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Background: Pre-clinical animal studies have demonstrated improved cerebral blood flow and neurological survival with Automated Head Up Position (AHUP) cardiopulmonary resuscitation (CPR) as compared to flat conventional (C) CPR. AHUP CPR consists of 1) automated head and thorax elevation 2) active compression decompression CPR and 3) an impedance threshold device. Subsequently, observational propensity-matched studies of out-of-hospital cardiac arrest (OHCA) patients demonstrated a time-dependent association between survival with intact neurological function (SNF) and application of AHUP CPR. However, comparison of AHUP CPR outcomes with contemporaneous C-CPR controls is lacking. Hypothesis: Use of AHUP CPR for OHCA by first responder agencies will demonstrate a higher incidence of SNF compared to C-CPR outcomes from a national registry Methods: Data from the previous 5 years (2020-2024) from an AHUP-CPR Registry comprised of OHCA patients routinely treated by first responders with AHUP CPR were compared with data from the Cardiac Arrest Registry to Enhance Survival (CARES). Patient demographics, arrest characteristics, ROSC, SHD, and SNF were recorded. SNF was defined as a Cerebral Performance Category 1 or 2 at hospital discharge. A two-sample test of proportions was used for outcome comparisons. Results: Nine AHUP registry sites (MN, FL, TN, IL, OK, VA, AL, IA, MI) were included. Summary 5-year demographics (Table 1) and clinical outcomes (Table 2) are presented. For 2020-2024 AHUP sites, the average time (mm:ss, SD) from 9-1-1 call to start of CPR was 9:09 (4:37) and time to start of AHUP CPR was 12:46 (5:57). The AHUP registry had a higher 5-yr incidence of SNF versus the CARES registry (difference 2.8%, 95% CI 1.8-3.8, p < 0.00001). This difference was consistent year over year (Figure 1). Secondary outcomes of sustained return of spontaneous circulation and survival to hospital discharge in the AHUP registry were also significantly higher than CARES registry data (Table 2). Conclusions: Over a 5-year period, an unadjusted analysis of aggregate data from two OHCA patient registries demonstrated that the incidence of survival with intact neurological function was higher in patients treated with AHUP CPR as part of first responder care versus patients treated with more conventional CPR methods.

ABSTRACT Suicidality contributes substantially to global morbidity and mortality, yet despite its heritability, its biological etiology remains largely elusive. We conducted multi-ancestry genome-wide association study meta-analyses of suicidal ideation (259,747 cases), suicide attempt (64,993 cases), suicide death (9,197 cases), and suicidal behavior (suicide attempt/ death, 75,300 cases), across 54 cohorts (e.g., the Psychiatric Genomics Consortium, Million Veteran Program, UK Biobank). We identified 77 significant loci across meta-analyses, including 59 previously unreported for suicidality. SNP-based heritability ranged from 2.0-6.7% and there were strong, yet incomplete, genetic correlations between suicidality phenotypes (0.70-0.88). Fine-mapping prioritized putative causal SNPs and 20 credible genes. Enrichment analyses implicated synaptic pathways and neuronal populations predominantly in subcortical brain regions (e.g., amygdala excitatory, medium spiny, hippocampal CA1-3). Together, these findings establish suicidality as a polygenic set of traits with both shared and distinct genetic influences, providing a foundation for future studies of suicide biology and etiology.

Abstract Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality globally, with particularly high burdens among people living with HIV (PLWH) in low‐resource settings like Nigeria. Effective early detection remains a major challenge due to limited access to imaging‐based surveillance and the low sensitivity of current biomarkers such as alpha‐fetoprotein (AFP). We conducted an epigenome‐wide association study (EWAS) of circulating cell‐free DNA (ccfDNA) methylation in a Nigerian cohort of HIV‐positive individuals ( n = 245), spanning HCC, cirrhosis (FibroScan ≥12.3 kPa), fibrosis (FibroScan ≥7.6 and <12.3 kPa), and HCC‐free without fibrosis (FibroScan <7.6 kPa) groups. Using random forest modeling, we developed and evaluated a ccfDNA methylation classifier (ccfDNAmRF) for HCC risk prediction. We identified 73 CpG sites significantly associated with HCC (false discovery rate <0.01). The ccfDNAmRF model demonstrated strong discriminatory power, achieving 100% sensitivity and 80%–91% specificity for distinguishing HCC from cirrhosis, fibrosis, and HCC‐free groups (area under the curve [AUC]: 92%–97%). Combining ccfDNA methylation risk scores with AFP further improved classification accuracy (AUC up to 98.5%). Notably, ccfDNA methylation patterns displayed clear dose–response relationships across the disease spectrum, supporting their utility for early‐stage detection and risk stratification. Our findings highlight the promise of ccfDNA methylation biomarkers as a non‐invasive, blood‐based screening tool for improving early identification of HCC cases among PLWH.

