Citations

Objective: To determine whether sleep apnea–specific hypoxic burden (SASHB) is associated with self-reported hypertension beyond conventional obstructive sleep apnea metrics in rail workers. Methods: Cross-sectional study of 84 Argentine rail workers undergoing home sleep apnea testing. Associations between SASHB and hypertension were evaluated using adjusted logistic regression. Drowsy driving was examined as an unadjusted exploratory secondary outcome. Results: Higher SASHB was independently associated with hypertension in the fully adjusted model (OR per SD 2.42; 95% CI 1.24–5.29; p=0.015). Higher SASHB was also associated with more severe self-reported drowsy driving in unadjusted exploratory ordinal analyses (OR per SD 1.78; 95% CI 1.09–3.28; p=0.035). Conclusions: SASHB may provide complementary information beyond conventional OSA metrics for cardiovascular risk assessment in occupational populations.

Background With improvements in in vitro culture techniques, there has been a steady shift in practice to transfer in vitro fertilisation (IVF) embryos at the blastocyst-stage to increase pregnancy rates per embryo transfer (ET) and reduce the risk of multiple pregnancy. In patients with fewer embryos (≤5 zygotes), fresh cleavage-stage ET is still commonly performed to reduce the risk of cycle cancellation if no embryo survives to the blastocyst-stage in vitro. However, evidence for improved outcomes with cleavage-stage embryo transfer in this subgroup of patients is lacking. We will compare blastocyst-stage to cleavage-stage ET with regard to cumulative live birth rates (CLBR) per oocyte retrieval and other patient-centred cycle outcomes in patients with ≤5 zygotes. Methods and analysis Multicentre, randomised pragmatic comparative effectiveness trial with superiority design comparing blastocyst-stage to cleavage-stage ET in patients with ≤5 zygotes. This trial will enrol and randomise 1126 women aged 18–44 undergoing IVF to either fresh cleavage-stage or blastocyst-stage ET at eleven IVF centres. Surplus embryos will be vitrified at the blastocyst-stage. The primary outcome is the CLBR per oocyte retrieval. Secondary outcomes include: multiple pregnancy, pregnancy loss <20 weeks and cycle cancellation. Exploratory outcomes include: live birth per fresh ET, ectopic pregnancy, time to pregnancy, stillbirth, preterm birth, financial burden, patient distress and facilitators and barriers for patient involvement and implementation. All primary analyses will be conducted according to the intent-to-treat principle. We also will report per-protocol analyses as a sensitivity analysis. A multidisciplinary stakeholder team, including a 5-patient stakeholder panel, will participate in study design, conduct and oversight. Ethics and dissemination The Institutional Review Board at Beth Israel Deaconess Medical Center (BIDMC) provides central regulatory oversight. Results will inform timing of embryo transfer in patients with ≤5 zygotes and will be disseminated through academic publications, meeting presentations and communications to advocacy groups and patient participants. Trial registration number NCT06746129 .

Transfers are high-risk events, and outside hospital admissions lack standardized processes to ensure timely delivery of essential clinical information. We piloted a novel, standardized process for outside admissions to a single academic medical center’s resident- and hospital medicine-attending-based medicine services. Following literature review, Epic UserWeb review, and frontline physician input, a workflow and templated electronic health record accept note were developed to centralize outside admission documentation. Completed by physicians during real-time communication with outside physicians, the template captures key clinical data and incorporates a communication checklist. Physician education was delivered electronically and in person. Subjective attending and resident perceptions were assessed via electronic prepost surveys administered 1 week before and 90 days after implementation. Secondarily, exploratory patient clinical outcomes were assessed through 90-day prepost manual retrospective chart review. Survey responses were obtained from 60/38 residents and 12/7 attendings (pre/post). Documentation sufficiency on patient arrival was directionally promising among residents (21.7% vs 39.5%, P = 0.062). Satisfaction with the admission process and perceived patient safety improved significantly among residents and attendings ( P ≤ 0.036). Most respondents rated the note as useful or very useful (84% residents; 86% attendings), and attendings reported reduced time managing outside admissions. The intervention was associated with exploratory, nonsignificant reductions in rapid response team activation, intensive care unit transfer, 30-day readmission, mortality, and length of stay compared with preintervention patients. A standardized documentation and communication process improved physician satisfaction and perceived patient safety, with promising exploratory patient outcomes. Further study is warranted to assess impact at scale.

