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The aim of our systematic review and meta-analysis was to quantitatively synthesise the effects of school-based peer-led interventions on leaders’ academic, psychosocial, behavioural, and physical outcomes. Eligible studies were those that: (i) evaluated a school-based peer-led intervention using an experimental or quasi-experimental study design, (ii) included an age-matched control or comparison group, and (iii) evaluated the impact of the intervention on one or more leader outcomes. Medline, Sportdiscus, Psychinfo, Embase, and Scopus online databases were searched on the 24th of October, 2022 which yielded 13,572 results, with 31 included in the narrative synthesis and 12 in the meta-analysis. We found large positive effects for leaders’ attitudes toward bullying (d = 1.02), small-to-medium positive effects for leaders’ literacy (d = 0.39), and small positive effects for leaders’ self-esteem (d = 0.18). There were mixed findings for behavioural outcomes and null effects for physical outcomes. Notable limitations of this research are the inclusion of a relatively small number of studies, and high heterogeneity in those included. Our findings have the potential to inform educational practice, but also highlight the need for further research examining the mechanisms that might account for the observed effects. Our systematic review was prospectively registered with PROSPERO (CRD42021273129).

Background Evidence suggests that physical self-concept is associated with physical activity in children and adolescents, but no systematic review of this literature has been conducted. Objective The primary aim of this systematic review and meta-analysis was to determine the strength of associations between physical activity and physical self-concept (general and sub-domains) in children and adolescents. The secondary aim was to examine potential moderators of the association between physical activity and physical self-concept. Methods A systematic search of six electronic databases (MEDLINE, CINAHL, SPORTDiscus, ERIC, Web of Science and Scopus) with no date restrictions was conducted. Random effects meta-analyses with correction for measurement were employed. The associations between physical activity and general physical self-concept and sub-domains were explored. A risk of bias assessment was conducted by two reviewers. Results The search identified 64 studies to be included in the meta-analysis. Thirty-three studies addressed multiple outcomes of general physical self-concept: 28 studies examined general physical self-concept, 59 examined perceived competence, 25 examined perceived fitness, and 55 examined perceived appearance. Perceived competence was most strongly associated with physical activity ( r  = 0.30, 95 % CI 0.24–0.35, p  < 0.001), followed by perceived fitness ( r  = 0.26, 95 % CI 0.20–0.32, p  < 0.001), general physical self-concept ( r  = 0.25, 95 % CI 0.16–0.34, p  < 0.001) and perceived physical appearance ( r  = 0.12, 95 % CI 0.08–0.16, p  < 0.001). Sex was a significant moderator for general physical self-concept ( p  < 0.05), and age was a significant moderator for perceived appearance ( p  ≤ 0.01) and perceived competence ( p   <  0.05). No significant moderators were found for perceived fitness. Conclusion Overall, a significant association has been consistently demonstrated between physical activity and physical self-concept and its various sub-domains in children and adolescents. Age and sex are key moderators of the association between physical activity and physical self-concept.

This study aimed to assess the feasibility and efficacy of the Great Leaders Active StudentS (GLASS) program, a school-based peer-led physical activity and object control skill intervention. The study employed a quasi-experimental design. The study was conducted in two elementary schools, one intervention and one comparison, in Newcastle, New South Wales (NSW), Australia from April to June 2015 (N=224 students). Peer leaders (n=20) in the intervention school received training to deliver two 30-min object control skill sessions per week to students in Kindergarten, Grades 1 and 2 (5–8 years, n=83) over one school term (10 weeks). The primary outcome was pedometer assessed physical activity during school hours. Secondary outcomes included students’ object control skill competency and peers’ leadership self-efficacy and teacher ratings of peers’ leadership skills. Almost all (19/20) GLASS sessions were delivered by peer leaders who reported high acceptability of the program. The treatment-by-time interaction for students’ physical activity during school hours was not significant (p=0.313). The intervention effect on students’ overall object control skills was statistically significant (mean difference 5.8 (95% CI 4.1, 7.4; p<0.001)). Teacher-rated peer leadership significantly improved (0.70; 95% CI 0.38–1.01); p<.001)). The GLASS program was found to be both feasible and acceptable. The intervention also resulted in improvements in students’ overall object control skills as well as teacher-rated peers’ leadership behaviours. Future fully powered trials using peer leaders to deliver fundamental movement skill (FMS) programs are warranted.

