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

Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005). INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. FUNDING: UK National Institute for Health Research Health Technology Assessment

Proprioceptive performance of bilateral upper and lower limb joints: side-general and site-specific effects

Superiority of the left upper limb in proprioception tasks performed by right-handed individuals has been attributed to better utilization of proprioceptive information by a non-preferred arm/hemisphere system. However, it is undetermined whether this holds for multiple upper and lower limb joints. Accordingly, the present study tested active movement proprioception at four pairs of upper and lower limb joints, after selecting twelve participants with both strong right arm and right leg preference. A battery of versions of the active movement extent discrimination apparatus were employed to generate the stimuli for movements of different extents at the ankle, knee, shoulder and fingers on the right and left sides of the body, and discrimination scores were derived from participants’ responses. Proprioceptive performance on the non-preferred left side was significantly better than the preferred right side at all four joints tested (overall F(1, 11) = 36.36, p < 0.001, partial η(2) = 0.77). In the 8 × 8 matrix formed by all joints, only correlations between the proprioceptive accuracy scores for the right and left sides at the same joint were significant (ankles 0.93, knees 0.89, shoulders 0.87, fingers 0.91, p ≤ 0.001; all others r ≤ 0.40, p ≥ 0.20). The results point to both a side-general effect and a site-specific effect in the integration of proprioceptive information during active movement tasks, whereby the non-preferred limb/hemisphere system is specialized in the utilization of the best proprioceptive sources available at each specific joint, but the combination of sources employed differs between body sites

Neuromuscular Fatigue and Muscle Damage After a Women's Rugby Sevens Tournament

Purpose:To examine relationships between on-field game movement patterns and changes in markers of neuromuscular fatigue and muscle damage during a 2-d women’s rugby sevens tournament.Methods:Female national (mean ± SD n = 12, 22.3 ± 2.5 y, 1.67 ± 0.04 m, 65.8 ± 4.6 kg) and state (n = 10, 24.4 ± 4.3 y, 1.67 ± 0.03 m, 66.1 ± 7.9 kg) representative players completed baseline testing for lower-body neuromuscular function (countermovement-jump [CMJ] test), muscle damage (capillary creatine kinase [CK]), perceived soreness, and perceived recovery. Testing was repeated after games on days 1 and 2 of the tournament. GPS (5-Hz) data were collected throughout the tournament (4−6 games/player).Results:National players were involved in greater on-field movements for total time, distance, high-speed running (&gt;5 m/s), and impacts &gt;10 g (effect size [ES] = 0.55−0.97) and displayed a smaller decrement in performance from day 1 to day 2. Despite this, state players had a much greater 4-fold increase (ΔCK = 737 U/L) in CK compared with the 2-fold increase (ΔCK = 502 U/L) in national players (ES = 0.73). Both groups had similar perceived soreness and recovery while CMJ performance was unchanged. High-speed running and impacts &gt;10 g were largely correlated (r = .66−.91) with ΔCK for both groups.Conclusion:A 2-day women’s rugby sevens tournament elicits substantial muscle damage; however, there was little change in lower-body neuromuscular function. Modest increases in CK can largely be attributed to high-speed running and impacts &gt;10 g that players typically endure.</jats:sec

High-intensity cycle interval training improves cycling and running performance in triathletes

