tbuckley/cabot-search huggingface dataset:
Abstract MP56: Sleep Regularity Modifies The Association Of Visceral Adiposity With Elevated Blood Pressure In Adolescents
Authors: Natasha Morales-Ghinaglia, Susan L Calhoun, Fan He, Jason Liao, Alexandros N Vgontzas, Edward O Bixler, Duanping Liao, Julio Fernandez-Mendoza
Journal: Circulation (2022)

Introduction: Although obesity, insufficient sleep and sleep apnea are known risk factors for elevated blood pressure, the circadian timing of sleep is also involved in metabolic and blood pressure regulation. As a result, sleep irregularity, which is highly prevalent in adolescents, may be a potential risk factor for obesity-related adverse cardiovascular outcomes. Hypothesis: We hypothesize that greater sleep irregularity increases the impact of visceral adiposity on elevated blood pressure in adolescents. Methods: We analyzed cross-sectional data from the Penn State Child Cohort follow-up study, a random population-based sample of 303 adolescents (16.2 ± 2.2 year old; 47.5% female; 21.5% racial/ethnic minority) who had complete at-home 7-night (at least 5) actigraphy (ACT) data and in-lab dual-energy X-ray absorptiometry (DEXA) scan and polysomnography (PSG) data. ACT-measured sleep duration and sleep midpoint were calculated as the intra-individual mean of the 7-night total sleep time and the midpoint (zeroed to midnight) of the sleep period, respectively. ACT-measured sleep regularity was calculated as the intra-individual standard deviation of the 7-night sleep midpoint. DEXA-measured visceral adipose tissue (VAT) was the primary predictor. Systolic (SBP) and diastolic (DBP) blood pressure, measured three times in the seated position, were the primary outcomes. Multivariable linear regression models tested sleep midpoint and sleep regularity as effect modifiers of VAT on SBP/DBP levels, while simultaneously adjusting for sex, race/ethnicity, age, ACT-measured sleep duration and PSG-measured apnea/hypopnea index. Results: Significant interactions were found between sleep regularity and VAT on SBP (p-interaction=0.009) and DBP (p-interaction=0.039), while not between mean sleep midpoint and VAT (p-interactions=0.210 and 0.883). These findings remained valid even after further adjusting for body mass index percentile (p-interactions=0.006 and 0.034). Among adolescents with high sleep irregularity (≥ 45 minutes; n=124), each standard deviation increase in VAT was associated with a 5.55 (0.91) and 3.07 (0.70) mmHg increase in SBP and DBP, respectively (both p&lt;0.001). Among those with low sleep irregularity (&lt; 45 minutes; n=179) VAT was not significantly associated with SBP [0.69 (0.99), p=0.488] or DBP [0.04 (0.77), p=0.956]. Conclusions: An irregular circadian timing of sleep may increase the impact of visceral adiposity on elevated blood pressure in adolescents. These data support that sleep irregularity, independent of sleep apnea and insufficient sleep, may contribute to the development of cardiovascular sequelae associated with central obesity.
Single-Cell Analysis Reveals EP4 as a Target for Restoring T-Cell Infiltration and Sensitizing Prostate Cancer to Immunotherapy
Authors: Shihong Peng, Pan Hu, Yu-Tian Xiao, Weiqiang Lu, Dandan Guo, Shixiu Hu, Jiayi Xie, Minna Wang, Weiwei Yu, Junjie Yang, Huang Chen, Xiaomin Zhang, Yasheng Zhu, Ye Wang, Yue Yang, Guanghui Zhu, Sujun Chen, Jian Wang, Bo Zhang, Weidong Chen, Huangan Wu, Zhenliang Sun, Tao Ding, Hankun Zhang, Zhengfang Yi, Mingyao Liu, Shancheng Ren
Journal: Clinical Cancer Research (2021)

