Search results
Found 30691 matches for
Recognised for the part he played in the discovery of anti-TNF therapy, Dr Feldmann is now exploring whether the antibody can be effective for COVID-19.
Systematic review and meta-analysis of mobilisation following open reduction and internal fixation of hand fractures.
Delayed mobilisation following open reduction and internal fixation (ORIF) of hand fractures may contribute to stiffness and poor functional recovery. The aim of this systematic review and meta-analysis was to evaluate whether timing of mobilisation post-ORIF impacts patient-reported and clinical post-operative outcomes. The review was conducted according to the Cochrane Handbook and was reported in concordance with PRISMA guidelines. All studies reporting mobilisation regimens following ORIF performed within two weeks of metacarpal or phalangeal fractures were included. Of 794 abstracts screened, 53 studies were included, evaluating 1822 hand fractures treated with ORIF. We found differences between mobilisation timing in patient-reported outcome measures (PROMs), adverse events and time to radiological fracture union. Immediate mobilisation (≤1 day of ORIF) had the shortest mean bone healing time of 38.7 days (95% CI 34.3, 42.3) compared to early mobilisation (≤7 days) (49.6 days [95% CI 42.8, 56.5]). Delayed mobilisation (>7 days) had the lowest rate of adverse events at 9.3% [95% CI 5.6, 15.2] compared to early mobilisation at 25.0% [95% CI 17.1, 35.0]. However, variable outcome reporting and inconsistent diagnostic criteria limited definitive conclusions. The current literature on post-ORIF mobilisation is heterogeneous. Our meta-analysis demonstrated wide variability in outcomes across different regimens, with overlapping confidence intervals across most summary estimates. A definitive, multi-centre RCT comparing time to mobilisation post-ORIF, including comprehensive outcome reporting and cost-effectiveness analysis, is warranted to inform clinical practice.
Computerized adaptive testing with the I-HaND scale for monitoring patients with upper limb nerve pathology.
The Impact of Hand Nerve Disorders scale is a patient-reported outcome measure for upper limb nerve pathology. We aimed to assess its structural validity using item response theory and to develop computerized adaptive testing algorithms. We conducted a series of psychometric studies to assess constructs measured, applied an item response theory model to the data, then developed computerized adaptive testing algorithms. The results showed two distinct factors: 'Motor Function' and 'Pain'. We developed two separate computerized adaptive tests which reduced the number of questions from six ('Pain') and 16 ('Motor Function') to a median of three questions each at a high level of precision (standard error of measurement <0.3). For optimal measurement precision, the Impact of the Hand Nerve Disorders scale should be divided into two subscales and administered through computerized adaptive testing. In some circumstances (such as screening for specific issues) it may be preferable to administer all 32 items.
Early detection to improve outcome in people with undiagnosed psoriatic arthritis: the PROMPT research programme including RCT
Background Longitudinal observational studies suggest that patients who present early to secondary care with psoriatic arthritis have a better outcome. Outcome needs to be measured including domains important to patients. Objectives To identify disease activity and impact outcomes important to patients with psoriatic arthritis in comparison to existing ones (Patient-Reported Outcome Measurement Study). To assess the validity of new measures of disease activity in psoriatic arthritis derived from patient engagement (ASSESSment of modified composite disease measures study). To explore patients’ experiences of diagnosis in psoriatic arthritis? (Experiences of screening and diaGnosis from the perspective of pAtients with PSoriasis and psoriatic arthritis study). To identify modifiable risk factors for the development of psoriatic arthritis using the Clinical Practice Research Datalink (EPIdemiology of psoriatiC arthritis study). To compare the performance of screening tools for detecting undiagnosed psoriatic arthritis (COMparison of Psoriatic Arthritis scREening tools study). To investigate the clinical effectiveness (Total bUrDen Of psoRiasis trial) and cost-effectiveness (COSt of screening for Psoriatic Arthritis study) of detecting undiagnosed psoriatic arthritis. Design and methods Mixed methods using data from patient focus groups, a multicentre cohort study, primary care health records (Clinical Practice Research Datalink) and a prospective randomised clinical trial (Total bUrDen Of psoRiasis trial, COMparison of Psoriatic Arthritis scREening tools study, COSt of screening for Psoriatic Arthritis study). Setting and participants Focus groups and cohort studies of 221 patients with psoriatic arthritis including newly diagnosed cases (Patient-Reported Outcome Measurement Study, ASSESSment of modified composite disease measures study, experiences of screening and diaGnosis from the perspective of pAtients with PSoriasis and psoriatic arthritis study) and 2225 patients with psoriasis from primary care not known to have psoriatic arthritis from 135 randomised general practices (COMparison of Psoriatic Arthritis scREening tools study, Total bUrDen Of psoRiasis trial randomised clinical trial, COSt of screening for Psoriatic Arthritis study). Intervention Randomised controlled trial comparing the early