tbuckley/cabot-search huggingface dataset:
Abstract C38: HNF4a regulates progression and molecular subtype of pancreatic ductal adenocarcinoma
Authors: Soledad A. Camolotto, Luke Torre-Healy, Veronika Belova, Jeffrey Vahrenkamp, Kris Berrett, Chris Stubben, Jay Gertz, Richard Moffit, Eric L. Snyder
Journal: Cancer Research (2019)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive malignancy in which the vast majority of patients succumb to disease. Transcriptomic analysis has identified two major molecular subtypes of PDAC, classical and basal-like. The classical subtype is associated with an increased response rate to standard-of-care therapies and improved overall survival. Furthermore, classical tumors have higher levels of lineage specifiers that regulate endodermal differentiation, including the nuclear receptor HNF4a. We now show that HNF4a expression is functionally tied to induction and maintenance of the classical subtype of PDAC. We used multiple preclinical models to investigate HNF4a in PDAC. We first used the KPC (KrasLSL-G12D/+; Trp53F/+; Pdx1-Cre) mouse model in which we deleted Hnf4a at the time of tumor initiation (KPC-Hnf4aF/F). We then derived cell lines from these HNF4a-negative mouse tumors, rescued HNF4a, and analyzed their proliferation and viability in vitro. Additionally, we used a sequential recombination strategy to derive murine PDAC organoid cultures in which Hnf4a could be deleted in vitro. Finally, in a retrospective analysis, we investigated clinical and molecular associations with HNF4a expression in PDAC patients from TCGA. Our data in genetically engineered mouse models show that loss of HNF4a causes increased tumorigenicity and decreased overall survival. In cell lines, rescue of HNF4a expression impairs proliferation and alters differentiation state. In organoid cultures, Hnf4a deletion changes the in vivo three-dimensional growth pattern, resulting in a more malignant phenotype. In all of these model systems, RNA sequencing shows that loss of HNF4a expression results in a significant loss of classical subtype gene expression. In PDAC patients, HNF4a expression was strongly correlated with classical subtype gene expression (R = .71) and was mildly associated with better survival (p = .088). Taken together, our data suggest that HNF4a is a key lineage specifier within a larger transcriptional network that regulates the growth and molecular subtype of PDAC. Thus, we anticipate that these data will advance the development of novel therapeutics that take advantage of HNF4a’s important role in the classical subtype of this disease. Citation Format: Soledad A. Camolotto, Luke Torre-Healy, Veronika Belova, Jeffrey Vahrenkamp, Kris Berrett, Chris Stubben, Jay Gertz, Richard Moffit, Eric L. Snyder. HNF4a regulates progression and molecular subtype of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C38.
Adherence in children using positive airway pressure therapy: a big-data analysis
Authors: Rakesh Bhattacharjee, Adam V Benjafield, Jeff Armitstead, Peter A Cistulli, Carlos M Nunez, Jean-Louis D Pepin, Holger Woehrle, Yang Yan, Atul Malhotra
Journal: The Lancet Digital Health (2019)

Positive airway pressure (PAP) has become a prominent treatment for children with sleep-disordered breathing. However, there are no large-scale studies to clarify whether PAP is well tolerated in children, and which factors are associated with better adherence to PAP therapy. In this study, we aimed to clarify adherence patterns of PAP therapy in a large paediatric population.We did a cross-sectional big-data analysis in children from Oct 1, 2014, to Aug 1, 2018, using existing data derived from PAP devices uploaded nightly in the AirView cloud database. The AirView database is a usage tracking system available to all patients who are assigned PAP therapy, which requires consent from the patient or parent or guardian. All patients older than 4 years and younger than 18 years who used continuous or automated PAP devices were evaluated. Only patients living in the USA and enrolled with a single insurance company were included. If patients were participating in an engagement programme, programme onset must have been within 7 days of therapy onset. Our primary outcome was the proportion of patients who used PAP continuously over 90 days. The primary outcome was assessed in all patients who met the age inclusion criterion and had reliable age data available. Data on missing PAP use were imputed as zero, but data on other metrics were not imputed and excluded from analysis.We used data recorded from Oct 1, 2014, to Aug 1, 2018. Of 40 140 children screened, 36 058 (89·8%) were US residents and 20 553 (90·1%) of them met the eligibility criteria and had accessible data (mean age 13·0 years [SD 3·7]). On the basis of 90 days of monitoring data, 12 699 (61·8%) patients continuously used PAP. Factors significantly associated with adherence included age group, residual apnoea-hypopnoea index, use and onset of patient engagement programmes, PAP pressure, and nightly median PAP mask leak, all over the 90-day study period.To our knowledge, our study represents the largest analysis of children using PAP therapy to date. The findings suggest that adherence to PAP therapy is lower than in previous reports from adults. However, numerous actionable factors were associated with improvements in adherence and should be used strategically in clinical decision making to improve PAP adherence in children.ResMed.
US Supreme Court allows Kentucky’s abortion ultrasound law to stand
Authors: Owen Dyer
Journal: BMJ (2019)

