The cumulative impact of baseline comorbidities on outcomes of chimeric antigen receptor T-cell (CAR-T) therapy is not well established. Therefore, we developed and validated a Cellular Therapy Comorbidity Index (CT-CI) to predict outcomes following CD19-directed CAR-T therapy for large B-cell lymphoma (LBCL). Patients aged 18 or older receiving commercial CAR-T therapy for LBCL during 2017 to 2020 were selected from the Center for International Blood and Marrow Transplant Research registry. Patients were randomly assigned to training or validation cohorts. Comorbidities given weighted scores comprised the CT-CI, which was then validated for overall survival (OS) prognostication. A total of 1916 patients from 97 medical centers were included, with a median age of 64 years (19-91 years). About 70% of patients had comorbidities, such as cardiac disease (12%); diabetes (14%); hepatic dysfunction (mild, 8%; moderate to severe, 2%); psychiatric disturbance (18%); and pulmonary dysfunction (moderate, 15%; severe, 12%). The CT-CI was calculated, stratified patients in 3 categories, and was associated with increased mortality. Patients with higher CT-CI scores had worse OS (CT-CI 1: hazard ratio [HR], 1.37 [95% confidence interval [CI], 1.16-1.62; P < .001]; CT-CI 2: HR, 1.49 [95% CI, 1.17-1.89; P = .001]; CT-CI ≥ 3: HR, 2.55 [95% CI, 1.90-3.42; P< .001]). Higher CT-CI scores predicted treatment-related mortality and relapse. There was no correlation between the CT-CI score and CAR-T-related toxicities. The novel CT-CI score stratifies the effect of patient comorbidities on survival after CAR-T therapy and can be used for clinical decision-making and treatment selection in high-risk populations. However, comorbidities and fear of increased toxicity should not preclude patients from this effective therapy.

Type 2 inflammation at barrier surfaces is an evolutionarily conserved response that promotes immunity to helminth parasites, allergic inflammation and tissue repair1-4. Direct sensing of environmental triggers by epithelial cells initiates type 2 inflammation, and signals derived from neurons can modulate immune responses5-8. However, how diverse sensory inputs from epithelial, neuronal and immune cells are coordinated and integrated remains unclear. Here we identify that TRPV1+ pain-sensing nociceptors co-opt chemosensory epithelial tuft cells to initiate a cascade of tissue responses that drive type 2 inflammation. Chemogenetic silencing or chemical ablation of TRPV1+ nociceptors results in a significant reduction in intestinal tuft cells and defective anti-helminth type 2 immunity. By contrast, chemogenetic activation of TRPV1+ nociceptors leads to remodelling of CGRP+ nerve fibres, significantly increased CGRP expression, enhanced tuft cell accumulation and protective anti-helminth type 2 immunity. Using spatial transcriptomic and single-cell RNA sequencing analyses, we reveal that nociceptor activation promotes rapid epithelial progenitor cell proliferation and differentiation. Mechanistically, intestinal epithelial cell-intrinsic and tuft cell-intrinsic expression of CGRP receptor subunits are required for tuft cell responses and type 2 immunity to helminth infection. Together, these results identify sensory convergence of a neuronal-epithelial tuft cell circuit as a critical upstream determinant of type 2 immunity and tissue adaptation.

A previous controlled human influenza transmission trial produced minimal transmission using nasal inoculation of an egg adapted virus. Therefore, we implemented a new trial with naturally infected Donors. We recruited healthy Recipients for four, two-week hotel quarantine cohorts and naturally infected, qRT-PCR confirmed Donors for two cohorts. Five Donors (mean age: 21; 80% female; two H1N1, three H3N2, one for cohort 24b and 4 for 24c, Jan-Feb 2024) exposed Recipients (mean age: 36; 55% female, eight in cohort 24b and 3 in 24c) in a hotel room with limited ventilation but a high air recirculation rate. We collected exhaled breath, ambient and personal bioaerosols, fomite swabs, and sera, and analyzed samples using dPCR and fluorescent focus assays, hemagglutination inhibition (HAI) assay, and enzyme-linked immunosorbent assay (ELISA). Compared with previously studied community-acquired influenza cases, we detected viral RNA (44%) and culturable virus (6%) less frequently and measured fewer viral RNA copies (79 - 8.9 × 103 copies/30-min) in Donors' exhaled fine aerosols. One of 23 surface swab samples was culture positive. At admission, 8 of 11 Recipients had HAI titers ≤10 but 9 of 11 had stronger binding antibody responses than Donors against vaccine strains corresponding to Donor viruses. No Recipient developed influenza-like illness, PCR-positive respiratory samples, or serological evidence of infection. Potential explanations and insights regarding lack of transmission include importance of cough and seasonal variation in viral aerosol shedding by Donors, of potential cross-reactive immunity in middle-aged Recipients with decades of exposure, and of exposure to concentrated exhaled breath plumes limited by rapid air mixing from environmental controls that distributed aerosols evenly. Future trials over multiple seasons, Donors that cough, younger recipients, and environments that preserve normal exhaled breath plumes will be required to observe transmission from naturally infected Donors under controlled conditions and generate new insights into influenza transmission dynamics.

