Alberta Children's Hospital

Importance: Emerging research suggests that the global prevalence of child and adolescent mental illness has increased considerably during COVID-19. However, substantial variability in prevalence rates have been reported across the literature. Objective: To ascertain more precise estimates of the global prevalence of child and adolescent clinically elevated depression and anxiety symptoms during COVID-19; to compare these rates with prepandemic estimates; and to examine whether demographic (eg, age, sex), geographical (ie, global region), or methodological (eg, pandemic data collection time point, informant of mental illness, study quality) factors explained variation in prevalence rates across studies. Data Sources: Four databases were searched (PsycInfo, Embase, MEDLINE, and Cochrane Central Register of Controlled Trials) from January 1, 2020, to February 16, 2021, and unpublished studies were searched in PsycArXiv on March 8, 2021, for studies reporting on child/adolescent depression and anxiety symptoms. The search strategy combined search terms from 3 themes: (1) mental illness (including depression and anxiety), (2) COVID-19, and (3) children and adolescents (age ≤18 years). For PsycArXiv, the key terms COVID-19, mental health, and child/adolescent were used. Study Selection: Studies were included if they were published in English, had quantitative data, and reported prevalence of clinically elevated depression or anxiety in youth (age ≤18 years). Data Extraction and Synthesis: A total of 3094 nonduplicate titles/abstracts were retrieved, and 136 full-text articles were reviewed. Data were analyzed from March 8 to 22, 2021. Main Outcomes and Measures: Prevalence rates of clinically elevated depression and anxiety symptoms in youth. Results: Random-effect meta-analyses were conducted. Twenty-nine studies including 80 879 participants met full inclusion criteria. Pooled prevalence estimates of clinically elevated depression and anxiety symptoms were 25.2% (95% CI, 21.2%-29.7%) and 20.5% (95% CI, 17.2%-24.4%), respectively. Moderator analyses revealed that the prevalence of clinically elevated depression and anxiety symptoms were higher in studies collected later in the pandemic and in girls. Depression symptoms were higher in older children. Conclusions and Relevance: Pooled estimates obtained in the first year of the COVID-19 pandemic suggest that 1 in 4 youth globally are experiencing clinically elevated depression symptoms, while 1 in 5 youth are experiencing clinically elevated anxiety symptoms. These pooled estimates, which increased over time, are double of prepandemic estimates. An influx of mental health care utilization is expected, and allocation of resources to address child and adolescent mental health concerns are essential.

BACKGROUND: The aim of this study was to revise the 2003 Fenton Preterm Growth Chart, specifically to: a) harmonize the preterm growth chart with the new World Health Organization (WHO) Growth Standard, b) smooth the data between the preterm and WHO estimates, informed by the Preterm Multicentre Growth (PreM Growth) study while maintaining data integrity from 22 to 36 and at 50 weeks, and to c) re-scale the chart x-axis to actual age (rather than completed weeks) to support growth monitoring. METHODS: Systematic review, meta-analysis, and growth chart development. We systematically searched published and unpublished literature to find population-based preterm size at birth measurement (weight, length, and/or head circumference) references, from developed countries with: Corrected gestational ages through infant assessment and/or statistical correction; Data percentiles as low as 24 weeks gestational age or lower; Sample with greater than 500 infants less than 30 weeks. Growth curves for males and females were produced using cubic splines to 50 weeks post menstrual age. LMS parameters (skew, median, and standard deviation) were calculated. RESULTS: Six large population-based surveys of size at preterm birth representing 3,986,456 births (34,639 births < 30 weeks) from countries Germany, United States, Italy, Australia, Scotland, and Canada were combined in meta-analyses. Smooth growth chart curves were developed, while ensuring close agreement with the data between 24 and 36 weeks and at 50 weeks. CONCLUSIONS: The revised sex-specific actual-age growth charts are based on the recommended growth goal for preterm infants, the fetus, followed by the term infant. These preterm growth charts, with the disjunction between these datasets smoothing informed by the international PreM Growth study, may support an improved transition of preterm infant growth monitoring to the WHO growth charts.

