Very early versus delayed mobilization after stroke: systematic review and meta-analysis

No abstract available

Economic Evaluation Plan (EEP) for A Very Early Rehabilitation Trial (AVERT): An international trial to compare the costs and cost-effectiveness of commencing out of bed standing and walking training (very early mobilization) within 24 h of stroke onset with usual stroke unit care

Rationale: A key objective of A Very Early Rehabilitation Trial is to determine if the intervention, very early mobilisation following stroke, is cost-effective. Resource use data were collected to enable an economic evaluation to be undertaken and a plan for the main economic analyses was written prior to the completion of follow up data collection. Aim and hypothesis To report methods used to collect resource use data, pre-specify the main economic evaluation analyses and report other intended exploratory analyses of resource use data. Sample size estimates: Recruitment to the trial has been completed. A total of 2,104 participants from 56 stroke units across three geographic regions participated in the trial. Methods and design: Resource use data were collected prospectively alongside the trial using standardised tools. The primary economic evaluation method is a cost-effectiveness analysis to compare resource use over 12 months with health outcomes of the intervention measured against a usual care comparator. A cost-utility analysis is also intended. Study outcome: The primary outcome in the cost-effectiveness analysis will be favourable outcome (modified Rankin Scale score 0-2) at 12 months. Cost-utility analysis will use health-related quality of life, reported as quality-adjusted life years gained over a 12 month period, as measured by the modified Rankin Scale and the Assessment of Quality of Life. Discussion: Outcomes of the economic evaluation analysis will inform the cost-effectiveness of very early mobilisation following stroke when compared to usual care. The exploratory analysis will report patterns of resource use in the first year following stroke

AVERT2(a very early rehabilitation trial, a very effective reproductive trigger): retrospective observational analysis of the number of babies born to trial staff

Objective: To report the number of participants needed to recruit per baby born to trial staff during AVERT, a large international trial on acute stroke, and to describe trial management consequences. Design: Retrospective observational analysis. Setting: 56 acute stroke hospitals in eight countries. Participants: 1074 trial physiotherapists, nurses, and other clinicians. Outcome measures: Number of babies born during trial recruitment per trial participant recruited. Results: With 198 site recruitment years and 2104 patients recruited during AVERT, 120 babies were born to trial staff. Births led to an estimated 10% loss in time to achieve recruitment. Parental leave was linked to six trial site closures. The number of participants needed to recruit per baby born was 17.5 (95% confidence interval 14.7 to 21.0); additional trial costs associated with each birth were estimated at 5736 Australian dollars on average. Conclusion: The staff absences registered in AVERT owing to parental leave led to delayed trial recruitment and increased costs, and should be considered by trial investigators when planning research and estimating budgets. However, the celebration of new life became a highlight of the annual AVERT collaborators’ meetings and helped maintain a cohesive collaborative group

The Effects of a Multiflavonoid Supplement on Vascular and Hemodynamic Parameters following Acute Exercise

Antioxidants can decrease oxidative stress and combined with acute exercise they may lead to further decreases in blood pressure. The purpose of this study was to investigate the effects of 2 weeks of antioxidant supplementation on vascular distensibility and cardiovascular hemodynamics during postexercise hypotension. Methods. Twenty young subjects were randomized to placebo (n = 10) or antioxidant supplementation (n = 10) for two weeks. Antioxidant status, vascular distensibility, and hemodynamics were obtained before, immediately, and 30 minutes after an acute bout of aerobic exercise both before and after supplementation. Results. Two weeks of antioxidant supplementation resulted in a greater systolic blood pressure (SBP) decrease during postexercise hypotension (PEH) and significant decreases in augmentation index versus placebo (12.5% versus 3.5%, resp.). Also ferric-reducing ability of plasma (FRAP) increased significantly (interaction P = 0.024) after supplementation. Conclusion. Supplementation showed an additive effect on PEH associated with increased FRAP values and decreases in systolic blood pressure and augmentation index

Exploring post acute rehabilitation service use and outcomes for working age stroke survivors (≤65 years) in Australia, UK and South East Asia: data from the international AVERT trial

Objectives: Information about younger people of working age (≤65 years), their post stroke outcomes and rehabilitation pathways can highlight areas for further research and service change. This paper describes: (1) baseline demographics; (2) post acute rehabilitation pathways; and (3) 12-month outcomes; disability, mobility, depression, quality of life, informal care and return to work of working age people across three geographic regions (Australasia (AUS), South East (SE) Asia and UK). Design: This post hoc descriptive exploration of data from the large international very early rehabilitation trial (A Very Early Rehabilitation Trial (AVERT)) examined the four common post acute rehabilitation pathways (inpatient rehabilitation, home with community rehabilitation, inpatient rehabilitation then community rehabilitation and home with no rehabilitation) experienced by participants in the 3 months post stroke and describes their 12-month outcomes. Setting: Hospital stroke units in AUS, UK and SE Asia. Participants: Patients who had an acute stroke recruited within 24 hours who were ≤65 years. Results: 668 participants were ≤65 years; 99% lived independently, and 88% no disability (modified Rankin Score (mRS)=0) prior to stroke. We had complete data for 12-month outcomes for n=631 (94%). The proportion receiving inpatient rehabilitation was higher in AUS than other regions (AUS 52%; UK 25%; SE Asia 23%), whereas the UK had higher community rehabilitation (UK 65%; AUS 61%; SE Asia 39%). At 12 months, 70% had no or little disability (mRS 0–2), 44% were depressed, 28% rated quality of life as poor or worse than death. For those working prior to stroke (n=228), only 57% had returned to work. A noteworthy number of working age survivors received no rehabilitation services within 3 months post stroke. Conclusions: There was considerable variation in rehabilitation pathways and post acute service use across the three regions. At 12 months, there were high rates of depression, poor quality of life and low rates of return to work. Trial registration number: Australian New Zealand Clinical Trials Registry (ACTRN12606000185561)

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe

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

Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes

publisher: Elsevier articletitle: Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes journaltitle: Cell articlelink: https://doi.org/10.1016/j.cell.2018.05.046 content_type: article copyright: © 2018 Elsevier Inc

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