identification of psoriatic arthritis by annual rheumatological assessment (enhanced surveillance) in people with psoriasis identified in primary care (n = 1123) with standard care (n = 1102). Participants with suspected inflammatory arthritis were referred to the local rheumatology clinic for an assessment of psoriatic arthritis (enhanced surveillance arm: at baseline, 12 and 24 months; standard care arm: at 24 months). Data sources Cohort studies of incident psoriasis (n = 90,189) or psoriatic arthritis (n = 6783) patients from the Clinical Practice Research Datalink (EPIdemiology of psoriatiC arthritis study). Cost-effective analysis using data collected in Total bUrDen Of psoRiasis trial. Modelling exercise to extrapolate screening performance from Total bUrDen Of psoRiasis trial to long-term costs and quality-adjusted life-years (COSt of screening for Psoriatic Arthritis study). Main outcome measure In Total bUrDen Of psoRiasis trial the primary outcome was the Health Assessment Questionnaire Disability Index at 24 months post registration in participants diagnosed with psoriatic arthritis. Results Patient-Reported Outcome Measurement Study: Patients rated pain and fatigue as the most important outcomes when receiving treatment for psoriatic arthritis. ASSESSment of modified composite disease measures study: Shortened versions of visual analogue scales performed well in detecting treatment change and responsiveness over 6 months. Experiences of screening and diaGnosis from the perspective of pAtients with PSoriasis and psoriatic arthritis study: Missed opportunities for psoriatic arthritis diagnosis has implications for well-being including mental health, and there is a need for provision of psychological support and self-management guidance. Screening for psoriatic arthritis was generally regarded as a positive experience. EPIdemiology of psoriatiC arthritis study: Bayesian networks identified clusters of symptoms that can accurately predict the development of psoriatic arthritis (area under the curve 0.73, 95% CI 0.70 to 0.75). Obesity is a modifiable lifestyle factor that increases the risk of developing psoriatic arthritis and diminishes linearly over a 10-year period with a reduction in body mass index. Diabetes, cardiovascular disease, uveitis and Crohn’s disease are associated with psoriatic arthritis and may appear early in the disease course. COMparison of Psoriatic Arthritis scREening tools study: The Psoriasis Epidemiology Screening Tool questionnaire remains the preferred screening tool, given its simplicity with no significant differences in performance (sensitivity: 0.625, specificity: 0.757, area under the curve 0.787) compared to COmparisoN of ThreE Screening Tools to detect psoriatic arthritis in patients with psoriasis. Total bUrDen Of psoRiasis trial: The primary analysis population consisted of 87 participants with a positive diagnosis of psoriatic arthritis: 64 in enhanced surveillance, 23 in standard care (overall mean Health Assessment Questionnaire Disability Index score at 24 months was 0.45). The adjusted odds ratio for achieving a Health Assessment Questionnaire Disability Index score of 0 at 24 months post registration in enhanced surveillance compared to standard care was 0.64 (95% CI 0.17 to 2.38), and the adjusted odds ratio of achieving a higher (non-zero) Health Assessment Questionnaire Disability Index score at 24 months post registration in enhanced surveillance relative to standard care arm was 1.12 (95% CI 0.67 to 1.86), indicating no evidence of a difference between the two treatment groups (p = 0.6612). COSt of screening for Psoriatic Arthritis study: The within-trial cost-effectiveness analysis suggests that enhanced surveillance may be associated with higher mean quality-adjusted life-years, although the difference was very small (+0.002, 95% CI –0.03 to 0.03), and lower mean costs (−£120.54, 95% CI –£540.57 to £288.99). Using the cost-effectiveness model based on the sensitivity, specificity and the psoriatic arthritis incidence from the Total bUrDen Of psoRiasis trial, Psoriasis Epidemiology Screening Tool is the most expensive and has the highest lifetime quality-adjusted life-years with an incremental cost-effectiveness ratio of £14,964 per additional quality-adjusted life-year compared to CONTEST, CONTESTjt and no screening using a lifetime time horizon. Limitations The Total bUrDen Of psoRiasis trial was underpowered due to a lower proportion of patients developing psoriatic arthritis than expected (87 compared to 148) and disruption to follow-up due to the coronavirus pandemic. COSt of screening for Psoriatic Arthritis study analyses were limited by the extent of missing data. Conclusion The benefit of early detection of psoriatic arthritis in a primary care psoriasis population remains unproven. Surveillance for undiagnosed psoriatic arthritis generally detects mild cases as measured by physical function. Patients rate pain and fatigue as the most important outcomes. Future work Five-year follow-up of Total bUrDen Of psoRiasis trial participants to investigate longer-term benefits of earlier diagnosis comparing treatment arms and to assess risk factors for psoriatic arthritis development is underway. Trial registration This trial is registered as Current Controlled Trials ISRCTN38877516. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research programme (NIHR award ref: RP-PG-1212-20007) and is published in full in Programme Grants for Applied Research; Vol. 13, No. 6. See the NIHR Funding and Awards website for further award information.