BACKGROUND: Intracranial atherosclerosis (ICAS) is associated with an increased risk of early recurrent ischemic stroke. We evaluated whether biomarkers of impaired distal perfusion—specifically, anterior circulation borderzone infarct, and hypoperfusion mismatch volume—were associated with recurrent ischemic stroke within 90 days. METHODS: The BIORISK ICAS (Biomarkers and Recurrence Risk in Symptomatic Intracranial Atherosclerosis) is a multicenter retrospective international study (35 sites) that included hospitalized patients with symptomatic ICAS (50%–99% luminal stenosis of the intracranial vertebral, basilar, distal internal carotid, or proximal middle cerebral artery) from January 2019 to June 2024. The primary outcome was recurrent ischemic stroke in the territory of the symptomatic artery within 90 days. In the primary analysis, the exposure was an acute anterior circulation borderzone infarct. In secondary analysis of the subset with presentation within 72 hours of last known normal and perfusion imaging completed, the exposure of interest was prespecified as hypoperfusion mismatch volume at T max (time to maximum) threshold of 6 seconds, dichotomized at the Youden index. We performed multivariable Cox regression to test associations between exposure variables and the outcome, adjusting for clinically relevant variables and those associated with the outcome ( P <0.1). RESULTS: Of 2050 patients with symptomatic ICAS, 1737 (84.7%) presented within 72 hours of symptom onset, among whom 509 (29.3%) underwent perfusion imaging. The primary analysis included 1891 patients; 174 (9.2%) patients had recurrent ischemic stroke in the symptomatic arterial territory. In adjusted Cox regression models, there was an association between anterior circulation borderzone infarct and recurrent ischemic stroke at 90 days (adjusted hazard ratio, 1.40 [95% CI, 1.02–1.93]). In the perfusion imaging analysis, hypoperfusion mismatch of ≥10 mL was associated with recurrent ischemic stroke (adjusted hazard ratio, 1.83 [95% CI, 1.03–3.28]). CONCLUSIONS: Biomarkers of impaired distal perfusion, anterior circulation borderzone infarct, and hypoperfusion mismatch were associated with increased risk of recurrent ischemic stroke. These findings support the use of perfusion imaging in ICAS as well as future trials investigating early reperfusion in high-risk patients with ICAS.