Background Children living with disability have poorer health outcomes than their typically developing peers. They are less physically active and at increased risk of chronic disease. Teacher-led, whole-of-school physical activity interventions are promising levers for population-level change, but are seldom tested among children with disability. We aimed to evaluate the effect of a blended teacher-professional learning program (online and in-person) on fundamental movement skills (FMS) and physical activity among children with intellectual disability. Methods In this cluster randomized clinical trial, we randomized 20 government-funded primary schools, including 238 consenting students (Grades 2–5; aged 8–11 years at baseline). Ten schools received the blended teacher-professional learning intervention and 10 were assigned as waitlist controls. The professional learning was designed to support teachers as they implemented a whole-of-school intervention designed to enhance FMS and increase physical activity levels. The school-based intervention was mostly online learning, followed by lesson observations and site visits from project staff. Blinded assessors measured FMS competency using the Test of Gross Motor Development-3. Secondary outcomes were self-concept, enjoyment, wellbeing, 300-yard run time, and accelerometer-measured physical activity. Results We found no significant group-by-time effects for the primary outcome (FMS competency: b = 1.07 [95% CI -3.70, 5.84], p  =.658) or any secondary outcomes. Conclusions A school-based intervention did not improve FMS competency or physical activity in children with intellectual disability. Results may be attenuated by the COVID-19 pandemic. Alternatively, low intensity teacher-professional learning interventions may not be enough to improve FMS or physical activity among children with intellectual disability. Trial registration Australian New Zealand Clinical Trials Registry registration number: ACTRN12620000405910 , registered: 25/03/2020.

Burkholderia pseudomallei causes the potentially fatal disease melioidosis. It is generally accepted that B. pseudomallei is a noncommensal bacterium and that any culture-positive clinical specimen denotes disease requiring treatment. Over a 23-year study of melioidosis cases in Darwin, Australia, just one patient from 707 survivors has developed persistent asymptomatic B. pseudomallei carriage. To better understand the mechanisms behind this unique scenario, we performed whole-genome analysis of two strains isolated 139 months apart. During this period, B. pseudomallei underwent several adaptive changes. Of 23 point mutations, 78% were nonsynonymous and 43% were predicted to be deleterious to gene function, demonstrating a strong propensity for positive selection. Notably, a nonsense mutation inactivated the universal stress response sigma factor RpoS, with pleiotropic implications. The genome underwent substantial reduction, with four deletions in chromosome 2 resulting in the loss of 221 genes. The deleted loci included genes involved in secondary metabolism, environmental survival, and pathogenesis. Of 14 indels, 11 occurred in coding regions and 9 resulted in frameshift mutations that dramatically affected predicted gene products. Disproportionately, four indels affected lipopolysaccharide biosynthesis and modification. Finally, we identified a frameshift mutation in both P314 isolates within wcbR , an important component of the capsular polysaccharide I locus, suggesting virulence attenuation early in infection. Our study illustrates a unique clinical case that contrasts a high-consequence infectious agent with a long-term commensal infection and provides further insights into bacterial evolution within the human host. IMPORTANCE Some bacterial pathogens establish long-term infections that are difficult or impossible to eradicate with current treatments. Rapid advances in genome sequencing technologies provide a powerful tool for understanding bacterial persistence within the human host. Burkholderia pseudomallei is considered a highly pathogenic bacterium because infection is commonly fatal. Here, we document within-host evolution of B. pseudomallei in a unique case of human infection with ongoing chronic carriage. Genomic comparison of isolates obtained 139 months (11.5 years) apart showed a strong signal of adaptation within the human host, including inactivation of virulence and immunogenic factors, and deletion of pathways involved in environmental survival. Two global regulatory genes were mutated in the 139-month isolate, indicating extensive regulatory changes favoring bacterial persistence. Our study provides insights into B. pseudomallei pathogenesis and, more broadly, identifies parallel evolutionary mechanisms that underlie chronic persistence of all bacterial pathogens. Some bacterial pathogens establish long-term infections that are difficult or impossible to eradicate with current treatments. Rapid advances in genome sequencing technologies provide a powerful tool for understanding bacterial persistence within the human host. Burkholderia pseudomallei is considered a highly pathogenic bacterium because infection is commonly fatal. Here, we document within-host evolution of B. pseudomallei in a unique case of human infection with ongoing chronic carriage. Genomic comparison of isolates obtained 139 months (11.5 years) apart showed a strong signal of adaptation within the human host, including inactivation of virulence and immunogenic factors, and deletion of pathways involved in environmental survival. Two global regulatory genes were mutated in the 139-month isolate, indicating extensive regulatory changes favoring bacterial persistence. Our study provides insights into B. pseudomallei pathogenesis and, more broadly, identifies parallel evolutionary mechanisms that underlie chronic persistence of all bacterial pathogens.

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5–20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson’s disease gene involved in dopamine regulation, PARK2 , is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations. Post-traumatic stress disorder (PTSD) is a common mental health problem. Here, the authors report a GWAS from the Psychiatric Genomics Consortium in which they identify two risk loci in European ancestry and one locus in African ancestry individuals and find that PTSD is genetically correlated with several other psychiatric traits.

Post-traumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 new). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (for example, GRIA1 , GRM8 and CACNA1E ), developmental, axon guidance and transcription factors (for example, FOXP2 , EFNA5 and DCC ), synaptic structure and function genes (for example, PCLO , NCAM1 and PDE4B ) and endocrine or immune regulators (for example, ESR1 , TRAF3 and TANK ). Additional top genes influence stress, immune, fear and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation. Multi-ancestry genome-wide analyses identify 95 loci associated with post-traumatic stress disorder and implicate candidate genes, pathways and neurobiological systems underlying its pathophysiology.

