Background: Vaccine co-administration can increase vaccination coverage. We assessed the safety, reactogenicity, and immunogenicity of concomitant administration of Ad26.COV2.S COVID-19 vaccine with seasonal influenza vaccines.
Methods: This non-inferiority, Phase 3, randomised, double-blind study enrolled 859 healthy adults and was conducted between 02 November 2021 and 28 November 2022. Participants aged ≥18-64 years were randomised to receive a seasonal quadrivalent standard dose (SD) influenza vaccine (Afluria Quadrivalent, Seqirus) concomitantly with Ad26.COV2.S (Coad_SD) or placebo (0.9% NaCl; Control_SD) on Day 1 and placebo or Ad26.COV2.S on Day 29. Participants aged ≥65-years were randomised to the Coad_SD or Control_SD groups, or to Coad_HD or Control_HD groups that received a seasonal quadrivalent HD (high-dose) influenza vaccine (Fluzone High-Dose Quadrivalent, Sanofi Pasteur Inc) in the same schedules. The primary outcomes were haemagglutinin inhibition titres against the four influenza vaccine strains at Day 29, and SARS-CoV-2 Spike-specific antibodies at Day 29 in the Coad_SD group and Day 57 in the Control-SD group, with a non-inferiority margin (Control-SD group/Coad_SD group) of 1.5. Reactogenicity and safety were assessed in all participants (NCT05091307).
Findings: Non-inferiority criteria for concomitant administration in the SD groups were met for SARS-CoV-2 Spike-specific antibodies (ratio 1.11, 95% CI 0.97-1.26) and haemagglutinin inhibition titres for all influenza strains (A/H3N2 1.23, 95% CI 1.05-1.45; B/Victoria 0.99, 95% CI 0.84-1.19; B/Yamagata, 1.03, 95% CI 0.88-1.21) except A/H1N1 (1.28, 95% CI 1.09-1.53) for which the upper limit of the 95% CI was >1.5. Concomitant administration of Ad26.COV2.S and SD influenza vaccine induced robust immune responses in terms of SARS-CoV-2 Spike-specific antibodies and haemagglutinin inhibition to all four influenza strains. Seroconversion and seroprotection rates against all influenza vaccine strains were comparable in the Coad and Control groups. Anti-Spike antibodies 28 days after receiving Ad26.COV2.S were similar whether administered with influenza vaccine or alone. Antibody responses persisted at least 6 months post-vaccination in all groups. The reactogenicity and safety profile following co-administration was consistent with the known safety profiles of the study vaccines. No safety concerns were identified. Coadministration was immunogenic and well tolerated in adults aged ≥65 years who received HD influenza vaccine.
Interpretation: Co-administration of seasonal influenza vaccine with Ad26.COV2.S was immunogenic with an acceptable safety profile, supporting co-administration of these vaccines.
Funding: Janssen Vaccines & Prevention BV and Biomedical Advanced Research and Development Authority.
Background: Randomized clinical trials (RCTs) are fundamental to evidence-based medicine, but their real-world impact on clinical practice often remains unmonitored. Leveraging large-scale real-world data can enable systematic monitoring of RCT effects. We aimed to develop a reproducible framework using real-world data to assess how major RCTs influence medical practice, using two pivotal surgical RCTs in gynaecologic oncology as an example-the LACC (Laparoscopic Approach to Cervical Cancer) and LION (Lymphadenectomy in Ovarian Neoplasms) trials.
Methods: We utilized data from the French National Health Insurance Database (SNDS), covering 98.8% of France's population. We analysed patients who underwent radical hysterectomy for cervical cancer (2013-2022) and patients who underwent cytoreductive surgery for ovarian cancer (2014-2022). Bayesian structural time series analysis assessed the causal effects of the LACC and LION trials on the discontinuation of minimally invasive surgery (MIS) and lymphadenectomy, respectively. Analyses were stratified by hospital type, academic status, research mission, domain expertise, human resources, and financial condition.
