed. Available studies which showed an efficacy show methodological weaknesses so that this approach can not be generally recommended for clinical practice at the time now. Approaches reducing house dust mite in the surroundings of patients with atopic dermatitis can have an effect on the skin condition so that at least in mite sensitized patients this approach appears to be reasonable. The specific immunotherapy with house dust mite showed clinical efficacy in a controlled study and in some open studies. The education of patients with atopic dermatitis or their parents is a further efficient approach in the management of this chronic skin disease. Interdisciplinary approaches in patients' education containing also psychological elements appear to be an attractive new approach for the treatment of atopic dermatitis. Phototherapy is a further possibility of intervention in atopic dermatitis in adolescent or adult patients. The available evidence points to the fact that UVB radiation (both small and broad spectrum), UVA-1 radiation and balneo-phototherapy are efficient therapeutical options for atopic dermatitis. The systemic treatment with the immunosuppressive substance cyclosporine A is efficient in the treatment of severe atopic dermatitis. Cyclosoprine A is approved for the treatment of adult patients with this skin disease. The immunosuppressive substance azathioprine showed a high clinical efficacy in two controlled studies for severe atopic dermatitis in adults. There are still controversial results for the application of antagonists to leucotriens in the treatment of atopic dermatitis: in some open studies a therapeutical efficacy was described which was, however, not reproducible in a newer controlled study. The phosphodiesterase-4-inhibitor cipamphyllin was efficient in the treatment of atopic dermatitis in a controlled study but weaker than a topical class II (i. e. moderate strength) corticosteroide. The HTA assessment further describes so-called complementary therapeutical approaches which have either not properly been studied in controlled clinical trials or which have been shown to be of no value for the treatment of atopic dermatitis. Altogether six full health-economic evaluations were found which did not cover the whole therapy spectrum of atopic dermatitis. The choice of the most cost effective treatment option of topic corticosteroids depends less on application frequency, but rather on the drug price and more used or unused quantity of the standard packages, so even smallest improvements justify a more frequent application. The results from health economic evaluations of calcineurin-inhibitors are not reliable. The therapy of severe atopic dermatitis in adults with ciclosporin shows comparable cost effectiveness in comparison to UVA/UVB therapy. The spectrum of therapeutical procedures has increased for atopic dermatitis but is still not sufficient. The spectrum of established substances is much smaller compared to psoriasis, another chronic and common inflammatory skin disease. There is need for the development new substances which can be applied topically and which are aimed to treat atopic dermatitis in early childhood. Another need for new developments can be found for the treatment of severe atopic dermatitis in adults. The spectrum of therapeutical procedures has increased for atopic dermatitis but is still not sufficient. The spectrum of established substances is much smaller compared to psoriasis, another chronic and common inflammatory skin disease. There is need for the development new substances which can be applied topically and which are aimed to treat atopic dermatitis in early childhood. Another need for new developments can be found for the treatment of severe atopic dermatitis in adults. Due to lack of health economic evaluations therapy decisions in the treatment of atopic dermatitis must take place on the basis of clinical decision criteria. The prescription of topic corticosteroids should prefer low priced drugs. Reliable statements about the cost effectiveness of the new calcineurin-inhibitors tacrolimus and pimecrolimus.

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This review considered the role of the anal Pap test as a screening test for anal dysplasia in patients at high risk of anal SCC. The screening process is now thought to be improved with the addition of testing for the human papillomavirus (HPV) in high-risk populations. High-resolution anoscopy (a method to view the rectal area, using an anoscope, a lighted instrument inserted into the rectum) rather than routine anoscopy-guided biopsy, is also now considered to be the diagnostic standard. TARGET POPULATION AND CONDITION Anal cancer, like cervical cancer, is a member of a broader group of anogenital cancers known to be associated with sexually transmitted viral HPV infection. Human papillomavirus is extremely prevalent, particularly in young, sexually active populations. Sexual practices involving receptive anal intercourse lead to significantly elevated risk for anal dysplasia and cancer, particularly in those with immune dysfunctions. Anal cancer is rare. It occurs at a rate of about 1 to 2 per 100,000 in the general population. It is the least common of the lower gastrointestinal cancers, representing about 4% of them, in contrast to colorectal cancers, which remain the third most commonly diagnosed malignancy. Certain segments of the population, however, such as HIV-positive men and women, other chronic immune-suppressed patients (e.g., after a transplant), injection drug users, and women with genital dysplasia /cancer, have a high susceptibility to anal cancer. Those with the highest identified risk for anal cancer are HIV-positive homosexual and bisexual men, at a rate of 70 per 100,000 men. The risk for anal cancer is reported to be increasing dramatically in HIV-positive males and females, particularly since the introduction of highly active antiretroviral therapy in the mid-1990s. The introduction of effective viral therapy has been said to have transformed the AIDS epidemic in developed countries into a chronic disease state of long-term immunosuppression. In Ontario, there are about 25,000 people living with HIV infection; more than 6,000 of these are women. About 28% of the newly diagnosed HIV infections are in women, a doubling since 1999. It has also been estimated that 1 of 3 people living with HIV do no know it. HEALTH TECHNOLOGY DESCRIPTION: Anal Pap test screening involves the blind insertion of a swab into the anal canal and fixing cells either on a slide or in fluid for cytological examination. Anal cytology classified by the standardized Bethesda System is the same classification used for cervical cytology. It has 4 categories: normal, atypical squamous cells of uncertain significance, or squamous intraepithelial lesions which are further classified into low- or high-grade lesions. Abnormal cytological findings are subjected to further evaluations by high-resolution anoscopy, a technique similar to cervical colposcopy, and biopsy. Several HPV deoxyribonucleic acid detection technologies such as the Hybrid 11 Capture and the polymerase chain reaction are available to detect and differentiate HPV viral strains. Unlike cervical cancer, there are no universally accepted guidelines or standards of care for anal dysplasia. Moreover, there are no formal screening programs provincially, nationally, or internationally. The New York State Department of Health AIDS Institute has recently recommended (March 2007) annual anal pap testing in high-risk groups. In Ontario, reimbursement exists only for Pap tests for cervical cancer screening. That is, there is no reimbursement for anal Pap testing in men or women, and HPV screening tests for cervical or anal cancer are also not reimbursed. The scientific evidence base was evaluated through a systematic literature review. Assessments of current practices were obtained through consultations with various agencies and individuals including the Ministry of Health and Long-Term Care AIDS Bureau; Public Health Infectious Diseases Branch, Ministry of Health and Long-Term Care; Cancer Care Ontario; HIV/AIDS researchers; pathology experts; and HIV/AIDS clinical program directors. An Ontario-based budget impact was also done. No direct evidence was found for the existence of controlled studies evaluating the effectiveness of anal Pap test screening programs for impact on anal cancer morbidity or mortality. In addition, no studies were found on the use of HPV DNA testing in the screening or diagnostic setting for anal dysplasia. The reported prevalence of HPV infection in high-risk groups, particularly HIV-positive males, however, was sufficiently high to preclude any utility of HPV testing as an adjunct to anal Pap testing. Nine reports involving studies in the United States, United Kingdom, and Canada were identified that evaluated the performance characteristics of anal Pap test screening for anal dysplasia. All involved hospital-based specialty HIV/AIDS care clinics with mainly HIV-positive males. All studies involved experienced pathologists, so the results generally represent best-case scenarios. Estimates of anal Pap test sensitivity and specificity were highly variable, and depended on the varying prevalence of cytology abnormality and differential thresholds for abnormality for both cytology and histopathology. In the largest study of HIV-positive males, sensitivity varied from 46% (95% confidence interval [CI], 36%-56%) to 69% (95% CI, 60%-78%). Specificity ranged from 59% (95% CI, 53%-65%) to 81% (95% CI, 76%-85%). In the only study of HIV-negative males, sensitivity ranged from 26% (95% CI, 5%-47%) to 47% (95% CI, 26%-68%). Specificity ranged from 81% (95% CI, 76%-85%) to 92% (95% CI, 89%-95%). In comparison, cervical Pap testing has also been evaluated mainly in settings where there is a high prevalence of the disease, and estimates of sensitivitykij and specificity were also low and highly variable. In a systematic review involving cervical Pap testing, sensitivity ranged from 30% to 87% (mean, 47%) and specificity from 86% to 100% (mean, 95%). No direct evidence exists to support the effectiveness of an anal Pap test screening program to reduce anal cancer mortality or morbidity. There are, however, strong parallels with cervical pap testing for cervical cancer. Sexually transmitted HPV viral infection is currently the acknowledged common causative agent for both anal and cervical cancer. Anal cancer rates in high-risk populations are approaching those of cervical cancer before the implementation of Pap testing. The anal Pap test, although it has been mainly evaluated only in HIV-positive males, has similar operating characteristics of sensitivity and specificity as the cervical Pap test. In general, the treatment options for precancer dysplasia in the cervix and the anus are similar, but treatment involving a definitive surgical resection in the anus is more limited because of the higher risk of complications. A range of ablative therapies has been applied for anal dysplasia, but evidence on treatment effectiveness, tolerability and durability, particularly in the HIV-positive patient, is limited.

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To investigate the changes of fatty acid oxidase in the placenta of preeclampsia cases with different clinical features, and the relationship with oxidative stress and inflammatory response. To study the correlation of serum free fatty acid (FFA) and triglycerides (TG) level in early second trimester with the molecular changes of the long-chain fatty acid oxidase in the third trimester. This was prospective cohort study, in which cases with singleton pregnancies who archived in Haidian Maternal and Children's Hospital, Beijing, from January 1st 2012 to May 31st, with regular prenatal care were included. Doppler ultrasound was used for screening for the presence of early diastolic notch of uterine artery at 22-24 weeks of gestation. All the 101 cases with the early diastolic notch of uterine artery were included as the notch group, and 377 cases without the early diastolic notch of uterine artery were included as the non-notch group. The perinatal outcomes and the incidence of hypertensive disorders in pregnancy of the two groups were observed. The serum level of FFA and TG was tested, and the mRNA and protein expression of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), P47-phox subunit of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, p38 mitogen-activated protein kinase a (p38MAPK-α) and cyclooxygenase-2 (COX-2) were detected using real-time quantitative PCR and western blot. The relationship between serum level of FFA and TG and the mRNA and protein expression of LCHAD, NADPH P47-phox, p38MAPK-α and COX-2 of the placental tissue specimens were analyzed. (1) In the notch group, there were 9 cases of early-onset preeclampsia, 15 cases of late-onset preeclampsia and 10 cases of gestational hypertension;and there were 8 cases of late-onset preeclampsia and 18 cases of gestational hypertension in the non-notch group. 15 cases with normal blood pressure in each group were randomly selected as the control group. (2)The serum level of TG of cases of early-onset preeclampsia, late-onset preeclampsia and gestational hypertension in the notch group were (2.0 ± 0.8), (1.8 ± 0.6)and (1.9 ± 0.7)mmol/L, and that of FFA were(0.68 ± 0.26), (0.52 ± 0.10) and (0.52 ± 0.17)mmol/L, respectively. The serum level of TG of cases of late-onset preeclampsia and gestational hypertension in the non-notch group were (1.6 ± 0.6) and (1.4 ± 0.4)mmol/L, and that of FFA were (0.49 ± 0.11) and (0.48 ± 0.05)mmol/L, respectively. The serum level of TG and FFA in the control group were (1.4 ± 0.5) and (0.52 ± 0.06)mmol/L, respectively. The TG level of the notch group was higher than that of the control group, and the difference was statistically significant (P &lt; 0.05). The FFA level of the early-onset preeclampsia in the notch group was higher than that of late-onset preeclampsia in the notch group, late-onset preeclampsia in the non-notch group and the control group, and the difference was statistically significant (P &lt; 0.05). (3) The mRNA expression of LCHAD in the placenta of early-onset preeclampsia in the notch group was significantly lower than that of the late-onset preeclampsia in the notch group, late-onset preeclampsia in the non-notch group and the control group (P &lt; 0.01). The mRNA expression of NADPH P47-phox of the early-onset preeclampsia in the notch group were significantly higher than that of late-onset preeclampsia in the notch group, late-onset preeclampsia in the non-notch group and the control group (P &lt; 0.01). The mRNA expression of p38MAPK-α of the early-onset preeclampsia in the notch group were significantly higher than that of late-onset preeclampsia in the notch group, late-onset preeclampsia in the non-notch group and the control group (P &lt; 0.01). The mRNA expression of COX-2 of the early-onset preeclampsia in the notch group were significantly higher than that of late-onset preeclampsia in the notch group, late-onset preeclampsia in the non-notch group and the control group (P &lt; 0.01). (4)The protein expression of LCHAD in the placenta of early-onset preeclampsia in the notch group, late-onset preeclampsia in the notch group and gestational hypertension in the notch group were significantly lower than that of the control group (P &lt; 0.01); and the protein expression of LCHAD in the placenta of early-onset preeclampsia in the notch group was significantly lower than that of late-onset preeclampsia in the non-notch group (P &lt; 0.01). The protein expression of NADPH P47-phox in the placenta of early-onset preeclampsia in the notch group was significantly higher than that of late-onset preeclampsia in the non-notch group and control group (P &lt; 0.05). The protein expression of p38MAPK-α in the placenta of early-onset preeclampsia in the notch group was significantly higher than that of late-onset preeclampsia in the notch group, late-onset preeclampsia in the non-notch group and control group (P &lt; 0.01). The protein expression of COX-2 in the placenta of early-onset preeclampsia in the notch group, late-onset preeclampsia in the notch group, gestational hypertension in the notch group, late-onset preeclampsia in the non-notch group, and gestational hypertension in the non-notch group, were significantly higher than that of control group (P &lt; 0.01). (5)The blood concentration of maternal FFA in the early-onset preeclampsia in the notch group was significantly negatively correlated with the mRNA and protein expression of placental LCHAD (r = -0.810, -0.932, P &lt; 0.01). There was no correlation between maternal TG level and the mRNA and protein expression of placental LCHAD in each group(P &gt; 0.05). (6)The mRNA expression of placental LCHAD in the early-onset preeclampsia in the notch group was significantly negatively correlated with the mRNA expression of placental NADPH P47-phox and COX-2 (r = - 0.877, -0.762, P &lt; 0.05). The mRNA expression of placental LCHAD in the control group was significantly negatively correlated with the mRNA expression of placental COX-2 (r = -0.565, P &lt; 0.01). The protein expression of placental LCHAD in the early-onset preeclampsia in the notch group was significantly negatively correlated with the protein expression of NADPH P47-phox (r = -0.818, P &lt; 0.01). The protein expression of placental LCHAD in the control group was significantly negatively correlated with the protein expression of COX-2 (r = -0.502, P &lt; 0.01). The placental mRNA and protein expression of long-chain fatty acid oxidation enzymes were different in different clinical features of preeclampsia, which were reduced more obviously in the early-onset preeclampsia in the notch group than that of the late-onset preeclampsia in the notch group, and were negatively correlated with the elevated serum FFA level, significantly enhanced oxidative stress and inflammatory response, but with no correlation with serum TG level.

