Trans-ethnic and Ancestry-Specific Blood-Cell Genetics in 746,667 Individuals from 5 Global Populations.

Most loci identified by GWASs have been found in populations of European ancestry (EUR). In trans-ethnic meta-analyses for 15 hematological traits in 746,667 participants, including 184,535 non-EUR individuals, we identified 5,552 trait-variant associations at p < 5 × 10-9, including 71 novel associations not found in EUR populations. We also identified 28 additional novel variants in ancestry-specific, non-EUR meta-analyses, including an IL7 missense variant in South Asians associated with lymphocyte count in vivo and IL-7 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 EUR-only results. We explored the clinical significance and predictive value of trans-ethnic variants in multiple populations and compared genetic architecture and the effect 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.

The Polygenic and Monogenic Basis of Blood Traits and Diseases.

Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation.

Is there a role for autologous conditioned serum injections in osteoarthritis? A systematic review and meta-analysis of randomised controlled trials.

OBJECTIVE: To assess whether patient reported outcome measures (PROMs) improve after autologous conditioned serum (ACS) administration in patients with osteoarthritis. METHODS: Databases and clinical trial registers were searched to March 2024 for randomised controlled trial (RCTs) comparing ACS vs comparators/controls. Primary outcomes were pain, function and stiffness measured with Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and visual analogue scale (VAS). Secondary outcome was complications. Risk of bias (RoB) and certainty of evidence were assessed using RoB 2 and the Grades of Recommendation, Assessment, Development and Evaluation Working Group (GRADE) respectively. Meta-analysis was undertaken using RevMan v5.4. Results are presented as standardised mean differences (SMD) or mean differences (MD) with 95% confidence intervals (CI). Sensitivity analysis compared all comparators and saline control. RESULTS: Five RCTs were identified (n = 741 participants); two (n = 529 participants) compared ACS against saline (placebo). Three studies were "some concern" and two studies "high risk" for bias. Analysis comparing ACS with all comparators significantly favoured ACS at 6 months for WOMAC: SMD -0.61 (95% CI -1.01 to -0.21; p = 0.003); and VAS: SMD -1.24 (95% CI -2.11 to -0.38; p = 0.005); with high heterogeneity. Comparing ACS with saline, there was no significant difference in WOMAC or VAS at 6 months: SMD -0.40 (95% CI -0.93 to 0.12; p = 0.13) and MD -9.87 (95% CI -27.73 to 7.98, p = 0.28). Complications were similar: ACS (24.8%) vs saline (24.4%), with serious complications rare. CONCLUSION: There is currently insufficient data to support the use of ACS in osteoarthritis with conflicting results when compared to alternative therapies and saline control, with high heterogeneity. Before consideration as a potential treatment, a high-quality multicentre RCT is required to assess the efficacy of ACS.

Inequalities in provision of hip and knee replacement surgery for osteoarthritis by age, sex, and social deprivation in England between 2007-2017: A population-based cohort study of the National Joint Registry.

BACKGROUND: While the United Kingdom National Health Service aimed to reduce social inequalities in the provision of joint replacement, it is unclear whether these gaps have reduced. We describe secular trends in the provision of primary hip and knee replacement surgery between social deprivation groups. METHODS AND FINDINGS: We used the National Joint Registry to identify all hip and knee replacements performed for osteoarthritis from 2007 to 2017 in England. The Index of Multiple Deprivation (IMD) 2015 was used to identify the relative level of deprivation of the patient living area. Multilevel negative binomial regression models were used to model the differences in rates of joint replacement. Choropleth maps of hip and knee replacement provision were produced to identify the geographical variation in provision by Clinical Commissioning Groups (CCGs). A total of 675,342 primary hip and 834,146 primary knee replacements were studied. The mean age was 70 years old (standard deviation: 9) with 60% and 56% of women undergoing hip and knee replacements, respectively. The overall rate of hip replacement increased from 27 to 36 per 10,000 person-years and knee replacement from 33 to 46. Inequalities of provision between the most (reference) and least affluent areas have remained constant for both joints (hip: rate ratio (RR) = 0.58, 95% confidence interval [0.56, 0.60] in 2007, RR = 0.59 [0.58, 0.61] in 2017; knee: RR = 0.82 [0.80, 0.85] in 2007, RR = 0.81 [0.80, 0.83] in 2017). For hip replacement, CCGs with the highest concentration of deprived areas had lower overall provision rates, and CCGs with very few deprived areas had higher provision rates. There was no clear pattern of provision inequalities between CCGs and deprivation concentration for knee replacement. Study limitations include the lack of publicly available information to explore these inequalities beyond age, sex, and geographical area. Information on clinical need for surgery or patient willingness to access care were unavailable. CONCLUSIONS: In this study, we found that there were inequalities, which remained constant over time, especially in the provision of hip replacement, by degree of social deprivation. Providers of healthcare need to take action to reduce this unwarranted variation in provision of surgery.

A Platelet Function Modulator of Thrombin Activation Is Causally Linked to Cardiovascular Disease and Affects PAR4 Receptor Signaling.

