Children's Hospital of Pittsburgh

These pediatric hypertension guidelines are an update to the 2004 "Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents." Significant changes in these guidelines include (1) the replacement of the term "prehypertension" with the term "elevated blood pressure," (2) new normative pediatric blood pressure (BP) tables based on normal-weight children, (3) a simplified screening table for identifying BPs needing further evaluation, (4) a simplified BP classification in adolescents ≥13 years of age that aligns with the forthcoming American Heart Association and American College of Cardiology adult BP guidelines, (5) a more limited recommendation to perform screening BP measurements only at preventive care visits, (6) streamlined recommendations on the initial evaluation and management of abnormal BPs, (7) an expanded role for ambulatory BP monitoring in the diagnosis and management of pediatric hypertension, and (8) revised recommendations on when to perform echocardiography in the evaluation of newly diagnosed hypertensive pediatric patients (generally only before medication initiation), along with a revised definition of left ventricular hypertrophy. These guidelines include 30 Key Action Statements and 27 additional recommendations derived from a comprehensive review of almost 15 000 published articles between January 2004 and July 2016. Each Key Action Statement includes level of evidence, benefit-harm relationship, and strength of recommendation. This clinical practice guideline, endorsed by the American Heart Association, is intended to foster a patient- and family-centered approach to care, reduce unnecessary and costly medical interventions, improve patient diagnoses and outcomes, support implementation, and provide direction for future research.

BACKGROUND/AIMS: The diagnostic criteria for polycystic ovary syndrome (PCOS) in adolescence are controversial, primarily because the diagnostic pathological features used in adult women may be normal pubertal physiological events. Hence, international pediatric and adolescent specialty societies have defined criteria that have sufficient evidence to be used for the diagnosis of PCOS in adolescents. METHODS: The literature has been reviewed and evidence graded to address a series of questions regarding the diagnosis of PCOS during adolescence including the following: clinical and biochemical evidence of hyperandrogenism, criteria for oligo-anovulation and polycystic ovary morphology, diagnostic criteria to exclude other causes of hyperandrogenism and amenorrhea, role of insulin resistance, and intervention. RESULTS AND CONCLUSION: Features of PCOS overlap normal pubertal development. Hence, caution should be taken before diagnosing PCOS without longitudinal evaluation. However, treatment may be indicated even in the absence of a definitive diagnosis. While obesity, insulin resistance, and hyperinsulinemia are common findings in adolescents with hyperandrogenism, these features should not be used to diagnose PCOS among adolescent girls. © 2015 S. Karger AG, Basel.

autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

There is pressing urgency to understand the pathogenesis of the severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2), which causes the disease COVID-19. SARS-CoV-2 spike (S) protein binds angiotensin-converting enzyme 2 (ACE2), and in concert with host proteases, principally transmembrane serine protease 2 (TMPRSS2), promotes cellular entry. The cell subsets targeted by SARS-CoV-2 in host tissues and the factors that regulate ACE2 expression remain unknown. Here, we leverage human, non-human primate, and mouse single-cell RNA-sequencing (scRNA-seq) datasets across health and disease to uncover putative targets of SARS-CoV-2 among tissue-resident cell subsets. We identify ACE2 and TMPRSS2 co-expressing cells within lung type II pneumocytes, ileal absorptive enterocytes, and nasal goblet secretory cells. Strikingly, we discovered that ACE2 is a human interferon-stimulated gene (ISG) in vitro using airway epithelial cells and extend our findings to in vivo viral infections. Our data suggest that SARS-CoV-2 could exploit species-specific interferon-driven upregulation of ACE2, a tissue-protective mediator during lung injury, to enhance infection.

OBJECTIVE: To report the autoantigens of a new category of treatment-responsive paraneoplastic encephalitis. METHODS: Analysis of clinical features, neuropathological findings, tumors, and serum/cerebrospinal fluid antibodies using rat tissue, neuronal cultures, and HEK293 cells expressing subunits of the N-methyl-D-aspartate receptor (NMDAR). RESULTS: Twelve women (14-44 years) developed prominent psychiatric symptoms, amnesia, seizures, frequent dyskinesias, autonomic dysfunction, and decreased level of consciousness often requiring ventilatory support. All had serum/cerebrospinal fluid antibodies that predominantly immunolabeled the neuropil of hippocampus/forebrain, in particular the cell surface of hippocampal neurons, and reacted with NR2B (and to a lesser extent NR2A) subunits of the NMDAR. NR2B binds glutamate and forms heteromers (NR1/NR2B or NR1/NR2A/NR2B) that are preferentially expressed in the adult hippocampus/forebrain. Expression of functional heteromers (not single subunits) was required for antibody binding. Eleven patients had teratoma of the ovary (six mature) and one a mature teratoma in the mediastinum; five of five tumors examined contained nervous tissue that strongly expressed NR2 subunits and reacted with patients' antibodies. Tumor resection and immunotherapy resulted in improvement or full recovery of eight of nine patients (paralleled by decreased antibody titers); two of three patients without tumor resection died of neurological deterioration. Autopsies showed extensive microgliosis, rare T-cell infiltrates, and neuronal degeneration predominantly involving, but not restricted to, the hippocampus. INTERPRETATION: Antibodies to NR2B- and NR2A-containing heteromers of the NMDAR associate with a severe but treatment-responsive encephalitis. Our findings provide a diagnostic test and suggest a model of autoimmune NMDAR-related encephalitis with broad implications for other immune-mediated disorders of memory, behavior, and cognition.

OBJECTIVE: The Androgen Excess Society (AES) charged a task force to review all available data and recommend an evidence-based definition for polycystic ovary syndrome (PCOS), whether already in use or not, to guide clinical diagnosis and future research. PARTICIPANTS: Participants included expert investigators in the field. EVIDENCE: Based on a systematic review of the published peer-reviewed medical literature, by querying MEDLINE databases, we tried to identify studies evaluating the epidemiology or phenotypic aspects of PCOS. CONSENSUS PROCESS: The task force drafted the initial report, following a consensus process via electronic communication, which was then reviewed and critiqued by the AES Board of Directors. No section was finalized until all members were satisfied with the contents and minority opinions noted. Statements that were not supported by peer-reviewed evidence were not included. CONCLUSIONS: Based on the available data, it is the view of the AES Task Force on the Phenotype of PCOS that there should be acceptance of the original 1990 National Institutes of Health criteria with some modifications, taking into consideration the concerns expressed in the proceedings of the 2003 Rotterdam conference. A principal conclusion was that PCOS should be first considered a disorder of androgen excess or hyperandrogenism, although a minority considered the possibility that there may be forms of PCOS without overt evidence of hyperandrogenism but recognized that more data are required before validating this supposition. Finally, the task force recognized, and fully expects, that the definition of this syndrome will evolve over time to incorporate new research findings.

Leber's congenital amaurosis (LCA) is a group of inherited blinding diseases with onset during childhood. One form of the disease, LCA2, is caused by mutations in the retinal pigment epithelium-specific 65-kDa protein gene (RPE65). We investigated the safety of subretinal delivery of a recombinant adeno-associated virus (AAV) carrying RPE65 complementary DNA (cDNA) (ClinicalTrials.gov number, NCT00516477 [ClinicalTrials.gov]). Three patients with LCA2 had an acceptable local and systemic adverse-event profile after delivery of AAV2.hRPE65v2. Each patient had a modest improvement in measures of retinal function on subjective tests of visual acuity. In one patient, an asymptomatic macular hole developed, and although the occurrence was considered to be an adverse event, the patient had some return of retinal function. Although the follow-up was very short and normal vision was not achieved, this study provides the basis for further gene therapy studies in patients with LCA.

