A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways

Worldwide trends in underweight and obesity from 1990 to 2022: a pooled analysis of 3663 population-representative studies with 222 million children, adolescents, and adults

Background Underweight and obesity are associated with adverse health outcomes throughout the life course. We estimated the individual and combined prevalence of underweight or thinness and obesity, and their changes, from 1990 to 2022 for adults and school-aged children and adolescents in 200 countries and territories. Methods We used data from 3663 population-based studies with 222 million participants that measured height and weight in representative samples of the general population. We used a Bayesian hierarchical model to estimate trends in the prevalence of different BMI categories, separately for adults (age ≥20 years) and school-aged children and adolescents (age 5–19 years), from 1990 to 2022 for 200 countries and territories. For adults, we report the individual and combined prevalence of underweight (BMI <18·5 kg/m2) and obesity (BMI ≥30 kg/m2). For schoolaged children and adolescents, we report thinness (BMI <2 SD below the median of the WHO growth reference) and obesity (BMI >2 SD above the median). Findings From 1990 to 2022, the combined prevalence of underweight and obesity in adults decreased in 11 countries (6%) for women and 17 (9%) for men with a posterior probability of at least 0·80 that the observed changes were true decreases. The combined prevalence increased in 162 countries (81%) for women and 140 countries (70%) for men with a posterior probability of at least 0·80. In 2022, the combined prevalence of underweight and obesity was highest in island nations in the Caribbean and Polynesia and Micronesia, and countries in the Middle East and north Africa. Obesity prevalence was higher than underweight with posterior probability of at least 0·80 in 177 countries (89%) for women and 145 (73%) for men in 2022, whereas the converse was true in 16 countries (8%) for women, and 39 (20%) for men. From 1990 to 2022, the combined prevalence of thinness and obesity decreased among girls in five countries (3%) and among boys in 15 countries (8%) with a posterior probability of at least 0·80, and increased among girls in 140 countries (70%) and boys in 137 countries (69%) with a posterior probability of at least 0·80. The countries with highest combined prevalence of thinness and obesity in school-aged children and adolescents in 2022 were in Polynesia and Micronesia and the Caribbean for both sexes, and Chile and Qatar for boys. Combined prevalence was also high in some countries in south Asia, such as India and Pakistan, where thinness remained prevalent despite having declined. In 2022, obesity in school-aged children and adolescents was more prevalent than thinness with a posterior probability of at least 0·80 among girls in 133 countries (67%) and boys in 125 countries (63%), whereas the converse was true in 35 countries (18%) and 42 countries (21%), respectively. In almost all countries for both adults and school-aged children and adolescents, the increases in double burden were driven by increases in obesity, and decreases in double burden by declining underweight or thinness. Interpretation The combined burden of underweight and obesity has increased in most countries, driven by an increase in obesity, while underweight and thinness remain prevalent in south Asia and parts of Africa. A healthy nutrition transition that enhances access to nutritious foods is needed to address the remaining burden of underweight while curbing and reversing the increase in obesit