Dual antiplatelet therapy reduces ischemic events in cardiovascular disease, but it increases bleeding risk. Thrombin receptors PAR1 and PAR4 are drug targets, but the role of thrombin in platelet aggregation remains largely unexplored in large populations. We performed a genome-wide association study (GWAS) of platelet aggregation in response to full-length thrombin, followed by clinical association analyses, Mendelian randomization, and functional characterization including iPSC-derived megakaryocyte and platelet experiments. We identified a single sentinel variant in the GRK5 locus (rs10886430-G, p = 3.0 × 10-42) associated with increased thrombin-induced platelet aggregation (ß = 0.70, SE = 0.05). We show that disruption of platelet GRK5 expression by rs10886430-G is associated with enhanced platelet reactivity. The proposed mechanism of a GATA1-driven megakaryocyte enhancer is confirmed in allele-specific experiments. Utilizing further data, we demonstrate that the allelic effect is highly platelet- and thrombin-specific and not likely due to effects on thrombin levels. The variant is associated with increased risk of cardiovascular disease outcomes in UK BioBank, most strongly with pulmonary embolism. The variant associates with increased risk of stroke in the MEGASTROKE, UK BioBank, and FinnGen studies. Mendelian randomization analyses in independent samples support a causal role for rs10886430-G in increasing risk for stroke, pulmonary embolism, and venous thromboembolism through its effect on thrombin-induced platelet reactivity. We demonstrate that G protein-coupled receptor kinase 5 (GRK5) promotes platelet activation specifically via PAR4 receptor signaling. GRK5 inhibitors in development for the treatment of heart failure and cancer could have platelet off-target deleterious effects. Common variants in GRK5 may modify clinical outcomes with PAR4 inhibitors, and upregulation of GRK5 activity or signaling in platelets may have therapeutic benefits.

The STAR care pathway for patients with chronic pain after total knee replacement: four-year follow-up of a randomised controlled trial.

BACKGROUND: The Support and Treatment After Replacement (STAR) care pathway is a clinically important and cost-effective intervention found to improve pain outcomes over one year for people with chronic pain three months after total knee replacement (TKR). We followed up STAR trial participants to evaluate the longer-term clinical- and cost-effectiveness of this care pathway. METHODS: Participants who remained enrolled on the trial at one year were contacted by post at a median of four years after randomisation and invited to complete a questionnaire comprising the same outcomes collected during the trial. We captured pain (co-primary outcome using the Brief Pain Inventory (BPI) pain severity and interference scales; scored 0-10, best to worst), function, neuropathic characteristics, emotional aspects of pain, health-related quality of life, and satisfaction. Electronic hospital informatics data on hospital resource use for the period of one to four years post-randomisation were collected from participating hospital sites. The economic evaluation took an National Health Service (NHS) secondary care perspective, with a four-year time horizon. RESULTS: Overall, 226/337 (67%) of participants returned completed follow-up questionnaires, yielding adjusted between-group differences in BPI means of -0.42 (95% confidence interval, CI (-1.07, 0.23); p = 0.20) for pain severity and - 0.64 (95% CI -1.41, 0.12); p = 0.10) for pain interference. Analysis using a multiple imputed data set (n = 337) showed an incremental net monetary benefit in favour of the STAR care pathway of £3,525 (95% CI -£990 to £8,039) at a £20,000/QALY willingness-to-pay threshold, leading to a probability that the intervention was cost-effective of 0.94. CONCLUSIONS: The magnitude of the longer-term benefits of the STAR care pathway are uncertain due to attrition of trial participants; however, there is a suggestion of some degree of sustained clinical benefit at four years. The care pathway remained cost-effective at four years. TRIAL REGISTRATION: ISRCTN: 92,545,361.

The effectiveness of non-pharmacological sleep interventions for people with chronic pain: a systematic review and meta-analysis.

