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SUMMARYMost loci identified by GWAS have been found in populations of European ancestry (EA). In trans-ethnic meta-analyses for 15 hematological traits in 746,667 participants, including 184,535 non-EA individuals, we identified 5,552 trait-variant associations at P−9, including 71 novel loci not found in EA populations. We also identified novel ancestry-specific variants not found in EA, including an IL7 missense variant in South Asians associated with lymphocyte count in vivo and IL7 secretion levels in vitro. Fine-mapping prioritized variants annotated as functional, and generated 95% credible sets that were 30% smaller when using the trans-ethnic as opposed to the EA-only results. We explored the clinical significance and predictive value of trans-ethnic variants in multiple populations, and compared genetic architecture and the impact of natural selection on these blood phenotypes between populations. Altogether, our results for hematological traits highlight the value of a more global representation of populations in genetic studies.

Time is important now. Time was, for a long time, only abstractly relevant—usually in the quiet moments following a holiday, or birthday, or funeral[...]

BACKGROUND: Periprosthetic joint infection (PJI) is a serious complication of total knee arthroplasty. Two-stage revision is the most widely used technique and considered as the most effective for treating periprosthetic knee infection. The one-stage revision strategy is an emerging alternative option, however, its performance in comparison to the two-stage strategy is unclear. We therefore sought to ask if there was a difference in re-infection rates and other clinical outcomes when comparing the one-stage to the two-stage revision strategy.OBJECTIVE: Our first objective was to compare re-infection (new and recurrent infections) rates for one- and two-stage revision surgery for periprosthetic knee infection. Our second objective was to compare between the two revision strategies, clinical outcomes as measured by postoperative Knee Society Knee score, Knee Society Function score, Hospital for Special Surgery knee score, WOMAC score, and range of motion.DESIGN: Systematic review and meta-analysis.DATA SOURCES: MEDLINE, EMBASE, Web of Science, Cochrane Library, reference lists of relevant studies to August 2015, and correspondence with investigators.STUDY SELECTION: Longitudinal (prospective or retrospective cohort) studies conducted in generally unselected patients with periprosthetic knee infection treated exclusively by one- or two-stage revision and with re-infection outcomes reported within two years of revision surgery. No clinical trials comparing both revision strategies were identified.REVIEW METHODS: Two independent investigators extracted data and discrepancies were resolved by consensus with a third investigator. Re-infection rates from 10 one-stage studies (423 participants) and 108 two-stage studies (5,129 participants) were meta-analysed using random-effect models after arcsine transformation.RESULTS: The rate (95% confidence intervals) of re-infection was 7.6% (3.4-13.1) in one-stage studies. The corresponding re-infection rate for two-stage revision was 8.8% (7.2-10.6). In subgroup analyses, re-infection rates remained generally similar for several study-level and clinically relevant characteristics. Postoperative clinical outcomes of knee scores and range of motion were similar for both revision strategies.LIMITATIONS: Potential bias owing to the limited number of one-stage revision studies and inability to explore heterogeneity in greater detail.CONCLUSIONS: Available evidence from aggregate published data suggest the one-stage revision strategy may be as effective as the two-stage revision strategy in treating infected knee prostheses in generally unselected patients. Further investigation is warranted.SYSTEMATIC REVIEW REGISTRATION: PROSPERO 2015: CRD42015017327.

Total hip replacement (THR) and total knee replacement (TKR) are two common elective orthopaedic procedures, and the provision of physiotherapy for patients after discharge is variable, with evidence for best practice remaining uncertain.To determine the standard physiotherapy service offered to patients following discharge after THR and TKR.A telephone survey was carried with clinicians at 24 high-volume NHS orthopaedic centres in England and Wales. Information was gathered on standard physiotherapy provision and categorized into; no routine physiotherapy, outpatient physiotherapy (including one-to-one and group), home-based physiotherapy or other physiotherapy (including telephone consultation and drop-in services).No centres surveyed referred patients to outpatient physiotherapy as a routine pathway of care following THR. Eleven centres provided group physiotherapy to patients after discharge following TKR compared with five centres providing one-to-one outpatient physiotherapy.The provision of physiotherapy following discharge after TKR is a more common practice than after THR, where ongoing physiotherapy is provided depending upon clinical need. Group exercises are the favoured destination for patients following TKR in high-volume centres.