Immunotherapies targeting immune checkpoint molecules have shown promising treatment for a subset of cancers; however, many "cold" tumors, such as prostate cancer, remain unresponsive. We aimed to identify a potential targetable marker relevant to prostate cancer and develop novel immunotherapy.Analysis of transcriptomic profiles at single-cell resolution was performed in clinical patients' samples, along with integrated analysis of multiple RNA-sequencing datasets. The antitumor activity of YY001, a novel EP4 antagonist, combined with anti-programmed cell death protein 1 (PD-1) antibody was evaluated both in vitro and in vivo.We identified EP4 (PTGER4) as expressed in epithelial cells and various immune cells and involved in modulating the prostate cancer immune microenvironment. YY001, a novel EP4 antagonist, inhibited the differentiation, maturation, and immunosuppressive function of myeloid-derived suppressor cells (MDSC) while enhancing the proliferation and anticancer functions of T cells. Furthermore, it reversed the infiltration levels of MDSCs and T cells in the tumor microenvironment by overturning the chemokine profile of tumor cells in vitro and in vivo. The combined immunotherapy demonstrated a robust antitumor immune response as indicated by the robust accumulation and activation of CD8+ cytotoxic T cells, with a significantly decreased MDSC ratio and reduced MDSC immunosuppression function.Our study identified EP4 as a specific target for prostate cancer immunotherapy and demonstrated that YY001 inhibited the growth of prostate tumors by regulating the immune microenvironment and strongly synergized with anti-PD-1 antibodies to convert completely unresponsive prostate cancers into responsive cancers, resulting in marked tumor regression, long-term survival, and lasting immunologic memory.
Increasing Incidence of Early-Onset Colorectal Cancer
Authors: Frank A. Sinicrope
Journal: New England Journal of Medicine (2022)

Early-onset disease (at <50 years of age) accounts for 10% of colorectal cancer cases, and the incidence is increasing, particularly in high-income countries. Patients often present with advanced disease in the left colon. One in six patients has deficient DNA mismatch repair. Screening is now recommended to begin at 45 years of age.
10P Treatment-free survival (TFS) in metastatic non-small cell lung cancer (mNSCLC) patients (pts) treated with 1L nivolumab plus ipilimumab (NIVO+IPI) or platinum doublet chemotherapy (PDC) in CheckMate (CM) 227
Authors: S. Peters, J. Penrod, J. Li, S. Lubinga, R. Gupta, J. Bushong, J. Rizzo, S. Ramalingam
Journal: Annals of Oncology (2022)
Abstract 067: Outcome Preferences Related To Cardiovascular Preventive Therapies In Older Adults: An Online Survey
Authors: Frances M Wang, Henock G Yebyo, Cynthia Boyd, Milo A Puhan, Kuni Matsushita, Michael J Blaha, Nancy Schoenborn
Journal: Circulation (2022)

Background: Personalized cardiovascular disease (CVD) preventive therapy for older adults is important and emphasized in current clinical guidelines. Older adults often have multiple chronic conditions, are at higher risk for medication side effects, and may have different preferences when weighing multiple health outcomes. However, little is known about preferences for outcomes related to CVD preventive therapies in older adults. Methods: In May 2021, using an online panel, we surveyed US older adults (age 65-84 years) on outcome preferences related to statin (benefit-related outcomes: heart attack and stroke; side effect-related outcomes: diabetes, abnormal liver test, and muscle pain) or aspirin (benefit-related outcomes: heart attack and stroke; side effects: brain bleed, bowel bleed, and stomach ulcer). We used best-worst scaling, a novel stated-preference research method, to quantify relative outcome priorities. A standardized score was calculated for each outcome to indicate the strength of preference, ranging from -1.0 (least worrisome) to +1.0 (most worrisome). Results: 304 participants (median age 75, 45% male) completed the statin survey and 303 participants (median age 74, 46% male) completed the aspirin survey. In both surveys, stroke and heart attack, the two benefit outcomes from CVD prevention, were considered significantly more worrisome than outcomes related to side effects of the preventive therapies ( Table ). The general trend was similar for those age 65-74 vs. 75-84, although those age 75-84 tended to worry more about stroke than heart attack. Conclusions: Older adults considered the outcomes related to the benefits of CVD preventive therapies more important than outcomes related to the therapies’ side effects. These results suggest that older adults tend to prioritize the benefits of CVD preventive therapies over their side effects. Integrating individualized patient preferences with risk prediction to guide personalized shared decision-making is an important next step.
A Pandemic Lesson for Global Lung Diseases: Exacerbations Are Preventable
Authors: William Cookson, Miriam Moffatt, Garth Rapeport, Jennifer Quint
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Section:ChooseTop of pageAbstract <<Circulation of Respirator...Pandemic Effects on Exace...Acute Bacterial Infection...Postpandemic Return of Co...Known Roles of Viral Exac...Bacterial Transmission an...Ecology of Airway Microbi...Therapeutic ImplicationsConclusionsReferences
Abstract 013: Metabolomic Profiles And Ideal Cardiovascular Health: Insights From The Framingham Heart Study (fhs)
Authors: Yi Li, Ayana R Gray, Liying Xue, Charlotte Andersson, Darae Ko, Emelia J Benjamin, Daniel Levy, Ramachandran S Vasan, Martin Larson, Jian Rong, Chunyu Liu, Vanessa Xanthakis, Jessica L Fetterman, Deepa M Gopal
Journal: Circulation (2022)