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Can additional genetic variants for circulating anti-Müllerian hormone (AMH) levels be identified through a genome-wide association study (GWAS) meta-analysis including a large sample of premenopausal women? We identified four loci associated with AMH levels at P &lt; 5 × 10-8: the previously reported MCM8 locus and three novel signals in or near AMH, TEX41 and CDCA7. AMH is expressed by antral stage ovarian follicles in women, and variation in age-specific circulating AMH levels has been associated with disease outcomes. However, the physiological mechanisms underlying these AMH-disease associations are largely unknown. We performed a GWAS meta-analysis in which we combined summary statistics of a previous AMH GWAS with GWAS data from 3705 additional women from three different cohorts. In total, we included data from 7049 premenopausal female participants of European ancestry. The median age of study participants ranged from 15.3 to 48 years across cohorts. Circulating AMH levels were measured in either serum or plasma samples using different ELISA assays. Study-specific analyses were adjusted for age at blood collection and population stratification, and summary statistics were meta-analysed using a standard error-weighted approach. Subsequently, we functionally annotated GWAS variants that reached genome-wide significance (P &lt; 5 × 10-8). We also performed a gene-based GWAS, pathway analysis and linkage disequilibrium score regression and Mendelian randomization (MR) analyses. We identified four loci associated with AMH levels at P &lt; 5 × 10-8: the previously reported MCM8 locus and three novel signals in or near AMH, TEX41 and CDCA7. The strongest signal was a missense variant in the AMH gene (rs10417628). Most prioritized genes at the other three identified loci were involved in cell cycle regulation. Genetic correlation analyses indicated a strong positive correlation among single nucleotide polymorphisms for AMH levels and for age at menopause (rg = 0.82, FDR = 0.003). Exploratory two-sample MR analyses did not support causal effects of AMH on breast cancer or polycystic ovary syndrome risk, but should be interpreted with caution as they may be underpowered and the validity of genetic instruments could not be extensively explored. The full AMH GWAS summary statistics will made available after publication through the GWAS catalog (https://www.ebi.ac.uk/gwas/). Whilst this study doubled the sample size of the most recent GWAS, the statistical power is still relatively low. As a result, we may still lack power to identify more genetic variants for AMH and to determine causal effects of AMH on, for example, breast cancer. Also, follow-up studies are needed to investigate whether the signal for the AMH gene is caused by reduced AMH detection by certain assays instead of actual lower circulating AMH levels. Genes mapped to the MCM8, TEX41 and CDCA7 loci are involved in the cell cycle and processes such as DNA replication and apoptosis. The mechanism underlying their associations with AMH may affect the size of the ovarian follicle pool. Altogether, our results provide more insight into the biology of AMH and, accordingly, the biological processes involved in ovarian ageing. Nurses' Health Study and Nurses' Health Study II were supported by research grants from the National Institutes of Health (CA172726, CA186107, CA50385, CA87969, CA49449, CA67262, CA178949). The UK Medical Research Council and Wellcome (217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the listed authors, who will serve as guarantors for the contents of this article. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). Funding for the collection of genotype and phenotype data used here was provided by the British Heart Foundation (SP/07/008/24066), Wellcome (WT092830M and WT08806) and UK Medical Research Council (G1001357). M.C.B., A.L.G.S. and D.A.L. work in a unit that is funded by the University of Bristol and UK Medical Research Council (MC_UU_00011/6). M.C.B.'s contribution to this work was funded by a UK Medical Research Council Skills Development Fellowship (MR/P014054/1) and D.A.L. is a National Institute of Health Research Senior Investigator (NF-0616-10102). A.L.G.S. was supported by the study of Dynamic longitudinal exposome trajectories in cardiovascular and metabolic non-communicable diseases (H2020-SC1-2019-Single-Stage-RTD, project ID 874739). The Doetinchem Cohort Study was financially supported by the Ministry of Health, Welfare and Sports of the Netherlands. The funder had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Ansh Labs performed the AMH measurements for the Doetinchem Cohort Study free of charge. Ansh Labs was not involved in the data analysis, interpretation or reporting, nor was it financially involved in any aspect of the study. R.M.G.V. was funded by the Honours Track of MSc Epidemiology, University Medical Center Utrecht with a grant from the Netherlands Organization for Scientific Research (NWO) (022.005.021). The Study of Women's Health Across the Nation (SWAN) has grant support from the National Institutes of Health (NIH), DHHS, through the National Institute on Aging (NIA), the National Institute of Nursing Research (NINR) and the NIH Office of Research on Women's Health (ORWH) (U01NR004061; U01AG012505, U01AG012535, U01AG012531, U01AG012539, U01AG012546, U01AG012553, U01AG012554, U01AG012495). The SWAN Genomic Analyses and SWAN Legacy have grant support from the NIA (U01AG017719). The Generations Study was funded by Breast Cancer Now and the Institute of Cancer Research (ICR). The ICR acknowledges NHS funding to the NIHR Biomedical Research Centre. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent official views of the funders. The Sister Study was funded by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (Z01-ES044005 to D.P.S.); the AMH assays were supported by the Avon Foundation (02-2012-065 to H.B. Nichols and D.P.S.). The breast cancer genome-wide association analyses were supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the 'Ministère de l'Économie, de la Science et de l'Innovation du Québec' through Genome Québec and grant PSR-SIIRI-701, The National Institutes of Health (U19 CA148065, X01HG007492), Cancer Research UK (C1287/A10118, C1287/A16563, C1287/A10710) and The European Union (HEALTH-F2-2009-223175 and H2020 633784 and 634935). All studies and funders are listed in Michailidou et al. (Nature, 2017). F.J.M.B. has received fees and grant support from Merck Serono and Ferring BV. D.A.L. has received financial support from several national and international government and charitable funders as well as from Medtronic Ltd and Roche Diagnostics for research that is unrelated to this study. N.S. is scientific consultant for Ansh Laboratories. The other authors declare no competing interests.

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The primary objective of this guideline is to provide Canadian physicians up-to-date, accurate information and recommendations regarding: i) impact of pregnancy and lactation on risk of breast cancer; ii) prognosis of breast cancer diagnosed during pregnancy and lactation; iii) risk of recurrence of breast cancer with the occurrence of subsequent pregnancies; iv) feasibility of breastfeeding and its impact on the prognosis of women with breast cancer. This guideline reviews evidence on whether pregnancy and breastfeeding change the lifetime risk for breast cancer in women, and whether breast cancer diagnosed during pregnancy or during lactation has a different prognosis. It offers the clinician advice on the diagnostic options to help identify breast cancer in pregnancy and/or during lactation, and offers evidence-based recommendations in managing an ongoing pregnancy and/or lactation when treatment for breast cancer is being planned. It also offers recommendations to clinicians in counselling their patients regarding future pregnancy and future breastfeeding for women who have been treated for breast cancer. These guidelines should help physicians counsel patients using evidence-based recommendations. These recommendations may also improve the prognosis of patients diagnosed with breast cancer during pregnancy and lactation, or of those patients who had breast cancer and are contemplating future pregnancies. A Medline search was carried out for all publications from 1990 through 2000, in the English language, related to breast cancer and pregnancy in terms of diagnosis, prognosis, and treatment, as well as for breast cancer and breastfeeding, with particular focus on impact of treatment of breast cancer on lactation and prognosis of breast cancer after lactation. The authors submitted the manuscript for review to members of the Breast Disease Committee, who also validated the levels of evidence. The final manuscript was submitted to the SOGC Council for approval and dissemination. The levels of evidence for recommendations have been determined using the criteria described by the Canadian Task Force on the Periodic Health Examination. Canadian physicians will be able to counsel their patients on the impact of pregnancy and lactation on a woman's lifetime risk for breast cancer. Physicians and patients will be empowered to decide how to manage pregnancy and lactation when breast cancer is diagnosed in pregnancy, and to appreciate the ramifications of reproduction and breastfeeding after breast cancer. This guideline identifies areas where good evidence is lacking and advocates research in those areas. Women should be counselled regarding their risk for breast cancer and be informed that: 1. There is good evidence that there is a transient increase in risk of breast cancer in the first three to four years after delivery of a singleton baby (II-2B). Subsequently, their lifetime risk seems lower than that of women who remain nulliparous (II-2B). 2. There is good evidence that the risk for premenopausal breast cancer is reduced with lactation (II-2A). This protective effect seems to be best for women who had extended periods of breastfeeding during their lifetime (ll-2B). Women with familial risks could potentially benefit most from breastfeeding (II-2C). Since breast milk is the ideal nutrient for the newborn, and since breastfeeding is a modifiable risk factor, all women should be encouraged to breastfeed their children (II-2A). 3. All women should be encouraged to practice breast self-examination in pregnancy and during lactation (II-2B). Clinicians should screen all pregnant patients for breast cancer with thorough breast examination early in pregnancy (III-B). The clinician is advised to examine the breast in the postpartum period if the woman is not breastfeeding. The obstetrician is advised to examine the breast at any time in the postpartum period if the woman presents with breast symptoms (III-B). 4. Physicians should be encouraged to use ultrasltrasonography, mammography, needle aspiration, or breast biopsies to assess suspicious breast masses in pregnancy and during lactation, in the same timely fashion as for non-pregnant or non-lactating women (II-2A). Interruption of lactation during investigation is not necessary, nor is it recommended unless nuclear studies are entertained (III-B). 5. Once breast cancer is diagnosed, a multidisciplinary approach should be taken. This includes the obstetrician, surgeons, medical and radiation oncologists, and breast cancer counsellors (II-2A). 6. In early pregnancy, the patient should be counselled regarding the effect of proposed therapy on the fetus and on overall maternal prognosis. Termination of pregnancy should be discussed, but the patient should be counselled that prognosis is not altered by termination of pregnancy. Women should be advised that premature menopause may result from breast cancer treatments, especially if chemotherapy is given to patients who are past the age of 30. (II-2C) 7. Up until now, modified radical mastectomy was the cornerstone of surgical treatment of breast cancer during pregnancy. Adjuvant chemotherapy should be entertained and, if required, administered without delay. The patient should be counselled regarding the effect of chemotherapy on the fetus and/or the future reproductive potential of the patient (II-2B). In the third trimester, the risks and benefits of early delivery versus continuation of pregnancy, and the effect of chemotherapy on the fetus, should be addressed (II-2B). Women undergoing chemotherapy or tamoxifen treatment should not breastfeed (III-B). 8. Women treated for breast cancer and who wish to become pregnant should be counselled that pregnancy is possible and does not seem to be associated with a worse prognosis for their breast cancer (II-3C). However, they should be made aware that the evidence to support such advice is relatively poor. 9. Since most breast cancer recurrences appear within two to three years after initial diagnosis, patients should be advised to postpone pregnancy for three years (III-C). If a patient has axillary node involvement, the recommendation to defer pregnancy should be extended to five years, but this recommendation is based on opinion only (III-C). Prior to attempting pregnancy, a breast cancer survivor should be referred for a full oncologic evaluation. 10. There is no evidence that breastfeeding increases the risk of breast cancer recurring or of a second breast cancer developing, nor that it carries any health risk to the child. Women previously treated for breast cancer, who do not show any evidence of residual tumour, should be encouraged to breastfeed their children (III-B). Level of evidence, quality of research in the recruited publications, and ensuing recommendations were reviewed and discussed by members of the SOGC Breast Disease Committee as well as by a member of the Gynaecological Oncology Committee. External reviewers with expertise in the area were also solicited for comments and criticism.

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Toxicity studies were performed with a chemically defined mixture of 25 groundwater contaminants, using dose levels considered to have environmental relevance. The mixture contained 19 organic compounds and six metals (shown below); the selection of these compounds was based primarily on the frequency of their occurrence in United States Environmental Protection Agency surveys of groundwater contamination in the vicinity of hazardous waste disposal sites. This report focuses primarily on 26-week drinking water toxicity studies with male and female F344/N rats and B6C3F(1) mice. The endpoints evaluated included histopathology, clinical pathology, neurobehavioral studies, and reproductive toxicity. Additional studies using this same chemical mixture are briefly reviewed in this report and include an evaluation of spermatogenesis in B6C3F(1) mice exposed to the chemical mixture for 13 weeks, a continuous breeding study with Sprague-Dawley rats and CD-1(R) Swiss mice, studies of myelotoxicity in B6C3F(1) mice exposed to the chemical mixture for up to 31.5 weeks, studies of immunosuppression in B6C3F(1) mice exposed for up to 13 weeks, in vitro mutagenicity assays in Salmonella typhimurium and Escherichia coli, and measures of genetic damage in bone marrow and peripheral blood of F344/N rats and B6C3F(1) mice in 2-week drinking water studies. In a 26-week drinking water study in which rats were administered the chemical mixture at composite contaminant concentrations of 0, 11, 38, 113, or 378 ppm, no deaths occurred and the body weight gain of high-dose males was slightly less than that of the controls. Water consumption decreased with dose and was 24% to 28% less than that of the controls at the highest concentration. Changes in organ weights occurred primarily in high-dose rats and included increased absolute and relative liver and kidney weights in females, increased relative kidney weight in males, and decreased absolute and relative thymus weights in males and females. Hematologic assessments indicated that rats receiving 378 ppm developed a microcytic anemia consistent with that accompanying iron depletion. Multiple foci of inflammation occurred in the liver of exposed rats. In high-dose females, these liver lesions were especially prominent and included bile duct and oval cell hyperplasia. Inflammation also occurred in the mesenteric lymph nodes, the adrenal gland, and the spleen. The amount of hemosiderin in the spleens of rats receiving the higher concentrations of the chemical mixture was less than normal. Components of a chemical mixture of 25 groundwater contaminants include acetone, aroclor 1260, arsenic, benzene, cadmium, carbon tetrachloride, chlorobenzene, chloroform, chromium, 1,1-dichloroethane, 1,2-dichloroethane, 1,1-dichloroethylene, 1,2-trans-dichloroethylene, di(2-ethylhexyl) phthalate, ethylbenzene, lead, mercury, methylene chloride, nickel, phenol, tetrachloroethylene, toluene, 1,1,1-trichloroethane, trichloroethylene, xylenes. In a 26-week study in which mice were exposed to the chemical mixture at concentrations of 0, 11, 38, 113, and 378 ppm in drinking water, there were no clear adverse effects noted in survival, weight gain, clinical pathology parameters, or histopathologic evaluations. Water consumption decreased with increasing dose, and water consumption by high-dose mice was approximately 40% less than that by the controls. In neurobehavioral assessments, no clear treatment-related effects were observed in measures of forelimb and hindlimb grip strength, hindlimb footsplay, motor activity, response to a thermal stimulus, or startle response in rats or mice evaluated at 6-week intervals throughout the 26- week drinking water studies. There were no effects on sperm morphology or motility or on estrous cycle length in rats or mice receiving the chemical mixture during the 26-week studies. Sperm concentration was decreased in F(1) CD-1(R) Swiss mice during continuous breeding studies, although there were no clear adverse effects on the fertility of Sprague-Dawley rats or CD-1(R) Swiss mice in th CD-1&amp;reg; Swiss mice in these studies. Pup weight, the number of live males, and the number of male pups per litter were slightly decreased in dosed rats in the continuous breeding study in rats; the number of live female mouse pups in litters born of the F(0) and F(1) generations was decreased in the 378 ppm group. The significance of these observations, if any, is not known. F(1) mice receiving 378 ppm had increased incidences of hepatic inflammation compared to the controls. In female B6C3F(1) mice that received the chemical mixture in drinking water at concentrations as high as 756 ppm for 2 weeks or 378 ppm for 13 weeks, assessments of immune function showed suppression of hematopoietic stem cells and antigen-induced antibody-forming cells. This was manifested by impaired resistance to challenge with a nonlethal strain of mouse malaria, Plasmodium yoelii. Additional evidence of an adverse effect on hematopoietic stem cells was demonstrated by decreases in the in vitro colony-forming ability of granulocyte-macrophage progenitor cells and erythroid precursor cells isolated from female mice that had received the chemical mixture at a concentration of 378 or 756 ppm in 31.5 week studies. Potential genotoxic effects of the chemical mixture to the bone marrow of F344/N rats and B6C3F(1) mice were assessed in 2-week drinking water studies with concentrations as high as 756 ppm. Small increases in sister chromatid exchanges and micronucleated polychromatic erythrocytes occurred in the bone marrow of dosed male mice, and micronucleated polychromatic erythrocytes were also increased in dosed female mice. The chemical mixture did not induce mutations in Salmonella typhimurium strains TA98 and TA100 and did not induce DNA damage in Escherichia coli with or without metabolic activation. In summary, rats receiving drinking water containing a mixture of 25 common groundwater contaminants at levels of potential environmental relevance developed inflammatory lesions in the liver, spleen, lymph nodes, and adrenal gland, as well as evidence of an iron deficiency anemia. The inflammatory lesions could not be predicted based on the known toxic effects of the individual components of the chemical mixture. Mice exposed to similar concentrations of the chemical mixture did not show adverse effects in a standard toxicity study but developed deficits in bone marrow function, evidence of genetic damage, hepatic inflammation, and immunosuppression in other studies that generally included exposures to higher concentrations or exposures of longer duration. A no-observed-adverse-effect level for histologic injury (granulomatous inflammation of the liver) was 11 ppm in rats; however, no clear evidence for histologic injury was seen in mice exposed to concentrations of the chemical mixture as high as 378 ppm in a standard 26-week study. NOTE: These studies were supported in part by funds from the Comprehensive Environmental Response, Compensation, and Liability Act trust fund (Superfund) by an interagency agreement with the Agency for Toxic Substances and Disease Registry, U.S. Public Health Service.

