Table_1_Serial Backward Locomotor Treadmill Training Improves Bidirectional Walking Performance in Chronic Stroke.docx

Background and Research QuestionWalking impairment remains a major limitation to functional independence after stroke. Yet, comprehensive and effective strategies to improve walking function after stroke are presently limited. Backward Locomotor Treadmill Training (BLTT) is a promising training approach for improving walking function; however, little is known about its mechanism of effect or the relationship between backward walking training and resulting overground forward walking performance. This study aims to determine the effects of serial BLTT on spatial aspects of backward and forward walking in chronic post-stroke individuals with residual walking impairment.MethodsThirty-nine adults (>6 months post-stroke) underwent 6 days of BLTT (3 × /week) over 2 weeks. Outcome measures included PRE-POST changes in backward and forward walking speeds, paretic and non-paretic step lengths, and single-support center of pressure distances. To determine the association between BLTT and overground walking, correlation analyses comparing training-related changes in these variables were performed.ResultsWe report an overall improvement in BLTT and overground walking speeds, bilateral step lengths, and single-support center of pressure distances over six training sessions. Further, there were weak positive associations between PRE-POST changes in BLTT speed, BLTT paretic step length, and overground forward walking speed.Conclusion and SignificanceOur findings suggest that individuals with chronic post-stroke walking impairment experience improvements in spatial walking measures during BLTT and overground. Therefore, BLTT may be a potential adjunctive training approach for post-stroke walking rehabilitation.</p

Loci associated with ischaemic stroke and its subtypes (SiGN): a genome-wide association study

BACKGROUND:The discovery of disease-associated loci through genome-wide association studies (GWAS) is the leading genetic approach to the identification of novel biological pathways underlying diseases in humans. Until recently, GWAS in ischaemic stroke have been limited by small sample sizes and have yielded few loci associated with ischaemic stroke. We did a large-scale GWAS to identify additional susceptibility genes for stroke and its subtypes.METHODS:To identify genetic loci associated with ischaemic stroke, we did a two-stage GWAS. In the first stage, we included 16?851 cases with state-of-the-art phenotyping data and 32?473 stroke-free controls. Cases were aged 16 to 104 years, recruited between 1989 and 2012, and subtypes of ischaemic stroke were recorded by centrally trained and certified investigators who used the web-based protocol, Causative Classification of Stroke (CCS). We constructed case-control strata by identifying samples that were genotyped on nearly identical arrays and were of similar genetic ancestral background. We cleaned and imputed data by use of dense imputation reference panels generated from whole-genome sequence data. We did genome-wide testing to identify stroke-associated loci within each stratum for each available phenotype, and we combined summary-level results using inverse variance-weighted fixed-effects meta-analysis. In the second stage, we did in-silico lookups of 1372 single nucleotide polymorphisms identified from the first stage GWAS in 20?941 cases and 364?736 unique stroke-free controls. The ischaemic stroke subtypes of these cases had previously been established with the Trial of Org 10?172 in Acute Stroke Treatment (TOAST) classification system, in accordance with local standards. Results from the two stages were then jointly analysed in a final meta-analysis.FINDINGS:We identified a novel locus (G allele at rs12122341) at 1p13.2 near TSPAN2 that was associated with large artery atherosclerosis-related stroke (first stage odds ratio [OR] 1·21, 95% CI 1·13-1·30, p=4·50?×?10-8; joint OR 1·19, 1·12-1·26, p=1·30?×?10-9). Our results also supported robust associations with ischaemic stroke for four other loci that have been reported in previous studies, including PITX2 (first stage OR 1·39, 1·29-1·49, p=3·26?×?10-19; joint OR 1·37, 1·30-1·45, p=2·79?×?10-32) and ZFHX3 (first stage OR 1·19, 1·11-1·27, p=2·93?×?10-7; joint OR 1·17, 1·11-1·23, p=2·29?×?10-10) for cardioembolic stroke, and HDAC9 (first stage OR 1·29, 1·18-1·42, p=3·50?×?10-8; joint OR 1·24, 1·15-1·33, p=4·52?×?10-9) for large artery atherosclerosis stroke. The 12q24 locus near ALDH2, which has previously been associated with all ischaemic stroke but not with any specific subtype, exceeded genome-wide significance in the meta-analysis of small artery stroke (first stage OR 1·20, 1·12-1·28, p=6·82?×?10-8; joint OR 1·17, 1·11-1·23, p=2·92?×?10-9). Other loci associated with stroke in previous studies, including NINJ2, were not confirmed.INTERPRETATION:Our results suggest that all ischaemic stroke-related loci previously implicated by GWAS are subtype specific. We identified a novel gene associated with large artery atherosclerosis stroke susceptibility. Follow-up studies will be necessary to establish whether the locus near TSPAN2 can be a target for a novel therapeutic approach to stroke prevention. In view of the subtype-specificity of the associations detected, the rich phenotyping data available in the Stroke Genetics Network (SiGN) are likely to be crucial for further genetic discoveries related to ischaemic stroke.</p

