EClinicalMedicine最新文献

Background: Effective weight reduction interventions may significantly reduce obesity-related atherosclerotic cardiovascular disease (ASCVD) risk. However, evidence on the association between optimal body mass index (BMI) target and long-term ASCVD risk was limited.

Methods: Pooled individual-level data from participants with obesity/overweight randomized to tirzepatide or placebo in SURMOUNT-1 (December 2019-April 2022; NCT04184622), -3 (March 2021-April 2023; NCT04657016), and -CN trials (September 2021-December 2022; NCT05024032) were analyzed. Ten-year ASCVD risk was calculated using the American College of Cardiology/American Heart Association Pooled Cohort Equations. A mixed model for repeated measures analysis was used to compare percent change in ASCVD risk from baseline by achieved BMI group (<25 kg/m², ≥25 kg/m²) at trial end, with terms including achieved BMI group, time point, achieved-BMI-group-by-time-point interaction, and baseline covariates.

Findings: Among 2691 participants included, 495 (18.4%) achieved BMI <25 kg/m² at trial end. In addition to a significantly higher proportion being treated with tirzepatide (98.2% vs 66.8%), the BMI <25 kg/m² group also had a higher proportion of females and lower mean BMI at baseline compared with the BMI ≥25 kg/m² group (P < 0.001 for all). After adjusting for baseline covariates, relative to baseline, participants achieving BMI <25 kg/m² had a significantly greater percent reduction in predicted ASCVD risk (39.4% vs 10.6%, P < 0.001) compared to the BMI ≥25 kg/m² group. Among those with baseline intermediate-to-high ASCVD risk, reduction remained greater in the BMI <25 kg/m² group (25.6%) than the BMI ≥25 kg/m² group (9.0%; P < 0.001). Significantly greater improvements were also observed in blood pressure and lipids for the BMI <25 kg/m² group (P < 0.001).

Interpretation: Achieving BMI <25 kg/m², primarily with tirzepatide, was associated with a significantly greater 10-year ASCVD risk reduction compared with those whose BMI remained at 25 kg/m² or greater. These findings suggest potential cardiovascular benefits associated with targeting BMI <25 kg/m² in the long-term weight management.

Funding: This study was funded by Eli Lilly and Company.

Background: Survivin, an inhibitor of apoptosis protein (IAP), is highly expressed in various cancers but has weak immunogenicity as a self-derived tumour-associated antigen (TAA). OVM-200, a survivin recombinant overlapping peptide (ROP) vaccine, consists of overlapping peptides linked by the target sequence (LRMK) for cathepsin S, preserving T-cell and most antibody epitopes. OVM-200 elicits both cellular and humoral immune responses against survivin-expressing cancer cells. This phase 1a, multicentre, open-label trial (OVM-200-100) evaluates OVM-200 as a therapeutic vaccine in patients with non-small cell lung, ovarian, and prostate cancer. This Phase 1 trial is also the first time the ROP technology platform has been used in human trials.

Methods: Twelve eligible patients received three subcutaneous OVM-200 doses at 2-week intervals using a 3 + 3 dose-escalation design. Four dose levels (250, 500, 1000, and 2000 μg) were tested to determine the optimal dose for phase 1b. The primary endpoint was safety and tolerability, while secondary endpoints included immunogenicity (antibody and T-cell response) and tumour response (RECIST criteria). This trial was registered with ClinicalTrials.gov (NCT05104515) and EudraCT (2021-001545-12) and took place from 28/09/2021 to 04/05/2023.

Findings: OVM-200 was well tolerated, with no serious adverse drug reactions (ADRs) or dose-limiting toxicities (DLTs). All adverse events were Grade 1 injection site reactions (ISRs). The 2000 μg dose group achieved the highest median anti-survivin IgG titre (1:327,680) at the end of the study (EOS) and a median ELISpot T cell response of 1282 SFU per million cells on day 22. Disease stabilisation (SD) was observed in 6 of 12 patients (50%), including all 3 patients (100%) in the 2000 μg group, some of which were stabilisations of limited duration. Based on these findings, the 2000 μg dose was selected for further evaluation in phase 1b.