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An original objective of these multidisciplinary studies was to determine the position of the Aleuts in the Aleutian ecosystem with time depth. This has been done in a variety of ways (7, 14, 20, 21). One of the most useful approaches is the construction of life expectancy tables. The greater longevity of Aleuts compared with Eskimos represents an effective biological and cultural human adaptation within this ecosystem. The Aleuts defined their ecosystem by expanding to the limits of the area they could effectively exploit with their complex technology, population structure, and population deployment system. Their intellectual achievements played a tangible role in their longevity in the pre-Russian period, and their sophisticated knowledge of human anatomy is both a causal and a consequential correlate of their longevity. From the Aleut point of view, the food resources were diverse, abundant, and accessible, and they also provided fabricational materials necessary for their complex material culture. The Aleuts successfully hunted the world's largest range of sea mammals, from the sea otter to the whales. At the same time, extensive use of invertebrates easily available on the ice-free strandflats enabled disadvantaged sectors of the population to make important contributions to their own food supply and thus improve life expectancy. The rich food and fabricational materials antedate the Holocene history of Nikolski Bay and the arrival of the ancestral Aleuts. The natural resources of this area are fundamentally related to the former peninsular extension of Beringia and the permanent upwelling system in Samalga Pass (22). Sea otters, seals, and sea lions were present when the first Aleuts came to the area. Nikolski Bay has been an ideal place to obtain samples representing the entire Holocene Epoch. The earliest Asiatic migrants came from Siberia and traversed the southern coastline of Beringia. They established a large and permanent village on the northern arm of Nikolski Bay and remained there while expanding to the far ends of the Aleutian domain in the sixth millennium of their residence. The record of cultural change spans a lithic revolution. It begins with a conservative unifacial core and blade industry that preserves several Asiatic traits but includes stone lamps, dishes, an image of the deity, and the use of red ochre. Between 7000 and 6000 years ago bifacially flaked and stemmed points appear, with some continuing elements of the old unifacial industry. This transition culture continues to about 4500 years ago, when the standard sequence seen in the old midden of Chaluka takes form. This culture continues, adding and subtracting various elements but always maintaining a distinctive configuration through time, to the present Aleuts, whose connection with the first Anangula settlement includes having remembered an older Aleut designation, "the place of the blades," and collecting eggs on its flanks. The dating of events inside Nikolski Bay and the identification of the Asiatic elements do throw light on human migration from Siberia into Alaska. The Aleuts and Eskimos may well have been a part of a single population system of Bering Sea Mongoloids who expanded along the Siberian coasts and across the southern Beringian coasts. The population that reached Nikolski Bay became Aleuts. Those closer to the old mouth of the Kuskokwim River and further north became Eskimos. The rise of sea level presented no problems to marine-adapted people. Instead it presented more opportunities in the form of more coastline to exploit. The ancestors of the American Indians migrated earlier through the interior of Beringia. The double-thumb hypothesis of Hrdlicka (23) is useful now for interpreting human migration into the New World. He suggested that if the Eskimos were physically related to the Indians as the thumb of one hand is to the fingers, then a second thumb is necessary to represent the Aleuts, who are also distinctive. The Bering Sea Mongoloids as a group (Aleuts, Eskimos, Chukchi, Koryaks, and probably Kamchadals) are distinguished from the Indians by both genetic traits such as the presence of blood group B, which is absent in the Indians, and morphological configurations such as the unusually broad, low ascending portions of the mandible. This magnitude of difference fits very well with a geographic difference in point of origin, separate route of entry into the New World across Beringia, and the maintenance of separation by many geographic, economic, and cultural barriers. Earlier investigators in the Aleutians compiled invaluable bodies of information. The Russian W. J. Jochelson worked in the Aleutians and the American A. Hrdlicka in Siberia. The problems common to both sides of the Bering Sea have now been studied by Soviet and American scholars at the same time, in the same place, and with the same specimens. It has been pleasant and informative to work directly with the Siberian authorities on Siberia in the Aleutians. In summary, I submit the following eight conclusions: 1) Increased longevity, rather than rapid population turnover, served as a major form of population adaptation and resource management among the Aleuts. Because people lived longer, genetic and cultural wastage was minimized. 2) Cranial vault change, from narrow to broad, has been the result of evolution within the population. 3) The Aleuts have continuously occupied Nikolski Bay, Umnak Island, for 8700 years. During this time sea level has risen and the coastline configuration has changed. 4) Siberian characteristics of the Anangula core and blade industry have been identified, and a transition culture, which links the earliest Anangula tool tradition with the later Aleut culture of Chaluka, has been discovered. 5) Organic remains of human occupation have been used to precisely date geological events of the Holocene Epoch for 8700 of its 10,000 years. Major volcanic eruptions occurred, at exponentially increasing intervals, 10,000, 9000, 7000 and 3000 years ago. 6) The earliest Aleut culture has preserved its Asiatic template because of the coastal entry route from Siberia and subsequent isolation of the population. The abundant lithic remains indicate a complex and diverse material culture. 7) The known similarity of Aleuts to Asiatic populations plus our Holocene time scale suggest a slower rate of human evolution than was assumed when a later date of entry into the Aleutians was accepted. 8) In the broadest perspective, these findings are relevant to understanding the entry of man (Aleuts, Eskimos, and Indians) into the New World in that other migrant populations originating in Siberia may also have entered the New World with a sophisticated and complex culture.

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The term 'medically unexplained symptoms' is used to cover a wide range of persistent bodily complaints for which adequate examination and appropriate investigations do not reveal sufficiently explanatory structural or other specified pathologies. A wide range of interventions may be delivered to patients presenting with medically unexplained symptoms in primary care. Many of these therapies aim to change the behaviours of the individual who may have worsening symptoms. An evidence synthesis to determine the clinical effectiveness and cost-effectiveness of behavioural modification interventions for medically unexplained symptoms delivered in primary care settings was undertaken. Barriers to and facilitators of the effectiveness and acceptability of these interventions from the perspective of patients and service providers were evaluated through qualitative review and realist synthesis. Full search strategies were developed to identify relevant literature. Eleven electronic sources were searched. Eligibility criteria - for the review of clinical effectiveness, randomised controlled trials were sought. For the qualitative review, UK studies of any design were included. For the cost-effectiveness review, papers were restricted to UK studies reporting outcomes as quality-adjusted life-year gains. Clinical searches were conducted in November 2015 and December 2015, qualitative searches were conducted in July 2016 and economic searches were conducted in August 2016. The databases searched included MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO and EMBASE. Updated searches were conducted in February 2019 and March 2019. Adult participants meeting the criteria for medically unexplained symptoms, including somatoform disorders, chronic unexplained pain and functional somatic syndromes. Behavioural interventions were categorised into types. These included psychotherapies, exercise-based interventions, multimodal therapies (consisting of more than one intervention type), relaxation/stretching/social support/emotional support, guided self-help and general practitioner interventions, such as reattribution. <iEvidence synthesis</i: a network meta-analysis was conducted to allow a simultaneous comparison of all evaluated interventions in a single coherent analysis. Separate network meta-analyses were performed at three time points: end of treatment, short-term follow-up (&lt; 6 months since the end of treatment) and long-term follow-up (≥ 6 months after the end of treatment). Outcomes included physical and psychological symptoms, physical functioning and impact of the illness on daily activities. <iEconomic evaluation</i: within-trial estimates of cost-effectiveness were generated for the subset of studies where utility values (or quality-adjusted life-years) were reported or where these could be estimated by mapping from Short Form questionnaire-36 items or Short Form questionnaire-12 items outcomes. Fifty-nine studies involving 9077 patients were included in the clinical effectiveness review. There was a large degree of heterogeneity both between and within intervention types, and the networks were sparse across all outcomes. At the end of treatment, behavioural interventions showed some beneficial effects when compared with usual care, in particular for improvement of specific physical symptoms [(1) pain: high-intensity cognitive-behavioural therapy (CBTHI) standardised mean difference (SMD) 0.54 [95% credible interval (CrI) 0.28 to 0.84], multimodal SMD 0.52 (95% CrI 0.19 to 0.89); and (2) fatigue: low-intensity cognitive-behavioural therapy (CBTLI) SMD 0.72 (95% CrI 0.27 to 1.21), relaxation/stretching/social support/emotional support SMD 0.87 (95% CrI 0.20 to 1.55), graded activity SMD 0.51 (95% CrI 0.14 to 0.93), multimodal SMD 0.52 (95% CrI 0.14 to 0.92)] and psychological outcomes [(1) anxiety CBTHI SMD 0.52 (95% CrI 0.06 to 0.96); (2) depression CBTHI SMD 0.80 (95% CrI 0.26 to 1.38); and (3) emotional distress other psychotherapy SMD 0.58 (95% CrI 0.05 to 1.13), relaxation/stretching/social support/emotional support SMD 0.66 (95% CrI 0.18 to 1.28) and sport/exercise SMD 0.49 (95% CrI 0.03 to 1.01)]. At short-term follow-up, behavioural interventions showed some beneficial effects for specific physical symptoms [(1) pain: CBTHI SMD 0.73 (95% CrI 0.10 to 1.39); (2) fatigue: CBTLI SMD 0.62 (95% CrI 0.11 to 1.14), relaxation/stretching/social support/emotional support SMD 0.51 (95% CrI 0.06 to 1.00)] and psychological outcomes [(1) anxiety: CBTHI SMD 0.74 (95% CrI 0.14 to 1.34); (2) depression: CBTHI SMD 0.93 (95% CrI 0.37 to 1.52); and (3) emotional distress: relaxation/stretching/social support/emotional support SMD 0.82 (95% CrI 0.02 to 1.65), multimodal SMD 0.43 (95% CrI 0.04 to 0.91)]. For physical functioning, only multimodal therapy showed beneficial effects: end-of-treatment SMD 0.33 (95% CrI 0.09 to 0.59); and short-term follow-up SMD 0.78 (95% CrI 0.23 to 1.40). For impact on daily activities, CBTHI was the only behavioural intervention to show beneficial effects [end-of-treatment SMD 1.30 (95% CrI 0.59 to 2.00); and short-term follow-up SMD 2.25 (95% CrI 1.34 to 3.16)]. Few effects remained at long-term follow-up. General practitioner interventions showed no significant beneficial effects for any outcome. No intervention group showed conclusive beneficial effects for measures of symptom load (somatisation). A large degree of heterogeneity was found across individual studies in the assessment of cost-effectiveness. Several studies suggested that the interventions produce fewer quality-adjusted life-years than usual care. For those interventions that generated quality-adjusted life-year gains, the mid-point incremental cost-effectiveness ratios (ICERs) ranged from £1397 to £129,267, but, where the mid-point ICER fell below £30,000, the exploratory assessment of uncertainty suggested that it may be above £30,000. Sparse networks meant that it was not possible to conduct a metaregression to explain between-study differences in effects. Results were not consistent within intervention type, and there were considerable differences in characteristics between studies of the same type. There were moderate to high levels of statistical heterogeneity. Separate analyses were conducted for three time points and, therefore, analyses are not repeated-measures analyses and do not account for correlations between time points. Behavioural interventions showed some beneficial effects for specific medically unexplained symptoms, but no one behavioural intervention was effective across all medically unexplained symptoms. There was little evidence that these interventions are effective for measures of symptom load (somatisation). General practitioner-led interventions were not shown to be effective. Considerable heterogeneity in interventions, populations and sparse networks mean that results should be interpreted with caution. The relationship between patient and service provider is perceived to play a key role in facilitating a successful intervention. Future research should focus on testing the therapeutic effects of the general practitioner-patient relationship within trials of behavioural interventions, and explaining the observed between-study differences in effects within the same intervention type (e.g. with more detailed reporting of defined mechanisms of the interventions under study). This study is registered as PROSPERO CRD42015025520. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in <iHealth Technology Assessment</i; Vol. 24, No. 46. See the NIHR Journals Library website for further project information.

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". we must guard against the acquisition of unwarranted influence, whether sought or unsought, by the military industrial complex." Dwight D. Eisenhower, 34th President of the United States (1953-1961). Farewell Address, January 17, 1961. If Ike were with us today, he might well expand his views on power and influence to include modern American medicine. The corporatization of health care in the United States has moved rapidly in recent years. Physicians are now in a position that requires us to adapt to an increasingly Darwinian existence. Years of training to be "rugged individualists" pushing the frontiers of medical knowledge have not equipped us to fight corporate battles, nor to justify our treatment decisions to bean counters. When the most important consideration becomes the bottom line, then innovation, creativity, and research diminish in importance. They will, in fact, be selected against because they cost money. Up to now, these have been the hallmarks of American medicine, and we must strive to maintain our position of American leadership in biotechnology. New developments in cancer treatment include expensive technological "bells and whistles" which physicians must ultimately evaluate objectively, despite lush advertisements from companies with obvious vested interests, and authoritative testimonials from biased investigators who presumably believe in their own work to the point of straining credulity and denying common sense. The 3-D image that was created by a computer may look beautiful (and cost accordingly), but it is hard to believe that it can fundamentally change the outcome of patients when it does not add any new data that bear on basic issues. For example, where is the exact edge of the tumor? If one pays through the nose for increasing precision where there is no new accuracy, the purchase appears less attractive, perhaps, than the hype of the salesman or the enthusiasm of a neurosurgeon or a "stereotactic" radiation oncologist (showing biased data, if any at all). For radiation therapy, the 20th century has largely represented progress by creating larger, higher energy machines for treatment. Now, with the 21st century on the horizon, x-ray treatment parameters have probably been optimized over the past 10 years or so. We see no obvious advantage in an x-ray beam beyond about 18 MeV, and none for electrons beyond 20-25 MeV. Exotic particles such as protons, neutrons, and negative pions, though expensive and difficult to deliver, have not yielded yet significant gains in either local control or survival. A variety of new afterloading machines, such as pulsed high dose rate machines, have also been developed with no clear biologic advantage over more standard remote afterloaders. Thus, new equipment will be exploiting issues of convenience, efficiency, and increased throughput (translate: economic improvement, not biological superiority). Today's technology is vastly ahead of our biologic understanding of malignant cells. Our true challenge for the 21st century is to understand the biology of malignant cells and to bring our technology to bear on the biological aspects of cancer. To improve results, cellular manipulations of some sort will probably be necessary. Perhaps these will be mediated through gene therapy, although the manipulation of some genes, to the exclusion of all others, in only tumor cells and in all tumor cells may be a biological challenge beyond our limitations. One is reminded of another time, a decade or two ago, when some tumor immunologists were predicting monoclonal antibodies would soon replace other modalities. Eventually, over time, the immunologists began to appreciate the enormous adaptability that cancer cells possess; the cells are much more than passive receptacles of antigens simply waiting to be destroyed by antibodies. Drugs which affect the function of specific oncogenes, such as the farnesyl transferase inhibitor effect on ras genes, are also quite promising. Clearly, however, there are not "magic bullets" for most cancers. The effects of gene manipulation on patient outcome, if any, are likely to be found only in the setting of combined modality therapy. The most promising clinical research from the last decade or so reinforces the utility of a combined approach in treating cancers. Unfortunately, combined treatments and the development of new combined treatments are expensive. In today's world of corporate medicine and managed care, academic centers are under considerable pressures. They are perceived as being too expensive, and thus they are in danger of being shut out of contractual arrangements with third-party representatives. If these centers are to survive, they must reform themselves: One, they must establish meaningful relationships with community hospitals and community physicians. Two, the academic programs must learn to minimize charges and deliver a true multidisciplinary service to patients in an efficient way. Three, the centers must learn to invest wisely in new technologies that community hospitals cannot and will not be expected to support. This "wisdom" refers to selection of technology that truly may have impact on the outcome of patients' lives by early detection or by treatment. The euphoria associated with projected gains of some investigational treatments can be misleading: randomized prospective trials have shown in the past that postoperative radiation following a complete resection of lung cancer, breast cancer, or rectal cancer adds a major improvement to local control, but with relatively little improvement in survival. How many times will it be necessary for companies and self-impressed investigators to rediscover this particular wheel? We must remember that every new therapy costs money, so we must focus our research time and money in promising areas. If cost is allowed to be the most important mitigator of health care, research as we know it will end. The relative lack of new therapies means that some people will die prematurely because of our lack of foresight. As scientists, we must be seen as providers of a value-added product. Improvement in cancer cure rates has been frustratingly slow. We work against a clever, tenacious adversary - both in the clinic and in the corporate board room. It is our responsibility to tout our accomplishments, admit our failures, and provide progressively better basic and clinical research with an eye toward future improvements in outcome. We must not be seen as yet another special interest come to drink at the well of public spending, but as advocates for the public good. If we fail to become important to those who control medical spending, we will be unable to make any important long-term contribution to those who matter most - our patients.

