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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
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/S2213-2600(22)00186-2 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. 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/S2213-2600(22)00186-2
Presentation of B-cell lymphoma in childhood and adolescence: a systematic review and meta-analysis
Background: The diagnosis of B-cell lymphoma, one of the commonest cancers seen in childhood and adolescence, is challenging. There is a crucial need to identify and delineate the prevalence of associated symptoms in order to improve early diagnosis. Aims: To identify clinical presentations associated with childhood and adolescent B-cell lymphomas and estimate symptom prevalence. Methods: A systematic review of observational studies and meta-analysis of proportions was carried out. Medline and EMBASE were systematically searched, with no language restrictions, from inception to 1st August 2022. Observational studies with at least 10 participants, exploring clinical presentations of any childhood and adolescent lymphoma, were selected. Proportions from each study were inputted to determine the weighted average (pooled) proportion, through random-effects meta-analysis. Results: Studies reported on symptoms, signs and presentation sites at diagnosis of 12,207 children and adolescents up to the age of 20. Hodgkin’s lymphoma most frequently presented with adenopathy in the head-and-neck region (79% [95% CI 58%-91%]), whilst non-Hodgkin’s lymphoma presented abdominally (55% [95% CI 43%-68%]). Symptoms associated with lymphoma included cervical lymphadenopathy (48% [95% CI 20%-77%]), peripheral lymphadenopathy (51% [95% CI 37%-66%]), B-symptoms (40% [95% CI 34%-44%]), fever (43% [95% CI 34%-54%]), abdominal mass (46% [95% CI 29%-64%]), weight loss (53% [95% CI 39%-66%]), head-and-neck mass (21% [95% CI 6%-47%]), organomegaly (29% [95% CI 23%-37%]), night sweats (19% [95% CI 10%-32%]), abdominal pain (28% [95% CI 15%-47%]), bone pain (17% [95% CI 10%-28%]) and abnormal neurology (11% [95% CI 3%-28%]). Conclusion: This systematic review and meta-analysis of proportions provides insight into the heterogeneous clinical presentations of B-cell lymphoma in childhood and adolescence and provides estimates of symptom prevalence. This information is likely to increase public and clinical awareness of lymphoma presentations and aid earlier diagnosis. This review further highlights the lack of studies exploring childhood and adolescent lymphoma presentations in primary care, where patients are likely to present at the earliest stages of their disease.
Identifying early symptoms associated with a diagnosis of childhood, adolescent and young adult cancers: a population-based nested case-control study
Background: Childhood, teenage and young adult (CTYA, 0–24 years) cancers are rare and diverse, making timely diagnosis challenging. We aim to explore symptoms and symptom combinations associated with a subsequent cancer diagnosis and to establish their timeframe. Methods: Using the QResearch Database, we carried out a matched nested case-control study. Associations between pre-specified symptoms encountered in primary care and a subsequent diagnosis of any cancer were explored using conditional logistic regression. Median diagnostic intervals were used to split symptoms into “late” and “early” timeframes to identify relevant early symptoms. Results: 3186 cases and 50,576 controls were identified from a cohort of 3,424,771 CTYA. We identified 12 novel associations, of which hemiparesis [OR 90.9 (95%CI 24.7-335.1), PPV = 1.6%], testicular swelling [OR 186.7 (95%CI 86.1-404.8), PPV = 2.4%] and organomegaly [OR 221.6 (95%CI 28.3-1735.9), PPV = 5.4%] had significant positive predictive values (PPV). Limb pain, a known marker of serious illness in children, was a recurrent early symptom across cancer subtypes. Similar clinical presentations were observed across childhood and TYA cancers. Discussion: Using the largest cohort to date, we provide novel information on the time-varying predictive utility of symptoms in the diagnosis of CTYA cancers. Our findings will help to raise clinical and public awareness of symptoms, stratify those at higher-risk and ultimately aid earlier diagnosis.
Integrating Mobile Health App Data Into Electronic Medical or Health Record Systems and Its Impact on Health Care Delivery and Patient Health Outcomes: Scoping Review.
