QuickDASH and PRWE Are Not Optimal Patient-Reported Outcome Measures After Distal Radial Fracture Due to Ceiling Effect:Potential Implications for Future Research

BACKGROUND: The aim of this study was to determine the floor and ceiling effects for both the QuickDASH (shortened version of the Disabilities of the Arm, Shoulder and Hand [DASH] questionnaire) and the PRWE (Patient-Rated Wrist Evaluation) following a distal radial fracture (DRF). Secondary aims were to determine the degree to which patients with a floor or ceiling effect felt that their wrist was "normal" according to the Normal Wrist Score (NWS) and if there were patient factors associated with achieving a floor or ceiling effect.METHODS: A retrospective cohort study of patients in whom a DRF was managed at the study center during a single year was undertaken. Outcome measures included the QuickDASH, PRWE, EuroQol-5 Dimensions-3 Levels (EQ-5D-3L), and NWS.RESULTS: There were 526 patients with a mean age of 65 years (range, 20 to 95 years), and 421 (80%) were female. Most patients were managed nonsurgically (73%, n = 385). The mean follow-up was 4.8 years (range, 4.3 to 5.5 years). A ceiling effect was observed for both the QuickDASH (22.3% of patients with the best possible score) and the PRWE (28.5%). When defined as a score that differed from the best available score by less than the minimum clinically important difference (MCID) for the scoring system, the ceiling effect increased to 62.8% for the QuickDASH and 60% for the PRWE. Patients who had a ceiling score on the QuickDASH and the PWRE had a median NWS of 96 and 98, respectively, and those who had a score within 1 MCID of the ceiling score reported a median NWS of 91 and 92, respectively. On logistic regression analysis, a dominant-hand injury and better health-related quality of life were the factors associated with both QuickDASH and PRWE ceiling scores (all p &lt; 0.05).CONCLUSIONS: The QuickDASH and PRWE demonstrate ceiling effects when used to assess the outcome of DRF management. Some patients achieving ceiling scores did not consider their wrist to be "normal." Future research on patient-reported outcome assessment tools for DRFs should aim to limit the ceiling effect, especially for individuals or groups that are more likely to achieve a ceiling score.LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.</p

Surgical Versus Nonsurgical Management of Humeral Shaft Fractures:a systematic review and meta-analysis of randomised trials

Introduction: The aim was to compare operative and non-operative management for adults with humeral shaft fractures, in terms of patient-reported upper limb function, health-related quality of life (HRQoL), radiographic outcomes and complications.Methods: MEDLINE, Embase, CINAHL (Cumulative Index to Nursing and Allied Health Literature), PubMed, CENTRAL (Cochrane Central Register of Controlled Trials), ClinicalTrials.gov, ISRCTN (International Clinical Trials Registry) and OpenGrey (Repository for Grey Literature in Europe) were searched in September 2021. All published prospective randomised trials comparing operative and non-operative management of humeral shaft fractures in adults were included. Of 715 studies identified, five were included in the systematic review and four in the meta-analysis. Data were extracted by two independent reviewers according to the PRISMA statement. Methodological quality was assessed using the revised Cochrane risk-of-bias tool for randomised trials. Pooled data were analysed using a random-effects model.Results: The meta-analysis comprised 292 patients (mean age 41yrs [18-83], 67% male). Surgery was associated with superior DASH and Constant-Murley scores at six months (mean DASH difference 7.6, p=0.01; mean Constant-Murley difference 8.0, p=0.003) but there was no difference at one year (DASH, p=0.30; Constant-Murley, p=0.33). No differences in HRQoL or pain scores were found. Surgery was associated with a lower risk of nonunion (0.7% versus 15.7%; odds ratio [OR] 0.13, p=0.004). The number-needed-to-treat (NNT) with surgery to avoid one nonunion was 7. Surgery was associated with a higher risk of transient radial nerve palsy (17.4% versus 0.7%; OR 8.23, p=0.01) but not infection (OR 3.57, p=0.13). Surgery was also associated with a lower risk of re-intervention (1.4% versus 19.3%; OR 0.14, p=0.04).Conclusions: Surgery may confer an early functional advantage to adults with humeral shaft fractures, but this is not sustained beyond six months. The lower risk of nonunion should be balanced against the higher risk of transient radial nerve palsy.<br/

