tbuckley/cabot-search huggingface dataset:
A phase II study of TAS-102 (FTD/TPI) in combination with ramucirumab (RAM) in advanced, refractory gastric (GC) or gastroesophageal junction (GEJ) adenocarcinomas (GEAs).
Authors: Rutika Mehta, Richard D. Kim, Maria E Martinez Jimenez, Kirsten Blue, Trenton Avriett, Emily Kelbert, Kara Miller, Christopher Ray, Tiffany Valone, Woojoo Lee, Youngchul Kim, Dae Won Kim
Journal: Journal of Clinical Oncology (2022)

302 Background: The RAINBOW trial established the standard of care for treatment of metastatic GEAs with ramucirumab and paclitaxel after failure of fluoropyrimidine and platinum-based chemotherapy. While the combination achieved an objective response rate (ORR) of 28%, the incidence of any grade neuropathy was 46%. Therefore, there is an unmet need for novel treatment combinations that minimize the long-term toxicity of neuropathy. In a recently published Asian study, the combination of RAM+TAS-102 showed good disease control and acceptable toxicity profile. Methods: This was a single arm, single institution phase II trial using the combination of TAS-102 plus RAM in refractory GEAs. Patients (pts) received RAM 8mg/kg intravenously on day 1 and 15, and TAS-102 35mg/m 2 orally twice daily on days 1-5 and days 8-12 every 28-day cycle. The primary endpoint was 6-months overall survival (OS) rate and secondary endpoints were progression free survival (PFS), ORR and safety profile. The trial was registered at www.clinicaltrials.gov (NCT03686488). Results: At data cut-off of August 15, 2021, 23 pts were enrolled. Baseline demographics are as follows: median age of 62 years (range: 23-74), median lines of prior therapy of 1 (1: 14 pts vs ≥2: 9 pts) and location of primary tumor (GEJ:19 vs GC: 4). 6-month OS rate was 56.2%. Median OS was 6.2 month (95% CI: 5.4-7.0) and median PFS was 4.9 months with median observation of 2.3 months. Of 17 evaluable pts defined as more than one baseline imaging, 1 (6%) had partial response (PR) and 15 (88%) had stable disease (RECIST v1.1). Eleven pts came off the study due to progression of disease, 8 for toxicities and 4 for consent withdrawal. Most common treatment-emergent adverse events (TEAEs) were diarrhea (39%), fatigue (39%) and hypertension (39%). Total 11 pts (48%) experienced grade 3 and 4 TEAEs, and most common Gr3 and 4 TEAEs were neutropenia (17%) and anemia (13%). Conclusions: The combination of RAM and TAS-102 showed very similar disease control rate as the study in Asia. The combination has now shown modest activity in advanced GEAs and should be investigated further now in the context of patients receiving immunotherapy-based treatment as first-line treatment. A randomized phase II study is currently enrolling patients with ramucirumab and TAS-102 or paclitaxel. Clinical trial information: NCT03686488.
Abstract 60: Inducible Arrythmogenicity of Direct Current Electroporation Ablation: Insight from a Series of Acute Canine Studies
Authors: Alan Sugrue, Chance Witt, Christopher V DeSimone, Deepak Padnanabhan, Ammar Killu, Niyada Naksuk, Suraj Kapa, Samuel J Asirvatham
Journal: Circulation Research (2017)

Background: The use of direct current electroporation has the potential for significant utility because of its non-thermal approach to tissue destruction. However, the fear of inducibility of cardiac arrhythmias (particular ventricular fibrillation) when using electroporation remains of concern due to membrane poration and ion flux during periods of vulnerability occurring in ventricular repolarization. Objectives: Critically examine the incidence of arrhythmias in a series of acute canine studies to retrospectively determine cause and safe electoporative dosing margins. Methods: We performed electroporation ablation in 6 acute canine studies. These were experimental studies performed at sites critical in arrhytmogenesis. Sites included the pulmonary veins, left atrial appendage, superior vena cavae, right atrium and ventricle. Electroporation was delivered using an ECG gating algorithm so that QRS complexes are tagged and direct current energy is not delivered during the vulnerable portion of the T wave. Results: In 6 acute canine experiments, we delivered a total of 62 electroporation applications for ablation purposes. The average electroporation dosage delivered involved an average of 1427 Volts (range 750-3000 V), Pulse length of 100 ms, and number of pulses of 20.2 (range 10-100). AF was induced in 27.4% of electroporiatve applications. Atrial flutter/tachycardia occurred in 8.1%. VF occurred in only one application at a location of the left superior pulmonary vein. Conclusion: These data suggest that induction of VF is relatively uncommon with ECG gating and highlight its importance when using this modality. However, the induction of AF occurs with higher frequency. The actual mechanism as to why this occurs requires further systematic study.
Care of the Patient Using Cannabis
Authors: Arthur Robin Williams, Kevin P. Hill
Journal: Annals of Internal Medicine (2020)