BACKGROUND: Mobile health (mHealth) apps are increasingly being used to capture patient health data, provide information, and guide self-management, with reported improvements in health care service delivery and outcomes. However, the impact of integrating mHealth app data into electronic medical record or electronic health record (EMR/EHR) systems remains underexplored. OBJECTIVE: This study aims to identify what is known about the impact of integrating mHealth app data into EMR/EHR systems on health care delivery and patient outcomes. METHODS: A scoping review was conducted to identify original studies that investigated the integration of patient-facing mHealth app data into EMR/EHR systems and the impact on health care outcomes. The PubMed, Embase, Web of Science, Cochrane Library, CINAHL, ProQuest, and PsycINFO databases were searched for papers published between January 2014 and July 2024. Two authors independently screened and extracted data on study characteristics, mHealth app features, details of integration with EMR/EHR systems, and effects on health care delivery and patient outcomes. RESULTS: Nineteen studies with 113,135 participants were included. Among these, 6 were randomized clinical trial studies, 8 were conducted in the United States, 12 occurred in hospital settings, 15 involved adult participants, and 6 targeted diabetes management. Main features of the apps and EMR/EHR systems can be categorized into tracking or recording health data (n=19), app data integrated into EMR/EHR systems (n=19), app data summarized or presented on EMR/EHR interface (n=19), communication with the health care team (n=12), reminders or alerts (n=10), synchronization with other apps or devices (n=8), educational information (n=4), and using existing portal credentials to app access (n=2). Most studies reported benefits of integrating the app and EMR/EHR, such as enhanced patient education and self-management (n=5), real-time data recorded and shared with clinicians (n=4), support for clinical decision-making (n=3), improved communication between patients and clinicians (n=7), and improved patient outcomes (n=13). Challenges identified included high drop-off rates in app usage (n=3), limited accessibility due to device restrictions (n=3), incompatibility between mHealth apps and EMR/EHR systems (n=3), increased clinical workload in response to additional information (n=3), data accuracy issues due to network connectivity (n=1), and data security concerns (n=1). CONCLUSIONS: Evidence suggests that the effective integration of mHealth app data into EMR/EHR systems can enhance both clinicians' health care delivery and patients' health outcomes. However, current literature is limited, and future opportunities remain to examine the impact on long-term outcomes, such as mortality, readmissions, and costs, and assess the scalability and sustainability of integration among more broader health conditions and disabilities across diverse health care settings.
The cost-effectiveness of specialist hospital discharge and intermediate care services for patients who are homeless
Background: Recognising the diverse healthcare needs of the population, there is a growing emphasis on tailoring hospital discharge processes to address the unique challenges faced by individuals who are homeless, aiming to enhance the efficiency and effectiveness of post-hospitalisation care for this vulnerable demographic. This study aimed to evaluate the costs and consequences of specialist hospital discharge and intermediate care (support after discharge) services for people who are homeless in England. Methods: We estimated the comparative costs and consequences of different types of specialist care provided by 17 homeless hospital discharge and intermediate care services. We compared ‘clinically-led’ (multidisciplinary) services with those that were ‘housing-led’ (uniprofessional). A retrospective observational study was conducted to estimate effectiveness and costs for two'intervention groups'(clinically-led and housing-led) and a previously published RCT for'standard care'. Use of resources data for specialist care was sourced through linkage with Hospital Episode Statistics. The measure of effectiveness was the number of bed days avoided (in terms of hospital stays for all readmissions in the follow-up period) per homeless user. Additional secondary analysis of three services looked at quality-adjusted life years (QALYs) and service delivery costs. The perspective adopted was NHS in England. Results: Data from the comparative analysis showed that specialist homeless hospital discharge (HHD) care is likely to be cost-effective compared with standard care. Patients accessing specialist care use fewer bed days per year (including both planned and unplanned readmissions). Patients using specialist care have more planned readmissions to hospital and, overall, use more NHS resources than those who use standard care. We interpret this as a positive outcome indicating that specialist care is likely to work more effectively than standard care to improve access to healthcare for this marginalised group. Specialist care remained cost-effective over a range of sensitivity analyses. Secondary analyses of three specific schemes found better QALY outcomes, but results are not generalisable to all 17 schemes. Conclusion: Specialist HHD services are likely to be cost-effective for the NHS compared with standard care, although further research is needed to access patient level data for both costs and outcomes to conduct a rigorous statistical analysis between groups and address possible underlying biases due to data coming from non-randomised study design.
