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The most important factor influencing maternal vaccination uptake is healthcare professional (HCP) recommendation. However, where data are available, one-third of pregnant women remain unvaccinated despite receiving a recommendation. Therefore, it is essential to understand the significance of other factors and distinguish between vaccines administered routinely and during outbreaks. This is the first systematic review and meta-analysis (PROSPERO: CRD 42019118299) to examine the strength of the relationships between identified factors and maternal vaccination uptake. We searched MEDLINE, Embase Classic & Embase, PsycINFO, CINAHL Plus, Web of Science, IBSS, LILACS, AfricaWideInfo, IMEMR, and Global Health databases for studies reporting factors that influence maternal vaccination. We used random-effects models to calculate pooled odds ratios (OR) of being vaccinated by vaccine type. We screened 17,236 articles and identified 120 studies from 30 countries for inclusion. Of these, 49 studies were eligible for meta-analysis. The odds of receiving a pertussis or influenza vaccination were ten to twelve-times higher among pregnant women who received a recommendation from HCPs. During the 2009 influenza pandemic an HCP recommendation increased the odds of antenatal H1N1 vaccine uptake six times (OR 6.76, 95% CI 3.12-14.64, I2 = 92.00%). Believing there was potential for vaccine-induced harm had a negative influence on seasonal (OR 0.22, 95% CI 0.11-0.44 I2 = 84.00%) and pandemic influenza vaccine uptake (OR 0.16, 95% CI 0.09-0.29, I2 = 89.48%), reducing the odds of being vaccinated five-fold. Combined with our qualitative analysis the relationship between the belief in substantial disease risk and maternal seasonal and pandemic influenza vaccination uptake was limited. The effect of an HCP recommendation during an outbreak, whilst still powerful, may be muted by other factors. This requires further research, particularly when vaccines are novel. Public health campaigns which centre on the protectiveness and safety of a maternal vaccine rather than disease threat alone may prove beneficial.

BACKGROUNDDespite growing preclinical evidence that glucagon-like peptide1 receptor agonists (GLP-1RAs) could be repurposed to treat alcohol use disorder (AUD), clinical evidence is scarce. Additionally, the potential impact of dipeptidyl peptidase-4 inhibitors (DPP-4Is) on alcohol intake is largely unknown.METHODSWe conducted a large cohort study using 2008-2023 electronic health records data from the U.S. Department of Veterans Affairs. Changes in Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) scores were compared between propensity-score-matched GLP-1RA recipients, DPP-4I recipients, and unexposed comparators. We further tested the effects of 2 DPP-4Is, linagliptin and omarigliptin, on binge-like alcohol drinking in mice and operant oral alcohol self administration in alcohol-dependent rats, models previously used to show a significant effect of the GLP-1RA semaglutide in reducing alcohol intake.RESULTSGLP-1RA recipients reported a greater reduction in AUDIT-C scores than unexposed individuals (difference-in-difference [DiD]: 0.09 [95% CI: 0.03, 0.14], P = 0.0025) and DPP-4I recipients (DiD: 0.11 [95% CI: 0.05,0.17], P = 0.0002). Reductions in drinking were more pronounced among individuals with baseline AUD (GLP-1RA versus unexposed: 0.51 [95% CI: 0.29,0.72], P < 0.0001; GLP-1RA versus DPP-4I: 0.65 [95% CI: 0.43,0.88], P < 0.0001) and baseline hazardous drinking (GLP-1RA versus unexposed: 1.38 [95% CI: 1.07,1.69], P < 0.0001; GLP-1RA versus DPP-4I: 1.00 [95% CI: 0.68,1.33], P < 0.0001). There were no differences between DPP-4I recipients and unexposed individuals. The latter results were confirmed via a reverse translational approach. Specifically, neither linagliptin nor omarigliptin reduced alcohol drinking in mice or rats. The rodent experiments also confirmed target engagemhent, as both DPP-4Is reduced blood glucose levels.CONCLUSIONConvergent findings across humans, mice, and rats indicated that GLP-1RAs, but not DPP-4Is, reduce alcohol consumption and may be efficacious in treating AUD.FUNDINGThis work was supported by the National Institutes of Health Intramural Research Program (ZIA DA000635, ZIA DA000644, ZIA DA000602), National Institute on Alcohol Abuse and Alcoholism extramural funding (R01 AA030041, P01 AA029545, U01 AA026224, U24 AA020794, U01 AA020790, U10 AA013566), the U.S. Department of Veterans Affairs (I01BX004820), and an Alkermes Pathways Research Award.