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The role of infections in pathogenesis of atherosclerosis has been a point of extensive discussion and research. Chronic infection has been proposed to account for the formation and progression of atherosclerotic plaques. Gastric mucosal damage caused by Helicobacter pylori (H. pylori) involves various bacterial and host-dependent toxic substances that have been recently associated with increased risk of coronary artery disease (CAD). This study was designed to: 1) to determine the seroprevalence of H. pylori and its cytotoxin associated gene A (CagA) in patients with and without CAD (group A), 2) to evaluate the influence of infection with H. pylori expressing CagA (Cytotoxin associated gene A--as a determinant of high virulence) on coronary arterial lumen reduction in patients after percutaneous transluminal coronary angioplasty (PTCA) with stent (group B), 3) to assess the effect of H. pylori eradication on coronary artery lumen reduction after PTCA (group C), 4) to determine the influence of the H. pylori eradication on plasma levels of cytokines, lipids and coagulation factors in the same patients before and after PTCA (group C) and 5) to analyse coronary specimens in patients with severe CAD for the presence of H. pylori originated specific DNA (Group D). Group A included 96 patients with CAD (subgroup I) and 96 patients without CAD (subgroup II). For H. pylori seroprevalence, plasma anti-H. pylori and anti-CagA IgG were examined by ELISA and Western blot. Group B included 135 patients (86 male, 49 female, mean age 67 +/- 12 years) who had underwent PTCA with stent implantation initially and recoronaro-angiography about 6 months afterwards. All patients were tested for H. pylori--specific antibodies (IgG and CagA). Patients were divided into three subgroup "a": 34 patients with H. pylori IgG and CagA seropositivity, subgroup "b": 37 patients infected with H. pylori positive and CagA negative germs and subgroup "c": 64 patients with H. pylori IgG sero-negativity serving as control group. For all patients coronary lumen loss (percentage) in the dilated segment was measured at the end of PTCA and during re-coronaro-angiography and obtained values were considered taking into account the major risk factors of CAD (hypertension, hyperlipidemia, diabetes, obesity and smoking). Group C included 40 patients with significant single-vessel CAD and H. pylori infection confirmed by 13C-urea breath test (UBT) and serologically using anti-H. pylori and anti-CagA IgG. In addition, plasma interleukin (IL)-1beta and IL-8 and tumor necrosis factor alpha (TNFalpha) levels were measured by ELISA. Plasma total triglycerides, cholesterol, low (LDL) and high density lipoproteins (HDL), homocysteine levels, as well as some clotting factors such as thromboplastin and fibrinogen levels, thrombin time and platelet count were determined. All patients of group B undergoing PTCA were divided into two matched subgroups I and II used in exploratory study; subgroup I (20 patients) received H. pylori eradication triple-therapy for one week (Clarithromycin, Amoxicillin and Omeprazole), while subgroup II (20 patients) received similarly prepared placebo for the same time period starting immediately after PTCA. Six months after PTCA, the H. pylori status was re-assessed by UBT and found to be negative in all but two patients of subgroup I subjected to H. pylori therapy. Coronary angiography and laboratory tests were repeated in both subgroups of group B included into the trial and the reduction in coronary artery lumen in these subgroups was compared to baseline after PTCA considered as 100%. Large atherosclerotic plaques from coronary endatherectomy were obtained in 46 consecutive patients (9 female, 37 male, mean age 63 +/- 9 years) during coronary bypass procedures (group D). Serum was analysed for positive IgG antibodies specific for H. pylori by enzyme-linked-immunosorbent assay (ELISA). Antibodies specific for the CagA were detected by immunoblot analysis. Polymerase chain reaction (PCR) was used to identify bacterial DNA with primers encoding for the 16 S ribosomal RNA of H. pylori. Sequence analysis of PCR-products confirmed the specificity of the gene products for H. pylori. Coronary artery biopsies from 19 autopsies from a Forensic Medicine Department without coronary atherosclerosis were examined as a control group. The H. pylori seropositivity reached 69.79% (67 pts) of CAD (subgroup I of group A) and it was significantly higher than that in controls without CAD (subgroup II)--40.62% (39 pts), the odds ratio (OR) being 3.38 95% CI: 1.8598-6.1306 for H. pylori in CAD. CagA IgG detection was also significantly higher (58.20%) in CAD group than in controls (35.89%) giving the OR about 2.49 (95% CI: 1.1012-5.6175). Mean lumen loss in group B in H. pylori-positive subjects was 37.0% +/- 17.3%, whereas for H. pylori negative patients 29.9 +/- 13.8% were measured compared to initial values following PTCA (p = 0.0196). Even subgroup analysis and analysis regarding risk factors show significantly higher lumen loss for H. pylori-positive patients (especially CagA positive) compared to H. pylori negative patients. Mean coronary artery lumen reduction in patients undergoing PTCA + H. pylori eradication therapy (subgroup I of group C) was found to be significantly (P &lt; 0.05) smaller compared to PTCA + placebo-treated subgroup II (22% vs 41%). The plasma cytokines such as TNFalpha, IL-1beta and IL-8 were significantly lower after the H. pylori-eradication in PTCA patients, while changes in plasma lipids, homocysteine and clotting factors were not significantly affected by H. pylori eradication. In group D thirty two patients (69.5%) were H. pylori-seropositive, 14 patients out of 32 H. pylori-positive were CagA positive. Eighteen of these patients showed positive results for H. pylori DNA, whereas 4 patients of the seronegative group also showed positive DNA results, but all 4 had undergone eradication therapy within the past two years. A total of 22 patients (47.8%) of the CAD group and none of the 19 controls revealed positive DNA assessed by PCR. Out of 14 anti-Cag A positive patients 11 showed positive detection of H. pylori DNA (p = 0.015) 1) There is a significant link between CAD and infection with H. pylori, especially expressing CagA proteins; 2) Patients infected with CagA-positive H. pylori show significantly greater coronary artery lumen loss and arterial re-stenosis after PTCA with stent implantation; 3) H. pylori eradication significantly attenuates the reduction in coronary artery lumen in CAD patients after PTCA possibly due to the elimination of chronic inflammation and the decline in proinflammatory cytokine release and 4) The identification of DNA in atherosclerotic plaques of patients with severe CAD supports the hypothesis that infection with H. pylori (especially CagA positive) may influence the development of atherosclerosis.

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Studies were conducted to compare outcomes when four chemicals were evaluated under typical NTP bioassay conditions as well as under protocols employing dietary restriction. Specific experiments were designed to evaluate the effect of diet restriction on the sensitivity of the bioassay toward chemical-induced chronic toxicity and carcinogenicity and to evaluate the effect of weight-matched control groups on the sensitivity of the bioassays. Two chemicals, butyl benzyl phthalate and t-butylhydroquinone, were administered in feed; one chemical, salicylazosulfapyridine, was administered in corn oil by gavage; and one chemical, scopolamine hydrobromide trihydrate, was administered in distilled water by gavage. In each of four protocols, the effects of the chemical were assessed by a comparison between a group exposed to a single dose concentration of the study chemical and a nonexposed control group. F344/N rats and B6C3F1 mice were fed NIH-07 diet either ad libitum or in amounts that restricted mean body weights according to the following design requirements. For the core bioassay, groups of 50 to 60 ad libitum-fed animals were allotted to a control group and three dosed groups for approximately 104 weeks or up to 128 weeks (t-butylhydroquinone study). The comparison between the control group and the group receiving the highest dose was used to represent the outcome of the bioassay under ad libitum feeding protocols. In a second comparison, outcomes from the group receiving the highest dose were compared with a weight-matched group of 50 to 60 untreated controls; the weight-matched controls received feed in amounts restricted so that the mean body weight matched the mean body weight of the dosed group. Two additional groups of 48 to 60 animals (one control and one dosed group) were offered feed in amounts that limited the mean body weight of the control group to approximately 85% that of the controls fed ad libitum under the first protocol. Animals assigned to this dietary restriction paradigm were evaluated after 104 weeks or 130 weeks (t-butylhydroquinone). A fourth protocol was em- loyed to evaluate whether an additional period of exposure (up to 1 year) would influence the neoplasm profile of animals fed a restricted diet. Two groups of approximately 50 animals (one control and one dosed group) in the butyl benzyl phthalate, salicylazosulfapyridine, and scopolamine hydrobromide trihydrate studies received restricted diets, as under the third protocol, for 3 years or until survival in either group was reduced to 20%. Butyl benzyl phthalate caused an increased incidence of pancreatic acinar cell neoplasms in ad libitum-fed male rats relative to ad libitum-fed and weight-m atched controls. This change did not occur in rats in the restricted feed protocol after 2 years; however, acinar cell adenomas were observed in three exposed, feed-restricted males at 30 months. Feed restriction is known to influence the incidence of pancreatic acinar cell neoplasms and may have prevented the full expression of this chemical-induced effect. Butyl benzyl phthalate also caused an increased incidence of urinary bladder neoplasms in female rats in the 32-month restricted feed protocol. The incidences of urinary bladder neoplasms were not significantly increased in female rats in any of the 2-year protocols, suggesting that the length of study, and not body weight, was the primary factor in the detection of this carcinogenic response. Salicylazosulfapyridine caused an increased incidence of urinary bladder papillomas in male rats fed ad libitum relative to ad libitum-fed and weight- matched controls. This increase was associated with an increased incidence of urinary bladder calculi; the incidences of urinary bladder concretions, dilatation, and hyperplasia were also increased in dosed males. The incidences of urinary bladder papillomas and calculi were not increased in male rats receiving salicylazosulfapyridine that were fed restricted diets. In male mice, salicylazosulfapyridine caused an increased incidence of liver neoplasms relative tsms relative to the ad libitum-fed and weight-matched controls. This increase did not occur in the restricted feed protocols. Liver neoplasms in mice are greatly influenced by body weight, and the marked mean body weight reduction observed in dosed male mice in the restricted feed protocols may have overridden the carcinogenic response. Neither t-butylhydroquinone nor scopolamine hydro bromide trihydrate caused increased neoplasm incidences under any of the experimental protocols. Results consistently show that feed restriction caused decreased incidences of neoplasms and nonneoplastic lesions at a variety of anatomic sites in control and dosed animals. Furthermore, the sensitivity of the bioassay to detect a carcinogenic response was altered by dietary restriction: two of the four chemicals caused increased incidences of neoplasms at three sites when evaluated under a standard ad libitum feeding protocol for 104 weeks. When control and dosed groups were subjected to dietary restriction, none of these three sites was detected as a target of carcinogenesis after 2 to 3 years. Rather, one different site of carcinogenesis was detected after 32 months. When dosed animals in the ad libitum feeding protocol were compared to weight-matched control groups, three sites were identified as targets of carcinogenesis and corresponded to the three sites discovered under the ad libitum feeding protocol. The magnitude of the response was greater when the weight-matched controls protocol was used. Dietary restriction of dosed and control animals decreased the sensitivity of these carcinogenesis bioassays. Regarding the future use of dietary restriction regimens in long-term studies, only limited conclusions can be drawn because only four chemicals were evaluated and none of these proved to be a strong carcinogen. However, the results of these studies are consistent with previous findings that dietary restriction increases survival rates and decreases the incidences of neoplasms and nonneoplastic lesions at a variety of sites in rats and mice. This association between reduced body weights and decreased neoplasm incidences underlines the necessity that the doses selected for chronic studies not exceed "minimally toxic doses" so that no marked body weight reductions (or increases) will occur in the dosed groups. Such body weight changes complicate the detection of carcinogenic effects. The following tables summarize and compare the findings from ad libitum-fed, weight-matched, and feed-restricted groups for each chemical. Tabular Summary of Dietary Restriction Study of Butyl Benzyl Phthalate is available in web version of this document. TabularSummary of the Dietary Restriction Study of t-Butylhydroquinone is available in web version of this document. TabularSummary of the Dietary Restriction Studies of Salicylazosulfapyridine is available in web version of this document. TabularSummary of the Dietary Restriction Study of Scopolamine Hydrobromide Trihydrate is available in web version of this document.

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Single-sided deafness refers to profound sensorineural hearing loss or non-functional hearing in one ear, with normal or near-normal hearing in the other ear. Its hallmark is the inability to localize sound and hear in noisy environments. Conductive hearing loss occurs when there is a mechanical problem with the conduction of sound vibrations. Mixed hearing loss is a combination of sensorineural and conductive hearing loss. Conductive and mixed hearing loss, which frequently affect both ears, create additional challenges in learning, employment, and quality of life. Cochlear implants and bone-conduction implants may offer objective and subjective benefits of hearing for people with these conditions who are deemed inappropriate candidates for standard hearing aids and do not meet the current indication (i.e., bilateral deafness) for publicly funded cochlear implants in Canada. We conducted a health technology assessment, which included an evaluation of clinical benefits and harms, cost-effectiveness, budget impact, and patient preferences and values related to implantable devices for single-sided deafness and conductive or mixed hearing loss. We performed a systematic literature search for systematic reviews and cost-effectiveness studies of cochlear implants and bone-conduction implants, compared to no interventions, for these conditions in adults and children. We conducted cost-utility analyses and budget impact analyses from the perspective of the Ontario Ministry of Health to examine the impact of publicly funding both types of hearing implants for the defined populations. We also interviewed 22 patients and parents of children about their experience with hearing loss and hearing implants. We included 20 publications in the clinical evidence review. For adults and children with single-sided deafness, cochlear implantation when compared with no treatment improves speech perception in noise (% correct responses: 43% vs. 15%, <iP</i &lt; .01; GRADE: Moderate), sound localization (localization error: 14° vs. 41°, <iP</i &lt; .01; GRADE: Moderate), tinnitus (Visual Analog Scale, loudness: 3.5 vs. 8.5, <iP</i &lt; .01; GRADE: Moderate), and hearing-specific quality of life (Speech Spatial and Qualities of Hearing Scale, speech: 5.8 vs. 2.6, <iP</i = .01; spatial: 5.7 vs. 2.3, <iP</i &lt; .01; GRADE: Moderate); for children, speech and language development also improve (GRADE: Moderate). For those with single-sided deafness in whom cochlear implantation is contraindicated, bone-conduction implants when compared with no intervention provide clinically important functional gains in hearing thresholds (36-41 dB improvement in pure tone audiometry and 38-56 dB improvement in speech reception threshold, <iP</i &lt; .05; GRADE: Moderate) and improve speech perception in noise (signal-to-noise ratio -2.0 vs. 0.6, <iP</i &lt; .05 for active percutaneous devices; signal-to-noise ratio improved by 1.3-2.5 dB, <iP</i &lt; .05 for active transcutaneous devices; GRADE: Moderate) and hearing-specific quality of life (Abbreviated Profile for Hearing Aid Benefit, ease of communication: 12%-53% vs. 24%-59%; background noise: 18%-48% vs. 33%-79%; listening in reverberant condition: 26%-55% vs. 41%-65%, <iP</i &lt; .05 [active percutaneous devices]; ease of communication: 7% vs. 20%; background noise: 46% vs. 69%; listening in reverberant condition: 27% vs. 43%; <iP</i &lt; .05 [active transcutaneous devices]; Children's Home Inventory for Listening Difficulties score 7.3 vs. 3.4; <iP</i &lt; .05 [passive transcutaneous devices]; GRADE: Moderate). For those with conductive or mixed hearing loss, bone-conduction implants when compared with no intervention improve hearing thresholds (improved 19-45 dB [active percutaneous devices], improved 24-37 dB [active transcutaneous devices], improved 31 dB [passive transcutaneous devices], and improved 21-49 dB [active transcutaneous middle-ear implants]; GRADE: Moderate), speech perception (% correct: 77%-93% vs. &lt; 25%; <iP</i &lt; .05 [active transcutaneous devices], % speech recognition: 55%-98% vs. 0-72%; <iP</i &lt; .05 [active transcutaneous middle-ear implants]; GRADE: Moderate), and hearing-specific quality of life and subjective benefits of hearing (GRADE: Moderate).In the cost-utility analyses, cochlear implants for adults and children with single-sided deafness provided greater health gains for an incremental cost, compared with no intervention. On average, the incremental cost-effectiveness ratio (ICER) was between $17,783 and $18,148 per quality-adjusted life-year (QALY). At a willingness-to-pay of $100,000 per QALY, 70% of the simulations were considered cost-effective. For the same population, bone-conduction implants were not likely to be cost-effective compared with no intervention (ICER: $402,899-$408,350/QALY). Only 38% of simulations were considered cost-effective at a willingness-to-pay of $100,000 per QALY. For adults and children with conductive or mixed hearing loss, bone-conduction implants may be cost-effective compared with no intervention (ICER: $74,155-$87,580/QALY). However, there was considerable uncertainty in the results. At a willingness-to-pay of $100,000 per QALY, only 50% to 55% of simulations were cost-effective. In sensitivity analyses, results were most sensitive to changes in health-related utilities (measured using generic quality-of-life tools), highlighting the limitations of currently published data (i.e., small sample sizes and short follow-up).For people with single-sided deafness, publicly funding cochlear implants in Ontario would result in an estimated additional cost of $2.8 million to $3.6 million in total over the next 5 years, and an additional $0.8 million would be required for bone-conduction implants for this population. For people with conductive or mixed hearing loss, publicly funding bone-conduction implants would cost an estimated additional $3.1 million to $3.3 million in total over the next 5 years.In interviews, people with single-sided deafness and conductive or mixed hearing loss reported that standard hearing aids did not meet their expectations; therefore, they chose to undergo surgery for an implantable device. Most participants with experience of a cochlear implant or bone-conduction implant spoke positively about being able to hear better and enjoy a better quality of life. People with a cochlear implant reported additional benefits: binaural hearing, better sound localization, and better hearing in noisy areas. Cost and access were barriers to receiving an implantable device. Based on evidence of moderate quality, cochlear implantation and bone-conduction implants improve functional and patient-important outcomes in adults and children with single-sided deafness and conductive or mixed hearing loss. Qualitative results of interviews with patients are consistent with the findings of the systematic reviews we examined.Among people with single-sided deafness, cochlear implants may be cost-effective compared with no intervention, but bone-conduction implants are unlikely to be. Among people with conductive or mixed hearing loss, bone-conduction implants may be cost-effective compared with no intervention. Results and uncertainty are mainly driven by changes in health utilities associated with having a hearing implant. Hence, further research on utility values in this population is warranted with larger sample sizes and longer follow-up.The 5-year cost of publicly funding both types of hearing implant for single-sided deafness and conductive or mixed hearing loss in Ontario is estimated to be $6.7 million to $7.8 million.

