EClinicalMedicine最新文献

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: People with diabetes are at increased risk of hospitalisation, morbidity, and mortality following SARS-CoV-2 infection. Long-term outcomes for people with diabetes previously hospitalised with COVID-19 are, however, unknown. This study aimed to determine the longer-term physical and mental health effects of COVID-19 in people with and without diabetes.

Methods: The PHOSP-COVID study is a multicentre, long-term follow-up study of adults discharged from hospital between 1 February 2020 and 31 March 2021 in the UK following COVID-19, involving detailed assessment at 5 and 12 months after discharge. The association between diabetes status and outcomes were explored using multivariable linear and logistic regressions.

Findings: People with diabetes who survived hospital admission with COVID-19 display worse physical outcomes compared to those without diabetes at 5- and 12-month follow-up. People with diabetes displayed higher fatigue (only at 5 months), frailty, lower physical performance, and health-related quality of life and poorer cognitive function. Differences in outcomes between diabetes status groups were largely consistent from 5 to 12-months. In regression models, differences at 5 and 12 months were attenuated after adjustment for BMI and presence of other long-term conditions.

Interpretation: People with diabetes reported worse physical outcomes up to 12 months after hospital discharge with COVID-19 compared to those without diabetes. These data support the need to reduce inequalities in long-term physical and mental health effects of SARS-CoV-2 infection in people with diabetes.

Funding: UK Research and Innovation and National Institute for Health Research. The study was approved by the Leeds West Research Ethics Committee (20/YH/0225) and is registered on the ISRCTN Registry (ISRCTN10980107).

Background: Targeted next-generation sequencing (tNGS) is promising alternative to phenotypic drug susceptibility testing (pDST) for detecting drug-resistant tuberculosis (DRTB). This study explored the potential cost-effectiveness of tNGS for the diagnosis of DR-TB across 3 settings: India, South Africa and Georgia.

Methods: To inform WHO guideline development group (GDG) on tNGS we developed a stochastic decision analysis model and assessed cost-effectiveness of tNGS for DST among rifampicin resistance individuals. We also assessed tNGS as initial test for TB drug resistance in bacteriologically confirmed TB. Diagnostic accuracy and cost data were sourced from a systematic review conducted for GDG, covering studies published until September 2022. The primary outcome was incremental cost (2021 US$) per disability-adjusted life year (DALY) averted.

Findings: tNGS when compared with in-country DST, tNGS proved cost-effective in South Africa (ICER: $15,619/DALY averted, WTP: $21,165) but not in Georgia (ICER: $18,375/DALY averted, WTP: $15,069). In India, tNGS dominated in-country DST practice, providing greater health impact at lower cost. When comparing tNGS with universal pDST, tNGS was dominated by pDST in all three countries. In Georgia, using tNGS as initial test for TB drug-resistance compared to Xpert MTB/Rif followed by pDST appeared cost-effective. Scenario with 50% reduction in tNGS test kit costs made tNGS cost-effective across all three countries, while a high Bedaquiline resistance prevalence (30%) led to a worsening cost-effectiveness.

Interpretation: tNGS may be cost-effective in India, South Africa and Georgia when comprehensive DST is not routinely performed. Thus, existing DST practice and healthcare infrastructure should be considered before implementation and scale-up of tNGS.

Funding: Global Tuberculosis Program, World Health Organization (2022/1249364-0).

Background: Endemic in more than 20 countries, Chagas disease affects 6.3 million people worldwide, leading to 28,000 new infections and 7700 deaths each year. Previous meta-analyses on antiparasitic treatment need updates to encompass recent studies and to assess key clinically meaningful endpoints. This study aims to evaluate the impact of antitrypanosomal therapy in preventing or reducing disease progression and mortality in chronic Chagas disease.

Methods: We performed a systematic review and meta-analysis of studies reporting the cardiovascular outcomes of antitrypanosomal therapy in patients with chronic Chagas disease. We searched Ovid Embase, Ovid MEDLINE, Ovid Global Health, Scopus, Web of Science Core Collection, Cochrane Library, PubMed, Google Scholar, and Virtual Health Library databases from inception to May 18, 2024. We included aggregated data from randomized controlled studies and observational reports (full articles and abstracts) featuring antiparasitic interventions with benznidazole or nifurtimox compared to a control group. Primary outcomes were electrocardiogram (ECG) changes, disease progression, cardiovascular death, and overall mortality. A customized risk of bias scale assessed the methodological quality of studies, and a random-effects model estimated the pooled risk ratios. This investigation was registered in PROSPERO (CRD42023495755).

Findings: Out of 4666 reports screened, 23 met the pre-specified inclusion criteria (8972 participants). Compared to no treatment or placebo, antiparasitic treatment led to a reduction in i) ECG changes (17 studies, 4994 participants: risk ratio (RR): 0.48, 95% CI 0.36-0.66, p < 0.001; I ² = 76.4%) with a number needed to treat (NNT) of 5; ii) disease progression (12 studies, 5722 participants: RR: 0.35, 95% CI 0.23-0.51, p < 0.001; I ² = 72.4%) NNT of 6; iii) cardiovascular death (7 studies, 5662 participants: RR: 0.44, 95% CI 0.21-0.95, p = 0.04; I ² = 50.5%) NNT of 22; and iv) overall mortality (10 studies, 7694 participants: RR: 0.54, 95% CI 0.34-0.87, p < 0.001; I ² = 60%) NNT of 23.