Introduction: The American Heart Association’s framework “ideal cardiovascular health” (CVH) focuses on modifiable risk factors to reduce the overall burden of cardiovascular disease (CVD). Metabolomics provide important pathobiological insights into risk factors and CVD development. Whether circulating metabolites relate to CVH status and mediate the relations of CVH score with atrial fibrillation (AF) and heart failure (HF) has not been explored. Hypothesis: We hypothesized: a) CVH score associates with metabolites; and b) metabolites mediate the relation of CVH score with incident AF and HF. Methods and Results: We analyzed 3056 adults (mean age 54 years; 54% women) in FHS Offspring Cohort (Exam 5); 2059 participants had metabolomics data. Each metabolite measurement was log transformed and standardized for data normalization. Using linear mixed models, CVH score was associated with 144 metabolites (false discovery rate, q-value &lt; 0.05), adjusting for age, sex, estimated glomerular filtration rate (eGFR) and family structure. Of these 144 metabolites, 65 metabolites overlapped with key cardiometabolic components of the CVH score (body mass index, blood pressure, and fasting blood sugar). In mediation analyses (adjusting for age, sex, eGFR), no metabolites mediated the relation between CVH score and incident AF. However, 11 metabolites (C36:4 phosphatidylcholine, isocitrate, glycerol, ornithine, aminoadipate, 3-indolepropionic acid, cystathionine, asparagine, alpha-hydroxybutyrate, phosphorylated saccharides, and C52:5 triacylglycerol) partially mediated the association between CVH score and incident HF in multivariable-adjusted models. Conclusion: Multiple metabolites associate with the CVH score and many of the metabolites are specifically associated with the cardiometabolic components of the CVH score. Several metabolic signatures, particularly lipids and tricarboxylic acid cycle intermediates, partially mediated the relation between CVH score and incident HF. Our findings lend insight into the role of metabolites in the relations of modifiable cardiovascular risk factors with incident HF.
Impact of Follow-up 18F-FDG PET on the Management in Patients With Lung Cancer
Authors: Hai-Jeon Yoon, Kyoungjune Pak
Journal: Clinical Nuclear Medicine (2021)