Navigating the complexities of end-stage kidney disease (ESKD) from risk factors to outcome: insights from the UK Biobank cohort
Background: The global prevalence of end-stage kidney disease (ESKD) is increasing despite optimal management of traditional risk factors such as hyperglycaemia, hypertension, and dyslipidaemia. This study examines the influence of cardiorenal risk factors, socioeconomic status, and ethnic and cardiovascular comorbidities on ESKD outcomes in the general population. Methods: This cross-sectional study analysed data from 502,408 UK Biobank study participants recruited between 2006 and 2010. Multivariable logistic regression models were fitted to assess risk factors for ESKD, with results presented as adjusted odds ratio (aOR) and 95% confidence intervals (95% CI). Results: A total of 1191 (0.2%) of the study participants reported ESKD. Diabetes increased ESKD risk by 62% [1.62 (1.36–1.93)], with early-onset diabetes (before age 40) conferring higher odds compared to later-onset (after age 40) [2.26 (1.57–3.24)]. Similarly, early-onset hypertension (before age 40), compared to later onset (after age 40), increased ESKD odds by 73% [1.73 (1.21–2.44)]. Cardiovascular comorbidities, including stroke, hypertension, myocardial infarction and angina, were strongly associated with ESKD [5.97 (3.99–8.72), 5.35 (4.38–6.56), 4.94 (3.56–6.78), and 4.89 (3.47–6.81)], respectively. Males were at 22% higher risk of ESKD than females [1.22 (1.04–1.43)]. Each additional year of diabetes duration increased ESKD odds by 2% [1.02 (1.01–1.03)]. Non-white ethnicity, compared to white and socioeconomically most deprived, compared to the least deprived quintiles, were at 70% and 83% higher odds of ESKD. Each unit of HbA1c rise increased the odds of ESKD by 2%. Compared to microalbuminuria, macroalbuminuria increased the odds of ESKD by almost 10-fold [9.47 (7.95–11.27)] while normoalbuminuria reduced the odds by 73% [0.27 (0.22–0.32)]. Conclusions: Early onset of diabetes and hypertension, male sex, non-white ethnicity, deprivation, poor glycaemic control, and prolonged hyperglycaemia are significant risk factors for ESKD. These findings highlight the complexity of ESKD and the need for multifactorial targeted interventions in high-risk populations. Clinical trial number: Not applicable.
AZD1222 effectiveness against severe COVID-19 in individuals with comorbidity or frailty: The RAVEN cohort study
Objectives: Despite being prioritized during initial COVID-19 vaccine rollout, vulnerable individuals at high risk of severe COVID-19 (hospitalization, intensive care unit admission, or death) remain underrepresented in vaccine effectiveness (VE) studies. The RAVEN cohort study (NCT05047822) assessed AZD1222 (ChAdOx1 nCov-19) two-dose primary series VE in vulnerable populations. Methods: Using the Oxford-Royal College of General Practitioners Clinical Informatics Digital Hub, linked to secondary care, death registration, and COVID-19 datasets in England, COVID-19 outcomes in 2021 were compared in vaccinated and unvaccinated individuals matched on age, sex, region, and multimorbidity. Results: Over 4.5 million AZD1222 recipients were matched (mean follow-up ∼5 months); 68% were ≥50 years, 57% had high multimorbidity. Overall, high VE against severe COVID-19 was demonstrated, with lower VE observed in vulnerable populations. VE against hospitalization was higher in the lowest multimorbidity quartile (91.1%; 95% CI: 90.1, 92.0) than the highest quartile (80.4%; 79.7, 81.1), and among individuals ≥65 years, higher in the ‘fit’ (86.2%; 84.5, 87.6) than the frailest (71.8%; 69.3, 74.2). VE against hospitalization was lowest in immunosuppressed individuals (64.6%; 60.7, 68.1). Conclusions: Based on integrated and comprehensive UK health data, overall population-level VE with AZD1222 was high. VEs were notably lower in vulnerable groups, particularly the immunosuppressed.