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The year 2020 has been marked by the coronavirus disease 2019 (COVID-19) pandemic, caused by an RNA virus called SARS-COV2 (severe acute respiratory syndrome coronavirus). The fight against this epidemic has become the center of our daily clinical practice as well as of our private lives, in which avoiding infection has become one of our most important goals. Even though COVID-19 is a potentially lethal disease, especially for the elderly and people with chronic diseases, it did not cause all the other life-threatening diseases to vanish. On the contrary, many scheduled medical activities and procedures, especially preventive and non-urgent internal and surgical activities, had to be postponed due to COVID-19 crisis. This interruption in the health care system can negatively affect the diagnosis and management of our patients with other health issues, namely malignant skin tumors, of which melanoma is the most aggressive. In this letter, we as dermatovenereologists from the Croatian Referral Centre of The Ministry of Health for Melanoma needed to express our concern regarding the increasing number of patients with delayed diagnosis of skin cancer, with special emphasis on melanoma detection and treatment. In the last few months, a large number of our newly-diagnosed patients with melanoma, as well as those with non-melanoma skin cancers, reported that they had noticed a suspicious skin lesion a few months ago but decided not to seek help from dermatologist due to the worrisome epidemiologic situation. In the current environment, clinical skin examination may be viewed as less important and thus postponed, but neglecting melanoma throughout the virus outbreak may lead to increased rates of morbidity, mortality, and consequently a greater financial burden for the health system (1). There are several reasons for such a relaxed attitude towards skin health in our patients. Unlike cardiac, pulmonary, or digestive difficulties, which patients consider life-threatening and for which they seek emergency care despite the coronavirus pandemic, skin tumors do not cause great subjective or significantly noticeable objective symptoms. Moreover, all of the skin tumors and especially melanoma , mostly present as small changes of just a few millimeters in diameter in the early stage at which they are prognostically most favorable. For the average person with no medical education, such small lesions usually do not cause any concern as they have no awareness of the fact that small and inconspicuous skin lesions may be dangerous and potentially even lethal. According to the recommendations concerning patient management during COVID-19 pandemic, oncological examinations should still be performed regularly (2). In spite of that, the cancelation of appointments, especially by patients who are being monitored for high-risk lesions, is inevitable when COVID-19 is disrupting everyone's lives. With the pandemic evolving and no clear solutions in sight, now is the time to emphasize the importance of self-examination and teledermatology in early melanoma diagnosis. Even though diagnosing and managing pigmented skin lesions usually requires face-to-face examinations and dermoscopy as a crucial tool in early melanoma detection, in these times, and especially for people with a higher risk of SARS-COV2 infection, remote communication could prevent delays resulting in worse prognosis and could also eliminate the risk of infecting healthcare workers. Moreover, teledermatology can also be initiated by doctors asking patients to monitor lesions between clinical visits (3). However, we should not rely solely on this technology but should instead assess every patient individually and insist on a face-to-face examination for those at greater risk, with the aim that, if necessary, surgery be performed in timely manner. The collaboration between general practitioners and dermatologists represents an important aspect of achieving the most rational and effective health care in terms of performing triage of patients who can be assessed by teledermatology as well as referring to hospital centers those who need face-to-face examination and further treatment. During the first breakout of the epidemic in March 2020, the multidisciplinary team for melanoma from the Croatian National Referral Melanoma Centre provided recommendations for the management of patients with melanoma during COVID epidemic, designed according to the guidelines of the National Comprehensive Cancer Network (NCCN) (4) and considering the specifics of health care and clinical practice in the Republic of Croatia. Due to epidemic circumstances, preventive actions such as Euromelanoma and many other campaigns that included massive preventive skin examinations of the population and which were conducted for years by Croatian dermatologists throughout the country, could not be organized this year. This is particularly worrisome because on average about 800 patients are diagnosed with melanoma annually in Croatia, of which 60 during public health preventive actions. Despite these circumstances, we were able to maintain public awareness of the importance of early skin cancer recognition by sending the message through different media such as newspapers, television, and social media (Facebook and Instagram). We find that now more than ever it is essential to remind and teach the population about the importance of regular monthly skin self-examinations and recognition of atypical lesions. Clearly, a thorough dermatological examination includes full skin examination from head to toe. Herein we would also like to remind our readers that most skin cancers develop in the head and neck area, which is the most UV-exposed part of the body. Therefore, despite the epidemic conditions, the removal of patients' masks and thorough inspection of the face is mandatory. We find it most practical and efficient to perform the body and scalp examination first, followed by the face examination after the patient gets dressed. Prior to removal of the mask, we ask the patient not to talk during close examination. Even though this could make dermoscopic examination harder to perform, we strongly suggest wearing a protective shield and mask during close examination whenever possible. Between patients, the examining room should be disinfected and ventilated. As doctors, we live in uncertain times when we are heavily burdened by the currently unstoppable COVID epidemic, always awaiting new instructions from the state administration every day and wondering whether perhaps tomorrow we dermatologists will be assigned solely to the service of patients with COVID-19. In the end, we would like to once again remind you that despite the ravaging COVID pandemic and all the epidemiological measures that come with it, other diseases still exist. It is expected of us to draw attention to the still growing incidence of skin cancers and the serious consequences that can occur as a result of a delayed diagnosis.

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Electric and magnetic fields are associated with the production, transmission, and use of electricity; thus, the potential for human exposure is high. These elec-tric and magnetic fields are predominantly of low fre-quency (60 Hz in the United States and 50 Hz in Europe) and generally of low intensity. Because some epidemiology studies and initiation/promotion studies in rats have suggested a potential for increased breast cancer rates with increasing magnetic field exposure, the ability of 50- and 60-Hz magnetic fields to pro-mote mammary gland tumors initiated by the administration of 7,12-dimethylbenz(a)anthracene (DMBA) was examined in female Sprague-Dawley rats in 13- and 26-week whole-body exposure studies. Additional animals were evaluated for changes in pineal gland and serum melatonin concentrations. FIRST 13-WEEK STUDY: Groups of 100 female Sprague-Dawley rats were ad-ministered 20 mg DMBA (four weekly gavage doses of 5 mg in sesame oil) and exposed to 1 G 50-Hz, 5 G 50-Hz, or 1 G 60-Hz magnetic fields for 18.5 hours per day, 7 days per week, for 13 weeks. A group of 100 rats administered 20 mg DMBA served as DMBA controls. A group of 100 vehicle control rats was administered only sesame oil on the same schedule. Additional groups of 10 rats receiving similar treatment were evaluated for pineal gland and serum melatonin concentrations at 4, 8, or 12 weeks. All vehicle control rats survived to the end of the study. Of the animals administered 20 mg DMBA, 6 rats in the DMBA control group, 13 in the DMBA/1 G 50-Hz group, eight in the DMBA/5 G 50-Hz group, and five in the DMBA/1 G 60-Hz group died or were removed from the study prior to the final necropsy. Final mean body weights and body weight gains of the DMBA/1 G 50-Hz and DMBA/1 G 60-Hz groups and the mean body weight gain of the DMBA/5 G 50-Hz group were slightly greater than those of the DMBA control group. Clinical findings including torso masses and ulcers (on the mammary masses) were attributed to DMBA administration. The numbers of palpable mammary gland tumors, tumor sizes, and total tumor areas in DMBA/magnetic field groups were similar to those in the DMBA control group. Relative to the DMBA control group, exposure to magnetic fields did not significantly affect overall incidences of mammary gland neoplasms or nonneoplastic lesions in the DMBA/magnetic field groups. SECOND 13-WEEK STUDY: Groups of 100 female Sprague-Dawley rats were ad-ministered 8 mg DMBA (four weekly gavage doses of 2 mg in sesame oil) and exposed to 1 G 50-Hz or 5 G 50-Hz magnetic fields for 18.5 hours per day, 7 days per week, for 13 weeks. A group of 100 female rats administered 8 mg DMBA served as DMBA controls. Additional groups of 10 rats receiving similar treatment were evaluated for pineal gland and serum melatonin concentrations at 4, 8, or 12 weeks. Except for one rat in the DMBA/5 G 50-Hz group, all rats survived until the end of the study. Final mean body weights of DMBA/magnetic field groups were similar to those of the DMBA control group. Clinical findings including torso masses and ulcers were attributed to DMBA administration. The numbers of palpable mammary gland tumors, tumor sizes, and total tumor areas in DMBA/magnetic field groups were similar to those in the DMBA control group. Relative to the DMBA control group, exposure to magnetic fields did not significantly affect overall incidences of mammary gland neoplasms or nonneoplastic lesions in the DMBA/magnetic field groups. 26-WEEK STUDY: Groups of 100 female Sprague-Dawley rats were administered 10 mg DMBA (in sesame oil) by gavage followed by exposure to 1 G 50-Hz, 5 G 50-Hz, or 1 G 60-Hz magnetic fields for 18.5 hours per day, 7 days per week, for 26 weeks. A group of 100 female rats administered 10 mg DMBA served as DMBA controls. Another 100 vehicle control rats were administered only sesame oil. Additional groups of 10 rats receiving similar treatment were evaluated for pineal gland and serum melatonin concentrations at 4, 8, or 12 weeks. All rats in the vehicle control group survived until the end of the study. Twelve rats in the DMBA control group, 15 in the DMBA/1 G 50-Hz group, 9 in the DMBA/5 G 50-Hz group, and six in the DMBA/1 G 60-Hz group died or were removed during the study. The final mean body weights and body weight gains of the DMBA/1 G 50-Hz and DMBA/5 G 50-Hz groups were significantly greater than those of the DMBA control group. Clinical findings including torso masses, abscesses, and ulcers were attributed to DMBA administration. The pineal gland melatonin concentrations of DMBA/5 G 50-Hz and DMBA/1 G 60-Hz rats were significantly greater than that of the DMBA controls at week 12; however, these data were highly variable between individual animals within each group. The numbers of palpable mammary gland tumors, tumor sizes, and total tumor areas in DMBA/magnetic field groups were similar to those in the DMBA controls. The incidences of mammary gland carci-noma (including multiple) in the DMBA/1 G 60-Hz group were significantly decreased relative to the DMBA control group. CONCLUSIONS: In an initiation/promotion study in which female Sprague-Dawley rats were initiated by four weekly doses of 5 mg DMBA per rat beginning at 50 days of age and exposed to 50-Hz magnetic fields at 1 or 5 G field intensities or to 1 G 60-Hz magnetic fields for 13 weeks, there was no evidence that magnetic fields promoted the development of mammary gland neoplasms. The prevalence and multiplicity of mammary gland carcinomas in all DMBA groups limited the ability of this assay to detect a promoting effect of magnetic fields. In an initiation/promotion study in which female Sprague-Dawley rats were initiated by four weekly doses of 2 mg DMBA per rat beginning at 50 days of age and exposed to 50-Hz magnetic fields at 1 or 5 G field intensities for 13 weeks, there was no evidence that magnetic fields promoted the development of mammary gland neoplasms. In an initiation/promotion study in which female Sprague-Dawley rats were initiated by a single 10 mg DMBA dose at 50 days of age and then exposed to 50-Hz magnetic fields at 1 or 5 G field intensities or to 1 G 60-Hz magnetic fields for 26 weeks, there was no evidence that magnetic fields promoted the development of mammary gland neoplasms.

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2-Amino-4-nitrophenol is used to color semipermanent hair dyes and in the manufacture of mordant dyes for leather, nylon, silk, wool, and fur. 2-Amino-4-nitrophenol was nominated by the National Cancer Institute for toxicology and carcinogenesis studies because of widespread human exposure associated with its manufacture and use. Toxicology and carcinogenesis studies were conducted by administering 2-amino-4-nitrophenol (98% pure) in corn oil by gavage, 5 days per week, to groups of F344/N rats and B6C3F1 mice of each sex in 15-day, 13-week, and 2-year studies. Fifteen-Day and Thirteen-Week Studies: During the 15-day studies, rats and mice received doses of 0, 313, 625, 1,250, 2,500, or 5,000 mg/kg. All rats that received 2,500 or 5,000 mg/kg and all female rats that received 1,250 mg/kg died before the end of the studies. Final mean body weights of chemically exposed rats surviving to the end of the studies were comparable to those of vehicle controls. Diarrhea was observed in all groups of exposed rats except those receiving 313 mg/kg. All mice that received 2,500 or 5,000 mg/kg, 2/5 males and all females that received 1,250 mg/kg, and 1/5 females that received 313 mg/kg died before the end of the studies. Final mean body weights of exposed mice surviving until the end of the studies were comparable to those of vehicle controls. In 13-week studies, F344/N rats and B6C3F1 mice of each sex received 2-amino-4-nitrophenol at doses of 0, 62.5, 125, 250, 500, or 1,000 mg/kg. All rats that received 1,000 mg/kg and 2/10 males and 2/10 females that received 500 mg/kg died before the end of the studies. The final mean body weight of male rats that received 500 mg/kg was reduced 10% compared with that of vehicle controls; final mean body weights of all other surviving exposed rat groups were comparable to those of vehicle controls. Diarrhea and lethargy were observed for rats that received 500 or 1,000 mg/kg. All male mice and most females that received 1,000 mg/kg and 4/10 females that received 500 mg/kg died before the end of the studies. Final mean body weights of chemically exposed mice were comparable to those of vehicle controls. No compound-related clinical signs were observed in mice during the studies. Mineralization of the renal cortex and degeneration of the renal tubular epithelium were observed in male and female rats that received 1,000 mg/kg and in males that received 500 mg/kg. Degeneration and necrosis of the renal tubular epithelium was observed in 5/10 male and 3/10 female mice that received 1,000 mg/kg. Body Weight and Survival in the Two-Year Studies: In the 2-year studies, rats and mice received 2-amino- 4- nitrophenol at doses of 0, 125, or 250 mg/kg. Mean body weights of male rats that received 250 mg/kg were 8%-10% lower than those of vehicle controls throughout most of the 2-year study. Mean body weights of female rats were comparable to those of vehicle controls. Soft stools and occasional diarrhea were observed in chemically exposed rats starting 6 months after the beginning of the studies. Survival of male rats that received 250 mg/kg was markedly lower than that of vehicle controls after week 89 (final survival: vehicle control, 32/50; 125 mg/kg group, 24/50; 250 mg/kg group, 10/50). Survival of female rats was comparable among all groups (final survival: 25/50; 27/50; 31/50). Mean body weights of male and female mice that received 250 mg/kg were comparable to those of vehicle controls; the mean body weights of female mice that received 125 mg/kg were as much as 17% greater than that of vehicle controls. Survival of all mouse groups was comparable during the 2-year studies (final survival: male-- 28/50; 29/50; 23/50; female--28/50; 31/50; 30/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Pigmentation of the small and large intestines was present in exposed rats but not in vehicle controls. Ulcers and erosive lesions of the digestive tract were observed in male rats that received 250 mg/kg and to a lesser extent in male rats that received 125 mg/kg. A carcinoma of the colon occurrkg. A carcinoma of the colon occurred in one male rat that received 250 mg/kg; no other neoplasms were observed in the gastrointestinal tract of rats. No pigmentation, ulcers, or erosive lesions were found in the digestive tract of mice. The severity of nephropathy was markedly greater in exposed male rats than in vehicle controls. Associated with the nephropathy were nonneoplastic lesions indicative of reduced renal function and secondary hyperparathyroidism, including parathyroid hyperplasia, mineralization of various organs, and fibrous osteodystrophy. Renal tubular cell hyperplasia (1/50; 4/48; 5/50) and renal cortical (tubular cell) adenomas (0/50; 1/48; 3/50) occurred in male rats. Renal cortical adenomas are infrequently observed in male F344/N rats (historical incidence, 0.5&amp;percnt;). More preputial gland adenomas or carcinomas (combined) were observed in low dose male rats than in vehicle controls (3/50; 10/48; 3/50), whereas the incidences of clitoral gland neoplasms were decreased in dosed female rats (9/50; 6/50; 1/49). Hemangiomas or hemangiosarcomas (combined) occurred in male mice that received 2-amino-4-nitrophenol (0/50; 1/50; 5/50); each tumor was present at a different site. The historical control incidence is 11&amp;percnt; at the study laboratory and 6&amp;percnt; in 2-year NTP studies. Genetic Toxicology: 2-Amino-4-nitrophenol was mutagenic in Salmonella typhimurium strains TA98 and TA100 with metabolic activation. 2-Amino-4-nitrophenol was not mutagenic in strains TA1535 or TA1537. 2-Amino-4-nitrophenol was mutagenic in the mouse lymphoma L5178Y/TK&amp;plusmn; assay without metabolic activation. It was not tested with activation. 2-Amino-4-nitrophenol induced sister chromatid exchanges (SCEs) and chromosomal aberrations in Chinese hamster ovary cells in the presence and absence of metabolic activation. Audit: The data, documents, and pathology materials from the 2-year studies of 2-amino-4-nitrophenol were audited at the NTP Archives. The audit findings show that the conduct of the studies is documented adequately and support the data and results given in this Technical Report. Conclusions: Under the conditions of these 2-year gavage studies, there was some evidence of carcinogenic activity of 2-amino-4-nitrophenol for male F344/N rats, as shown by increased incidences of renal cortical (tubular cell) adenomas. The incidences of renal tubular cell hyperplasia were also increased in male rats exposed to 2-amino-4-nitrophenol. The survival of male rats that received 2-amino-4-nitrophenol was reduced compared with survival of vehicle control male rats. There was no evidence of carcinogenic activity of 2-amino-4-nitrophenol for female F344/N rats or for male or female B6C3F1 mice that received 125 or 250 mg/kg per day.

