tbuckley/cabot-search huggingface dataset:
Exercise Training-Induced Repolarization Abnormalities Masquerading as Congenital Long QT Syndrome
Authors: Federica Dagradi, Carla Spazzolini, Silvia Castelletti, Matteo Pedrazzini, Maria-Christina Kotta, Lia Crotti, Peter J. Schwartz
Journal: Circulation (2020)

The diagnosis of long QT syndrome (LQTS) is rather straightforward. We were surprised by realizing that, despite long-standing experience, we were making occasional diagnostic errors by considering as affected subjects who, over time, resulted as not affected. These individuals were all actively practicing sports-an observation that helped in the design of our study.We focused on subjects referred to our center by sports medicine doctors on suspicion of LQTS because of marked repolarization abnormalities on the ECG performed during the mandatory medical visit necessary in Italy to obtain the certificate of eligibility to practice sports. They all underwent our standard procedures involving both a resting and 12-lead ambulatory ECG, an exercise stress test, and genetic screening.There were 310 such consecutive subjects, all actively practicing sports with many hours of intensive weekly training. Of them, 111 had a normal ECG, different cardiac diseases, or were lost to follow-up and exited the study. Of the remaining 199, all with either clear QTc prolongation and/or typical repolarization abnormalities, 121 were diagnosed as affected based on combination of ECG abnormalities with positive genotyping (QTc, 482±35 ms). Genetic testing was negative in 78 subjects, but 45 were nonetheless diagnosed as affected by LQTS based on unequivocal ECG abnormalities (QTc, 472±33 ms). The remaining 33, entirely asymptomatic and with a negative family history, showed an unexpected and practically complete normalization of the ECG abnormalities (their QTc shortened from 492±37 to 423±25 ms [P<0.001]; their Schwartz score went from 3.0 to 0.06) after detraining. They were considered not affected by congenital LQTS and are henceforth referred to as "cases." Furthermore, among them, those who resumed similarly heavy physical training showed reappearance of the repolarization abnormalities.It is not uncommon to suspect LQTS among individuals actively practicing sports based on marked repolarization abnormalities. Among those who are genotype-negative, >40% normalize their ECG after detraining, but the abnormalities tend to recur with resumption of training. These individuals are not affected by congenital LQTS but could have a form of acquired LQTS. Care should be exercised to avoid diagnostic errors.
Endoscopic ultrasound-guided radiofrequency ablation of pancreatic microcystic serous cystic neoplasms: a retrospective study
Authors: Dongwook Oh, Sung Woo Ko, Dong-Wan Seo, Seung-Mo Hong, Jin Hee Kim, Tae Jun Song, Do Hyun Park, Sung Koo Lee, Myung-Hwan Kim
Journal: Endoscopy (2020)

Abstract Background Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) has been increasingly used for the management of various solid pancreatic tumors. This study aimed to evaluate the feasibility and safety of EUS-RFA for serous cystic neoplasms (SCNs). Methods 13 patients with microcystic SCNs with honeycomb appearance underwent EUS-RFA using a 19-gauge RFA needle. Before ablation, cystic fluid was aspirated until a thin layer of fluid remained. Results EUS-RFA was successful in all patients. Seven patients underwent a single session and the remaining six patients underwent a second session of EUS-RFA. One patient (7.7 %) experienced self-limited abdominal pain after EUS-RFA. During a median follow-up period of 9.21 months (interquartile range [IQR] 5.93 – 15.38), the median volume of the SCNs decreased from 37.82 mL (IQR 15.03 – 59.53) at baseline to 10.95 mL (IQR 4.79 – 32.39) at the end of follow-up. A radiologic partial response was achieved in eight patients (61.5 %). Conclusions EUS-RFA is technically feasible and showed an acceptable rate of adverse events for patients with SCNs. A long-term follow-up study is required to evaluate the efficacy of EUS-RFA.
UCP1-dependent and UCP1-independent metabolic changes induced by acute cold exposure in brown adipose tissue of mice
Authors: Yuko Okamatsu-Ogura, Masashi Kuroda, Rie Tsutsumi, Ayumi Tsubota, Masayuki Saito, Kazuhiro Kimura, Hiroshi Sakaue
Journal: Metabolism (2020)