CONTEXT: Understanding the incidence and subsequent mortality following hip fracture is essential to measuring population health and the value of improvements in health care. OBJECTIVE: To examine trends in hip fracture incidence and resulting mortality over 20 years in the US Medicare population. DESIGN, SETTING, AND PATIENTS: Observational study using data from a 20% sample of Medicare claims from 1985-2005. In patients 65 years or older, we identified 786,717 hip fractures for analysis. Medication data were obtained from 109,805 respondents to the Medicare Current Beneficiary Survey between 1992 and 2005. MAIN OUTCOME MEASURES: Age- and sex-specific incidence of hip fracture and age- and risk-adjusted mortality rates. RESULTS: Between 1986 and 2005, the annual mean number of hip fractures was 957.3 per 100,000 (95% confidence interval [CI], 921.7-992.9) for women and 414.4 per 100,000 (95% CI, 401.6-427.3) for men. The age-adjusted incidence of hip fracture increased from 1986 to 1995 and then steadily declined from 1995 to 2005. In women, incidence increased 9.0%, from 964.2 per 100,000 (95% CI, 958.3-970.1) in 1986 to 1050.9 (95% CI, 1045.2-1056.7) in 1995, with a subsequent decline of 24.5% to 793.5 (95% CI, 788.7-798.3) in 2005. In men, the increase in incidence from 1986 to 1995 was 16.4%, from 392.4 (95% CI, 387.8-397.0) to 456.6 (95% CI, 452.0-461.3), and the subsequent decrease to 2005 was 19.2%, to 369.0 (95% CI, 365.1-372.8). Age- and risk-adjusted mortality in women declined by 11.9%, 14.9%, and 8.8% for 30-, 180-, and 360-day mortality, respectively. For men, age- and risk-adjusted mortality decreased by 21.8%, 25.4%, and 20.0% for 30-, 180-, and 360-day mortality, respectively. Over time, patients with hip fracture have had an increase in all comorbidities recorded except paralysis. The incidence decrease is coincident with increased use of bisphosphonates. CONCLUSION: In the United States, hip fracture rates and subsequent mortality among persons 65 years and older are declining, and comorbidities among patients with hip fractures have increased.

Given the recent spate of reports of vitamin D deficiency, there is a need to reexamine our understanding of natural and other sources of vitamin D, as well as mechanisms whereby vitamin D synthesis and intake can be optimized. This state-of-the-art report from the Drug and Therapeutics Committee of the Lawson Wilkins Pediatric Endocrine Society was aimed to perform this task and also reviews recommendations for sun exposure and vitamin D intake and possible caveats associated with these recommendations.

Inosine modulates antitumor immunity Checkpoint blockade immunotherapy harnesses the immune system to kill cancer cells and has been used with great success to treat certain tumors, but not all cancer patients respond. The efficacy of checkpoint blockade immunotherapy has been shown to depend on the presence of distinct, beneficial bacteria residing in the gut of patients, but how the microbiome mediates such beneficial effects is unclear. Mager et al. found that specific bacteria produce a metabolite called inosine that enhances the effect of checkpoint blockade immunotherapy (see the Perspective by Shaikh and Sears). In mouse models, inosine, together with proinflammatory stimuli and immunotherapy, strongly enhanced the antitumor capacities of T cells in multiple tumor types, including colorectal cancer, bladder cancer, and melanoma. Science , this issue p. 1481 ; see also p. 1427