Interpretation: OVM-200 is well tolerated and induces a robust humoral response, with a considerable cellular response and preliminary evidence of disease stabilisation. Phase 1b is ongoing to further evaluate its safety and efficacy at the selected dose.

Funding: Oxford Vacmedix UK Ltd.

Background: This single-arm, phase 2 trial investigated the safety, efficacy, and biomarkers associated with combining nivolumab, an immune checkpoint inhibitor, with definitive chemoradiotherapy in patients with operable or inoperable oesophageal squamous cell carcinoma (OSCC) because these have not been well established.

Methods: In this multicentre, single-arm, phase 2 feasibility trial, eligible patients (aged 20-75 years) with histologically confirmed OSCC, Eastern Cooperative Oncology Group performance status of 0-1, and adequate organ and bone marrow functions were enrolled from five Japanese institutions. The treatment involved concurrent chemoradiotherapy (cisplatin and 5-fluorouracil) with nivolumab, followed by maintenance nivolumab for up to 1 year. The primary endpoint was safety, defined as ≤10% incidence of grade ≥4 non-haematological toxicity and ≤15% incidence of grade ≥3 pneumonitis. Secondary endpoints included complete response, progression-free survival, and overall survival. Biomarker analyses of 51 immuno-related genes were performed on pretreatment biopsy specimens. This trial is registered in the Japan Registry of Clinical Trials, jRCT1091220408, and was terminated early due to slow patient enrolment.

Findings: Between January 2019 and September 2021, 42 patients were enrolled and included in the safety analysis set, whereas 41 patients who received at least one post-baseline tumour assessment comprised the efficacy analysis set. The trial met its primary safety endpoint with only 5% of patients (2 of 41) experiencing grade 3 pneumonitis. The most common adverse events of were oesophagitis, constipation, and lymphopenia, and no treatment-related deaths occurred. 1-year overall survival was 92.7% (95% CI 79.0-97.6), and 1-year progression-free survival was 65.4% (95% CI 48.6-77.9). The overall complete response rate was 73% (30 of 41; 95% CI 58-84%). Exploratory biomarker analyses were conducted to investigate immune-related gene expression, but these findings should be regarded as hypothesis-generating.

Interpretation: Nivolumab combined with definitive chemoradiotherapy is feasible and showed acceptable toxicity in patients with OSCC. Further validation of exploratory biomarker findings is warranted in larger controlled studies.

Funding: Ono Pharmaceutical.

Background: Cutaneous leishmaniasis (CL) is a vector-borne parasitic disease endemic in Palestine, especially in Jericho and Jenin, and remains a major public health concern. This study aimed to identify risk and protective factors for CL infection in the West Bank.

Methods: We conducted a case-control study across multiple districts of the West Bank between February 2024 and February 2025. The study included 96 patients diagnosed with CL (cases) and 96 matched controls from the same localities, matched by age and sex. Case data were retrieved from Ministry of Health records, while controls completed a self-administered questionnaire. Sociodemographic, environmental, and behavioral variables were collected. Statistical analysis was performed using Epi Info 7.2.4.0, with odds ratios (OR) and 95% confidence intervals (CI) calculated, and multivariate logistic regression. Fisher's exact test and chi-square test were applied, with P < 0.05 considered statistically significant.

Findings: A total of 192 participants were enrolled (96 cases, 96 controls), with a median age of 14 years (IQR 6-35). Children under 14 years accounted for 53% of cases. Females represented 49% of cases and 54% of controls. Most cases resided in villages (61%) compared to urban areas. Patients and their parents had significantly lower educational attainment compared to controls P < 0.001 . Environmental risk factors included the presence of rock hyrax near homes (OR = 8.56, 95% CI: 4.05-18.08), caves and crevices (OR = 8.98, 95% CI: 4.53-17.82), domestic animals (OR = 3.34, 95% CI: 1.75-6.38), and domestic dogs (OR = 2.41, 95% CI: 1.28-4.52). Protective factors included painting interior walls (OR = 0.27, 95% CI: 0.14-0.53) and pesticide spraying in households (OR = 0.13, 95% CI: 0.05-0.35). After adjusting for other covariates in the multivariate logistic regression analysis, only the father's years of education, household size, and the presence of rock hyrax in the residential area, along with stone fences around the house, remained significantly associated with CL.