The growing worldwide prevalence of type 2 diabetes mellitus in the young, as underlined by an earlier International Diabetes Federation (IDF) Consensus Statement 1, has highlighted a significant shortfall of data on the epidemiology of the disorder and the identification and treatment of children and adolescents at risk of progression to this disease. Urbanization, unhealthy diets, and increasingly sedentary lifestyles have contributed to increase the prevalence of childhood obesity, particularly in developing countries 2. Current treatment initiatives include school-based programs addressing physical activity and diet, which have been conducted with mixed success in reducing adiposity. There are limited safety data supporting the use of drugs for the treatment of obesity and related conditions such as type 2 diabetes in children and adolescents, and non-compliance in this population suggests that pharmacotherapy is unlikely to be effective long term 1. Although criteria have now been developed for bariatric surgery in teenagers 3, there are few evidence-based data available to support the increasing use of this modality in adolescents. Governments and society in general must be made more aware of the problems associated with obesity and the likelihood of progression to the metabolic syndrome in children and adolescents. Obesity, particularly in the central (abdominal) region, has been determined as a key factor in the etiology of type 2 diabetes 2. The prediction of health risks associated with obesity in youth is improved by the additional inclusion of waist circumference (WC) measure to the body mass index (BMI) percentile 4, 5. Such observations reinforce the importance of including WC in the assessment of childhood obesity to identify those at increased metabolic risk as a result of excess abdominal fat 5. The role of obesity can clearly be demonstrated in Japan, where a parallel increase in type 2 diabetes and obesity in children has occurred over the past few decades 6. Central (abdominal) obesity is also a key component in the IDF definition of metabolic syndrome in adults 2. The link between obesity, metabolic syndrome, and type 2 diabetes has already been characterized in adult populations 2. At present, 50–80% of almost 250 million adults worldwide with diabetes 7 are at risk of death from cardiovascular disease. Those with the metabolic syndrome are also at increased risk being twice as likely to die from, and three times as likely to have, cardiovascular complications as compared with those without the syndrome 8, 9. In addition, adults with the metabolic syndrome have a fivefold greater risk of developing type 2 diabetes 10. Already, one-quarter of the world’s adult population have metabolic syndrome 11, 12, and this condition is appearing with increasing frequency in children and adolescents, driven by the growing obesity epidemic in this young population 13-15. In 2004, the World Health Organization (WHO) reported that an estimated 22 million children younger than 5 yr of age and 10% of school-aged children, between 5 and 17 yr, were overweight or obese 16. WHO predicts that the prevalence of childhood obesity in developed and developing countries will continue to increase as has been seen in recent years. For example, from 1985 to 1997, in young Australians, the prevalence of overweight and obesity combined doubled and that of obesity trebled 17. In Thailand, the prevalence of obesity in those aged 5–12 yr increased from 12.2 to 15.6% in just 2 yr 18. In 2003–2004, 17.1% of children aged 2–19 yr in the USA were obese 19. Obesity is associated with an increase in cardiovascular risk factors (also indicators of metabolic syndrome) 20, and the persistence of these indicators from childhood and adolescence to young adulthood has been shown in several studies, including the Quebec Family Study 21, 22. Recently, the IDF released its guidelines for defining and diagnosing the metabolic syndrome in adults 2. The intention was to rationalize the existing multiple definitions of the syndrome and to avoid the confusion that arose as a result of conflicting opinions on the value of each set of criteria. The use of a single unified definition makes it possible to estimate the global prevalence of metabolic syndrome and make valid comparisons between nations. However, to date, there has not been a unified definition that can be used to assess risk in children and adolescents, and existing adult-based definitions of the metabolic syndrome may not be appropriate to address the problem in this age group. A study of adolescents using modified National Cholesterol Education Program (NCEP) [Adult Treatment Panel III (ATP III)] criteria 23 identified that 12% of the study group had the metabolic syndrome 24. When the ≥95th percentile of BMI was used as a cutoff point in the same study group, 31.3% were identified as having the syndrome, more than double of those previously found to be at risk. Duncan et al. 25 studied 991 adolescents (aged 12–19 yr) from National Health and Nutrition Examination Study (NHANES) 1999–2000 and used the ATP III definition modified for age. The overall prevalence of a metabolic syndrome phenotype among US adolescents increased from 4.2% in NHANES III (1988–1992) to 6.4% in NHANES 1999–2000. Based on population-weighted estimates, they estimated that more than 2 million US adolescents currently have a metabolic syndrome phenotype. In a population-based study of a Canadian Qji-Cree community involving 236 children aged 10–19 yr, Retnakaran et al. reported that 18.6% of the children met the criteria for the metabolic syndrome based on a pediatric metabolic syndrome definition based on the ATP III definition, and they used the ATP III definition modified for age and gender 26. Goodman et al. reported on a school-based, cross-sectional study of 1513 black, white, and Hispanic teenagers 27. Overall, the prevalence of ATP III-defined metabolic syndrome was 4.2% and that of the WHO-defined metabolic syndrome was 8.4%. The metabolic syndrome was found almost exclusively among obese teenagers in whom prevalence of the ATP III-defined metabolic syndrome was 19.5% and prevalence of WHO-defined metabolic syndrome 28 was 38.9%. No race or sex differences were present for ATP III definition. However, non-white teenagers were more likely to have metabolic syndrome by WHO criteria, and it was more common among girls if the WHO definition was used. Chi et al. have recently undertaken a literature review on definitions of the metabolic syndrome in children and adolescents published in the past decade 29. They noted that the prevalence of metabolic syndrome in pre-adolescent girls varies widely because of disagreement among proposed definitions of metabolic syndrome in pediatrics. They called for a consensus definition for the metabolic syndrome in children, which would allow researchers to make better temporal, biological, environmental, and social comparisons between data sets. The American College of Endocrinology definition 30 is not ideal in pediatric subjects as WC is rarely measured in children, and nomograms have only recently become available 31 for some ethnic groups but are not available for all. A recent paper has suggested yet another set of criteria with age- and gender-specific cutoff points 32. The variety of cutoff points used for the different components in this paper underlines the need for a single consistent definition with easily measurable components. Therefore, to date, no formal definition for the diagnosis of the metabolic syndrome in children and adolescents has been developed. The rapid increase in obesity highlights the urgency for a definition that could be used to further understand who is at high risk and to distinguish them from those with ‘simple’ uncomplicated obesity. The metabolic syndrome in adults is defined as a cluster of cardiovascular and diabetes risk factors including abdominal obesity, dyslipidemia, glucose intolerance, and hypertension 2. While the danger associated with clustering of components of the metabolic syndrome has been demonstrated in adults, where the presence of three or more components significantly increases the risk for coronary heart disease death/non-fatal myocardial infarction and the onset of new diabetes 33, few, if any, outcome data in children exist. While one definition, although with gender- and ethnicity-specific cutoff points, is suitable for use in the at-risk adult population 2, transposing a single definition to children and adolescents is problematic. Blood pressure, lipid levels, and anthropometric variables change with age and pubertal development. Puberty impacts on fat distribution and is known to cause a decrease both in insulin sensitivity, of approximately 30% with a complementary increase in insulin secretion 34, and in adiponectin levels 35. Therefore, single cutoff points cannot be used to define abnormalities in children. Instead, values above the 90th, 95th, or 97th percentile for gender and age are used. However, there has not been universal agreement as to which level to use for the criteria for the metabolic syndrome. The importance of the early identification of children at risk of developing the metabolic syndrome and subsequently progressing to type 2 diabetes and cardiovascular disease in later life must not be underestimated. From birth and before, circumstances can predispose a child to conditions such as obesity or dysglycemia. The presence of maternal gestational diabetes 36, low birth weight 37, infant feeding practices 38, early adiposity rebound 39, and genetic factors may all contribute to a child’s future level of risk. Being raised in an ‘obesogenic’ environment can also have a strong impact, as can the influence of socioeconomic factors 40, with weight gain often being observed as a positive correlate to affluence in developing countries. Longitudinal outcome studies and further research on the progression and etiology of the metabolic syndrome are urgently required to ascertain the long-term outcomes of abdominal obesity and clustering of the components of metabolic syndrome in at-risk children and to help improve future definitions of the syndrome. This new IDF definition of metabolic syndrome in children and adolescents was developed during a consensus workshop that brought together experts in the field of the metabolic syndrome and pediatrics. The purpose of the new definition of metabolic syndrome in children and adolescents is to expand on the IDF recommendations for managing type 2 diabetes in the young 1 and to provide a useful and unified tool for identifying those at risk. A clinically accessible diagnostic tool, avoiding measurements that may only be available in research settings, is needed to identify the metabolic syndrome in children and adolescents globally. This need has prompted the IDF to develop a definition that has used the limited data available from existing studies in youth. As with the adult criteria, we look on these new criteria as a starting point. As new information emerges, they can be modified. Inspired, in part, by the IDF worldwide definition of metabolic syndrome in adults 2, this new definition builds on previous studies investigating the prevalence of metabolic syndrome in children and adolescents, which have used modified adult criteria with varying cutoff points 12-14, 41, 42 (Table 1). The wide variety of cutoff points used has emphasized the need for a single consistent set of criteria, which is easily measurable and can be used as the basis for future work 29. Because of the developmental challenges presented by the age-related differences in children and adolescents, the new IDF definition of metabolic syndrome has been divided according to the following age groups: 6 to <10, 10 to <16, and ≥16 yr (Table 2). In all the three age groups, abdominal obesity is the ‘sine qua non’. We suggest that below the age of 10 yr, the metabolic syndrome as an entity is not diagnosed, although a strong message for weight reduction will be made for these children. At the age of 10 yr and more, a diagnosis of metabolic syndrome can be made. It requires the presence of abdominal obesity plus the presence of two or more of the other components (elevated triglycerides, low high-density lipoprotein (HDL)-cholesterol, high blood pressure, and elevated plasma glucose). The IDF adult criteria 2 can be used for adolescents aged ≥16 yr, while a modified version of these criteria will be applied to those aged 10 to <16 yr (use 90th percentile cutoff point for waist and <40 mg/dL of HDL for both sexes). On the basis of emerging new data, these criteria may change in the future. In adults, insulin resistance and abdominal obesity are considered to be significant causative factors in the development of the metabolic syndrome 9, 43, 44. The link between obesity, insulin resistance, and the risk of developing the metabolic syndrome has also been described in children 22, 27. With measurement of insulin resistance considered to be impractical for clinical use, abdominal adiposity was positioned as the ‘sine qua non’ in the IDF definition of metabolic syndrome in adults 2 and is recognized to be an independent risk factor for the development of cardiovascular disease in adults 45. Abdominal obesity can be easily assessed using the simple measure of WC, which is known to correlate more strongly with visceral adipose tissue (VAT) than BMI in adults 46 and is a strong predictor of cardiovascular disease risk factors in children 47. The correlation between WC and VAT has also been more recently demonstrated in children 48, further strengthening the existing evidence that WC is an effective measure of abdominal obesity 49 in the youth population. In children and adolescents, a number of studies have demonstrated a similar link between childhood obesity and elevated cardiovascular risk in later life. The Bogalusa Heart study showed that childhood overweight is related to the development of adverse risk factors (BMI, lipids, insulin, diabetes mellitus, and blood pressure) in adulthood and is attributable to the strong persistence of weight status from childhood to adulthood 50. Of the overweight children in the Bogalusa Heart study (BMI ≥95th percentile), 77% remained obese in adulthood. Furthermore, the Muscatine study demonstrated that in young adults, excess weight was the earliest predictor of coronary artery calcification 51. The ATP III definition, applied to a cohort of individuals aged 12–19 yr (NHANES III), identified that 4% of those studied were found to have the metabolic syndrome, with 80% of those meeting the criteria of being overweight 13. Using a modified version of the ATP III definition, metabolic syndrome in adolescents has also been linked to high levels of C-reactive protein, a pro-inflammatory marker. Of the five components of metabolic syndrome, C-reactive protein was higher only among those with abdominal obesity 41. Waist circumference in children is an independent predictor of insulin resistance, lipid levels, and blood pressure 4, 52-54– all components of metabolic syndrome. Moreover, in obese youth with similar BMI, insulin sensitivity is lower in those with high VAT and high waist/hip ratio 53, 54. Furthermore, insulin sensitivity decreases and insulin levels increase with increasing WC percentiles 3. These data, combined with the unequivocal evidence of the dangers of abdominal obesity in adulthood, support the use of abdominal obesity as the ‘sine qua non’ for the diagnosis of metabolic syndrome in children and adolescents. Percentiles rather than absolute values of WC have been used in the new criteria to compensate for varying degrees of development and ethnicity in the youth population. WC percentile data are becoming increasingly available worldwide 31, 55-58. Children with a WC >90th percentile are more likely to have multiple risk factors than those with a WC below this level 59. Several studies attempting to estimate the prevalence of metabolic syndrome in children and adolescents have already used the 90th percentile as a cutoff point for WC 13, 14, 41. We have also chosen to use the 90th percentile as a cutoff point for WC based on this existing evidence and aim to reassess criteria and cutoff points in 5 yr and modify the guidelines, if necessary, based on the new outcome data. Previous studies investigating the metabolic syndrome in children and adolescents have used a range of cutoff points primarily based on ATP III criteria for categorizing additional components of the syndrome, i.e., triglycerides, HDL-cholesterol, blood pressure, and fasting glucose (Table 1) 12-14, 41, 42. Other definitive sources include the National High Blood Pressure Education Program, which recommends blood pressure cutoff points of >90th or >95th percentile adjusted for height, age, and gender to identify ‘high normal’ blood pressure or prehypertension and high blood pressure or hypertension in children and adolescents 60. Cutoff points for impaired fasting glucose have previously followed recommendations by the American Diabetes Association (ADA) [100–125 mg/dL (≥5.6–6.9 mmol/L)] 61 and the NCEP/ATP III in adults [≥110 mg/dL (6.1 mmol/L)] 23, although the latter has recently changed to the lower ADA recommended levels 62. Criteria for defining lipid (triglyceride and HDL-cholesterol) imbalances are even less consistent in the youth population, with recommendations by the NCEP/ATP III (age specific), NHANES III (age and gender specific), and the National Growth and Health Study (age, gender, and ethnic specific), employing either absolute value or percentile cutoff points. In view of this lack of consistency, we believe that use of the adult levels for the present is wise until further information is available. We recommend the following topics as priorities for future research: Develop a better understanding of the relationship between body fat and its distribution in children and adolescents, e.g., dual energy X-ray absorptiometry (DEXA), WC, BMI, and height and weight percentiles; a) Explore whether early growth patterns predict future adiposity and features of the metabolic syndrome, diabetes, and cardiovascular disease and b) explore whether low birth weight predicts future metabolic syndrome, diabetes, and cardiovascular disease; Perform factor analysis in children and adolescents to establish grouping of metabolic characteristics – adiposity, dyslipidemia, hyperinsulinemia, hypoadiponectinemia, and insulin resistance; Investigate how should obesity in children could be better defined, e.g., weight/height, WC etc.; Develop ethnic-specific normal ranges for WC, ideally based on healthy values; Perform ethnic-specific studies of WC etc. vs. abdominal (truncal) fat based on magnetic resonance imaging and DEXA; Support studies of adiponectin, leptin, etc. in children and adolescents to determine if they may be predictors of metabolic syndrome in adulthood; Initiate long-term studies of multi-ethnic cohorts followed into adulthood to determine the natural history and effectiveness of intervention strategies, particularly lifestyle. In conclusion, to combat any conflict that could arise from these multiple interpretations of the metabolic syndrome in children and adolescents, the IDF consensus group has aimed primarily at developing a simple, easy-to-apply definition to begin using in the clinical setting. In the absence of definitive research findings at this time, the proposed IDF definition of the metabolic syndrome in children and adolescents (Table 2) adheres to the absolute values presented in the adult definition 2, with the exception of WC. As described previously, until such time that outcome data from studies in children and adolescents indicate otherwise, WC percentiles are recommended for use. Early detection, followed by treatment in the form of lifestyle intervention and possibly pharmacotherapy, if its safety has been clearly demonstrated, is vital in halting the progression of this syndrome pathway in the adolescent population. It is likely that this will reduce morbidity and mortality in adulthood, as well as minimize the global socioeconomic burden of cardiovascular disease and type 2 diabetes. The workshop was sponsored by an unrestricted educational grant to the IDF Task Force on Epidemiology and Prevention from sanofi-aventis.