OBJECTIVE: About two thirds of people with chronic pain report problems sleeping. We aimed to evaluate the effectiveness of non-pharmacological sleep interventions for improving sleep in people with chronic pain. DESIGN: We conducted a systematic review of non-pharmacological and non-invasive interventions to improve sleep quality or duration for adults with chronic non-cancer pain evaluated in a randomised controlled trial. Our primary outcome of interest was sleep; secondary outcomes included pain, health-related quality of life, and psychological wellbeing. We searched the Cochrane Library, MEDLINE, Embase, PsycINFO and CINAHL from inception to April 2020. After screening, two reviewers evaluated articles and extracted data. Meta-analysis was conducted using a random effects model. Risk of bias was assessed with the Cochrane tool. RESULTS: We included 42 trials involving 3346 people randomised to 94 groups, of which 56 received an intervention targeting sleep. 10 studies were of fair and 32 of good methodological quality. Overall risk of bias was judged to be low in 11, high in 10 and unclear in 21 studies. In 9 studies with 385 people randomised, cognitive behavioural therapy for insomnia showed benefit post-treatment compared with controls for improved sleep quality, standardised mean difference - 1.23 (95%CI -1.76, - 0.70; p < 0.00001). The effect size was only slightly reduced in meta-analysis of 3 studies at low risk of bias. The difference between groups was lower at 3 and 6 months after treatment but still favoured cognitive behavioural therapy for insomnia. Pain, anxiety and depression were reduced post-treatment, but evidence of longer term benefit was lacking. There was no evidence that sleep hygiene interventions were effective in improving sleep and there was some evidence in comparative studies to suggest that cognitive behavioural therapy for insomnia was more effective than sleep hygiene. Numerous other interventions were evaluated in small numbers of studies, but evidence was insufficient to draw conclusions about effectiveness. CONCLUSIONS: Cognitive behavioural therapy for insomnia is an effective treatment to improve sleep for people with chronic pain, but further high-quality primary research is required to explore combined CBT content that will ensure additional improvements to pain, quality of life and psychological health and longer-term maintenance of benefits. Primary research is also needed to evaluate the effectiveness of interventions for which insufficient evidence exists. TRIAL REGISTRATION: PROSPERO registration number: CRD42019093799 .

Obesity and revision surgery, mortality, and patient-reported outcomes after primary knee replacement surgery in the National Joint Registry: A UK cohort study.

BACKGROUND: One in 10 people in the United Kingdom will need a total knee replacement (TKR) during their lifetime. Access to this life-changing operation has recently been restricted based on body mass index (BMI) due to belief that high BMI may lead to poorer outcomes. We investigated the associations between BMI and revision surgery, mortality, and pain/function using what we believe to be the world's largest joint replacement registry. METHODS AND FINDINGS: We analysed 493,710 TKRs in the National Joint Registry (NJR) for England, Wales, Northern Ireland, and the Isle of Man from 2005 to 2016 to investigate 90-day mortality and 10-year cumulative revision. Hospital Episodes Statistics (HES) and Patient Reported Outcome Measures (PROMs) databases were linked to the NJR to investigate change in Oxford Knee Score (OKS) 6 months postoperatively. After adjustment for age, sex, American Society of Anaesthesiologists (ASA) grade, indication for operation, year of primary TKR, and fixation type, patients with high BMI were more likely to undergo revision surgery within 10 years compared to those with "normal" BMI (obese class II hazard ratio (HR) 1.21, 95% CI: 1.10, 1.32 (p < 0.001) and obese class III HR 1.13, 95% CI: 1.02, 1.26 (p = 0.026)). All BMI classes had revision estimates within the recognised 10-year benchmark of 5%. Overweight and obese class I patients had lower mortality than patients with "normal" BMI (HR 0.76, 95% CI: 0.65, 0.90 (p = 0.001) and HR 0.69, 95% CI: 0.58, 0.82 (p < 0.001)). All BMI categories saw absolute increases in OKS after 6 months (range 18-20 points). The relative improvement in OKS was lower in overweight and obese patients than those with "normal" BMI, but the difference was below the minimal detectable change (MDC; 4 points). The main limitations were missing BMI particularly in the early years of data collection and a potential selection bias effect of surgeons selecting the fitter patients with raised BMI for surgery. CONCLUSIONS: Given revision estimates in all BMI groups below the recognised threshold, no evidence of increased mortality, and difference in change in OKS below the MDC, this large national registry shows no evidence of poorer outcomes in patients with high BMI. This study does not support rationing of TKR based on increased BMI.

Patients Receiving a Primary Unicompartmental Knee Replacement Have a Higher Risk of Revision but a Lower Risk of Mortality Than Predicted Had They Received a Total Knee Replacement: Data From the National Joint Registry for England, Wales, Northern Ireland, and the Isle of Man.

BACKGROUND: To determine unicompartmental (UKR) and total knee replacement (TKR) revision rates, compare UKR revision rates with what they would have been had they received TKR instead, and assess subsequent re-revision and 90-day mortality rates. METHODS: Using National Joint Registry data, we estimated UKR and TKR revision and mortality rates. Flexible parametric survival modeling (FPM) was used to model failure in TKR and make estimates for UKR. Kaplan-Meier estimates were used to compare cumulative re-revision for revised UKRs and TKRs. RESULTS: Ten-year UKR revision rates were 2.5 times higher than expected from TKR, equivalent to 70 excess revisions/1000 cases within 10 years (5861 excess revisions in this cohort). Revision rates were 2.5 times higher for the highest quartile volume UKR surgeons compared to the same quartile for TKR and 3.9 times higher for the lowest quartiles respectively. Re-revision rates of revised TKRs (10 years = 17.5%, 95% confidence interval [CI] 16.4-18.7) were similar to revised UKRs (15.2%, 95% CI 13.4-17.1) and higher than revision rates following primary TKR (3.3%, 95% CI 3.1-3.5). Ninety-day mortality rates were lower after UKR compared with TKR (0.08% vs 0.33%) and lower than predicted had UKR patients received a TKR (0.18%), equivalent to 1 fewer death per 1000 cases. CONCLUSION: UKR revision rates were substantially higher than TKR even when demographics and caseload differences were accounted for; however, fewer deaths occur after UKR. This should be considered when forming treatment guidelines and commissioning services. Re-revision rates were similar between revised UKRs and TKRs, but considerably higher than for primary TKR, therefore UKR cannot be considered an intermediate procedure.