Creating a Modified Version of the Cambridge Multimorbidity Score to Predict Mortality in People Older Than 16 Years: Model Development and Validation
Background: No single multimorbidity measure is validated for use in NHS (National Health Service) England’s General Practice Extraction Service Data for Pandemic Planning and Research (GDPPR), the nationwide primary care data set created for COVID-19 pandemic research. The Cambridge Multimorbidity Score (CMMS) is a validated tool for predicting mortality risk, with 37 conditions defined by Read Codes. The GDPPR uses the more internationally used Systematized Nomenclature of Medicine clinical terms (SNOMED CT). We previously developed a modified version of the CMMS using SNOMED CT, but the number of terms for the GDPPR data set is limited making it impossible to use this version. Objective: We aimed to develop and validate a modified version of CMMS using the clinical terms available for the GDPPR. Methods: We used pseudonymized data from the Oxford-Royal College of General Practitioners Research and Surveillance Centre (RSC), which has an extensive SNOMED CT list. From the 37 conditions in the original CMMS model, we selected conditions either with (1) high prevalence ratio (≥85%), calculated as the prevalence in the RSC data set but using the GDPPR set of SNOMED CT codes, divided by the prevalence included in the RSC SNOMED CT codes or (2) conditions with lower prevalence ratios but with high predictive value. The resulting set of conditions was included in Cox proportional hazard models to determine the 1-year mortality risk in a development data set (n=500,000) and construct a new CMMS model, following the methods for the original CMMS study, with variable reduction and parsimony, achieved by backward elimination and the Akaike information stopping criterion. Model validation involved obtaining 1-year mortality estimates for a synchronous data set (n=250,000) and 1-year and 5-year mortality estimates for an asynchronous data set (n=250,000). We compared the performance with that of the original CMMS and the modified CMMS that we previously developed using RSC data. Results: The initial model contained 22 conditions and our final model included 17 conditions. The conditions overlapped with those of the modified CMMS using the more extensive SNOMED CT list. For 1-year mortality, discrimination was high in both the derivation and validation data sets (Harrell C=0.92) and 5-year mortality was slightly lower (Harrell C=0.90). Calibration was reasonable following an adjustment for overfitting. The performance was similar to that of both the original and previous modified CMMS models. Conclusions: The new modified version of the CMMS can be used on the GDPPR, a nationwide primary care data set of 54 million people, to enable adjustment for multimorbidity in predicting mortality in people in real-world vaccine effectiveness, pandemic planning, and other research studies. It requires 17 variables to produce a comparable performance with our previous modification of CMMS to enable it to be used in routine data using SNOMED CT.
COVID-19 vaccine effectiveness against hospitalisation and death of people in clinical risk groups during the Delta variant period: English primary care network cohort study
Background: COVID-19 vaccines have been shown to be highly effective against hospitalisation and death following COVID-19 infection. COVID-19 vaccine effectiveness estimates against severe endpoints among individuals with clinical conditions that place them at increased risk of critical disease are limited. Methods: We used English primary care medical record data from the Oxford-Royal College of General Practitioners Research and Surveillance Centre sentinel network (N > 18 million). Data were linked to the National Immunisation Management Service database, Second Generation Surveillance System for virology test data, Hospital Episode Statistics, and death registry data. We estimated adjusted vaccine effectiveness (aVE) against COVID-19 infection followed by hospitalisation and death among individuals in specific clinical risk groups using a cohort design during the delta-dominant period. We also report mortality statistics and results from our antibody surveillance in this population. Findings: aVE against severe endpoints was high, 14–69d following a third dose aVE was 96.4% (95.1%–97.4%) and 97.9% (97.2%–98.4%) for clinically vulnerable people given a Vaxzevria and Comirnaty primary course respectively. Lower aVE was observed in the immunosuppressed group: 88.6% (79.1%–93.8%) and 91.9% (85.9%–95.4%) for Vaxzevria and Comirnaty respectively. Antibody levels were significantly lower among the immunosuppressed group than those not in this risk group across all vaccination types and doses. The standardised case fatality rate within 28 days of a positive test was 3.9/1000 in people not in risk groups, compared to 12.8/1000 in clinical risk groups. Waning aVE with time since 2nd dose was also demonstrated, for example, Comirnaty aVE against hospitalisation reduced from 96.0% (95.1–96.7%) 14–69days post-dose 2–82.9% (81.4–84.2%) 182days+ post-dose 2. Interpretation: In all clinical risk groups high levels of vaccine effectiveness against severe endpoints were seen. Reduced vaccine effectiveness was noted among the immunosuppressed group.