The past 2 decades have seen a revolution in legal access to cannabis, driven largely by activists and business interests. As a result, the population of cannabis users nationwide—especially daily users—has grown significantly. An estimated 4.5–7 million persons in the United States now meet criteria for cannabis use disorder annually. This article focuses on the effects of cannabis use, intoxication, and withdrawal while also reviewing the developmental pathways of cannabis use disorder as well as evidence-based pharmacologic and psychosocial treatments.
Serum periostin among infants with severe bronchiolitis and risk of developing asthma: A prospective multicenter cohort study
Authors: Makiko Nanishi, Michimasa Fujiogi, Robert J. Freishtat, Claire E. Hoptay, Cindy S. Bauer, Michelle D. Stevenson, Carlos A. Camargo, Kohei Hasegawa
Journal: Allergy (2022)

Infants hospitalized for bronchiolitis (severe bronchiolitis) are at high risk for developing childhood asthma. However, the pathobiological link between these conditions remains unclear. We examined the longitudinal relationship of periostin (an extracellular matrix protein upregulated in response to type 2 inflammation) during bronchiolitis with the subsequent development of asthma.In a 17-center prospective cohort study of infants (aged <1 year) with severe bronchiolitis, we measured the serum periostin level at hospitalization and grouped infants into 3 groups: low, intermediate, and high levels. We examined their association with asthma development by age 6 years and investigated effect modification by allergic predisposition (eg, infant's IgE sensitization).The analytic cohort consists of 847 infants with severe bronchiolitis (median age, 3 months). Overall, 28% developed asthma by age 6 years. In the multivariable model adjusting for nine patient-level factors, compared to the low periostin group, the asthma risk was significantly higher among infants in the intermediate group (23% vs. 32%, OR 1.68, 95%CI 1.12-2.51, p = .01) and non-significantly higher in the high-level group (28%, OR 1.29, 95%CI 0.86-1.95, p = .22). In the stratified analysis, infants with IgE sensitization had a significantly higher risk for developing asthma (intermediate group, OR 4.76, 95%CI 1.70-13.3, p = .002; high group, OR 3.19, 95%CI 1.08-9.36, p = .04). By contrast, infants without IgE sensitization did not have a significantly higher risk (p > .15).In infants with severe bronchiolitis, serum periostin level at bronchiolitis hospitalization was associated with asthma risk by age 6 years, particularly among infants with an allergic predisposition.
Comparative efficacy of high and low dose of interferon alfa-2b in chronic hepatitis C: A randomized controlled trial NC Tassopoulos*, G Karvountzis**. G Touloumi***, J Delladetsima****, GV Papatheodoridis*, A Katsoulidou***, G Retalis****, A Hatzakis***. *First Dept. of Medicine, Western Attica General Hospital, Athens, **State Dept. of Medicine, Hippokration General Hospital, Athens, ***Dept. of Hygiene and Epidemiology, Athens University Medical School, Athens, ****Laboratory of Pathology, …
Journal: Hepatology (1995)
Correction: Death after flumazenil
Authors: Andrew Elliott
Journal: BMJ (1989)

three patients who required vitrectomy in the past 12 months were from this district (which has a population of 400 000).Sufficient treatment is hard to define but includes assessment of location, size, and number of effective burns; the counter on the laser photocoagulator is not a good guide.Never- theless, patients often need more than the 2000 burns that Dr Richardson and his colleagues regard as being indisputably adequate, and even as many as 13000 burns have been necessary and effective on occasion.2Although it is gratifying to have the technology to salvage some vision in patients with late complications of diabetic retinopathy, how much better it would be to prevent these complications in the first place.Screening for sight threatening diabetic retinopathy followed by timely, adequate photo- coagulation is effective in minimising blindness; vitrectomy should become a rare sign of failure of this service.Diabetes is the commonest cause of registrable blindness in people of working age.Provision of screening and photocoagulation services for diabetic retinopathy must merit a high priority in every district.
Evaluation of baseline <i>BRAF</i> V600E mutation in circulating tumor DNA and efficacy response from the BEACON study.
Authors: Scott Kopetz, Danielle A. Murphy, Jie Pu, Rona Yaeger, Fortunato Ciardiello, Jayesh Desai, Eric Van Cutsem, Harpreet Singh Wasan, Takayuki Yoshino, Elena Elez, Adele Golden, Zhou Zhu, Xiaosong Zhang, Josep Tabernero
Journal: Journal of Clinical Oncology (2022)