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013

SummaryBackground The Global Burden of Disease, Injuries, and Risk Factor study 2013 (GBD 2013) is the fi rst of a series ofannual updates of the GBD. Risk factor quantifi cation, particularly of modifi able risk factors, can help to identifyemerging threats to population health and opportunities for prevention. The GBD 2013 provides a timely opportunityto update the comparative risk assessment with new data for exposure, relative risks, and evidence on the appropriatecounterfactual risk distribution.Methods Attributable deaths, years of life lost, years lived with disability, and disability-adjusted life-years (DALYs)have been estimated for 79 risks or clusters of risks using the GBD 2010 methods. Risk–outcome pairs meetingexplicit evidence criteria were assessed for 188 countries for the period 1990–2013 by age and sex using three inputs:risk exposure, relative risks, and the theoretical minimum risk exposure level (TMREL). Risks are organised into ahierarchy with blocks of behavioural, environmental and occupational, and metabolic risks at the fi rst level of thehierarchy. The next level in the hierarchy includes nine clusters of related risks and two individual risks, with moredetail provided at levels 3 and 4 of the hierarchy. Compared with GBD 2010, six new risk factors have been added:handwashing practices, occupational exposure to trichloroethylene, childhood wasting, childhood stunting, unsafesex, and low glomerular fi ltration rate. For most risks, data for exposure were synthesised with a Bayesian metaregressionmethod, DisMod-MR 2.0, or spatial-temporal Gaussian process regression. Relative risks were based onmeta-regressions of published cohort and intervention studies. Attributable burden for clusters of risks and all riskscombined took into account evidence on the mediation of some risks such as high body-mass index (BMI) throughother risks such as high systolic blood pressure and high cholesterol.Findings All risks combined account for 57·2% (95% uncertainty interval [UI] 55·8–58·5) of deaths and 41·6%(40·1–43·0) of DALYs. Risks quantifi ed account for 87·9% (86·5?89·3) of cardiovascular disease DALYs, rangingto a low of 0% for neonatal disorders and neglected tropical diseases and malaria. In terms of global DALYs in2013, six risks or clusters of risks each caused more than 5% of DALYs: dietary risks accounting for 11·3 milliondeaths and 241·4 million DALYs, high systolic blood pressure for 10·4 million deaths and 208·1 million DALYs,child and maternal malnutrition for 1·7 million deaths and 176·9 million DALYs, tobacco smoke for 6·1 milliondeaths and 143·5 million DALYs, air pollution for 5·5 million deaths and 141·5 million DALYs, and high BMI for4·4 million deaths and 134·0 million DALYs. Risk factor patterns vary across regions and countries and with time.In sub-Saharan Africa, the leading risk factors are child and maternal malnutrition, unsafe sex, and unsafe water,sanitation, and handwashing. In women, in nearly all countries in the Americas, north Africa, and the MiddleEast, and in many other high-income countries, high BMI is the leading risk factor, with high systolic bloodpressure as the leading risk in most of Central and Eastern Europe and south and east Asia. For men, high systolicblood pressure or tobacco use are the leading risks in nearly all high-income countries, in north Africa and theMiddle East, Europe, and Asia. For men and women, unsafe sex is the leading risk in a corridor from Kenya toSouth Africa.Interpretation Behavioural, environmental and occupational, and metabolic risks can explain half of global mortalityand more than one-third of global DALYs providing many opportunities for prevention. Of the larger risks, theattributable burden of high BMI has increased in the past 23 years. In view of the prominence of behavioural riskfactors, behavioural and social science research on interventions for these risks should be strengthened. Manyprevention and primary care policy options are available now to act on key risks.</p