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Background To report our recommended methodology for extracting and then confirming research uncertainties – areas where research has failed to answer a research question – derived from previously published literature during a broad scope Priority Setting Partnership (PSP) with the James Lind Alliance (JLA). Methods This process was completed in the UK as part of the PSP for “Common Conditions Affecting the Hand and Wrist”, comprising of health professionals, patients and carers and reports the data (uncertainty) extraction phase of this. The PSP followed the robust methodology dictated by the JLA and sought to identify knowledge gaps, termed “uncertainties” by the JLA. Published Cochrane Systematic Reviews, Guidelines and Protocols, NICE (National Institute for Health and Care Excellence) Guidelines, and SIGN (Scottish Intercollegiate Guidelines Network) Guidelines were screened for documented “uncertainties”. A robust method of screening, internally verifying and then checking uncertainties was adopted. This included independent screening and data extraction by multiple researchers and use of a PRISMA flowchart, alongside steering group consensus processes. Selection of research uncertainties was guided by the scope of the Common Conditions Affecting the Hand and Wrist PSP which focused on “common” hand conditions routinely treated by hand specialists, including hand surgeons and hand therapists limited to identifying questions concerning the results of intervention, and not the basic science or epidemiology behind disease. Results Of the 2358 records identified (after removal of duplicates) which entered the screening process, 186 records were presented to the PSP steering group for eligibility assessment; 79 were deemed within scope and included for the purpose of research uncertainty extraction (45 full Cochrane Reviews, 18 Cochrane Review protocols, 16 Guidelines). These yielded 89 research uncertainties, which were compared to the stakeholder survey, and added to the longlist where necessary; before derived uncertainties were checked against non-Cochrane published systematic reviews. Conclusions In carrying out this work, beyond reporting on output of the Common Conditions Affecting the Hand and Wrist PSP, we detail the methodology and processes we hope can inform and facilitate the work of future PSPs and other evidence reviews, especially those with a broader scope beyond a single disease or condition.

Purpose The purpose of this study is to assess the feasibility of conducting a large, multicentre randomised controlled trial (RCT) comparing needle fasciotomy with limited fasciectomy for treatment of Dupuytren’s contractures. Design The design of this study is a parallel, two-arm, multicentre, randomised feasibility trial with embedded QuinteT Recruitment Intervention. Participants Patients aged 18 years or over who were referred from primary to secondary care for treatment of a hand with Dupuytren’s contractures of one or more fingers of more than 30° at the metacarpophalangeal (MCP) and/or proximal interphalangeal (PIP) joints and well-defined cord(s). Patients were excluded if they had undergone previous Dupuytren’s contracture surgery on the same hand. Methods Potential participants were screened for eligibility. Recruited participants randomised (1:1) to treatment with either needle fasciotomy or limited fasciectomy and followed-up for up to 6 months after treatment. Data on recruitment rates, completion of follow-up, and procedure costs were collected. Four patient reported outcome measures (PROMs) and objective outcome measures were collected before intervention and 6 weeks and 6 months afterwards. Results One hundred and fifty-three of 267 (57%) primary-care referrals for Dupuytren’s contractures met the eligibility criteria for the study. Seventy-one of the 153 (46%) agreed to participate and were randomly allocated to treatment with needle fasciotomy or limited fasciectomy. Sixty-seven of these underwent their allocated treatment, two were crossovers from limited fasciectomy to needle fasciotomy, and two (both allocated limited fasciectomy) received no treatment. Fifty-nine participants (85%) completed 6-month follow-up PROMs. Participants felt the MYMOP, PEM and URAM PROMs allowed them to better describe how their treatment affected their hand function than the DASH PROM. The estimated costs of limited fasciectomy (in an operating theatre) and needle fasciotomy (in a clinic room) were £777 and £111 respectively. Conclusion A large RCT comparing treatment of Dupuytren’s contractures by needle fasciotomy and limited fasciectomy is feasible. Data from this study will help determine the number of sites and duration of recruitment required to complete an adequately powered RCT and will assist the selection of PROMs in future studies on the treatment of Dupuytren’s contractures. (Level 1 feasibility study). Trial registration Trial registered with ISRCTN (registration number: ISRCTN11164292 ), date assigned - 28/08/2015.

Fifteen per cent of acute fractures of the scaphoid waist fail to unite if treated non-operatively in plaster, resulting in persistent loss of function. Suspected risk factors for non-union include proximal fracture fragment avascularity and assessments of fracture displacement and comminution. This series of studies investigated whether one can accurately identify which scaphoid waist fractures will unite with plaster treatment. They suggest that proximal fracture fragment vascularity is not a predictor of outcome. In contrast, assessments of fracture displacement on magnetic resonance imaging (MRI) and computed tomography (CT) but not scaphoid series radiographs can be used to predict outcome. Undisplaced fractures are benign and unite reliably with 4–8 weeks’ treatment in plaster. Displaced fractures with 3mm or more gapping have a significant non-union rate if treated in plaster and might be better treated operatively. Use of MRI/CT may allow reliable, cost effective treatment of acute fractures through the scaphoid waist.