Choice of Prosthetic Implant Combinations in Total Hip Replacement: Cost-Effectiveness Analysis Using UK and Swedish Hip Joint Registries Data.

BACKGROUND: Prosthetic implants used in total hip replacements (THR) have a range of bearing surface combinations (metal-on-polyethylene, ceramic-on-polyethylene, ceramic-on-ceramic, and metal-on-metal), head sizes (small [<36 mm in diameter] and large [≥36 mm in diameter]), and fixation techniques (cemented, uncemented, hybrid, and reverse hybrid). These can influence prosthesis survival, patients' quality of life, and healthcare costs. OBJECTIVES: To compare the lifetime cost-effectiveness of implants for patients of different age and sex profiles. METHODS: We developed a Markov model to compare the cost-effectiveness of various implants against small-head cemented metal-on-polyethylene implants. The probability that patients required 1 or more revision surgeries was estimated from analyses of more than 1 million patients in the UK and Swedish hip joint registries, for men and women younger than 55, 55 to 64, 65 to 74, 75 to 84, and 85 years and older. Implant and healthcare costs were estimated from local procurement prices, national tariffs, and the literature. Quality-adjusted life-years were calculated using published utility estimates for patients undergoing THR in the United Kingdom. RESULTS: Small-head cemented metal-on-polyethylene implants were the most cost-effective for men and women older than 65 years. These findings were robust to sensitivity analyses. Small-head cemented ceramic-on-polyethylene implants were most cost-effective in men and women younger than 65 years, but these results were more uncertain. CONCLUSIONS: The older the patient group, the more likely that the cheapest implants, small-head cemented metal-on-polyethylene implants, were cost-effective. We found no evidence that uncemented, hybrid, or reverse hybrid implants were the most cost-effective option for any patient group. Our findings can influence clinical practice and procurement decisions for healthcare payers worldwide.

Exome-chip meta-analysis identifies association between variation in ANKRD26 and platelet aggregation.

Previous genome-wide association studies (GWAS) have identified several variants associated with platelet function phenotypes; however, the proportion of variance explained by the identified variants is mostly small. Rare coding variants, particularly those with high potential for impact on protein structure/function, may have substantial impact on phenotype but are difficult to detect by GWAS. The main purpose of this study was to identify low frequency or rare variants associated with platelet function using genotype data from the Illumina HumanExome Bead Chip. Three family-based cohorts of European ancestry, including ~4,000 total subjects, comprised the discovery cohort and two independent cohorts, one of European and one of African American ancestry, were used for replication. Optical aggregometry in platelet-rich plasma was performed in all the discovery cohorts in response to adenosine diphosphate (ADP), epinephrine, and collagen. Meta-analyses were performed using both gene-based and single nucleotide variant association methods. The gene-based meta-analysis identified a significant association (P = 7.13 × 10-7) between rare genetic variants in ANKRD26 and ADP-induced platelet aggregation. One of the ANKRD26 SNVs - rs191015656, encoding a threonine to isoleucine substitution predicted to alter protein structure/function, was replicated in Europeans. Aggregation increases of ~20-50% were observed in heterozygotes in all cohorts. Novel genetic signals in ABCG1 and HCP5 were also associated with platelet aggregation to ADP in meta-analyses, although only results for HCP5 could be replicated. The SNV in HCP5 intersects epigenetic signatures in CD41+ megakaryocytes suggesting a new functional role in platelet biology for HCP5. This is the first study to use gene-based association methods from SNV array genotypes to identify rare variants related to platelet function. The molecular mechanisms and pathophysiological relevance for the identified genetic associations requires further study.

One- and two-stage surgical revision of infected elbow prostheses following total joint replacement: a systematic review.