Development of a multicentre cohort study to understand the role of MRI and ultrasound in the diagnosis of acute haematogenous bone and joint infection in children (the PIC Bone study) : a study protocol.
AIMS: Bone and joint infections (BJI) in children are rare but can be serious. Differentiating BJI from other conditions with similar symptoms is critical. Advanced imaging (ultrasound scans (USS) and MRI) is often required to confirm the diagnosis. The differing merits of imaging type and regional variation in access to advanced imaging can lead to diagnostic uncertainty and treatment variation. The aim of this study is to evaluate the diagnostic accuracy of MRI and USS for the investigation of BJI in children, and develop and validate prediction models to aid the diagnosis of BJI in children. A nested qualitative sub-study will explore acceptability of the imaging to children, parents, and health practitioners. METHODS: A multicentre retrospective cohort of children (aged < 16 years) with suspected diagnosis of BJI will be used to estimate the diagnostic accuracy of the two imaging methods and develop the prediction models. The models will be evaluated in a second cohort of prospectively recruited children. Diagnostic test accuracy will be estimated overall, and separately for children aged under and over five years. The prediction models will be fit using logistic regression, with candidate predictors chosen based on clinical plausibility and from a review of the literature. Continuous predictors will be examined for non-linearity with confirmed BJI using fractional polynomials. Multiple imputation will be used to replace missing values. Internal validation will be carried out using bootstrapping. Model performance will be assessed with discrimination and calibration. DISCUSSION: Ethical approval for this study (registration: ISRCTN15471635) was granted (REC reference 23/WM/0027). Informed consent is being obtained from participants in the prospective cohort and the qualitative sub-study. Study findings will be published in an open access journal and presented at relevant national and international conferences. Relevant charities and associations are being engaged to promote awareness of the project.
An update on periprosthetic joint infection for UK trainees
An infection of any surgically replaced joint represents a complex medical, social, and economic problem. Infection, and the complications therein, can represent a potential significant threat to a patient's limb, life, and livelihood. We explore the role of the microbiome in normal function and implications of dysbiosis in the development of periprosthetic joint infection; and the essential role of early accurate diagnosis and collaboration between surgeons, infectious diseases specialists/microbiologists and allied health teams. The management of prosthetic joint infections should take place in a multidisciplinary team (MDT). Despite the general principles of management outlined in this review, surgical and antimicrobial management is patient-specific, considering the cultured organism and its sensitivities, and the patient's overall health, comorbidities, their function, goals and expectations.
Recovery after partial knee arthroplasty and daycare surgery
UKA is a minimally invasive procedure that allows for safe, efficient care with fewer perioperative complications, leading to higher patient satisfaction and improved cost-effectiveness. The philosophy of marginal gains has enabled day case arthroplasty to become feasible. Patients are assessed for suitability for daycase surgery, and any patients at risk of unstable conditions are excluded from the day of surgery discharge pathway. Patients are informed about the perioperative plan and given consistent advice to prepare for same day discharge. Anaesthetic of choice is GA, and premedication is intravenous. Antibiotics are administered before induction. Surgery is performed in the supine position with a thigh support and a high thigh tourniquet using Oxford microplasty instrumentation. Post-operatively, patients are allowed to eat and drink freely, receive rescue analgesia, and are mobilised fully weight bearing with crutches. Patients are provided with post-operative analgesics, laxatives and anti-emetics, have direct access to a 24-hour telephone helpline service, are admitted overnight, receive same post-operative instructions, return to UKA clinic on fifth post-operative day for physiotherapy, and are reviewed at 6 weeks. Introducing an effective outpatient arthroplasty protocol requires a multidisciplinary approach, with a consistent team message and good patient education to achieve successful same day discharge. Financial savings from a safe and effective day of surgery discharge pathway are considerable.
