tbuckley/cabot-search huggingface dataset:
Abstract MP19: Impact of Change in Bedtime Variability on Body Composition: Secondary Findings From the Go Red for Women Strategically Focused Research Network
Authors: Marie-Pierre St-Onge, Ayanna Campbell, Faris M Zuraikat, Bin Cheng
Journal: Circulation (2020)

Variability in daily sleep duration and unstable bedtimes are emerging sleep-related factors that have been linked to metabolic syndrome. For example, in longitudinal studies, the odds of developing metabolic syndrome over 6.3 y median follow-up are 1.36 for every 1 h increase in sleep onset variability (standard deviation of bedtimes measured over 7 nights of actigraphy) in fully adjusted models. However, whether reducing bedtime variability improves markers of disease risk has not been tested. Here, we assessed whether body composition was impacted by changes in bedtime variability over a 6-wk period during which women were instructed to maintain healthy, habitual sleep patterns. This was a single arm of a randomized trial originally designed to test the impact of sleep restriction on cardiometabolic risk factors. Women, aged 20 y and older and with body mass index 20-33 kg/m 2 were recruited. All women were required to have adequate sleep duration of 7-9 h/night, determined over 2 wk using wrist-worn actigraphy. Upon randomization, women were given bed and wake time prescriptions aligned with their average screening bed and wake times in order to ensure maintenance of adequate sleep duration over the 6 wk study phase. The alternate phase required women to delay their bedtimes to achieve sleep restriction. Only data from the adequate sleep phase were used for the present analyses. Bedtime variability and body composition data were available for 37 women (age 34.9±12.4 y, BMI 24.7±2.9 kg/m 2 , screening sleep duration 7.58±0.49 h/night). Body composition was measured at baseline (0 wk) and endpoint (6 wk) using magnetic resonance imaging. Bedtime and sleep data were collected weekly using wrist actigraphy. Change in bedtime variability was calculated as the difference in the standard deviation of bedtimes measured during the 2-wk screening period and the 6-wk study phase. Sleep duration did not differ between screening and the average of 6 wk of the sleep phase (-4.8±24.7min, P=0.24). Average percent change in bedtime SD was 24.4±25.2% in those who increased their bedtime variability and -39.9±23.5% in those who reduced their bedtime variability. Results showed that, compared to women who increased or did not change (n=8) bedtime variability, women who reduced their bedtime variability (n=29) during the intervention had significant reductions in total (reduced: -0.52±0.98 vs increase/no change: 0.63±0.41 L, P&lt;0.001) and subcutaneous adipose tissue (reduced: -0.48±0.86 vs increase/no change: 0.56±0.31 L, P&lt;0.001). Thus, results provide novel preliminary information showing that reducing bedtime variability can improve body composition over time. Given that bedtimes are highly individualized, this may provide an easy public health message to maintain healthy sleep hygiene, particularly stable bedtime routine, to achieve better weight management and reduced CVD risk.
Long-term survival following colon cancer surgery: Variation associated with choice of anesthesia
Authors: R. Christopherson, K. E. James, M. Tableman, P. Marshall, A. L. Kline, F. E. Johnson
Journal: Journal of Clinical Oncology (2007)

17015 Background: VA Cooperative Trial 345 randomized patients having abdominal surgery to unsupplemented general anesthesia (UGA) or epidural-supplemented general anesthesia (ESGA). The long-term clinical significance of the type of anesthesia for patients having surgery for colon cancer has not been well studied. We compared survival of patients with colon cancer randomized to ESGA to survival of those randomized to UGA. Methods: Survival of colon cancer patients was not a primary trial end point. We conducted a post hoc analysis of the colon cancer patients in the trial using TNM staging data from patient records. A Cox survival model was used to test the effects of pathological stage, type of anesthesia and other covariates on survival. Results: 177 patients were evaluable. In both trial arms, survival was similar (P = 0.23) until 4.56 years. After 4.56 years, patients assigned to UGA had significantly better survival (P = 0.01). In both trial arms, the survival in patients without metastases was similar initially, but those who received UGA had significantly better survival later. A similar statistically significant pattern was evident in patients with metastases. The long-term survival benefit of UGA was even more pronounced among patients with metastases and a diagnosis of alcoholism. Conclusions: This study provides the first evidence that ESGA may worsen long-term survival in colon cancer patients, especially those with metastases and alcoholism. Epidural anesthesia affects visceral blood flow, immunological parameters, post-operative pain and other physiological variables, which could explain these findings. Additional studies to confirm or refute these unexpected findings are warranted. No significant financial relationships to disclose.
Screening for Hepatitis C Virus Infection in Adolescents and Adults
Authors: Roger Chou, Tracy Dana, Rongwei Fu, Bernadette Zakher, Jesse Wagner, Shaun Ramirez, Sara Grusing, Janice H. Jou
Journal: JAMA (2020)

