Chen W et al. · Jul 1, 2026
Chimeric Antigen Receptor (CAR)-T cell is an immunotherapy which revolutionised the treatment of relapsed/refractory lymphoma and leukaemia. It is shown to have a higher response rate, higher mid-to-long term overall survival, and lower toxicity than standard treatments. However, due to a lack of dose-limiting toxicity (DLT) and unclear dose-effect relationship, traditional phase I designs of clinical trials cannot lead to accurate selections of the optimal dose (OD). Beside clinical outcomes, the CAR-T cell expansion from serial blood samples is measured at various time points. We propose a novel early phase dose-finding design for CAR-T cells, using both toxicity and activity endpoints to locate the OD. The number of CAR-T cells measured in the peripheral blood is used to indicate activity, which is more sensitive than the short-term clinical responses traditionally used. A Bi-Exponential model is used for the repeated measures of the number of cells for each patient, and is estimated under a Bayesian framework. The model is motivated by biological concerns and is flexible enough to accommodate different shapes of the cell-expansion curve. Three criteria for activity are considered: (1) the number of cells at specific time points, (2) the duration before all cells are eliminated, (3) the area under the cell-expansion curve. Simulation studies show that the OD can be selected with high accuracy even under small sample sizes.
Medicine
Li PWC et al. · Jul 1, 2026
Background ICU survivors frequently develop post-intensive care syndrome (PICS), a cluster of persistent physical, cognitive and psychological impairments that substantially impair recovery and quality of life. Existing rehabilitation approaches are predominantly monomodal and exercise-focused, yielding inconsistent outcomes and failing to address the multidimensional burden of PICS adequately. Aim To evaluate the feasibility and preliminary efficacy of COMBAT-ICU, a home-based Combined Activity and Cognitive Intervention for ICU survivors at risk of PICS. Study design A parallel, three-arm, assessor-blinded pilot randomised controlled trial randomised 36 ICU survivors (1:1:1) to COMBAT-ICU-an 8-week blended program of progressive physical exercise and computerised cognitive training delivered via supervised home visits and online sessions-an exercise-only group or an attention control group. The primary outcomes were feasibility (recruitment, retention and intervention adherence) and safety; secondary exploratory outcomes encompassed PICS severity, physical capacity, cognition, mental health and health-related quality of life (HRQoL). Results COMBAT-ICU was feasible and safe (36 ICU survivors randomised), with no serious adverse events recorded, retention exceeding 82% at follow-up and session adherence exceeding 90%. COMBAT-ICU produced significantly greater reductions in PICS severity versus attention control at post-intervention (p = 0.014, d = -0.50) and follow-up (p = 0.043, d = -0.45). It also yielded clinically meaningful moderate-to-large effect sizes for walking endurance, global cognition, short-term memory and HRQoL index scores compared with attention control and consistently outperformed exercise-only across cognitive and HRQoL domains. Between-group differences in anxiety and depressive symptoms were small across all active groups. Conclusions COMBAT-ICU is feasible and shows promising preliminary efficacy in mitigating PICS. Integrating cognitive and physical training within a home-based blended delivery model may confer synergistic benefits beyond exercise alone, providing domain-specific effect size estimates and a compelling rationale for definitive multicentre trials. Relevance to clinical practice Multidomain home-based rehabilitation is a viable post-discharge strategy for ICU survivors. COMBAT-ICU offers an evidence-informed, scalable framework to enhance survivorship care, pending confirmation in larger, fully powered trials. Trial registration The trial was registered at ClinicalTrials.gov (NCT06117761).
