tbuckley/cabot-search huggingface dataset:
Mechanisms of gut bacterial metabolism of dietary polyphenols into bioactive compounds
Authors: Sara Alqudah, Jan Claesen
Journal: Gut Microbes (2024)

The fruits and vegetables we consume as part of our diet are rich in bioactive metabolites that can prevent and ameliorate cardiometabolic diseases, cancers, and neurological conditions. Polyphenols are a major metabolite family that has been intensively investigated in this context. However, for these compounds to exert their optimal bioactivity, they rely on the enzymatic capacity of an individual's gut microbiota. Indeed, for most polyphenols, the human host is restricted to more basic metabolism such as deglycosylation and hepatic conjugation. In this review, we discuss the mechanisms by which gut bacteria metabolize the core scaffold of polyphenol substrates, and how their conversion into bioactive small molecules impacts host health.
Metabolic rewiring controlled by HIF-1α tunes IgA-producing B-cell differentiation and intestinal inflammation
Authors: Xianyi Meng, Sahar Asadi-Asadabad, Shan Cao, Rui Song, Zhen Lin, Mohammed Safhi, Yi Qin, Estelle Tcheumi Tactoum, Verena Taudte, Arif Ekici, Dirk Mielenz, Stefan Wirtz, Georg Schett, Aline Bozec
Journal: Cellular and Molecular Immunology (2024)

Abstract Germinal centers where B cells undergo clonal expansion and antibody affinity maturation are hypoxic microenvironments. However, the function of hypoxia-inducible factor (HIF)-1α in immunoglobulin production remains incompletely characterized. Here, we demonstrated that B cells lacking HIF-1α exhibited significantly lower glycolytic metabolism and impaired IgA production. Loss of HIF-1α in B cells affects IgA-producing B-cell differentiation and exacerbates dextran sodium sulfate (DSS)-induced colitis. Conversely, promoting HIF-1α stabilization via a PHD inhibitor roxadustat enhances IgA class switching and alleviates intestinal inflammation. Mechanistically, HIF-1α facilitates IgA class switching through acetyl-coenzyme A (acetyl-CoA) accumulation, which is essential for histone H3K27 acetylation at the Sα region. Consequently, supplementation with acetyl-CoA improved defective IgA production in Hif1a -deficient B cells and limited experimental colitis. Collectively, these findings highlight the critical importance of HIF-1α in IgA class switching and the potential for targeting the HIF-1α-dependent metabolic‒epigenetic axis to treat inflammatory bowel diseases and other inflammatory disorders.
Digital Doppelgängers and Lifespan Extension: What Matters?
Authors: Samuel Iglesias, Brian D. Earp, Cristina Voinea, Sebastian Porsdam Mann, Anda Zahiu, Nancy S. Jecker, Julian Savulescu
Journal: The American Journal of Bioethics (2024)

There is an ongoing debate about the ethics of research on lifespan extension: roughly, using medical technologies to extend biological human lives beyond the current "natural" limit of about 120 years. At the same time, there is an exploding interest in the use of artificial intelligence (AI) to create "digital twins" of persons, for example by fine-tuning large language models on data specific to particular individuals. In this paper, we consider whether digital twins (or digital doppelgängers, as we refer to them) could be a path toward a kind of life extension-or more precisely, a kind of person extension-that does not rely on biological continuity. We discuss relevant accounts of consciousness and personal identity and argue that digital doppelgängers may at least help us achieve some of the aims or ostensible goods of person-span extension, even if they may not count as literal extensions of our personhood on dominant philosophical accounts. We also consider relational accounts of personhood and discuss how digital doppelgängers may be able to extend personhood in a relational sense, or at least secure some of the goods associated with relevant relationships. We conclude by suggesting that a research program to investigate such issues is relevant to ongoing debates about the ethics of extending the human lifespan.
Abstract Su1003: Prospective Assessment of Myocardial Function&amp;Systemic Inflammation after Pediatric Cardiac Arrest: Results from a Pilot Study Utilizing Echocardiogram&amp;Circulating Plasma Biomarkers
Authors: Monique Gardner, Alanah McKelvey, Yan Wang, Fang Chen, Ryan Morgan, Kathryn Graham, Robert Berg, Laura Mercer-Rosa, Nadir Yehya, Alexis Topjian
Journal: Circulation (2024)