A 2013 review for the US Preventive Services Task Force (USPSTF) of hepatitis C virus (HCV) screening found interferon-based antiviral therapy associated with increased likelihood of sustained virologic response (SVR) and an association between achieving an SVR and improved clinical outcomes. New direct-acting antiviral (DAA) regimens are available.
Structural determinants of long-term functional outcomes in young children with cystic fibrosis
Authors: Lidija Turkovic, Daan Caudri, Tim Rosenow, Oded Breuer, Conor Murray, Harm A.W.M. Tiddens, Fiona Ramanauskas, Sarath C. Ranganathan, Graham L. Hall, Stephen M. Stick
Journal: European Respiratory Journal (2020)

Background Accelerated lung function decline in individuals with cystic fibrosis (CF) starts in adolescence with respiratory complications being the most common cause of death in later life. Factors contributing to lung function decline are not well understood, in particular its relationship with structural lung disease in early childhood. Detection and management of structural lung disease could be an important step in improving outcomes in CF patients. Methods Annual chest computed tomography (CT) scans were available from 2005 to 2016 as a part of the AREST CF cohort for children aged 3 months to 6 years. Annual spirometry measurements were available for 89.77% of the cohort (167 children aged 5–6 years) from age 5 to 15 years through outpatient clinics at Perth Children's Hospital (Perth, Australia) and The Royal Children's Hospital in Melbourne (Melbourne, Australia) (697 measurements, mean± sd age 9.3±2.1 years). Results Children with a total CT score above the median at age 5–6 years were more likely to have abnormal forced expiratory volume in 1 s (FEV 1 ) (adjusted hazard ratio 2.67 (1.06–6.72), p=0.037) during the next 10 years compared to those below the median chest CT score. The extent of all structural abnormalities except bronchial wall thickening were associated with lower FEV 1 Z-scores. Mucus plugging and trapped air were the most predictive sub-score (adjusted mean change −0.17 (−0.26 – −0.07) p&lt;0.001 and −0.09 (−0.14 – −0.04) p&lt;0.001, respectively). Discussion Chest CT identifies children at an early age who have adverse long-term outcomes. The prevention of structural lung damage should be a goal of early intervention and can be usefully assessed with chest CT. In an era of therapeutics that might alter disease trajectories, chest CT could provide an early readout of likely long-term success.
Mesenchymal stem cell-derived magnetic extracellular nanovesicles for targeting and treatment of ischemic stroke
Authors: Han Young Kim, Tae Jung Kim, Lami Kang, Young-Ju Kim, Min Kyoung Kang, Jonghoon Kim, Ju Hee Ryu, Taeghwan Hyeon, Byung-Woo Yoon, Sang-Bae Ko, Byung-Soo Kim
Journal: Biomaterials (2020)
The use of stereotactic radiotherapy boost to improve local control in patients with locally advanced nasopharyngeal carcinoma (NPC)
Authors: Q. Le, W. Hara, S. D. Chang, H. A. Pinto, M. J. Kaplan, D. R. Goffinet
Journal: Journal of Clinical Oncology (2007)