Stroke prevention guidance for patients with atrial fibrillation (AF) uses evidence generated from randomised controlled trials (RCTs). However, applicability to patient groups excluded from trials remains unknown. Real-world patient data provide an opportunity to evaluate outcomes in a trial analogous population of direct oral anticoagulants (DOACs) users and in patients otherwise excluded from RCTs; however, there remains uncertainty on the validity of methods and suitability of the data. Successful reference trial emulation can support the generation of evidence around treatment effects in groups excluded or underrepresented in trials. We used linked United Kingdom primary care data to investigate whether we could emulate the pivotal ARISTOTLE trial (apixaban versus warfarin) and extend the analysis to investigate the impact of warfarin time in therapeutic range (TTR) on results. Patients with AF in the UK Clinical Practice Research Datalink (CPRD Aurum) prescribed apixaban or warfarin from 1 January 2013 to 31 July 2019 were selected. ARISTOTLE eligibility criteria were applied to this population and matched to the RCT apixaban arm on baseline characteristics creating a trial-analogous apixaban cohort; this was propensity-score matched to warfarin users in the CPRD Aurum. ARISTOTLE outcomes were assessed using Cox proportional hazards regression stratified by prior warfarin exposure status during 2.5 years of patient follow-up and results benchmarked against the trial results before treatment effectiveness was further evaluated based on (warfarin) TTR. The dataset comprised 8,734 apixaban users and propensity-score matched 8,734 warfarin users. Results [hazard ratio (95% confidence interval)] confirmed apixaban noninferiority for stroke or systemic embolism (SE) [CPRD 0.98 (0.82,1.19) versus trial 0.79 (0.66,0.95)] and death from any cause [CPRD 1.03 (0.93,1.14) versus trial 0.89 (0.80,0.998)] but did not indicate apixaban superiority. Absolute event rates for stroke/SE were similar for apixaban in CPRD Aurum and ARISTOTLE (1.27%/year), whereas a lower event rate was observed for warfarin (CPRD Aurum 1.29%/year, ARISTOTLE 1.60%/year). Analysis by TTR suggested similar effectiveness of apixaban compared with poorly controlled warfarin (TTR < 0.75) for stroke/SE [0.91 (0.73, 1.14)], all-cause death [0.94 (0.84, 1.06)], and superiority for major bleeding [0.74 (0.63, 0.86)]. However, when compared with well-controlled warfarin (TTR ≥ 0.75), apixaban was associated with an increased hazard for all-cause death [1.20 (1.04, 1.37)], and there was no significant benefit for major bleeding [1.08 (0.90, 1.30)]. The main limitation of the study's methodology are the risk of residual confounding, channelling bias and attrition bias in the warfarin arm, and selection bias and misclassification in the analysis by TTR. Analysis of noninterventional data generated results demonstrating noninferiority of apixaban versus warfarin consistent with prespecified benchmarking criteria. Unlike in ARISTOTLE, superiority of apixaban versus warfarin was not seen, possible due to the lower proportion of Asian patients and higher proportion of patients with well-controlled warfarin compared to ARISTOTLE. This methodological template can be used to investigate treatment effects of oral anticoagulants in patient groups excluded from or underrepresented in trials and provides a framework that can be adapted to investigate treatment effects for other conditions.

IntroductionObservational data are increasingly used to study and draw causal inferences about the effects of treatments. Target trial emulation (TTE) is a framework for mitigating biases in causal investigations through specification of an observational study, targeting a specific causal research question, based on a real or hypothetical randomised controlled trial. Investigations into the effects of treatment discontinuation are of growing interest and particularly relevant in cystic fibrosis (CF), where treatment burden is high and new transformative therapies are becoming widespread. We aim to use the TTE framework to investigate the effect of discontinuation of inhaled corticosteroids (ICS) on clinical outcomes in people with CF. Our observational emulation will be based on the CF WISE (Withdrawal of Inhaled Steroids Evaluation) trial (PMID:16556691).Methods and analysisTwo study designs proposed for investigating treatment effects using observational data are the prevalent new-user design and the sequential trials design. Each design uses different but related methods to address similar causal questions; however, the comparability between them remains uncertain. We will conduct a population-based cohort study using data from the UK CF Registry between January 2016 and June 2018 and apply these designs. We will specify the target trial protocol for each study design. Estimates for the causal effects of discontinuing ICS will be obtained and compared with those from the CF-WISE trial.Ethics and disseminationThis study has received approval from the UK CF Registry Research Committee for both the research and access to data. Ethical approval has also been granted by the LSHTM Ethics Committee. The UK CF Registry has NHS Research Ethics Committee approval (REC reference: 24/EE/0012). The findings from this project will be submitted to peer-reviewed journals and presented at academic conferences.