BACKGROUND: Prosthetic joint infection (PJI) is a challenging complication of total elbow replacement (TER). Potential surgical treatments include one- or two-stage revision; however, the best treatment for elbow PJI is not clearly defined. We conducted a systematic review in accordance with PRISMA guidelines to compare the clinical effectiveness of one- and two-stage revision surgery for elbow PJI using re-infection (recurrent and new infections) rates; mortality; clinical measures of function, pain, and satisfaction; and non-infection related adverse events. METHODS: MEDLINE, Embase, Web of Science, and The Cochrane Library were searched up to June 2019 to identify observational cohort studies and randomised controlled trials (RCTs) that had recruited patients with elbow PJI following TER and treated with one- or two-stage revision. Of 96 retrieved articles, 2 one-stage and 6 two-stage revision studies were eligible. No RCT was identified. Arcsine transformation was used in estimating rates with 95% confidence intervals (CIs). RESULTS: Staphylococcus aureus was the most common causative organism for PJI of the elbow (24 of 71 elbow PJIs). The re-infection rate (95% CI) for one-stage (7 elbows) ranged from 0.0% (0.0-79.3) to 16.7% (3.0-56.4) and that for two-stage revision (87 elbows) from 0.0% (0.0-49.0) to 20.0% (3.6-62.4). Non-infection related adverse event rate for one-stage (based on a single study) was 16.7% (3.0-56.4) and that for two-stage ranged from 11.8% (4.7-26.6) to 20.0% (3.6-62.4). There were no mortality events recorded following one- or two-stage revision surgery and postoperative clinical measures of function, pain, and satisfaction could not be effectively compared because of limited data. CONCLUSIONS: No strong conclusions can be drawn because of limited data. The one-stage revision may be potentially at least as clinically effective as two-stage revision, but further data is needed. There are clear gaps in the existing literature and studies are urgently warranted to assess the clinical effectiveness of one- and two-stage revision strategies for PJI following TER. SYSTEMATIC REVIEW REGISTRATION: PROSPERO 2018: CRD42018118002 .

One- and two-stage surgical revision of peri-prosthetic joint infection of the hip: a pooled individual participant data analysis of 44 cohort studies.

One-stage and two-stage revision strategies are the two main options for treating established chronic peri-prosthetic joint infection (PJI) of the hip; however, there is uncertainty regarding which is the best treatment option. We aimed to compare the risk of re-infection between the two revision strategies using pooled individual participant data (IPD). Observational cohort studies with PJI of the hip treated exclusively by one- or two-stage revision and reporting re-infection outcomes were retrieved by searching MEDLINE, EMBASE, Web of Science, The Cochrane Library, and the WHO International Clinical Trials Registry Platform; as well as email contact with investigators. We analysed IPD of 1856 participants with PJI of the hip from 44 cohorts across four continents. The primary outcome was re-infection (recurrence of infection by the same organism(s) and/or re-infection with a new organism(s)). Hazard ratios (HRs) for re-infection were calculated using Cox proportional frailty hazards models. After a median follow-up of 3.7 years, 222 re-infections were recorded. Re-infection rates per 1000 person-years of follow-up were 16.8 (95% CI 13.6-20.7) and 32.3 (95% CI 27.3-38.3) for one-stage and two-stage strategies respectively. The age- and sex-adjusted HR of re-infection for two-stage revision was 1.70 (0.58-5.00) when compared with one-stage revision. The association remained consistently absent after further adjustment for potential confounders. The HRs did not vary importantly in clinically relevant subgroups. Analysis of pooled individual patient data suggest that a one-stage revision strategy may be as effective as a two-stage revision strategy in treating PJI of the hip.

Outcomes following hip and knee replacement in diabetic versus nondiabetic patients and well versus poorly controlled diabetic patients: a prospective cohort study.

Background and purpose - The impact of diabetes and glycemic control before joint replacement on clinical and patient-reported outcomes is unclear. We compared pain, function, complications, and length of hospital stay in diabetic and nondiabetic patients receiving primary total hip (THR) or knee replacement (TKR) and compared these outcomes in patients with poorly controlled versus well-controlled diabetes. Patients and methods - We conducted a prospective cohort study of patients undergoing primary THR (n = 300) or TKR (n = 287) for osteoarthritis. Self-reported diabetes and glycemic control (HbA1c ≤ or >7%) extracted from medical notes were used. Adjusted comparisons were performed with generalized linear models including body mass index (BMI) and comorbidities. Results - Diabetes prevalence was 11% (THR 8%; TKR 14%). Diabetic patients were more likely to have a higher BMI and greater number of comorbidities. The median length of hospital stay was 1 day longer in diabetic patients (p = 0.004), but this attenuated after adjustments for BMI and comorbidities (p = 0.3). Inpatient pain was greater for diabetic patients but attenuated following adjustment. The 12-month postoperative WOMAC subscales were similar by diabetes status following adjustment. There was little evidence of difference in outcomes according to glycemic control. Interpretation - The associations between diabetes and worse postoperative outcomes in patients undergoing THR or TKR for osteoarthritis appear to be predominantly due to associated obesity and comorbidities. In diabetic patients there is little evidence of association between postoperative outcome and preoperative glycemic control. The underlying mechanisms and causal pathways of obesity, diabetes, and multimorbidity that lead to worse outcomes after joint replacement are not well known.

Comparison of group-based outpatient physiotherapy with usual care after total knee replacement: a feasibility study for a randomized controlled trial.