The mental health risk factors for primary healthcare workers (PHWs) following the Coronavirus Disease 2019 pandemic and the differences by urbanicity remain unclear. In this study, we aimed to identify key factors of anxiety and depression among PHWs in urban and rural settings in China. This cross-sectional study was conducted in all 31 provinces in mainland China, between 1 May and 31 October 2022. A total of 3,769 PHWs, including family physicians, nurses, public health professionals, pharmacists, and other medical staff, were recruited from 44 urban community health service centers and 27 rural township hospitals. The Bayesian Additive Regression Tree model was employed to identify risk factors of anxiety and depression. Among 3,769 PHWs, 1,006 (26.7%) worked in urban areas and 2,763 (73.3%) in rural areas. Occupational satisfaction significantly influenced anxiety in both urban and rural practitioners. For urban PHWs, living with family (odds ratio (OR): 0.42, 95% confidence interval (CI): 0.28-0.62) and self-rated health (fair: OR: 0.31, 95% CI: 0.23-0.42; good: OR: 0.13, 95% CI: 0.09-0.20) were key factors of anxiety. For rural PHWs, after-work exercise (rarely: OR: 0.28, 95% CI: 0.11-0.76; frequently: OR: 0.15, 95% CI: 0.05-0.44) played a critical role. Depression was associated with after-work exercise, self-rated health, and occupational satisfaction for all PHWs. Additionally, living with family (OR: 0.51, 95% CI: 0.34-0.75) and organizational support satisfaction (satisfied: OR: 0.28, 95% CI: 0.19-0.42) were significant for urban practitioners. Risk factors such as occupational satisfaction, health, and family relations significantly influence PHW mental health in China, with notabledifferences by urbanicity. Tailored mental health interventions are recommended to address urban-rural disparities.

Skin findings are often among the earliest signs of genetic disease but remain underused in diagnostic evaluation, especially in complex or multisystem cases. We aimed to examine how dermatologic features contribute to genetic diagnoses in patients evaluated through the Undiagnosed Diseases Network (UDN). We conducted a retrospective study of 2849 individuals referred to the UDN from 2015 to 2025. All underwent comprehensive clinical evaluation and genome-wide sequencing. Skin findings were identified using Human Phenotype Ontology (HPO) terms and assessed for their association with diagnostic yield and time to diagnosis using odds ratios, Fisher's exact tests, and t-tests. A confirmed genetic diagnosis was made in 911 individuals. Eighteen were diagnosed with a primary genodermatosis, including four with somatic mosaicism, three of whom required biopsy of affected skin for confirmation. Skin-related HPO terms were present in about one-third of both diagnosed and undiagnosed individuals. While general skin findings were not predictive, specific features were strongly associated with diagnosis. These included café au lait macules (odds ratio 6.75), decreased palmar creases (odds ratio 5.61), and prominent fingertip pads (odds ratio 2.36). In contrast, bruising susceptibility was associated with a lower likelihood of diagnosis. Diagnostic delay was shorter for primary dermatologic disorders, though not statistically significant. Skin features, even subtle ones, can provide powerful diagnostic clues in rare diseases. Integrating focused dermatologic evaluation and tissue-specific testing, particularly for suspected mosaicism, can enhance diagnostic accuracy and shorten the path to answers for patients and families.

Highly pathogenic H5N1 avian influenza viruses of clade 2.3.4.4b cause sporadic human infections and currently raise concerns about a new influenza pandemic. Heterogeneities in disease severity have been observed in the past and are reported among infected farm workers in the United States. These may be attributed to differences in pre-existing H5N1 cross-reactive antibodies. In this study, we characterize H5N1 cross-reactive antibody landscapes in the current population (#NCT05794412 and #NCT01022905) and assess the effect of AS03-adjuvanted pandemic H1N1 and non-adjuvanted seasonal influenza vaccination on H5N1 cross-neutralizing and IgG antibody titers targeting a range of influenza virus-derived antigens. We detect H5N1 cross-neutralizing antibodies using a vesicular stomatitis virus-based pseudovirus system that correlate well with antibodies inhibiting the spread of authentic H5N1 viruses, anti-group 1 hemagglutinin stalk and anti-trimeric hemagglutinin antibodies. Additionally, we find that AS03-adjuvanted pandemic H1N1 vaccination increases H5N1 cross-reactive antibodies significantly in a pandemic H1N1 immunologically partially naïve population. Furthermore, we show that immune imprinting causes distinct H5N1 cross-reactive antibody patterns pre-vaccination.

Percutaneous left atrial appendage occlusion (LAAO) has traditionally been performed under general anesthesia (GA) to maintain patient comfort and immobility, especially in the setting of transesophageal echocardiography. We aimed to compare the safety and efficacy of conscious sedation (CS) compared to GA for LAAO, concurrent with the expansion of intracardiac echocardiography guidance. A systematic search of the PubMed, Embase, Cochrane Central, and Scopus databases was conducted through December 2024 for studies comparing CS versus GA for LAAO. For outcomes of procedural complications and characteristics, random-effects models were used to calculate the mean difference (MD), odds ratio (OR), and risk ratio (RR) effect estimates with 95% confidence intervals (CIs). Four studies with 1540 patients undergoing LAAO were included (CS = 678, GA = 862). CS was associated with significantly shorter total procedural time [MD -11.95 min; 95% CI -19.52 to -2.78; p = 0.009] and a lower volume of contrast media [MD -31.90 mL; 95% CI -56.72 to -7.08; p = 0.01]. No significant differences were noted for total fluoroscopy time, total length of hospital stay, device success, all-cause mortality, cardiovascular mortality, stroke, device-related thrombus, and peri-device leak > 5 mm. Percutaneous LAAO using CS allows for faster procedures and lower contrast media volumes compared to GA without compromising device success and clinical outcomes. Randomized studies with longer follow-ups are necessary to understand the long-term outcomes of percutaneous LAAO using CS.