Purpose The incidence of lung cancer has increased steadily. We meta-analyzed to assess the impact of 18 F-FDG PET on the management of lung cancer to detect recurrence/metastasis. Materials and Methods We performed systematic searches of Medline and Embase databases for English-language publications. All published studies regarding the impact of PET on the management of patients with lung cancer in detection of recurrence/metastasis were searched. The proportion of management change (%) defined as the percentage of patients who changed management after FDG PET to patients who had FDG PET was calculated. The data from each study were analyzed using MedCalc Statistical Software version 14.12.0 (MedCalc Software, Ostend, Belgium). Results Eight studies including 523 patients were eligible for inclusion in the study. The impact of 18 F-FDG PET for the purpose of detecting recurrence/metastasis in patients with lung cancer was evaluated using management change rates, which were ranged from 28.6% to 79.2% with a pooled effect of 61.4% (95% confidence interval, 49.5%–72.7%; I 2 = 85.7%). In a subgroup analysis, impact of 18 F-FDG PET was evaluated in studies of patients with non–small cell lung cancer with indication of abnormal findings of conventional imaging, elevated tumor markers, and clinical symptoms with the pooled rate of management change of 62.2% (95% confidence interval, 44.2%–78.5%; I 2 = 88.0%). Conclusions We have highlighted that 18 F-FDG PET has a major impact on the management of patients with recurrent lung cancer. These findings suggest that 18 F-FDG PET should be performed in patients with lung cancer, especially in cases involving equivocal or suspicious recurrence/metastasis on conventional imaging, elevated tumor markers, or clinical symptoms during follow-up.
Abstract P196: Hand Grip Strength, Gait Speed And Incident Heart Failure In Older Adults
Authors: Veronica Manzo, Mahim Naveed, Anne Newman, Traci Bartz, Javed Butler, Calvin Hirsch, Venkatesh Murthy, Jorge Kizer
Journal: Circulation (2022)

Title: Hand Grip Strength, Gait Speed and Incident Heart Failure in Older Adults Introduction: Heart failure (HF) is predominantly a disorder of older adults. Its cardinal feature, decreased exercise tolerance, results from both central (cardiac) and peripheral (skeletal muscle) dysfunction. Skeletal muscle weakness and frailty are common aspects of aging that are associated with vascular disease and may predispose to HF onset. Although simple measures of physical function like hand grip strength and gait speed have been linked to disability and mortality, their individual associations with incident HF in elders remain unclear. The relationship of these measures with onset of HF subtypes has not been previously studied. Hypothesis: We tested the hypothesis that lower grip strength and gait speed are independently associated with higher risk of HF and its subtypes (preserved [HFpEF] and reduced [HFrEF]). Methods: A total of 7,144 participants free of prevalent HF with available muscle measures were pooled from two prospective older cohorts, the Cardiovascular Health Study (n=4584) and the Health, Aging, and Body Composition Study (Health ABC) (n=2560). Grip strength was assessed by dynamometry, and gait speed based on a short-distance walk (calibrated to ~4 m in both studies). In a secondary analysis, we evaluated thigh muscle strength, assessed by isokinetic dynamometry in Health ABC only. Incident HF and its subtypes were adjudicated with similar methods in both studies. Cox models were fitted to estimate risks of incident HF after adjustment for potential confounders (age, sex, race/ethnicity, body mass index, smoking, alcohol, systolic blood pressure, antihypertensive medication, diabetes, coronary heart disease, cerebrovascular disease, peripheral artery disease, atrial fibrillation, forced expiratory volume in 1 second, albumin, estimated glomerular filtration rate). Results: Median age was 72, 42.2% were male, and 22.9% Black. Lower gait speed was significantly associated with higher incident HF (HR per SD = 1.16 [95% CI = 1.10-1.23]) after full adjustment, but this was not observed for lower grip strength (HR per SD = 1.02 [0.95-1.10]). Gait speed showed consistent inverse associations with both HF subtypes: HFpEF: HR per SD = 1.23 [1.10-1.36]); HFrEF (HR per SD = 1.15 [1.03-1.27]). Thigh muscle strength was not significantly associated with incident HF in Health ABC (HR per SD = 1.11 [0.95-1.30]). There was no evidence of effect modification by race or by cohort. Conclusion: In two prospective cohorts of older adults of mixed race, lower gait speed, but not strength, was associated with higher risk of HF and its subtypes. Whether this readily obtainable measure of functional capacity could be used for HF risk stratification and targeting of preventive interventions will require further study.
Bones and adrenal organogenesis: how embryonic osteocalcin influences lifelong adrenal function
Authors: Typhanie Dumontet, Gary D. Hammer
Journal: Journal of Clinical Investigation (2022)