Autoimmunity in inflammatory bowel disease: a holobiont perspective.
Adaptive immunity towards self-antigens (autoimmunity) and intestinal commensal microbiota is a key feature of inflammatory bowel disease (IBD). Considering mucosal adaptive immunity from a holobiont perspective, where the host and its microbiome form a single physiological unit, emphasises the challenge of avoiding damaging responses to self-antigen and symbiotic microbial communities in the gut while protecting against potential pathogens. Intestinal tolerance mechanisms prevent maladaptive T and B cell responses to microbial, environmental, and self-antigens, which drive inflammation. We discuss the spectrum of antimicrobial and autoantibody responses and highlight mechanisms by which common IBD-associated adaptive immune responses contribute to disease.
Public availability of randomized clinical trial protocols: A repeated meta-research study.
OBJECTIVE: Making protocols of randomized clinical trials (RCT) publicly available is important for the trustworthiness and quality of medical research. In a previous study assessing 326 RCTs with ethical approval in 2012, only 36% had a publicly available protocol. We aimed to generate current evidence on the availability of RCT protocols and to evaluate changes over time. STUDY DESIGN AND SETTING: Using a representative sample of RCTs approved in 2016 in Switzerland, Canada, Germany, and the UK, we investigated the number of available protocols by searching PubMed, Google Scholar, trial registries, and Google. Up to June 2024, we systematically searched for (i) protocols available as peer-reviewed publications, (ii) protocols attached to trial registries and (iii) protocols shared with result publications of RCTs. We used multivariable logistic regression to examine the association of protocol availability with trial characteristics such as sample size, drug vs. non-drug interventions, multicenter vs. single center status, and RCT approval in 2016 vs. 2012. RESULTS: Of the 347 included RCTs, 228 (66%) had an available protocol. Forty-three percent (150/347) of the protocols were available as files on trial registries, 26% (91/347) as supplementary material to result publication, and 23% (81/347) as peer-reviewed publications. Protocol availability improved over time in industry trials (83.4% in 2016 vs. 34.6% in 2012). Protocol availability for non-industry trials remained low (46.4% 2016 vs. 38.1% 2012). Multicenter trials (206/256; 77.7% vs single-center trials 22/82; 26.8%) and larger sample size (>500 participants 68/77; 88.3%, 100-500 participants 131/191; 68.6%, <100 participants 29/79; 36.7%) showed higher protocol availability. CONCLUSION: The availability of protocols increased in RCTs approved in 2016 compared to RCTs from 2012. This was mainly driven by industry sponsored trials. Efforts to further improve protocol availability should be continued, especially in non-industry sponsored RCTs.
Threaded rods versus arthrodesis nail as a static spacer for two-stage revision total knee arthroplasty.
INTRODUCTION: A spacer is required to maintain limb length and alignment and to provide a stable limb for mobilisation in two-stage revision total knee arthroplasty (rTKA) for periprosthetic joint infection (PJI). Static spacers are indicated in cases of massive bone loss, compromised soft tissues, and ligamentous and/or extensor mechanism insufficiency. The aim of this study was to compare the use of Ilizarov rods to arthrodesis nails for static spacer constructs in first-stage rTKA for PJI. METHODS: This was a retrospective cohort study of 40 patients who underwent two-stage rTKA for PJI between 2019 and 2022. Static spacers were used in all cases, constructed from Ilizarov rods 20 patients and nails in 20 patients. Data collected included number of previous revisions, patient age at first revision, comorbidities and identified organisms. Groups were compared based on outcome measures including complications, reoperations, length of stay and re-revision rates. RESULTS: The use of Ilizarov rods showed higher rates of intraoperative complications (5% vs. 0%), readmissions (55% vs. 5%), and interstage re-operations (50% vs. 10%). Spacer-related complications occurred in 10 of 20 cases (50%) in the Ilizarov rod group, all due to spacer fractures, compared to none in the nail group (0%) (p
Pair wave function symmetry in UTe2 from zero-energy surface state visualization.