Interpretation: We found compelling evidence that antiparasitic treatment significantly reduces the risk of ECG changes, disease progression, cardiovascular death, and overall mortality in chronic Chagas disease. Although the quality of evidence ranges from low to intermediate, with considerable heterogeneity across studies, the potential benefits are substantial. These findings support the broader use of trypanocidal therapy in the management of Chagas disease, though further research remains necessary.

Funding: This study had no funding source.

Background: Female Lynch syndrome carriers have an increased risk of developing endometrial cancer. Regardless, research on endometrial carcinoma tumorigenesis is scarce and no uniform, evidence-based gynaecological management guidelines exist. We therefore described gynaecological surveillance and surgery outcomes in a nation-wide Lynch syndrome cohort.

Methods: For this retrospective cohort study, female Lynch syndrome carriers, prospectively registered in the Dutch Lynch syndrome database (StOET), were included up to February 28th 2022. Carriers were linked to the Dutch national pathology (PALGA) database. The number of carriers with/without gynaecological surveillance, number of index carriers with endometrial carcinoma before Lynch syndrome diagnosis were assessed, as well as uptake of risk-reducing surgery and characteristics of endometrial carcinomas including the requisite for adjuvant therapy according to current guidelines. Overall survival after endometrial carcinoma diagnosis was analyzed using Kaplan Meier time to event analyses, cumulative incidence was calculated after adjusting for competing risks (death and prophylactic hysterectomy).

Findings: In total, 1046 registered female Lynch syndrome carriers were eligible for surveillance, of whom 313 (30.0%) did not have surveillance and 21.4% (n = 224 of 1046) opted for prophylactic hysterectomy. In carriers with surveillance, more cases of endometrial carcinoma and hyperplasia were found than in those without (37 endometrial carcinomas (7.3%) and 28 hyperplasias (5.5%) in 506 carriers with surveillance versus 14 (2.6%) and 4 (0.7%) in 540 carriers without surveillance, respectively); carriers with surveillance were generally younger than those without (median 56 years [IQR 48-65] versus median 65 years [IQR 49-75] at database assembly, respectively; p < 0.0001). Endometrial carcinomas were predominantly of endometrioid type and FIGO stage IA, regardless of surveillance. Adjuvant external beam radiotherapy was required in one patient in both groups. Overall survival after endometrial carcinoma diagnosis did not differ between carriers with or without surveillance or carriers with endometrial carcinoma before LS diagnosis (p = 0.51). For all endometrial carcinomas together, including index carriers, cumulative incidence was 22.7% at age 70.

Interpretation: In a nation-wide cohort of Lynch syndrome carriers, nearly one-third of eligible carriers did not undergo gynaecological surveillance. Endometrial carcinomas diagnosed during surveillance were slightly more often stage FIGO IA, but this did not seem to substantially decrease the requisite for adjuvant therapy or affect overall survival, questioning effectiveness of current gynaecological management. Prospective research should further assess this, as well as patient preferences.

Funding: None.

This systematic review evaluated the effectiveness of community-wide screening for pulmonary tuberculosis (TB) in high-burden areas by analysing randomised controlled trials (RCTs). The review focused on interventions offering TB screening to entire communities, comparing them to standard care or alternative approaches. The main outcome assessed was microbiologically confirmed TB diagnoses, including rates and prevalence. We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, WHO Global Index Medicus, Web of Science, and trial registries up to 27 May 2024, without language restrictions. Screening, data extraction, and risk of bias assessment were done in duplicate. Results were not pooled. Certainty of the evidence was assessed using GRADE. PROSPERO: CRD42023453356. We included six cluster-RCTs after screening 2460 titles/abstracts and 86 full-text articles. The evidence for symptom screening was very uncertain. We found that sputum smear microscopy screening may result in little to no difference in the prevalence of culture-confirmed TB (n = 962,655, RR 1.09; 95% CI: 0.86-1.38, 1 RCT, low certainty evidence). Community-wide nucleic acid amplification test (NAAT) screening probably reduces the prevalence of NAAT-positive TB (n = 105,108, RR 0.56; 95% CI: 0.40-0.78, 1 RCT, moderate certainty evidence). Community-wide screening for pulmonary TB may reduce TB prevalence if done annually with an accurate screening test and high coverage.

With the impending 'retirement' of bronchial thermoplasty (BT) for the treatment of patients with asthma, there is much to learn from this real-world experiment that will help us develop more effective future therapies with the same primary target i.e., airway smooth muscle (ASM) remodelling. This viewpoint discusses initial controversy surrounding BT (lack of an effect on forced expiratory volume in 1 s), its underutilisation, and importantly how non-standard diagnostics successfully demonstrated therapeutic response which escaped traditional lung function metrics. It is anticipated that the next iteration of BT (likely in a drug form) will have an overall greater effect on the health care system by virtue of evoking ASM remodelling as a treatable trait, and after appropriately drawing on lessons learned from the ∼fifteen-year BT saga.