Implementation of chronic kidney disease guidelines for sodium-glucose co-transporter-2 inhibitor use in primary care in the UK: a cross-sectional study
Background: The cardiovascular and kidney benefits of sodium-glucose co-transporter-2 (SGLT2) inhibitors in people with chronic kidney disease (CKD) are well established. The implementation of updated SGLT2 inhibitor guidelines and prescribing in the real-world CKD population remains largely unknown. Methods: A cross-sectional study of adults with CKD registered with UK primary care practices in the Oxford-Royal College of General Practitioners Research and Surveillance Centre network on the 31st December 2022 was undertaken. Pseudonymised data from electronic health records held securely within the Oxford-Royal College of General Practitioners Clinical Informatics Digital Hub (ORCHID) were extracted. An update to a previously described ontological approach was used to identify the study population, using a combination of Systematized Nomenclature of Medicine Clinical Terms (SNOMED CT) indicating a diagnosis of CKD and laboratory confirmed CKD based on Kidney Disease: Improving Global Outcomes (KDIGO) diagnostic criteria. We examined the extent to which SGLT2 inhibitor guidelines apply to and are then implemented in adults with CKD. A logistic regression model was used to identify factors associated with SGLT2 inhibitor prescribing, reported as odds ratios (ORs) with 95% confidence intervals (CI). The four guidelines under investigation were the United Kingdom Kidney Association (UKKA) Clinical Practice Guideline SGLT2 Inhibition in Adults with Kidney Disease (October 2021), American Diabetes Association (ADA) and KDIGO Consensus Report on Diabetes Management in CKD (October 2022), National Institute for Health and Care Excellence (NICE) Guideline Type 2 Diabetes in Adults: Management (June 2022), and NICE Technology Appraisal Dapagliflozin for Treating CKD (March 2022). Findings: Of 6,670,829 adults, we identified 516,491 (7.7%) with CKD, including 32.8% (n = 169,443) who had co-existing type 2 diabetes (T2D). 26.8% (n = 138,183) of the overall CKD population had a guideline directed indication for SGLT2 inhibitor treatment. A higher proportion of people with CKD and co-existing T2D were indicated for treatment, compared to those without T2D (62.8% [n = 106,468] vs. 9.1% [n = 31,715]). SGLT2 inhibitors were prescribed to 17.0% (n = 23,466) of those with an indication for treatment, and prescriptions were predominantly in those with co-existing T2D; 22.0% (n = 23,464) in those with T2D, and <0.1% (n = 2) in those without T2D. In adjusted multivariable analysis of people with CKD and T2D, females (OR 0.69, 95% CI 0.67–0.72, p <0.0001), individuals of Black ethnicity (OR 0.84, 95% CI 0.77–0.91, p <0.0001) and those of lower socio-economic status (OR 0.72, 95% CI 0.68–0.76, p <0.0001) were less likely to be prescribed an SGLT2 inhibitor. Those with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 had a lower likelihood of receiving an SGLT2 inhibitor, compared to those with an eGFR ≥60 mL/min/1.73 m2 (eGFR 45–60 mL/min/1.73 m2 OR 0.65, 95% CI 0.62–0.68, p <0.0001, eGFR 30–45 mL/min/1.73 m2 OR 0.73, 95% CI 0.69–0.78, p <0.0001, eGFR 15–30 mL/min/1.73 m2 OR 0.52, 95% CI 0.46–0.60, p <0.0001, eGFR <15 mL/min/1.73 m2 OR 0.03, 95% CI 0.00–0.23, p = 0.0037, respectively). Those with albuminuria (urine albumin-to-creatinine ratio 3–30 mg/mmol) were less likely to be prescribed an SGLT2 inhibitor, compared to those without albuminuria (OR 0.78, 95% CI 0.75–0.82, p <0.0001). Interpretation: SGLT2 inhibitor guidelines in CKD have not yet been successfully implemented into clinical practice, most notably in those without co-existing T2D. Individuals at higher risk of adverse outcomes are paradoxically less likely to receive SGLT2 inhibitor treatment. The timeframe between the publication of guidelines and data extraction may have been too short to observe changes in clinical practice. Enhanced efforts to embed SGLT2 inhibitors equitably into routine care for people with CKD are urgently needed, particularly in those at highest risk of adverse outcomes and in the absence of T2D. Funding: None.