Interpretation: CL remains endemic in parts of Palestine, particularly among children and rural populations. Socioeconomic and environmental factors play a critical role, highlighting the need for health education, improved housing, and vector control to reduce transmission.

Funding: This study received no funding.

Background: The neuroprotective effects of normobaric hyperoxia (NBHO) for treating acute ischemic stroke (AIS) remain unclear. This systematic review and meta-analysis evaluated the safety and functional outcomes of NBHO in AIS patients.

Methods: We searched major databases until November 13, 2025, for randomized controlled trials (RCTs) comparing NBHO (≥2 h within 24 h of onset) with room air or low-flow oxygen in adult patients with AIS. Two reviewers independently screened studies, with disagreements resolved by a third reviewer. The primary outcome was functional independence (modified Rankin Scale [mRS] scores 0-2) at three months. Secondary outcomes included reduced disability (ordinal shift across mRS grades 0-6), early neurological recovery (changes in National Institutes of Health Stroke Scale [NIHSS] within 7 days), and infarct volume changes. Safety outcomes included 90-day mortality, symptomatic intracranial hemorrhage (sICH), and pneumonia. Outcomes eligible for meta-analysis were analyzed using a random-effects model (Paule-Mandel heterogeneity estimation) with Hartung-Knapp-Sidik-Jonkman (HKSJ) adjustment for the primary analysis and without HKSJ adjustment for secondary analysis. Registration: PROSPERO (CRD42024584308).

Findings: Eight RCTs involving 804 participants were included. Six studies (n = 746) showed that NBHO improved functional independence (RR 1.28, HKSJ 95% CI 1.07-1.51; P = 0.015), reduced disability (cOR 1.72, HKSJ 95% CI 1.35-2.20; P = 0.002), and lowered mortality (RR 0.62, HKSJ 95% CI 0.39-0.99; P = 0.047) at three months. NBHO also decreased NIHSS scores at 72 h (MD -2.18, HKSJ 95% CI -3.45 to -0.90; P = 0.009) across five studies, though effects at other timepoints were significant only in secondary analysis. NBHO did not increase the risk of sICH (RR 0.79, HKSJ 95% CI 0.45-1.40; P = 0.347). Among patients receiving endovascular therapy (five studies), NBHO did not increase the risk of pneumonia (RR 0.97, HKSJ 95% CI 0.61-1.55; P = 0.863). Results for infarct volume and subgroup analyses were inconclusive due to limited data.

Interpretation: In this meta-analysis of predominantly Chinese populations, NBHO may improve functional independence, reduce disability, and lower mortality at three months, and promote early neurological recovery at 72 h without compromising safety. Generalizability to other ethnic groups requires confirmation.

Funding: This work is supported by the Cultivation Program of Clinical Research Special Project of The Second Affiliated Hospital of Army Medical University (Grant No. 2024F037).

Background: The HOST-IDEA trial demonstrated non-inferiority of 3-to-6-month dual antiplatelet therapy (DAPT) to 12-month DAPT for net adverse clinical event (NACE) at 1 year in patients undergoing percutaneous coronary intervention (PCI) with third-generation drug-eluting stents (DES). We evaluated the long-term outcomes of abbreviated antiplatelet therapy following PCI with third-generation DES.

Methods: In the open-label, adjudicator-blinded, multicentre, randomised HOST-IDEA trial, 2013 patients from 37 hospitals in South Korea were randomly allocated to 3-to-6-month (n = 1002) or 12-month (n = 1011) DAPT between January 2016 and May 2021. The primary outcome was NACE at 3 years, comprising cardiac death, target vessel myocardial infarction (TVMI), clinically driven target lesion revascularisation (CD-TLR), stent thrombosis, and major bleeding (Bleeding Academic Research Consortium type 3 or 5). Major secondary outcomes were target lesion failure (TLF)-comprising cardiac death, TVMI, and CD-TLR-and major bleeding at 3 years. To evaluate the efficacy and safety of >1-year DAPT, patients event-free at 1 year were classified into >1-year and ≤1-year DAPT groups and matched using a propensity score. These 3-year clinical outcomes were prespecified in the published protocol as mandatory clinical follow-up. HOST-IDEA is registered with ClinicalTrials.gov, NCT02601157.