[...]considering the retraction of several Surgisphere articles,7 a code sharing mandate might have flagged concerns with these papers earlier, given how difficult it would be to generate code for data management and analysis that never took place. 10.1093/aje/kwad007 36627249 3 Morton C Devito N Morley J. Software development skills for health data researchers. Prevalence and predictors of data and code sharing in the medical and health sciences: systematic review with meta-analysis of individual participant data.

Background Direct oral anticoagulants (DOACs) have been reported to be associated with a higher risk of mortality compared with an older alternative, warfarin using primary care data in the United Kingdom (UK). However, other studies observed contradictory findings. We therefore aimed to investigate the association between mortality and warfarin, compared with DOACs. Methods We conducted cohort studies using UK Clinical Practice Research Datalink (CPRD) Aurum and Hong Kong Clinical Data Analysis and Reporting System (CDARS) to identify the association between warfarin and hazard of mortality, compared to DOACs. Individuals with non-valvular atrial fibrillation aged ≥ 18 years who had first anticoagulant therapy (warfarin or DOAC) during 1/1/2011–31/12/2019 were included. Results Compared with DOAC use, a lower hazard of all-cause mortality was found in warfarin users (hazard ratio (HR) = 0.81, 95% confidence interval (CI) = 0.77–0.86) in CPRD; while a higher hazard was observed in warfarin users (HR = 1.31, 95% CI = 1.24–1.39) in CDARS, versus DOAC users. In our exploratory analysis, consistent results were seen in both databases when stratified warfarin users by time in therapeutic range (TTR) using post-baseline measurements: a lower hazard of all-cause mortality in warfarin users with TTR ≥ 65% (CPRD: HR = 0.68, 95% CI = 0.65–0.72; CDARS: HR = 0.86, 95% CI = 0.77–0.96) and increased hazard in warfarin users with TTR < 65% (CPRD: HR = 1.14, 95% CI = 1.05–1.23; CDARS: HR = 1.59, 95% CI = 1.50–1.69), versus DOAC users. Conclusions The differences in hazard of all-cause mortality associated with warfarin compared with DOAC, in part may depend on anticoagulation control in warfarin users. Notably, this study is unable to establish a causal relationship between warfarin and mortality stratified by TTR, versus DOACs, requiring future studies for further investigation.

ObjectiveTo characterise factors associated with COVID-19 vaccine uptake among people with kidney disease in England.DesignRetrospective cohort study using the OpenSAFELY-TPP platform, performed with the approval of NHS England.SettingIndividual-level routine clinical data from 24 million people across GPs in England using TPP software. Primary care data were linked directly with COVID-19 vaccine records up to 31 August 2022 and with renal replacement therapy (RRT) status via the UK Renal Registry (UKRR).ParticipantsA cohort of adults with stage 3–5 chronic kidney disease (CKD) or receiving RRT at the start of the COVID-19 vaccine roll-out was identified based on evidence of reduced estimated glomerular filtration rate (eGFR) or inclusion in the UKRR.Main outcome measuresDose-specific vaccine coverage over time was determined from 1 December 2020 to 31 August 2022. Individual-level factors associated with receipt of a 3-dose or 4-dose vaccine series were explored via Cox proportional hazards models.Results992 205 people with stage 3–5 CKD or receiving RRT were included. Cumulative vaccine coverage as of 31 August 2022 was 97.5%, 97.0% and 93.9% for doses 1, 2 and 3, respectively, and 81.9% for dose 4 among individuals with one or more indications for eligibility. Delayed 3-dose vaccine uptake was associated with younger age, minority ethnicity, social deprivation and severe mental illness—associations that were consistent across CKD severity subgroups, dialysis patients and kidney transplant recipients. Similar associations were observed for 4-dose uptake.ConclusionAlthough high primary vaccine and booster dose coverage has been achieved among people with kidney disease in England, key disparities in vaccine uptake remain across clinical and demographic groups and 4-dose coverage is suboptimal. Targeted interventions are needed to identify barriers to vaccine uptake among under-vaccinated subgroups identified in the present study.

