EClinicalMedicine最新文献

Background: Despite progress in reducing global tuberculosis (TB) incidence, ongoing funding disruptions threaten to reverse gains. Timely, accurate diagnosis integrated with rapid treatment is critical to reducing morbidity, mortality, and transmission-but remains costly, particularly for decentralized approaches. As global health budgets tighten, identifying the optimal cost for molecular TB diagnostics instruments is critical to inform scale-up decisions.

Methods: We developed a probabilistic patient pathway model to assess the cost-effectiveness of decentralizing TB testing across primary healthcare facilities in high-burden settings. Scenarios varied by facility testing density (low, medium, high) and anticipated testing volume increases (none, partial, full). We included the effects of instrument downtime and calculated the maximum instrument + warranty prices at which fully decentralized testing would be considered cost-effective at a $500/disability-adjusted life year (DALY) averted threshold.

Findings: Decentralization with increased testing averted up to 23% more DALYs than centralized testing but was not cost-effective at current instrument + warranty prices. Partial decentralization to the largest 20% of facilities approached cost-effectiveness (<$1000/DALY) with full testing increase. For full decentralization to meet the $500/DALY threshold, maximum viable instrument + warranty prices for low-throughput instruments ranged from $0 (no uptake increase) to $410-$6048 (increased testing uptake, low- to high-testing density settings).

Interpretation: At current prices, decentralized molecular TB testing is unlikely to be cost-effective, even with improved uptake, systemwide. However, meaningful reductions in instrument + warranty costs could make both full and partial decentralization viable. As countries face tighter budgets, clear price targets for cost-effectiveness can help guide procurement and investment decisions in TB diagnostics.

Funding: BMGF, Willem Bakhuys Roozenboomstichting.

Background: The number of transgender and gender-diverse (TGD) minors seeking medical care continues to increase, however data on long-term effects of gender-affirming hormone therapy (GAHT) started in adolescence remain limited.

Methods: This single center study (Ghent University Hospital, Belgium) included a cohort of TGD individuals registered female at birth (RFAB, n = 91) and registered male at birth (RMAB, n = 26) who commenced GAHT during adolescence and were followed into adulthood for up to 10 years. Participants were enrolled retrospectively between September 2023 and December 2024. Outcomes assessed cross-sectionally included areal bone mineral density (aBMD), body composition, handgrip strength, and overall life satisfaction. Lifestyle factors such as alcohol and tobacco use, illicit drug use, and physical inactivity were also examined. Retrospective longitudinal data on aBMD and body composition from the start of medical gender-affirming treatment to the moment of study participation were also analyzed.

Findings: Median age at start of GAHT 17.2 (1.7) years for RFAB, 17.0 (2.2) years for RMAB; median GAHT duration at the enrollment 6.0 (2.4) years and 6.6 (3.4) years, respectively. aBMD z-scores remained within the normal range for both RFAB and RMAB participants, with scores aligning more closely to sex registered at birth (SRAB) in RFAB, and to affirmed gender (AG) in RMAB participants. Bone density was influenced by BMI, vitamin D levels, and smoking status, with those who had received GnRH agonists showing lower aBMD at specific sites. No pathological fractures were reported. Body composition shifted toward AG-typical fat and lean mass distribution, with some RFAB individuals exhibiting elevated visceral fat area. Handgrip strength in RFAB participants approached cisgender male reference values, while RMAB individuals showed intermediate values. Psychosocial outcomes indicated generally good self-rated health and life satisfaction, although a subset of participants, particularly among RMAB, reported lower life satisfaction.

Interpretation: Long-term GAHT initiated during adolescence promotes alignment of bone density, body composition, and muscle strength consistent with gender identity, without evidence of clinically significant adverse effects. Modifiable lifestyle factors remain important determinants of skeletal health. Overall, participants reported good general health and life satisfaction.

Funding: This work was supported by a project grant from the Research Foundation Flanders (FWO; GE065819N).