Findings: At 3 years, clinical follow-up was completed in 955 patients (95.3%) and 966 patients (95.5%) in the 3-to-6-month and 12-month DAPT groups, respectively. The median follow-up duration was 1095 days (IQR 1095-1095). The primary outcome occurred in 7.7% and 8.2% of patients in the 3-to-6-month and 12-month DAPT groups, respectively (HR 0.94; 95% CI 0.69-1.29; P = 0.71). The risks of TLF (HR 0.92; 95% CI 0.62-1.36; P = 0.66) and major bleeding (HR 0.96; 95% CI 0.59-1.56; P = 0.88) were comparable between the two groups. Among patients who were event-free at 1 year, 583 remained on DAPT, while 1259 switched to single antiplatelet therapy within the 1 year. In the matched cohort, there was some evidence of a higher risk of TLF in the >1-year DAPT group (HR 2.56; 95% CI 0.99-6.60; P = 0.05), whereas major bleeding risk was significantly higher with >1-year DAPT (HR 4.44; 95% CI 1.26-15.57; P = 0.02).

Interpretation: 3-to-6-month and 12-month DAPT showed comparable 3-year clinical outcomes in patients undergoing PCI with third-generation DES. However, extending DAPT beyond 1 year was associated with increased major bleeding without additional ischemic benefits. Further studies are warranted to validate these findings and identify patient subsets who may benefit from extended DAPT.

Funding: Biotronik Korea (Seongnam si, Gyeonggi-do, South Korea) and B. Braun Korea (Seoul, South Korea).

Background: The mistreatment of women during facility-based childbirth is widespread in sub-Saharan Africa and has a negative impact on women's mental health. We aimed to examine the association between childbirth-related mistreatment and postpartum depression in Ethiopia and Guinea.

Methods: Between May 2023 and February 2024, we conducted a prospective longitudinal survey of pregnant women recruited from 22 health facilities in Addis Ababa, Ethiopia, and 20 health facilities in Conakry, Guinea. Participants were surveyed during the third trimester in health facilities and were followed up in the community for a second survey, which was conducted between 6 and 16 weeks postpartum. Depression was assessed using the Edinburgh Postnatal Depression Scale (EPDS), and mistreatment was measured across seven categories. We used multilevel mixed effects Poisson regression to assess the association between the number of mistreatment categories experienced and women's postpartum depression scores.

Findings: Of the 859 women enrolled during pregnancy, 711 women completed the postpartum survey. 87.4% of women in Addis Ababa and 71.2% in Conakry had experienced at least one category of mistreatment. Symptoms suggestive of postpartum depression (EPDS ≥11) were reported by 20.9% of women in Addis Ababa and 31.0% in Conakry. After adjusting for antepartum depression, intimate partner violence, and other sociodemographic, obstetric, and health service-related characteristics, experience of each additional mistreatment category was associated with a 5% increase in women's postpartum depression scores (adjusted incidence rate ratio [AIRR] = 1.05, 95% CI: 1.01-1.09). Among women without symptoms suggestive of antepartum depression (EPDS <11), the effect was even greater, with an 11% increase in postpartum depression scores (AIRR = 1.11; 95% CI: 1.06-1.17).

Interpretation: The strong association between mistreatment and postpartum depression, particularly among women without antenatal depressive symptoms, highlights the potential causal role of mistreatment and underscores the urgent need for coordinated, evidence-informed, and context-appropriate strategies to promote respectful maternity care and safeguard women's mental health.

Funding: Research Foundation Flanders (FWO file number 1261923N) and the Institute of Tropical Medicine (ITM), Antwerp, Belgium, with support from the Flemish Government Department of Economy, Science and Innovation (EWI) and the Belgian Federal Directorate-General for Development Cooperation and Humanitarian Aid (DGD).