Osteocalcin is a hormone produced in bones by osteoblasts during bone formation. Numerous studies have demonstrated that adrenal gland-derived glucocorticoids inhibit osteocalcin production, which can ultimately cause deleterious bones loss. This loss establishes a unidirectional endocrine relationship between the adrenal glands and bone, however, whether osteocalcin reciprocally regulates glucocorticoid secretion remains unclear. In this issue of the JCI, Yadav and colleagues address how bone-derived osteocalcin influences adrenal organogenesis and function. Using a large variety of animal models, the authors established that embryonic osteocalcin signaling, specifically through the GPR158 receptor, regulates postnatal adrenal steroid concentrations throughout life. This work has translational potential, and we await future investigations that determine whether modulating osteocalcin levels could promote endogenous adrenocortical function in adrenocortical hypoplasia and glucocorticoid deficiency.
Immunosuppressant Medication Use in Patients with Kidney Allograft Failure: A Prospective Multicenter Canadian Cohort Study
Authors: Greg Knoll, Patricia Campbell, Michaël Chassé, Dean Fergusson, Tim Ramsay, Priscilla Karnabi, Jeffrey Perl, Andrew A. House, Joseph Kim, Olwyn Johnston, Rahul Mainra, Isabelle Houde, Dana Baran, Darin J. Treleaven, Lynne Senecal, Lee Anne Tibbles, Marie-Josée Hébert, Christine White, Martin Karpinski, John S. Gill
Journal: Journal of the American Society of Nephrology (2022)

Significance Statement Current recommendations suggest discontinuation of immunosuppressants 1 year after kidney transplant failure. In this first prospective multicenter study of 269 patients with kidney transplant failure in 16 Canadian centers, most patients were prescribed immunosuppressants for longer than 2 years. Continued use of immunosuppressants was not associated with an increased risk of death or hospitalized infection. However, the continued use of immunosuppressants did not prevent rejection of the failed allograft or an increase in anti-HLA antibodies, possibly due to inadequate drug exposure. The findings challenge current recommendations and highlight the need for a controlled trial of immunosuppressant use in patients with transplant failure. Background Patients with kidney transplant failure have a high risk of hospitalization and death due to infection. The optimal use of immunosuppressants after transplant failure remains uncertain and clinical practice varies widely. Methods This prospective cohort study enrolled patients within 21 days of starting dialysis after transplant failure in 16 Canadian centers. Immunosuppressant medication use, death, hospitalized infection, rejection of the failed allograft, and anti-HLA panel reactive antibodies were determined at 1, 3, 6, and 12 months and and then twice yearly until death, repeat transplantation, or loss to follow-up. Results The 269 study patients were followed for a median of 558 days. There were 33 deaths, 143 patients hospitalized for infection, and 21 rejections. Most patients (65%) continued immunosuppressants, 20% continued prednisone only, and 15% discontinued all immunosuppressants. In multivariable models, patients who continued immunosuppressants had a lower risk of death (hazard ratio [HR], 0.40; 95% confidence interval [CI], 0.17 to 0.93) and were not at increased risk of hospitalized infection (HR, 1.81; 95% CI, 0.82 to 4.0) compared with patients who discontinued all immunosuppressants or continued prednisone only. The mean class I and class II panel reactive antibodies increased from 11% to 27% and from 25% to 47%, respectively, but did not differ by immunosuppressant use. Continuation of immunosuppressants was not protective of rejection of the failed allograft (HR, 0.81; 95% CI, 0.22 to 2.94). Conclusions Prolonged use of immunosuppressants &gt;1 year after transplant failure was not associated with a higher risk of death or hospitalized infection but was insufficient to prevent higher anti-HLA antibodies or rejection of the failed allograft.
Abstract P237: Matrix Metalloproteinases (MMPs) And Risk Of Incident Hemorrhagic And Ischemic Stroke: The Atherosclerosis Risk In Communities Study (ARIC)
Authors: Yuekai Ji, Pamela L Lutsey, Weihong Tang, Kamakshi Lakshminarayan, Ron C Hoogeveen, Christie M Ballantyne
Journal: Circulation (2022)