BackgroundBrown adipose tissue (BAT) is a site of metabolic thermogenesis mediated by mitochondrial uncoupling protein 1 (UCP1) and represents a target for a therapeutic intervention in obesity. Cold exposure activates UCP1-mediated thermogenesis in BAT and causes drastic changes in glucose, lipid, and amino acid metabolism; however, the relationship between these metabolic changes and UCP1-mediated thermogenesis is not fully understood.MethodsWe conducted metabolomic and GeneChip array analyses of BAT after 4-h exposure to cold temperature (10 °C) in wild-type (WT) and UCP1-KO mice.ResultsCold exposure largely increased metabolites of the glycolysis pathway and lactic acid levels in WT, but not in UCP1-KO, mice, indicating that aerobic glycolysis is enhanced as a consequence of UCP1-mediated thermogenesis. GeneChip array analysis of BAT revealed that there were 2865 genes upregulated by cold exposure in WT mice, and 838 of these were upregulated and 74 were downregulated in UCP1-KO mice. Pathway analysis revealed the enrichment of genes involved in fatty acid (FA) β oxidation and triglyceride (TG) synthesis in both WT and UCP1-KO mice, suggesting that these metabolic pathways were enhanced by cold exposure independently of UCP1-mediated thermogenesis. FA and cholesterol biosynthesis pathways were enhanced only in UCP1-KO mice. Cold exposure also significantly increased the BAT content of proline, tryptophan, and phenylalanine amino acids in both WT and UCP1-KO mice. In WT mice, cold exposure significantly increased glutamine content and enhanced the expression of genes related to glutamine metabolism. Surprisingly, aspartate was almost completely depleted after cold exposure in UCP1-KO mice. Gene expression analysis suggested that aspartate was actively utilized after cold exposure both in WT and UCP1-KO mice, but it was replenished from intracellular N-acetyl-aspartate in WT mice.ConclusionsThese results revealed that cold exposure induces UCP1-mediated thermogenesis-dependent glucose utilization and UCP1-independent active lipid metabolism in BAT. In addition, cold exposure largely affects amino acid metabolism in BAT, especially UCP1-dependently enhances glutamine utilization. These results contribute a comprehensive understanding of UCP1-mediated thermogenesis-dependent and thermogenesis-independent metabolism in BAT.
Six Months of Hybrid Closed-Loop Versus Manual Insulin Delivery With Fingerprick Blood Glucose Monitoring in Adults With Type 1 Diabetes: A Randomized, Controlled Trial
Authors: Sybil A. McAuley, Melissa H. Lee, Barbora Paldus, Sara Vogrin, Martin I. de Bock, Mary B. Abraham, Leon A. Bach, Morton G. Burt, Neale D. Cohen, Peter G. Colman, Elizabeth A. Davis, Christel Hendrieckx, D. Jane Holmes-Walker, Joey Kaye, Anthony C. Keech, Kavita Kumareswaran, Richard J. MacIsaac, Roland W. McCallum, Catriona M. Sims, Jane Speight, Stephen N. Stranks, Vijaya Sundararajan, Steven Trawley, Glenn M. Ward, Alicia J. Jenkins, Timothy W. Jones, David N. O’Neal, David N. O’Neal, Sybil A. McAuley, Melissa H. Lee, Barbora Paldus, Catriona M. Sims, Richard J. MacIsaac, Glenn M. Ward, Peter G. Colman, Neale D. Cohen, Leon A. Bach, Kavita Kumareswaran, Stephen N. Stranks, Morton G. Burt, D. Jane Holmes-Walker, Roland W. McCallum, Joey Kaye, Jane Speight, Christel Hendrieckx, Jennifer Halliday, Sienna Russell-Green, Steven Trawley, Alicia J. Jenkins, Andrzej Januszewski, Anthony C. Keech, Sara Vogrin, Vijaya Sundararajan, Hanafi Mohammed Husin, Philip M. Clarke, Timothy W. Jones, Elizabeth A. Davis, Martin I. de Bock, Mary B. Abraham, Geoff R. Ambler, Fergus J. Cameron, Jan M. Fairchild, Bruce R. King
Journal: Diabetes Care (2020)