The histiocytoses are rare disorders characterized by the accumulation of macrophage, dendritic cell, or monocyte-derived cells in various tissues and organs of children and adults. More than 100 different subtypes have been described, with a wide range of clinical manifestations, presentations, and histologies. Since the first classification in 1987, a number of new findings regarding the cellular origins, molecular pathology, and clinical features of histiocytic disorders have been identified. We propose herein a revision of the classification of histiocytoses based on histology, phenotype, molecular alterations, and clinical and imaging characteristics. This revised classification system consists of 5 groups of diseases: (1) Langerhans-related, (2) cutaneous and mucocutaneous, and (3) malignant histiocytoses as well as (4) Rosai-Dorfman disease and (5) hemophagocytic lymphohistiocytosis and macrophage activation syndrome. Herein, we provide guidelines and recommendations for diagnoses of these disorders.

STUDY QUESTION: What is the recommended assessment and management of women with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertise and consumer preference? SUMMARY ANSWER: International evidence-based guidelines, including 166 recommendations and practice points, addressed prioritized questions to promote consistent, evidence-based care and improve the experience and health outcomes of women with PCOS. WHAT IS KNOWN ALREADY: Previous guidelines either lacked rigorous evidence-based processes, did not engage consumer and international multidisciplinary perspectives, or were outdated. Diagnosis of PCOS remains controversial, and assessment and management are inconsistent. The needs of women with PCOS are not being adequately met and evidence practice gaps persist. STUDY DESIGN, SIZE, DURATION: International evidence-based guideline development engaged professional societies and consumer organizations with multidisciplinary experts and women with PCOS directly involved at all stages. Appraisal of Guidelines for Research and Evaluation (AGREE) II-compliant processes were followed, with extensive evidence synthesis. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework was applied across evidence quality, feasibility, acceptability, cost, implementation and ultimately recommendation strength. PARTICIPANTS/MATERIALS, SETTING, METHODS: Governance included a six continent international advisory and a project board, five guideline development groups, and consumer and translation committees. Extensive health professional and consumer engagement informed guideline scope and priorities. Engaged international society-nominated panels included pediatrics, endocrinology, gynecology, primary care, reproductive endocrinology, obstetrics, psychiatry, psychology, dietetics, exercise physiology, public health and other experts, alongside consumers, project management, evidence synthesis and translation experts. In total, 37 societies and organizations covering 71 countries engaged in the process. Twenty face-to-face meetings over 15 months addressed 60 prioritized clinical questions involving 40 systematic and 20 narrative reviews. Evidence-based recommendations were developed and approved via consensus voting within the five guideline panels, modified based on international feedback and peer review, with final recommendations approved across all panels. MAIN RESULTS AND THE ROLE OF CHANCE: The evidence in the assessment and management of PCOS is generally of low to moderate quality. The guideline provides 31 evidence based recommendations, 59 clinical consensus recommendations and 76 clinical practice points all related to assessment and management of PCOS. Key changes in this guideline include: (i) considerable refinement of individual diagnostic criteria with a focus on improving accuracy of diagnosis; (ii) reducing unnecessary testing; (iii) increasing focus on education, lifestyle modification, emotional wellbeing and quality of life; and (iv) emphasizing evidence based medical therapy and cheaper and safer fertility management. LIMITATIONS, REASONS FOR CAUTION: Overall evidence is generally low to moderate quality, requiring significantly greater research in this neglected, yet common condition, especially around refining specific diagnostic features in PCOS. Regional health system variation is acknowledged and a process for guideline and translation resource adaptation is provided. WIDER IMPLICATIONS OF THE FINDINGS: The international guideline for the assessment and management of PCOS provides clinicians with clear advice on best practice based on the best available evidence, expert multidisciplinary input and consumer preferences. Research recommendations have been generated and a comprehensive multifaceted dissemination and translation program supports the guideline with an integrated evaluation program. STUDY FUNDING/COMPETING INTEREST(S): The guideline was primarily funded by the Australian National Health and Medical Research Council of Australia (NHMRC) supported by a partnership with ESHRE and the American Society for Reproductive Medicine. Guideline development group members did not receive payment. Travel expenses were covered by the sponsoring organizations. Disclosures of conflicts of interest were declared at the outset and updated throughout the guideline process, aligned with NHMRC guideline processes. Full details of conflicts declared across the guideline development groups are available at https://www.monash.edu/medicine/sphpm/mchri/pcos/guideline in the Register of disclosures of interest. Of named authors, Dr Costello has declared shares in Virtus Health and past sponsorship from Merck Serono for conference presentations. Prof. Laven declared grants from Ferring, Euroscreen and personal fees from Ferring, Euroscreen, Danone and Titus Healthcare. Prof. Norman has declared a minor shareholder interest in an IVF unit. The remaining authors have no conflicts of interest to declare. The guideline was peer reviewed by special interest groups across our partner and collaborating societies and consumer organizations, was independently assessed against AGREE-II criteria, and underwent methodological review. This guideline was approved by all members of the guideline development groups and was submitted for final approval by the NHMRC.

The present guidelines are the most recent data on postoperative nausea and vomiting (PONV) and an update on the 2 previous sets of guidelines published in 2003 and 2007. These guidelines were compiled by a multidisciplinary international panel of individuals with interest and expertise in PONV under the auspices of the Society for Ambulatory Anesthesia. The panel members critically and systematically evaluated the current medical literature on PONV to provide an evidence-based reference tool for the management of adults and children who are undergoing surgery and are at increased risk for PONV. These guidelines identify patients at risk for PONV in adults and children; recommend approaches for reducing baseline risks for PONV; identify the most effective antiemetic single therapy and combination therapy regimens for PONV prophylaxis, including nonpharmacologic approaches; recommend strategies for treatment of PONV when it occurs; provide an algorithm for the management of individuals at increased risk for PONV as well as steps to ensure PONV prevention and treatment are implemented in the clinical setting.

The mitochondrial electron transport chain utilizes a series of electron transfer reactions to generate cellular ATP through oxidative phosphorylation. A consequence of electron transfer is the generation of reactive oxygen species (ROS), which contributes to both homeostatic signaling as well as oxidative stress during pathology. In this graphical review we provide an overview of oxidative phosphorylation and its inter-relationship with ROS production by the electron transport chain. We also outline traditional and novel translational methodology for assessing mitochondrial energetics in health and disease.

We propose a model wherein chronic stress results in glucocorticoid receptor resistance (GCR) that, in turn, results in failure to down-regulate inflammatory response. Here we test the model in two viral-challenge studies. In study 1, we assessed stressful life events, GCR, and control variables including baseline antibody to the challenge virus, age, body mass index (BMI), season, race, sex, education, and virus type in 276 healthy adult volunteers. The volunteers were subsequently quarantined, exposed to one of two rhinoviruses, and followed for 5 d with nasal washes for viral isolation and assessment of signs/symptoms of a common cold. In study 2, we assessed the same control variables and GCR in 79 subjects who were subsequently exposed to a rhinovirus and monitored at baseline and for 5 d after viral challenge for the production of local (in nasal secretions) proinflammatory cytokines (IL-1β, TNF-α, and IL-6). Study 1: After covarying the control variables, those with recent exposure to a long-term threatening stressful experience demonstrated GCR; and those with GCR were at higher risk of subsequently developing a cold. Study 2: With the same controls used in study 1, greater GCR predicted the production of more local proinflammatory cytokines among infected subjects. These data provide support for a model suggesting that prolonged stressors result in GCR, which, in turn, interferes with appropriate regulation of inflammation. Because inflammation plays an important role in the onset and progression of a wide range of diseases, this model may have broad implications for understanding the role of stress in health.

