Study protocol for Running for health (Run4Health CP) : a multicentre, assessor-blinded randomised controlled trial of 12 weeks of two times weekly Frame Running training versus usual care to improve cardiovascular health risk factors in children and youth with cerebral palsy

Introduction: Children and youth with moderate-severe (Gross Motor Function Classification System (GMFCS) levels II–V) cerebral palsy (CP) participate less frequently in physical activities compared with peers without CP and have elevated risk of cardiorespiratory morbidity and mortality in adulthood. Frame Running (RaceRunning) is a new athletics discipline that is an accessible option for physical activity participation for people with moderate-severe CP. There is no high-quality evidence for the effect of Frame Running on cardiovascular disease in children and young people with CP. The primary aim of this study is to conduct a randomised controlled trial of the effect of 12 weeks of Frame Running training on risk factors for cardiovascular disease. Methods and analysis: Sixty-two children and youth with CP (age 8–20 years) in GMFCS levels II–V will be recruited across four sites and randomised to receive either 12 weeks of Frame Running training two times weekly for 60 min, or usual care. Outcomes will be measured at baseline, immediately postintervention (primary endpoint) and 12 weeks later for retention of training effects. The primary outcome is cardiorespiratory fitness as measured by distance covered on Six Minute RaceRunner Test with 1 min heart rate recovery. Other outcomes include blood pressure, objectively measured physical activity, body mass index, waist circumference, percentage body fat, gross motor function capacity, community participation, feasibility, tolerability and safety. Adverse events will be monitored, and participants and their caregivers will be interviewed to discern their experiences of participation in Frame Running. Ethics and dissemination: The Children’s Health Queensland Hospital and Health Service and the University of Queensland Human Research Ethics Committees have approved this study. Results will be disseminated in peer-reviewed journals and scientific conferences; through professional and athletic organisations; and to people with CP and their families. Trial registration number: ACTRN12621000317897; Australian New Zealand Clinical Trials Registry number

Correlates of high-impact physical activity measured objectively in older British adults

© The Author(s) 2017. Background Exposure to higher magnitude vertical impacts is thought to benefit bone health. The correlates of this high-impact physical activity (PA) in later life are unknown. Methods Participants were from the Cohort for Skeletal Health in Bristol and Avon, Hertfordshire Cohort Study and MRC National Survey of Health and Development. Associations of demographic, behavioural, physiological and psychological factors with vertical acceleration peaks ≥1.5 g (i.e. high-impact PA) from 7-day hip-worn accelerometer recordings were examined using linear regression. Results A total of 1187 participants (mean age = 72.7 years, 66.6% females) were included. Age, sex, education, active transport, selfreported higher impact PA, walking speed and self-rated health were independently associated with high-impact PA whereas BMI and sleep quality showed borderline independent associations. For example, differences in log-high-impact counts were 0.50 (P < 0.001) for men versus women and -0.56 (P < 0.001) for worst versus best self-rated health. Our final model explained 23% of between-participant variance in high impacts. Other correlates were not associated with high-impact activity after adjustment. Conclusions Besides age and sex, several factors were associated with higher impact PA in later life. Our findings help identify characteristics of older people that might benefit from interventions designed to promote osteogenic PA

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Rehabilitation versus surgical reconstruction for non-acute anterior cruciate ligament injury (ACL SNNAP): a pragmatic randomised controlled trial

BackgroundAnterior cruciate ligament (ACL) rupture is a common debilitating injury that can cause instability of the knee. We aimed to investigate the best management strategy between reconstructive surgery and non-surgical treatment for patients with a non-acute ACL injury and persistent symptoms of instability.MethodsWe did a pragmatic, multicentre, superiority, randomised controlled trial in 29 secondary care National Health Service orthopaedic units in the UK. Patients with symptomatic knee problems (instability) consistent with an ACL injury were eligible. We excluded patients with meniscal pathology with characteristics that indicate immediate surgery. Patients were randomly assigned (1:1) by computer to either surgery (reconstruction) or rehabilitation (physiotherapy but with subsequent reconstruction permitted if instability persisted after treatment), stratified by site and baseline Knee Injury and Osteoarthritis Outcome Score—4 domain version (KOOS4). This management design represented normal practice. The primary outcome was KOOS4 at 18 months after randomisation. The principal analyses were intention-to-treat based, with KOOS4 results analysed using linear regression. This trial is registered with ISRCTN, ISRCTN10110685, and ClinicalTrials.gov, NCT02980367.FindingsBetween Feb 1, 2017, and April 12, 2020, we recruited 316 patients. 156 (49%) participants were randomly assigned to the surgical reconstruction group and 160 (51%) to the rehabilitation group. Mean KOOS4 at 18 months was 73·0 (SD 18·3) in the surgical group and 64·6 (21·6) in the rehabilitation group. The adjusted mean difference was 7·9 (95% CI 2·5–13·2; p=0·0053) in favour of surgical management. 65 (41%) of 160 patients allocated to rehabilitation underwent subsequent surgery according to protocol within 18 months. 43 (28%) of 156 patients allocated to surgery did not receive their allocated treatment. We found no differences between groups in the proportion of intervention-related complications.InterpretationSurgical reconstruction as a management strategy for patients with non-acute ACL injury with persistent symptoms of instability was clinically superior and more cost-effective in comparison with rehabilitation management