Introduction: Matrix metalloproteinases (MMPs), belong to a family of zinc-dependent endopeptidases, have been found to induce stroke through its role in extracellular matrix destruction. MMPs also affect the stroke prognosis by disrupting blood brain barrier during stroke. Genetic association studies suggest that MMPs are involved in the pathogenesis of both ischemic and hemorrhagic stroke. Hypothesis: High MMP-2, MMP-9 and ratio of MMP-9/TIMP-1 are associated with higher risk of ischemic and hemorrhagic stroke. Method: After exclusion of missing data and prevalent stroke, 11,393 ARIC participants were followed from midlife (visit 3; 1993-1995) and 4,924 participants followed from late life (visit 5; 2011-2013) to 2019. Plasma levels of MMPs were measured by SOMAscan version 4 assay. Stroke cases were reviewed and adjudicated by neurologists. We used Cox models to examine the relationship between MMPs and stroke risk. Result: Mean age of participants were 60±5.7 at visit 3 and 76±5.2 at visit 5. At visit 3 55% were female and 21% Black. A total of 1,013 ischemic and 127 hemorrhagic strokes occurred over 22.34 years of follow-up for the visit 3 analysis and 319 ischemic and 30 hemorrhagic strokes over 7.24 years for the visit 5 analysis. A significant and positive association was detected for MMP-2 at visit 3 baseline for hemorrhagic stroke (HR (95% CI): 2.28 (1.14-4.57)) and at visit 5 baseline with ischemic stroke (1.65 (1.08-2.53)), after covariate adjustment. No associations were observed with MMP-9 and TIMP-1. Conclusion: Results of MMP-2 indicate a possible relationship with MMPs and stroke subtypes, but were not consistent. Though no significance were found for MMP-9 and TIMP-1, their direction of associations with stroke was consistent with the hypothesis.
Radiomics-Based Precision Phenotyping Identifies Unstable Coronary Plaques From Computed Tomography Angiography
Authors: Andrew Lin, Márton Kolossváry, Sebastien Cadet, Priscilla McElhinney, Markus Goeller, Donghee Han, Jeremy Yuvaraj, Nitesh Nerlekar, Piotr J. Slomka, Mohamed Marwan, Stephen J. Nicholls, Stephan Achenbach, Pál Maurovich-Horvat, Dennis T.L. Wong, Damini Dey
Journal: JACC. Cardiovascular imaging (2022)
Spontaneous intracranial hypotension: searching for the CSF leak
Authors: Tomas Dobrocky, Patrick Nicholson, Levin Häni, Pasquale Mordasini, Timo Krings, Waleed Brinjikji, Jeremy K Cutsforth-Gregory, Ralph Schär, Christoph Schankin, Jan Gralla, Vitor M Pereira, Andreas Raabe, Richard Farb, Jürgen Beck, Eike I Piechowiak
Journal: The Lancet Neurology (2022)
Incidental Intrahepatic Hepatocellular Cholangiocarcinoma Detected on 68Ga-PSMA PET/CT
Authors: Christine Kang, James Yuheng Jiang, Marco Enoch Lee, Lily Shen, Robert Mansberg
Journal: Clinical Nuclear Medicine (2022)

A 69-year-old man with intermediate-risk prostate cancer and a mildly elevated prostate-specific antigen of 8.2 μg/L was referred for 68Ga-prostate-specific membrane antigen (68Ga-PSMA) PET/CT for primary staging. An incidental intensely 68Ga-PSMA-avid hepatic focus was seen on PSMA PET and subsequent FDG PET/CT and MRI cholangiogram. This was confirmed to be hepatocellular cholangiocarcinoma on subsequent histopathological examination.