BACKGROUND: Ewing's sarcoma and primitive neuroectodermal tumor of bone are closely related, highly malignant tumors of children, adolescents, and young adults. A new drug combination, ifosfamide and etoposide, was highly effective in patients with Ewing's sarcoma or primitive neuroectodermal tumor of bone who had a relapse after standard therapy. We designed a study to test whether the addition of these drugs to a standard regimen would improve the survival of patients with newly diagnosed disease. METHODS: Patients 30 years old or younger with Ewing's sarcoma, primitive neuroectodermal tumor of bone, or primitive sarcoma of bone were eligible. The patients were randomly assigned to receive 49 weeks of standard chemotherapy with doxorubicin, vincristine, cyclophosphamide, and dactinomycin or experimental therapy with these four drugs alternating with courses of ifosfamide and etoposide. RESULTS: A total of 518 patients met the eligibility requirements. Of 120 patients with metastatic disease, 62 were randomly assigned to the standard-therapy group and 58 to the experimental-therapy group. There was no significant difference in five-year event-free survival between the treatment groups (P=0.81). Among the 398 patients with nonmetastatic disease, the mean (+/-SE) five-year event-free survival among the 198 patients in the experimental-therapy group was 69+/-3 percent, as compared with 54+/-4 percent among the 200 patients in the standard-therapy group (P=0.005). Overall survival was also significantly better among patients in the experimental-therapy group (72+/-3.4 percent vs. 61+/-3.6 percent in the standard-therapy group, P=0.01). CONCLUSIONS: The addition of ifosfamide and etoposide to a standard regimen does not affect the outcome for patients with metastatic disease, but it significantly improves the outcome for patients with nonmetastatic Ewing's sarcoma, primitive neuroectodermal tumor of bone, or primitive sarcoma of bone.

The goal of this update regarding the diagnosis and care of persons with disorders of sex development (DSDs) is to address changes in the clinical approach since the 2005 Consensus Conference, since knowledge and viewpoints change. An effort was made to include representatives from a broad perspective including support and advocacy groups. The goal of patient care is focused upon the best possible quality of life (QoL). The field of DSD is continuously developing. An update on the clinical evaluation of infants and older individuals with ambiguous genitalia including perceptions regarding male or female assignment is discussed. Topics include biochemical and genetic assessment, the risk of germ cell tumor development, approaches to psychosocial and psychosexual well-being and an update on support groups. Open and on-going communication with patients and parents must involve full disclosure, with the recognition that, while DSD conditions are life-long, enhancement of the best possible outcome improves QoL. The evolution of diagnosis and care continues, while it is still impossible to predict gender development in an individual case with certainty. Such decisions and decisions regarding surgery during infancy that alters external genital anatomy or removes germ cells continue to carry risk.

<h3>Objective.</h3> —To examine the hypothesis that diverse ties to friends, family, work, and community are associated with increased host resistance to infection. <h3>Design.</h3> —After reporting the extent of participation in 12 types of social ties (eg, spouse, parent, friend, workmate, member of social group), subjects were given nasal drops containing 1 of 2 rhinoviruses and monitored for the development of a common cold. <h3>Setting.</h3> —Quarantine. <h3>Participants.</h3> —A total of 276 healthy volunteers, aged 18 to 55 years, neither seropositive for human immunodeficiency virus nor pregnant. <h3>Outcome Measures.</h3> —Colds (illness in the presence of a verified infection), mucus production, mucociliary clearance function, and amount of viral replication. <h3>Results.</h3> —In response to both viruses, those with more types of social ties were less susceptible to common colds, produced less mucus, were more effective in ciliary clearance of their nasal passages, and shed less virus. These relationships were unaltered by statistical controls for prechallenge virus-specific antibody, virus type, age, sex, season, body mass index, education, and race. Susceptibility to colds decreased in a dose-response manner with increased diversity of the social network. There was an adjusted relative risk of 4.2 comparing persons with fewest (1 to 3) to those with most (6 or more) types of social ties. Although smoking, poor sleep quality, alcohol abstinence, low dietary intake of vitamin C, elevated catecholamine levels, and being introverted were all associated with greater susceptibility to colds, they could only partially account for the relation between social network diversity and incidence of colds. <h3>Conclusions.</h3> —More diverse social networks were associated with greater resistance to upper respiratory illness.

