Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures

Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Effect of prophylactic administration of recombinant human granulocyte colony-stimulating factor (filgrastim) on the frequency of nosocomial infections in patients with acute traumatic brain injury or cerebral hemorrhage. The Filgrastim Study Group

OBJECTIVE: To determine whether the use of prophylactic recombinant human granulocyte colony-stimulating factor (filgrastim) reduces the frequency of nosocomial infections in patients with either acute traumatic brain injury or cerebral hemorrhage. DESIGN: Randomized, placebo-controlled, double-blind, multicenter phase II study. SETTING: Intensive care units of seven medical centers. PATIENTS: Patients with either acute traumatic brain injury or cerebral hemorrhage who were intubated within 6 hrs of admission and who were expected to be ventilated for \u3e72 hrs. INTERVENTIONS: Patients were randomized to receive daily subcutaneous injections of placebo (n = 21) or one of two doses of filgrastim (75 microg [n = 20] or 300 microg [n = 20]) for 10 days or until the absolute neutrophil count was \u3e75,000 cells/mm3 or until extubation. MEASUREMENTS AND MAIN RESULTS: End points included increase in absolute neutrophil count, safety of filgrastim, and frequency of nosocomial infections (pneumonia, bacteremia, and urinary tract infection). Filgrastim caused a dose-dependent increase in absolute neutrophil count. There were no differences in the frequency of pneumonia or urinary tract infection; however, there was a dose-dependent decrease in the frequency of bacteremias (p \u3c .05). Adverse events were similar among the three groups. There was one case of acute respiratory distress syndrome in the placebo group. CONCLUSION: In this patient population, use of filgrastim was safe and the agent appeared to reduce the risk of primary bacteremias but had no beneficial effects on mortality, length of stay, or other nosocomial infections

An Evaluation of the Use of Guidelines in Prehospital Management of Brain Injury

OBJECTIVES: The Brain Trauma Foundation (BTF) Guidelines for Prehospital Management of Traumatic Brain Injury (TBI) are intended to standardize treatment and improve outcomes in severe TBI patients. The key guideline components focus on airway management, blood pressure support, Glasgow Coma Score assessment, and transport. The purposes of this study were to determine if providers could learn and retain the guidelines (education), assess if providers would use the guidelines in practice (implementation), and evaluate the effect of guideline implementation on patients (outcomes). METHODS: Data were collected prospectively on all trauma patients for five months. Providers were then educated on the TBI guidelines over two months, and five additional months of data were collected. A knowledge test was given before and after the course and three months later to assess education. To assess implementation, data were analyzed to determine whether providers were using the key interventions more consistently after education. The clinical courses of TBI patients before and after guideline implementation were measured to assess outcomes. RESULTS: Knowledge of TBI care improved significantly after education and remained elevated at three months (62% vs. 82% vs. 79%, p \u3c 0.001). For the 1,044 patients seen, providers demonstrated higher rates of appropriate care, resulting in lower rates of hypoxia (2.8% vs. 1.1%, p=0.010) and hypotension (4.8% vs. 2.0%, p=0.018). Mortality was significantly decreased (34.6% vs. 17.0%, p=0.039), and rates of patients with maximum functional scores at 14 days significantly increased (Glasgow Outcome Score 44.2% vs. 66.0%, p=0.025; Rancho Los Amigos Scale 55.9% vs. 77.3%, p=0.045). CONCLUSION: Providers were able to learn and implement the BTF guidelines, and outcomes in TBI patients were significantly improved. All emergency medical services providers should be trained in these potentially lifesaving guidelines

Associations between Social Support from Family, Friends, and Teachers and depressive Symptoms in Adolescents

Accepted: 17 June 2017Approximately 20% of adolescents develop depressive symptoms. Family, friends, and teachers are crucial sources of social support for adolescents, but it is unclear whether social support impacts adolescents directly (principle-effect model) or by moderating the effect of stress (stress-buffer model) and whether each source of social support remains meaningful when their influence is studied simultaneously. To help fill this gap, we followed 1452 Australian students (average age at enrollment = 13.1, SD = 0.5; range: 11-16 years; 51.9% female) for 5 years. Based on our findings, each source of support is negatively related to depressive symptoms one year later when studied independently but when combined, only family and teacher support predicted depressive symptoms. Family support in all grades and teacher support in grade 8 to 10 but not in grade 11 directly impacted adolescent depressive symptoms 1 year later. Family support in grades 8 and 11 also buffered against the negative impact of stress on depressive symptoms one year later. Based on the unexpected findings, the most important limitations seem to be that the used instruments do not allow for a separation of different groups of friends (e.g., classmates, same-gender peers, romantic partners), types of social support, and stress. In addition, the high, nonrandom attrition rate with adolescents reporting less social support, more stressful events, a higher frequency of depressive symptoms, and/or being of Torres Strait Islander or Aboriginal background limits the generalizability of our findings. Summarized, our findings demonstrate that adolescents facing stress might benefit more from family support compared to their peers without stressful life events and that friends may have a weaker presence in adolescent lives than expected.Patrick Pössel, Shelby M. Burton, Bridget Cauley, Michael G. Sawyer, Susan H. Spence, Jeanie Sheffiel