BackgroundDespite the problem of inadequate recruitment to randomised trials, there is little evidence to guide researchers on decisions about how people are effectively recruited to take part in trials. The PRioRiTy study aimed to identify and prioritise important unanswered trial recruitment questions for research. The PRioRiTy study - Priority Setting Partnership (PSP) included members of the public approached to take part in a randomised trial or who have represented participants on randomised trial steering committees, health professionals and research staff with experience of recruiting to randomised trials, people who have designed, conducted, analysed or reported on randomised trials and people with experience of randomised trials methodology.MethodsThis partnership was aided by the James Lind Alliance and involved eight stages: (i) identifying a unique, relevant prioritisation area within trial methodology; (ii) establishing a steering group (iii) identifying and engaging with partners and stakeholders; (iv) formulating an initial list of uncertainties; (v) collating the uncertainties into research questions; (vi) confirming that the questions for research are a current recruitment challenge; (vii) shortlisting questions and (viii) final prioritisation through a face-to-face workshop.ResultsA total of 790 survey respondents yielded 1693 open-text answers to 6 questions, from which 1880 potential questions for research were identified. After merging duplicates, the number of questions was reduced to 496. Questions were combined further, and those that were submitted by fewer than 15 people and/or fewer than 6 of the 7 stakeholder groups were excluded from the next round of prioritisation resulting in 31 unique questions for research. All 31 questions were confirmed as being unanswered after checking relevant, up-to-date research evidence. The 10 highest priority questions were ranked at a face-to-face workshop. The number 1 ranked question was “How can randomised trials become part of routine care and best utilise current clinical care pathways?” The top 10 research questions can be viewed at www.priorityresearch.ie.ConclusionThe prioritised questions call for a collective focus on normalising trials as part of clinical care, enhancing communication, addressing barriers, enablers and motivators around participation and exploring greater public involvement in the research process.

Background Neurodegeneration is the pathological substrate that causes major disability in secondary progressive multiple sclerosis. A synthesis of preclinical and clinical research identified three neuroprotective drugs acting on different axonal pathobiologies. We aimed to test the efficacy of these drugs in an efficient manner with respect to time, cost, and patient resource. Methods We did a phase 2b, multiarm, parallel group, double-blind, randomised placebo-controlled trial at 13 clinical neuroscience centres in the UK. We recruited patients (aged 25-65 years) with secondary progressive multiple sclerosis who were not on disease-modifying treatment and who had an Expanded Disability Status Scale (EDSS) score of 4•0-6•5. Participants were randomly assigned (1:1:1:1) at baseline, by a research nurse using a centralised web-based service, to receive twice-daily oral treatment of either amiloride 5 mg, fluoxetine 20 mg, riluzole 50 mg, or placebo for 96 weeks. The randomisation procedure included minimisation based on sex, age, EDSS score at randomisation, and trial site. Capsules were identical in appearance to achieve masking. Patients, investigators, and MRI readers were unaware of treatment allocation. The primary outcome measure was volumetric MRI percentage brain volume change (PBVC) from baseline to 96 weeks, analysed using multiple regression, adjusting for baseline normalised brain volume and minimisation criteria. The primary analysis was a complete-case analysis based on the intention-to-treat population (all patients with data at week 96). This trial is registered with ClinicalTrials. gov, NCT01910259.

Introduction One way to slow the spread of resistant bacteria is by improved stewardship of antibiotics: using them more carefully and reducing the number of prescriptions. With an estimated 7%–10% of antibiotic prescriptions globally originating from dental practices and up to 80% prescribed unnecessarily, dentistry has an important role to play. To support the design of new stewardship interventions through knowledge transfer between contexts, this study aimed to identify factors associated with the decision to prescribe antibiotics to adults presenting with acute conditions across primary care (including dentistry). Methods Two reviews were undertaken: an umbrella review across primary healthcare and a systematic review in dentistry. Two authors independently selected and quality assessed the included studies. Factors were identified using an inductive thematic approach and mapped to the Theoretical Domains Framework (TDF). Comparisons between dental and other settings were explored. Registration number: PROSPERO_CRD42016037174. Results Searches identified 689 publications across primary care and 432 across dental care. Included studies (nine and seven, respectively) were assessed as of variable quality. They covered 46 countries, of which 12 were low and middle-income countries (LMICs). Across the two reviews, 30 factors were identified, with ‘patient/condition characteristics’, ‘patient influence’ and ‘guidelines & information’ the most frequent. Two factors were unique to dental studies: ‘procedure possible’ and ‘treatment skills’. No factor related only to LMICs. Conclusions A comprehensive list of factors associated with antibiotic prescribing to adults with acute conditions in primary care settings around the world has been collated and should assist theory-informed design of new context-specific stewardship interventions.

