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Effect of a 2-week interruption in methotrexate treatment versus continued treatment on COVID-19 booster vaccine immunity in adults with inflammatory conditions (VROOM study): a randomised, open label, superiority trial.
BACKGROUND: Immunosuppressive treatments inhibit vaccine-induced immunity against SARS-CoV-2. We evaluated whether a 2-week interruption of methotrexate treatment immediately after the COVID-19 vaccine booster improved antibody responses against the S1 receptor-binding domain (S1-RBD) of the SARS-CoV-2 spike protein compared with uninterrupted treatment in patients with immune-mediated inflammatory diseases. METHODS: We did an open-label, prospective, two-arm, parallel-group, multicentre, randomised, controlled, superiority trial in 26 hospitals in the UK. We recruited adults from rheumatology and dermatology clinics who had been diagnosed with an immune-mediated inflammatory disease (eg, rheumatoid arthritis, psoriasis with or without arthritis, axial spondyloarthritis, atopic dermatitis, polymyalgia rheumatica, and systemic lupus erythematosus) and who were taking low-dose weekly methotrexate (≤25 mg per week) for at least 3 months. Participants also had to have received two primary vaccine doses from the UK COVID-19 vaccination programme. We randomly assigned the participants (1:1), using a centralised validated computer randomisation program, to suspend methotrexate treatment for 2 weeks immediately after their COVID-19 booster (suspend methotrexate group) or to continue treatment as usual (continue methotrexate group). Participants, investigators, clinical research staff, and data analysts were unmasked, while researchers doing the laboratory analyses were masked to group assignment. The primary outcome was S1-RBD antibody titres 4 weeks after receiving the COVID-19 booster vaccine dose, assessed in the intention-to-treat population. This trial is registered with ISRCT, ISRCTN11442263; following the pre-planned interim analysis, recruitment was stopped early. FINDINGS: Between Sept 30, 2021 and March 3, 2022, we recruited 340 participants, of whom 254 were included in the interim analysis and had been randomly assigned to one of the two groups: 127 in the continue methotrexate group and 127 in the suspend methotrexate group. Their mean age was 59·1 years, 155 (61%) were female, 130 (51%) had rheumatoid arthritis, and 86 (34%) had psoriasis with or without arthritis. After 4 weeks, the geometric mean S1-RBD antibody titre was 22 750 U/mL (95% CI 19 314-26 796) in the suspend methotrexate group and 10 798 U/mL (8970-12 997) in the continue methotrexate group, with a geometric mean ratio (GMR) of 2·19 (95% CI 1·57-3·04; p<0·0001; mixed-effects model). The increased antibody response in the suspend methotrexate group was consistent across methotrexate dose, administration route, type of immune-mediated inflammatory disease, age, primary vaccination platform, and history of SARS-CoV-2 infection. There were no intervention-related serious adverse events. INTERPRETATION: A 2-week interruption of methotrexate treatment for people with immune-mediated inflammatory diseases resulted in enhanced boosting of antibody responses after COVID-19 vaccination. This intervention is simple, low-cost, and easy to implement, and could potentially translate to increased vaccine efficacy and duration of protection for susceptible groups. FUNDING: National Institute for Health and Care Research.
Benefits outweigh the risks: a consensus statement on the risks of physical activity for people living with long-term conditions
Introduction The benefits of physical activity for people living with long-term conditions (LTCs) are well established. However, the risks of physical activity are less well documented. The fear of exacerbating symptoms and causing adverse events is a persuasive barrier to physical activity in this population. This work aimed to agree clear statements for use by healthcare professionals about medical risks of physical activity for people living with LTCs through expert consensus. These statements addressed the following questions: (1) Is increasing physical activity safe for people living with one or more LTC? (2) Are the symptoms and clinical syndromes associated with common LTCs aggravated in the short or long term by increasing physical activity levels? (3) What specific risks should healthcare professionals consider when advising symptomatic people with one or more LTCs to increase their physical activity levels? Methods Statements were developed in a multistage process, guided by the Appraisal of Guidelines for Research and Evaluation tool. A patient and clinician involvement process, a rapid literature review and a steering group workshop informed the development of draft symptom and syndrome-based statements. We then tested and refined the draft statements and supporting evidence using a three-stage modified online Delphi study, incorporating a multidisciplinary expert panel with a broad range of clinical specialties. Results Twenty-eight experts completed the Delphi process. All statements achieved consensus with a final agreement between 88.5%–96.5%. Five ‘impact statements’ conclude that (1) for people living with LTCs, the benefits of physical activity far outweigh the risks, (2) despite the risks being very low, perceived risk is high, (3) person-centred conversations are essential for addressing perceived risk, (4) everybody has their own starting point and (5) people should stop and seek medical attention if they experience a dramatic increase in symptoms. In addition, eight symptom/syndrome-based statements discuss specific risks for musculoskeletal pain, fatigue, shortness of breath, cardiac chest pain, palpitations, dysglycaemia, cognitive impairment and falls and frailty. Conclusion Clear, consistent messaging on risk across healthcare will improve people living with LTCs confidence to be physically active. Addressing the fear of adverse events on an individual level will help healthcare professionals affect meaningful behavioural change in day-to-day practice. Evidence does not support routine preparticipation medical clearance for people with stable LTCs if they build up gradually from their current level. The need for medical guidance, as opposed to clearance, should be determined by individuals with specific concerns about active symptoms. As part of a system-wide approach, consistent messaging from healthcare professionals around risk will also help reduce cross-sector barriers to engagement for this population.
