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

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

Skin Only or Silo Closure in the Critically Ill Patient with an Open Abdomen

Background: The morbidity and mortality of various open abdominal techniques remains unclear. Methods: A retrospective review was made of all trauma or general surgery patients who underwent an open abdominal closure from January 1997 to December 2000, at a large urban acute care hospital. Data are mean ± SD. Results: From 1997 to 2000, 181 patients (aged 39.8 ± 16.5 years) had an open abdomen for abdominal infection, planned reexploration, abdominal compartment syndrome, inability to reapproximate fascia, or as part of a “damage control” procedure. Twenty-three patients went on to develop an abdominal compartment syndrome. Gastrointestinal fistulas occurred in 26 patients, and 9 patients had a dehiscence. The overall mortality was 44.7%. Of the survivors, 52% went on to fascial closure, requiring 1 to 7 additional abdominal operations. Conclusions: The morbidity of the open abdomen varies with the particular indication. Gastrointestinal fistulas are the most common acute complication and an abdominal wall hernia, the most common chronic complication