Medicine
Khan MA et al. · Jul 1, 2026
Background and objective Cutaneous leishmaniasis (CL) remains a significant public health concern in endemic regions of Pakistan, particularly in ecologically diverse and resource-limited areas. This study aimed to investigate the epidemiology, risk factors, lesion characteristics, seasonal trends and spatial distribution of CL in District Bajaur, Khyber Pakhtunkhwa, Pakistan. Methods A cross-sectional observational study was conducted in 2022, including clinically suspected and laboratory-confirmed CL cases from all nine tehsils of District Bajaur. Demographic information, lesion characteristics (site, type and number), season of presentation and regional distribution were collected using a structured questionnaire. Statistical analyses included univariate and multivariate logistic regression, multinomial regression, Poisson regression, stratified analyses and interaction modelling. Spatial clustering was evaluated using Z-scores, Moran's I statistics and GIS-based risk mapping. Results CL prevalence was significantly higher among males, younger individuals, unmarried participants and during the summer season. Lesions were predominantly located on exposed body parts, especially the hands and face, with dry lesions and single-lesion presentations being most common. Multivariate analysis identified male gender, younger age, unmarried status, summer season, dry lesion type and single lesions as independent risk factors. Stratified and interaction analyses indicated an elevated risk among young males during the summer. Spatial analysis revealed significant clustering of cases, with Khar, Loe Mamund and Salarzai identified as high-risk tehsils. A clinician-friendly risk scoring system was developed to estimate individual infection probability. Conclusion CL in District Bajaur is influenced by a complex interaction of demographic, clinical, seasonal and spatial factors. These findings emphasize the importance of targeted surveillance, vector control strategies and risk-based interventions to reduce disease burden in endemic regions.
Medicine
Yuan Q et al. · Jun 24, 2026
Objective Adenosquamous carcinoma (ASC) of the lung, containing both adenocarcinoma (AC) and squamous cell carcinoma (SCC) components, is associated with aggressive behavior and poor prognosis. Due to overlapping imaging features with AC and SCC, its preoperative diagnosis remains challenging. This study aimed to compare CT and pathological characteristics among ASC, AC, and SCC; identify key differentiators. Methods This retrospective study included 27 patients with pathologically confirmed ASC who underwent surgical resection from November 2018 to January 2025. Forty cases each of AC and SCC, matched for age, sex, and smoking history, were selected for comparison. Clinical, radiological, and pathological features were analyzed. Variables with statistical significance (P Results Compared with SCC, ASC lesions were more peripheral and associated with higher distance ratios (DR), pleural retraction, spiculation, and lymph node metastasis (LNM). Compared with AC, ASC tumors were larger, more often solid, and exhibited lobulation, bronchial cutoff sign, and advanced staging. Among the evaluated analyses, the combined pathology-imaging approach showed the highest discriminatory performance, with AUCs of 0.909 (ASC vs SCC) and 0.900 (ASC vs AC). LNM and DR were more strongly associated with ASC relative to SCC, whereas larger tumor size, ill-defined margins, and advanced stage were more strongly associated with ASC relative to AC. Conclusion Certain CT imaging features, especially DR and LNM, were associated with ASC and may provide useful information for preoperative radiological assessment and subtype stratification.
Medicine
White DL et al. · Jun 15, 2026
Background U.S. military veterans deployed to the Persian Gulf to serve in the 1990-1991 Gulf War (GWVs) have expressed concerns about potential increased risk of experiencing adverse COVID-related health outcomes given broad near-unique exposure to multiple diverse toxic agents during deployment and ongoing ~30% prevalence of Gulf War Illness (GWI+), a chronic, medically unexplained multi-symptom disorder associated with inflammation and immune dysregulation. Methods We conducted a retrospective study in the largest nationwide research cohort of 1990-1991Gulf War era veterans (GWEVs) enrolled in the VA's nationwide Million Veteran Program (MVP) to interrogate: 1) if deployed GWVs had increased risk for testing positive for novel SARS-CoV-2 infection (COVID+), COVID-related hospitalization, ICU admission, or death in 2020 (pre-vaccine period); and 2) if deployed GWVs with GWI+ had particularly increased susceptibility. COVID outcomes ascertained using VA's COVID Data Resource; GWI+ determined using CDC severe criteria in surveyed GWV subcohort. Findings Our overall GWEV cohort (N = 136,868) had mean age 60.7 years, with 84% male, 27% African-American, and 22% deployed; n = 26,141 COVID-tested in 2020. COVID test-positivity (COVID+) was slightly higher in deployed GWVs (18.8% vs. 17.2% in non-deployed GWEVs, p = 0.005). In multivariable logistic models, there were neither strong nor significant associations between deployment and testing COVID+, COVID-related hospitalization or ICU admission (adjusted [adj] ORs ranged from 0.90-1.06, all p-values >0.05), nor significant differences in COVID-related mortality. Preliminary analysis in our pre-pandemic surveyed deployed GWV subcohort (N = 1,643 COVID-tested, 39% GWI+, 18.4% testing-COVID+, 10.6% COVID+ hospitalized) suggested GWI+ potentially associated with significantly increased COVID-hospitalization risk (adjOR=2.21, 95%CI: 1.02-4.81, p = 0.04); though no significant excess was observed for COVID-related ICU admission or mortality. Conclusions Our findings demonstrated that overall deployment to serve in the 1990-1991 Gulf War was not associated with increased COVID-related health risks among Gulf War era veterans using VA healthcare system in early pre-vaccine pandemic era. Preliminary findings suggesting association between Gulf War Illness and potential increased COVID-related hospitalization risk among deployed Gulf War veterans in the early pandemic era warrants replication and ongoing evaluation to assess if it persists in the era of COVID vaccination, oral anti-COVID medications and new viral variants.
