Alberta Children's Hospital Research Institute

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Embase, MEDLINE, and Cochrane Central Register of Controlled Trials) from January 1, 2020, to February 16, 2021, and unpublished studies were searched in PsycArXiv on March 8, 2021, for studies reporting on child/adolescent depression and anxiety symptoms.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.

Peer Reviewed

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.

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.

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.

Importance: The existing literature on sexting among youth shows that sexting is a predictor of sexual behavior and may be associated with other health outcomes and risky behaviors. However, there remains a lack of consensus on the prevalence of sexting, which is needed to inform future research, intervention, and policy development. Objective: To provide a meta-analytic synthesis of studies examining the prevalence of multiple forms of sexting behavior, analyzed by age, sex, geography, and method of sexting. Data Sources: In an academic setting, electronic searches in MEDLINE, PsycINFO, EMBASE, and Web of Science were conducted for the period January 1990 to June 2016, yielding 1147 nonduplicate records. Study Selection: Studies were included if participants were younger than 18 years and the prevalence of sexting explicit images, videos, or messages was reported. Data Extraction and Synthesis: Literature review and data extraction followed established PRISMA guidelines. Two independent reviewers extracted all relevant data. Random-effects meta-analyses were used to derive the mean prevalence rates. Thirty-nine studies met final inclusion criteria. Main Outcomes and Measures: Meta-analyses of the prevalence of sending, receiving, and forwarding without consent, as well as having one's sext forwarded without consent. Results: Among 39 included studies, there were 110 380 participants; the mean age was 15.16 years (age range, 11.9-17.0 years), and on average 47.2% were male. Studies were available for sending (n = 34), receiving (n = 20), forwarding without consent (n = 5), and having a sext forwarded without consent (n = 4). The mean prevalences for sending and receiving sexts were 14.8% (95% CI, 12.8%-16.8%) and 27.4% (95% CI, 23.1%-31.7%), respectively. Moderator analyses revealed that effect sizes varied as a function of child age (prevalence increased with age), year of data collection (prevalence increased over time), and sexting method (higher prevalence on mobile devices compared with computers). The prevalence of forwarding a sext without consent was 12.0% (95% CI, 8.4%-15.6%), and the prevalence of having a sext forwarded without consent was 8.4% (95% CI, 4.7%-12.0%). Conclusions and Relevance: The prevalence of sexting has increased in recent years and increases as youth age. Further research focusing on nonconsensual sexting is necessary to appropriately target and inform intervention, education, and policy efforts.

BACKGROUND: The senses of touch and proprioception evoke a range of perceptions and rely on the ability to detect and transduce mechanical force. The molecular and neural mechanisms underlying these sensory functions remain poorly defined. The stretch-gated ion channel PIEZO2 has been shown to be essential for aspects of mechanosensation in model organisms. METHODS: We performed whole-exome sequencing analysis in two patients who had unique neuromuscular and skeletal symptoms, including progressive scoliosis, that did not conform to standard diagnostic classification. In vitro and messenger RNA assays, functional brain imaging, and psychophysical and kinematic tests were used to establish the effect of the genetic variants on protein function and somatosensation. RESULTS: Each patient carried compound-inactivating variants in PIEZO2, and each had a selective loss of discriminative touch perception but nevertheless responded to specific types of gentle mechanical stimulation on hairy skin. The patients had profoundly decreased proprioception leading to ataxia and dysmetria that were markedly worse in the absence of visual cues. However, they had the ability to perform a range of tasks, such as walking, talking, and writing, that are considered to rely heavily on proprioception. CONCLUSIONS: Our results show that PIEZO2 is a determinant of mechanosensation in humans. (Funded by the National Institutes of Health Intramural Research Program.).

