tbuckley/cabot-search huggingface dataset:
Homicide Deaths Among Adult Cohabitants of Handgun Owners in California, 2004 to 2016
Authors: David M. Studdert, Yifan Zhang, Erin E. Holsinger, Lea Prince, Alexander F. Holsinger, Jonathan A. Rodden, Garen J. Wintemute, Matthew Miller
Journal: Annals of Internal Medicine (2022)

Although personal protection is a major motivation for purchasing firearms, existing studies suggest that people living in homes with firearms have higher risks for dying by homicide. Distribution of those risks among household members is poorly understood.To estimate the association between living with a lawful handgun owner and risk for homicide victimization.This retrospective cohort study followed 17.6 million adult residents of California for up to 12 years 2 months (18 October 2004 through 31 December 2016). Cohort members did not own handguns, but some started residing with lawful handgun owners during follow-up.California.17 569 096 voter registrants aged 21 years or older.Homicide (overall, by firearm, and by other methods) and homicide occurring in the victim's home.Of 595 448 cohort members who commenced residing with handgun owners, two thirds were women. A total of 737 012 cohort members died; 2293 died by homicide. Overall rates of homicide were more than twice as high among cohabitants of handgun owners than among cohabitants of nonowners (adjusted hazard ratio, 2.33 [95% CI, 1.78 to 3.05]). These elevated rates were driven largely by higher rates of homicide by firearm (adjusted hazard ratio, 2.83 [CI, 2.05 to 3.91]). Among homicides occurring at home, cohabitants of owners had sevenfold higher rates of being fatally shot by a spouse or intimate partner (adjusted hazard ratio, 7.16 [CI, 4.04 to 12.69]); 84% of these victims were female.Some cohort members classified as unexposed may have lived in homes with handguns. Residents of homes with and without handguns may have differed on unobserved traits associated with homicide risk.Living with a handgun owner is associated with substantially elevated risk for dying by homicide. Women are disproportionately affected.The National Collaborative on Gun Violence Research, the Fund for a Safer Future, the Joyce Foundation, Stanford Law School, and the Stanford University School of Medicine.
Abstract P072: Elevated Coronary Artery Calcification In Highly Active Men: Role Of Exercise Intensity Versus Duration
Authors: Andjelka Pavlovic, Laura F Defina, David Leonard, Beth B Wright, Steve Farrell, Kerem Shuval, Ben Levine
Journal: Circulation (2022)

Introduction: While living a physically active lifestyle is associated with many health benefits, recent evidence suggests that high volume physical activity (PA) may contribute to coronary artery calcification (CAC). Whether exercise intensity or duration contributes more to CAC elevation is unknown. Hypothesis: Higher PA intensity, but not duration, predicts elevated CAC. Methods: We studied 25,801 apparently healthy men who completed a self-report PA questionnaire and underwent EBT or MDCT scans as part of a preventive physical examination. Participants were categorized into two CAC groups (≥100 or &lt;100 Agatston units (AU)) and three PA groups (≥3000, 1500 – 2999, and &lt;1500 MET-minutes/week (MET-min/wk)). An exploratory classification tree model identified maximum intensity of activity as the second most important predictor of CAC≥100 AU after age. As such, maximal intensity of activity ≥8 METs was entered as a predictor in subsequent logistic regression models that were adjusted for age, current smoking status, body mass index, glucose, total cholesterol, and systolic blood pressure. We also included categories of PA duration ≥5 or &lt;5 hours/week, the current PA Guidelines recommendation for increased performance. Results: The mean age was 52 years, and 6,075 men had CAC≥100 AU. Regardless of CAC category, the ≥3000 MET-min/wk group had more favorable glucose and lipid profiles compared to the &lt;1500 group. The average PA volume reported in the most highly active group (≥3000 MET-min/wk) was 4626 MET-min/wk with all participants reporting ≥5 hours of PA/week. In the fully adjusted model, maximum exercise intensity ≥8 METs was associated with lower risk of CAC≥100 AU (Relative risk (RR): 0.93, 95% Confidence interval (CI): 0.88 – 0.98, p = 0.004), while total duration of ≥5 hours/week trended in the opposite direction yet without significance (RR: 1.07, CI 95%: 0.98 – 1.17, p = 0.14). Prevalence of CAC≥100 AU was highest among those engaging only in activities &lt;8 METs and for a total duration ≥5 hours/week. Conversely, the lowest prevalence of CAC≥100 AU was found in the higher intensity, lower duration group (≥8 METs, &lt;5 hours/week). Jointly, maximum intensity ≥8 METs was associated with a lower risk of CAC≥100 AU (RR: 0.92, CI 95%: 0.88 – 0.97, p =0.003) only among those with a total duration &lt;5 hours/week. Conclusions: Exercise intensity ≥8 METs was associated with a lower likelihood of men patients presenting with clinically significant CAC while exercise duration of ≥5 hours/week trended in the opposite direction. These novel findings should be considered by clinicians when counseling highly active men with elevated CAC on their exercise prescriptions.
Abstract EP37: Single Dose Aspirin At The First Sign Chest Pain: Reducing Myocardial Infarction Deaths For Us Adults
Authors: Rienna G Russo, Kazem Rahimi, Daniel Wikler, Goodarz Danaei
Journal: Circulation (2022)