Although nodal spin-triplet topological superconductivity appears probable in uranium ditelluride (UTe2), its superconductive order parameter Δk remains unestablished. In theory, a distinctive identifier would be the existence of a superconductive topological surface band, which could facilitate zero-energy Andreev tunneling to an s-wave superconductor and also distinguish a chiral from a nonchiral Δk through enhanced s-wave proximity. In this study, we used s-wave superconductive scan tips and detected intense zero-energy Andreev conductance at the UTe2 (0-11) termination surface. Imaging revealed subgap quasiparticle scattering interference signatures with a-axis orientation. The observed zero-energy Andreev peak splitting with enhanced s-wave proximity signifies that Δk of UTe2 is a nonchiral state: B1u, B2u, or B3u. However, if the quasiparticle scattering along the a axis is internodal, then a nonchiral B3u state is the most consistent for UTe2.
Incidence and prevalence of asthma, chronic obstructive pulmonary disease and interstitial lung disease between 2004 and 2023: harmonised analyses of longitudinal cohorts across England, Wales, South-East Scotland and Northern Ireland.
BACKGROUND: We describe the epidemiology of asthma, chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) from 2004 to 2023 in England, Wales, Scotland and Northern Ireland (NI) using a harmonised approach. METHODS: Data from the National Health Service England (NHSE), Clinical Practice Research Datalink Aurum in England, Secure Anonymised Information Linkage Databank in Wales, DataLoch in South-East Scotland and the Honest Broker Service in NI were used. A harmonised approach to COPD, asthma and ILD case definitions, study designs and study populations across the four nations was performed. Age-sex-standardised incidence rates and point prevalence were calculated between 2004 and 2023 depending on data availability. Logistic and negative binomial regression compared incidence and prevalence rates between the start and end of each study period. Linear extrapolation projected incidence rates between 2020 and 2023 to illustrate how observed and projected rates differed. RESULTS: Incidence rates were lower in 2019 versus 2005 for asthma (England: incidence rate ratio 0.89, 95% CI 0.88 to 0.90; Wales: 0.66, 0.65 to 0.68; Scotland: 0.67, 0.64 to 0.71; NI: 0.84, 0.81 to 0.86), COPD (England: 0.83, 0.82 to 0.85; Wales: 0.67, 0.65 to 0.69) and higher for ILD (England: 3.27, 3.05 to 3.50; Wales: 1.39, 1.27 to 1.53; Scotland: 1.63, 1.36 to 1.95; NI: 3.03, 2.47 to 3.72). In NHSE, the incidence of asthma was similar in June 2023 versus November 2019, but lower for COPD and higher for ILD. Prevalence of asthma in 2019 in England, Wales, Scotland and NI was 9.7%, 15.9%, 13.2% and 7.0%, respectively, for COPD 4.5%, 5.1%, 4.4% and 3.0%, and for ILD 0.4%, 0.5%, 0.6% and 0.3%. Projected incidence rates were 2.8, 3.4 and 1.8 times lower for asthma, COPD and ILD compared with observed rates at the height of the pandemic. INTERPRETATION: Asthma, COPD and ILD affect over 10 million people across the four nations, and a substantial number of diagnoses were missed during the pandemic.
A systematic review of the association between early comprehensive geriatric assessment and outcomes in hip fracture care for older people.
AIMS: Performance indicators are increasingly used to improve the quality of healthcare provided to hip fracture patients. Joint care, under orthopaedic surgeons and physicians with an interest in older patients, is one of the more common indicators of high-quality care. In this systematic review, we investigated the association between 'comprehensive geriatric assessment' and patient outcomes following hip fracture injury. METHODS: In total, 12 electronic databases and other sources were searched for evidence, and the methodological quality of studies meeting the inclusion criteria was assessed. The protocol for this suite of related systematic reviews was registered with PROSPERO (ID: CRD42023417515). RESULTS: A total of 24,591 articles were reviewed, and 39 studies met the inclusion criteria for the review, involving a total of 25,363 patients aged over 60 years with a hip fracture. There were five randomized clinical trials, three quasi-experimental studies, two non-randomized parallel group control trials, 22 pre-/post-intervention studies, and seven retrospective cohort studies, conducted between January 1992 and December 2021. The timing and content of a comprehensive geriatric assessment was ill-defined in many studies and care pathways were heterogeneous, which precluded meta-analysis of the data. Early comprehensive geriatric assessment was associated with improved outcomes in 31 of the 36 (86%) patient-reported outcomes, including improved mobility (acute/long-term), functional status, and better quality of life. In total, 155 out of 219 (70.78%) clinical outcomes derived from hospital records showed a positive association with early comprehensive geriatric review, including reduced preoperative time and length of hospital stay, reduced incidence of postoperative complications, fewer hospital readmissions, and lower mortality. CONCLUSION: Early comprehensive geriatric assessments after hip fracture in older people is associated with improved patient-reported outcomes and better clinical outcomes such as reduced incidence of complications, length of hospital stay, preoperative waiting time, and mortality. Standardization of the definitions of 'early' and 'comprehensive' geriatric assessments and consistent reporting of care pathway models would improve future evidence synthesis.