This guideline has been approved by the American Association for the Study of Liver Diseases and represents the position of the Association. These recommendations provide a data-supported approach. They are based on the following: (1) formal review and analysis of the recently-published world literature on the topic (Medline search); (2) American College of Physicians Manual for Assessing Health Practices and Designing Practice Guidelines1; (3) guideline policies, including the AASLD Policy on the Development and Use of Practice Guidelines and the American Gastroenterological Association Policy Statement on Guidelines2; and (4) the experience of the authors in the specified topic. Intended for use by physicians, these recommendations suggest preferred approaches to the diagnostic, therapeutic and preventative aspects of care. They are intended to be flexible, in contrast to standards of care, which are inflexible policies to be followed in every case. Specific recommendations are based on relevant published information. To more fully characterize the available evidence supporting the recommendations, the AASLD Practice Guidelines Committee has adopted the classification used by the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) workgroup with minor modifications (Table 1).3 The strength of recommendations in the GRADE system are classified as strong (class 1) or weak (class 2). The quality of evidence supporting strong or weak recommendations is designated by one of three levels: high (level A), moderate (level B), or low-quality (level C). AASLD, American Association for the Study of Liver Diseases; AIH, autoimmune hepatitis; CCA, cholangiocarcinoma; ERC, endoscopic retrograde cholangiography; FISH, fluorescent in situ hybridization; IBD, inflammatory bowel disease; IgG, immunoglobulin G; MRC, magnetic resonance cholangiography; OLT, orthotopic liver transplantation; OR, odds ratio; PET, positron emission tomography; PSC, primary sclerosing cholangitis; SSC, secondary sclerosing cholangitis; UC, ulcerative colitis; UDCA, ursodeoxycholic acid. Primary sclerosing cholangitis (PSC) is a chronic, cholestatic liver disease characterized by inflammation and fibrosis of both intrahepatic and extrahepatic bile ducts,4 leading to the formation of multifocal bile duct strictures. PSC is likely an immune mediated, progressive disorder that eventually develops into cirrhosis, portal hypertension and hepatic decompensation, in the majority of patients.5 Small duct PSC is a disease variant which is characterized by typical cholestatic and histological features of PSC but normal bile ducts on cholangiography.6 PSC overlap syndromes are conditions with diagnostic features of both PSC and other immune mediated liver diseases including autoimmune hepatitis and autoimmune pancreatitis.7 Secondary sclerosing cholangitis (SSC) is characterized by a similar multifocal biliary stricturing process due to identifiable causes such as long-term biliary obstruction, infection, and inflammation which in turn leads to destruction of bile ducts and secondary biliary cirrhosis.8 Immunoglobulin G4 (IgG4)-positive sclerosing cholangitis might represent a separate entity.9 A diagnosis of PSC is made in patients with a cholestatic biochemical profile, when cholangiography (e.g., magnetic resonance cholangiography [MRC], endoscopic retrograde cholangiography [ERC], percutaneous transhepatic cholangiography) shows characteristic bile duct changes with multifocal strictures and segmental dilatations, and secondary causes of sclerosing cholangitis have been excluded.8 Patients who present with clinical, biochemical and histological features compatible with PSC, but have a normal cholangiogram, are classified as small duct PSC.6 Clinical and cholangiographic findings resembling PSC have been described in patients with choledocholithiasis, surgical trauma of the biliary tree, intra-arterial chemotherapy, and recurrent pancreatitis.8 Other conditions reported to mimic PSC are listed in Table 2. Distinguishing primary from SSC may be challenging because PSC patients may have undergone bile duct surgery or have concomitant intraductal stone disease or even cholangiocarcinoma (CCA). The clinical history, distribution of cholangiographic findings, and the presence or absence of inflammatory bowel disease (IBD), have to be taken into consideration when determining if an abnormal cholangiogram is due to PSC or secondary processes.8 The clinical presentation is variable; typical symptoms include right upper quadrant abdominal discomfort, fatigue, pruritus, and weight loss.10 Episodes of cholangitis (i.e., fever and chills) are very uncommon features at presentation, in the absence of prior biliary surgery or instrumentation such as ERC.11 Physical examination is abnormal in approximately half of symptomatic patients at the time of diagnosis; jaundice, hepatomegaly, and splenomegaly are the most frequent abnormal findings. Many patients with PSC are asymptomatic with no physical abnormalities at presentation. The diagnosis is made incidentally when persistently cholestatic liver function tests are investigated. Approximately 60%–80% of patients with PSC have concomitant IBD, most often ulcerative colitis (UC).12 Serum biochemical tests usually indicate cholestasis; elevation of serum alkaline phosphatase is the most common biochemical abnormality in PSC.5, 10, 13 However, a normal alkaline phosphatase activity does not exclude the diagnosis. Serum aminotransferase levels are elevated in the majority of patients (2–3 times upper limits of normal), but like the alkaline phosphatase can also be in the normal range. Serum bilirubin levels are normal at diagnosis in the majority of patients. IgG serum levels are modestly elevated in approximately 60% of patients (1.5 times the upper limit of normal).14 A wide range of autoantibodies can be detected in the serum of patients with PSC indicating an altered state of immune responsiveness or immune regulation.15 Most are present at low prevalence rates and at relatively low titers (Table 3). They have no role in the routine diagnosis of PSC including the perinuclear antineutrophil cytoplasmic antibody which is nonspecific, although it may draw attention to colon involvement in a cholestatic syndrome. Transabdominal ultrasound (US) is usually nondiagnostic and may even be normal, although bile duct wall thickening and/or focal bile duct dilatations are often identified. However, gallbladder abnormalities, including wall thickening, gallbladder enlargement,16 gallstones, cholecystitis, and mass lesions, are identified in up to 41% of patients with PSC who undergo US examinations.17 The findings on computed tomography (CT) cross-sectional or coronal imaging of the upper abdomen are also nonspecific. CT imaging can detect thickening of the bile ducts with contrast enhancement consistent with inflammation, saccular dilatations of the intrahepatic ducts, heterogenous bile duct dilatation, document the presence of portal hypertension (i.e., varices, splenomegaly, and ascites), and identify mass lesions.18-22 It should be noted that lymphadenopathy in the abdomen is common in PSC and should not be over interpreted as metastases or a lymphoproliferative disorder.22 No information exists on the emerging technology of CT cholangiography for the diagnosis or evaluation of PSC. Traditionally, ERC was regarded as the gold standard in diagnosing PSC.23, 24 However, ERC is an invasive procedure associated with potentially serious complications such as pancreatitis and bacterial cholangitis. Indeed, ERC is associated with hospitalization in up to 10% of PSC patients undergoing the procedure25 MRC, which is non-invasive and avoids radiation exposure, has become the diagnostic imaging modality of choice when PSC is suspected. ERC and MRC have comparable diagnostic accuracy, although the visualization of bile ducts may be less than optimal for certain patients with MRC.26 Sensitivity and specificity of MRC is ≥80% and ≥87%, respectively, for the diagnosis of PSC.26, 27 However, it should be noted that that patients with early changes of PSC may be missed by MRC, and ERC still has a useful role in excluding large duct PSC where MRC views may not be optimal. A cholangiographic assessment of the extrahepatic and intrahepatic biliary tree is required to establish a diagnosis of large duct PSC.24 The characteristic cholangiographic findings include multifocal, short, annular strictures alternating with normal or slightly dilated segments producing a "beaded" pattern.23, 24 Long, confluent strictures may also be observed although these are worrisome for the development of superimposed cholangiocarcinoma.23 Both the intra- and extrahepatic bile ducts are usually involved, although a subset of patients (<25%) may only have intrahepatic disease. Conversely, lesions confined to the extrahepatic ducts are quite unusual (usually <5%) and should only be diagnosed in the presence of adequate filling of the intrahepatic ducts. The gallbladder, cystic duct and pancreatic duct may also be involved in PSC patients.23 Liver histological findings maybe compatible with a diagnosis of PSC, but in general the changes at an early stage are non-specific although usually indicating some form of biliary disease. Periductal concentric ("onion-skin") fibrosis is a classic histopathologic finding of PSC, but this observation is infrequent in PSC liver biopsy specimens and may also be observed in SSC. A retrospective study in 138 patients with cholangiographic features of PSC suggested that liver biopsy rarely adds useful diagnostic information.28 In the presence of an abnormal cholangiogram, a liver biopsy is therefore not required to establish a diagnosis of large duct PSC, although is essential in suspected small duct PSC, and for the assessment of possible overlap syndromes. In PSC patients with disproportionately elevated serum aminotransferase values, especially if the antinuclear antigen and/or smooth muscle antigen is positive and/or serum IgG levels are elevated, a liver biopsy may identify features of a PSC–autoimmune hepatitis (AIH) overlap syndrome. PSC-AIH overlap syndrome is a disorder mainly described in children and young adults.29-37 It is characterized by the clinical, biochemical, and histological features of AIH in the presence of cholangiographic findings identical to PSC.38, 39 Diagnosis of an overlap syndrome by use of the modified AIH score was established in 8% of 113 PSC patients from the Netherlands,40 in 1.4% of 211 PSC patients from the United States,41 in 17% of 41 PSC patients from Italy,42 and in 6.1% of 264 patients with AIH from England.37 Autoimmune pancreatitis (AIP) is a clinical entity characterized by stricturing of the pancreatic duct, focal or generalized pancreatic enlargement, a raised serum immunoglobulin G4 (IgG4) level, a lymphoplasmacytic infiltrate on biopsy, and a response to corticosteroid therapy.43 AIP in association with intrahepatic and extrahepatic bile duct stricturing similar to those present in PSC is termed autoimmune pancreatitis–sclerosing cholangitis (AIP-SC). Pancreatic abnormalities are not universally found, suggesting that IgG4-associated cholangitis (IAC) may be a more appropriate term to describe the condition.44 A recent study found an elevated serum IgG4 level (>140 mg/dL) in 9% of a cohort of 127 patients with PSC.45 In comparison to patients with PSC with normal IgG4 concentrations, the former group had significantly higher levels of alkaline phosphatase and bilirubin, in addition to higher PSC Mayo risk scores. An association with IBD was less likely in those with elevated IgG4 levels, although biliary and pancreatic involvement were similar in both groups.45 Whether PSC and AIP represent different ends of the same disease spectrum or are separate clinical entities is of debate, although current evidence favors the latter. In patients with cholestatic biochemical profile, we recommend indirect (MRC) or direct cholangiography (ERCP) for making the diagnosis of PSC (1A). We recommend against routine liver biopsy for the diagnosis of PSC in patients with typical cholangiographic findings (1B). In patients with a normal ERC or MRC, we recommend a liver biopsy to diagnose small duct PSC (1B). In patients with disproportionately elevated aminotransferases, we recommend performing a liver biopsy to diagnose or exclude overlap syndrome (1B). In all patients with possible PSC, we suggest measuring serum IgG4 levels to exclude IgG4-associated sclerosing cholangitis (2C). Algorithm for the diagnosis of PSC. A "dominant stricture" has been defined as a stenosis with a diameter of ≤1.5 mm in the common bile duct or of ≤1 mm in the hepatic duct.46, 47 It is a frequent finding and occurs