The United States’ highest court has declined to review a Kentucky law that requires doctors performing abortions to perform fetal ultrasounds and show them to patients, even if the patient asks them not to.

The Kentucky Ultrasound Informed Consent Act allows the patient to close her eyes if she wishes not to see the image, but the physician is obliged to display it, verbally pointing out any visible body parts. Failure to comply is punishable by six figure fines and referral to the state medical board.

The law also requires the doctor to make the fetal heartbeat audible if …
Somatostatin secretion by Na+-dependent Ca2+-induced Ca2+ release in pancreatic delta cells
Authors: Elisa Vergari, Geoffrey Denwood, Albert Salehi, Quan Zhang, Julie Adam, Ahmed Alrifaiy, Ingrid Wernstedt Asterholm, Anna Benrick, Margarita V. Chibalina, Lena Eliasson, Claudia Guida, Thomas G. Hill, Alexander Hamilton, Reshma Ramracheya, Frank Reimann, Nils J. G. Rorsman, Ioannis Spilliotis, Andrei I. Tarasov, Jonathan N. Walker, Patrik Rorsman, Linford J. B. Briant
Journal: Nature Metabolism (2020)
Acute hypoxaemic respiratory failure in immunocompromised patients: abandon bronchoscopy or make it better?
Authors: Philippe R. Bauer, Sylvie Chevret, Elie Azoulay
Journal: European Respiratory Journal (2019)

<b>The decision-making process regarding whether to perform bronchoscopy in acute respiratory failure in immunosuppressed patients is complex and does not depend solely on severity</b>http://bit.ly/2O9cjcq
Effect of Teaching Bayesian Methods Using Learning by Concept vs Learning by Example on Medical Students’ Ability to Estimate Probability of a Diagnosis
Authors: John E. Brush, Mark Lee, Jonathan Sherbino, Judith C. Taylor-Fishwick, Geoffrey Norman
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Clinicians use probability estimates to make a diagnosis. Teaching students to make more accurate probability estimates could improve the diagnostic process and, ultimately, the quality of medical care. <h3>Objective</h3> To test whether novice clinicians can be taught to make more accurate bayesian revisions of diagnostic probabilities using teaching methods that apply either explicit conceptual instruction or repeated examples. <h3>Design, Setting, and Participants</h3> A randomized clinical trial of 2 methods for teaching bayesian updating and diagnostic reasoning was performed. A web-based platform was used for consent, randomization, intervention, and testing of the effect of the intervention. Participants included 61 medical students at McMaster University and Eastern Virginia Medical School recruited from May 1 to September 30, 2018. <h3>Interventions</h3> Students were randomized to (1) receive explicit conceptual instruction regarding diagnostic testing and bayesian revision (concept group), (2) exposure to repeated examples of cases with feedback regarding posttest probability (experience group), or (3) a control condition with no conceptual instruction or repeated examples. <h3>Main Outcomes and Measures</h3> Students in all 3 groups were tested on their ability to update the probability of a diagnosis based on either negative or positive test results. Their probability revisions were compared with posttest probability revisions that were calculated using the Bayes rule and known test sensitivity and specificity. <h3>Results</h3> Of the 61 participants, 22 were assigned to the concept group, 20 to the experience group, and 19 to the control group. Approximate age was 25 years. Two participants were first-year; 37, second-year; 12, third-year; and 10, fourth-year students. Mean (SE) probability estimates of students in the concept group were statistically significantly closer to calculated bayesian probability than the other 2 groups (concept, 0.4%; [0.7%]; experience, 3.5% [0.7%]; control, 4.3% [0.7%];<i>P</i> &lt; .001). Although statistically significant, the differences between groups were relatively modest, and students in all groups performed better than expected, based on prior reports in the literature. <h3>Conclusions and Relevance</h3> The study showed a modest advantage for students who received theoretical instruction on bayesian concepts. All participants' probability estimates were, on average, close to the bayesian calculation. These findings have implications for how to teach diagnostic reasoning to novice clinicians. <h3>Trial Registration</h3> ClinicalTrials.gov identifier:NCT04130607
US Sues Gilead, Alleging PrEP Drugs Infringe on HHS Patents
Authors: Rita Rubin
Journal: JAMA (2019)