Association between preoperative glycaemic control (HbA1c) and early outcomes following primary hip and knee arthroplasty.
AIMS: This study investigates the relationship between diabetes mellitus (DM), glycated haemoglobin (HbA1c), and postoperative outcomes among patients undergoing hip and knee arthroplasty. METHODS: We conducted a single-centre cohort study of patients who underwent primary hip or knee arthroplasty between June 2008 and December 2019 and for whom preoperative HbA1c had been recorded. Cases were categorized by preoperative HbA1c as 'diabetes' (≥ 48 mmol/mol), 'prediabetes' (≥ 42 mmol/mol and < 48 mmol/mol), 'no diabetes' (< 42 mmol/mol), or in 'remission' (preoperative HbA1c < 42 mmol/mol but having a historic HbA1c result ≥ 42 mmol/mol). Multivariable logistic regression and restricted cubic splines were used to examine the association between diabetes status, HbA1c, and early postoperative outcomes. RESULTS: Analysis of 9,454 procedures (18.4% diabetes, 23.5% prediabetes, 49.7% no diabetes, 8.4% in remission) revealed that DM was associated with a 50% greater likelihood of experiencing one or more postoperative complications (odds ratio (OR) 1.47 (95% CI 1.26 to 1.71)), a 60% greater risk of acute kidney injury or electrolyte abnormality (OR 1.57 (95% CI 1.33 to 1.87)), and more than double the risk of postoperative urinary tract infection (OR 2.25 (95% CI 1.15 to 4.52)) and deep surgical site infection (OR 2.03 (95% CI 1.05 to 3.86)) compared to individuals without diabetes. There was a substantial increase in complication risk as HbA1c entered prediabetes range with no evidence of a plateau or threshold effect, and a profound reduction in the risk of almost all recorded complications for patients in remission from previously elevated HbA1c. CONCLUSION: DM was associated with an increased risk of almost all measured early postoperative complications. Interventions to reduce elevated HbA1c, to any degree, may benefit patient outcomes, however these must be balanced with the risk of iatrogenic harm.
Effects of temporarily suspending low-dose methotrexate treatment for 2 weeks after SARS-CoV-2 vaccine booster on vaccine response in immunosuppressed adults with inflammatory conditions: protocol for a multicentre randomised controlled trial and nested mechanistic substudy (Vaccine Response On/Off Methotrexate (VROOM) study)
This article consists of a citation of a published article describing research funded by the Efficacy and Mechanism Evaluation programme under project number NIHR134607, and is provided as as part of the complete record of research outputs for this project. The original publication is available at: https://doi.org/10.1136/bmjopen-2022-062599 Introduction It is unknown if a temporary break in long-term immune-suppressive treatment after vaccination against COVID-19 improves vaccine response. The objective of this study was to evaluate if a 2-week interruption in low-dose weekly methotrexate treatment after SARS-CoV-2 vaccine boosters enhances the immune response compared with continuing treatment in adults with autoimmune inflammatory conditions. Methods and analysis An open-label, pragmatic, prospective, parallel group, randomised controlled superiority trial with internal feasibility assessment and nested mechanistic substudy will be conducted in rheumatology and dermatology clinics in approximately 25 UK hospitals. The sample size is 560, randomised 1:1 to intervention and usual care arms. The main outcome measure is anti-spike receptor-binding domain (RBD) antibody level, collected at prebooster (baseline), 4 weeks (primary outcome) and 12 weeks (secondary outcome) post booster vaccination. Other secondary outcome measures are patient global assessments of disease activity, disease flares and their treatment, EuroQol 5- dimention 5-level (EQ-5D-5L), self-reported adherence with advice to interrupt or continue methotrexate, neutralising antibody titre against SARS-CoV-2 (mechanistic substudy) and oral methotrexate biochemical adherence (mechanistic substudy). Analysis of B-cell memory and T-cell responses at baseline and weeks 4 and 12 will be investigated subject to obtaining additional funding. The principal analysis will be performed on the groups as randomised (ie, intention to treat). The difference between the study arms in anti-spike RBD antibody level will be estimated using mixed effects model, allowing for repeated measures clustered within participants. The models will be adjusted for randomisation factors and prior SARS-CoV-2 infection status. Ethics and dissemination This study was approved by the Leeds West Research Ethics Committee