ObjectivePancreatic ductal adenocarcinoma (PDAC) is commonly diagnosed at an advanced stage. Liquid biopsy approaches may facilitate detection of early stage PDAC when curative treatments can be employed.DesignTo assess circulating marker discrimination in training, testing and validation patient cohorts (total n=426 patients), plasma markers were measured among PDAC cases and patients with chronic pancreatitis, colorectal cancer (CRC), and healthy controls. Using CA19-9 as an anchor marker, measurements were made of two protein markers (TIMP1, LRG1) and cell-free DNA (cfDNA) pancreas-specific methylation at 9 loci encompassing 61 CpG sites.ResultsComparative methylome analysis identified nine loci that were differentially methylated in exocrine pancreas DNA. In the training set (n=124 patients), cfDNA methylation markers distinguished PDAC from healthy and CRC controls. In the testing set of 86 early stage PDAC and 86 matched healthy controls, CA19-9 had an area under the receiver operating characteristic curve (AUC) of 0.88 (95% CI 0.83 to 0.94), which was increased by adding TIMP1 (AUC 0.92; 95% CI 0.88 to 0.96; p=0.06), LRG1 (AUC 0.92; 95% CI 0.88 to 0.96; p=0.02) or exocrine pancreas-specific cfDNA methylation markers at nine loci (AUC 0.92; 95% CI 0.88 to 0.96; p=0.02). In the validation set of 40 early stage PDAC and 40 matched healthy controls, a combined panel including CA19-9, TIMP1 and a 9-loci cfDNA methylation panel had greater discrimination (AUC 0.86, 95% CI 0.77 to 0.95) than CA19-9 alone (AUC 0.82; 95% CI 0.72 to 0.92).ConclusionA combined panel of circulating markers including proteins and methylated cfDNA increased discrimination compared with CA19-9 alone for early stage PDAC.

Interleukin 17C (IL-17C) modulates epithelial inflammation and has a possible role in atopic dermatitis (AD) pathology. Four randomized clinical studies (Phase 1 and 2) investigated the safety, tolerability, efficacy, and pharmacokinetic profile of the anti-IL-17C monoclonal antibody MOR106 for up to 12 weeks (NCT03568071: n = 207 adults with moderate–severe AD; NCT03689829 Part 1: n = 32 healthy males; NCT03689829 Part 2: n = 44 adults with moderate–severe AD; and NCT03864627: n = 76 adults with moderate–severe AD). In these studies, MOR106 was either administered intravenously (i.v.) every 2 or 4 weeks at doses between 1–10 mg/kg, or subcutaneously (s.c.), either as a single dose or doses every 2 weeks at 320 mg. Overall, MOR106 was well-tolerated, and the safety profile was consistent with monoclonal antibodies approved for AD. Bioavailability following s.c. dosing was 55%, and steady-state drug levels were reached at 2–4 weeks. Ongoing studies were terminated following a futility analysis of the Phase 2 placebo-controlled dose-finding study (NCT03568071) due to a low probability for achieving the primary efficacy endpoint. Cumulatively, MOR106 demonstrated ineffectiveness for the treatment of AD, but its safety and pharmacokinetic characteristics warrant further drug development in other indications. Funding: sponsored by Galapagos NV; funded by Novartis AG.

BackgroundCurrently, little is known regarding the optimal technique for the abdominal phase of RAMIE. The aim of this study was to investigate the outcome of robot-assisted minimally invasive esophagectomy (RAMIE) in both the abdominal and thoracic phase (full RAMIE) compared to laparoscopy during the abdominal phase (hybrid laparoscopic RAMIE).MethodsThis retrospective propensity-score matched analysis of the International Upper Gastrointestinal International Robotic Association (UGIRA) database included 807 RAMIE procedures with intrathoracic anastomosis between 2017 and 2021 from 23 centers.ResultsAfter propensity-score matching, 296 hybrid laparoscopic RAMIE patients were compared to 296 full RAMIE patients. Both groups were equal regarding intraoperative blood loss (median 200 ml versus 197 ml, p = 0.6967), operational time (mean 430.3 min versus 417.7 min, p = 0.1032), conversion rate during abdominal phase (2.4% versus 1.7%, p = 0.560), radical resection (R0) rate (95.6% versus 96.3%, p = 0.8526) and total lymph node yield (mean 30.4 versus 29.5, p = 0.3834). The hybrid laparoscopic RAMIE group showed higher rates of anastomotic leakage (28.0% versus 16.6%, p = 0.001) and Clavien Dindo grade 3a or higher (45.3% versus 26.0%, p < 0.001). The length of stay on intensive care unit (median 3 days versus 2 days, p = 0.0005) and in-hospital (median 15 days versus 12 days, p < 0.0001) were longer for the hybrid laparoscopic RAMIE group.ConclusionsHybrid laparoscopic RAMIE and full RAMIE were oncologically equivalent with a potential decrease of postoperative complications and shorter (intensive care) stay after full RAMIE.