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Differences in survival for advanced-stage colorectal cancer (CRC) patients by lines of therapy received in a U.S. local oncology practice.
Authors: Susan H Foltz Boklage, Charles Kreilick, Carl V Asche, Sally Haislip, James W. Gilmore, Stephen Szabo, Todd E. Williamson, Satish Valluri, Brian S. Seal
Journal: Journal of Clinical Oncology (2012)

e14106 Background: Improvements in survival for advanced-stage colorectal cancer (CRC) patients who receive chemotherapy have been reported. We compared survival rates for patients with 3+ vs. &lt;3 lines of therapy using electronic medical records of a local oncology practice in Georgia, USA. Methods: The Georgia Cancer Specialist (GCS) EMR Database (1/1/2005–07/ 31/2010) was used. The database contains data on patient demographics, cancer diagnostic information, chemotherapy and non-chemotherapy drugs administered written prescriptions, chemotherapy/radiation protocols, chemotherapy protocol changes, office visit information, and hospitalizations. Patients newly diagnosed with CRC between 01/01/05 and 06/31/10 treated with systemic therapy for CRC were identified. Patients were followed from initial CRC diagnosis to death, loss to follow-up, or end of study. Patients were categorized by number of lines of therapy received (1, 2, 3+) and original stage at diagnosis (III b/c, IV, unknown). Survival following initial line of therapy was evaluated using Cox proportional hazards models controlling forstage at diagnosis, type of 1 st line treatment, and other patient characteristics. Results: The study included 704 patients with a median age of 63 years (age range 26-85 years) at diagnosis and 49% (n=345) female. 45% (n=317) and 42% (n=296) had stage IV and III b/c CRC at diagnosis, respectively. 53% (n=373) received only 1 st line treatment, 27% (n=190) received 1 st and 2 nd line treatment and 20% (n=141) received 3 rd line and beyond. The median follow up was 431 days and death was reported in 27%(n=190) of subjects. The multivariate Cox proportional hazard analysis indicated that there was no statistical difference in survival between patients who received 2 nd line of therapy vs. 3 plus lines of therapy (HR=1.42; p&lt;0.067). Conclusions: A non-statistical significant association between 2 nd and more than 3 total lines of therapy in survival was found in subjects diagnosed with stage III B/C and IV. However the trend towards survival was present, indicating that some patients could benefit from the addition of 3 rd line but it would require additional studies to confirm this.
Patient-reported Quality of Life Outcomes in Patients Treated for Muscle-invasive Bladder Cancer with Radiotherapy ± Chemotherapy in the BC2001 Phase III Randomised Controlled Trial
Authors: Robert A. Huddart, Emma Hall, Rebecca Lewis, Nuria Porta, Malcolm Crundwell, Peter J. Jenkins, Christine Rawlings, Jean Tremlett, Leila Campani, Carey Hendron, Syed A. Hussain, Nicholas D. James
Journal: European Urology (2019)