Making sense scientific claims in advertising. A study of scientifically aware consumers

Evidence that science is becoming increasingly embedded in culture comes from the proliferation of discourses of ethical consumption, sustainability, and environmental awareness. Al Gore's recent award, along with UN's Inter-governmental Panel on Climate Change (IPCC) of the Nobel peace prize - provided a recent high profile linking of consumption and science. It is not clear to what extent the public at large engages in evaluating the scientific merits of the arguments about the link between human consumption and global environmental catastrophes. But on a local scale, we are routinely required to evaluate, scientific and pseudoscientific claims in advertising. Since advertising is used to sell products, the discourse of scientifically framed claims is being used to persuade consumers of the benefits of these products. In the case of functional foods and cosmetics, such statements are deployed to promote the health benefits and effectiveness of their products. This exploratory study examines the views of British consumers about the scientific and pseudoscientific claims made in advertisements for foods, with particular reference to functional foods, and cosmetics. The participants in the study all worked in scientific environments, though they were not all scientists. The study found that scientific arguments that were congruent with existing health knowledge tended to be accepted while pseudoscientific knowledge was regarded skeptically and concerns were raised over the accuracy and believability of the pseudoscientific claims. It appears that scientific awareness may play a part in consumers' ability to critically examine scientifically and pseudoscientifically based advertising claims. © SAGE Publications

Whole-genome sequencing reveals host factors underlying critical COVID-19

Altres ajuts: Department of Health and Social Care (DHSC); Illumina; LifeArc; Medical Research Council (MRC); UKRI; Sepsis Research (the Fiona Elizabeth Agnew Trust); the Intensive Care Society, Wellcome Trust Senior Research Fellowship (223164/Z/21/Z); BBSRC Institute Program Support Grant to the Roslin Institute (BBS/E/D/20002172, BBS/E/D/10002070, BBS/E/D/30002275); UKRI grants (MC_PC_20004, MC_PC_19025, MC_PC_1905, MRNO2995X/1); UK Research and Innovation (MC_PC_20029); the Wellcome PhD training fellowship for clinicians (204979/Z/16/Z); the Edinburgh Clinical Academic Track (ECAT) programme; the National Institute for Health Research, the Wellcome Trust; the MRC; Cancer Research UK; the DHSC; NHS England; the Smilow family; the National Center for Advancing Translational Sciences of the National Institutes of Health (CTSA award number UL1TR001878); the Perelman School of Medicine at the University of Pennsylvania; National Institute on Aging (NIA U01AG009740); the National Institute on Aging (RC2 AG036495, RC4 AG039029); the Common Fund of the Office of the Director of the National Institutes of Health; NCI; NHGRI; NHLBI; NIDA; NIMH; NINDS.Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care or hospitalization after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Empagliflozin in Patients with Chronic Kidney Disease

Background The effects of empagliflozin in patients with chronic kidney disease who are at risk for disease progression are not well understood. The EMPA-KIDNEY trial was designed to assess the effects of treatment with empagliflozin in a broad range of such patients. Methods We enrolled patients with chronic kidney disease who had an estimated glomerular filtration rate (eGFR) of at least 20 but less than 45 ml per minute per 1.73 m(2) of body-surface area, or who had an eGFR of at least 45 but less than 90 ml per minute per 1.73 m(2) with a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 200. Patients were randomly assigned to receive empagliflozin (10 mg once daily) or matching placebo. The primary outcome was a composite of progression of kidney disease (defined as end-stage kidney disease, a sustained decrease in eGFR to &lt; 10 ml per minute per 1.73 m(2), a sustained decrease in eGFR of &amp; GE;40% from baseline, or death from renal causes) or death from cardiovascular causes. Results A total of 6609 patients underwent randomization. During a median of 2.0 years of follow-up, progression of kidney disease or death from cardiovascular causes occurred in 432 of 3304 patients (13.1%) in the empagliflozin group and in 558 of 3305 patients (16.9%) in the placebo group (hazard ratio, 0.72; 95% confidence interval [CI], 0.64 to 0.82; P &lt; 0.001). Results were consistent among patients with or without diabetes and across subgroups defined according to eGFR ranges. The rate of hospitalization from any cause was lower in the empagliflozin group than in the placebo group (hazard ratio, 0.86; 95% CI, 0.78 to 0.95; P=0.003), but there were no significant between-group differences with respect to the composite outcome of hospitalization for heart failure or death from cardiovascular causes (which occurred in 4.0% in the empagliflozin group and 4.6% in the placebo group) or death from any cause (in 4.5% and 5.1%, respectively). The rates of serious adverse events were similar in the two groups. Conclusions Among a wide range of patients with chronic kidney disease who were at risk for disease progression, empagliflozin therapy led to a lower risk of progression of kidney disease or death from cardiovascular causes than placebo