in 45% to 58% of patients during follow up.5, 46, 48 It should always raise the suspicion of the presence of a cholangiocarcinoma (CCA), because this malignant complication of PSC occurs frequently as a stenotic ductal lesion in the perihilar region. Although CCA may develop in approximately 10%–15% of PSC patients, stenotic lesions are far more often benign than malignant in nature.49 The distinction between a dominant stricture and CCA is difficult; the diagnosis of CCA is discussed below in this guideline. The goal of an endoscopic or percutaneous therapeutic approach to the management of patients with PSC is to relieve biliary obstruction. The stricturing disease of PSC may cause extrahepatic ductal obstruction and therefore lead to symptoms and decompensation of liver function. Some 15%–20% of patients will experience obstruction from discrete areas of narrowing within the extrahepatic biliary tree.24, 50, 51 It is generally agreed that patients with symptoms from dominant strictures such as cholangitis, jaundice, pruritus, right upper quadrant pain or worsening biochemical indices, are appropriate candidates for therapy. The percutaneous approach is associated with increased morbidity but similar efficacy as the endoscopic approach and is reserved for patients who have proximal dominant strictures with a failed endoscopic approach.52, 53 Before any attempt at endoscopic therapy, brush cytology and/or endoscopic biopsy should be obtained to help exclude a superimposed malignancy. The best therapeutic endoscopic approach is still debated; multiple techniques have been utilized such as sphincterotomy, catheter or balloon dilatation, and stent placement.51-54 Of these, only endoscopic biliary sphincterotomy and balloon dilatation with or without stent placement have been found to be of value.51-59 Because injecting contrast agent into an obstructed duct may precipitate cholangitis, perioperative antibiotics should be administered. Sphincterotomy alone has been performed in small subsets of patients, usually when stent placement was unsuccessful. In these small uncontrolled groups, bilirubin and alkaline phosphatase levels did improve.54 Indeed, the biliary sphincter of Oddi may be involved by the sclerosing process and therefore contribute to biliary obstruction. Nevertheless, sphincterotomy is rarely used alone, but rather to facilitate balloon dilatation, stent placement or stone extraction.55 Stricture dilatation can be accomplished through balloons or coaxial dilators. Balloon dilatation has been shown to be effective alone.52, 56, 57 It may be performed periodically with or without stenting. However, biliary stenting has been shown to be associated with increased complications when compared to endoscopic dilatation only and should be reserved for strictures that are refractory to dilatation.52-57 At this time there has not been a randomized controlled study to evaluate the effectiveness of endoscopic therapy. Still, much indirect evidence by large retrospective studies, suggest that endoscopic therapy results in clinical improvement and prolonged survival. Baluyut et al. evaluated their population of patients with PSC and dominant strictures who underwent endoscopic balloon dilatation and found that the observed 5-year survival rate was significantly better than that predicted by the Mayo Risk Score (83% versus 65%, P = 0.027).58 This is the first study to suggest that therapy may actually impact the natural history of the disease. More recently, Gluck et al. described a 20 year experience with endoscopic therapy for 84 symptomatic patients with PSC.59 Similar to the Baluyut study, observed patient survival was higher than expected by the Mayo Risk Score.59 All therapeutic endoscopy comes with risk. In the two largest reported series of patients with long follow-up, the risk of complications was 7.3%–20%. The complications were mild without need for surgical intervention.58, 59 The most common complications were pancreatitis, cholangitis, biliary tract perforation and hemorrhage. Focal biliary tract obstruction, whether benign or malignant, has been the primary indication for the nontransplant surgical management of PSC. Despite limitations of the accuracy of current diagnostic modalities for malignancy in PSC, diagnostic laparotomy has little clinical value. The rationale for surgical management in PSC is bypass of an obstruction caused by a dominant stricture. Non-transplant surgical approaches include biliary bypass by cholangio-enterostomy or resection of the extrahepatic biliary stricture and Roux Y hepaticojejunostomy.60, 61 Biliary bypass alone has been employed infrequently because dominant strictures are typically hilar. Moreover, the intrahepatic ducts are variably involved which limits the access and quality of these ducts for bypass.60 Biliary bypass has no role in PSC patients with cirrhosis. Extrahepatic bile duct resection and Roux Y hepaticojejunostomy with or without stenting for dominant strictures is controversial.53, 61 Current evidence suggests that selected patients with non-cirrhotic stage PSC have an overall survival of 83% at 5 years and 60% at 10 years and a readmission free rate from cholangitis of 57% at 3 years for such an approach.62 Bilirubin levels > 2 mg/dL and cirrhosis are associated with decreased survival. No data regarding surgical management have shown that either bypass or resection of a dominant stricture affect natural history or disease progression. Most patients, who have not had biliary tree instrumented, have negative microbial bile cultures.63, 64 However, dominant strictures can induce stagnation of bile resulting in bacterial colonization and secondary cholangitis. This can be the first presentation of the disease occurring in 6.1% of PSC patients in one recent study.65 Furthermore, severe recurrent cholangitis may play a role in the progression of the disease. The relevance of a bile duct stricture was demonstrated by documenting bacterial infection of the bile in 15 out of 37 PSC patients (40.5%) with a dominant stricture but not in the absence of such stenosis; short-course antibiotic treatment proved not very effective in eradicating bacteria from the bile ducts of patients with dominant strictures.66 However, most patients respond to therapeutic drainage of the obstruction plus antibiotics. Occasional patients with recurrent bacterial cholangitis may benefit from prophylactic long term antibiotics. Rarely, recurrent cholangitis can be so severe as to become the primary indication for OLT.67 The management of in PSC patients should consideration of a dominant stricture. In the absence of a dominant the management of is similar to that for in primary biliary cirrhosis. the AASLD Guidelines on the of In patients with in serum bilirubin and/or worsening progressive bile duct dilatation on imaging studies, and/or cholangitis, we recommend performing an ERC to exclude a dominant stricture (1B). In patients with dominant strictures from PSC, we recommend management with endoscopic dilatation with or without stenting (1B). In patients with dominant strictures from PSC in an endoscopic approach is biliary tract dilatation by percutaneous cholangiography with or without stenting should be (1B). We recommend performing brush cytology and/or endoscopic biopsy to exclude a superimposed malignancy prior to endoscopic therapy for dominant strictures (1B). In patients with dominant strictures refractory to endoscopic and/or percutaneous we recommend surgical therapy in selected patients without cirrhosis (1B). We recommend therapy with of bile duct obstruction in dominant strictures to cholangitis (1A). In patients with recurrent bacterial cholangitis, we recommend the use of prophylactic long-term antibiotics (1B). In patients with refractory bacterial cholangitis, we recommend evaluation for liver (1B). cirrhosis is present in a patient with PSC, portal hypertension will develop because it of the natural history of all patients with cirrhosis. is the with cirrhosis in the is a of the presence of also in PSC. Of PSC patients diagnosed at Mayo = had varices, of which had and had of and of were level, and disease. for the presence of stage and levels, the odds of less than for the presence of was Similar were in in a hypertension be present in patients with PSC who not have cirrhosis, but this is Of liver performed during for biliary tract underwent in the of had PSC. Of the patients with portal hypertension as the indication for OLT, was in and portal in at may contribute as an indication for OLT.67 The management of portal hypertension in patients with PSC does not from patients and has been discussed in prior AASLD is the term used for the associated with liver The diagnosis is made by is characterized by a between and standard below the observed in young normal and as a The of in PSC is between and The with mass with of the with and with of the although this was not should be for in all diagnosed patients with PSC. Although information is it is to for at year and to is in patients with and in of may be therapy a improvement in in have been associated with which be in patients with in these patients therapy is an approach. We recommend to exclude or at diagnosis at year (1B). In patients with hepatic we suggest the use of and for therapy (2C). In patients with hepatic we suggest the use of therapy in addition to and (2C). In patients with and varices, we suggest the use of of therapy rather than (2C). PSC is associated with In most series of patients from and the prevalence of IBD in PSC has been in the range 50, The most frequent of IBD in PSC is UC, which is diagnosed in the patients with to have disease which usually the Conversely, PSC has been diagnosed in between and of patients with and was found in a large group of The prevalence of PSC IBD patients is to because data that cholangiography is out in of patients. The diagnosis and classification of IBD in PSC are based on diagnostic including findings on with multiple Because is a common a is Moreover, as IBD in PSC may be present with little or no clinical evidence of bowel disease and a diagnosis of IBD has in of follow-up, a with multiple is in all PSC patients at the with is negative for IBD, it is if a in the absence of symptoms should be over IBD may be diagnosed at any time during the of PSC. In the majority of the diagnosis of IBD that of PSC, even by IBD and PSC are diagnosed of IBD can also some years the diagnosis of PSC, and IBD may present liver for PSC may be diagnosed at any time during the of IBD, and may present years clinical and endoscopic features of IBD in PSC from those of IBD without evidence of disease (Table et compared patients with PSC who had IBD with a group of patients with the PSC patients, had UC, had and had The PSC patients more frequently had versus versus and versus than the It is a general experience that the colitis associated with PSC usually is This observation also in PSC, that typically as confined to the small bowel is not associated with it has been noted that the colitis may not always have features of 84 A classification of the IBD in PSC may be and can between The presence of or involvement may for be interpreted by some as or rather than 84 IBD in children with PSC is also characterized by often with and mild clinical Although symptoms of IBD in PSC be from those of IBD without the bowel disease in PSC to a more The IBD can also have a prolonged In a study of 27 PSC patients with IBD, patients reported disease activity during the first time diagnosis of IBD, followed by a patients had disease mild or disease in the majority of patients had some complication of IBD during the observation PSC patients who have an have an increased risk of compared to patients with without for this complication are Although one suggests that patients with PSC and an increased risk of development of in the compared with patients without PSC and that these patients should undergo in of patients should be out to the findings. is associated with an increased risk of Indeed, a including studies, that patients with and PSC are at an increased risk of and compared with patients with alone, with In a recent study, PSC patients with IBD and were found to be at of IBD than patients who had IBD and without PSC versus P = The time from of colitis diagnosis of similar in the two versus 20 P = the increased risk of in patients with PSC, at one to two year from the time of diagnosis of PSC in patients with as by associated with PSC to have a for the proximal with up to a A is therefore during to the increased risk of in patients with PSC who have are to be to patients with has been suggested to the risk of in patients with PSC and with was associated with a decreased prevalence