Abstract The sections in this article are: Regulation of the Upper Airway During Exercise Anatomy and Physiology of the Upper Airway Contractile Properties and Endurance of Upper Airway Muscles Changes in Upper Airway Flow Resistance During Exercise Upper Airway Muscle Activities during Exercise Oronasal Distribution of Respiratory Airflow Effects of Exercise on Passive Respiratory Mechanics Elastic Properties Total Lung Capacity Expiratory Flow Rates, Vital Capacity, and Residual Volume Breathing Pattern During Exercise Mechanical Breathing Pattern Methods of Assessment of Respiratory Muscle Contraction Pattern of Respiratory Muscle Contraction Influence of Sensory Feedback on Breathing Pattern Influence of Respiratory Mechanics on Breathing Pattern Influence of Duration of Exercise on Breathing Pattern Influence of Mode of Exercise on Breathing Pattern Breathing Pattern during Recovery from Exercise Physiological Implications of Exercise Breathing Pattern Importance of Respiratory Load in Regulation of Exercise Hyperpnea Helium‐Oxygen Unloading Unloading with Pressure Assist Conclusion Locomotor‐Respiration Interdependence Entrainment—the Most Obvious Locomotor‐Respiratory Interaction How Does Entrainment Effect Ventilation? Is there Stronger Evidence to Support a Significant Biomechanical Effect of Locomotion on Respiration in Dogs? Are Biomechanical Effects Important in Entrainment in Humans? Locomotory: Respiratory Interactions, Independent of Entrainment Conclusion Respiratory Muscle Perfusion and Energetics Oxygen Cost of Hyperpnea Respiratory Muscle Blood Flow Exercise‐Induced Respiratory Muscle Fatigue Respiratory System Design Assessment of Diaphragm Fatigue in Animal Models Glycogen Depletion Fiber Type Recruitment Definition of Fatigue Task Failure vs. Objective Assessment of Fatigue Contractile Changes with Fatigue Predicting Respiratory Muscle Fatigue During Exercise Application of Resting Tests to Respiratory Muscle Function During Exercise Assessment of Respiratory Muscle Fatigue in Humans Volitional Tests Volitional Tests Applied to Exercise Nonvolitional Tests Bilateral Phrenic Nerve Stimulation ( BPNS ) Characteristics of Diaphragm Fatigue High‐ vs. Low‐Frequency Fatigue Sites and Mechanisms of Respiratory Muscle Fatigue Central Fatigue in Humans Neurotransmission Fatigue Bilateral Phrenic Nerve Stimulation Applied to Exercise Short‐Term Exercise Endurance Exercise Factors Contributing to the Decline in Twitch Pdi Following Exercise Role of Diaphragmatic Force Output in Fatigue Consequences of Exercise‐Induced Diaphragmatic Fatigue Fatigue vs. Task Failure Does Training of Respiratory Muscles Affect Exercise Performance? Altered Respiratory Muscle Recruitment with Fatigue Physical Training Effects on Respiratory Muscles Respiratory Muscle Morphology and Contractile Properties Whole‐Body Training: Effects on Rodent Respiratory Muscles Whole‐Body Exercise: Effects on Human Respiratory Muscle Performance Specific Respiratory Muscle Training Respiratory Sensation During Exertion Mechanisms of Respiratory Sensations during Exercise Methods of Assessing Respiratory Sensations Respiratory Movements An Urge to Breathe A Sense of Respiratory Effort Respiratory Sensation as a Respiratory Controller during Exercise Respiratory Sensation as a Limiting Factor during Exercise Conclusions Summary—Pulmonary System Limitations and Their Effects on Exercise Performance Absence of Pulmonary System Limitations in the Normally Fit Contrasting Adaptabilities: Demand vs. Capacity Alveolar Capillary Diffusion Surface of the Lung Ventilatory Limitations/Constraints Inadequate Alveolar Ventilation and Limitations Endurance Exercise Performance Special Circumstances Favoring Pulmonary Limitations to Exercise Performance in Health Hypoxia of High Altitudes Aging Effects on Pulmonary Limitations

Abstract The SNF2 family chromatin remodeler HELLS has emerged as an important regulator of cell proliferation, genome stability, and several cancer pathways. Significant upregulation of HELLS has been reported in 33 human cancer types. While HELLS has been implicated in DNA damage response, its function in DNA repair is poorly understood. Here, we report a new regulatory link between HELLS and single-strand break (SSB) repair in cellular responses to DNA alkylation damage. We found that loss of HELLS impairs SSB repair and selectively sensitizes cells to DNA alkylating agents and PARP inhibitors (PARPi). Our data reveal non-epistatic interactions between HELLS and PARP1 and suggest that HELLS functionally compensates for PARP1 deficiency in promoting cell survival in response to DNA alkylation damage. Furthermore, we found that HELLS is co-expressed with PARP1 in cancer cells, and its loss is synthetic lethal with homologous recombination deficiency (HRD). This work unveils new functions of HELLS in modulating SSB repair and responses to clinically relevant DNA alkylation damage, thus offering new insights into the potential therapeutic value of targeting HELLS in cancer.

Abstract Molecular profiling reveals that up to 40% of advanced biliary tract cancers (BTCs) harbor actionable genomic alterations amenable to matched targeted therapies. However, conventional trial designs typically evaluate these agents in pretreated populations, resulting in approvals for later-line use. Notably, 25–44% of patients with advanced BTC may become ineligible for treatment after first-line therapy due to disease progression or functional decline, thus the real-world survival outcomes with matched therapies remains poorly characterized. This international collaborative study includes data from Mayo Clinic, Duke Cancer Institute, and National Cancer Center East (Japan), as well as a combined dataset from the SCRUM-Japan GOZILA, MONSTAR-SCREEN-1, and MONSTAR-SCREEN-2 projects. We assessed overall survival (OS) of patients based on the presence of actionable alterations and the receipt of matched therapy. To adjust for confounding, we applied propensity score weighting with inverse probability of treatment and multivariate Cox regression modeling, controlling for age, sex, tumor location, prior resection, and mutational subgroup. Among 1,049 patients that were analyzed, 358 (34.1%) harbored actionable alterations, with 160 (44.7%) receiving matched targeted therapy. The matched group (patients with actionable tumors who received a matched therapy) were significantly associated with longer median OS (23.3 months; 95% CI: 19.5–30.4) compared to the unmatched group (14.7 months; 95% CI: 12.8–17.9) and those with non-actionable tumors (17.1 months; 95% CI: 15.5–18.7; HR 0.57, 95% CI: 0.46–0.71; p < 0.0001). The unmatched group also was associated with the lowest three-year OS rate (13% vs. 35% in matched and 19% in actionable groups, respectively; p<0.0001). On multivariable analysis with patients who received ≥2 lines of therapy, receipt of matched therapy remained an independent predictor of improved OS (HR 0.62; 95% CI 0.43–0.90). These findings support the early integration of targeted therapies in BTC management and underscore the need to overcome systemic barriers to treatment access.

Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death in the United States and worldwide. HCC screening among patients at elevated risk is associated with improved early detection and overall survival, but current ultrasound-based screening strategies are challenged by low adherence and suboptimal sensitivity. Blood-based screening tests have the potential to enhance adherence and improve early-stage HCC detection if they can demonstrate favorable performance compared with ultrasound-based screening. Here we present the design and rationale for ALTUS (A lternative to Ultrasound), a prospective, longitudinal, multicenter study in the United States to investigate the performance of the multi-target HCC blood test (mt-HBT) for the detection of HCC in a screening population. Methods: Adults with liver cirrhosis or chronic hepatitis B infection will be enrolled to undergo standard-of-care screening imaging and concurrent blood collection for the mt-HBT. All participants will undergo contrast-enhanced CT or MRI imaging with central radiology LI-RADS assessment as the reference method to determine HCC status. Participants without an identified malignancy will undergo a second screening visit and blood collection, and longitudinal clinical and imaging data will be collected up to 18 months from enrollment. The primary study objectives are to demonstrate that the mt-HBT is non-inferior to ultrasound for early-stage HCC sensitivity and to assess mt-HBT HCC specificity. The secondary objective is to assess mt-HBT overall sensitivity. Results: ALTUS is in progress with readout of the primary analysis expected in 2025. Conclusions: This prospective head-to-head comparison of the mt-HBT versus ultrasound will provide novel data regarding the performance and utility of the mt-HBT for HCC screening.

262 Background: According to the American Cancer Society, nearly half (47%) of cancer patients and survivors incurred medical debts to pay for cancer care, although most (98%) had health care coverage (2024 Survivor Views Survey). The financial toxicity from high cost of cancer care is itself a risk factor for cancer mortality – hazard ratio of 1.8 among those requiring bankruptcy protection (Ramsey SD, J Clin Oncol 2016). Charity care, also known as financial assistance, plays a vital role in alleviating the medical debt for low-income patients. The Affordable Care Act requires non-profit hospitals to publish charity care policies to maintain their tax-exempt status. We studied the criteria for hospital charity care among NCI-designated cancer centers in the US. Methods: We included all NCI-designated cancer centers with a clinical program as of December 1, 2024. We searched their cancer center websites for charity care eligibility policies in 2024 and obtained the following information: income limit as percentage of the federal poverty guidelines (FPG), eligibility criteria beyond income, and supporting documents required for charity care application. Cancer centers were grouped into the following regions based on US Census classification: Northeast, Midwest, South, and West. Results: We found 64 NCI-designated clinical cancer centers - all non-profit institutions. Charity care policies were readily available. The median income cutoffs for free and discounted care were 200% of the FPG (range, 100%-600%) and 400% of the FPG (range, 200%-800%), respectively. These income cutoffs were similar among the four geographic regions. Most centers (52%) allowed not only uninsured but also underinsured or insured patients experiencing hardship. A minority of the policies (13%) applied different rules for insured patients. Majority of the centers (52%) allowed financial assistance when medical bills exceed a certain hardship limit even if income cutoffs were not met. Only 3 centers (5%) required medical bills to exceed a minimum threshold for eligibility. Residency requirements included US citizenship or permanent residency (27%), state (33%), service area (14%), county (2%), not necessary (11%) or not stated (34%). Most policies (64%) mentioned investigating a patient's assets. Specific documents required for submission included income (98%), pay stub (88%), tax return (84%), asset (73%), proof of residency/citizenship (44%), and bank account (61%). Conclusions: NCI-designated cancer centers apply a relatively uniform range of financial eligibility criteria for free and discounted charity care. Approximately 1 in 4 centers require evidence of US citizenship or permanent residency while 1 in 2 centers restrict eligibility to in-state residents. Future studies into the awareness, accessibility, and utilization of charity care will provide insight into how to optimize this resource for the neediest population.