Thrombocytopenic, thromboembolic and haemorrhagic events following second dose with BNT162b2 and ChAdOx1: self-controlled case series analysis of the English national sentinel cohort
Background: Thrombosis associated with thrombocytopenia was a matter of concern post first and second doses of BNT162b2 and ChAdOx1 COVID-19 vaccines. Therefore, it is important to investigate the risk of thrombocytopenic, thromboembolic and haemorrhagic events following a second dose of BNT162b2 and ChAdOx1 COVID-19 vaccines. Methods: We conducted a large-scale self-controlled case series analysis, using routine primary care data linked to hospital data, among 12.3 million individuals (16 years old and above) in England. We used the nationally representative Oxford-Royal College of General Practitioners (RCGP) sentinel network database with baseline and risk periods between 8th December 2020 and 11th June 2022. We included individuals who received two vaccine (primary) doses of the BNT162b2 mRNA (Pfizer-BioNTech) and two vaccine doses of ChAdOx1 nCoV-19 (Oxford-AstraZeneca) vaccines in our analyses. We carried out a self-controlled case series (SCCS) analysis for each outcome using a conditional Poisson regression model with an offset for the length of risk period. We reported the incidence rate ratios (IRRs) and 95% confidence intervals (CI) of thrombocytopenic, thromboembolic (including arterial and venous events) and haemorrhagic events, in the period of 0–27 days after receiving a second dose of BNT162b2 or ChAdOx1 vaccines compared to the baseline period (14 or more days prior to first dose, 28 or more days after the second dose and the time between 28 or more days after the first and 14 or more days prior to the second dose). We adjusted for a range of potential confounders, including age, sex, comorbidities and deprivation. Findings: Between December 8, 2020 and February 11, 2022, 6,306,306 individuals were vaccinated with two doses of BNT162b2 and 6,046,785 individuals were vaccinated with two doses of ChAdOx1. Compared to the baseline, our analysis show no increased risk of venous thromboembolic events (VTE) for both BNT162b2 (IRR 0.71, 95% CI: 0.65–0.770) and ChAdOx1 (IRR 0.91, 95% CI: 0.84–0.98); and similarly there was no increased risk for cerebral venous sinus thrombosis (CVST) for both BNT162b2 (IRR 0.87, 95% CI: 0.41–1.85) and ChAdOx1 (IRR 1.73, 95% CI: 0.82–3.68). We additionally report no difference in IRR for pulmonary embolus, and deep vein thrombosis, thrombocytopenia, including idiopathic thrombocytopenic purpura (ITP), and haemorrhagic events post second dose for both BNT162b2. Interpretation: Reassuringly, we found no associations between increased risk of thrombocytopenic, thromboembolic and haemorrhagic events post vaccination with second dose for either of these vaccines. Funding: Data and Connectivity: COVID-19 Vaccines Pharmacovigilance study.
A comparison of sodium-glucose co-transporter 2 inhibitor kidney outcome trial participants with a real-world chronic kidney disease primary care population
Background: Observational studies suggest sodium-glucose co-transporter 2 (SGLT2) inhibitor kidney outcome trials are not representative of the broader population of people with chronic kidney disease (CKD). However, there are limited data on the generalizability to those without co-existing type 2 diabetes (T2D), and the representativeness of the Study of Heart and Kidney Protection with Empagliflozin (EMPA-KIDNEY) trial has not been adequately explored. We hypothesized that SGLT2 inhibitor kidney outcome trials are more representative of people with co-existing T2D than those without, and that EMPA-KIDNEY is more representative than previous trials. Methods: A cross-sectional analysis of adults with CKD in English primary care was conducted using the Oxford-Royal College of General Practitioners Clinical Informatics Digital Hub. The proportions that met the eligibility criteria of SGLT2 inhibitor kidney outcome trials were determined, and their characteristics described. Logistic regression analyses were performed to identify factors associated with trial eligibility. Results: Of 6 670 829 adults, 516 491 (7.7%) with CKD were identified. In the real-world CKD population, 0.9%, 2.2% and 8.0% met the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE), Dapagliflozin and Renal Outcomes and Cardiovascular Mortality in Patients with Chronic Kidney Disease (DAPA-CKD) and EMPA-KIDNEY eligibility criteria, respectively. All trials were more representative of people with co-existing T2D than those without T2D. Trial participants were 9-14 years younger than the real-world CKD population, and had more advanced CKD, including higher levels of albuminuria. A higher proportion of the CREDENCE (100%), DAPA-CKD (67.6%) and EMPA-KIDNEY (44.5%) trial participants had T2D compared with the real-world CKD population (32.8%). Renin-angiotensin system inhibitors were prescribed in almost all trial participants, compared with less than half of the real-world CKD population. Females were under-represented and less likely to be eligible for the trials. Conclusion: SGLT2 inhibitor kidney outcome trials represent a subgroup of people with CKD at high risk of adverse kidney events. Our study highlights the importance of complementing trials with real-world studies, exploring the effectiveness of SGLT2 inhibitors in the broader population of people with CKD.