6056 Background: To determine the long term outcomes and delayed side effects in patients receiving stereotactic radiotherapy (SRT) as a boost following external beam radiotherapy (EBRT) for locally advanced NPC. Methods: 82 NPC patients received a STR boost after EBRT at our institution between 9/1992 and 5/2006. Nine patients had T1, 31 had T2, 12 had T3, and 30 had T4 tumors (1997 AJCC staging). Sixteen patients had stage II, 20 had stage III, and 46 had stage IV neoplasms. Most patients received 66 Gy of EBRT followed by a single fraction STR boost of 7–15 Gy, delivered 2–6 weeks after EBRT. 70 patients also received cisplatin-based chemotherapy delivered concurrently with and adjuvant to EBRT. Results: At median follow-up of 40.7 months for living patients (range: 6.5 –144.2 months), there was only 1 local failure in a patient with a T4 tumor. At five years, the freedom from local relapse rate was 98%, freedom from nodal relapse was 83%, freedom from distant metastasis was 68%, freedom from any relapse was 67% and overall survival was 69%. Late toxicity included unresolved V2 or V3 numbness in 2, radiation-related retinopathy in 1, carotid aneurysm in 1, and radiographic temporal lobe necrosis in 9 patients, of which 2 were symptomatic with seizures. All but one patient with temporal lobe necrosis had intracranial tumor extension at diagnosis. Conclusions: STR boost after EBRT resulted in excellent local control. However, the incidence of temporal lobe necrosis approached 11% in these patients and higher in patients with intracranial extension. Improved target delineation and dose homogeneity of radiation delivery for both EBRT and STR is important to avoid long-term complications. No significant financial relationships to disclose.
A Computational Pipeline to Predict Cardiotoxicity
Authors: Pei-Chi Yang, Kevin R. DeMarco, Parya Aghasafari, Mao-Tsuen Jeng, John R.D. Dawson, Slava Bekker, Sergei Y. Noskov, Vladimir Yarov-Yarovoy, Igor Vorobyov, Colleen E. Clancy
Journal: Circulation Research (2020)

Rationale: Drug-induced proarrhythmia is so tightly associated with prolongation of the QT interval that QT prolongation is an accepted surrogate marker for arrhythmia. But QT interval is too sensitive a marker and not selective, resulting in many useful drugs eliminated in drug discovery. Objective: To predict the impact of a drug from the drug chemistry on the cardiac rhythm. Methods and Results: In a new linkage, we connected atomistic scale information to protein, cell, and tissue scales by predicting drug-binding affinities and rates from simulation of ion channel and drug structure interactions and then used these values to model drug effects on the hERG channel. Model components were integrated into predictive models at the cell and tissue scales to expose fundamental arrhythmia vulnerability mechanisms and complex interactions underlying emergent behaviors. Human clinical data were used for model framework validation and showed excellent agreement, demonstrating feasibility of a new approach for cardiotoxicity prediction. Conclusions: We present a multiscale model framework to predict electrotoxicity in the heart from the atom to the rhythm. Novel mechanistic insights emerged at all scales of the system, from the specific nature of proarrhythmic drug interaction with the hERG channel, to the fundamental cellular and tissue-level arrhythmia mechanisms. Applications of machine learning indicate necessary and sufficient parameters that predict arrhythmia vulnerability. We expect that the model framework may be expanded to make an impact in drug discovery, drug safety screening for a variety of compounds and targets, and in a variety of regulatory processes.
Genomic Variants of Cytarabine Sensitivity Associated with Treatment-Related Mortality in Pediatric AML: A Report from the Children's Oncology Group
Authors: Christine L. Phillips, Adam Lane, Robert B. Gerbing, Todd A. Alonzo, Alyss Wilkey, Gretchen Radloff, Beverly Lange, Eric R. Gamazon, M. Eileen Dolan, Stella M. Davies
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Cytarabine is an effective treatment for AML with associated toxicities including treatment related mortality (TRM). The purpose is to determine the clinical relevance of SNPs identified through the use of HapMap lymphoblastoid cell-based models, in predicting cytarabine response and toxicity in AML. Experimental Design: We tested clinical significance of SNPs associated with cytarabine sensitivity in children with AML treated on Children's Oncology Group regimens (CCG 2941/2961). Endpoints included overall survival (OS), event-free survival (EFS), and TRM. Patients who received bone marrow transplant were excluded. We tested 124 SNPs associated with cytarabine sensitivity in HapMap cell lines in 348 children to determine whether any associated with treatment outcomes. In addition, we tested five SNPs previously associated with TRM in children with AML in our independent dataset of 385 children. Results: Homozygous variant genotypes of rs2025501 and rs6661575 had increased in vitro cellular sensitivity to cytarabine and were associated with increased TRM. TRM was particularly increased in children with variant genotype randomized to high-dose cytarabine (rs2025501: P = 0.0024 and rs6661575 P = 0.0188). In analysis of previously reported SNPs, only the variant genotype rs17202778 C/C was significantly associated with TRM (P &amp;lt; 0.0001). Conclusions: We report clinical importance of two SNPs not previously associated with cytarabine toxicity. Moreover, we confirm that SNP rs17202778 significantly impacts TRM in pediatric AML. Cytarabine sensitivity genotypes may predict TRM and could be used to stratify to standard versus high-dose cytarabine regimens, warranting further study in prospective AML trials.
Phase II trial of docetaxel (T), cisplatin (P), and cetuximab (E) followed by concurrent radiation (RT), P, and E in locally advanced head and neck squamous cell carcinoma (HNSCC)
Authors: A. Argiris, M. V. Karamouzis, D. E. Heron, R. Smith, R. Ferris, S. Lai, S. Kim, B. Branstetter, J. Johnson, J. Grandis
Journal: Journal of Clinical Oncology (2007)