Operative vs Nonoperative Management of Unstable Medial Malleolus Fractures:A Randomized Clinical Trial

IMPORTANCE: Unstable ankle fractures are routinely managed operatively. However, because of soft tissue and implant-related complications, recent literature has reported on the nonoperative management of well-reduced medial malleolus fractures after fibular stabilization, but with limited evidence supporting the routine application.OBJECTIVE: To assess the superiority of internal fixation of well-reduced (displacement ≤2 mm) medial malleolus fractures compared with nonfixation after fibular stabilization.DESIGN, SETTING, AND PARTICIPANTS: This superiority, pragmatic, parallel, prospective randomized clinical trial was conducted from October 1, 2017, to August 31, 2021. A total of 154 adult participants (≥16 years) with a closed, unstable bimalleolar or trimalleolar ankle fracture requiring surgery at an academic major trauma center in the UK were assessed. Exclusion criteria included injuries with no medial-sided fracture, open fractures, neurovascular injury, and the inability to comply with follow-up. Data analysis was performed in July 2022 and confirmed in September 2023.INTERVENTIONS: Once the lateral (and where appropriate, posterior) malleolus had been fixed and satisfactory intraoperative reduction of the medial malleolus fracture was confirmed by the operating surgeon, participants were randomly allocated to fixation (n = 78) or nonfixation (n = 76) of the medial malleolus.MAIN OUTCOME AND MEASURE: Olerud-Molander Ankle Score (OMAS) 1 year after randomization (range, 0-100 points, with 0 indicating worst possible outcome and 100 indicating best possible outcome).RESULTS: Among 154 randomized participants (mean [SD] age, 56.5 [16.7] years; 119 [77%] female), 144 (94%) completed the trial. At 1 year, the median OMAS was 80.0 (IQR, 60.0-90.0) in the fixation group compared with 72.5 (IQR, 55.0-90.0) in the nonfixation group (P = .17). Complication rates were comparable. Significantly more patients in the nonfixation group developed a radiographic nonunion (20% vs 0%; P &lt; .001), with 8 of 13 clinically asymptomatic; 1 patient required surgical reintervention for this. Fracture type and reduction quality appeared to influence fracture union and patient outcome.CONCLUSIONS AND RELEVANCE: In this randomized clinical trial comparing internal fixation of well-reduced medial malleolus fractures with nonfixation, after fibular stabilization, fixation was not superior according to the primary outcome. However, 1 in 5 patients developed a radiographic nonunion after nonfixation, and although the reintervention rate to manage this was low, the future implications are unknown. These results support selective nonfixation of anatomically reduced medial malleolar fractures after fibular stabilization.TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03362229.</p

A study of National Health Service management of chronic osteoarthritis and low back pain

AIM: To describe treatment and referral patterns and National Health Service resource use in patients with chronic pain associated with low back pain or osteoarthritis, from a Primary Care perspective. BACKGROUND: Osteoarthritis and low back pain are the two commonest debilitating causes of chronic pain, with high health and social costs, and particularly important in primary care. Understanding current practice and resource use in their management will inform health service and educational requirements and the design and optimisation of future care. METHOD: Multi-centre, retrospective, descriptive study of adults (⩾18 years) with chronic pain arising from low back pain or osteoarthritis, identified through primary care records. Five general practices in Scotland, England (two), Northern Ireland and Wales. All patients with a diagnosis of low back pain or osteoarthritis made on or before 01/09/2006 who had received three or more prescriptions for pain medication were identified and a sub-sample randomly selected then consented to an in-depth review of their medical records (n=264). Data on management of chronic pain were collected retrospectively from patients’ records for three years from diagnosis (‘newly diagnosed’ patients) or for the most recent three years (‘established’ patients). FINDINGS: Patients received a wide variety of pain medications with no overall common prescribing pattern. GP visits represented the majority of the resource use and ‘newly diagnosed’ patients were significantly more likely to visit their GP for pain management than ‘established’ patients. Although ‘newly diagnosed’ patients had more referrals outside the GP practice, the number of visits to secondary care for pain management was similar for both groups. CONCLUSION: This retrospective study confirmed the complexity of managing these causes of chronic pain and the associated high resource use. It provides an in-depth picture of prescribing and referral patterns and of resource use