OBJECTIVE To investigate glycemic and psychosocial outcomes with hybrid closed-loop (HCL) versus user-determined insulin dosing with multiple daily injections (MDI) or insulin pump (i.e., standard therapy for most adults with type 1 diabetes). RESEARCH DESIGN AND METHODS Adults with type 1 diabetes using MDI or insulin pump without continuous glucose monitoring (CGM) were randomized to 26 weeks of HCL (Medtronic 670G) or continuation of current therapy. The primary outcome was masked CGM time in range (TIR; 70–180 mg/dL) during the final 3 weeks. RESULTS Participants were randomized to HCL (n = 61) or control (n = 59). Baseline mean (SD) age was 44.2 (11.7) years, HbA1c was 7.4% (0.9%) (57 [10] mmol/mol), 53% were women, and 51% used MDI. HCL TIR increased from (baseline) 55% (13%) to (26 weeks) 70% (10%) with the control group unchanged: (baseline) 55% (12%) and (26 weeks) 55% (13%) (difference 15% [95% CI 11, 19]; P &amp;lt; 0.0001). For HCL, HbA1c was lower (median [95% CI] difference −0.4% [−0.6, −0.2]; −4 mmol/mol [−7, −2]; P &amp;lt; 0.0001) and diabetes-specific positive well-being was higher (difference 1.2 [95% CI 0.4, 1.9]; P &amp;lt; 0.0048) without a deterioration in diabetes distress, perceived sleep quality, or cognition. Seventeen (9 device-related) versus 13 serious adverse events occurred in the HCL and control groups, respectively. CONCLUSIONS In adults with type 1 diabetes, 26 weeks of HCL improved TIR, HbA1c, and their sense of satisfaction from managing their diabetes compared with those continuing with user-determined insulin dosing and self-monitoring of blood glucose. For most people living with type 1 diabetes globally, this trial demonstrates that HCL is feasible, acceptable, and advantageous.
Autophagy in Human Diseases
Authors: Noboru Mizushima, Beth Levine
Journal: New England Journal of Medicine (2020)

Autophagy is a complex process of intracellular degradation of senescent or malfunctioning organelles. Dysregulated autophagy is associated with certain cancers, neurodegenerative diseases, immune dysfunction, and aging. Therapies aimed at regulating autophagy are being developed.
A Highly Sensitive Immunohistochemical Assay to Detect Braf V600E Mutations in Patients with Colorectal Cancer
Authors: J. Desai, F. Day, A. Muranyi, S. Singh, K. Shanmugam, T. Grogan, P. Gibbs, D. Williams, O. Sieber, P. Waring
Journal: Annals of Oncology (2012)
NRF2 Activation Promotes Aggressive Lung Cancer and Associates with Poor Clinical Outcomes
Authors: Anju Singh, Anneleen Daemen, Dorothee Nickles, Sang-Min Jeon, Oded Foreman, Kuladeep Sudini, Florian Gnad, Stephane Lajoie, Naina Gour, Wayne Mitzner, Samit Chatterjee, Eun-Ji Choi, Buvana Ravishankar, Amy Rappaport, Namrata Patil, Mark McCleland, Leisa Johnson, George Acquaah-Mensah, Edward Gabrielson, Shyam Biswal, Georgia Hatzivassiliou
Journal: Clinical Cancer Research (2020)

Purpose:. Stabilization of the transcription factor NRF2 through genomic alterations in KEAP1 and NFE2L2 occurs in a quarter of patients with lung adenocarcinoma and a third of patients with lung squamous cell carcinoma. In lung adenocarcinoma, KEAP1 loss often co-occurs with STK11 loss and KRAS-activating alterations. Despite its prevalence, the impact of NRF2 activation on tumor progression and patient outcomes is not fully defined.Experimental Design:. We model NRF2 activation, STK11 loss, and KRAS activation in vivo using novel genetically engineered mouse models. Furthermore, we derive a NRF2 activation signature from human non–small cell lung tumors that we use to dissect how these genomic events impact outcomes and immune contexture of participants in the OAK and IMpower131 immunotherapy trials.Results:. Our in vivo data reveal roles for NRF2 activation in (i) promoting rapid-onset, multifocal intrabronchiolar carcinomas, leading to lethal pulmonary dysfunction, and (ii) decreasing elevated redox stress in KRAS-mutant, STK11-null tumors. In patients with nonsquamous tumors, the NRF2 signature is negatively prognostic independently of STK11 loss. Patients with lung squamous cell carcinoma with low NRF2 signature survive longer when receiving anti–PD-L1 treatment.Conclusions:. Our in vivo modeling establishes NRF2 activation as a critical oncogenic driver, cooperating with STK11 loss and KRAS activation to promote aggressive lung adenocarcinoma. In patients, oncogenic events alter the tumor immune contexture, possibly having an impact on treatment responses. Importantly, patients with NRF2-activated nonsquamous or squamous tumors have poor prognosis and show limited response to anti–PD-L1 treatment.
19P A prospective study about BRCA1/BRCA2 germline mutations in hereditary breast /ovarian cancer patients
Authors: W. Ben Kridis, D. Ben Ayed-Guerfali, N. Ammous-Boukhris, W. Ayedi, S. Charfi, T. Boudawara, J. Daoud, A. Khanfir, R. Mokdad-Gargouri
Journal: Annals of Oncology (2020)
Coronaviruses and gastrointestinal diseases
Authors: Xi Luo, Guan-Zhou Zhou, Yan Zhang, Li-Hua Peng, Li-Ping Zou, Yun-Sheng Yang
Journal: Military Medical Research (2020)