BC2001, the largest randomised trial of bladder-sparing treatment for muscle-invasive bladder cancer, demonstrated improvement of local control and bladder cancer–specific survival from the addition of concomitant 5-fluorouracil and mitomycin C to radiotherapy. To determine the impact of treatment on the health-related quality of life (HRQoL) of BC2001 participants. 458 UK patients with T2-T4a N0 M0 transitional cell carcinoma of the bladder. Patients were randomised to the chemotherapy comparison (radiotherapy, 178, or chemoradiotherapy, 182); and/or to the radiotherapy comparison (standard, 108, or reduced high-dose volume radiotherapy, 111). Patients completed Functional Assessment of Cancer Therapy—Bladder (FACT-BL) questionnaires at baseline, end of treatment (EoT), and 6, 12, 24, 36, 48, and 60 months after radiotherapy. The primary endpoint was change from baseline in the bladder cancer subscale (BLCS) at 12 months. Data were available for 331 (92%) and 204 (93%) participants at baseline and for 192 (54%) and 114 (52%) at 12 months for the chemotherapy and radiotherapy comparisons, respectively. HRQoL declined at EoT (BLCS –5.06 [99% confidence interval: –6.12 to –4.00, p < 0.001]; overall FACT-B TOTAL score –8.22 [–10.76 to –5.68, p < 0.01]), recovering to baseline at 6 months and remaining similar to baseline subsequently. There was no significant difference between randomised groups at any time point. Immediately following (chemo)radiotherapy, a significant proportion of patients report declines in HRQoL, which improve to baseline after 6 months. Two-thirds of patients report stable or improved HRQoL on long-term follow-up. There is no evidence of impairment in HRQoL resulting from the addition of chemotherapy. Quality of life of bladder cancer patients treated with radiotherapy ± chemotherapy deteriorates during treatment, but improves to at least pretreatment levels within 6 months. Addition of chemotherapy to radiotherapy does not affect patient-reported quality of life.
Intracranial Activity of Gefitinib and Capmatinib in a Patient with Previously Treated Non–Small Cell Lung Cancer Harboring a Concurrent EGFR Mutation and MET Amplification
Authors: Justin F. Gainor, Sara E. Stevens, Henning Willers, Helen A. Shih, Rebecca S. Heist
Journal: Journal of Thoracic Oncology (2019)
Ethics in Publication part 3: Conflicts of Interest
Authors: Michael Wallace, Deborah Bowman, Hilary Hamilton-Gibbs, Peter D. Siersema
Journal: Endoscopy (2019)

Publication information This article is being published jointly in Gastrointestinal Endoscopy and Endoscopy. Copyright © 2020 by the American Society for Gastrointestinal Endoscopy and Georg Thieme Verlag KG
Diversity in the medical workforce is better for patients
Authors: Rachel Pilling, Ishani Salpadoru
Journal: BMJ (2019)

When considering medical school admissions, the ultimate question is which candidates will make the best doctors.1