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It has been previously reported that a filterable microorganism belonging to the genus Leptospira has been recovered from the blood or organs of human beings suffering from the disease known as yellow fever in Guayaquil, and that the organism, which has been termed Leptospira icteroides, induces in certain experimental animals the characteristic symptoms and lesions observed in the patients from whom it was isolated. It has also been previously shown that the serum from patients recovering from an attack of yellow fever in Guayaquil had the power to agglutinate and dissolve the organism when introduced into the peritoneal cavity of a normal guinea pig (Pfeiffer phenomenon). Moreover, the guinea pigs which had once been inoculated with the blood of yellow fever patients without succumbing to the infection, notwithstanding the fact that they had shown a definite febrile reaction after 4 to 5 days, were found to be refractory to a subsequent inoculation of a culture of Leptospira icteroides All these observations pointed to the possible relation of this organism to the disease known as yellow fever in Guayaquil. The demonstration of the filterability of the organism and the transmission of the infection with the same organism by Stegomyia calopus have further strengthened the probable etiological significance of the organism in yellow fever. It was by no means a simple problem to determine the relation existing between Leptospira icteroides and Leptospira icterohaemorrhagiae. An experiment reported in a previous paper seemed to justify the view that the two leptospiras are closely related but not identical, yet it was necessary to exhaust various other modes of differentiation before the distinction between them was firmly established. The present paper continues this phase of the inquiry in further detail. There have been taken up here the phenomena of agglutination, the reaction of Pfeiffer, complement fixation, the protective properties of various monovalent and polyvalent immune sera, and active immunity. As the result of experiments in connection with these immunity phenomena the following data are presented. Monovalent immune sera prepared by several successive injections in an animal naturally refractory to Leptospira icteroides possess the power to agglutinate in vitro not only the homologous strains, but also all other strains of icteroides tested. On the other hand, a slight effect, or none at all, has been observed when these immune sera have been mixed in vitro with various strains of Leptospira icterohaemorrhagiae. A similar relation exists between the monovalent anti-icterohaemorrhagiae sera and the various strains of Leptospira icteroides; that is, there is a slight agglutinating effect in some instances upon the icteroides strains, but it is never so strong as that occurring in tests against the icterohaehagiae strains. The Pfeiffer reaction gave a sharper differentiation between the two groups, for in most instances the phenomenon was specific for the group. There were occasional doubtful reactions, but not enough to warrant a confusion of the two groups. Polyvalent immune sera, one specific for icteroides, and the other for icterohaemorrhagiae, showed a high titer of neutralizing power for the cultures of the homologous groups. It was found, however, that the action of the sera is by no means absolutely specific, because the injection of a sufficient amount of the anti-icteroides serum apparently prevented a fatal outcome in a guinea pig inoculated with multiple minimum lethal doses of a culture of Leptospira icterohaemorrhagiae, and vice versa. The specificity of the serum was demonstrated only when it was used in smaller quantities. More or less specificity was shown by the complement fixation reaction, but it was not absolute. Weak fixation occurred when the anti-icteroides serum was mixed with one or the other of the icterohaemorrhagiae strains and vice versa, and strong fixation occurred only when the antiserum was mixed with one of the icteroides strains. The question naturally arises whether or not this apparent specificity is due to the homology of the serum and not altogether to a difference in genus of the strains. In other words, it is justifiable to question whether all these variations in the degree of intensity of the reaction are not due to strain variations of the same genus. This question is not finally settled by the present investigation, in which only four icteroides and nine icterohaemorrhagiae strains have been carefully studied. Nevertheless, on the basis of the findings with these thirteen strains, it seems probable that Leptospira icteroides and Leptospira icterohaemorrhagiae are closely allied but are nevertheless distinct in their immunological reactions. Perhaps the difference between the two may amount to that between subspecies or races. It has been pointed out earlier that the pathogenicity of the two is also distinct, inasmuch as icteroides produces chiefly icterus and nephritis and icterohaemorrhagiae hemorrhage and nephritis, the icterus being less and the hemorrhage more prominent in the evolution of the latter infection. In the study of active immunity-exclusive of vaccination-difficulty has been experienced in the evaluation of the results, owing to the existence of natural resistance to infection among guinea pigs. A guinea pig may recover from the inoculation of Leptospira icteroides and then resist a subsequent inoculation with a virulent strain of Leptospira icterohaemorrhagiae, a condition simulating that brought about by the identity of the two organisms. However, the refractoriness of such an animal to icterohaemorrhagiae may be due to its natural immunity to it. In the present study, therefore, only those guinea pigs were selected which had reacted typically-though in mild degree -to the icteroides infection, in order to determine whether they were subsequently immune to the inoculation of icterohaemorrhagiae. Indeed, by this mode of experimentation it was found that the guinea pigs which had once passed through an attack of the icteroides infection were absolutely immune to a second infection with the same organism but reacted severely and sometimes fatally to a later inoculation of icterohaemorrhagiae. Although there were a number of instances in which a previous infection with icteroides did not confer any perceptible immunity upon the guinea pigs against icterohaemorrhagiae, another group of guinea pigs showed a considerable resistance to the icterohaemorrhagiae infection as compared with those which had never been inoculated with icteroides. There is not much doubt, therefore, that an icteroides attack brings about, in some instances at least, a certain degree of resistance to the icterohaemorrhagiae infection. Hence the study of the phenomena of active immunity strongly indicates that icteroides is closely related immunologically to icterohaemorrhagiae.

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Apparently, then, we are confronted with this result,-that citrate plasma which causes little or no constriction of the stretched artery ring, little or no slowing of the flow through the frog perfusion preparation, while the corresponding serum produces a marked effect on both preparations, will affect the intestine or uterus preparation practically in the same way as the corresponding serum. Hirudin plasma and serum exert on the intestine and uterus preparations practically the same effect, causing a marked increase of tone. On the artery ring preparation, there is a difference although it is not so strongly marked as in the case of the citrate material. The frog perfusion preparation, as regards the effect of the hirudin material, seems to occupy an intermediate position between the intestine and uterus on the one hand, and the artery ring on the other. Of the three plasmas, the peptone plasma most closely resembles serum in its action on the artery rings. Like the other plasmas its effect on the intestine and uterus does not differ appreciably from that of the serum. From these observations the following conclusions seem justified. A change occurs in shed blood which confers on it the property of constricting artery rings and of slowing the flow through the perfused frog preparation. If this property is in any degree possessed by circulating blood it is at least markedly increased after the blood is shed. The change, whatever it may be, does not entail any essential alteration in the action of the blood on intestine and uterus segments. The tone-increasing property developed in the shed blood may, therefore, so far as the four test objects included in the present survey are concerned, be looked upon as especially affecting the blood vessels and probably their smooth muscle directly. This need not imply that the pressor substance, if it is a single definite substance developed in the shed blood, exerts no action on the smooth muscle of the intestine and uterus preparations, but merely that its action on these objects is masked by the general action of the serum and plasma, so that in the presence of the other constituents common to serum and plasma, its effect is inconspicuous or not to be detected at all, while on the blood vessel preparations, especially the artery rings, the effect of the pressor substance is the dominant one, and the general action of the serum and plasma is feeble or undetectable. It is not the clotting process as such, i.e., the actual change of fibrinogen into fibrin, that is responsible for the differences between serum and plasma revealed by the biological tests employed but some process which precedes or accompanies the clotting and which may or may not be causally related to it. Changes in formed elements of the blood under the influence of the changed conditions (contact with foreign bodies, restriction of gaseous exchange, etc.). which blood encounters as soon as it leaves the living vessels, are known to occur. Among these it is to be assumed are the changes which condition the differences between plasma and serum under discussion.(16) Even if these changes represent preliminary stages in coagulation (liberation of the factors necessary to the formation of thrombin, for instance), they may still occur to a greater or less extent in blood which is prevented in certain ways from clotting since it is known that the procedures by which the various non-coagulable plasmas are obtained break at different points the chain of events which normally ends in coagulation. A procedure which simply supplies sufficient antithrombin to neutralize the thrombin which has been allowed to form in normal amount may not interfere at all with the changes in the formed elements, and the pressor property of the resulting plasma may then be as marked as that of the serum. On the other hand, a procedure which binders clotting by preventing or diminishing the alterations in the cells, for example, the addition of a substance which acts as a preservative for blood platelets, will very likely yield a plasma with little or no pressor effect in comparison with the serum. The mere prevention of clotting, then, except in so far as it is an index of the prevention of changes in the formed elements may have little significance in preventing the development of the pressor property. Indeed it is conceivable that the alterations in the cells which are connected with the development of this property may even be wholly or partially independent of the cell changes concerned in coagulation. In this case it might be possible to obtain blood which would clot without developing the pressor property. The main results which seem to follow from our observations may be thus summarized: 1. The substance, or property, developed in shed blood by which it causes constriction of artery rings, is not developed, or at least not mainly developed, in connection with the actual change of fibrinogen to fibrin, since the constrictor action of different plasmas differs greatly, while the absence of coagulation is common to all. 2. The development of the constrictor substance, or property, is associated with changes undergone probably by formed elements of the blood when it is shed. These changes may be identical with the alterations, or with some of the alterations, preliminary to clotting. It is possible, however, that there may be changes connected with the development of the pressor property which, although concomitant with the liberation of the substances concerned in the production of thrombin, are yet quite independent of the clotting process. Our observations do not enable us to decide definitely between these possibilities. 3. The constrictor substance, or property, developed in shed blood acts especially on blood vessels and does not equally affect the other organs examined. This follows from the fact that a plasma and serum which differ markedly in their action on the blood vessels may have practically the same action on the intestine or uterus segments, an action which must therefore reside mainly, at least, in the original plasma itself. 4. The indication that the serum acts especially on blood vessels increases the interest of the suggestion that this action may play an important part in the prompt sealing of wounded vessels in addition to the mechanical effect of the clot, or by coming into operation before the clot has fully formed.

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Colorectal cancer (CRC) is the third most common cancer in the UK: incidence increases with age, median age at diagnosis being over 70 years. Approximately 25% of cases occur in individuals with a family history of CRC, including 5% caused by familial adenomatous polyposis (FAP) or hereditary non-polyposis CRC (HNPCC). Most develop from adenomatous polyps arising from the intestine lining. Individuals with these polyps undergo polypectomy and are invited for endoscopic surveillance. Screening via faecal occult blood testing has been rolled out across the UK. To evaluate the clinical effectiveness and cost-effectiveness of drug and micronutrient interventions for the prevention of CRC and/or adenomatous polyps. Interventions considered include: non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin and cyclo-oxygenase-2 (COX-2) inhibitors; folic acid; calcium; vitamin D and antioxidants (including vitamin A, vitamin C, vitamin E, selenium and beta-carotene). Chemoprevention was assessed in the general population, in individuals at increased risk of CRC, and in individuals with FAP or HNPCC. A systematic review identified randomised controlled trials (RCTs) assessing drug and nutritional agents for the prevention of CRC or adenomatous polyps. A separate search identified qualitative studies relating to individuals' views, attitudes and beliefs about chemoprevention. MEDLINE, MEDLINE In-Process &amp; Other Non-Indexed Citations, EMBASE, CINAHL, the Cochrane Database of Systematic Reviews, Cochrane CENTRAL Register of Controlled Trials, DARE, NHS-EED (NHS Economic Evaluation Database), HTA database, Science Citation Index, BIOSIS previews and the Current Controlled Trials research register were searched in June 2008. Data were extracted by one reviewer and checked by a second. The synthesis methods used were systematic review and meta-analysis for RCTs and qualitative framework synthesis for qualitative studies. A health economic model was developed to assess the cost-effectiveness of chemoprevention for two populations with different levels of risk of developing CRC: the general population and an intermediate-risk population. The search identified 44 relevant RCTs and six ongoing studies. A small study of aspirin in FAP patients produced no statistically significant reduction in polyp number but a possible reduction in polyp size. There was a statistically significant 21% reduction in risk of adenoma recurrence [relative risk (RR) 0.79, 95% confidence interval (CI) 0.68 to 0.92] in an analysis of aspirin versus no aspirin in individuals with a history of adenomas or CRC. In the general population, a significant 26% reduction in CRC incidence was demonstrated in studies with a 23-year follow-up (RR 0.74, 95% CI 0.57 to 0.97). Non-aspirin NSAID use in FAP individuals produced a non-statistically significant reduction in adenoma incidence after 4 years of treatment and follow-up and reductions in polyp number and size. In individuals with a history of adenomas there was a statistically significant 34% reduction in adenoma recurrence risk (RR 0.66, 95% CI 0.60 to 0.72) and a statistically significant 55% reduction in advanced adenoma incidence (RR 0.45, 95% CI 0.35 to 0.58). No studies assessed the effect of non-aspirin NSAIDs in the general population. There were no studies of folic acid in individuals with FAP or HNPCC. There was no significant effect of folic acid versus placebo on adenoma recurrence (RR 1.16, 95% CI 0.97 to 1.39) or advanced adenoma incidence in individuals with a history of adenomas. In the general population there was no significant effect of folic acid on risk of CRC (RR 1.13, 95% CI 0.77 to 1.64), although studies were of relatively short duration. Calcium use by FAP patients produced no significant reduction in polyp number or disease progression. In individuals with a history of adenomas there was a statistically significant 18% reduction in risk of adenoma recurrence (RR 0.82, 95% CI 0.69 to 0.98) and a non-significant reduction in risk of advanced adenomas (RR 0.77, 95% CI 0.50 to 1.17). In the general population there was no significant effect of calcium on risk of CRC (RR 1.08, 95% CI 0.87 to 1.34), although studies were of relatively short duration. There were no studies of antioxidant use in individuals with FAP or HNPCC, and in individuals with a history of adenomas no statistically significant differences in relative risk of adenoma recurrence were found. In the general population there was no difference in incidence of CRC (RR 1.00, 95% CI 0.88 to 1.13) with antioxidant use compared with no antioxidant use. Twenty studies reported qualitative findings concerning chemoprevention. People are more likely to use NSAIDs if there is a strong perceived need. Perceptions of risk and benefit also influence decision-making and use. People have fewer concerns about using antioxidants or other supplements, but their perception of the benefits of these agents is less well-defined. The model analysis suggested that the most cost-effective age-range policy in the general population would be to provide chemoprevention to all individuals within the general population from age 50 to 60 years. The use of aspirin in addition to screening within the general population is likely to result in a discounted cost per life-year gained of around 10,000 pounds and a discounted cost per quality-adjusted life-year (QALY) gained of around 23,000 pounds compared with screening alone. In the intermediate-risk group the most economically viable age-range policy would be to provide chemoprevention to individuals following polypectomy aged 61 to 70 years. Calcium is likely to have a discounted cost per QALY gained of around 8000 pounds compared with screening alone. Although aspirin in addition to screening should be more effective and less costly than screening alone, under the current assumptions of benefits to harms of aspirin and calcium, aspirin is expected to be extendedly dominated by calcium. Whilst a number of studies were included in the review, the duration of follow-up was generally insufficient to detect an effect on cancer incidence. Given the uncertainties and ambiguities in the evidence base, the results of the health economic analysis should be interpreted with caution. Aspirin and celecoxib may reduce recurrence of adenomas and incidence of advanced adenomas in individuals with an increased risk of CRC and calcium may reduce recurrence of adenomas in this group. COX-2 inhibitors may decrease polyp number in patients with FAP. There is some evidence for aspirin reducing the incidence of CRC in the general population. Both aspirin and NSAIDs are associated with adverse effects so it will be important to consider the risk-benefit ratio before recommending these agents for chemoprevention. The economic analysis suggests that chemoprevention has the potential to represent a cost-effective intervention, particularly when targeted at intermediate-risk populations following polypectomy.