Importance: There is considerable public and scientific debate as to whether screen use helps or hinders early child development, particularly the development of language skills. Objective: To examine via meta-analyses the associations between quantity (duration of screen time and background television), quality (educational programming and co-viewing), and onset of screen use and children's language skills. Data Sources: Searches were conducted in MEDLINE, Embase, and PsycINFO in March 2019. The search strategy included a publication date limit from 1960 through March 2019. Study Selection: Inclusion criteria were a measure of screen use; a measure of language skills; and statistical data that could be transformed into an effect size. Exclusion criteria were qualitative studies; child age older than 12 years; and language assessment preverbal. Data Extraction and Synthesis: The following variables were extracted: effect size, child age and sex, screen measure type, study publication year, and study design. All studies were independently coded by 2 coders and conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Main Outcomes and Measures: Based on a priori study criteria, quantity of screen use included duration of screen time and background television, quality of screen use included co-viewing and exposure to educational programs, and onset of screen use was defined as the age children first began viewing screens. The child language outcome included assessments of receptive and/or expressive language. Results: Participants totaled 18 905 from 42 studies included. Effect sizes were measured as correlations (r). Greater quantity of screen use (hours per use) was associated with lower language skills (screen time [n = 38; r = -0.14; 95% CI, -0.18 to -0.10]; background television [n = 5; r = -0.19; 95% CI, -0.33 to -0.05]), while better-quality screen use (educational programs [n = 13; r = 0.13; 95% CI, 0.02-0.24]; co-viewing [n = 12; r = 0.16; 95% CI, 0.07-.24]) were associated with stronger child language skills. Later age at screen use onset was also associated with stronger child language skills [n = 4; r = 0.17; 95% CI, 0.07-0.27]. Conclusions and Relevance: The findings of this meta-analysis support pediatric recommendations to limit children's duration of screen exposure, to select high-quality programming, and to co-view when possible.

Alterations in white matter (WM) microstructure have been implicated in the pathophysiology of major depressive disorder (MDD). However, previous findings have been inconsistent, partially due to low statistical power and the heterogeneity of depression. In the largest multi-site study to date, we examined WM anisotropy and diffusivity in 1305 MDD patients and 1602 healthy controls (age range 12-88 years) from 20 samples worldwide, which included both adults and adolescents, within the MDD Working Group of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) consortium. Processing of diffusion tensor imaging (DTI) data and statistical analyses were harmonized across sites and effects were meta-analyzed across studies. We observed subtle, but widespread, lower fractional anisotropy (FA) in adult MDD patients compared with controls in 16 out of 25 WM tracts of interest (Cohen's d between 0.12 and 0.26). The largest differences were observed in the corpus callosum and corona radiata. Widespread higher radial diffusivity (RD) was also observed (all Cohen's d between 0.12 and 0.18). Findings appeared to be driven by patients with recurrent MDD and an adult age of onset of depression. White matter microstructural differences in a smaller sample of adolescent MDD patients and controls did not survive correction for multiple testing. In this coordinated and harmonized multisite DTI study, we showed subtle, but widespread differences in WM microstructure in adult MDD, which may suggest structural disconnectivity in MDD.

Once an MRS dataset has been acquired, several important steps must be taken to obtain the desired metabolite concentration measures. First, the data must be preprocessed to prepare them for analysis. Next, the intensity of the metabolite signal(s) of interest must be estimated. Finally, the measured metabolite signal intensities must be converted into scaled concentration units employing a quantitative reference signal to allow meaningful interpretation. In this paper, we review these three main steps in the post-acquisition workflow of a single-voxel MRS experiment (preprocessing, analysis and quantification) and provide recommendations for best practices at each step.

Importance: Although concussion treatment guidelines advocate rest in the immediate postinjury period until symptoms resolve, no clear evidence has determined that avoiding physical activity expedites recovery. Objective: To investigate the association between participation in physical activity within 7 days postinjury and incidence of persistent postconcussive symptoms (PPCS). Design, Setting, and Participants: Prospective, multicenter cohort study (August 2013-June 2015) of 3063 children and adolescents aged 5.00-17.99 years with acute concussion from 9 Pediatric Emergency Research Canada network emergency departments (EDs). Exposures: Early physical activity participation within 7 days postinjury. Main Outcomes and Measures: Physical activity participation and postconcussive symptom severity were rated using standardized questionnaires in the ED and at days 7 and 28 postinjury. PPCS (≥3 new or worsening symptoms on the Post-Concussion Symptom Inventory) was assessed at 28 days postenrollment. Early physical activity and PPCS relationships were examined by unadjusted analysis, 1:1 propensity score matching, and inverse probability of treatment weighting (IPTW). Sensitivity analyses examined patients (≥3 symptoms) at day 7. Results: Among 2413 participants who completed the primary outcome and exposure, (mean [SD] age, 11.77 [3.35] years; 1205 [39.3%] females), PPCS at 28 days occurred in 733 (30.4%); 1677 (69.5%) participated in early physical activity including light aerobic exercise (n = 795 [32.9%]), sport-specific exercise (n = 214 [8.9%]), noncontact drills (n = 143 [5.9%]), full-contact practice (n = 106 [4.4%]), or full competition (n = 419 [17.4%]), whereas 736 (30.5%) had no physical activity. On unadjusted analysis, early physical activity participants had lower risk of PPCS than those with no physical activity (24.6% vs 43.5%; Absolute risk difference [ARD], 18.9% [95% CI,14.7%-23.0%]). Early physical activity was associated with lower PPCS risk on propensity score matching (n = 1108 [28.7% for early physical activity vs 40.1% for no physical activity]; ARD, 11.4% [95% CI, 5.8%-16.9%]) and on inverse probability of treatment weighting analysis (n = 2099; relative risk [RR], 0.74 [95% CI, 0.65-0.84]; ARD, 9.7% [95% CI, 5.7%-13.7%]). Among only patients symptomatic at day 7 (n = 803) compared with those who reported no physical activity (n = 584; PPCS, 52.9%), PPCS rates were lower for participants of light aerobic activity (n = 494 [46.4%]; ARD, 6.5% [95% CI, 5.7%-12.5%]), moderate activity (n = 176 [38.6%]; ARD, 14.3% [95% CI, 5.9%-22.2%]), and full-contact activity (n = 133 [36.1%]; ARD, 16.8% [95% CI, 7.5%-25.5%]). No significant group difference was observed on propensity-matched analysis of this subgroup (n = 776 [47.2% vs 51.5%]; ARD, 4.4% [95% CI, -2.6% to 11.3%]). Conclusions and Relevance: Among participants aged 5 to 18 years with acute concussion, physical activity within 7 days of acute injury compared with no physical activity was associated with reduced risk of PPCS at 28 days. A well-designed randomized clinical trial is needed to determine the benefits of early physical activity following concussion.