OBJECTIVES: To develop evidence-based recommendations for clinicians caring for children (including infants, school-aged children, and adolescents) with septic shock and other sepsis-associated organ dysfunction. DESIGN: A panel of 49 international experts, representing 12 international organizations, as well as three methodologists and three public members was convened. Panel members assembled at key international meetings (for those panel members attending the conference), and a stand-alone meeting was held for all panel members in November 2018. A formal conflict-of-interest policy was developed at the onset of the process and enforced throughout. Teleconferences and electronic-based discussion among the chairs, co-chairs, methodologists, and group heads, as well as within subgroups, served as an integral part of the guideline development process. METHODS: The panel consisted of six subgroups: recognition and management of infection, hemodynamics and resuscitation, ventilation, endocrine and metabolic therapies, adjunctive therapies, and research priorities. We conducted a systematic review for each Population, Intervention, Control, and Outcomes question to identify the best available evidence, statistically summarized the evidence, and then assessed the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach. We used the evidence-to-decision framework to formulate recommendations as strong or weak, or as a best practice statement. In addition, "in our practice" statements were included when evidence was inconclusive to issue a recommendation, but the panel felt that some guidance based on practice patterns may be appropriate. RESULTS: The panel provided 77 statements on the management and resuscitation of children with septic shock and other sepsis-associated organ dysfunction. Overall, six were strong recommendations, 52 were weak recommendations, and nine were best-practice statements. For 13 questions, no recommendations could be made; but, for 10 of these, "in our practice" statements were provided. In addition, 49 research priorities were identified. CONCLUSIONS: A large cohort of international experts was able to achieve consensus regarding many recommendations for the best care of children with sepsis, acknowledging that most aspects of care had relatively low quality of evidence resulting in the frequent issuance of weak recommendations. Despite this challenge, these recommendations regarding the management of children with septic shock and other sepsis-associated organ dysfunction provide a foundation for consistent care to improve outcomes and inform future research.