BACKGROUND: Antibiotic use in human medicine, veterinary medicine, and agriculture has been linked to the rise of antibiotic resistance globally. We did a systematic review and meta-analysis to summarise the effect that interventions to reduce antibiotic use in food-producing animals have on the presence of antibiotic-resistant bacteria in animals and in humans. METHODS: On July 14, 2016, we searched electronic databases (Agricola, AGRIS, BIOSIS Previews, CAB Abstracts, MEDLINE, Embase, Global Index Medicus, ProQuest Dissertations, Science Citation Index) and the grey literature. The search was updated on Jan 27, 2017. Inclusion criteria were original studies that reported on interventions to reduce antibiotic use in food-producing animals and compared presence of antibiotic-resistant bacteria between intervention and comparator groups in animals or in human beings. We extracted data from included studies and did meta-analyses using random effects models. The main outcome assessed was the risk difference in the proportion of antibiotic-resistant bacteria. FINDINGS: A total of 181 studies met inclusion criteria. Of these, 179 (99%) described antibiotic resistance outcomes in animals, and 81 (45%) of these studies were included in the meta-analysis. 21 studies described antibiotic resistance outcomes in humans, and 13 (62%) of these studies were included in the meta-analysis. The pooled absolute risk reduction of the prevalence of antibiotic resistance in animals with interventions that restricted antibiotic use commonly ranged between 10 and 15% (total range 0-39), depending on the antibiotic class, sample type, and bacteria under assessment. Similarly, in the human studies, the pooled prevalence of antibiotic resistance reported was 24% lower in the intervention groups compared with control groups, with a stronger association seen for humans with direct contact with food-producing animals. INTERPRETATION: Interventions that restrict antibiotic use in food-producing animals are associated with a reduction in the presence of antibiotic-resistant bacteria in these animals. A smaller body of evidence suggests a similar association in the studied human populations, particularly those with direct exposure to food-producing animals. The implications for the general human population are less clear, given the low number of studies. The overall findings have directly informed the development of WHO guidelines on the use of antibiotics in food-producing animals. FUNDING: World Health Organization.

IMPORTANCE: Approximately one-third of children experiencing acute concussion experience ongoing somatic, cognitive, and psychological or behavioral symptoms, referred to as persistent postconcussion symptoms (PPCS). However, validated and pragmatic tools enabling clinicians to identify patients at risk for PPCS do not exist. OBJECTIVE: To derive and validate a clinical risk score for PPCS among children presenting to the emergency department. DESIGN, SETTING, AND PARTICIPANTS: Prospective, multicenter cohort study (Predicting and Preventing Postconcussive Problems in Pediatrics [5P]) enrolled young patients (aged 5-<18 years) who presented within 48 hours of an acute head injury at 1 of 9 pediatric emergency departments within the Pediatric Emergency Research Canada (PERC) network from August 2013 through September 2014 (derivation cohort) and from October 2014 through June 2015 (validation cohort). Participants completed follow-up 28 days after the injury. EXPOSURES: All eligible patients had concussions consistent with the Zurich consensus diagnostic criteria. MAIN OUTCOMES AND MEASURES: The primary outcome was PPCS risk score at 28 days, which was defined as 3 or more new or worsening symptoms using the patient-reported Postconcussion Symptom Inventory compared with recalled state of being prior to the injury. RESULTS: In total, 3063 patients (median age, 12.0 years [interquartile range, 9.2-14.6 years]; 1205 [39.3%] girls) were enrolled (n = 2006 in the derivation cohort; n = 1057 in the validation cohort) and 2584 of whom (n = 1701 [85%] in the derivation cohort; n = 883 [84%] in the validation cohort) completed follow-up at 28 days after the injury. Persistent postconcussion symptoms were present in 801 patients (31.0%) (n = 510 [30.0%] in the derivation cohort and n = 291 [33.0%] in the validation cohort). The 12-point PPCS risk score model for the derivation cohort included the variables of female sex, age of 13 years or older, physician-diagnosed migraine history, prior concussion with symptoms lasting longer than 1 week, headache, sensitivity to noise, fatigue, answering questions slowly, and 4 or more errors on the Balance Error Scoring System tandem stance. The area under the curve was 0.71 (95% CI, 0.69-0.74) for the derivation cohort and 0.68 (95% CI, 0.65-0.72) for the validation cohort. CONCLUSIONS AND RELEVANCE: A clinical risk score developed among children presenting to the emergency department with concussion and head injury within the previous 48 hours had modest discrimination to stratify PPCS risk at 28 days. Before this score is adopted in clinical practice, further research is needed for external validation, assessment of accuracy in an office setting, and determination of clinical utility.