162 Background: In the randomized phase 3 BEACON study, encorafenib + binimetinib + cetuximab (triplet) and encorafenib + cetuximab (doublet) regimens improved overall survival (OS) and objective response rate (ORR) versus standard of care (control) in patients (pts) with previously treated BRAF V600E-mutant metastatic colorectal cancer. To identify whether detection of a BRAF V600E mutation in baseline circulating tumor DNA (ctDNA) correlated with response, we evaluated the status and allele frequency of BRAF V600E compared with clinical outcomes. Methods: Plasma samples were collected at Cycle 1 Day 1 and end of treatment for ctDNA analysis and analyzed using GuardantOMNI. Variant allele frequency (VAF) of BRAF V600E was grouped into high (&gt; median) and low (≤median) categories. Low VAF samples included those where BRAF V600E mutation was not detected or no ctDNA was detected. ORR, based on blinded independent central review, and OS were compared between treatment arms according to VAF levels. ORR comparisons used Chi-square test and logistic regression. OS was summarized using the Kaplan-Meier method. HRs and 95% CIs were estimated using a Cox model. Additional correlation analyses between BRAF V600E status in baseline tumor tissue, as well as clonality, will be presented. Results: Baseline plasma samples were analyzed from 544 of 631 pts in the ctDNA analysis: 88.3% (196/222) in the triplet arm, 86.6% (187/216) in the doublet arm, and 83.4% (161/193) in the control arm. BRAF V600E mutations were detected in 90.4% (492/544) of pts (90.3% [177/196] triplet, 90.4% [169/187] doublet, and 90.7% [146/161] control). Pts with BRAF V600E mutations with high VAF had significantly ( P≤0.0001) increased ORR (95% CI) in the triplet and doublet arms (27.3% [19.5–36.8] and 15.9% [9.7–25.0], respectively) compared with control (0% [0.0–4.3]). Similar response trends were observed in pts with BRAF V600E mutations with low VAF (triplet: 28.9% [20.8–38.9]; doublet: 25.3% [17.7–34.6]; control: 5.3% [2.1–12.8]). OS decreased in BRAF V600E pts with high VAF (median OS [95% CI]: triplet 7.2 [6.0–8.0] months, n = 99; doublet 5.4 [4.4–6.1] months, n = 88; control 4.2 [3.4–4.8] months, n = 85) compared with pts with low VAF (triplet 14.8 [10.2–19.8] months, n = 97; doublet 14.8 [11.7–23.0] months, n = 99; control 9.3 [7.5–11.3] months, n = 76). Conclusions: ctDNA analyses showed the majority of pts in BEACON analyzed at baseline had a detectable BRAF V600E mutation. Increased response rates were observed in pts treated with triplet or doublet therapy compared with control, independent of VAF. Pts with a higher VAF for BRAF V600E may have a worse prognosis. Clinical trial information: NCT04607421.
Effectiveness of BNT162b2 COVID-19 booster vaccine against covid-19 related symptoms and hospitalization in England
Authors: Nick Andrews, Julia Stowe, Freja Kirsebom, Samuel Toffa, Ruchira Sachdeva, Charlotte Gower, Mary Ramsay, Jamie Lopez Bernal
Journal: Nature Medicine (2022)