Background: Myocardial function and systemic inflammation and their impact on outcomes after pediatric cardiac arrest is understudied. We aimed to prospectively evaluate the association of early myocardial dysfunction and systemic inflammation with hospital mortality. We also sought to identify correlations between arrest characteristics and outcomes with echocardiographic myocardial function and circulating inflammatory biomarkers to inform future study design. We hypothesized that worse myocardial function and higher levels of inflammation would be associated with hospital mortality. Methods: We prospectively enrolled children &lt;18 who received CPR &gt; 1 minute after in- or out-of-hospital cardiac arrest and were admitted to an intensive care unit. We excluded subjects on extracorporeal life support, or within 7 days of bypass. We obtained echocardiograms for global longitudinal and circumferential strain (GLS, GCS) and blood samples for measure of 15 biomarkers within 36 hours of arrest. Clinical data, GLS and GCS, and log-transformed biomarker levels were compared between non-survivors and survivors. Correlations between variables was made with Spearman rho coefficients (ρ). Univariate logistic regression tested the associations between exposures and hospital mortality. In this pilot, p&lt;0.1 was deemed significant for future study. Results: We included 38 subjects with echocardiography; 20 of which had blood samples. Median age was 2.5 years (IQR 0.8-7.1); 57% (n=23) had out-of-hospital arrests and median CPR duration was 10 minutes (IQR 3.5-16.1). Ten subjects (26%) died prior to hospital discharge. GLS (OR 0.98, p=0.72) and GCS (OR 0.92, p=0.22) were not associated with mortality, while MMP-1 (OR 1.67, p=0.09) and IL-8 (OR 2.7, p=0.08) suggested association with mortality. CPR duration was not associated with GLS and GCS but was moderately correlated with MMP-1 (ρ=0.41) and ST2 (ρ=0.51). CXCL10 and TNFa (ρ=0.74), IL-10 and TNFa (ρ=0.70), IL-10 and CXCL10 (ρ=0.83), sRAGE and IL-6 (ρ=0.72) were strongly correlated. MMP-1 and IL-8 (ρ=0.75) and MMP-9 and ST2 were strongly inversely correlated (ρ=-0.72). Conclusion: This pilot study found preliminary associations between inflammatory biomarkers, including including MMP-1 and IL-18, and hospital mortality, but not between echocardiographic function and morality. Larger studies will further investigate the association of myocardial dysfunction and inflammation with pediatric post-cardiac arrest outcomes.
Abstract Sa906: Topological Distribution of <i>KCNH2</i> Variants and Genotype-Phenotype Relationship in Patients with Long QT Syndrome
Authors: Kui Hong, Hongyu Liu, zh Jiang, Yang Shen, Yuhao Su, Ying Shao
Journal: Circulation (2024)

Aims: The aim of this study was to investigate the topological distribution of single nucleotide variants (SNVs) in KCNH2 in patients with long QT syndrome (LQTS) and to explore the relationships between genotypes and phenotypes. Methods: Information on KCNH2 variants in LQTS patients was retrospectively obtained from the HGMD, ClinVar and PubMed databases through October 2022. SNV pathogenicity was classified according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Unpaired t tests and Fisher's exact tests were used to analyze the SNV distributions across structural and functional domains, and their correlations with clinical phenotypes. Results: A total of 2826 variants were obtained; 2152 were SNVs, 1328 of which were non-synonymous SNVs (nsSNVs) associated with LQTS. Enrichment analysis revealed that 602 pathogenic (P) and likely pathogenic (LP) nsSNVs were significantly enriched in the Cyto2, S5, S6, H5, and Extra3. In addition, 759 nsSNVs were enriched in the Per-Arnt-Sim (PAS) and selectivity filter (SF) functional domain. The P and LP nsSNVs remained enriched in the PAS, SF, and cyclic nucleotide binding domain (cNBD). Clinical data showed that patients with nsSNVs located at S5-H5-S6, PAS and SF regions were associated with increased risk of life-threatening cardiac events, including Torsade de Pointes and sudden cardiac death, and were predominantly female. Furthermore, nsSNVs enriched in N-terminus region, S5-H5-S6 region and PAS domain were associated with an increased risk of syncope. Conclusion: The KCNH2 nsSNVs located at the S5-H5-S6 region, and the PAS and SF domains are associated with increased risk of life-threatening cardiac events.
Abstract Su106: Cardiac Protection using Inhaled Argon During Resuscitation from Cardiac Arrest in Rats
Authors: Matthew Barajas, Takuro Oyama, Hisham Kashif, Aayush Kumar, Zhu Li, Matthias Riess
Journal: Circulation (2024)