Do baseline patient reported outcome measures predict changes in self-reported function, following a chronic pain rehabilitation programme?
Background Interdisciplinary pain management programmes, based on cognitive-behavioural principles, aim to improve physical and psychological functioning and enhance self-management in people living with chronic pain. Currently there is insufficient evidence about whether psychological, biological or social factors are predictive of positive outcomes following pain rehabilitation. This study aims to evaluate predictors of change in Brief Pain Inventory – pain interference score (BPI) in a clinical data set to determine whether age, sex and baseline outcome measures are predictive of improvement in pain interference following pain rehabilitation. Methods A retrospective, pragmatic observational analysis of routinely collected clinical data in two pain rehabilitation programmes, Balanced Life Programme (BLP) and Get Back Active (GBA) was conducted. Standard regression and hierarchical regression analyses were used to identify predictors of change to assess temporal changes in BPI. Responder analysis was also conducted. Results Standard regression analyses of 208 (BLP) and 310 (GBA) patients showed that higher baseline BPI and better physical performance measures predicted better improvement in BPI across both programmes. Hierarchical regression showed that age and sex accounted for 2.7% (BLP) and 0.002% (GBA) of the variance in change in BPI. After controlling for age and sex, the other measures explained an additional 23% (BLP) and 19% (GBA) of the variance, p = < .001 where BPI and physical performance measures were consistently statistically significant predictors, p < .05. Responder analysis also showed that pain interference and physical performance were significantly associated with improvement ( p = < .0005). Conclusions The combination of high self-reported pain interference and better physical performance measures may be a useful indicator of who would benefit from interdisciplinary rehabilitation. Further validation of the results is required.
The impact of the MMed research requirement on registrar training and specialist registration in South Africa: An internet e-survey
Background. Since 2011, the Health Professions Council of South Africa (HPCSA) requires completion of a Master of Medicine (MMed) research component by registrars, before specialist registration. Objective. To determine the impact of the research requirement on training and specialist registration. Methods. A closed, de-identified cross-sectional e-survey was distributed to College of Medicine of South Africa (CMSA) Fellows passing their specialist examination between 2018 and 2022. The primary outcome was the proportion of registrars completing their MMed and clinical training within the stipulated time. Secondary outcomes were: (i) proportion unlikely to complete the MMed during training; (ii) factors contributing to MMed completion; (iii) publication rates; and (iv) whether a structured learning programme was preferred for research methodology. A Likert scale identified factors influencing completion, including administrative aspects (supervision, statistical support, ethics approval process, time allocated for research, funding, and marking timelines), and the influence of the requirement for the performance of research on mental wellness. Results. The survey invitation was emailed to 3 646 participants; 564 (15.5%) responded, across 26 specialist CMSA disciplines. Overall, 273/564 (51.6%) specialists completed their MMed research component and CMSA examinations within the stipulated registrar training completion time. For secondary outcomes, 230/563 (40.8%) respondents required extension of the stipulated training time. In 291/564 (48.4%), the MMed was not completed during the stipulated training time, with 61/291 (21.0%) respondents not receiving an extension for completion. For 183/563 (32.5%) respondents, MMed submission was required by the university before specialist examination. Of these, 121/183 (66.1%) wrote their examination within the training time; 44/183 (24%) within 6 months of completion; and 18/183 (9.8%) >6 months after completion. Likert scale responses showed that >50% of respondents considered all the factors being assessed to be a barrier to the conduction of their research, with the exception of good supervision (304/563, 54%). The strongest associations with successful completion of the MMed research were good supervision (54%), access to statistical support (40%), and an uncomplicated and efficient ethics approval process (39.6%). Overall, 229/564 (40.62%) MMed research components were published. A structured research learning programme was preferred by 413/564 (73.2%) respondents. A total of 335/564 (59.4%) indicated that the MMed did not add value to training. Conclusion. Nearly half of registrars could not register as specialists when their training was complete, due to non-completion of their MMed research component. All the factors examined were considered to be contributing to non-completion of the MMed by the majority of participants, with the exception of access to good supervision. A structured integrated learning programme, including research methodology, statistics, appraisal of the literature, and scientific writing, should be introduced as an alternative to the requirement for original research, which should no longer be compulsory. Registrars wishing to do original research should be strongly supported.