Background:\ud \ud Cardiac rehabilitation is an important component of recovery from coronary events but uptake and adherence to such programmes are below the recommended levels. This aim is to update a previous non-Cochrane systematic review which examined interventions that may potentially improve cardiac patient uptake and adherence in rehabilitation or its components and concluded that there is insufficient evidence to make specific recommendations.\ud \ud Objectives\ud \ud To determine the effects of interventions to increase patient uptake of, and adherence to, cardiac rehabilitation.\ud \ud Search strategy:\ud \ud A previous systematic review identified studies published prior to June 2001. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (Issue 4 2007), MEDLINE (2001 to January 2008), EMBASE (2001 to January 2008), CINAHL (2001 to January 2008), PsycINFO (2001 to January 2008), Web of Science: ISI Proceedings (2001 to April 2008), and NHS Centre for Reviews and Dissemination (CRD) databases (Health Technology Assessment (HTA) and Database of Abstracts of Reviews of Effects (DARE)) from 2001 to January 2008. Reference lists of identified systematic reviews and randomised control trials (RCTs) were also checked for additional studies.\ud \ud Selection criteria:\ud \ud Adults with myocardial infarction, coronary artery bypass graft, percutaneous transluminal coronary angioplasty, heart failure, angina, or coronary heart disease eligible for cardiac rehabilitation and randomised or quasi-randomised trials of interventions to increase uptake or adherence to cardiac rehabilitation or any of its component parts. Only studies reporting a measure of adherence were included.\ud \ud Data collection and analysis\ud \ud Titles and abstracts of all identified references were screened for eligibility by two reviewers independently and full papers of potentially relevant trials were obtained and checked. Included studies were assessed for risk of bias by two reviewers.\ud \ud Main results:\ud \ud Ten studies were identified, three of interventions to improve uptake of cardiac rehabilitation and seven of interventions to increase adherence. Meta-analysis was not possible due to multiple sources of heterogeneity. All three interventions targeting uptake of cardiac rehabilitation were effective. Two of seven studies intended to increase adherence had a significant effect. Only one study reported the non-significant effects of the intervention on cardiovascular risk factors and no studies reported data on mortality, morbidities, costs or health care resource utilisation.\ud \ud Authors' conclusions:\ud \ud There is some evidence to suggest that interventions to increase the uptake of cardiac rehabilitation can be effective. Few practice recommendations for increasing adherence to cardiac rehabilitation can be made at this time. Interventions targeting patient identified barriers may increase the likelihood of success. Further high quality research is needed.\ud

Primary prevention programmes in many countries attempt to reduce mortality and morbidity due to coronary heart disease (CHD) through risk factor modification. It is widely believed that multiple risk factor intervention using counselling and educational methods is efficacious and cost-effective and should be expanded. Recent trials examining risk factor changes have cast considerable doubt on the effectiveness of these multiple risk factor interventions.To assess the effects of multiple risk factor intervention for reducing cardiovascular risk factors, total mortality, and mortality from CHD among adults without clinical evidence of established cardiovascular disease.MEDLINE was searched for the original review to 1995. This was updated by searching the Cochrane Central Register of Controlled Trials on The Cochrane Library Issue 3 2001, MEDLINE (2000 to September 2001) and EMBASE (1998 to September 2001).Intervention studies using counselling or education to modify more than one cardiovascular risk factor in adults from general populations, occupational groups, or high risk groups. Trials of less than 6 months duration were excluded.Data were extracted by two reviewers independently. Investigators were contacted to obtain missing information.A total of 39 trials were found of which ten reported clinical event data. In the ten trials with clinical event end-points, the pooled odds ratios for total and CHD mortality were 0.96 (95% confidence intervals (CI) 0.92 to 1.01) and 0.96 (95% CI 0.89 to 1.04) respectively. Net changes in systolic and diastolic blood pressure, and blood cholesterol were (weighted mean differences) -3.6 mmHg (95% CI -3.9 to -3.3 mmHg), -2.8 mmHg (95% CI -2.9 to -2.6 mmHg) and -0.07 mMol/l (95% CI -0.8 to -0.06 mMol/l) respectively. Odds of reduction in smoking prevalence was 20% (95% CI 8% to 31%). Statistical heterogeneity between the studies with respect to mortality and risk factor changes was due to trials focusing on hypertensive participants and those using considerable amounts of drug treatment.The pooled effects suggest multiple risk factor intervention has no effect on mortality. However, a small, but potentially important, benefit of treatment (about a 10% reduction in CHD mortality) may have been missed. Risk factor changes were relatively modest, were related to the amount of pharmacological treatment used, and in some cases may have been over-estimated because of regression to the mean effects, lack of intention to treat analyses, habituation to blood pressure measurement, and use of self-reports of smoking. Interventions using personal or family counselling and education with or without pharmacological treatments appear to be more effective at achieving risk factor reduction and consequent reductions in mortality in high risk hypertensive populations. The evidence suggests that such interventions have limited utility in the general population.