Caspase-2-Mediated Cleavage of Mdm2 Creates a p53-Induced Positive Feedback Loop

Caspase-2 is an evolutionarily conserved caspase, yet its biological function and cleavage targets are poorly understood. Caspase-2 is activated by the p53 target gene product PIDD (also known as LRDD) in a complex called the Caspase-2-PIDDosome. We show that PIDD expression promotes growth arrest and chemotherapy resistance by a mechanism that depends on Caspase-2 and wild-type p53. PIDD-induced Caspase-2 directly cleaves the E3 ubiquitin ligase Mdm2 at Asp 367, leading to loss of the C-terminal RING domain responsible for p53 ubiquitination. As a consequence, N-terminally truncated Mdm2 binds p53 and promotes its stability. Upon DNA damage, p53 induction of the Caspase-2-PIDDosome creates a positive feedback loop that inhibits Mdm2 and reinforces p53 stability and activity, contributing to cell survival and drug resistance. These data establish Mdm2 as a cleavage target of Caspase-2 and provide insight into a mechanism of Mdm2 inhibition that impacts p53 dynamics upon genotoxic stress.Virginia and D.K. Ludwig Fund for Cancer Research (Postdoctoral Fellowship)Human Frontier Science Program (Strasbourg, France) (Fellowship)National Cancer Institute (U.S.) (Cancer Center Support (Core) Grant P30-CA14051

Feasibility of aspirin and/or vitamin D3 for men with prostate cancer on active surveillance with Prolaris® testing

OBJECTIVES: To test the feasibility of a randomised controlled trial (RCT) of aspirin and/or vitamin D3 in active surveillance (AS) low/favourable intermediate risk prostate cancer (PCa) patients with Prolaris® testing. PATIENTS AND METHODS: Newly-diagnosed low/favourable intermediate risk PCa patients (PSA ≤ 15 ng/ml, International Society of Urological Pathology (ISUP) Grade Group ≤2, maximum biopsy core length <10 mm, clinical stage ≤cT2c) were recruited into a multi-centre randomised, double-blind, placebo-controlled study (ISRCTN91422391, NCT03103152). Participants were randomised to oral low dose (100 mg), standard dose (300 mg) aspirin or placebo and/or vitamin D3 (4000 IU) versus placebo in a 3 × 2 factorial RCT design with biopsy tissue Prolaris® testing. The primary endpoint was trial acceptance/entry rates. Secondary endpoints included feasibility of Prolaris® testing, 12-month disease re-assessment (imaging/biochemical/histological), and 12-month treatment adherence/safety. Disease progression was defined as any of the following (i) 50% increase in baseline PSA, (ii) new Prostate Imaging-Reporting and Data System (PI-RADS) 4/5 lesion(s) on multi-parametric MRI where no previous lesion, (iii) 33% volume increase in lesion size, or radiological upstaging to ≥T3, (iv) ISUP Grade Group upgrade or (v) 50% increase in maximum cancer core length. RESULTS: Of 130 eligible patients, 104 (80%) accepted recruitment from seven sites over 12 months, of which 94 patients represented the per protocol population receiving treatment. Prolaris® testing was performed on 76/94 (81%) diagnostic biopsies. Twelve-month disease progression rate was 43.3%. Assessable 12-month treatment adherence in non-progressing patients to aspirin and vitamin D across all treatment arms was 91%. Two drug-attributable serious adverse events in 1 patient allocated to aspirin were identified. The study was not designed to determine differences between treatment arms. CONCLUSION: Recruitment of AS PCa patients into a multi-centre multi-arm placebo-controlled RCT of minimally-toxic adjunctive oral drug treatments with molecular biomarker profiling is acceptable and safe. A larger phase III study is needed to determine optimal agents, intervention efficacy, and outcome-associated biomarkers

Developing an impact library for forecasting surface water flood risk

During surface water flooding events, emergency responders require detailed information on the risks posed in order to provide an appropriate and effective response. Few early warning systems quantitatively estimate the risk and impacts of surface water flooding. Improvements in computational processing capability, availability of new datasets and developments in forecasting models means that the forecasting information currently being supplied by the Flood Forecasting Centre can be improved upon through the application of a timely, impact‐based model. This article presents a novel approach to collating receptor datasets into a pre‐calculated Impact Library for use in a Hazard Impact Model (HIM) that will operate using real‐time probabilistic rainfall and surface runoff forecasts for England and Wales. The HIM provides an approach suitable for modelling flood impacts. Initial results are presented for a case study covering the 2012 floods in the North East of England. Information generated by the HIM provides additional benefits beyond current methods. Features include operator access to 1 km 15 min spatial–temporal data, analysis of individual impact criteria and modular refinement of the Impact Library to suit different situations. The HIM has been developed in partnership via the Natural Hazards Partnership