Method of Anesthesia and Perioperative Risk Factors, Maternal Anesthesia Complications, and Neonatal Mortality Following Cesarean Delivery in Africa: A Substudy of a 7-day Prospective Observational Cohort Study
(Anesth Analg. 2024;138(6):1275-1284. doi: 10.1213/ANE.0000000000006750) A key finding of the African Surgical Outcomes Study (ASOS) was that general anesthesia (GA) was linked to higher maternal and neonatal risk and that cesarean delivery (CD) in Africa was 50 times higher than in high-income countries. The ASOS recruited consecutive patients 18 years or older who had inpatient surgery in 183 hospitals in 22 African countries over a 7-day period between February 2016 and May 2016. This ASOS substudy of the obstetric cohort was designed primarily to estimate the association between preoperative risk factors and the outcome of the type of anesthesia administered. The secondary aim was to estimate the association between the method of anesthesia and maternal and neonatal outcomes.
Outcomes after surgery for children in Africa (ASOS-Paeds): a 14-day prospective observational cohort study.
BACKGROUND: Safe anaesthesia and surgery are a public health imperative. There are few data describing outcomes for children undergoing anaesthesia and surgery in Africa. We aimed to get robust epidemiological data to describe patient care and outcomes for children undergoing anaesthesia and surgery in hospitals in Africa. METHODS: This study was a 14-day, international, prospective, observational cohort study of children (aged <18 years) undergoing surgery in Africa. We recruited as many hospitals as possible across all levels of care (first, second, and third) providing surgical treatment. Each hospital recruited all eligible children for a 14-day period commencing on the date chosen by each participating hospital within the study recruitment period from Jan 15 to Dec 23, 2022. Data were collected prospectively for consecutive patients on paper case record forms. The primary outcome was in-hospital postoperative complications within 30 days of surgery and the secondary outcome was in-hospital mortality within 30 days after surgery. We also collected hospital-level data describing equipment, facilities, and protocols available. This study is registered with ClinicalTrials.gov, NCT05061407. FINDINGS: We recruited 8625 children from 249 hospitals in 31 African countries. The mean age was 6·1 (SD 4·9) years, with 5675 (66·0%) of 8600 children being male. Most children (6110 [71·2%] of 8579 patients) were from category 1 of the American Society of Anesthesiologists Physical Status score undergoing elective surgery (5325 [61·9%] of 8604 patients). Postoperative complications occurred in 1532 (18·0%) of 8515 children, predominated by infections (971 [11·4%] of 8538 children). Deaths occurred in 199 (2·3%) of 8596 patients, 169 (84·9%) of 199 patients following emergency surgeries. Deaths following postoperative complications occurred in 166 (10·8%) of 1530 complications. Operating rooms were reported as safe for anaesthesia and surgery for neonates (121 [54·3%] of 223 hospitals), infants (147 [65·9%] of 223 hospitals), and children younger than 6 years (188 [84·3%] of 223 hospitals). INTERPRETATION: Outcomes following anaesthesia and surgery for children in Africa are poor, with complication rates up to four-fold higher (18% vs 4·4-14%) and mortality rates 11-fold higher than high-income countries in a crude, unadjusted comparison (23·15 deaths vs 2·18 deaths per 1000 children). To improve surgical outcomes for children in Africa, we need health system strengthening, provision of safe environments for anaesthesia and surgery, and strategies to address the high rate of failure to rescue. FUNDING: Jan Pretorius Research Fund of the South African Society of Anaesthesiologists and Association of Anesthesiologists of Uganda.