6051 Background: E is a chimeric IgG1 monoclonal antibody against the external domain of the epidermal growth factor receptor that may enhance the efficacy of RT and chemotherapy. Our goal was to incorporate E in the induction and subsequent chemoradiotherapy of HNSCC. We report our preliminary results with TPE induction. Methods: Patients (pts) had pathologically documented HNSCC stage III/IV or selected stage II (base of tongue, hypopharynx, or nasopharynx), no prior therapy, ECOG PS 0–1, and adequate hematologic, kidney and liver laboratory parameters. Induction consisted of T 75 mg/m 2 day 1, P 75 mg/m 2 day 1, and E 250 mg/m 2 days 1,8, and 15 (after an initial dose of 400 mg/m 2 on cycle 1, day 1), repeated every 21 days × 3 cycles. Subsequently, pts received RT 70 Gy (2 Gy/day) with concurrent P 30 mg/m 2 and E 250 mg/m 2 weekly, followed by maintenance E for 6 months. Prophylactic antibiotics were given on days 5–14 of each TPE cycle. Tumor assessment was performed after induction (primary endpoint) and 8 weeks after RT. Sample size was 39; one-stage design; target overall response rate (ORR): 80%. Results: 21 pts have been enrolled to date: median age 55 (39–74); Male/Female: 18/3; primary site: oropharynx (n=13), larynx (n=5), and other (n=3); stage III/IV: 4/17. In 16 evaluable pts, ORR to TPE was 15/16 (94%), CR: 2, PR 13, SD 1. For the primary site (12 evaluable): CR 6, PR 5, SD 1; for the lymph nodes (14 evaluable): CR 1, PR: 12, SD 1. The pt with SD discontinued E in the first cycle due to recurring infusion reaction. Another patient had a grade (G) 3 infusion reaction on the first E administration and was removed from study. Other serious toxicities during TPE (n=20): grade (G) 3/4 neutropenia (n=4/n=7) without incidence of neutropenic fever, G 3 anemia (n=1), G 3 thrombocytopenia (n=1), G 3/4 hypomagnesemia (n=2/n=1), G 3 rash (n=1), G 3 fatigue (n=4), and G 3 diarrhea (n=1). 1 pt had sudden death due to myocardial infarction (autopsy) after the third cycle of TPE. Subsequent RT plus P and E was feasible. 10 pts completed RT and all remain progression-free. Conclusions: Preliminary results suggest that TPE has predictable and manageable toxicities and high activity in HNSCC. Accrual is ongoing and updated data will be available. No significant financial relationships to disclose.
Abstract 21251: Lipase Maturation Factor 1 Plays a Lipase-Independent Role in Energy Metabolism and Adiposity
Authors: Nicole Ehrhardt, Hui Mao, Candy Bedoya, Miklos Peterfy
Journal: Circulation (2017)