Introduction: Acute myocardial infarction (AMI) is a leading cause of morbidity, mortality, and healthcare costs in the United States (US). Aspirin is an effective, low-cost pharmaceutical that can significantly reduce mortality after AMI. The extent of self-administration of aspirin by individuals at the onset of an AMI is undocumented and must be assumed to be the rare exception. Even among adults admitted to an emergency room, only half receive aspirin within a few hours. Objective: The objective of this study was to evaluate the benefits and potential harms of adults self-administering a single dose of aspirin at the onset of chest pain in the US, including deaths delayed from AMI, deaths due to excessive bleeding, and costs per year of life saved (YOLS). Methods: Estimates of AMI incidence rate from the Global Burden of Disease study and population data from the US Census Bureau were used to derive a study cohort of adults over the age of 40 in the US in 2019. We conducted a systematic review to quantify the positive predictive value of a non-specific chest pain for AMI. A 25% relative risk reduction of mortality, based on the Second International Study of Infarct Survival (ISIS) Trial, was applied to case fatality rates of MI derived from a prior global review study. The main outcome was net deaths delayed from aspirin, calculated from deaths delayed post AMI accounting for deaths from excessive bleeding. Secondary outcomes included YOLS and cost of aspirin/YOLS, calculated summing the YOLS and dividing by total cost of aspirin for all adults experiencing chest pain. All analyses were stratified in 5-year age-sex groups. Results: Assuming all adults over the age of 40 years in the US took aspirin within 2 hours of chest pain onset, the total net deaths delayed in 2019 was estimated to be 81,810. There was a total of 83,226 deaths delayed post AMI, which was offset by 1,417 aspirin-related deaths from excess bleeding, leading to an estimated 869,727 YOLS. The cost of the pills was $423,066, translating to $0.49 per YOLS. Benefits were greatest among males and older adults between ages 65 to 75 years. Conclusions: For less than fifty cents per year of life saved, aspirin has the potential to save over 80,000 lives in the US. Benefits of reducing deaths post AMI outweighed the risk of bleeding from aspirin. As aspirin is cost-effective and easily-accessed, efforts should be made to promote ready access and timely use of aspirin within the first 2 hours of chest pain to reduce mortality associated with AMI in the US and abroad.
Effect of host genetics on the gut microbiome in 7,738 participants of the Dutch Microbiome Project
Authors: Esteban A. Lopera-Maya, Alexander Kurilshikov, Adriaan van der Graaf, Shixian Hu, Sergio Andreu-Sánchez, Lianmin Chen, Arnau Vich Vila, Ranko Gacesa, Trishla Sinha, Valerie Collij, Marjiolein A. Y. Klaassen, Laura A. Bolte, Milla F. Brandao Gois, Pieter B. T. Neerincx, Morris A. Swertz, Raul Aguirre-Gamboa, Patrick Deelen, Lude Franke, Jan A. Kuivenhoven, Esteban A. Lopera-Maya, Ilja M. Nolte, Serena Sanna, Harold Snieder, Morris A. Swertz, Judith M. Vonk, Cisca Wijmenga, Hermie J. M. Harmsen, Cisca Wijmenga, Jingyuan Fu, Rinse K. Weersma, Alexandra Zhernakova, Serena Sanna
Journal: Nature Genetics (2022)
Interferon-γ Impairs Human Coronary Artery Endothelial Glucose Metabolism by Tryptophan Catabolism and Activates Fatty Acid Oxidation
Authors: Laurel Yong-Hwa Lee, William M. Oldham, Huamei He, Ruisheng Wang, Ryan Mulhern, Diane E. Handy, Joseph Loscalzo
Journal: Circulation (2021)