Booster vaccination with messenger RNA (mRNA) vaccines has been offered to adults in England starting on 14 September 2021. We used a test-negative case–control design to estimate the relative effectiveness of a booster dose of BNT162b2 (Pfizer-BioNTech) compared to only a two-dose primary course (at least 175 days after the second dose) or unvaccinated individuals from 13 September 2021 to 5 December 2021, when Delta variant was dominant in circulation. Outcomes were symptomatic coronavirus disease 2019 (COVID-19) and hospitalization. The relative effectiveness against symptomatic disease 14–34 days after a BNT162b2 or mRNA-1273 (Moderna) booster after a ChAdOx1-S (AstraZeneca) and BNT162b2 as a primary course ranged from around 85% to 95%. Absolute vaccine effectiveness ranged from 94% to 97% and was similar in all age groups. Limited waning was seen 10 or more weeks after the booster. Against hospitalization or death, absolute effectiveness of a BNT162b2 booster ranged from around 97% to 99% in all age groups irrespective of the primary course, with no evidence of waning up to 10 weeks. This study provides real-world evidence of substantially increased protection from the booster vaccine dose against mild and severe disease irrespective of the primary course. A test-negative case–control analysis of data from the National Immunisation Management System in England demonstrates significant levels of increased protection against hospitalization or death from COVID with mRNA booster vaccines following a primary two-dose course of either ChAdOx1-S or BNT162b2 vaccines.
Consumption of Olive Oil and Risk of Total and Cause-Specific Mortality Among U.S. Adults
Authors: Marta Guasch-Ferré, Yanping Li, Walter C. Willett, Qi Sun, Laura Sampson, Jordi Salas-Salvadó, Miguel A. Martínez-González, Meir J. Stampfer, Frank B. Hu
Journal: Journal of the American College of Cardiology (2022)
Statin and aspirin for chemoprevention of hepatocellular carcinoma: Time to use or wait further?
Authors: Myung Ji Goh, Dong Hyun Sinn
Journal: Clinical and Molecular Hepatology (2022)

Preclinical studies highlighted potential therapeutic applications of aspirin and statins as anticancer agents based on their pleiotropic effects. Epidemiologic studies suggested the role of aspirin and statins in the chemoprevention of hepatocellular carcinoma (HCC). However, observational data is prone to bias, and no prospective randomized trials are currently available to assess the risks and benefits of statin or aspirin therapy for chemoprevention of HCC. It is therefore important for clinicians and researchers to be aware of the quality of current evidence regarding this issue. In this review, we summarize currently available evidence to assist clinicians with their decision to use statin or aspirin and provide information for further clinical investigations.
Impairment of gut microbial biotin metabolism and host biotin status in severe obesity: effect of biotin and prebiotic supplementation on improved metabolism
Authors: Eugeni Belda, Lise Voland, Valentina Tremaroli, Gwen Falony, Solia Adriouch, Karen E Assmann, Edi Prifti, Judith Aron-Wisnewsky, Jean Debédat, Tiphaine Le Roy, Trine Nielsen, Chloé Amouyal, Sébastien André, Fabrizio Andreelli, Matthias Blüher, Rima Chakaroun, Julien Chilloux, Luis Pedro Coelho, Maria Carlota Dao, Promi Das, Soraya Fellahi, Sofia Forslund, Nathalie Galleron, Tue H Hansen, Bridget Holmes, Boyang Ji, Helle Krogh Pedersen, Phuong Le, Emmanuelle Le Chatelier, Christian Lewinter, Louise Mannerås-Holm, Florian Marquet, Antonis Myridakis, Veronique Pelloux, Nicolas Pons, Benoit Quinquis, Christine Rouault, Hugo Roume, Joe-Elie Salem, Nataliya Sokolovska, Nadja B Søndertoft, Sothea Touch, Sara Vieira-Silva, Pilar Galan, Jens Holst, Jens Peter Gøtze, Lars Køber, Henrik Vestergaard, Torben Hansen, Serge Hercberg, Jean-Michel Oppert, Jens Nielsen, Ivica Letunic, Marc-Emmanuel Dumas, Michael Stumvoll, Oluf Borbye Pedersen, Peer Bork, Stanislav Dusko Ehrlich, Jean-Daniel Zucker, Fredrik Bäckhed, Jeroen Raes, Karine Clément
Journal: Gut (2022)