Effective cycle training for triathlon is a challenge for coaches. We compared the effects of two variants of cycle high-intensity interval training (HIT) on triathlon-specific cycling and running. Fourteen moderately-trained male triathletes (_VO2peak 58.7 ± 8.1 mL kg − 1 min − 1; mean ± SD) completed on separate occasions a maximal incremental test (_VO2peak and maximal aerobic power), 16 × 20 s cycle sprints and a 1-h triathlon-specific cycle followed immediately by a 5 km run time trial. Participants were then pair-matched and assigned randomly to either a long high-intensity interval training (LONG)(6 – 8 × 5 min efforts) or short high-intensity interval training (SHORT) (9 – 11 × 10, 20 and 40 s efforts) HIT cycle training intervention. Six training sessions were completed over 3 weeks before participants repeated the baseline testing. Both groups had an ~ 7% increase in _VO2peak (SHORT 7.3%, ± 4.6%; mean, ± 90% confidence limits; LONG 7.5%, ± 1.7%). There was a moderate improvement in mean power for both the SHORT (10.3%, ± 4.4%) and LONG (10.7%, ± 6.8%) groups during the last eight 20-s sprints. There was a small to moderate decrease in heart rate, blood lactate and perceived exertion in both groups during the 1-h triathlon-specific cycling but only the LONG group had a substantial decrease in the subsequent 5-km run time (64, ± 59 s). Moderately-trained triathletes should use both short and long high-intensity intervals to improve cycling physiology and performance. Longer 5-min intervals on the bike are more likely to benefit 5 km running performance

Physiological, anthropometric, and performance characteristics of rugby sevens players

Although the characteristics of 15-a-side rugby union players have been well defined, there is little information on rugby sevens players.\ud \ud PURPOSE:\ud \ud The authors profiled the anthropometric, physiological, and performance qualities of elite-level rugby sevens players and quantified relationships between these characteristics.\ud \ud METHODS:\ud \ud Eighteen male international rugby sevens players undertook anthropometric (body mass, height, sum of 7 skinfolds, lean-mass index), acceleration and speed (40-m sprint), muscle-power (vertical jump), repeated-sprint-ability (6 × 30-m sprint), and endurance (Yo-Yo Intermittent Recovery test and treadmill VO2max) testing. Associations between measurements were assessed by correlation analysis.\ud \ud RESULTS:\ud \ud Rugby sevens players had anthropometric characteristics (body mass 89.7 ± 7.6 kg, height 1.83 ± 0.06 m, sum of 7 skinfolds 52.2 ± 11.5 mm; mean ± SD) similar to those of backs in international 15-player rugby union. Acceleration and speed (40-m sprint 5.11 ± 0.15 s), muscle-power (vertical jump 66 ± 7 cm), and endurance (VO2max 53.8 ± 3.4 mL · kg-1 · min-1) qualities were similar to, or better than, those of professional 15-a-side players. Coefficients of variation ranged from 2.5% to 22%. Relative VO2max was largely correlated with Yo-Yo distance (r = .60, .21-.82; 90% confidence interval) and moderately correlated with 40-m sprint time (r = -.46, -.75 to -.02) and repeated-sprint ability (r = -.38, -.72 to .09).\ud \ud CONCLUSIONS:\ud \ud International rugby sevens players require highly developed speed, power, and endurance to tolerate the demands of competition. The small between-athletes variability of characteristics in rugby sevens players highlights the need for relatively uniform physical and performance standards in contrast with 15-a-side players

Association between Physical Functionality and Falls Risk in Community-Living Older Adults

Ageing-related declines in physiological attributes, such as muscle strength, can bring with them an increased risk of falls and subsequently greater risk of losing independence. These declines have substantial impact on an individual&apos;s functional ability. However, the precise relationship between falls risk and physical functionality has not been evaluated. The aims of this study were to determine the association between falls risk and physical functionality using objective measures and to create an appropriate model to explain variance in falls risk. Thirty-two independently living adults aged 65-92 years completed the FallScreen, the Continuous-Scale Physical Functional Performance 10 (CS-PFP10) tests, and the 12-Item Short-Form Health Survey (SF-12). The relationships between falls risk, physical functionality, and age were investigated using correlational and multiple hierarchical regression analyses. Overall, total physical functionality accounted for 24% of variance in an individual&apos;s falls risk while age explained a further 13%. The oldest-old age group had significantly greater falls risk and significantly lower physical functional performance. Mean scores for all measures showed that there were substantial (but not significant) differences between males and females. While increasing age is the strongest single predictor of increasing falls risk, poorer physical functionality was strongly, independently related to greater falls risk