Recent investigations have demonstrated early promising results using inhaled noble gas therapy during cardiopulmonary resuscitation. Despite characterization as chemically inert, they have demonstrated biological activity at varied enzyme and receptor sites. Importantly, their mechanism of action on ischemia reperfusion injury remains unelucidated.1 We aimed to determine the efficacy of inhaled argon on ameliorating cardiac dysfunction associated with fibrillatory arrest in a rat model. Fifteen male Sprague Dawley rats were utilized. Rats were mechanically ventilated via endotracheal tube and anesthetized with isoflurane. Femoral artery and vein were cannulated for pressure monitoring and drug delivery. An esophageal pacing probe provided low voltage current to induce fibrillatory arrest lasting a total of 7.5 minutes. CPR was initiated utilizing an automated chest compressor at a rate of 200/min with a controlled depth. Animals were randomly assigned to inhaled argon (70% with 30% O2) or control (70% N2 with 30% O2.) Defibrillation and epinephrine were given, in a standardized fashion. If return of spontaneous circulation (ROSC) was achieved, epinephrine drip was titrated to maintain a mean arterial pressure (MAP) of 70 mmHg. Data was collected at 15 min, 1 and 2 hr after ROSC. Data were analyzed using unpaired t-test. Significance set at p &lt;.05, two-tailed. There was no significant difference in rate of ROSC between groups (66% control vs 83% argon), however time to achieve ROSC was significantly reduced in the argon group, 350 v. 948 seconds, p = 0.02. Furthermore, animals treated with argon had increased survival time, 116 min vs 62 min control, p = 0.03. Decreased epinephrine requirement to maintain mean arterial pressure at 70 mmHg was seen in argon group 9.3 mcg min-1 vs 53.7 mcg min-1 in the control group, p = .04. There was no significant difference in peak lactate or other arterial blood gas markers. Inhaled argon therapy remains a promising novel treatment after prolonged cardiac arrest. While other animal models have suggested similar findings, this is the first description in a fibrillatory rat model. Continued evaluation should aim to elucidate mechanism of action after demonstration of model effectiveness.
Abstract Su107: The Role of TRPV2 Ion Channel in NAMPT Secretion During Cardiac Arrest
Authors: Xiangdong Zhu, Jing Li, Shaoxia Lin, Terry Vanden Hoek
Journal: Circulation (2024)

Introduction: Extracellular NAMPT functions as a novel damage-associated molecular pattern. It has been shown to be released from many cell types including neutrophils and cardiomyocytes. In a mouse model of cardiac arrest, increased plasma NAMPT correlates with inflammation, cardiovascular dysfunction and poor survival, and neutrophils are the major contributor to plasma NAMPT during cardiac arrest. However, the mechanisms of NAMPT release are currently not well understood. Hypothesis: We hypothesize that NAMPT release is regulated by a non-selective cation channel TRPV2. Methods: Human blood neutrophils were isolated by Percoll density gradient. TRPV2 channel activity was measured by calcium influx using Furo-4. The effect of TRPV2 agonist and inhibitor on the intracellular free Ca 2+ flux was performed by monitoring fluorometric kinetic readings. Extracellular NAMPT concentration in cell supernatants was measured by ELISA. Results: NAMPT release is affected by extracellular pH. The decrease in pHo from 7.4 to 7.0 significantly reduced the amount of eNAMPT from 8.31 ± 0.3 ng/ml to 1.72 ± 0.4 ng/ml. By contrast, the increase of the pHo from 7.4 to 7.8 enhanced NAMPT secretion into supernatant from 8.31 ± 0.3 ng/ml to 12.04 ± 0.3 ng/ml. We therefore reasoned that ion channels sensitive to pH change might play a role in NAMPT secretion. Several transient receptor potential (TRP) channels are exquisitely sensitive to extracellular pH. Calcium chelator EGTA at 1 mM completely blocked NAMPT release, which indicates a calcium channel is involved. 2-aminoethoxydiphenyl borate (2-APB) has been shown to stimulate many TRPV channels. 2-APB increased NAMPT release in a dose-dependent manner, and maximal release was induced by 1 mM 2-APB. Tranilast and piperlongumine, two structurally unrelated TRPV2 antagonists, significantly inhibited NAMPT release from neutrophils. By contrast, neither TRPV1 inhibitor SB366791 nor TRPV4 inhibitor GSK219384 has any effect on NAMPT release. Furthermore, TRPV2 inhibitors tranilast and piperlongumine blocked calcium influx induced by 2-APB. Conclusion: NAMPT release from neutrophils is regulated by TRPV2 channel-mediated calcium influx.
Abstract Su1012: Rate of Thoracic Skeletal Fractures with Circumferential Constriction Cardiopulmonary Resuscitation – Comparison to Historical Reports
Authors: Aidan Paradis, David Gaddy, Karen Moodie, Timothy Mader, Alexandre Dufresne, Christine Couturier, Simon Dufresne, Daniel Davis, Christopher Sims, Norman Paradis
Journal: Circulation (2024)