Objectives Gut microbiota is a key component in obesity and type 2 diabetes, yet mechanisms and metabolites central to this interaction remain unclear. We examined the human gut microbiome’s functional composition in healthy metabolic state and the most severe states of obesity and type 2 diabetes within the MetaCardis cohort. We focused on the role of B vitamins and B7/B8 biotin for regulation of host metabolic state, as these vitamins influence both microbial function and host metabolism and inflammation. Design We performed metagenomic analyses in 1545 subjects from the MetaCardis cohorts and different murine experiments, including germ-free and antibiotic treated animals, faecal microbiota transfer, bariatric surgery and supplementation with biotin and prebiotics in mice. Results Severe obesity is associated with an absolute deficiency in bacterial biotin producers and transporters, whose abundances correlate with host metabolic and inflammatory phenotypes. We found suboptimal circulating biotin levels in severe obesity and altered expression of biotin-associated genes in human adipose tissue. In mice, the absence or depletion of gut microbiota by antibiotics confirmed the microbial contribution to host biotin levels. Bariatric surgery, which improves metabolism and inflammation, associates with increased bacterial biotin producers and improved host systemic biotin in humans and mice. Finally, supplementing high-fat diet-fed mice with fructo-oligosaccharides and biotin improves not only the microbiome diversity, but also the potential of bacterial production of biotin and B vitamins, while limiting weight gain and glycaemic deterioration. Conclusion Strategies combining biotin and prebiotic supplementation could help prevent the deterioration of metabolic states in severe obesity. Trial registration number NCT02059538 .
Renin-angiotensin-aldosterone system gene polymorphisms as predictors of improvement in systolic performance in dilated cardiomyopathy A Tiago, D Skudicky, AJ Woodiwiss, GP Candy, R Brooksbank, K Sliwa, P Sareli, GR Norton. Dept Physiology, University of the Witwatersand, Johannesburg, South Africa, Dept Cardiology, Baragwanath Hospital, PO Bertsham, Johannesburg 2013, South Africa
Journal: Journal of the American College of Cardiology (2001)
Ulcers and therapy
Authors: Mucosal Microcirculation, In Vivo, D Kalia, S Mortono, N Jacob, M Reed, K Bardhan°, A Gibbons, M Jordinson, S Legon', J Calam
Journal: Gut (1996)

Background/Aims: The mechanisms by which Helicobacterpylori (H.pylori) infection results in gastric mucosal injury are unknown.This study aimed to assess i) whether H. pylori extracts could initiate an inflammatory response in viwvo in the rat gastric mucosal microcirculation ii) a possible role for mucosal mast cells.Methods: The gastric mucosa of anaesthetised rats was continuously superfused with extracts of H. pylori, Escherichia colt (E.coli) or distilled water (controls).Fluorescent in vivo microscopy was used to assess macromolecular leakage of fluorescein labelled albunin from mucosal vessels and to study leukocyte and platelet activity over 90 minutes.A separate group of animals were orally administered ketotifen, a mast cell stabiliser (100tg/100g bwt), prior to anaesthesia and subsequent H. pylori treatment.Results: H. pylori extracts induced albumin leakage with a peak of 11% at 5 minutes (P<0.02).There was significant increases in adherent platelet thrombi peaking at 15 minutes (P<0.001) and plateauing at this level and also circulating platelet emboli with a peak at 30 minutes (P<0.001).Although a significant increase (P<0.001) in the number of rolling leukocytes was seen (peak at 5 minutes), they did not become filly activated to adhere.A second topical application of H. pylori had no effect.These events were unique to H. pylori.Ketotifen pre treatment prevented macromolecular leakage but did not prevent platelet aggregation.Condusion: This is the first study in vivo to demonstrate the ability of H. pyloni extacts to promote an increase in microvessel permeability and platelet aggregation within gastric mucosal microvessels.Since ketotifen prevented only macromolecular leakage, separate mechanisms may be involved in H. pylori-induced microcirculatory changes.
Space Physiology and Medicine
Authors: Dana B. Mirkin
Journal: JAMA (1990)

At the risk of sounding maudlin, upon reading a book on the past 30 years of space flight one cannot help but become somewhat reflective and nostalgic. Growing up in the 1960s, when the United States achieved its goal of putting a man on the moon, it was assumed, by me at least, that permanent human habitation would exist on the moon and in earth orbit by the 1990s. As the 1980s draw to a close, outer space has turned out to be not only the final frontier but a difficult, slow, often tedious and controversial challenge that will engage generations to come. The enormity and complexity of any space undertaking, not to mention its cost, are almost beyond description and test the patience of those who daily deal with more pedestrian but more immediate and medically more important issues of greater concern to mankind such as the acquired immunodeficiency
THE FEAR OF DEATH: MORBID MANIFESTATIONS OF THE INSTINCT.
Journal: JAMA (2005)

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