and Health Research Authority (REC reference: 21/HRA/3483, IRAS 303827). Participants will be required to give written informed consent before taking part in the trial. Dissemination will be via peer review publications, newsletters and conferences. Results will be communicated to policymakers. Trial registration number ISRCTN11442263. Funding This publication was funded by the Efficacy and Mechanism Evaluation programme as a part of award number NIHR134607. This article reports on one component of the research award Vaccine Response On/Off Methotrexate (VROOM): does temporarily suspending methotrexate treatment for two weeks enhance COVID-19 vaccine response? A randomised controlled trial. For more information about this research please view the award page [https://fundingawards.nihr.ac.uk/award/NIHR134607] DOI https://doi.org/10.1136/bmjopen-2022-062599
Effect of a 2-week interruption in methotrexate treatment on COVID-19 vaccine response in people with immune-mediated inflammatory diseases (VROOM study): a randomised, open label, superiority trial
This article consists of a citation of a published article describing research funded by the Efficacy and Mechanism Evaluation programme under project number NIHR134607, and is provided as as part of the complete record of research outputs for this project. The original publication is available at: https://doi.org/10.1016/S2665-9913(23)00298-9 Summary Background Methotrexate is the first-line treatment for immune-mediated inflammatory diseases and reduces vaccine-induced immunity. We evaluated if a 2-week interruption of methotrexate treatment immediately after COVID-19 booster vaccination improved antibody response against the S1 receptor binding domain (S1-RBD) of the SARS-CoV-2 spike protein and live SARS-CoV-2 neutralisation compared with uninterrupted treatment in patients with immune-mediated inflammatory diseases. Method We did a multicentre, open-label, parallel-group, randomised, superiority trial in secondary-care rheumatology and dermatology clinics in 26 hospitals in the UK. Adults (aged ≥18 years) with immune-mediated inflammatory diseases taking methotrexate (≤25 mg per week) for at least 3 months, who had received two primary vaccine doses from the UK COVID-19 vaccination programme were eligible. Participants were randomly assigned (1:1) using a centralised validated computer program, to temporarily suspend methotrexate treatment for 2 weeks immediately after COVID-19 booster vaccination or continue treatment as usual. The primary outcome was S1-RBD antibody titres 4 weeks after COVID-19 booster vaccination and was assessed masked to group assignment. All randomly assigned patients were included in primary and safety analyses. This trial is registered with ISRCTN, ISRCTN11442263; following a pre-planned interim analysis, recruitment was stopped early. Finding Between Sept 30, 2021, and March 7, 2022, we screened 685 individuals, of whom 383 were randomly assigned: to either suspend methotrexate (n=191; mean age 58·8 years [SD 12·5], 118 [62%] women and 73 [38%] men) or to continue methotrexate (n=192; mean age 59·3 years [11·9], 117 [61%] women and 75 [39%] men). At 4 weeks, the geometric mean S1-RBD antibody titre was 25 413 U/mL (95% CI 22 227-29 056) in the suspend methotrexate group and 12 326 U/mL (10 538-14 418) in the continue methotrexate group with a geometric mean ratio (GMR) of 2·08 (95% CI 1·59-2·70; p<0·0001). No intervention-related serious adverse events occurred. Interpretation 2-week interruption of methotrexate treatment in people with immune-mediated inflammatory diseases enhanced antibody responses after COVID-19 booster vaccination that were sustained at 12 weeks and 26 weeks. There was a temporary increase in inflammatory disease flares, mostly self-managed. The choice to suspend methotrexate should be individualised based on disease status and vulnerability to severe outcomes from COVID-19. Funding National Institute for Health and Care Research. Funding This publication was funded by the Efficacy and Mechanism Evaluation programme as a part of award number NIHR134607. This article reports on one component of the research award Vaccine Response On/Off Methotrexate (VROOM): does temporarily suspending methotrexate treatment for two weeks enhance COVID-19 vaccine response? A randomised controlled trial. For more information about this research please view the award page [https://fundingawards.nihr.ac.uk/award/NIHR134607] DOI https://doi.org/10.1016/S2665-9913(23)00298-9
Core-shell microcapsules compatible with routine injection enable prime/boost immunization against malaria with a single shot.