Background: Endothelial cells depend on glycolysis for much of their energy production. Impaired endothelial glycolysis has been associated with various vascular pathobiologies, including impaired angiogenesis and atherogenesis. IFN-γ (interferon-γ)–producing CD4 + and CD8 + T lymphocytes have been identified as the predominant pathological cell subsets in human atherosclerotic plaques. Although the immunologic consequences of these cells have been extensively evaluated, their IFN-γ–mediated metabolic effects on endothelial cells remain unknown. The purpose of this study was to determine the metabolic consequences of the T-lymphocyte cytokine, IFN-γ, on human coronary artery endothelial cells. Methods: The metabolic effects of IFN-γ on primary human coronary artery endothelial cells were assessed by unbiased transcriptomic and metabolomic analyses combined with real-time extracellular flux analyses and molecular mechanistic studies. Cellular phenotypic correlations were made by measuring altered endothelial intracellular cGMP content, wound-healing capacity, and adhesion molecule expression. Results: IFN-γ exposure inhibited basal glycolysis of quiescent primary human coronary artery endothelial cells by 20% through the global transcriptional suppression of glycolytic enzymes resulting from decreased basal HIF1α (hypoxia-inducible factor 1α) nuclear availability in normoxia. The decrease in HIF1α activity was a consequence of IFN-γ–induced tryptophan catabolism resulting in ARNT (aryl hydrocarbon receptor nuclear translocator)/HIF1β sequestration by the kynurenine-activated AHR (aryl hydrocarbon receptor). In addition, IFN-γ resulted in a 23% depletion of intracellular nicotinamide adenine dinucleotide in human coronary artery endothelial cells. This altered glucose metabolism was met with concomitant activation of fatty acid oxidation, which augmented its contribution to intracellular ATP balance by &gt;20%. These metabolic derangements were associated with adverse endothelial phenotypic changes, including decreased basal intracellular cGMP, impaired endothelial migration, and a switch to a proinflammatory state. Conclusions: IFN-γ impairs endothelial glucose metabolism by altered tryptophan catabolism destabilizing HIF1, depletes nicotinamide adenine dinucleotide, and results in a metabolic shift toward increased fatty acid oxidation. This work suggests a novel mechanistic basis for pathological T lymphocyte–endothelial interactions in atherosclerosis mediated by IFN-γ, linking endothelial glucose, tryptophan, and fatty acid metabolism with the nicotinamide adenine dinucleotide balance and ATP generation and their adverse endothelial functional consequences.
Abstract 10920: Cost-Effectiveness of Pulmonary Vein Isolation with Epicardial Left Atrial Appendage Ligation for the Treatment of Non-Paroxysmal Atrial Fibrillation
Authors: Christopher C Cheung, Michael Ferguson, Louise H Anderson, Suneet Mittal, Dhanunjaya R Lakkireddy, David J Wilber, Randall J Lee, Thomas A Dewland
Journal: Circulation (2021)