Peer Reviewed

The health, fitness and other advantages of youth sports participation are well recognised. However, there are considerable challenges for all stakeholders involved-especially youth athletes-in trying to maintain inclusive, sustainable and enjoyable participation and success for all levels of individual athletic achievement. In an effort to advance a more unified, evidence-informed approach to youth athlete development, the IOC critically evaluated the current state of science and practice of youth athlete development and presented recommendations for developing healthy, resilient and capable youth athletes, while providing opportunities for all levels of sport participation and success. The IOC further challenges all youth and other sport governing bodies to embrace and implement these recommended guiding principles.

This paper presents the Sport Concussion Assessment Tool 5th Edition (SCAT5), which is the most recent revision of a sport concussion evaluation tool for use by healthcare professionals in the acute evaluation of suspected concussion. The revision of the SCAT3 (first published in 2013) culminated in the SCAT5. The revision was based on a systematic review and synthesis of current research, public input and expert panel review as part of the 5th International Consensus Conference on Concussion in Sport held in Berlin in 2016. The SCAT5 is intended for use in those who are 13 years of age or older. The Child SCAT5 is a tool for those aged 5-12 years, which is discussed elsewhere.

Ketogenic dietary therapies (KDTs) are established, effective nonpharmacologic treatments for intractable childhood epilepsy. For many years KDTs were implemented differently throughout the world due to lack of consistent protocols. In 2009, an expert consensus guideline for the management of children on KDT was published, focusing on topics of patient selection, pre-KDT counseling and evaluation, diet choice and attributes, implementation, supplementation, follow-up, side events, and KDT discontinuation. It has been helpful in outlining a state-of-the-art protocol, standardizing KDT for multicenter clinical trials, and identifying areas of controversy and uncertainty for future research. Now one decade later, the organizers and authors of this guideline present a revised version with additional authors, in order to include recent research, especially regarding other dietary treatments, clarifying indications for use, side effects during initiation and ongoing use, value of supplements, and methods of KDT discontinuation. In addition, authors completed a survey of their institution's practices, which was compared to responses from the original consensus survey, to show trends in management over the last 10 years.

BACKGROUND: Much disagreement exists as to whether postconcussion syndrome (PCS) is attributable to brain injury or to other factors such as trauma alone, preexisting psychosocial problems, or medicolegal issues. We investigated the epidemiology and natural history of PCS symptoms in a large cohort of children with a mild traumatic brain injury (mTBI) and compared them with children with an extracranial injury (ECI). METHODS: This investigation was a prospective, consecutive controlled-cohort study of 670 children who presented to a tertiary referral emergency department with mTBI and 197 children who presented with ECI. For all participants, data were collected by use of a telephone interview of a parent 7 to 10 days after injury. If a change from preinjury symptoms was reported by a parent, follow-up continued monthly until symptom resolution. Outcomes were measured by using the Post Concussion Symptom Inventory, Rivermead Postconcussion Symptom Questionnaire, Brief Symptom Inventory, and Family Assessment Device. RESULTS: There was a significant difference between the mTBI and ECI groups in their survival curves for time to symptom resolution (log rank [Mantel-Cox] 11.15, P < .001). Three months after injury, 11% of the children in the mTBI group were symptomatic (13.7% of children older than 6 years) compared with 0.5% of the children in the ECI group. The prevalence of persistent symptoms at 1 year was 2.3% in the mTBI group and 0.01% in the ECI group. Family functioning and maternal adjustment did not differ between groups. CONCLUSIONS: Among school-aged children with mTBI, 13.7% were symptomatic 3 months after injury. This finding could not be explained by trauma, family dysfunction, or maternal psychological adjustment. The results of this study provide clear support for the validity of the diagnosis of PCS in children.