Background The prevalence of reported penicillin allergy (PenA) and the impact these records have on health outcomes in the UK general population are unknown. Without such data, justifying and planning enhanced allergy services is challenging. Objectives To determine: (i) prevalence of PenA records; (ii) patient characteristics associated with PenA records; and (iii) impact of PenA records on antibiotic prescribing/health outcomes in primary care. Methods We carried out cross-sectional/retrospective cohort studies using patient-level data from electronic health records. Cohort study: exact matching across confounders identified as affecting PenA records. Setting: English NHS general practices between 1 April 2013 and 31 March 2014. Participants: 2.3 million adult patients. Outcome measures: prevalence of PenA, antibiotic prescribing, mortality, MRSA infection/colonization and Clostridioides difficile infection. Results PenA prevalence was 5.9% (IQR = 3.8%–8.2%). PenA records were more common in older people, females and those with a comorbidity, and were affected by GP practice. Antibiotic prescribing varied significantly: penicillins were prescribed less frequently in those with a PenA record [relative risk (RR)  = 0.15], and macrolides (RR = 4.03), tetracyclines (RR = 1.91) nitrofurantoin (RR = 1.09), trimethoprim (RR = 1.04), cephalosporins (RR = 2.05), quinolones (RR = 2.10), clindamycin (RR = 5.47) and total number of prescriptions were increased in patients with a PenA record. Risk of re-prescription of a new antibiotic class within 28 days (RR = 1.32), MRSA infection/colonization (RR = 1.90) and death during the year subsequent to 1 April 2013 (RR = 1.08) increased in those with PenA records. Conclusions PenA records are common in the general population and associated with increased/altered antibiotic prescribing and worse health outcomes. We estimate that incorrect PenA records affect 2.7 million people in England. Establishing true PenA status (e.g. oral challenge testing) would allow more people to be prescribed first-line antibiotics, potentially improving health outcomes.

Objectives Cardiovascular disease (CVD) is a major cause of mortality; periodontal disease (PD) affects up to 50% of the world's population. Observational evidence has demonstrated association between CVD and PD. Absent from the literature is a systematic review and meta‐analysis of longitudinal cohort studies quantifying CVD risk in PD populations compared to non‐PD populations. To examine the risk of incident CVD in people with PD in randomised controlled trials and longitudinal cohort studies. Material and Methods We searched Medline, EMBASE and Cochrane databases up to 9th Oct 2019 using keywords and MeSH headings using the following concepts: PD, CVD, longitudinal and RCT study design. CVD outcomes included but were not restricted to any CVD, myocardial infarction, coronary heart disease (CHD) and stroke. Diagnosis method and severity of PD were measured either clinically or by self‐report. Studies comparing incident CVD in PD and non‐PD populations were included. Meta‐analysis and meta‐regression was performed to determine risk of CVD in PD populations and examine the effects of PD diagnosis method, PD severity, gender and study region. Results Thirty‐two longitudinal cohort studies were included after full text screening; 30 were eligible for meta‐analysis. The risk of CVD was significantly higher in PD compared to non‐PD (relative risk [RR]: 1.20, 95% CI: 1.14–1.26). CVD risk did not differ between clinical or self‐reported PD diagnosis (RR = 0.97, 95% CI: 0.87–1.07,). CVD risk was higher in men (RR: 1.16, 95% CI: 1.08–1.25) and severe PD (RR: 1.25, 95% CI: 1.15–1.35). Among all types of CVD, the risk of stroke was highest (RR = 1.24; 95% CI:1.12–1.38), the risk of CHD was also increased (RR = 1.14; 95% CI:1.08–1.21). Conclusion This study demonstrated modest but consistently increased risk of CVD in PD populations. Higher CVD risk in men and people with severe PD suggests population‐targeted interventions could be beneficial.

No abstract

IntroductionThe major unmet need in multiple sclerosis (MS) is for neuroprotective therapies that can slow (or ideally stop) the rate of disease progression. The UK MS Society Clinical Trials Network (CTN) was initiated in 2007 with the purpose of developing a national, efficient, multiarm trial of repurposed drugs. Key underpinning work was commissioned by the CTN to inform the design, outcome selection and drug choice including animal models and a systematic review. This identified seven leading oral agents for repurposing as neuroprotective therapies in secondary progressive MS (SPMS). The purpose of the Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART) will be to evaluate the neuroprotective efficacy of three of these drugs, selected with distinct mechanistic actions and previous evidence of likely efficacy, against a common placebo arm. The interventions chosen were: amiloride (acid-sensing ion channel antagonist); fluoxetine (selective serotonin reuptake inhibitor) and riluzole (glutamate antagonist).Methods and analysisPatients with progressing SPMS will be randomised 1:1:1:1 to amiloride, fluoxetine, riluzole or matched placebo and followed for 96 weeks. The primary outcome will be the percentage brain volume change (PBVC) between baseline and 96 weeks, derived from structural MR brain imaging data using the Structural Image Evaluation, using Normalisation, of Atrophy method. With a sample size of 90 per arm, this will give 90% power to detect a 40% reduction in PBVC in any active arm compared with placebo and 80% power to detect a 35% reduction (analysing by analysis of covariance and with adjustment for multiple comparisons of three 1.67% two-sided tests), giving a 5% overall two-sided significance level. MS-SMART is not powered to detect differences between the three active treatment arms. Allowing for a 20% dropout rate, 110 patients per arm will be randomised. The study will take place at Neuroscience centres in England and Scotland.Ethics and disseminationMS-SMART was approved by the Scotland A Research Ethics Committee on 13 January 2013 (REC reference: 13/SS/0007). Results of the study will be submitted for publication in a peer-reviewed journal.Trial registration numbersNCT01910259; 2012-005394-31; ISRCTN28440672.

Attribute-based stated preference is a useful method with which to examine the preferences of people with MS in their choice of DMT. However, further research embracing the methodological recommendations identified, particularly greater use of qualitative methods in attribute development, is needed.