Exposure to adverse childhood experiences (ACEs), including maltreatment and family dysfunction, is a major contributor to the global burden of disease and disability. With a large body of international literature on ACEs having emerged over the past 25 years, it is timely to now synthetize the available evidence to estimate the global prevalence of ACEs and, through a series of moderator analyses, determine which populations are at higher risk. We searched studies published between January 1, 1998 and August 5, 2021 in Medline, PsycINFO and Embase. Study inclusion criteria were using the 8- or 10-item ACE Questionnaire (±2 items), reporting the prevalence of ACEs in population samples of adults, and being published in English. The review protocol was registered with PROSPERO (CRD42022348429). In total, 206 studies (208 sample estimates) from 22 countries, with 546,458 adult participants, were included. The pooled prevalence of the five levels of ACEs was: 39.9% (95% CI: 29.8-49.2) for no ACE; 22.4% (95% CI: 14.1-30.6) for one ACE; 13.0% (95% CI: 6.5-19.8) for two ACEs; 8.7% (95% CI: 3.4-14.5) for three ACEs, and 16.1% (95% CI: 8.9-23.5) for four or more ACEs. In subsequent moderation analyses, there was strong evidence that the prevalence of 4+ ACEs was higher in populations with a history of a mental health condition (47.5%; 95% CI: 34.4-60.7) and with substance abuse or addiction (55.2%; 95% CI: 45.5-64.8), as well as in individuals from low-income households (40.5%; 95% CI: 32.9-48.4) and unhoused individuals (59.7%; 95% CI: 56.8-62.4). There was also good evidence that the prevalence of 4+ ACEs was larger in minoritized racial/ethnic groups, particularly when comparing study estimates in populations identifying as Indigenous/Native American (40.8%; 95% CI: 23.1-59.8) to those identifying as White (12.1%; 95% CI: 10.2-14.2) and Asian (5.6%; 95% CI: 2.4-10.2). Thus, ACEs are common in the general population, but there are disparities in their prevalence. They are among the principal antecedent threats to individual well-being and, as such, constitute a pressing social issue globally. Both prevention strategies and downstream interventions are needed to reduce the prevalence and mitigate the severity of the effects of ACEs and thereby reduce their deleterious health consequences on future generations.