OBJECTIVE: To evaluate the feasibility of conducting a randomized controlled trial comparing group-based outpatient physiotherapy with usual care in patients following total knee replacement. DESIGN: A feasibility study for a randomized controlled trial. SETTING: One secondary-care hospital orthopaedic centre, Bristol, UK. PARTICIPANTS: A total of 46 participants undergoing primary total knee replacement. INTERVENTIONS: The intervention group were offered six group-based exercise sessions after surgery. The usual care group received standard postoperative care. Participants were not blinded to group allocation. OUTCOME MEASURES: Feasibility was assessed by recruitment, reasons for non-participation, attendance, and completion rates of study questionnaires that included the Lower Extremity Functional Scale and Knee Injury and Osteoarthritis Outcome Score. RESULTS: Recruitment rate was 37%. Five patients withdrew or were no longer eligible to participate. Intervention attendance was high (73%) and 84% of group participants reported they were 'very satisfied' with the exercises. Return of study questionnaires at six months was lower in the usual care (75%) than in the intervention group (100%). Mean (standard deviation) Lower Extremity Functional Scale scores at six months were 45.0 (20.8) in the usual care and 57.8 (15.2) in the intervention groups. CONCLUSION: Recruitment and retention of participants in this feasibility study was good. Group-based physiotherapy was acceptable to participants. Questionnaire return rates were lower in the usual care group, but might be enhanced by telephone follow-up. The Lower Extremity Functional Scale had high responsiveness and completion rates. Using this outcome measure, 256 participants would be required in a full-scale randomized controlled trial.

Replication and hematological characterization of human platelet reactivity genetic associations in men from the Caerphilly Prospective Study (CaPS).

Platelet reactivity, an important factor in hemostasis and chronic disease, has widespread inter-individual variability with a substantial genetic contribution. Previously, our group performed a genome-wide association study of platelet reactivity identifying single nucleotide polymorphisms (SNPs) associated with ADP- and epinephrine- induced aggregation, including SNPs in MRVI1, PIK3CG, JMJD1C, and PEAR1, among others. Here, we assessed the association of these previously identified SNPs with ADP-, thrombin-, and shear- induced platelet aggregation. Additionally, we sought to expand the association of these SNPs with blood cell counts and hemostatic factors. To accomplish this, we examined the association of 12 SNPs with seven platelet reactivity and various hematological measures in 1300 middle-aged men in the Caerphilly Prospective Study. Nine of the examined SNPs showed at least suggestive association with platelet reactivity. The strongest associations were with rs12566888 in PEAR1 to ADP-induced (p = 1.51 × 10(-7)) and thrombin-induced (p = 1.91 × 10(-6)) reactivity in platelet rich plasma. Our results indicate PEAR1 functions in a relatively agonist independent manner, possibly through subsequent intracellular propagation of platelet activation. rs10761741 in JMJD1C showed suggestive association with ADP-induced reactivity (p = 1.35 × 10(-3)), but its strongest associations were with platelet-related cell counts (p = 1.30 × 10(-9)). These associations indicate variation in JMJD1C influences pathways that modulate platelet development as well as those that affect reactivity. Associations with other blood cell counts and hemostatic factors were generally weaker among the tested SNPs, indicating a specificity of these SNPs' function to platelets. Future genome-wide analyses will further assess association of these genes and identify new genes important to platelet biology.

Assistive devices, hip precautions, environmental modifications and training to prevent dislocation and improve function after hip arthroplasty.