Sharing clinical research data is key for increasing the pace of medical discoveries that improve human health. However, concern about study participants' privacy, confidentiality, and safety is a major factor that deters researchers from openly sharing clinical data even after deidentification. This concern is further enhanced by the evolution of artificial intelligence (AI) approaches that pose an ever-increasing threat to the reidentification of study participants. Here, we discuss the challenges AI approaches create that are blurring the lines between identifiable, and non-identifiable data. We present a concept of pseudo-reidentification, and discuss how these challenges provide opportunities for rethinking open data sharing practices in clinical research. We highlight the novel open data sharing approach we have established as part of the AI-READI (Artificial Intelligence Ready, and Exploratory Atlas for Diabetes Insights) project, one of the four Data Generation Projects funded by the National Institutes of Health Common Fund's Bridge2AI Program.

Background: First-line PD-1 blockade plus chemotherapy has shown significant clinical benefit in metastatic gastric cancer. This study aimed to evaluate the efficacy and safety of sintilimab and S-1 plus intraperitoneal and intravenous paclitaxel as first-line treatment for patients with gastric cancer peritoneal metastasis (GCPM), as well as exploratory predictive biomarker analysis.

Methods: We conducted a single-arm, phase 2 trial at a single centre in China between Jan 1, 2022, and Dec 31, 2023. Patients with laparoscopically confirmed GCPM were treated with sintilimab (200 mg IV on D1), S-1 (40-60 mg orally twice a day for D1-14), and paclitaxel (20 mg/m² intraperitoneally and 50 mg/m² IV on D1 and 8), in cycles every 3 weeks. The primary efficacy endpoint was overall survival (OS) rate at 1 year. This study is registered with ClinicalTrials.gov, NCT05204173.

Findings: 38 patients were included. The median progression-free survival was 14.6 months (95% CI: 10.8-not reached [NR]) and OS was 18.4 months (95% CI: 15.0-NR). The post-hoc analysis showed the objective response rate was 57.9% and disease control rate was 94.7%. The most common treatment-related adverse events were anemia, glutamic oxaloacetic transaminase elevated, and leukopenia. Longitudinal analyses of plasma circulating tumor DNA showed that low baseline human genome equivalent was associated with favorable OS.

Interpretation: First-line sintilimab and S-1 plus intraperitoneal and intravenous paclitaxel showed promising therapeutic efficacy in patients with GCPM.

Funding: Natural Science Foundation of Shanghai, Shanghai Municipal Health Commission, National Science Foundation of China, and the Shanghai Hospital Development Center.

[This corrects the article DOI: 10.1016/j.eclinm.2025.103424.].

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: Routine antibiotic prophylaxis against pneumocystis jirovecii pneumonia (PJP) is recommended during concurrent temozolomide and radiotherapy (TMZ-RT) for glioma based on early small studies. However, true PJP risk may be far lower, raising questions about the value and harms of universal prophylaxis.

Methods: We conducted a systematic review (PROSPERO: CRD42021292396) of studies reporting PJP incidence among glioma patients treated with TMZ-RT. MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched from inception to May 1, 2025. Outcomes included overall PJP incidence and rates stratified by prophylaxis, corticosteroid exposure, and lymphopenia.

Findings: Of 3791 records, 35 studies (13,637 patients, 12,301 received TMZ-RT) met eligibility criteria. Across 24 studies confirming PJP, 71 cases occurred among 12,056 TMZ-RT patients-a pooled incidence of 0.74% (95% CI, 0.59-0.93%) with minimal heterogeneity (Q = 23.3, p = 0.44; I² = 1.4%). Seventeen studies detailed prophylaxis: 55.1% (2942/5341) of patients received it; PJP incidence was 0.8% (14/1765) with versus 0.3% (9/2719) without prophylaxis. Baseline corticosteroid exposure was reported in 13 studies (n = 5908: median 49.5%, range 27.3%-82.3%), and grade 3-4 lymphopenia in 15.2% (319/2102) of TMZ-RT patients. Incomplete study-level reporting precluded robust risk factor-adjusted analyses.

Interpretation: Across heterogeneous populations and study designs, the pooled PJP incidence associated with TMZ-RT was 0.74% (95% CI, 0.59-0.93%). Due to the heterogeneity in study populations and designs, lack of standardized diagnostic confirmation, and incomplete reporting of steroid administration, this finding should be interpreted with caution. Currently available evidence suggests the risk of PJP is lower than the commonly cited 3.5% threshold for prophylaxis. Well-designed prospective studies are needed to clarify true infection risk and inform prophylaxis decisions.

Funding: The Deanship of Graduate Studies and Scientific Research at Qassim University provided financial support for the article processing charge (APC) of this manuscript.

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.