Findings: Our nationwide cohorts included 7108 cervical cancer and 23,090 ovarian cancer patients treated across 596 centres. The LACC trial led to a 14.1% reduction in radical hysterectomies by MIS (275 fewer surgeries; 95% CI: -407 to -140), with academic centres showing 27.9% reduction compared to 2.5% increase in nonacademic centres. The LION trial resulted in a 22.6% reduction in lymphadenectomies (2358 fewer surgeries; 95% CI: -2708 to -2003), with academic centres achieving 31.1% reduction versus 15% in nonacademic centres. Significant variation was observed across medical settings. Centres with academic status, high research missions, substantial expertise, and robust resources were more responsive to trial outcomes, highlighting the influence of institutional and human factors on adopting new practices.
Interpretation: This study demonstrates that large-scale real-world data can effectively monitor the impact of RCTs on clinical practice. While validated here using surgical trials, this reproducible framework is adaptable to various health domains and can be implemented in any country with national electronic health databases. Systematic monitoring is essential to ensure effective implementation of RCT findings and to address disparities in the adoption of evidence-based practices.
Funding: None.
Background: Brain stimulation therapy (BST) has significant potential in treating psychiatric, movement, and cognitive disorders. Given the high prevalence of comorbidities among these disorders, we conducted an umbrella review to comprehensively assess the efficacy of BSTs in treating the core symptoms across these three categories of disorders.
Methods: We systematically searched for meta-analyses and network meta-analyses of randomized controlled trials with sham controls up to September 25, 2024, from databases including PubMed, PsycINFO, Embase, and the Cochrane Library. Our primary outcome was improvements in core symptoms. We evaluated quality using 11 criteria. We calculated pooled effect estimates for core symptoms based on the largest meta-analyses, then conducted sensitivity and subgroup analyses, and assessed heterogeneity, publication bias, and small-study effects. Finally, we synthesized effect sizes from all meta-analyses to provide a comprehensive overview of BSTs' efficacy. PROSPERO registration: CRD42023439090.
Findings: We included 198 articles with 108,377 patients evaluating 14 BSTs across 21 disorders. The largest meta-analysis showed a moderate standardized mean difference (SMD) of 0.56 (95% CI: 0.49, 0.64; I2 = 70%). Subgroup analyses revealed significant SMDs for psychiatric disorders (0.60; 95% CI: 0.49, 0.71; I2 = 66%), movement disorders (0.56; 95% CI: 0.42, 0.69; I2 = 79%), and cognitive disorders (0.46; 95% CI: 0.32, 0.61; I2 = 48%). SMDs were 0.44 (95% CI: 0.23, 0.65; I2 = 70%) for follow-up ≤1 month and 0.69 (95% CI: 0.43, 0.94; I2 = 84%) for follow-up >1 month. Compared to other conditions, BSTs show better therapeutic effects in treating depression, post-traumatic stress disorder, obsessive-compulsive disorder, pain, fibromyalgia, and post-stroke motor recovery.
Interpretation: This review explored the potential of BSTs for comorbidities of the three disorders from a disorder-specific perspective, providing a roadmap for their clinical application and future research.
Funding: This work was supported by the Anhui Natural Science Foundation (2023AH040086), Key Laboratory of Philosophy and Social Science of Anhui Province on Adolescent Mental Health and Crisis Intelligence Intervention (SYS2023B08), and the Joint Funds of the National Natural Science Foundation of China (U23A20424).
Background: Children from racial and ethnic minority groups are at greater risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but it is unclear whether they have increased risk for post-acute sequelae of SARS-CoV-2 (PASC). Our objectives were to assess whether the risk of respiratory and neurologic PASC differs by race/ethnicity and social drivers of health.