Ongoing challenges in diagnosing focal cortical dysplasia (FCD) mandate continuous research and consensus agreement to improve disease definition and classification. An International League Against Epilepsy (ILAE) Task Force (TF) reviewed the FCD classification of 2011 to identify existing gaps and provide a timely update. The following methodology was applied to achieve this goal: a survey of published literature indexed with ((Focal Cortical Dysplasia) AND (epilepsy)) between 01/01/2012 and 06/30/2021 (n = 1349) in PubMed identified the knowledge gained since 2012 and new developments in the field. An online survey consulted the ILAE community about the current use of the FCD classification scheme with 367 people answering. The TF performed an iterative clinico-pathological and genetic agreement study to objectively measure the diagnostic gap in blood/brain samples from 22 patients suspicious for FCD and submitted to epilepsy surgery. The literature confirmed new molecular-genetic characterizations involving the mechanistic Target Of Rapamycin (mTOR) pathway in FCD type II (FCDII), and SLC35A2 in mild malformations of cortical development (mMCDs) with oligodendroglial hyperplasia (MOGHE). The electro-clinical-imaging phenotypes and surgical outcomes were better defined and validated for FCDII. Little new information was acquired on clinical, histopathological, or genetic characteristics of FCD type I (FCDI) and FCD type III (FCDIII). The survey identified mMCDs, FCDI, and genetic characterization as fields for improvement in an updated classification. Our iterative clinico-pathological and genetic agreement study confirmed the importance of immunohistochemical staining, neuroimaging, and genetic tests to improve the diagnostic yield. The TF proposes to include mMCDs, MOGHE, and "no definite FCD on histopathology" as new categories in the updated FCD classification. The histopathological classification can be further augmented by advanced neuroimaging and genetic studies to comprehensively diagnose FCD subtypes; these different levels should then be integrated into a multi-layered diagnostic scheme. This update may help to foster multidisciplinary efforts toward a better understanding of FCD and the development of novel targeted treatment options.

It has long been claimed that "maltreatment begets maltreatment," that is, a parent's history of maltreatment increases the risk that his or her child will also suffer maltreatment. However, significant methodological concerns have been raised regarding evidence supporting this assertion, with some arguing that the association weakens in samples with higher methodological rigor. In the current study, the intergenerational transmission of maltreatment hypothesis is examined in 142 studies (149 samples; 227,918 dyads) that underwent a methodological quality review, as well as data extraction on a number of potential moderator variables. Results reveal a modest association of intergenerational maltreatment (k = 80; d = 0.45, 95% confidence interval; CI [0.37, 0.54]). Support for the intergenerational transmission of specific maltreatment types was also observed (neglect: k = 13, d = 0.24, 95% CI [0.11, 0.37]; physical abuse: k = 61, d = 0.41, 95% CI [0.33, 0.49]; emotional abuse: k = 18, d = 0.57, 95% CI [0.43, 0.71]; sexual abuse: k = 18, d = 0.39, 95% CI [0.24, 0.55]). Methodological quality only emerged as a significant moderator of the intergenerational transmission of physical abuse, with a weakening of effect sizes as methodological rigor increased. Evidence from this meta-analysis confirms the cycle of maltreatment hypothesis, although effect sizes were modest. Future research should focus on deepening understanding of mechanisms of transmission, as well as identifying protective factors that can effectively break the cycle of maltreatment.

Youth have very high participation and injury rates in sport. Sport is the leading cause of injury in youth. Sport injury reduces future participation in physical activity which adversely affects future health. Sport injury may lead to overweight/obesity and post-traumatic osteoarthritis. The objective of the systematic review and meta-analysis was to evaluate the efficacy of injury prevention neuromuscular training strategies in youth sport. Three electronic databases were systematically searched up to September 2014. Studies selected met the following criteria: original data; analytic prospective design; investigated a neuromuscular training prevention strategy intervention(s) and included outcomes for injury sustained during sport participation. Two authors assessed the quality of evidence using Downs and Black (DB) criteria. Meta-analyses including randomised controlled trials only (RCTs) to ensure study design homogeneity were completed for lower extremity and knee injury outcomes. Of 2504 potentially relevant studies, 25 were included. Meta-analysis revealed a combined preventative effect of neuromuscular training in reducing the risk of lower extremity injury (incidence rate ratio: IRR=0.64 (95% CI 0.49 to 0.84)). Though not statistically significant, the point estimate suggests a protective effect of such programmes in reducing the risk of knee injury (IRR=0.74 (95% CI 0.51 to 1.07)). There is evidence for the effectiveness of neuromuscular training strategies in the reduction of injury in numerous team sports. Lack of uptake and ongoing maintenance of such programmes is an ongoing concern. A focus on implementation is critical to influence knowledge, behaviour change and sustainability of evidence informed injury prevention practice.