To determine whether the effects of low-level lead exposure persist, we reexamined 132 of 270 young adults who had initially been studied as primary school-children in 1975 through 1978. In the earlier study, neurobehavioral functioning was found to be inversely related to dentin lead levels. As compared with those we restudied, the other 138 subjects had had somewhat higher lead levels on earlier analysis, as well as significantly lower IQ scores and poorer teachers' ratings of classroom behavior. When the 132 subjects were reexamined in 1988, impairment in neurobehavioral function was still found to be related to the lead content of teeth shed at the ages of six and seven. The young people with dentin lead levels greater than 20 ppm had a markedly higher risk of dropping out of high school (adjusted odds ratio, 7.4; 95 percent confidence interval, 1.4 to 40.7) and of having a reading disability (odds ratio, 5.8; 95 percent confidence interval, 1.7 to 19.7) as compared with those with dentin lead levels less than 10 ppm. Higher lead levels in childhood were also significantly associated with lower class standing in high school, increased absenteeism, lower vocabulary and grammatical-reasoning scores, poorer hand-eye coordination, longer reaction times, and slower finger tapping. No significant associations were found with the results of 10 other tests of neurobehavioral functioning. Lead levels were inversely related to self-reports of minor delinquent activity. We conclude that exposure to lead in childhood is associated with deficits in central nervous system functioning that persist into young adulthood.

OBJECTIVE: In response to the landmark 1999 report by the Institute of Medicine and safety initiatives promoted by the Leapfrog Group, our institution implemented a commercially sold computerized physician order entry (CPOE) system in an effort to reduce medical errors and mortality. We sought to test the hypothesis that CPOE implementation results in reduced mortality among children who are transported for specialized care. METHODS: Demographic, clinical, and mortality data were collected of all children who were admitted via interfacility transport to our regional, academic, tertiary-care level children's hospital during an 18-month period. A commercially sold CPOE program that operated within the framework of a general, medical-surgical clinical application platform was rapidly implemented hospital-wide over 6 days during this period. Retrospective analyses of pre-CPOE and post-CPOE implementation time periods (13 months before and 5 months after CPOE implementation) were subsequently performed. RESULTS: Among 1942 children who were referred and admitted for specialized care during the study period, 75 died, accounting for an overall mortality rate of 3.86%. Univariate analysis revealed that mortality rate significantly increased from 2.80% (39 of 1394) before CPOE implementation to 6.57% (36 of 548) after CPOE implementation. Multivariate analysis revealed that CPOE remained independently associated with increased odds of mortality (odds ratio: 3.28; 95% confidence interval: 1.94-5.55) after adjustment for other mortality covariables. CONCLUSIONS: We have observed an unexpected increase in mortality coincident with CPOE implementation. Although CPOE technology holds great promise as a tool to reduce human error during health care delivery, our unanticipated finding suggests that when implementing CPOE systems, institutions should continue to evaluate mortality effects, in addition to medication error rates, for children who are dependent on time-sensitive therapies.