Inadequate booster uptake threatens the success of immunization campaigns as seen with the recently rolled-out R21 malaria vaccine. The ability to administer both prime and boost immunizations with a single injection would therefore save lives and alleviate health care burdens. We present a platform for delayed delivery of the booster dose that is scalable with existing technology, easily injectable, and protective against malaria in vivo. Using chip-based microfluidics, we encapsulated the R21 malaria vaccine in polymer microcapsules that release their content weeks to months postinjection. Coinjecting microcapsules with the priming dose of the R21 vaccine elicited strong antibody responses in a mouse model and provided 85% of the protection of a standard prime/boost schedule. If confirmed in humans, these results would pave the way for rapid deployment of single-shot prime/boost vaccination, an urgently needed global health intervention.
User engagement in clinical trials of digital mental health interventions: a systematic review.
INTRODUCTION: Digital mental health interventions (DMHIs) overcome traditional barriers enabling wider access to mental health support and allowing individuals to manage their treatment. How individuals engage with DMHIs impacts the intervention effect. This review determined whether the impact of user engagement was assessed in the intervention effect in Randomised Controlled Trials (RCTs) evaluating DMHIs targeting common mental disorders (CMDs). METHODS: This systematic review was registered on Prospero (CRD42021249503). RCTs published between 01/01/2016 and 17/09/2021 were included if evaluated DMHIs were delivered by app or website; targeted patients with a CMD without non-CMD comorbidities (e.g., diabetes); and were self-guided. Databases searched: Medline; PsycInfo; Embase; and CENTRAL. All data was double extracted. A meta-analysis compared intervention effect estimates when accounting for engagement and when engagement was ignored. RESULTS: We identified 184 articles randomising 43,529 participants. Interventions were delivered predominantly via websites (145, 78.8%) and 140 (76.1%) articles reported engagement data. All primary analyses adopted treatment policy strategies, ignoring engagement levels. Only 19 (10.3%) articles provided additional intervention effect estimates accounting for user engagement: 2 (10.5%) conducted a complier-average-causal effect (CACE) analysis (principal stratum strategy) and 17 (89.5%) used a less-preferred per-protocol (PP) population excluding individuals failing to meet engagement criteria (estimand strategies unclear). Meta-analysis for PP estimates, when accounting for user engagement, changed the standardised effect to -0.18 95% CI (-0.32, -0.04) from - 0.14 95% CI (-0.24, -0.03) and sample sizes reduced by 33% decreasing precision, whereas meta-analysis for CACE estimates were - 0.19 95% CI (-0.42, 0.03) from - 0.16 95% CI (-0.38, 0.06) with no sample size decrease and less impact on precision. DISCUSSION: Many articles report user engagement metrics but few assessed the impact on the intervention effect missing opportunities to answer important patient centred questions for how well DMHIs work for engaged users. Defining engagement in this area is complex, more research is needed to obtain ways to categorise this into groups. However, the majority that considered engagement in analysis used approaches most likely to induce bias.
A randomised controlled test in virtual reality of the effects on paranoid thoughts of virtual humans' facial animation and expression.
Virtual reality (VR) is increasingly used in the study and treatment of paranoia. This is based on the finding that people who mistakenly perceive hostile intent from other people also perceive similar threat from virtual characters. However, there has been no study of the programming characteristics of virtual characters that may influence their interpretation. We set out to investigate how the animation and expressions of virtual humans may affect paranoia. In a two-by-two factor, between-groups, randomized design, 122 individuals with elevated paranoia rated their perceptions of virtual humans, set in an eye-tracking enabled VR lift scenario, that varied in facial animation (static or animated) and expression (neutral or positive). Both facial animation (group difference = 102.328 [51.783, 152.872], p