Methods: We conducted a retrospective cohort study of individuals <21 years seeking care at 24 health systems across the U.S, using electronic health record (EHR) data. Our cohort included those with a positive SARS-CoV-2 molecular, serology or antigen test, or with a COVID-19, multisystem inflammatory disease in children, or PASC diagnosis from February 29, 2020 to August 1, 2022. We identified children/youth with at least 2 codes associated with respiratory and neurologic PASC. We measured associations between sociodemographic and clinical characteristics and respiratory and neurologic PASC using odds ratios and 95% confidence intervals estimated from multivariable logistic regression models adjusted for other sociodemographic characteristics, social vulnerability index or area deprivation index, time period of cohort entry, presence and complexity of chronic respiratory (respectively, neurologic) condition and healthcare utilization.
Findings: Among 771,725 children in the cohort, 203,365 (26.3%) had SARS-CoV-2 infection. Among children with documented infection, 3217 children had respiratory PASC and 2009 children/youth had neurologic PASC. In logistic regression models, children <5 years (Odds Ratio [OR] 1.78, 95% CI 1.62-1.97), and of Hispanic White descent (OR 1.19, 95% CI 1.05-1.35) had higher odds of having respiratory PASC. Children/youth living in regions with higher area deprivation indices (OR 1.25, 95% CI 1.10-1.420 for 60-79th percentile) and with chronic complex respiratory conditions (OR 3.28, 95% CI 2.91-3.70) also had higher odds of respiratory PASC. In contrast, older (OR 1.57, 95% CI 1.40-1.77 for those aged 12-17 years), non-Hispanic White individuals and those with chronic pre-existing neurologic conditions (OR 2.04, 95% CI 1.78-2.35) were more likely to have a neurologic PASC diagnosis.
Interpretation: Racial and ethnic differences in healthcare utilization for neurologic and respiratory PASC may reflect social drivers of health and inequities in access to care.
Funding: National Institutes of Health.
Background: Phosphodiesterase 5 (PDE5) inhibitors, owing to their mechanism of action, have been gaining recognition as a potential case of drug repurposing and combination therapy for diabetes treatment. We aimed to examine the effect of long and short half-life PDE5 inhibitors have on Haemoglobin A1c (HbA1c) levels.
Methods: A systematic review and meta-analysis was conducted of randomised controlled trials (RCTs) in people with elevated HbA1c (>6%) to assess mean difference in HbA1c levels from baseline versus controls after any PDE5 inhibitor intervention of ≥4 weeks, excluding multiple interventions. Cochrane CENTRAL, PMC Medline, ClinicalTrials.gov, and WHO ICTRP were searched without language restrictions up to September 30, 2024. Summary data from published data were extracted. PRISMA and Cochrane guidelines used to extract and assess data using a random-effects meta-analysis. This study is registered with the Research Registry, reviewregistry1733.
Findings: Among 1096 studies identified, in analysis of 13 studies with 1083 baseline patients, long half-life PDE5 inhibitors (tadalafil, PF-00489791) had decreases in HbA1c while short half-life PDE5 inhibitors (sildenafil, avanafil) had no change. Five (38.5%) studies had a low risk of bias, and eight (61.5%) had some concerns. Long half-life inhibitors had significant mean decrease of -0.40% ([-0.66, -0.14], p = 0.002, I2 = 82%, 7.70% baseline HbA1c). Short half-life inhibitors had insignificant mean difference of +0.08% ([-0.16, 0.33], p = 0.51, I2 = 40%, 7.73% baseline HbA1c). In ≥8-week trials with participants with type 2 diabetes (T2D) and mean HbA1c ≥ 6.5%, long half-life inhibitors had significant mean decrease of -0.50% ([-0.83, -0.17], I2 = 88%, p = 0.003); short half-life inhibitors had significant mean increase of +0.36% ([0.03, 0.68], I2 = 3%, p = 0.03).