Abstract The effects of coronaviruses on the respiratory system are of great concern, but their effects on the digestive system receive much less attention. Coronaviruses that infect mammals have shown gastrointestinal pathogenicity and caused symptoms such as diarrhea and vomiting. Available data have shown that human coronaviruses, including the newly emerged SARS-CoV-2, mainly infect the respiratory system and cause symptoms such as cough and fever, while they may generate gastrointestinal symptoms. However, there is little about the relation between coronavirus and digestive system. This review specifically addresses the effects of mammalian and human coronaviruses, including SARS-CoV-2, on the digestive tract, helping to cope with the new virus infection-induced disease, COVID-19.
Prostatectomy Mortality
Authors: C. G. Scorer, S. J. Knight
Journal: BMJ (1962)

ACUTE GASTRO-INTESTINAL ILLNESS BRlTS 141MWLcia Joui,x&i before onset, canteen meals, household pets, contact with other simiar illness, and presence of schoolchildren in the family.The only factor that stood out clearly was the importance of schools and schoolchildren in Sonne dysentery.Age-specific secondary attack rates and serial intervals between cases in families showed differences in the bacteriological and clinical groups.In a therapeutic trial of neomycin and phthalyl- sulphathiazole in 83 patients, all bacteriologically negative, little difference in rate of recovery was found between those treated with either drug and kaolin and those treated with kaolin alone.We are indebted to Glaxo Laboratories for supplying the preparations used in the therapeutic trial; to Dr. C. E. D. Taylor, of the Virus Diagnostic Laboratory at Colindale, for the virus isolation tests; to Dr. Z. Bencid for his help in the analysis of the records; to Mr. F. T. M. Downing for technical assistance;
Role of unfolded proteins in lung disease
Authors: Kirsty L Bradley, Clare A Stokes, Stefan J Marciniak, Lisa C Parker, Alison M Condliffe
Journal: Thorax (2020)

The lungs are exposed to a range of environmental toxins (including cigarette smoke, air pollution, asbestos) and pathogens (bacterial, viral and fungal), and most respiratory diseases are associated with local or systemic hypoxia. All of these adverse factors can trigger endoplasmic reticulum (ER) stress. The ER is a key intracellular site for synthesis of secretory and membrane proteins, regulating their folding, assembly into complexes, transport and degradation. Accumulation of misfolded proteins within the lumen results in ER stress, which activates the unfolded protein response (UPR). Effectors of the UPR temporarily reduce protein synthesis, while enhancing degradation of misfolded proteins and increasing the folding capacity of the ER. If successful, homeostasis is restored and protein synthesis resumes, but if ER stress persists, cell death pathways are activated. ER stress and the resulting UPR occur in a range of pulmonary insults and the outcome plays an important role in many respiratory diseases. The UPR is triggered in the airway of patients with several respiratory diseases and in corresponding experimental models. ER stress has been implicated in the initiation and progression of pulmonary fibrosis, and evidence is accumulating suggesting that ER stress occurs in obstructive lung diseases (particularly in asthma), in pulmonary infections (some viral infections and in the setting of the cystic fibrosis airway) and in lung cancer. While a number of small molecule inhibitors have been used to interrogate the role of the UPR in disease models, many of these tools have complex and off-target effects, hence additional evidence (eg, from genetic manipulation) may be required to support conclusions based on the impact of such pharmacological agents. Aberrant activation of the UPR may be linked to disease pathogenesis and progression, but at present, our understanding of the context-specific and disease-specific mechanisms linking these processes is incomplete. Despite this, the ability of the UPR to defend against ER stress and influence a range of respiratory diseases is becoming increasingly evident, and the UPR is therefore attracting attention as a prospective target for therapeutic intervention strategies.
Association Between Parent Comfort With English and Adverse Events Among Hospitalized Children
Authors: Alisa Khan, H. Shonna Yin, Cindy Brach, Dionne A. Graham, Matthew W. Ramotar, David N. Williams, Nancy Spector, Christopher P. Landrigan, Benard P. Dreyer
Journal: JAMA Pediatrics (2020)