Importance: Excessive screen time is associated with delays in development; however, it is unclear if greater screen time predicts lower performance scores on developmental screening tests or if children with poor developmental performance receive added screen time as a way to modulate challenging behavior. Objective: To assess the directional association between screen time and child development in a population of mothers and children. Design, Setting, and Participants: This longitudinal cohort study used a 3-wave, cross-lagged panel model in 2441 mothers and children in Calgary, Alberta, Canada, drawn from the All Our Families study. Data were available when children were aged 24, 36, and 60 months. Data were collected between October 20, 2011, and October 6, 2016. Statistical analyses were conducted from July 31 to November 15, 2018. Exposures: Media. Main Outcomes and Measures: At age 24, 36, and 60 months, children's screen-time behavior (total hours per week) and developmental outcomes (Ages and Stages Questionnaire, Third Edition) were assessed via maternal report. Results: Of the 2441 children included in the analysis, 1227 (50.2%) were boys. A random-intercepts, cross-lagged panel model revealed that higher levels of screen time at 24 and 36 months were significantly associated with poorer performance on developmental screening tests at 36 months (β, -0.06; 95% CI, -0.10 to -0.01) and 60 months (β, -0.08; 95% CI, -0.13 to -0.02), respectively. These within-person (time-varying) associations statistically controlled for between-person (stable) differences. Conclusions and Relevance: The results of this study support the directional association between screen time and child development. Recommendations include encouraging family media plans, as well as managing screen time, to offset the potential consequences of excess use.

OBJECTIVE: Systematic review of possible long-term effects of sports-related concussion in retired athletes. DATA SOURCES: Ten electronic databases. STUDY SELECTION: 10 years after the injury. DATA EXTRACTION: Study population, exposure/outcome measures, clinical data, neurological examination findings, cognitive assessment, neuroimaging findings and neuropathology results. Risk of bias and level of evidence were evaluated by two authors. RESULTS: Following review of 3819 studies, 47 met inclusion criteria. Some former athletes have depression and cognitive deficits later in life, and there is an association between these deficits and multiple prior concussions. Former athletes are not at increased risk for death by suicide (two studies). Former high school American football players do not appear to be at increased risk for later life neurodegenerative diseases (two studies). Some retired professional American football players may be at increased risk for diminishment in cognitive functioning or mild cognitive impairment (several studies), and neurodegenerative diseases (one study). Neuroimaging studies show modest evidence of macrostructural, microstructural, functional and neurochemical changes in some athletes. CONCLUSION: Multiple concussions appear to be a risk factor for cognitive impairment and mental health problems in some individuals. More research is needed to better understand the prevalence of chronic traumatic encephalopathy and other neurological conditions and diseases, and the extent to which they are related to concussions and/or repetitive neurotrauma sustained in sports.

Stroke rehabilitation is a progressive, dynamic, goal-orientated process aimed at enabling a person with impairment to reach their optimal physical, cognitive, emotional, communicative, social and/or functional activity level. After a stroke, patients often continue to require rehabilitation for persistent deficits related to spasticity, upper and lower extremity dysfunction, shoulder and central pain, mobility/gait, dysphagia, vision, and communication. Each year in Canada 62,000 people experience a stroke. Among stroke survivors, over 6500 individuals access in-patient stroke rehabilitation and stay a median of 30 days (inter-quartile range 19 to 45 days). The 2015 update of the Canadian Stroke Best Practice Recommendations: Stroke Rehabilitation Practice Guidelines is a comprehensive summary of current evidence-based recommendations for all members of multidisciplinary teams working in a range of settings, who provide care to patients following stroke. These recommendations have been developed to address both the organization of stroke rehabilitation within a system of care (i.e., Initial Rehabilitation Assessment; Stroke Rehabilitation Units; Stroke Rehabilitation Teams; Delivery; Outpatient and Community-Based Rehabilitation), and specific interventions and management in stroke recovery and direct clinical care (i.e., Upper Extremity Dysfunction; Lower Extremity Dysfunction; Dysphagia and Malnutrition; Visual-Perceptual Deficits; Central Pain; Communication; Life Roles). In addition, stroke happens at any age, and therefore a new section has been added to the 2015 update to highlight components of stroke rehabilitation for children who have experienced a stroke, either prenatally, as a newborn, or during childhood. All recommendations have been assigned a level of evidence which reflects the strength and quality of current research evidence available to support the recommendation. The updated Rehabilitation Clinical Practice Guidelines feature several additions that reflect new research areas and stronger evidence for already existing recommendations. It is anticipated that these guidelines will provide direction and standardization for patients, families/caregiver(s), and clinicians within Canada and internationally.