Interpretation: At the well-controlled HbA1c of the participants, previous literature shows current diabetes treatments have similar HbA1c decreases, so the HbA1c mean difference of long half-life PDE5 inhibitors may indeed be clinically relevant. This suggests future investigation into PDE5 inhibitors as part of combination therapy or as therapy for high HbA1c individuals is needed, especially because of variable risk of biases, homogeneity, and sample sizes in our study.
Funding: None.
Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are extensively evaluated for the risk of suicidal behaviors or ideation; the influence of psychiatric history or obesity on this potential effect remains to be investigated. Therefore, we aimed to assess the association between GLP-1 RA and suicide or suicide attempt, considering these factors.
Methods: Patients ≥18 y who died by suicide or were hospitalized for suicide attempt (2013-2021) with at least one GLP-1 RA dispensing within the 180 preceding days were selected from the French National Health Data System (SNDS). A case-time-control design compared, for each patient, GLP-1 RA exposure in the 30 days preceding the outcome (composite of suicide or suicide attempt) to three earlier 30-day reference periods. Potential exposure trend bias was controlled using up to five time-controls matched on age, sex, psychiatric history, obesity, calendar time. Analyses were adjusted for time-varying confounders. Finally dipeptidyl peptidase-4 (DPP-4) inhibitors were studied as negative controls for potential biases.
Findings: This study included 1102 cases and 5494 controls. Mean case age was 57.4 years (SD 11.4); 44.6% were male, 67.6% had a recent psychiatric history and 51.3% had obesity. GLP-1 RA use was not associated with an increased risk of suicide or suicide attempt (OR, 0.62; 95% CI, 0.51-0.75), with consistent results for DPP-4 inhibitors (0.75; 0.67-0.84). Results obtained according to recent psychiatric history and obesity were comparable.
Interpretation: This large nationwide case-time-control study provides reassurance about the short-term psychiatric safety of GLP-1 RA, showing no specific risk for patients with psychiatric disorders or obesity.
Funding: French Medicines Agency.
Background: Fatigue during the acute phase of dengue infection can persist as post-infectious fatigue (PIF), potentially impacting quality of life. We aimed to determine the prevalence and risk factors of fatigue and PIF among dengue patients.
Methods: This systematic review and meta-analysis was registered in the PROSPERO (CRD42024543058). We searched PubMed, Ovid MEDLINE, Web of Science, Embase, and CINAHL from their inception to June 22, 2024. Observational studies reporting the prevalence of fatigue or PIF among dengue patients were included. We excluded case studies, review articles, conference abstracts, protocols, duplicate publications, and studies without full text. Quality assessment was performed using Hoy's risk of bias tool. Data were analyzed using R software version 4.3.3. A random-effects model pooled prevalence with 95% confidence intervals (CIs). Risk factors were identified using odd ratios (ORs) and 95% CIs or p values. Heterogeneity, moderator analysis, sensitivity analysis, and publication bias were also assessed.
Findings: From 715 identified studies, 40 were included for review. Of these, 37 studies were included in the meta-analysis for fatigue prevalence and nine studies for PIF prevalence, respectively involving 37,790 and 5045 dengue patients. The pooled prevalence of fatigue was 59.0% (95% CI 0.47-0.70), and that of PIF was 20.0% (95% CI 0.10-0.36), with significant heterogeneity but no significant moderators. Sensitivity analysis confirmed the robustness of this meta-analysis. Female sex (pooled OR = 1.65, 95% CI 1.27-2.14), dengue hemorrhagic fever (pooled OR = 1.80, 95% CI 1.02-3.16), and preexisting comorbidities (pooled OR = 2.14, 95% CI 1.36-3.38) were significant risk factors for PIF.
Interpretation: This meta-analysis highlights the high prevalence of fatigue and PIF among dengue patients, with several risk factors identified. Although the study has its limitations, these results can inform future studies to more standardized study designs, improved definitions, and systematic assessment methods for fatigue, PIF, and potential moderators. These are essential to better understand the mechanisms of fatigue in dengue patients and explore potential interventions.
Funding: None.
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