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Acidic solutions have been used for decades to treat a variety of skin conditions. Many of these solutions consist of organic acids with a hydroxy group on a carbon adjacent to the carbonyl carbon and are referred to as alpha-hydroxy acids (AHA). Organic acids with hydroxy groups on the second carbon from the carbonyl carbon are referred to as beta-hydroxy acids (BHA). Both AHA and BHA are used to treat various skin conditions. One of the most widely used AHA is glycolic acid, while salicylic acid is a commonly used BHA. Chemical peels containing 20% to 70% glycolic acid have been used by dermatologists to treat ichthyosis, acne, xerosis, actinic keratosis, seborrheic keratoses, warts, and psoriasis. AHA have recently been used to treat photoaged skin and are now included in many commercially available cosmetic skin treatments. When used in a formulation for a chemical peel, topical treatment of skin with AHA and BHA can result in removal of the stratum corneum, alteration of the skin's histology, and increased cell proliferation in the basal layer of the epidermis. Since AHA and BHA are used to correct photoaged skin, and since exposure to sunlight of skin treated with AHA or BHA is likely, studies were designed to determine the effects of topical application of creams containing AHA (0%, 4%, or 10% glycolic acid, pH 3.5) or BHA (0%, 2%, or 4% salicylic acid, pH 4.0) on the photocarcinogenesis of simulated solar radiation using a filtered 6.5 kW xenon arc light source [simulated solar light (SSL)]. Male and female Crl:SKH-1 (hr-/hr-) hairless mice were exposed to glycolic acid or salicylic acid alone or in combination with SSL for 40 weeks, and the mice were followed for an additional 12 weeks. 1-YEAR STUDY IN MICE: Groups of 36 male and 36 female mice were exposed to 0.0, 0.3, 0.6, or 0.9 minimal erythema dose (MED) of SSL during the afternoon (1200 to 1600 hours) 5 days per week for 40 weeks. Groups of 18 male and 18 female mice were treated in the morning (0800 to 1100 hours) with 2 mg/cm2 control cream, 4% glycolic acid cream, 10% glycolic acid cream, 2% salicylic acid cream, or 4% salicylic acid cream on the dorsal skin, and in the afternoon (1200 to 1600 hours) with 0.3 MED of SSL 5 days per week for 40 weeks. Additional groups of 18 male and 18 female mice were treated in the morning (0800 to 1100 hours) with 2 mg/cm2 control cream, 4% glycolic acid cream, 10% glycolic acid cream, 2% salicylic acid cream, or 4% salicylic acid cream on the dorsal skin, and in the afternoon (1200 to 1600 hours) with 0.6 MED of SSL 5 days per week for 40 weeks. All mice were held an additional 12 weeks following the end of treatment. There were no effects of SSL exposure or topical treatment on the body weights of the mice. Increasing doses of SSL resulted in an SSL-dose trend in survival, with the greatest dose of SSL causing the earliest removal. This effect was present in both the untreated and control cream treated mice. The only consistent effect of glycolic acid on survival was a dose-dependent increase in survival of females at 0.3 MED SSL. Survival was increased in mice exposed to 0.6 MED of SSL and treated with 2% and 4% salicylic acid compared to mice treated with 0.6 MED and treated only with the vehicle. This effect was not observed in the mice treated with 0.0 and 0.3 MED of SSL and salicylic acid compared to the control groups. The mean or median time to first skin tumor of at least 1 mm decreased with increasing SSL exposure concentration in mice that were not treated with cream. Addition of the control cream resulted in a decrease in the time to tumor at 0.3 and 0.6 MED of SSL in male and female mice. The addition of glycolic acid (4% or 10%) did not affect the time to tumor in male or female mice at either SSL dose when compared to mice receiving the control cream. When compared to mice receiving control cream, the inclusion of 4% salicylic acid in the cream increased the time to tumor for male mice receiving 0.3 or 0.6 MED of SSL and female mice receiving 0.3 MED of SSL. The results indicate that inclusion of glycolic acid in the topical cream had no effect on the time required to induce tumors by SSL; however, inclusion of salicylic acid at 4% in the cream was photoprotective, increasing the time required to achieve median tumor incidence at a corresponding dose of SSL and control cream. The skin tumors induced by SSL in mice were squamous cell papilloma, carcinoma in situ, and squamous cell carcinoma. Except for papilloma in male mice, the tumors were induced in a dose-dependent manner by SSL in male and female mice. In male and female mice treated with control cream, the exposure to SSL caused significant increases in the incidences of carcinoma in situ, squamous cell carcinoma, and the combined incidence of carcinoma in situ and squamous cell carcinoma. When male or female mice were exposed to 0.3 or 0.6 MED SSL, the inclusion of 4% or 10% glycolic acid did not affect the induction of skin neoplasms over the incidence detected when the control cream was used, with the single exception of a glycolic acid dose-trend in squamous cell carcinoma incidence in male mice receiving 0.3 MED SSL. The inclusion of salicylic acid in the cream that was topically applied to female mice did not affect squamous cell papilloma formation at either SSL dose. The incidence of carcinoma in situ was decreased in male and female mice at 0.3 MED SSL when treated with 4% salicylic acid. A salicylic acid dose-trend was also observed in both sexes at 0.3 MED SSL. These experiments investigated the impact of topical application of a cosmetic formulation containing 4% or 10% glycolic acid (pH 3.5) or 2% or 4% salicylic acid (pH 4) on the photocarcinogenesis of filtered 6.5 kW xenon arc simulated solar light (SSL) in SKH-1 hairless mice. Taking into consideration the survival data, time to tumor data, and the pathology results, glycolic acid did not alter the photocarcinogenesis of SSL, and salicylic acid was photoprotective, reducing the carcinogenicity of 0.3 MED SSL.

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Toluene is used to back-blend gasoline, as a chemical intermediate, and as a solvent; 920 million gallons were produced in the United States in 1988. Toxicology studies were conducted by administering toluene (greater than 99% pure) in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 13 weeks or by whole-body inhalation exposure for 14 or 15 weeks. NTP Toxicology and Carcinogenesis studies were conducted by whole-body inhalation exposure of F344/N rats and B6C3F1 mice of each sex for 15 months or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse L5178Y lymphoma cells, and Chinese hamster ovary cells. Thirteen-Week Gavage Studies: All rats that received the top dose of 5,000 mg/kg died during the first week, and 8/10 male rats that received 2,500 mg/kg died early. The final mean body weight of male rats that received 2,500 mg/kg was 19% lower than that of vehicle controls. Relative liver, kidney, and heart (female only) weights for rats that received the higher doses were greater than those for vehicle controls. Necrosis of the brain and hemorrhage of the urinary bladder were seen at increased incidences in dosed rats. All mice that received the top dose of 5,000 mg/kg died during the first week, and 40% of those that received 2,500 mg/kg died before the end of the 13-week gavage studies. The final mean body weight of males at 2,500 mg/kg was 16% lower than that of vehicle controls. At the higher doses, relative liver weights were increased for mice. Fifteen-Week and Fourteen-Week Inhalation Studies: Eight of 10 male rats exposed at the top exposure concentration of 3,000 ppm died during week 2. Final mean body weights of rats exposed at concentrations of 2,500 or 3,000 ppm were 14%-25% lower than that of controls. As in the gavage studies, the relative liver, kidney, and heart weights for rats exposed at the top two concentrations were increased compared with those for controls. No compound-related effects were seen on sperm; no adverse effects on the estrous cycle were observed. Five of 10 male mice and all female mice exposed at 3,000 ppm and 70% of female mice at 2,500 ppm died during the first 2 weeks. Final mean body weights of all exposed groups were 7%-13% lower than those of controls. Relative liver weights for mice exposed at 625 ppm or higher, relative lung weights for mice exposed at 1,250 ppm or higher, and relative kidney weights for female mice exposed at 1,250 ppm or higher were greater than those for controls. Centrilobular hypertrophy of the liver was observed in all male mice exposed at 2,500 ppm and 70% of male mice exposed at 3,000 ppm. No effects on sperm or the estrous cycle were observed. Fifteen-Month and Two-Year Inhalation Studies: Long-term studies were conducted by exposing groups of 60 rats of each sex to 0, 600, or 1,200 ppm toluene by inhalation, 6.5 hours per day, 5 days per week. Groups of 60 mice of each sex were exposed at 0, 120, 600, or 1,200 ppm on the same schedule. Ten animals per group (except male mice) were removed for toxicologic evaluation after being exposed for 15 months. All other animals were exposed to toluene for 103 weeks. In the 15-month inhalation studies, the incidences and severity of nonneoplastic lesions of the nasal cavity (degeneration of olfactory and respiratory epithelium and goblet cell hyperplasia) were increased in exposed rats. Minimal hyperplasia of the bronchial epithelium was seen in 4/10 female mice at 1,200 ppm. The severity of nephropathy was slightly increased in exposed female rats. No chemical-induced neoplasms were observed. Body Weight and Survival in the Two-Year Studies: Mean body weights of rats and mice were generally similar (yearly averages within 5%) among groups throughout the 2-year studies. No significant differences in survival were observed among rats or mice of either sex, although survival in all groups of male mice was lower than usual (male rats: control, 30/50; 600 ppm, 28/50; 1,200 ppm, 22/50; female rats: 33/50; 35/50; 30/50; male mice: control, 17/60; 120 ppm, 22/50; female rats: 33/50; 35/50; 30/50; male mice: control, 17/60; 120 ppm, 22/60; 600 ppm, 16/60; 1,200 ppm, 19/60; female mice: 30/50; 33/50; 24/50; 32/50). Scrotal, preputial, and penile lesions observed in male mice were associated with many of the early deaths and with animals killed in a moribund condition. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Nephropathy was seen in almost all rats, and the severity was somewhat increased in exposed rats. A rare renal tubular cell carcinoma in a female rat and an equally uncommon sarcoma of the kidney in another female rat were seen in the 1,200-ppm exposure group. Erosion of the olfactory epithelium and degeneration of the respiratory epithelium were increased in exposed rats. Inflammation of the nasal mucosa and metaplasia of the olfactory epithelium were increased in exposed female rats. A rare squamous cell carcinoma of the nasal mucosa was seen in one female rat at 1,200 ppm. A squamous cell papilloma of the forestomach was observed in one female rat at 1,200 ppm, and a squamous cell carcinoma was observed in a second female rat at 1,200 ppm. No chemically related neoplasms were found in male rats, and the one nasal, two kidney, and two forestomach neoplasms observed in female rats were considered not to be associated with inhalation exposed to toluene. For mice, no biologically important increases were observed for any nonneoplastic or neoplastic lesions. Genetic Toxicology: Toluene did not induce gene mutations in S. typhimurium strain TA98, TA100, TA1535, or TA1537 with or without exogenous metabolic activation. In the mouse lymphoma assay, toluene gave an equivocal response with and without exogenous metabolic activation. Toluene did not induce sister chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells in the presence or absence of exogenous metabolic activation. Conclusions: Under the conditions of these 2-year inhalation studies, there was no evidence of carcinogenic activity for male or female F344/N rats exposed to toluene at concentrations of 600 or 1,200 ppm. There was no evidence of carcinogenic activity for male or female B6C3F1 mice exposed by inhalation to toluene at concentrations of 120, 600, or 1,200 ppm for 2 years. Synonyms: monomethylbenzene; methylbenzene; toluol; phenylmethane; tolueen (Dutch); toluen (Czech), tolueno (Spanish); toluolo (Italian) Trade Name: Methacide

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Psychotherapy for sex offenders has only very recently started to develop in France. The French law on compulsory treatment for sex offenders was voted in 1998, and many mental health practitioners are not trained to treat such patients yet. In our ambulatory forensic consultation, sex offenders have been treated since 1992 and group psychotherapy has been offered to them since 1994. Our first therapeutic models were the North-American behavioural-cognitive therapy and Pithers' relapse prevention model. Behavioural-cognitive theory describes paedophilia as an acquired sexual preference maintained by positive reinforcement. Pithers (1990) considered that relapse only occurs in high-risk situations, and that high-risk situations always come after offence precursors. In North America, relapse prevention consists in helping paedophiles spot their high-risk situations and offence precursors, and enhance their skills to cope with such situations or to prevent them. Therapy programs were developed according to these models, aiming to help offenders develop such skills, ie empathy, social skills, cognitive restructuring, self-esteem, etc. Trying to apply these therapy programs in France, our team quickly realised that we would have to adapt them to French culture. On the one hand, behavioural-cognitive theory did not seem satisfactory enough in explaining paedophilic behaviour and paedophilic preference. On the other hand, behavioural-cognitive therapy made patients into children too much and increased resistance. Therapy based on programs seemed too rigid for French patients and therapists, and we often felt we were working on an issue that would have been much more accurate to work on a few sessions earlier, when this issue was spontaneously brought up by a patient. We believe change occurs all the more as issues are worked on at the right moment for the patient. Moreover, on a cultural point of view, we also realised the use of programs in psychotherapy was difficult to accept in France both by patients and therapists, as our culture is strongly influenced by psychoanalysis, especially free association. The use of a plethysmograph was also impossible in our country. We thus decided to use Pithers' relapse prevention model but to let our patients free to speak, so our therapy was not a program. Offences were analysed according to Pithers' ideas about high-risk situations and offence precursors. Most of the sessions were non-directive, but therapists offered each patient to work on his offence when they believed it was the right moment. Important issues (such as empathy, cognitive distortions, emotional control, etc.), were tackled as they came up, which seemed easier and less rigid as sessions were linked to patients' current pre- occupations. Post-group meetings enabled therapists to draw themes that seemed important to work on with each patient (empathy, consequences on victims, anger, cognitive distortions, emotional expression, relational issues, self-esteem, intimacy...). These issues were discussed the next time they were raised by the group. We were interested to notice that all important issues came up spontaneously from the group during the sessions as long as patients were free to share their concerns, without therapists having to set issues beforehand. Two case studies illustrate our method. Bernard was 40 when he first came to our consultation. Originally a teacher, he was dismissed and became a marketing man after being sentenced to five years of prison for sex offences on two 6-year-old girls. Bernard relapsed a few years after he got out of prison by sexually offending two girls, aged 10 and 13. At our first interview, Bernard had cognitive distortions about sexual education and always avoided sexually explicit words to describe the offences. He did not realise the consequences of his acts on the victims, but said he wanted to be treated because he felt lonely. He first described a sexual preference for adult women, but progressively aknoledged feeling attracted to female teenagers. He did not know why the offences occurred at such a moment in his life, and had no idea of his high-risk situations nor of his offence precursors. Bernard often confused his need for sex and his need for affection. After four years' participation to our relapse prevention group therapy, Bernard has clarified his sexual preferences : he has always been mostly attracted to girls from 6 to 10 years old. He has also always been attracted to women younger than him, and now seems to be mostly aroused by female teenagers. Working on his offences has helped him identify his high-risk situations and the strategies he used to get close to his victims and to be trusted by them and their single mothers. Bernard often offended when he was feeling lonely and rejected, after a break-up with a partner. Twice during these four years, Bernard found himself in such high-risk situations, but managed to stop before relapsing. However, empathy towards victims is still difficult to develop for Bernard. Neither has he yet managed to build a new relationship with a woman, as he still seems to suffer from an unhappy love affair he went through several years ago. This case study shows one of the limits of Pithers' relapse prevention model, if it is used mechanically. Indeed, we should logically have spotted as high-risk situations for Bernard interactions with 6 to 10 year-old girls. Helping him face his past and present sexual fantasies led Bernard realise his high-risk situations were now mainly about teenage girls, even if he had mostly been attracted to younger girls earlier in his life. After 2 to 3 years of therapy, we have quite often noticed this kind of evolution in sexual preferences in paedophiles, their preferences changing towards teenagers or young adults. In France, mental health professionals are often reluctant to follow sex offenders because of negative counter-transference and lack of specific training. However, first changes often occur quite quickly in paedophiles when they are offered group therapy. The group makes it easier to confront paedophiles to the reality of their offence and of their sexual fantasies. These patients often express being very relieved after the first sessions, as the group therapy is generally their first opportunity to express their feelings, sexual fantasies and thoughts about paedophilia. Pithers' model, used within a group were patients are free to speak in a human, warm and confronting atmosphere, seems clinically accurate and effective in helping paedophiles in France. We now need studies to check therapy effectiveness on relapse and to understand which therapy factors are efficient on sex offenders.