A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.Peer reviewe

Molecular mechanisms of ventilator-induced lung injury, Biotrauma

grantor: University of TorontoVentilator-induced lung injury is recognized as a source of significant morbidity and mortality in intensive care units. Until recently, studies examining the pathophysiology of this disorder focused almost exclusively on the physiological effects and structural sequelae of different ventilatory strategies. These studies demonstrated that ventilation at either extreme of lung volume is injurious, and can produce injury comparable to that observed with the acute respiratory distress syndrome. In this thesis we explored the hypothesis that there is an active cellular and molecular mediated component involved in the pathogenesis of ventilator-induced lung injury. Using an isolated rat lung model to assess the effect of ventilation on the lung independent of confounding hemodynamic or systemic effects, we demonstrated that ventilation with strategies that produced high end-inspiratory or low end-expiratory lung volume increased inflammatory cytokine production by the lung. The time course of production of TNFÃ at the protein and steady state mRNA levels was found to be dependent on both time and the particular ventilator strategy used. Increased TNFÃ appeared to precede signs of histologic injury, and was associated with evidence of surfactant dysfunction. In situ hybridization for TNFÃ and IL-6 revealed that injurious ventilation produced an increase in expression of these inflammatory cytokines by the vast airway and alveolar epithelium. In contrast, epithelial expression of these cytokines in lungs subjected to non-injurious ventilation was significantly less, and comparable to that seen in lungs freshly harvested. As the epithelium of the lung is exposed directly to the mechanical stresses of ventilation, further studies were performed 'in vitro' to assess whether cell stretch was responsible, in part, for inducing the changes in alveolar epithelial cytokine expression we observed. We conclude that mechanical ventilation can have a significant effect on the inflammatory response of the lung and that this may be important in the initiation and propagation of lung injury, as well as potentially the development of a persistent systemic inflammatory response. We speculate that the use of interventions that target the inflammatory sequelae of ventilation combined with manipulation of ventilatory parameters may reduce the morbidity and mortality of patients with acute respiratory failure.Ph.D

Prospective Study for the Detection of Vascular Injury in Adult and Pediatric Patients with Cervicothoracic Seat Belt Signs

BACKGROUND: A delayed diagnosis of injury to cervicothoracic vessels from blunt trauma may cause significant adverse sequelae. The association of a cervicothoracic seat belt sign with such an injury is unknown. METHODS: Algorithms were prospectively studied for the detection of occult vascular injury in patients with cervicothoracic seat belt signs. Patients with neck seat belt signs underwent arteriography or computed tomographic angiography (CTA). Those with thoracic seat belt signs underwent aortography/arteriography if a ruptured thoracic aorta or injury to a great vessel was suspected or a neurovascular abnormality was present. RESULTS: During a 17-month period, 797 patients were admitted to the trauma service secondary to motor vehicle crashes. One hundred thirty-one (16.4%) had cervical or thoracic seat belt signs. Four (3%) of the patients had carotid artery injuries, the presence of which was strongly associated with a Glasgow Coma Scale score \u3c 14, an Injury Severity Score \u3e 16 (p \u3c 0.0001), and the presence of a clavicle and/or first rib fracture (p \u3c 0.0037). Of the remaining patients, 17 had thoracic trauma. There were no vascular injuries in the children and only one had thoracic trauma. CONCLUSION: The algorithms are safe and accurate for the detection of cervicothoracic vascular injury in adult and pediatric patients with seat belt signs. The cervicothoracic seat belt mark and an abnormal physical examination are an effective combination in screening for cervicothoracic vascular injury

Prospective Study for the Detection of Vascular Injury in Adult and Pediatric Patients with Cervicothoracic Seat Belt Signs

BACKGROUND: A delayed diagnosis of injury to cervicothoracic vessels from blunt trauma may cause significant adverse sequelae. The association of a cervicothoracic seat belt sign with such an injury is unknown. METHODS: Algorithms were prospectively studied for the detection of occult vascular injury in patients with cervicothoracic seat belt signs. Patients with neck seat belt signs underwent arteriography or computed tomographic angiography (CTA). Those with thoracic seat belt signs underwent aortography/arteriography if a ruptured thoracic aorta or injury to a great vessel was suspected or a neurovascular abnormality was present. RESULTS: During a 17-month period, 797 patients were admitted to the trauma service secondary to motor vehicle crashes. One hundred thirty-one (16.4%) had cervical or thoracic seat belt signs. Four (3%) of the patients had carotid artery injuries, the presence of which was strongly associated with a Glasgow Coma Scale score \u3c 14, an Injury Severity Score \u3e 16 (p \u3c 0.0001), and the presence of a clavicle and/or first rib fracture (p \u3c 0.0037). Of the remaining patients, 17 had thoracic trauma. There were no vascular injuries in the children and only one had thoracic trauma. CONCLUSION: The algorithms are safe and accurate for the detection of cervicothoracic vascular injury in adult and pediatric patients with seat belt signs. The cervicothoracic seat belt mark and an abnormal physical examination are an effective combination in screening for cervicothoracic vascular injury