Medicine
Hernandez-Romieu AC et al. · Jun 12, 2026
The representativeness and timeliness of sentinel surveillance for endemic and emerging arboviral and respiratory diseases in low-resource settings are understudied. We compared laboratory-confirmed epidemic dengue, non-epidemic dengue, Zika, chikungunya, and COVID-19 (pre-Omicron and Omicron periods) cases reported in Puerto Rico's Sentinel Enhanced Dengue Surveillance System (SEDSS) with island-wide trends reported by the Department of Health's passive disease surveillance system (PADSS). We plotted trends over time to assess representativeness and used lagged cross-correlations to determine whether SEDSS reporting preceded PADSS. SEDSS trends were representative of island-wide trends for all pathogens. SEDSS preceded reporting in PADSS by up to three, eight, and two weeks for epidemic dengue, Zika, and pre-Omicron COVID-19, respectively. Increasing case trends for chikungunya occurred at broadly similar times in both systems, while temporal concordance was lower for non-epidemic dengue. In Puerto Rico, sentinel surveillance was representative of island-wide trends and could provide early warning for dengue epidemics and emerging diseases, such as Zika and COVID-19.
Medicine
Jain S et al. · Jun 11, 2026
Orthonairoviruses are rapidly emerging, tick-borne viruses including Crimean Congo hemorrhagic fever virus (CCHFV), a highly pathogenic virus requiring biosafety level 4 (BSL-4) containment. Recently discovered nairoviruses such as Yezo virus (YEZV) cause febrile illness and are spreading across East Asia. No vaccines or therapeutics exist for these emerging nairoviruses. Recombinant vesicular stomatitis virus (rVSV) systems are promising vaccine candidates for CCHFV and enable neutralization studies in lower containment laboratories; however, efficient rescue of rVSV expressing CCHFV glycoproteins has been technically challenging. Nairovirus glycoprotein precursor (GPC) processing requires cleavage by host protease subtilisin kexin isozyme-1 (SKI-1/S1P) to generate mature Gn, with frequent adaptive mutations observed in the RRLL cleavage site during rVSV-CCHFV rescue. Here, we investigated the role of PreGn cleavage in generating replication-competent rVSV-CCHFV. Targeted mutation of the SKI-1 cleavage site, resulting in uncleaved PreGn and immature Gn expression, markedly improved rVSV-CCHFV rescue efficiency when combined with Gc cytoplasmic tail truncation. This approach enabled robust generation of replication-competent rVSV-CCHFV across two genetically distinct strains (IbAr10200 and Turkey). To assess generalizability, we extended analysis to Hazara virus (HAZV) and YEZV. Unexpectedly, we efficiently rescued both rVSV-HAZV and rVSV-YEZV with intact cleavage sites, while cleavage mutations reduced their replication efficiency, indicating virus-specific requirements. Using human convalescent and animal sera, rVSV-CCHFV provided reliable neutralization assays with results comparable to authentic CCHFV under BSL-4 conditions. Animal and human CCHF-positive sera exhibited low, yet occasionally measurable, cross-neutralizing activity against VSV-HAZV. These findings define strategies for generating replication-competent rVSV vectors displaying nairovirus GPC and provide opportunities for studying neutralization in lower containment facilities.
Medicine