The Developmental Coordination Disorder Questionnaire (DCDQ) is a parent-completed measure designed to identify subtle motor problems in children of 8 to 14.6 years of age. The purpose of this study was to extend the lower age range to children aged 5 to 7 years, revise items to ensure clarity, develop new scoring, and evaluate validity of the revised questionnaire. Additional items with improved wording were generated by an expert panel. Analyses of internal consistency, factor loading, and qualitative/quantitative feedback from researchers, clinicians, and parents were used to select 15 items with the strongest psychometric properties. Internal consistency was high (alpha =. 94). The expanded questionnaire was completed by the parents of 287 children, aged 5–15 years, who were typically developing. Logistic regression modeling was used to generate separate cutoff scores for three age groups (overall sensitivity = 85%, specificity = 71%). The revised DCDQ was then compared to other standardized measures in a sample of 232 children referred for therapy services. Differences in scores between children with and without DCD (p <. 001) provide evidence of construct validity. Correlations between DCDQ scores and Movement Assessment Battery for Children (r =. 55) and Test of Visual-Motor Integration (r =. 42) scores support concurrent validity. The results provide evidence that the revised DCDQ is a valid clinical screening tool for DCD.

BACKGROUND: Breast milk nutrient content varies with prematurity and postnatal age. Our aims were to conduct a meta-analysis of preterm and term breast milk nutrient content (energy, protein, lactose, oligosaccharides, fat, calcium, and phosphorus); and to assess the influence of gestational and postnatal age. Additionally we assessed for differences by laboratory methods for: energy (measured vs. calculated estimates) and protein (true protein measurement vs. the total nitrogen estimates). METHODS: Systematic review results were summarized graphically to illustrate the changes in composition over time for term and preterm milk. Since breast milk fat content varies within feeds and diurnally, to obtain accurate estimates we limited the meta-analyses for fat and energy to 24-hour breast milk collections. RESULTS: Forty-one studies met the inclusion criteria: 26 (843 mothers) preterm studies and 30 (2299 mothers) term studies of breast milk composition. Preterm milk was higher in true protein than term milk, with differences up to 35% (0.7 g/dL) in colostrum, however, after postnatal day 3, most of the differences in true protein between preterm and term milk were within 0.2 g/dL, and the week 10-12 estimates suggested that term milk may be the same as preterm milk by that age. Colostrum was higher than mature milk for protein, and lower than mature milk for energy, fat and lactose for both preterm and term milk. Breast milk composition was relatively stable between 2 and 12 weeks. With milk maturation, there was a narrowing of the protein variance. Energy estimates differed whether measured or calculated, from -9 to 13%; true protein measurement vs. the total nitrogen estimates differed by 1 to 37%. CONCLUSIONS: Although breast milk is highly variable between individuals, postnatal age and gestational stage (preterm versus term) were found to be important predictors of breast milk content. Energy content of breast milk calculated from the macronutrients provides poor estimates of measured energy, and protein estimated from the nitrogen over-estimates the protein milk content. When breast milk energy, macronutrient and mineral content cannot be directly measured the average values from these meta-analyses may provide useful estimates of mother's milk energy and nutrient content.