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Hot spots are areas where concentrations of one or more air toxics--organic vapors or particulate matter (PM)--are expected to be elevated. The U.S. Environmental Protection Agency's (EPA*) screening values for air toxics were used in our definition of hot spots. According to the EPA, a screening value "is used to indicate a concentration of a chemical in the air to which a person could be continually exposed for a lifetime ... and which would be unlikely to result in a deleterious effect (either cancer or noncancer health effects)" (U.S. EPA 2006). Our characterization of volatile organic compounds (VOCs; namely 18 hydrocarbons, methyl tert-butyl ether [MTBE], acetone, and aldehydes) was added onto our ongoing National Cancer Institute-funded study of lung cancer and particulate pollutant concentrations (PM with an aerodynamic diameter &lt; or = 2.5 microm [PM2.5], elemental carbon [EC], and organic carbon [OC]) and source apportionment of the U.S. trucking industry. We focused on three possible hot spots within the trucking terminals: upwind background areas affected by nearby industrial parks; downwind areas affected by upwind and terminal sources; and the loading docks and mechanic shops within terminal as well as the interior of cabs of trucks being driven on city, suburban, and rural streets and on highways. In Phase 1 of our study, 15 truck terminals across the United States were each visited for five consecutive days. During these site visits, sorbent tubes were used to collect 12-hour integrated samples of hydrocarbons and aldehydes from upwind and downwind fence-line locations as well as inside truck cabs. Meteorologic data and extensive site information were collected with each sample. In Phase 2, repeat visits to six terminals were conducted to test the stability of concentrations across time and judge the representativeness of our previous measurements. During the repeat site visits, the sampling procedure was expanded to include real-time sampling for total hydrocarbon (HC) and PM2.5 at the terminal upwind and downwind sites and inside the truck cabs, two additional monitors in the yard for four-quadrant sampling to better characterize the influence of wind, and indoor sampling in the loading dock and mechanic shop work areas. Mean and median concentrations of VOCs across the sampling locations in and around the truck terminals showed significant variability in the upwind concentrations as well as in the intensity of exposures for drivers, loading-dock workers, and mechanics. The area of highest concentrations varied, although the lowest concentrations were always found in the upwind background samples. However, the downwind samples, which included the terminal's contribution, were on average only modestly higher than the upwind samples. In the truck terminal, the mechanic-shop-area concentrations were consistently elevated for many of the VOCs (including the xylenes, alkanes, and acetone) and particulates; the loading-dock concentrations had relatively high concentrations of 1,3-butadiene, formaldehyde, and acetaldehyde; and nonsmoking driver exposures were elevated for benzene, MTBE, styrene, and hexane. Also, the loading dock and yard background concentrations for EC and PM2.5 were highly correlated with many of the VOCs (50% of pairs tested with Spearman r &gt; 0.5 and 75% with r &gt; 0.4); in the mechanic shop VOCs were correlated with EC but not PM2.5 (r = 0.4-0.9 where significant); and for driver exposures VOC correlations with EC and PM2.5 were relatively low, with the exception of a few aromatics, primarily benzene (r = 0.4-0.5). A principal component analysis of background source characteristics across the terminal locations that had repeat site visits identified three different groupings of variables (the "components"). This analysis suggested that a strong primary factor for hydrocarbons (alkanes and aromatics) was the major contributor to VOC variability in the yard upwind measurement. Aldehydes and acetone, which loaded onto the second and third components, were responsible for a smaller contribution to VOC variability. A multi-layer exposure model was constructed using structural equation modeling techniques that significantly predicted the yard upwind concentrations of individual VOCs as a function of wind speed, road proximity, and regional location (R2 = 0.5-0.9). This predicted value for the yard background concentration was then used to calculate concentrations for the loading dock and mechanic shop. Finally, we conducted a detailed descriptive analysis of the real-time data collected in the yard and in truck cabs during the six repeat site visits, which included more than 50 12-hour sessions at each sampling location. The real-time yard monitoring results suggested that under some conditions there was a clear upwind-to-downwind trend indicating a terminal contribution, which was not apparent in the integrated sampling data alone. They also suggested a nonlinear relationship with wind speed: calm conditions (wind speed &lt; 2 mph) were associated with erratic upwind-downwind differences, lower wind speeds (2 to 10 mph) favored transport with little dilution, and higher wind speeds (&gt; 10 mph) favored dilution and dispersal (more so for VOCs than for PM). Finally, an analysis of the real-time data for driver exposures in trucks with a global positioning system (GPS) matched with geographic information system (GIS) data suggested a clear influence of traffic and industrial sources along a given route with peaks in driver exposures. These peaks were largely associated with traffic, major intersections, idling at the terminals, and pickup and delivery (P&amp;D) periods. However, VOCs and PM2.5 had different exposure patterns: VOCs exposures increased when the vehicle was stopped, and PM2.5 exposures increased during travel in traffic. All three types of testing sites--upwind and downwind fence-line locations and inside truck cabs while in heavy traffic--met the established definition for a hot spot by having periods with concentrations of pollutants that exceeded the EPA's screening values. Most frequently, the pollutants with concentrations exceeding the screening values were formaldehyde, acetaldehyde, and EC (which serves as a marker for diesel particulate); less frequently they were 1,3-butadiene and benzene. In the case of the downwind location of a single truck terminal without an aggregation of other sources, high concentrations of VOCs and PM were infrequent. Using structural equation modeling, a model was developed that could identify combinations of conditions and factors likely to produce hot spots. Source apportionment analyses showed that EC came predominantly from diesel emissions. As expected from the sites studied, organic vapors associated with vehicle emissions (C6-C8 alkanes and aromatics) were the predominant components of VOCs, followed by formaldehyde and acetaldehyde. For driver exposures, high VOC values were associated with stopped vehicles, and high PM2.5 values were associated with conditions during driving.

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Citral is used primarily as lemon flavoring in foods, beverages, and candies. It is also used as a lemon fragrance in detergents, perfumes, and other toiletries. Citral was nominated by the National Cancer Institute for study because of its widespread use in foods, beverages, cosmetics, and other consumer products and its structure as a representative beta-substituted vinyl aldehyde. Male and female F344/N rats and B6C3F1 mice were exposed to microencapsulated citral (greater than 96% pure) in feed for 14 weeks or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, mouse bone marrow cells, and mouse peripheral blood erythrocytes. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were fed diets containing starch microcapsules with a load of 31.3% citral. The concentration of citral in the diet was 3,900, 7,800, 15,600, or 31,300 ppm microencapsulated citral (equivalent to average daily doses of approximately 345, 820, 1,785, and 1,585 mg citral/kg body weight to males and 335, 675, 1,330, and 2,125 mg/kg to females) for 14 weeks. Additional groups of 10 male and 10 female rats received untreated feed (untreated controls) or feed containing placebo microcapsules (vehicle controls). In the second week of the study, all rats in the 31,300 ppm groups were killed moribund. Mean body weights of exposed males and females that survived to the end of the study were generally significantly less than those of the vehicle controls. Feed consumption by 15,600 and 31,300 ppm males and females was less than that by the vehicle controls during the first week of the study. Males and females in the 31,300 ppm groups exhibited listlessness, hunched posture, absent or slow paw reflex, and dull eyes. Exposure of rats to citral may have been associated with forestomach epithelial hyperplasia and hyperkeratosis, bone marrow atrophy and hemorrhage, and nephrotoxicity. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were fed diets containing 3,900, 7,800, 15,600, or 31,300 ppm microencapsulated citral (equivalent to average daily doses of approximately 745, 1,840, 3,915, and 8,110 mg/kg to males and 790, 1,820, 3,870, and 7,550 mg/kg to females) for 14 weeks. Additional groups of 10 male and 10 female mice received untreated feed (untreated controls) or feed containing placebo microcapsules (vehicle controls). In the second week of the study, four males in the 31,300 ppm group were killed moribund. Mean body weights of all exposed groups of males and females were significantly less than those of the vehicle controls. Feed consumption by females exposed to 7,800 ppm or greater was less than that by the vehicle controls during the first week of the study. By the end of the study, feed consumption by all exposed groups was greater than that by the vehicle controls. Mice in the 15,600 and 31,300 ppm groups were generally thin and lethargic; a few males in the 7,800 ppm group were also thin. The incidences of ovarian atrophy were significantly increased in females exposed to 15,600 or 31,300 ppm. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female F344/N rats were fed diets containing 1,000, 2,000, or 4,000 ppm microencapsulated citral for 2 years. Additional groups of 50 male and 50 female rats received untreated feed (untreated controls) or feed containing placebo microcapsules (vehicle controls). Dietary concentrations of 1,000, 2,000, and 4,000 ppm delivered average daily doses of approximately 50, 100, and 210 mg/kg to males and females. Survival of all exposed groups of males was significantly greater than that of the vehicle control group. Mean body weights of rats exposed to 4,000 ppm were generally less than those of the vehicle controls from week 49 (males) or 25 (females) to the end of the study. Feed consumption by exposed groups was similar to that by the vehicle controls. No neoplasms or nonneoplastic lesions were attributed to exposure to citral. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female B6C3F1 mice were fed diets containing 500, 1,000, or 2,000 ppm microencapsulated citral for 2 years. Additional groups of 50 male and 50 female mice received untreated feed (untreated controls) or feed containing placebo microcapsules (vehicle controls). Dietary concentrations of 500, 1,000, and 2,000 ppm delivered average daily doses of approximately 60, 120, and 260 mg/kg to males and females. Survival of exposed males and females was similar to that of the vehicle control groups. Mean body weights of mice exposed to 1,000 or 2,000 ppm were generally less than those of the vehicle controls throughout the study, and mean body weights of 500 ppm females were less from week 30 to the end of the study. Feed consumption by the exposed groups was similar to that by the vehicle controls. The incidences of malignant lymphoma occurred with a positive trend in female mice, and the incidence in 2,000 ppm females was significantly greater than that in the vehicle control group. Tissues most commonly affected by malignant lymphoma were the spleen, mesenteric lymph node, thymus, and, to a lesser extent, the ovary. Citral was not mutagenic in S. typhimurium strain TA98, TA100, TA1535, or TA1537 with or without induced rat or hamster liver S9 enzymes. In cytogenetic tests with cultured Chinese hamster ovary cells, citral induced sister chromatid exchanges with and without S9, but chromosomal aberrations were not significantly increased after exposure to citral, with or without S9. Negative results were obtained in an in vivo bone marrow micronucleus test in male B6C3F1 mice treated by intraperitoneal injection with 250 to 750 mg/kg daily for 3 days. Likewise, no increases in the frequencies of micronucleated erythrocytes were observed in peripheral blood samples collected from male and female mice within 24 hours of the final exposure in the 14-week study. In conclusion, citral gave negative results in in vitro and in vivo tests for genotoxicity, with the exception of the in vitro mammalian cell test for sister chromatid exchange induction Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of citral in male or female F344/N rats exposed to 1,000, 2,000, or 4,000 ppm. There was no evidence of carcinogenic activity of citral in male B6C3F1 mice exposed to 500, 1,000, or 2,000 ppm. There was equivocal evidence of carcinogenic activity in female B6C3F1 mice based on increased incidences of malignant lymphoma.

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Mirex (95% pure), formerly used a systemic insecticide and as a fire retardant, was studied for toxicologic and carcinogenic effects by administering diets containing 0, 0.1, 1.0, 10, 25, or 50 ppm mirex to groups of 52 F344/N rats of each sex for 104 weeks. Doses selected for the 2-year studies were based primarily on the effects on body weights and survival of rats in a 26-week study. During the first 6 months of the 2-year study, because of good survival and the absence of observable toxic effects in female rats, additional groups (termed second study) of 52 F344/N female rats were started at higher dietary concentrations of 0, 50, and 100 ppm mirex. Based on feed consumption data, the estimated average intake per day was 0, 0.007, 0.075, 0.75, 1.95, and 3.85 mg mirex/kg body weight for male rats and female rats in the first study, and 0, 3.9, and 7.7 mg/kg for female rats in the additional study. Body Weights, Feed Consumption, and Survival in Two-Year Studies: Mean body weights of male rats that received 25 or 50 ppm mirex were 5%-18% lower than those of the controls throughout most of the study; mean body weights of female rats that received 50 or 100 ppm mirex were 4%-18% lower than those of the controls after week 40; mean body weights of groups receiving 0.1, 1.0, or 10 ppm were similar to those of controls. Feed consumption by dosed male rats was 83%-91% that by controls, and that by dosed female rats was 86%-99% that by controls. The top dietary exposure groups of rats received the equivalent of 3.85 mg mirex/kg body weight, whereas the 100-ppm group of female rats (second study) averaged 7.7 mg/kg. At the end of the study, survival of male rats that received 25 or 50 ppm of mirex was lower than that of controls, whereas survival of all dosed groups of female rats was similar to that of controls (male: control, 44/52; 0.1 ppm, 37/52; 1 ppm, 36/52; 10 ppm, 37/52; 25 ppm, 19/52; 50 ppm, 15/52; female-- first study: 38/52; 38/52; 35/52; 41/52; 35/52; female-- second study: control, 44/52; 50 ppm, 44/52; 100 ppm, 39/52). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: The most notable compound-related effects were observed in the liver of male and female rats. Fatty metamorphosis, cytomegaly, angiectasis (males only), and necrosis of the liver were observed at increased incidences in dosed rats. The incidences of of neoplastic nodules of the liver were dose related, and in the 10-, 25-, and 50-ppm groups of males and the 50- and 100-ppm groups of females (second study), they were markedly greater than those in controls (52/group-- male: control, 3; 0.1 ppm, 5; 1 ppm, 5;10 ppm, 14; 25 ppm, 15; 50 ppm, 26; female (second study): control, 2; 50 ppm, 23; 100 ppm, 30). In the first study in female rats, the incidences of neoplastic nodules were not significantly different between control and dosed groups (10; 5; 4; 5; 9; 7). The 10 neoplastic nodules of the liver seen in the control group (19%) was significantly greater than the mean incidence observed historically (57/2,015; 2.8%). The incidences of hepatocellular carcinomas in control and dosed groups were relatively low and were not significantly different between groups. The incidences of pheochromocytomas of the adrenal gland occurred with a positive trend in male rats (8/51; 7/52; 13/52; 11/52; 18/51, 19/51); the incidences in the 25- and 50-ppm male rats were greater than that in controls; malignant pheochromocytomas were observed in 2 controls and in 2 mirex-exposed male rats. The incidence of pheochromocytomas in 50-ppm female rats in the first study was marginally greater than that in controls (control, 1/51; 50 ppm, 6/52); this borderline increase was not observed in the second female rat study and thus is not considered to be due to the dietary administration of mirex. Nephropathy occurred at similar incidences in control and mirex-exposed groups of male and female rats; however, the severity of this nonneoplastic lesion was judged to be slightly greater in the groups given 25, 50, or 100 ppm mirex (male: severe vs. moderate in controls; femas given 25, 50, or 100 ppm mirex (male: severe vs. moderate in controls; female: moderate to severe vs. moderate). Hyperplasia of the transitional epithelium of the kidney pelvis was observed in dosed male rats (0/51; 2/51; 2/52; 5/52; 14/51; 9/52). Transitional cell papillomas of the renal pelvis in male rats occurred with a positive trend (P&amp;lt;0.02) (0/51; 0/51; 0/52; 1/51; 3/52). The highest incidence previously observed in untreated male F344/N rats in NTP studies is 1/48, and the mean historical incidence is 5/1,968 (0.3&amp;percnt;). In both the first and second studies in female rats, the incidence of mononuclear cell leukemia showed dosed-related increases (first study: 8/52; 8/52; 11/52; 14/52; 18/52; 18/52; second study: 6/52; 9/52; 14/52). When the data from both studies are combined, the incidences are significantly increased in the 10-, 25-, 50-, and 100-ppm groups. The mean historical incidence is 19&amp;percnt; (375/2,021). For the thyroid gland, there was a positive trend for follicular cell neoplasms in male rats (0/51; 1/50; 0/47; 1/47; 0/35; 4/49) and a negative trend for C-cell neoplasms in male rats (8/51; 6/50; 4/47; 7/47; 3/35; 0/49) and infemale rats in the first study (12/50; 13/50; 7/48; 9/47; 6/48; 2/46). Neither observation is considered to be associated with the dietary administration of mirex. Genetic Toxicology: Mirex was not mutagenic in the Salmonella typhimurium-microsome assay when tested in a preincubation protocol in the presence or absence of exogenous metabolic activation in strains TA98, TA100, TA1535, or TA1537. Mirex did not induce either sister chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells in the presence or absence of S9. Conclusions: Under the conditions of these 2-year feed studies of mirex, there is clear evidence of carcinogenic activity for male and female F344/N rats, as primarily indicated by marked increased incidences of benign neoplastic nodules of the liver, as well as by increased incidences of pheochromocytomas of the adrenal gland and transitional cell papillomas of the kidney in males and by increased incidences of mononuclear cell leukemia in females. Nonneoplastic effects induced by mirex include cytomegaly, fatty metamorphosis, angiectasis (males only), and cellular necrosis in the liver. Synonyms and Trade Names: 1,1a,2,2,3,3a,4,5,5,5a,5b,6-dodecachlorooctahydro-1,3,4-metheno-1H-cyclobta[cd]pentalene; hexachloropentadiene dimer; dodecachloropentacyclodecane; perchloropentacyclodecane; hexachlorocyclopentadiene dimer; Dechloranereg.; Ferriamicidereg.

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