BACKGROUND: Total hip arthroplasty (THA) is one of the most common orthopaedic operations performed worldwide. Painful osteoarthritis of the hip is the primary indication for THA. Following THA, people have conventionally been provided with equipment, such as raised toilet seats and chairs, and educated to avoid activities that could cause the hip joint to be in a position of flexion over 90 degrees, or adduction or rotation past the midline. These aspects of occupational therapy have been advocated to reduce the risks of prosthesis dislocation. However, the appropriateness of these recommendations has been questioned. OBJECTIVES: To assess the effects of provision of assistive devices, education on hip precautions, environmental modifications and training in activities of daily living (ADL) and extended ADL (EADL) for people undergoing THA. SEARCH METHODS: We searched MEDLINE (1946 to April 2016), EMBASE (1947 to April 2016), the Cochrane Library including CENTRAL (Issue 4 of 12, 2016), Database of Reviews of Effects (DARE), Health Technology Assessment (HTA), Economic Evaluations Database (EED), CINAHL, PEDro and CIRRIE from inception to April 2016. In addition we checked Controlled Clinical Trials, Clinicaltrials.gov, the National Institutes of Health Trial Registry, the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) and the OpenGrey database from inception to April 2016. SELECTION CRITERIA: We included randomised controlled trials (RCTs), quasi-RCTs and cluster-RCTs that evaluated the effectiveness of the provision of assistive devices, education on hip precautions, environmental modifications, or training in ADL and EADL for people undergoing THA. The main outcomes of interest were pain, function, health-related quality of life (HRQOL), global assessment of treatment success, reoperation rate, hip dislocation and adverse events. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recognised by Cochrane. We conducted a systematic literature search using several databases and contacted corresponding authors, appraised the evidence using the Cochrane risk of bias tool, analysed the data using a narrative analysis approach (as it was not possible to conduct a meta-analysis due to heterogeneity in interventions), and interpreted all outcomes using the GRADE approach. MAIN RESULTS: We included three trials with a total of 492 participants who had received 530 THA. The evidence presented with a high risk of performance, detection and reporting bias.One study (81 participants) compared outcomes for participants randomised to the provision of hip precautions, equipment and functional restrictions versus no provision of hip precautions, equipment or functional restrictions. Due to the quality of evidence being very low, we are uncertain if the provision of hip precautions, equipment and functional restrictions improved function measured using the Harris Hip Score at 12 month follow-up, or health-related quality of life (HRQOL) measured by the Short Form-12 at four week follow-up, compared to not providing this. There were no incidences of hip dislocation or adverse events in either group during the initial 12 postoperative months. The study did not measure pain score, global assessment of treatment success or total adverse events.One study (265 participants; 303 THAs) evaluated the provision of hip precautions with versus without the prescription of postoperative equipment and restrictions to functional activities. Due to the quality of evidence being very low, we are uncertain if perceived satisfaction in the rate of recovery differed in people who were not prescribed postoperative equipment and restrictions (135/151 satisfied) compared to those prescribed equipment and restrictions (113/152) (risk ratio (RR) 0.83, 95% confidence interval (CI) 0.75 to 0.93; 265 participants, one trial; number needed to treat for an additional beneficial outcome (NNTB) = 7). Due to the low quality evidence, we are uncertain if the incidence of hip dislocation differed between participants provided with hip precautions with (1/152) compared to without providing equipment or restrictions post-THA (0/151) (RR 2.98, 95% CI 0.12 to 72.59). The study did not measure pain, function, HRQOL, re-operation rates or total adverse events.One study (146 participants) investigated the provision of an enhanced postoperative education and rehabilitation service on hospital discharge to promote functional ADL versus a conventional rehabilitation intervention in the community. This study was of very low quality evidence. We were uncertain if the provision of enhanced postoperative education and rehabilitation improved function at six months follow-up, when assessed using the Objective and Subjective Functional Capability Index (146 participants, one trial; P > 0.05; no numerical results provided) compared to conventional rehabilitation. The study did not measure pain score, HRQOL, global assessment of treatment success, hip dislocation, re-operation rate or total adverse events. AUTHORS' CONCLUSIONS: Very low quality evidence is available from single trials, thus we are uncertain if hip precautions with or without the addition of equipment and functional restrictions are effective in preventing dislocation and improving outcomes after THA. There is also insufficient evidence to support or refute the adoption of a postoperative community rehabilitation programme consisting of functional reintegration and education compared to conventional rehabilitation strategies based on functional outcomes.Further high-quality trials are warranted to assess the outcomes of different occupational therapy interventions both in the short and longer-term for those who undergo THA. An assessment of the impact of such interventions on pain and restriction on personal ADL, EADL and instrumental ADL is needed, and also of functional integration-type interventions rather than just hip precautions, equipment and restrictions.

A feasibility randomised controlled trial of pre-operative occupational therapy to optimise recovery for patients undergoing primary total hip replacement for osteoarthritis (PROOF-THR).

OBJECTIVE: To assess the feasibility of a pre-operative occupational therapy intervention for patients undergoing primary total hip replacement. DESIGN: Single blinded feasibility randomised controlled trial, with data collection prior to the intervention, and at 4, 12, and 26 weeks following surgery. SETTING: Recruitment from two NHS orthopaedic outpatient centres in the West Midlands, UK. SUBJECTS: Patients awaiting primary total hip replacement due to osteoarthritis were recruited. Following pre-operative assessment, patients were individually randomised to intervention or control by a computer-generated block randomisation algorithm stratified by age and centre. INTERVENTIONS: The intervention group received a pre-surgery home visit by an occupational therapist who discussed expectations, assessed home safety, and provided appropriate adaptive equipment. The control group received treatment as usual. OUTCOMES: The study assessed the feasibility of recruitment procedures, delivery of the intervention, appropriateness of outcome measures and data collection methods. Health related quality of life and resource use were recorded at 4, 12 and 26 weeks. RESULTS: Forty-four participants were recruited, 21 were randomised to the occupational therapy intervention and 23 to usual care. Analysis of 26 week data included 18 participants in the intervention group and 21 in the control. The intervention was delivered successfully with no withdrawals or crossovers; 5/44 were lost to follow-up with further missing data for participation and resource use. CONCLUSIONS: The feasibility study provided the information required to conduct a definitive trial. Burden of assessment would need to be addressed. A total of 219 patients would be required in an efficacy trial.

Effectiveness of physiotherapy exercise following total knee replacement: systematic review and meta-analysis.