Abstract Introduction We have shown that combining CAR T cells with oncolytic viruses (OVs) generates a subpopulation of highly cytotoxic CAR T cells that can mediate long-term solid tumor therapy. Methods To profile these CAR T cells, we used C57BL/6 mice bearing B16F10 tumors expressing EGFRviii, treated with anti-EGFRviii CAR T cells and the OV vesicular stomatitis virus (VSV). TCR signaling in CAR T cells was investigated using the novel Tocky transgenic mouse model, which reports T cell activation over time using an unstable fluorescent protein reporter of Nr4a3. We further investigated CAR T phenotypes using CyTOF and scRNA-Seq. Results Using an MHC I tetramer for the dominant VSV epitope VSV N52-59, we found that 20-50% of transfused CAR T adopted TCR specificity against VSV N (referred to as TCR-primed), indicating significant in vivo expansion. Ex vivo, these TCR-primed CAR T produced increased levels of granzyme B and IFNγ over tetramer-negative CAR T against either TCR or CAR targets. However, TCR-primed CAR T cells were notably less activated via Nr4a3 as compared to non-TCR-primed CAR T. CyTOF and scRNA-Seq analyses demonstrated a hypereffector phenotype among TCR-primed CAR, with increased expression of T-bet, CD44, granzyme B, IFNγ, and perforin. TCR sequencing revealed hyperexpansion of VSV N-specific CAR T cells and little overlap in clonotypes between CAR T co-treated with PBS versus VSV. These TCR-primed CAR T cells exhibited a CD4-helped phenotype with increased expression of chemotactic and migratory transcripts. When CAR T and OV were administered with antibody-mediated CD4 depletion, the TCR-primed CAR population was significantly diminished, emphasizing the importance of the immune triad for CAR T expansion. Conclusion Overall, CAR T cells that undergo endogenous anti-viral TCR priming and signaling adopt a unique phenotype that promotes their expansion and cytotoxic function. Interactions with CD4 T cells appear to be integral for the generation of this subpopulation of CD8 CAR T cells. Funding Source NIH Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)

PURPOSE Bone metastases (BM) occur in approximately 30% of patients with metastatic renal cell carcinoma (mRCC) and are associated with poor survival and symptomatic skeletal events (SSEs). Radium-223, an alpha-emitting bone-seeking radioisotope, and cabozantinib, a tyrosine kinase inhibitor, have demonstrated activity in BM. RADICAL (Alliance A031801; ClinicalTrials.gov identifier: NCT04071223 ) evaluated cabozantinib ± radium-223 in mRCC with BM. METHODS This phase II trial enrolled patients with mRCC of any histology with ≥1 BM. Patients were randomly assigned 1:1 to cabozantinib ± radium-223, stratified by osteoclast-targeted therapy (OTT), prior therapy, opioid use, and International mRCC Database Consortium (IMDC) risk. The primary end point was SSE-free survival (SSE-FS). Secondary end points included safety, objective response rate (ORR), progression-free survival, and overall survival (OS). A target of 124 evaluable patients was planned, with a prespecified interim futility analysis at 50% of expected SSE-FS events; the trial would stop if the stratified hazard ratio (sHR) > 1.0. RESULTS The prespecified interim futility analysis was conducted after 90 patients were enrolled and crossed the futility boundary, leading to closure at 98 patients. The final analysis included all 98 patients. Median age was 63 years, 82.7% had clear cell histology, and 79.6% were using an OTT. IMDC risk was favorable (18.4%), intermediate (67.3%), and poor (14.3%). Median follow-up was 13.1 months. Median SSE-FS for cabozantinib with radium-223 versus cabozantinib was 16.7 versus 17.6 months (sHR, 1.46 [90% CI, 0.86 to 2.51]). Median OS was 28.3 versus 19.7 months (sHR, 1.40 [95% CI, 0.70 to 2.79]). ORR was 19.4% versus 25.0% ( P = .78). Grade ≥3 adverse events were similar across arms (69.6% v 75.5%). CONCLUSION Radium-223 did not improve SSE-FS when added to cabozantinib. The combination demonstrated a manageable safety profile.

Objectives: To evaluate the association of a templated interhospital transfer (IHT) note on transfer appropriateness and clinical outcomes. Methods: We conducted a retrospective, single-center study of 100 IHTs to the Department of Medicine services between May and June 2023. The exposure was the type of documentation at the time of transfer, categorized as templated note, nontemplated note, or no note. The primary outcome was appropriateness of transfer, determined by 2 independent adjudicators using a standardized framework developed as part of the POINT Study. Documentation type by clinical specialty and reason for transfer were assessed, with statistical analyses of clinical outcomes limited to those with an incidence >5% (ie, escalation/downgrade in level of care within 24 h of transfer and 30 d mortality). Results: Among 100 transfers, 81 (81%) were deemed appropriate and 19 (19%) were deemed inappropriate. Documentation was present in 59%, including templated (35%) and nontemplated notes (24%). IHTs without documentation had the highest appropriateness rate (87.8%, 36/41), compared with templated notes (29/35, 82.9%; P =0.15) and nontemplated notes (66.7%, 16/24; P =0.042). Downgrades were more common in inappropriate transfers with nontemplated notes (50.0%, 4/8) than in appropriate transfers with templated notes (10.3%, 3/29; P =0.012). Conclusions: Structured IHT documentation was inconsistently used and did not predict the appropriateness of transfer. Transfers without documentation were most often appropriate, suggesting straightforward cases may not require formal notes. In contrast, nontemplated notes in inappropriate transfers showed high downgrade rates, implying that unstructured documentation may inflate perceived acuity. Further evaluation of documentation strategies is needed to support appropriate transfer decision-making.