Training needs for staff providing remote services in general practice: a mixed-methods study
Background Contemporary general practice includes many kinds of remote encounter. The rise in telephone, video and online modalities for triage and clinical care requires clinicians and support staff to be trained, both individually and as teams, but evidence-based competencies have not previously been produced for general practice. Aim To identify training needs, core competencies, and learning methods for staff providing remote encounters. Design and setting Mixed-methods study in UK general practice. Method Data were collated from longitudinal ethnographic case studies of 12 general practices; a multi-stakeholder workshop; interviews with policymakers, training providers, and trainees; published research; and grey literature (such as training materials and surveys). Data were coded thematically and analysed using theories of individual and team learning. Results Learning to provide remote services occurred in the context of high workload, understaffing, and complex workflows. Low confidence and perceived unmet training needs were common. Training priorities for novice clinicians included basic technological skills, triage, ethics (for privacy and consent), and communication and clinical skills. Established clinicians’ training priorities include advanced communication skills (for example, maintaining rapport and attentiveness), working within the limits of technologies, making complex judgements, coordinating multi-professional care in a distributed environment, and training others. Much existing training is didactic and technology focused. While basic knowledge was often gained using such methods, the ability and confidence to make complex judgements were usually acquired through experience, informal discussions, and on-the-job methods such as shadowing. Whole-team training was valued but rarely available. A draft set of competencies is offered based on the findings. Conclusion The knowledge needed to deliver high-quality remote encounters to diverse patient groups is complex, collective, and organisationally embedded. The vital role of non-didactic training, for example, joint clinical sessions, case-based discussions, and in-person, whole-team, on-the-job training, needs to be recognised.
Critical components of ‘Early Intervention in Psychosis’: national retrospective cohort study
Background Psychotic disorders are severe mental health conditions frequently associated with long-term disability, reduced quality of life and premature mortality. Early Intervention in Psychosis (EIP) services aim to provide timely, comprehensive packages of care for people with psychotic disorders. However, it is not clear which components of EIP services contribute most to the improved outcomes they achieve. Aims We aimed to identify associations between specific components of EIP care and clinically significant outcomes for individuals treated for early psychosis in England. Method This national retrospective cohort study of 14 874 EIP individuals examined associations between 12 components of EIP care and outcomes over a 3-year follow-up period, by linking data from the National Clinical Audit of Psychosis (NCAP) to routine health outcome data held by NHS England. The primary outcome was time to relapse, defined as psychiatric inpatient admission or referral to a crisis resolution (home treatment) team. Secondary outcomes included duration of admissions, detention under the Mental Health Act, emergency department and general hospital attendances and mortality. We conducted multilevel regression analyses incorporating demographic and service-level covariates. Results Smaller care coordinator case-loads and the use of clozapine for eligible people were associated with reduced relapse risk. Physical health interventions were associated with reductions in mortality risk. Other components, such as cognitive–behavioural therapy for psychosis (CBTp), showed associations with improvements in secondary outcomes. Conclusions Smaller case-loads should be prioritised and protected in EIP service design and delivery. Initiatives to improve the uptake of clozapine should be integrated into EIP care. Other components, such as CBTp and physical health interventions, may have specific benefits for those eligible. These findings highlight impactful components of care and should guide resource allocation to optimise EIP service delivery.