Vascular lipases including lipoprotein lipase (LPL), hepatic lipase (HL) and endothelial lipase (EL) are important determinants of plasma lipid homeostasis and coronary artery disease risk. The ER-resident lipase-chaperone Lipase Maturation Factor 1 (LMF1) plays a key role in the biogenesis of active vascular lipases and plasma lipid metabolism. While mice and humans harboring loss-of-function mutations in LMF1 exhibit deficiencies in all three vascular lipases and hypertriglyceridemia, detailed metabolic characterization of LMF1 deficiency has been hampered by the neonatal lethality of LMF1-/- mice. The goal of the present study was to investigate the metabolic consequences of combined lipase deficiency in the adult mouse. To overcome the lethality associated with whole-body LMF1 deficiency, we pursued a transgene rescue strategy involving cross-breeding of Mck-LMF1 transgenic and LMF1-/- mice. Mice expressing LMF1 exclusively in muscle tissue (Mck-LMF1-/-) exhibited normal survival and plasma lipid levels indicating that restoration of LPL activity in muscle only is sufficient to normalize plasma lipid metabolism in LMF1-/- mice. However, Mck-LMF1-/- mice also demonstrated decreased body weight (BW) and adiposity, reduced hepatic steatosis and improved insulin sensitivity; phenotypes that have not been observed in single-lipase deficient mouse models. Mechanistic studies revealed that decreased energy expenditure was responsible for diminished BW in Mck-LMF1-/- mice. To investigate the role of adipose tissue in this phenotype, we generated adipose-specific LMF1 knock-out (Ad-LMF1-KO) mice. While Ad-LMF1-KO mice exhibited hypertriglyceridemia, BW and adiposity remained unaffected indicating that adipose tissue was not the driver of lean phenotype in LMF1 deficiency. Furthermore, normolipemic heterozygous LMF1+/- mice exhibited lower BW and adiposity relative to wild-type littermates. Finally, we observed direct correlation between hepatic LMF1 expression and adiposity across ~100 inbred mouse strains in the Hybrid Mouse Diversity Panel. In conclusion, our results implicate hepatic LMF1 expression in energy metabolism and suggest that LMF1 plays a novel, lipase-independent role in metabolic regulation.
Care for Critically Ill Patients With COVID-19
Authors: Srinivas Murthy, Charles D. Gomersall, Robert A. Fowler
Journal: JAMA (2020)

This JAMA Insights article reviews care for the most severely ill patients with coronavirus disease 2019 (COVID-19), including standards of management of ARDS, preventing SARS-CoV-2 spread in health care settings, and surge preparation.
Abstract P411: Longitudinal Association Between Frailty and Arterial Stiffness in Community-dwelling Older Adults: The Atherosclerosis Risk in Communities Study
Authors: Alvin G Thomas, Anna Kucharska-Newton, Jingkai Wei, Priya Palta, Sheila Burgard, Michelle Meyer, Lee Stoner, Hirofumi Tanaka, Wilson Nadruz, B Gwen Windham, Lynne E Wagenknecht, Gerardo M Heiss
Journal: Circulation (2020)

Introduction: Frailty is predictive of cardiovascular disease and is suggested to co-occur with arterial stiffening, the hallmark of vascular aging. However, the temporal relationship is uncertain. Using the ARIC study, we examine the association of baseline frailty with cross-sectional and 5-year change in carotid-femoral pulse wave velocity (cfPWV) in older adults. Methods: Participants at visit 5 (2011-2013) were classified as frail (≥3 criteria), prefrail (1-2 criteria), or robust using the Fried frailty phenotype criteria (unintentional weight loss, exhaustion, grip strength, slow walking speed, and low physical activity). We measured cfPWV at visits 5 and 6/7 (2016-2019). We used linear regression with inverse-probability of attrition weights to estimate the association between frailty and 5-year change in cfPWV while accounting for loss-to-follow-up among survivors. Models were adjusted for age, sex, race-center, mean arterial pressure, height, heart rate, smoking, and time between visits. Results: Of 5,096 participants at visit 5 (58% female, 21% black, mean age 75 [SD 5.1] years), 296 (6%) were frail and 2403 (47%) prefrail. In adjusted analyses at visit 5, frail participants had 30 cm/s (95% CI: -9, 69; p=0.1) higher cfPWV and prefrail participants had 12 cm/s (95% CI: -5, 30; p=0.2) higher cfPWV than those classified as robust (Table 1). In longitudinal analyses adjusted for attrition, we observed a 3 cm/s (95% CI: -11, 19; p=0.6) and 6 cm/s (95% CI: 0, 12; p=0.05) greater annualized increase in cfPWV over ~5 years among frail and prefrail participants, respectively, relative to the rate of arterial stiffening among robust participants (26 cm/s per year). Conclusions: Compared to robust older adults, greater aortic stiffness was observed among frail community-dwelling adults. Changes in aortic stiffening over the course of 5 years were not materially influenced by frailty status at baseline. Frail older adults may present with greater arterial aging and its associated hemodynamic effects on target organs.