The effect of smoking on platelet aggregation appears to produce conflicting results, with some studies indicating an enhancement and others a decrease of aggregation. This epidemiological study of 120 male smokers, a subset of the Caerphilly Heart Disease Study, examined the relationship of two dimensions of smoking (time proximity of last cigarette before venepuncture and serum nicotine concentration) with threshold dose of adenosine diphosphate (ADP) necessary to induce platelet aggregation in whole blood. Means (range) of ADP threshold dose and nicotine concentration were 1.66 (0.5-2.5, censored) microM and 12.2 (0-35.2) ng/ml. Men smoking within 30 min of venepuncture demonstrated lower ADP threshold doses (-0.48 microM lower [95% C.I.: -0.95, -0.02])--reflecting increased sensitivity. Men with higher nicotine concentration had higher ADP threshold doses (Regression Coefficient: +0.032 microM per ng/ml [95% C.I.: 0.003, 0.062])--reflecting decreased sensitivity. Men smoking 30 min or more before venepuncture who also had high nicotine concentration (25-30 ng/ml) demonstrated the highest ADP threshold doses compared to never smokers and to men smoking the previous day (approximately 2.20 vs 1.86 and 1.81 microM). Relations involving nicotine concentration do not necessarily reflect a pharmacological effect although the potential for a short term nicotine mediated tolerance effect cannot be dismissed. These observations support an hypothesis suggesting a temporal sequence of platelet sensitization and desensitization during smoking.

This epidemiological study was undertaken to explore possible relationships among various haematological indices, prevalent ischaemic heart disease and platelet "function" as measured by two rather different methods. ADP-induced platelet impedance changes in whole blood were strongly associated with prevalent ischaemic heart disease in a general population of 49-66 year men at increased risk. Adenosine diphosphate (ADP) induced platelet aggregation in platelet rich plasma (PRP) at a constant platelet count and also the whole blood platelet count and red cell (RBC) count were strongly and independently related to ADP-induced platelet impedance changes. Both platelet count and platelet aggregation in PRP assessed by changes in optical density were directly related to increasing platelet "sensitivity" as measured by impedance changes in whole blood but RBC count was inversely related. Positive independent relationships between platelet impedance changes and plasma viscosity and fibrinogen were markedly attenuated when platelet count was taken into account, but this finding does not discount a role for these factors in platelet aggregation. No relationship was noted between white blood cell (WBC) count and platelet impedance changes; however, a significant inverse relationship was noted with platelet aggregation in PRP. These findings indicate that laboratory-based experimental findings can be observed in population based studies, and that these haematological factors may be important indicators of ischaemic disease in the population.

Adenosine diphosphate (ADP) and thrombin are agonists of platelet aggregation in which intracellular calcium plays a significant role as a signal transducer. Lead is a well established toxicological agent affecting intracellular mechanisms controlling free ionized calcium concentration in a number of cell lines. This epidemiological study is the first demonstration of a significant relationship between the extent of primary ADP-induced platelet aggregation measured by optical densitometry in platelet rich plasma (PRP) and blood lead concentration. High blood lead levels are associated with decreased aggregation in this population of 2,150 men aged 49-65 years. This is reflected by a negative regression relationship of -0.19% of maximal extent (PRP vs platelet poor plasma) of aggregation per microgram of Pb/dl (T = -3.82, p less than 0.001). In contrast, no relationship is noted between thrombin-induced aggregation and blood lead concentration. Smoking behaviour represents a potential confounder which may be the explanation for the observed relationship. However, because smoking status is simultaneously related to both ADP- and thrombin-induced aggregation, but is simultaneously related to ADP-induced aggregation and blood lead concentration in a different way, the observed relation is likely to be causal. The mechanisms by which ADP and thrombin effect intracellular calcium transduction signals appear to be distinctively different. The findings in this population-based study are not inconsistent with this difference.