Introduction: Electrical isolation of the left atrial appendage (LAA) using percutaneous epicardial ligation may improve catheter ablation outcomes for non-paroxysmal atrial fibrillation (AF) patients. Little is known regarding the cost effectiveness of this procedure. Hypothesis: We hypothesized that cost-effectiveness between pulmonary vein isolation (PVI) + LAA epicardial ligation using a percutaneous LARIAT ® Suture Delivery Device would be cost effective (CE) compared to PVI alone over 5 years. Methods: A Markov model simulated outcomes for a population with annual stroke risk of 4.6% (CHA 2 DS 2 -VASc score 3). Model inputs for procedure efficacy, stroke and bleed events, health utility, and event costs were estimated from literature. Procedure costs from Medicare rates were used. The model had a 5-year time-horizon and US payer perspective. Univariate and probabilistic sensitivity analyses (PSA) were performed. Outcomes were health care costs and quality-adjusted life-years (QALYs). In the base case, PVI + LAA ligation efficacy from published studies was 67% after 1-year, with an estimated 25% oral anticoagulant (OAC) utilization in PVI + LAA ligation patients in normal sinus rhythm 13-60 months after the index procedure. Cost effectiveness thresholds were evaluated with alternative PVI + LAA ligation efficacy and OAC utilization rates, including 1-year PVI + LAA ligation efficacies of 67%, 70%, 75%, and 80% and OAC utilization of 20-60%. Results: In the base case, PVI + LAA ligation had a mean 5-year cost of $72,865 with 3.25 QALYs and PVI alone had mean cost of $69,936 with 3.19 QALYs. The incremental cost-effectiveness ratio was $46,716; PVI + LAA ligation was CE at $50,000 per QALY gained. In PSA, 64% and 82% of simulations were CE at $50,000 and $100,000 per QALY gained, respectively. In various scenarios, procedure efficacy of 75% combined with OAC utilization of 50% or below yielded CE at $50,000 per QALY gained. Reduction of OAC utilization to 30% yielded CE at $50,000 per QALY gained, regardless of efficacy. Conclusions: In the base case, PVI + LAA ligation was CE at $50,000 per QALY gained when compared to PVI alone. The CE threshold for efficacy was 75% and OAC utilization was 30%. Cost savings were driven by reductions in OAC use and increased efficacy.
Abstract EP61: Short Sleep Duration, Late Sleep Timing, And Late Eating Timing: A Trilogy Of Behavioral Risk Factors For High Blood Pressure?
Authors: Elissa K Hoopes, Melissa Witman, Michele D'Agata, Talia Brookstein-Burke, Shannon M Robson, Susan K Malone, Namni Goel, Freda Patterson
Journal: Circulation (2022)

Introduction: Short sleep duration (&lt;7 h/night) is a risk factor for hypertension and other cardiovascular diseases (CVD). Not clear is if delayed timing of sleep or eating behaviors adds to this risk. We tested the hypothesis that later sleep and eating timing would be associated with higher blood pressure (BP), and that adults with short sleep + late behavior timing would have the highest BP vs those with one (short sleep OR late timing) or no risk behaviors (adequate sleep + early timing). Methods: Over a 14-day period, 30 healthy, non-shift working adults wore wrist actigraphs to evaluate sleep duration and onset timing, and completed image-assisted diet records to estimate eating onset (time of first caloric intake after awakening) and offset (time of last caloric intake before sleep). Fasted morning systolic (SBP) and diastolic BP (DBP) were obtained. Regression models of SBP and DBP tested associations with sleep onset, eating onset, and eating offset. Sleep duration (&lt;7 vs ≥7h) and behavior timing metrics (median split) were dichotomized, and ANOVAs compared BP between sleep duration + behavior timing groups. Results: Participants were 28±7y, 43% male, BMI 23.9±2.6 kg/m 2 , and BP 114±10/70±7 mmHg. Sleep duration was 6.8±0.8 h, sleep onset 23:45±1.3 h, eating onset 08:49±1.5 h, and eating offset 20:40±1.2 h. Independent of age and sex, later sleep onset was associated with higher SBP (B= 3.0±1.3 mmHg/h, p =0.03) and DBP (B= 2.5±0.9 mmHg/h, p =0.01). Later eating onset was associated with higher DBP (B= 2.1±0.9 mmHg/h, p =0.03), and later offset with higher SBP (B= 4.1±1.4 mmHg/h, p &lt;0.01) and DBP (B= 3.3±1.0 mmHg/h, p &lt;0.01). When grouped according to sleep duration and eating offset, short sleep + late timing participants exhibited higher DBP vs adequate sleep + early timing (75±7 vs 67±7, p =0.03) and tended to exhibit higher SBP and DBP vs short sleep OR late timing (both p =0.07). Conclusion: These data indicate later sleep and eating timing, especially in the setting of short sleep, exemplifies a chrono-behavioral phenotype of CVD risk.
Phase IIa clinical trial of complement C3 inhibitor AMY-101 in adults with periodontal inflammation
Authors: Hatice Hasturk, George Hajishengallis, John D. Lambris, Dimitrios C. Mastellos, Despina Yancopoulou
Journal: Journal of Clinical Investigation (2021)