BackgroundFractures of the shaft of the tibia often heal with some angulation. Although there is biomechanical evidence that such angulation alters load transmission through the joints of the lower limb, it is not clear whether it can eventually lead to osteoarthritis.MethodsOne hundred and sixty-four individuals who had sustained a tibial shaft fracture were assessed in a research clinic thirty to forty-three years after the injury. The subjects were evaluated with regard to self-reported lower limb joint pain, stiffness, and disability (assessed with the Western Ontario and McMaster Universities [WOMAC] osteoarthritis questionnaire); clinical signs of osteoarthritis; and radiographic evidence of osteophytes and joint-space narrowing in the knees, ankles, and subtalar joints.ResultsTwenty-two (15%) of the 151 subjects who reported no other knee injury reported at least moderate knee pain, and eight (6%) of the 145 subjects who reported no other ankle injury reported at least moderate ankle pain. Seventeen (13%) of the 135 subjects who reported no other knee or ankle injury reported at least moderate disability. The ipsilateral side demonstrated a higher prevalence than the contralateral side in terms of pain with passive ankle movement (nineteen versus nine subjects, p = 0.02), pain with passive subtalar movement (fifteen versus four subjects, p = 0.01), and radiographic signs of ankle joint space narrowing (twelve subjects versus one subject, p = 0.0055). Knee osteoarthritis was frequently bilateral. Forty-seven fractures (29%) healed with coronal angulation of ≥5°. Apart from an association between shortening of ≥10 mm and self-reported knee pain (p = 0.016), there were no significant univariate associations between these malunions and the development of osteoarthritis. Seventeen (15%) of 114 eligible subjects had overall malalignment of the lower limb, defined as a hip-knee-ankle angle outside the normal range of 6.25° of varus to 4.75° of valgus. This malalignment was due to the fracture malunion in nine subjects and predated the fracture in eight. In limbs with varus or valgus malalignment, there was an excess of subtalar stiffness (p = 0.04) and a nonsignificant trend toward more frequent knee pain. In limbs with varus malalignment, there was a nonsignificant trend toward more frequent radiographic evidence of osteoarthritis in the medial compartment of the knee joint. Most of the subjects in whom osteoarthritis was observed had normal overall alignment of the lower limb.ConclusionsThe thirty-year outcome after a tibial shaft fracture is usually good, although mild osteoarthritis is common. Fracture malunion is not the cause of the higher prevalence of symptomatic ankle and subtalar osteoarthritis on the side of the fracture. Although varus malalignment of the lower limb occurs occasionally and may cause osteoarthritis in the medial compartment of the knee, other factors are more important in causing osteoarthritis after a tibial shaft fracture.

Objectives-To investigate longterm pain and disability subsequent to a tibial shaft fracture treated conservatively. Design and setting-Subjects who had sustained a tibial shaft fracture more than 27 years ago were compared with those who had not. Subjects-572 fracture patients (identified from the records of the plaster room) aged over 16 at the time of injury were contacted and were compared with 2285 randomly selected subjects matched for age, sex, and general practice. Main outcome measures-Self reported knee pain; self reported GP's diagnosis of osteoarthritis; ability to climb stairs, walk 100 yards, to bend, kneel, or stoop; and SF-36 physical functioning score. Results-Subjects were reviewed between 27 and 41 years after tibial shaft fracture (mean 35 years). Fracture patients were more likely to suffer chronic knee pain (odds ratio 1.23; 95% confidence interval (CI) 1.00, 1.51) and report being given a diagnosis of osteoarthritis by their GP (odds ratio 1.46; 95% CI 1.08, 1.97). The ability to climb stairs, walk 100 yards, and bend, kneel, or stoop was less in the fracture group than the other subjects. The SF-36 physical function score was significantly lower in the fracture group. Conclusions-More than 27 years after a tibial shaft fracture, subjects have more knee pain than the rest of the population. They also have greater difficulty performing everyday physical activities. The excess morbidity may be due to injury factors or treatment factors, and further research is needed to investigate this important association further.