Children of parents expressing limited comfort with English (LCE) or limited English proficiency may be at increased risk of adverse events (harms due to medical care). No prior studies have examined, in a multicenter fashion, the association between language comfort or language proficiency and systematically, actively collected adverse events that include family safety reporting.To examine the association between parent LCE and adverse events in a cohort of hospitalized children.This multicenter prospective cohort study was conducted from December 2014 to January 2017, concurrent with data collection from the Patient and Family Centered I-PASS Study, a clinician-family communication and patient safety intervention study. The study included 1666 Arabic-, Chinese-, English-, and Spanish-speaking parents of general pediatric and subspecialty patients 17 years and younger in the pediatric units of 7 North American hospitals. Data were analyzed from January 2018 to May 2020.Language-comfort data were collected through parent self-reporting. LCE was defined as reporting any language besides English as the language in which parents were most comfortable speaking to physicians or nurses.The primary outcome was adverse events; the secondary outcome was preventable adverse events. Adverse events were collected using a systematic 2-step methodology. First, clinician abstractors reviewed patient medical records, solicited clinician reports, hospital incident reports, and family safety interviews. Then, review and consensus classification were completed by physician pairs. To examine the association of LCE with adverse events, a multivariable logistic regression was conducted with random intercepts to adjust for clustering by site.Of 1666 parents providing language-comfort data, 1341 (80.5%) were female, and the mean (SD) age of parents was 35.4 (10.0) years. A total of 147 parents (8.8%) expressed LCE, most of whom (105 [71.4%]) preferred Spanish. Children of parents who expressed LCE had higher odds of having 1 or more adverse events compared with children whose parents expressed comfort with English (26 of 147 [17.7%] vs 146 of 1519 [9.6%]; adjusted odds ratio, 2.1; 95% CI, 1.2-3.7), after adjustment for parent race and education, complex chronic conditions, length of stay, site, and the intervention period. Similarly, children whose parents expressed LCE were more likely to experience 1 or more preventable adverse events (adjusted odds ratio, 2.3; 95% CI, 1.2-4.2).Hospitalized children of parents expressing LCE were twice as likely to experience harms due to medical care. Targeted strategies are needed to improve communication and safety for this vulnerable group of children.
<i>KEAP1/NFE2L2</i> Mutations Predict Lung Cancer Radiation Resistance That Can Be Targeted by Glutaminase Inhibition
Authors: Michael S. Binkley, Young-Jun Jeon, Monica Nesselbush, Everett J. Moding, Barzin Y. Nabet, Diego Almanza, Christian Kunder, Henning Stehr, Christopher H. Yoo, Siyeon Rhee, Michael Xiang, Jacob J. Chabon, Emily Hamilton, David M. Kurtz, Linda Gojenola, Susie Grant Owen, Ryan B. Ko, June Ho Shin, Peter G. Maxim, Natalie S. Lui, Leah M. Backhus, Mark F. Berry, Joseph B. Shrager, Kavitha J. Ramchandran, Sukhmani K. Padda, Millie Das, Joel W. Neal, Heather A. Wakelee, Ash A. Alizadeh, Billy W. Loo, Maximilian Diehn
Journal: Cancer Discovery (2020)

Tumor genotyping is not routinely performed in localized non-small cell lung cancer (NSCLC) due to lack of associations of mutations with outcome. Here, we analyze 232 consecutive patients with localized NSCLC and demonstrate that KEAP1 and NFE2L2 mutations are predictive of high rates of local recurrence (LR) after radiotherapy but not surgery. Half of LRs occurred in tumors with KEAP1/NFE2L2 mutations, indicating that they are major molecular drivers of clinical radioresistance. Next, we functionally evaluate KEAP1/NFE2L2 mutations in our radiotherapy cohort and demonstrate that only pathogenic mutations are associated with radioresistance. Furthermore, expression of NFE2L2 target genes does not predict LR, underscoring the utility of tumor genotyping. Finally, we show that glutaminase inhibition preferentially radiosensitizes KEAP1-mutant cells via depletion of glutathione and increased radiation-induced DNA damage. Our findings suggest that genotyping for KEAP1/NFE2L2 mutations could facilitate treatment personalization and provide a potential strategy for overcoming radioresistance conferred by these mutations. SIGNIFICANCE: This study shows that mutations in KEAP1 and NFE2L2 predict for LR after radiotherapy but not surgery in patients with NSCLC. Approximately half of all LRs are associated with these mutations and glutaminase inhibition may allow personalized radiosensitization of KEAP1/NFE2L2-mutant tumors.This article is highlighted in the In This Issue feature, p. 1775.
Dysanapsis and COPD—Reply
Authors: Benjamin M. Smith, Eric A. Hoffman, R. Graham Barr
Journal: JAMA (2020)

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