BackgroundGingivitis and periodontitis are prevalent inflammatory diseases of the periodontal tissues. Current treatments are often ineffective or do not prevent disease recurrence. Uncontrolled complement activation and the resulting chronic gingival inflammation are hallmarks of periodontal diseases. We determined the efficacy and safety of a complement 3-targeted therapeutic, AMY-101, which was locally administered to adult patients with periodontal inflammation.MethodsThirty-two patients with gingival inflammation were enrolled in a randomized, placebo-controlled, double-blind, split-mouth phase IIa trial that followed a dose escalation study to select a safe and effective dose in an additional 8 patients. Half of the patient's mouth was randomly assigned to AMY-101 (0.1 mg/site) or placebo injections at sites of inflammation, administered on days 0, 7, and 14, and then evaluated for safety and efficacy outcomes on days 28, 60, and 90. The primary efficacy outcome was a change in gingival inflammation, measured by a modified gingival index (MGI), and secondary outcomes included changes in bleeding on probing (BOP), the amount of plaque, pocket depth, clinical attachment level, and gingival crevicular fluid levels of matrix metalloproteinases (MMPs) over 90 days.ResultsA once-weekly intragingival injection of AMY-101 for 3 weeks was safe and well tolerated in all participants and resulted in significant (P < 0.001) reductions in clinical indices measuring gingival inflammation (MGI and BOP). AMY-101 significantly (P < 0.05) reduced MMP-8 and MMP-9 levels, indicators of inflammatory tissue destruction. These therapeutic effects persisted for at least 3 months after treatment.ConclusionAMY-101 treatment resulted in a significant and sustainable reduction in gingival inflammation without adverse events and, we believe, merits further investigation for the treatment of periodontitis and other oral or peri-implant inflammatory conditions.Trial registrationClinicalTrials.gov identifier NCT03694444.FundingAmyndas Pharmaceuticals.
Novel intraoperative strategies for enhancing tumor control: Future directions
Authors: Alexander F Haddad, Manish K Aghi, Nicholas Butowski
Journal: Neuro-Oncology (2022)

Maximal safe surgical resection plays a key role in the care of patients with gliomas. A range of technologies have been developed to aid surgeons in distinguishing tumor from normal tissue, with the goal of increasing tumor resection and limiting postoperative neurological deficits. Technologies that are currently being investigated to aid in improving tumor control include intraoperative imaging modalities, fluorescent tumor makers, intraoperative cell and molecular profiling of tumors, improved microscopic imaging, intraoperative mapping, augmented and virtual reality, intraoperative drug and radiation delivery, and ablative technologies. In this review, we summarize the aforementioned advancements in neurosurgical oncology and implications for improving patient outcomes.
Therapeutic implications of activating noncanonical PIK3CA mutations in head and neck squamous cell carcinoma
Authors: Nan Jin, Bhumsuk Keam, Janice Cho, Michelle J. Lee, Hye Ryun Kim, Hayarpi Torosyan, Natalia Jura, Patrick K.S. Ng, Gordon B. Mills, Hua Li, Yan Zeng, Zohar Barbash, Gabi Tarcic, Hyunseok Kang, Julie E. Bauman, Mi-Ok Kim, Nathan K. VanLandingham, Danielle L. Swaney, Nevan J. Krogan, Daniel E. Johnson, Jennifer R. Grandis
Journal: Journal of Clinical Investigation (2021)

Alpelisib selectively inhibits the p110α catalytic subunit of PI3Kα and is approved for treatment of breast cancers harboring canonical PIK3CA mutations. In head and neck squamous cell carcinoma (HNSCC), 63% of PIK3CA mutations occur at canonical hotspots. The oncogenic role of the remaining 37% of PIK3CA noncanonical mutations is incompletely understood. We report a patient with HNSCC with a noncanonical PIK3CA mutation (Q75E) who exhibited a durable (12 months) response to alpelisib in a phase II clinical trial. Characterization of all 32 noncanonical PIK3CA mutations found in HNSCC using several functional and phenotypic assays revealed that the majority (69%) were activating, including Q75E. The oncogenic impact of these mutations was validated in 4 cellular models, demonstrating that their activity was lineage independent. Further, alpelisib exhibited antitumor effects in a xenograft derived from a patient with HNSCC containing an activating noncanonical PIK3CA mutation. Structural analyses revealed plausible mechanisms for the functional phenotypes of the majority of the noncanonical PIK3CA mutations. Collectively, these findings highlight the importance of characterizing the function of noncanonical PIK3CA mutations and suggest that patients with HNSCC whose tumors harbor activating noncanonical PIK3CA mutations may benefit from treatment with PI3Kα inhibitors.