Climate warming and increasing Vibrio vulnificus infections in North America

Vibrio vulnificus is an opportunistic bacterial pathogen, occurring in warm low-salinity waters. V. vulnificus wound infections due to seawater exposure are infrequent but mortality rates are high (~ 18%). Seawater bacterial concentrations are increasing but changing disease pattern assessments or climate change projections are rare. Here, using a 30-year database of V. vulnificus cases for the Eastern USA, changing disease distribution was assessed. An ecological niche model was developed, trained and validated to identify links to oceanographic and climate data. This model was used to predict future disease distribution using data simulated by seven Global Climate Models (GCMs) which belong to the newest Coupled Model Intercomparison Project (CMIP6). Risk was estimated by calculating the total population within 200 km of the disease distribution. Predictions were generated for different “pathways” of global socioeconomic development which incorporate projections of greenhouse gas emissions and demographic change. In Eastern USA between 1988 and 2018, V. vulnificus wound infections increased eightfold (10–80 cases p.a.) and the northern case limit shifted northwards 48 km p.a. By 2041–2060, V. vulnificus infections may expand their current range to encompass major population centres around New York (40.7°N). Combined with a growing and increasingly elderly population, annual case numbers may double. By 2081–2100 V. vulnificus infections may be present in every Eastern USA State under medium-to-high future emissions and warming. The projected expansion of V. vulnificus wound infections stresses the need for increased individual and public health awareness in these areas

FLORA: a novel method to predict protein function from structure in diverse superfamilies

Predicting protein function from structure remains an active area of interest, particularly for the structural genomics initiatives where a substantial number of structures are initially solved with little or no functional characterisation. Although global structure comparison methods can be used to transfer functional annotations, the relationship between fold and function is complex, particularly in functionally diverse superfamilies that have evolved through different secondary structure embellishments to a common structural core. The majority of prediction algorithms employ local templates built on known or predicted functional residues. Here, we present a novel method (FLORA) that automatically generates structural motifs associated with different functional sub-families (FSGs) within functionally diverse domain superfamilies. Templates are created purely on the basis of their specificity for a given FSG, and the method makes no prior prediction of functional sites, nor assumes specific physico-chemical properties of residues. FLORA is able to accurately discriminate between homologous domains with different functions and substantially outperforms (a 2–3 fold increase in coverage at low error rates) popular structure comparison methods and a leading function prediction method. We benchmark FLORA on a large data set of enzyme superfamilies from all three major protein classes (α, β, αβ) and demonstrate the functional relevance of the motifs it identifies. We also provide novel predictions of enzymatic activity for a large number of structures solved by the Protein Structure Initiative. Overall, we show that FLORA is able to effectively detect functionally similar protein domain structures by purely using patterns of structural conservation of all residues

One hundred research questions in conservation physiology for generating actionable evidence to inform conservation policy and practice

Environmental change and biodiversity loss are but two of the complex challenges facing conservation practitioners and policy makers. Relevant and robust scientific knowledge is critical for providing decision-makers with the actionable evidence needed to inform conservation decisions. In the Anthropocene, science that leads to meaningful improvements in biodiversity conservation, restoration and management is desperately needed. Conservation Physiology has emerged as a discipline that is well-positioned to identify the mechanisms underpinning population declines, predict responses to environmental change and test different in situ and ex situ conservation interventions for diverse taxa and ecosystems. Here we present a consensus list of 10 priority research themes. Within each theme we identify specific research questions (100 in total), answers to which will address conservation problems and should improve the management of biological resources. The themes frame a set of research questions related to the following: (i) adaptation and phenotypic plasticity; (ii) human-induced environmental change; (iii) human-wildlife interactions; (iv) invasive species; (v) methods, biomarkers and monitoring; (vi) policy, engagement and communication; (vii) pollution; (viii) restoration actions; (ix) threatened species; and (x) urban systems. The themes and questions will hopefully guide and inspire researchers while also helping to demonstrate to practitioners and policy makers the many ways in which physiology can help to support their decisions