PURPOSE: Epilepsy surgery is a safe surgical procedure, but it may be associated with cognitive changes. Estimates of the risk of decline in specific neuropsychological domains after epilepsy surgery would assist surgical decision making in clinical practice. The goal of this study was to conduct a systematic review to derive pooled estimates of the rate of losses and gains in neuropsychological functions after epilepsy surgery, using empirically based methods for quantifying cognitive change. METHODS: An extensive literature search using PubMed, EmBase, and the Cochrane database was conducted, yielding 5,061 articles on epilepsy surgery, with 193 on neuropsychological outcomes (IQ, memory, language, executive functioning, attention, and subjective cognitive changes). KEY FINDINGS: Of these, 23 met final eligibility criteria, with 22 studies involving temporal surgery only. Key aspects of inclusion criteria were N ≥ 20 and use of reliable change index or standardized regression-based change estimates. In addition to the proportion of patients experiencing losses and gains in each individual test, a single pooled estimate of gains and losses for each cognitive domain was derived using a random effects model. Weighted estimates indicated a risk to verbal memory with left-sided temporal surgery of 44%, twice as high as the rate for right-sided surgery (20%). Naming was reduced in 34% of left-sided temporal patients, with almost no patients with gains (4%). Pooled data on IQ, executive functioning, and attention indicated few patients show declines post surgery, but a substantial rate of improvement in verbal fluency with left-sided temporal surgery (27%) was found. Self-reported cognitive declines after epilepsy surgery were uncommon, and gains were reported in some domains where losses were found on objective tests (i.e., verbal memory and language). Variations in surgical techniques did not appear to have a large effect on cognitive outcomes, except for naming outcomes, which appeared better with more conservative resections. Sensitivity to postoperative changes differed across visual memory tests, but not verbal memory tests. Few conclusions could be made regarding cognitive risks and benefits of extratemporal epilepsy surgery, or of epilepsy surgery in children. SIGNIFICANCE: In sum, epilepsy surgery is associated with specific cognitive changes, but may also improve cognition in some patients. The results provide base rate estimates of expected cognitive gains and losses associated with epilepsy surgery that may prove useful in clinical settings.

BACKGROUND: Simulation-based research (SBR) is rapidly expanding but the quality of reporting needs improvement. For a reader to critically assess a study, the elements of the study need to be clearly reported. Our objective was to develop reporting guidelines for SBR by creating extensions to the Consolidated Standards of Reporting Trials (CONSORT) and Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statements. METHODS: An iterative multistep consensus-building process was used on the basis of the recommended steps for developing reporting guidelines. The consensus process involved the following: (1) developing a steering committee, (2) defining the scope of the reporting guidelines, (3) identifying a consensus panel, (4) generating a list of items for discussion via online premeeting survey, (5) conducting a consensus meeting, and (6) drafting reporting guidelines with an explanation and elaboration document. RESULTS: The following 11 extensions were recommended for CONSORT: item 1 (title/abstract), item 2 (background), item 5 (interventions), item 6 (outcomes), item 11 (blinding), item 12 (statistical methods), item 15 (baseline data), item 17 (outcomes/ estimation), item 20 (limitations), item 21 (generalizability), and item 25 (funding). The following 10 extensions were recommended for STROBE: item 1 (title/abstract), item 2 (background/rationale), item 7 (variables), item 8 (data sources/measurement), item 12 (statistical methods), item 14 (descriptive data), item 16 (main results), item 19 (limitations), item 21 (generalizability), and item 22 (funding). An elaboration document was created to provide examples and explanation for each extension. CONCLUSIONS: 00:00-00, 2016).

Snakes are limbless predators, and many species use venom to help overpower relatively large, agile prey. Snake venoms are complex protein mixtures encoded by several multilocus gene families that function synergistically to cause incapacitation. To examine venom evolution, we sequenced and interrogated the genome of a venomous snake, the king cobra (Ophiophagus hannah), and compared it, together with our unique transcriptome, microRNA, and proteome datasets from this species, with data from other vertebrates. In contrast to the platypus, the only other venomous vertebrate with a sequenced genome, we find that snake toxin genes evolve through several distinct co-option mechanisms and exhibit surprisingly variable levels of gene duplication and directional selection that correlate with their functional importance in prey capture. The enigmatic accessory venom gland shows a very different pattern of toxin gene expression from the main venom gland and seems to have recruited toxin-like lectin genes repeatedly for new nontoxic functions. In addition, tissue-specific microRNA analyses suggested the co-option of core genetic regulatory components of the venom secretory system from a pancreatic origin. Although the king cobra is limbless, we recovered coding sequences for all Hox genes involved in amniote limb development, with the exception of Hoxd12. Our results provide a unique view of the origin and evolution of snake venom and reveal multiple genome-level adaptive responses to natural selection in this complex biological weapon system. More generally, they provide insight into mechanisms of protein evolution under strong selection.