Most patients with chest pain do not have acute myocardial infarction (AMI), yet post-AMI rule-out disposition remains variable. Detectable but sub-99th percentile high-sensitivity cardiac troponin I (hs-cTnI) provides additional prognostic information. We evaluated the economic value of hs-cTnI-guided hospitalizations among non-AMI patients. We analyzed 1481 non-AMI chest pain visits with detectable baseline hs-cTnI across 29 U.S. emergency departments (2014–2016) in the prospective HIGH-US trial using the Atellica IM TnIH assay(Siemens Healthcare Diagnostics, Tarrytown, NY, US). We compared observed standard-of-care admissions with modeled pathways incorporating hs-cTnI thresholds and risk scores, assessing admission rates, costs, and diagnostic accuracy for 30-day death/MI. Overall, 1.0% (n = 15/1481) experienced 30-day death/MI. Standard-of-care admitted 59% of patients with 93% sensitivity and 41% specificity. The modeled pathway using hs-cTnI ≥ 5 ng/L plus non-low risk scores was associated with reduced projected admission of 41%, higher specificity of 60%, and the same 93% sensitivity. Estimated per-patient diagnostic costs were lower under Scenario 1 (noninvasive diagnostic testing only; $1025 vs. $1139) and under Scenario 2 (including inpatient/invasive procedures; $2672 vs. $3536). In subgroups, higher hs-cTnI thresholds conferred further economic benefit without compromising sensitivity. Incorporating sub-99th percentile hs-cTnI thresholds alongside risk scores may support more efficient resource use while maintaining safety, although findings require prospective validation.

Background Irritable bowel syndrome (IBS) is a complex disorder of gut-brain interaction, with heterogeneous symptoms, no available biomarkers and limited pathogenetic insight. Objective To identify genetic risk factors and actionable mechanisms for future clinical translation in IBS. Design We conducted a genome-wide association study (GWAS) meta-analysis of IBS in 2 775 539 individuals from 22 biobanks. IBS genetics was studied across multiple ancestries, different case definitions and symptom-related subtypes. Heritability and genetic correlations with other traits were estimated, and Mendelian randomisation was used to test causal relationships. GWAS data were functionally annotated and fine-mapped to prioritise tissues, cell types, pathways, candidate genes, specific mechanisms and druggable targets. Results Significant heritability was only detected in individuals of European ancestry, with near-identical genetic architecture across case definitions. Genetic correlations with GI, psychiatric and cardiometabolic traits were observed, including causal relationships with triglyceride (TG) levels. Functional annotation of IBS risk loci highlighted cell types and pathways relevant to brain, enteric neuro-glial and cardiometabolic domains, as well as actionable targets like GCKR, a regulator of TG metabolism. Druggability analyses converged on cardiometabolic mechanisms, including TG modulation. IBS polygenic risk scores were derived and showed a significant association with case status in an independent case-control dataset, supporting further evaluation in external population-based and clinically ascertained cohorts. Conclusions This study provides the most comprehensive assessment of IBS genetics to date, demonstrating reproducible polygenic inheritance. We link IBS risk to convergent neurogastrointestinal and novel cardiometabolic mechanisms, highlight specific biological pathways and actionable mechanisms and outline translational opportunities emerging from integrated computational analyses.

ABSTRACT Glioblastoma (GBM) is a highly aggressive brain tumor with a five-year survival rate of less than 5%. The current standard of care established 20 years ago includes maximal surgical resection and administration of alkylating agent temozolomide (TMZ). GBM is highly invasive, and GBM cells that evade surgical resection can become resistant to TMZ and develop new aggressive secondary tumors. Post-relapse there are few treatment options available to patients. Tissue engineering approaches suggest the opportunity to develop in vitro models of the GBM tumor microenvironment that may accelerate the discovery of novel therapies for GBM. Here, we report the adaptation of hydrogel microdroplets (microgels) to encapsulate GBM cells in a tailorable 3D matrix to assess patters of growth and to screen TMZ drug response using patient-derived xenograft (PDX) specimens. We exploit a unique aspect of the microgel system to account for the cellular heterogeneity within the tumor microenvironment (TME). We combine cell-laden microgels generated from TMZ-resistant and TMZ responsive variants of the same PDX specimens to create heterogeneous populations with varying levels of drug sensitivity. We demonstrate a range of drug resistance phenotypes as a function of the ratio of TMZ-responsive to resistance cells and identify the population required for TMZ-resistance to overtake take the response. We then investigate the influence of tumor mimetic shifts in hyaluronic acid bioavailability and hypoxia on patterns of TMZ resistance. We show exposure to matrix-bound hyaluronan increases TMZ resistance and the glioma stem cell population in both cell variants. Lastly, we report an increase in TMZ sensitivity but divergent changes in the GSC subfraction for TMZ resistant vs responsive GBM in the presence of hypoxia. Together, we demonstrate the versatility of cell-laden microgel approach to replicate heterogenous tumor populations, model shifts in the tumor microenvironment, and rapidly screen therapeutic response.