Background: IDH-wildtype glioblastoma is the most common malignant primary brain tumour in adults. As there is limited information on prognostic factors outside of clinical trials; thus, we conducted a retrospective study to characterise the glioblastoma population at our centre. Methods: Demographic, tumour molecular profiles, treatment, and survival data were collated for patients diagnosed with glioblastoma at our centre between July 2011 and December 2015. We used multivariate proportional hazard model associations with survival. Results: 490 patients were included; 60% had debulking surgery and 40% biopsy only. Subsequently, 56% had standard chemoradiotherapy, 25% had non-standard chemo/radio-therapy, and 19% had no further treatment. Overall survival was 9.2 months. In the multivariate analysis, longer survival was associated with debulking surgery vs. biopsy alone (14.9 vs. 8 months) (HR 0.54 [95% CI 0.41–0.70]), subsequent treatment after diagnosis (HR 0.12 [0.08–0.16]) (standard chemoradiotherapy [16.9 months] vs. non-standard regimens [9.2 months] vs. none [2.0 months]), tumour MGMT promotor methylation (HR 0.71 [0.58–0.87]), and younger age (hazard ratio vs. age < 50: 1.70 [1.26–2.30] for ages 50–59; 3.53 [2.65–4.70] for ages 60–69; 4.82 [3.54–6.56] for ages 70+). Conclusions: The median survival for patients with glioblastoma is less than a year. Younger age, debulking surgery, treatment with chemoradiotherapy, and MGMT promotor methylation are independently associated with longer survival.

Background Biological evidence suggests ursodeoxycholic acid (UDCA)—a common treatment of cholestatic liver disease—may prevent severe COVID-19 outcomes. We aimed to compare the hazard of COVID-19 hospitalisation or death between UDCA users versus non-users in a population with primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC). Methods With the approval of NHS England, we conducted a population-based cohort study using primary care records between 1 March 2020 and 31 December 2022, linked to death registration data and hospital records through the OpenSAFELY-TPP platform. Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between time-varying UDCA exposure and COVID-19 related hospitalisation or death, stratified by geographical region and considering models unadjusted and fully adjusted for pre-specified confounders. Results We identify 11,305 eligible individuals, 640 were hospitalised or died with COVID-19 during follow-up, 400 (63%) events among UDCA users. After confounder adjustment, UDCA is associated with a 21% relative reduction in the hazard of COVID-19 hospitalisation or death (HR 0.79, 95% CI 0.67–0.93), consistent with an absolute risk reduction of 1.35% (95% CI 1.07%–1.69%). Conclusions We found evidence that UDCA is associated with a lower hazard of COVID-19 related hospitalisation and death, support calls for clinical trials investigating UDCA as a preventative measure for severe COVID-19 outcomes. Costello et al. assess the impact of ursodeoxycholic acid (UDCA) treatment on COVID-19-related outcomes among people with chronic primary biliary cirrhosis and primary sclerosing cholangitis. Using a population-based cohort, they show that treatment with UDCA was associated with a reduced risk of COVID-19-related hospitalisation or death. Plain language summary Ursodeoxycholic acid is a drug used to treat liver disease. It has been proposed that it may prevent severe COVID-19 outcomes, however previous studies of this have had inconsistent results. We used electronic health records from people in the UK and identified people with two liver diseases: primary biliary cholangitis and primary sclerosing cholangitis. We looked at differences in hospitalisation and death between people taking UDCA and people who were not taking it. We found UDCA reduced the risk of severe COVID-19 outcomes by one-fifth. This suggests UDCA may help prevent serious COVID-19. Further clinical studies of UCDA should be undertaken, particularly in other groups with high risk or hospitalisation and death from COVID.

The frequency of, and risk factors for, long COVID are unclear among community-based individuals with a history of COVID-19. To elucidate the burden and possible causes of long COVID in the community, we coordinated analyses of survey data from 6907 individuals with self-reported COVID-19 from 10 UK longitudinal study (LS) samples and 1.1 million individuals with COVID-19 diagnostic codes in electronic healthcare records (EHR) collected by spring 2021. Proportions of presumed COVID-19 cases in LS reporting any symptoms for 12+ weeks ranged from 7.8% and 17% (with 1.2 to 4.8% reporting debilitating symptoms). Increasing age, female sex, white ethnicity, poor pre-pandemic general and mental health, overweight/obesity, and asthma were associated with prolonged symptoms in both LS and EHR data, but findings for other factors, such as cardio-metabolic parameters, were inconclusive. Current understanding of Long COVID is limited, in part, due to lack of evidence from population-representative studies. Here, the authors analyse data from ten UK population-based studies and electronic health records, and find wide variation in the frequency of Long COVID between studies but some consistent risk factors.