BACKGROUND: Rehabilitation, with an emphasis on physiotherapy and exercise, is widely promoted after total knee replacement. However, provision of services varies in content and duration. The aim of this study is to update the review of Minns Lowe and colleagues 2007 using systematic review and meta-analysis to evaluate the effectiveness of post-discharge physiotherapy exercise in patients with primary total knee replacement. METHODS: We searched MEDLINE, Embase, PsycInfo, CINAHL and Cochrane CENTRAL to October 4(th) 2013 for randomised evaluations of physiotherapy exercise in adults with recent primary knee replacement. Outcomes were: patient-reported pain and function, knee range of motion, and functional performance. Authors were contacted for missing data and outcomes. Risk of bias and heterogeneity were assessed. Data was combined using random effects meta-analysis and reported as standardised mean differences (SMD) or mean differences (MD). RESULTS: Searches identified 18 randomised trials including 1,739 patients with total knee replacement. Interventions compared: physiotherapy exercise and no provision; home and outpatient provision; pool and gym-based provision; walking skills and more general physiotherapy; and general physiotherapy exercise with and without additional balance exercises or ergometer cycling. Compared with controls receiving minimal physiotherapy, patients receiving physiotherapy exercise had improved physical function at 3-4 months, SMD -0.37 (95% CI -0.62, -0.12), and pain, SMD -0.45 (95% CI -0.85, -0.06). Benefit up to 6 months was apparent when considering only higher quality studies. There were no differences for outpatient physiotherapy exercise compared with home-based provision in physical function or pain outcomes. There was a short-term benefit favouring home-based physiotherapy exercise for range of motion flexion. There were no differences in outcomes when the comparator was hydrotherapy, or when additional balancing or cycling components were included. In one study, a walking skills intervention was associated with a long-term improvement in walking performance. However, for all these evaluations studies were under-powered individually and in combination. CONCLUSION: After recent primary total knee replacement, interventions including physiotherapy and exercise show short-term improvements in physical function. However this conclusion is based on meta-analysis of a few small studies and no long-term benefits of physiotherapy exercise interventions were identified. Future research should target improvements to long-term function, pain and performance outcomes in appropriately powered trials.

Promoting patient uptake and adherence in cardiac rehabilitation.

BACKGROUND: Cardiac rehabilitation is an important component of recovery from coronary events but uptake and adherence to such programs are below recommended levels. In 2010, our Cochrane review identified some evidence that interventions to increase uptake of cardiac rehabilitation can be effective but there was insufficient evidence to provide recommendations on intervention to increase adherence. In this review, we update the previously published Cochrane review. OBJECTIVES: To determine the effects, both harms and benefits, of interventions to increase patient uptake of, or adherence to, cardiac rehabilitation. SEARCH METHODS: We performed an updated search in January 2013 to identify studies published after publication of the previous systematic review. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 12, 2012), MEDLINE (Ovid), EMBASE (Ovid), CINAHL EBSCO, Conference Proceedings Citation Index - Science (CPCI-S) on Web of Science (Thomson Reuters), and National Health Service (NHS) Centre for Reviews and Dissemination (CRD) databases (Health Technology Assessment (HTA) and Database of Abstracts of Reviews of Effects (DARE)) on The Cochrane Library (Issue 4, 2012). We also checked reference lists of identified systematic reviews and randomised controlled trials (RCTs) for additional studies. We applied no language restrictions. SELECTION CRITERIA: Adults with myocardial infarction, coronary artery bypass graft, percutaneous transluminal coronary angioplasty, heart failure, angina, or coronary heart disease eligible for cardiac rehabilitation and RCTs or quasi-randomized trials of interventions to increase uptake or adherence to cardiac rehabilitation or any of its component parts. We only included studies reporting a primary outcome. DATA COLLECTION AND ANALYSIS: At least three authors independently screened titles and abstracts of all identified references for eligibility and obtained full papers of potentially relevant trials. At least two authors checked the selection. Three authors assessed included studies for risk of bias. MAIN RESULTS: The updated search identified seven new studies (880 participants) of interventions to improve uptake of cardiac rehabilitation and one new study (260 participants) of interventions to increase adherence. When added to the previous version of this review, we included 18 studies (2505 participants), 10 studies (1338 participants) of interventions to improve uptake of cardiac rehabilitation and eight studies (1167 participants) of interventions to increase adherence. We assessed the majority of studies as having high or unclear risk of bias. Meta-analysis was not possible due to multiple sources of heterogeneity. Eight of 10 studies demonstrated increased uptake of cardiac rehabilitation. Successful interventions to improve uptake of cardiac rehabilitation included: structured nurse- or therapist-led contacts, early appointments after discharge, motivational letters, gender-specific programs, and intermediate phase programs for older patients. Three of eight studies demonstrated improvement in adherence to cardiac rehabilitation. Successful interventions included: self monitoring of activity, action planning, and tailored counselling by cardiac rehabilitation staff. Data were limited on mortality and morbidity but did not demonstrate a difference in cardiovascular events or mortality except for one study that noted an increased rate of revascularization in the intervention group. None of the studies found a difference in health-related quality of life and there was no evidence of adverse events. No studies reported on costs or healthcare utilization. AUTHORS' CONCLUSIONS: We found only weak evidence to suggest that interventions to increase the uptake of cardiac rehabilitation are effective. Practice recommendations for increasing adherence to cardiac rehabilitation cannot be made. Interventions targeting patient-identified barriers may increase the likelihood of success. Further high-quality research is still needed.