Importance: There is a growing body of high-quality cohort-based research that has examined changes in child and adolescent mental health during the COVID-19 pandemic vs before the pandemic. Some studies have found that child and adolescent depression and anxiety symptoms have increased, while others have found these symptoms to have remained stable or decreased. Objective: To synthesize the available longitudinal cohort-based research evidence to estimate the direction and magnitude of changes in depression and anxiety symptoms in children and adolescents assessed before and during the pandemic. Data Sources: Medline, Embase, and PsycInfo were searched for studies published between January 1, 2020, and May 17, 2022. Study Selection: Included studies reported on depression and/or anxiety symptoms, had cohort data comparing prepandemic to pandemic estimates, included a sample of children and/or adolescents younger than 19 years, and were published in English in a peer-reviewed journal. Data Extraction and Synthesis: In total, 53 longitudinal cohort studies from 12 countries with 87 study estimates representing 40 807 children and adolescents were included. Main Outcomes and Measures: Standardized mean changes (SMC) in depression and anxiety symptoms from before to during the pandemic. Results: The analysis included 40 807 children and adolescents represented in pre-COVID-19 studies and 33 682 represented in during-COVID-19 studies. There was good evidence of an increase in depression symptoms (SMC, 0.26; 95% CI, 0.19 to 0.33). Changes in depression symptoms were most conclusive for study estimates among female individuals (SMC, 0.32; 95% CI, 0.21 to 0.42), study estimates with mid to high income (SMC, 0.35; 95% CI, 0.07 to 0.63), and study estimates sourced from North America (SMC, 0.25; 95% CI, 0.15 to 0.36) and Europe (SMC, 0.35; 95% CI, 0.17 to 0.53). There was strong evidence that anxiety symptoms increased slightly during the pandemic (SMC, 0.10; 95% CI, 0.04 to 0.16), and there was some evidence of an increase in study estimates with mid to high income. Conclusions: This systematic review and meta-analysis of longitudinal studies including children and adolescents found an increase in depression symptoms during the COVID-19 pandemic, particularly among female individuals and those from relatively higher-income backgrounds.

Snakes possess many extreme morphological and physiological adaptations. Identification of the molecular basis of these traits can provide novel understanding for vertebrate biology and medicine. Here, we study snake biology using the genome sequence of the Burmese python (Python molurus bivittatus), a model of extreme physiological and metabolic adaptation. We compare the python and king cobra genomes along with genomic samples from other snakes and perform transcriptome analysis to gain insights into the extreme phenotypes of the python. We discovered rapid and massive transcriptional responses in multiple organ systems that occur on feeding and coordinate major changes in organ size and function. Intriguingly, the homologs of these genes in humans are associated with metabolism, development, and pathology. We also found that many snake metabolic genes have undergone positive selection, which together with the rapid evolution of mitochondrial proteins, provides evidence for extensive adaptive redesign of snake metabolic pathways. Additional evidence for molecular adaptation and gene family expansions and contractions is associated with major physiological and phenotypic adaptations in snakes; genes involved are related to cell cycle, development, lungs, eyes, heart, intestine, and skeletal structure, including GRB2-associated binding protein 1, SSH, WNT16, and bone morphogenetic protein 7. Finally, changes in repetitive DNA content, guanine-cytosine isochore structure, and nucleotide substitution rates indicate major shifts in the structure and evolution of snake genomes compared with other amniotes. Phenotypic and physiological novelty in snakes seems to be driven by system-wide coordination of protein adaptation, gene expression, and changes in the structure of the genome.

Myopia is the most common childhood refractive disorder. Atropine inhibits myopia progression, but its mechanism is unknown. Here, we show that myopia-prevention by atropine requires production of nitric oxide (NO). Form-deprivation myopia (FDM) was induced in week-old chicks by diffusers over the right eye (OD); the left eye (OS) remained ungoggled. On post-goggling days 1, 3, and 5, OD received intravitreally 20 µL of phosphate-buffered saline (vehicle), or vehicle plus: NO source: L-arginine (L-Arg, 60-6,000 nmol) or sodium nitroprusside (SNP, 10-1,000 nmol); atropine (240 nmol); NO inhibitors: L-NIO or L-NMMA (6 nmol); negative controls: D-Arg (10 µmol) or D-NMMA (6 nmol); or atropine plus L-NIO, L-NMMA, or D-NMMA; OS received vehicle. On day 6 post-goggling, refractive error, axial length, equatorial diameter, and wet weight were measured. Vehicle-injected goggled eyes developed significant FDM. This was inhibited by L-Arg (ED50 = 400 nmol) or SNP (ED50 = 20 nmol), but not D-Arg. Higher-dose SNP, but not L-Arg, was toxic to retina/RPE. Atropine inhibited FDM as expected; adding NOS-inhibitors (L-NIO, L-NMMA) to atropine inhibited this effect dose-dependently, but adding D-NMMA did not. Equatorial diameter, wet weight, and metrics of control eyes were not affected by any treatment. In summary, intraocular NO inhibits myopia dose-dependently and is obligatory for inhibition of myopia by atropine.