Introduction: Traditional sternal piston-type CPR ( SP-CPR ) is associated with rib and sternal fractures in a large fraction of porcine cardiac arrest studies. Most investigators using SP-CPR “mold” the pig’s precordium to prevent piston movement and enhance the “cardiac pump.” This molding is essentially disruption of the sternocostal joints. Although circumferential constriction CPR ( CC-CPR ) applies more motive force to the chest, it spreads this force over a much larger area. This results in a less concentrated force which may cause less skeletal injury. Hypothesis: CC-CPR may be associated with a lower incidence of thoracic skeletal injury. Methods: Retrospective observational report of multiple porcine studies. Ventricular fibrillation was induced in female Yorkshire swine (n = 30, 28±5 kg). CPR was provided by means of pneumatic CC-CPR prototypes in all animals. Most received thoracoabdominal CPR with pneumatic bands around both the chest and the abdomen. Thoracic vest pressures ranged from 180–300mmHg with constriction rates from 80–120 per minute and duty cycles from 30-50%. Duration of resuscitation was typically 20 min. Examination for injuries was via visual inspection and palpation both externally and internally during postmortem by the team veterinarian. We used the fracture rates reported in previous porcine CPR studies as a historical control. Results: In this large series of porcine studies with CC-CPR, which included per-constriction forces as great as 400kg and relatively long intervals of resuscitation, only 2 rib fractures were found, a rate of 0.07 fractures per pig. No sternal or chondral injuries were detected. We found four prior studies, all using SP-CPR, that appeared to reliably report a CPR-related fracture rate. The average rate was 4.45±1.6 per animal. Sternocostal joint disruption from “molding” did not appear to be reported as injury in published studies. Conclusion: CC-CPR appears to be associated with a remarkably low rate of thoracic skeletal injury in porcine models, compared with historical controls. It is not known if this enhanced safety in animals will translate to patients in the clinical setting, most of whom will have received manual and/or sternal piston type CPR before CC-CPR can be initiated.
Abstract 4148118: Causes of Thirty Day Readmission Following ICD Placement in Heart Failure Patient with Amyloidosis
Authors: Vivek Jha, Badri Aryal, Taha Teaima, Andres Quevedo Ramirez, IMRAN AZIZ, Rohan Gajjar
Journal: Circulation (2024)

Background and Objectives: Data regarding readmission rate following ICD placement in heart failure patients with Cardiac amyloidosis are scare. We attempted to study 30-day readmission rate following ICD placement in these patients and the common causes of readmission. Methods: We utilized the Nationwide Readmission Database from 2016 to 2020 and included patients more than 18 years of age who were admitted for placement of Implantable Cardiac Defibrillator (ICD) and had secondary diagnosis of heart failure and amyloidosis. We used International Classification of Disease, Tenth Revision, Clinical Modification (ICD10 CM) codes to identify patients. The primary outcome was the 30-day readmission rate, and secondary outcomes were mortality rates, and common reasons for readmission. Results: We identified a total of 457 patients who underwent placement of ICD and had heart failure with amyloidosis, among which mean age was 69 years and 25.42% were females. The 30-day readmission rate was 19.50%. Mortality rate was higher in readmitted patients (7.12%) as compared to index admission (3.82%). Most common causes of readmission were hypertension and heart failure with CKD stage 1 to 4(22%), hypertensive heart disease with heart failure (8.35%), hypertensive heart disease with CKD 5 or ESRD (7.58%), Acute Kidney Injury (5.94%), Non-specific chest pain (5.56%), Organ specific amyloidosis (5.43%), Cellulitis (3.68%), Acute on chronic systolic heart failure (3.56%), and Acute systolic heart failure (3.17%) Conclusion: The thirty-day readmission rate was 19.50% and most common cause of readmission was hypertension and heart failure with CKD. Improvement of management strategies is needed to address these causes and improve patient outcomes.
Abstract Sa701: Sex disparities in receipt of bystander-initiated cardiopulmonary resuscitation and associated time measures
Authors: Audrey Blewer, Konstantin Krychtiuk, Harman Yonis, Monique Starks, Hayden B. Bosworth, Carolina Malta Hansen, Stephen Powell, Lisa Monk, Lisa Kaltenbach, Hussein Al-Khalidi, Steve Vandeventer, Bryan McNally, Sana M. Al-Khatib, Daniel Mark, Christopher Granger
Journal: Circulation (2024)