Some studies have suggested a link between antihypertensive medication and cancer, but the evidence is so far inconclusive. Thus, we aimed to investigate this association in a large individual patient data meta-analysis of randomised clinical trials. We searched PubMed, MEDLINE, The Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from Jan 1, 1966, to Sept 1, 2019, to identify potentially eligible randomised controlled trials. Eligible studies were randomised controlled trials comparing one blood pressure lowering drug class with a placebo, inactive control, or other blood pressure lowering drug. We also required that trials had at least 1000 participant years of follow-up in each treatment group. Trials without cancer event information were excluded. We requested individual participant data from the authors of eligible trials. We pooled individual participant-level data from eligible trials and assessed the effects of angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), β blockers, calcium channel blockers, and thiazide diuretics on cancer risk in one-stage individual participant data and network meta-analyses. Cause-specific fixed-effects Cox regression models, stratified by trial, were used to calculate hazard ratios (HRs). The primary outcome was any cancer event, defined as the first occurrence of any cancer diagnosed after randomisation. This study is registered with PROSPERO (CRD42018099283). 33 trials met the inclusion criteria, and included 260 447 participants with 15 012 cancer events. Median follow-up of included participants was 4·2 years (IQR 3·0–5·0). In the individual participant data meta-analysis comparing each drug class with all other comparators, no associations were identified between any antihypertensive drug class and risk of any cancer (HR 0·99 [95% CI 0·95–1·04] for ACEIs; 0·96 [0·92–1·01] for ARBs; 0·98 [0·89–1·07] for β blockers; 1·01 [0·95–1·07] for thiazides), with the exception of calcium channel blockers (1·06 [1·01–1·11]). In the network meta-analysis comparing drug classes against placebo, we found no excess cancer risk with any drug class (HR 1·00 [95% CI 0·93–1·09] for ACEIs; 0·99 [0·92–1·06] for ARBs; 0·99 [0·89–1·11] for β blockers; 1·04 [0·96–1·13] for calcium channel blockers; 1·00 [0·90–1·10] for thiazides). We found no consistent evidence that antihypertensive medication use had any effect on cancer risk. Although such findings are reassuring, evidence for some comparisons was insufficient to entirely rule out excess risk, in particular for calcium channel blockers. British Heart Foundation, National Institute for Health Research, Oxford Martin School.

Laser treatment for diabetic retinopathy is often associated with visual field reduction and other ocular side-effects. Our aim was to assess whether long-term lipid-lowering therapy with fenofibrate could reduce the progression of retinopathy and the need for laser treatment in patients with type 2 diabetes mellitus. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study was a multinational randomised trial of 9795 patients aged 50–75 years with type 2 diabetes mellitus. Eligible patients were randomly assigned to receive fenofibrate 200 mg/day (n=4895) or matching placebo (n=4900). At each clinic visit, information concerning laser treatment for diabetic retinopathy—a prespecified tertiary endpoint of the main study—was gathered. Adjudication by ophthalmologists masked to treatment allocation defined instances of laser treatment for macular oedema, proliferative retinopathy, or other eye conditions. In a substudy of 1012 patients, standardised retinal photography was done and photographs graded with Early Treatment Diabetic Retinopathy Study (ETDRS) criteria to determine the cumulative incidence of diabetic retinopathy and its component lesions. Analyses were by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN64783481. Laser treatment was needed more frequently in participants with poorer glycaemic or blood pressure control than in those with good control of these factors, and in those with a greater burden of clinical microvascular disease, but the need for such treatment was not affected by plasma lipid concentrations. The requirement for first laser treatment for all retinopathy was significantly lower in the fenofibrate group than in the placebo group (164 [3·4%] patients on fenofibrate vs 238 [4·9%] on placebo; hazard ratio [HR] 0·69, 95% CI 0·56–0·84; p=0·0002; absolute risk reduction 1·5% [0·7–2·3]). In the ophthalmology substudy, the primary endpoint of 2-step progression of retinopathy grade did not differ significantly between the two groups overall (46 [9·6%] patients on fenofibrate vs 57 [12·3%] on placebo; p=0·19) or in the subset of patients without pre-existing retinopathy (43 [11·4%] vs 43 [11·7%]; p=0·87). By contrast, in patients with pre-existing retinopathy, significantly fewer patients on fenofibrate had a 2-step progression than did those on placebo (three [3·1%] patients vs 14 [14·6%]; p=0·004). An exploratory composite endpoint of 2-step progression of retinopathy grade, macular oedema, or laser treatments was significantly lower in the fenofibrate group than in the placebo group (HR 0·66, 95% CI 0·47–0·94; p=0·022). Treatment with fenofibrate in individuals with type 2 diabetes mellitus reduces the need for laser treatment for diabetic retinopathy, although the mechanism of this effect does not seem to be related to plasma concentrations of lipids.

Household contacts of persons infected with SARS-CoV-2 are at risk for infection. A single subcutaneous injection of two anti–SARS-CoV-2 monoclonal antibodies in such persons within 4 days after the detection of infection in a household contact reduced this risk by two thirds in the first 28 days after exposure.