Introduction: Female sex is associated with lower rates of bystander cardiopulmonary resuscitation (B-CPR) in public. Telecommunicator CPR (T-CPR), or provision of CPR instructions when individuals call 9-1-1, is essential to improving B-CPR. Few investigations have examined how T-CPR impacts this known sex difference in receipt of B-CPR. Objectives: We sought to examine sex disparities in receipt of B-CPR and time measures with provision of T-CPR. We hypothesized that with provision of T-CPR instruction, there would be no sex disparity in the receipt of B-CPR. Methods: We conducted a retrospective cohort study of adult, non-traumatic out-of-hospital cardiac arrests (OHCA) from the North Carolina (NC) RACE-CARS trial ( NCT04660526) dispatch module. We examined differences between males and females in receipt of B-CPR (primary outcome) and time measures (secondary outcomes), including time to recognition and time to first compression (secs). Between-group comparisons were assessed using the Pearson’s Chi-square or Fisher’s exact test for categorical variables and the Wilcoxon rank-sum test for continuous variables. Results: From 7/2022-12/2023, RACE-CARS collected data on 8,839 OHCAs covering 52 counties in NC. After excluding pediatric, traumatic, EMS-witnessed, and healthcare facility arrests there were 2,398 OHCAs. Median (25 th , 75 th percentiles) age was 63 (49-74), 67% were White, and 37% were female. B-CPR was administered in 52% of the OHCAs (81% with telecommunicator assistance vs. 19% without). When the telecommunicator provided assistance vs when they did not, B-CPR was 44% vs. 9% for female patients and 40% vs. 11% for male patients; these sex differences were not statistically significant (p=ns). Median time to CPR recognition from call received (secs) was 87 (50-149) for females vs. 87 (53-160) for males. Median time to first compression from telecommunicator call to call received (secs) was 204 (147-275) for females vs. 207 (145-281) for males (p=ns). Conclusion: Telecommunicator CPR may potentially attenuate the known sex disparity in receipt of B-CPR. Understanding this may help inform future health policy and advocacy for prehospital systems of care. Future work may examine how T-CPR decreases sex variation and increases B-CPR especially in women.
Abstract Sa805: Diastolic Blood Pressure Response to Sodium Bicarbonate Administration in Pediatric In-Hospital Cardiac Arrest
Authors: Jill Sorcher, Nicole Duster, Monica Kleinman, Catherine Ross
Journal: Circulation (2024)

Background: Despite national guidelines recommending against its routine use, sodium bicarbonate (SB) is administered in approximately 50% of pediatric in-hospital cardiac arrests (p-IHCA). This may partially be explained by the commonly held belief that SB administration increases extracellular pH and mitigates myocardial depression associated with intra-arrest acidosis. However, physiologic response to SB during p-IHCA has not been previously described and may provide insight for its use during cardiopulmonary resuscitation (CPR). Aim: To explore diastolic blood pressure (DBP) response to SB administration during p-IHCA. Hypothesis: We hypothesized that SB administration would be associated with increased DBP. Methods: Retrospective single center study of patients ≤ 18 years old who experienced pulseless IHCA and received intra-arrest SB with an arterial line present from 2013 to 2023. Events in which epinephrine was given in the same minute as the first dose of SB were excluded. Events were divided into 30-second epochs for which the average DBP was calculated using stored monitor data. The 30-second epoch prior to the minute of SB administration was used as the baseline. The primary outcome was the change in DBP one minute post-SB administration, defined as the average of the 2 epochs after the full minute of SB administration. We also performed a sensitivity analysis, expanding the post-SB period as the 4 epochs (2 minutes) after SB administration for patients with ongoing CPR and without epinephrine administration in the interim period. Change in DBP was compared using a paired t-test. Results: In the 32 events included, the mean DBP 1minute post-SB administration significantly increased from 39.2 mmHg to 42.7 mmHg (mean difference 3.5, 95% CI: 0.4, 6.6, p = 0.03). Sensitivity analysis (n=24) at 2 minutes post-SB administration showed a change in mean DBP from 41.2 mmHg to 43.5 mmHg (mean difference 2.3 mmHg, 95% CI: -0.8, 5.05 p = 0.13). Conclusions: SB administration during p-IHCA was associated with a significant increase in DBP 1 minute post-SB, but the increase in DBP did not reach statistical significance when averaged over 2 minutes post-SB. Given known associations between DBP and outcomes in p-IHCA, these results support the need for further investigation of physiologic response and clinical outcomes associated with intra-arrest SB administration.