Logically, candidates who have performed well in exams in the past will perform well in the future. But is performance in medical school exams indicative of a “good” doctor? And who decides what a …
Familial myeloid malignancies with germline TET2 mutation
Authors: Nicolas Duployez, Laure Goursaud, Laurène Fenwarth, Claire Bories, Alice Marceau-Renaut, Thomas Boyer, Elise Fournier, Olivier Nibourel, Catherine Roche-Lestienne, Guillemette Huet, David Beauvais, Céline Berthon, Nathalie Cambier, Bruno Quesnel, Claude Preudhomme
Journal: Leukemia (2019)
Characteristics and Incidence of Concussion Among a US Collegiate Undergraduate Population
Authors: John Breck, Adam Bohr, Sourav Poddar, Matthew B. McQueen, Tracy Casault
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Concussion on university campuses is a significant health problem. Characterizing the incidence of concussion on college campuses may inform education and resource allocation policy at student health care centers. <h3>Objectives</h3> To establish a measure of concussion incidence among collegiate undergraduate students and to describe characteristics associated with concussion incidence, including sex, cause, and month. <h3>Design, Setting, and Participants</h3> This prospective cohort study included data from 3 academic years from August 2015 to April 2018 at a large, public university in the United States. Participants included any undergraduate student or varsity athlete who was diagnosed with at least 1 concussion during the academic year. <h3>Exposures</h3> Sport- and non–sport-related activities of undergraduate students. <h3>Main Outcomes and Measures</h3> Concussion diagnosis. <h3>Results</h3> Among 954 undergraduate students from the general undergraduate population with at least 1 concussion, including 502 men and 452 women, 1020 concussions were diagnosed in 3 academic years. During 2 academic years, a total of 80 concussions occurred among the varsity athlete population, including 26 men and 54 women. Overall, concussion incidence among both the general undergraduate population and varsity athletes was 132.4 (95% CI, 123.2-142.0) concussions per 10 000 students. Men sustained concussions at a rate of 126.1 (95% CI, 114.1-139.0) concussions per 10 000 students and women sustained concussions at a rate of 140.0 (95% CI, 126.2-155.3) concussions per 10 000 students for the 2016 to 2017 and 2017 to 2018 academic years. Concussion incidence peaked in August at the start of the academic year and the rate of non–sport-related concussions (81.0 [95% CI, 73.9-88.7] concussions per 10 000 students for academic years 2016-2017 and 2017-2018) was higher than the rate of sport-related concussions (51.5 [95% CI, 49.5-57.7] concussions per 10 000 students for academic years 2016-2017 and 2017-2018). <h3>Conclusions and Relevance</h3> This cohort study found concussions to be common among this US collegiate population. While concussion is often associated with sport, the incidence of non–sport-related concussion was higher than that of sport-related concussion throughout the academic year. Additional research is warranted to determine if this incidence measure among undergraduate students is generalizable to other university populations.
Chemotherapy accelerates immune-senescence and functional impairments of Vδ2pos T cells in elderly patients affected by liver metastatic colorectal cancer
Authors: Elena Bruni, Valentina Cazzetta, Matteo Donadon, Matteo Cimino, Guido Torzilli, Gianmarco Spata, Gloria Leonardi, Francesco Dieli, Joanna Mikulak, Domenico Mavilio
Journal: Journal for ImmunoTherapy of Cancer (2019)

Human (gamma delta) γδ T cells are unconventional innate-like lymphocytes displaying a broad array of anti-tumor activities with promising perspectives in cancer immunotherapy. In this context, Vδ2<sup>pos</sup> T cells represent the preferential target of several immunotherapy protocols against solid tumors. However, the impact of both aging and chemotherapy (CHT) on Vδ2<sup>pos</sup> T cells is still unknown. The present study evaluates with multi-parametric flow cytometry the frequencies, terminal differentiation, senescence and effector-functions of peripheral blood and tumor infiltrating Vδ2<sup>pos</sup> T cells purified from liver metastases (CLM) of patients affected by colorectal cancer (CRC) compared to those of sex- and age-matched healthy donors. The peripheral blood of CLM patients underwent CHT is characterized by decreased amounts of Vδ2<sup>pos</sup> T cells showing a relative increase of terminally-differentiated CD27<sup>neg</sup>/CD45RA<sup>pos</sup> (T<sub>EMRA</sub>) cells. The enrichment of this latter subset is associated with an increased expression of the senescent marker CD57. The acquisition of CD57 on T<sub>EMRA</sub> Vδ2<sup>pos</sup> T cells is also coupled with impairments in cytotoxicity and production of TNF-α and IFN-γ. These features resemble the acquisition of an immune-senescent profile by Vδ2<sup>pos</sup> T cells from CLM patients that received CHT, a phenomenon that is also associated with the loss of the co-stimulatory marker CD28 and with the induced expression of CD16. The group of CLM patients underwent CHT and older than 60 years old showed higher frequencies of CD57<sup>pos</sup> and T<sub>EMRA</sub> Vδ2<sup>pos</sup> T cells. Similar results were found for tumor infiltrating Vδ2<sup>pos</sup> T cell subset purified from CLM specimens of patients treated with&nbsp;CHT. The toxicity of CHT regimens also affects the homeostasis of Vδ2<sup>pos</sup> T cells by inducing higher frequencies of circulating CD57<sup>pos</sup> T<sub>EMRA</sub> subset in CLM underwent CHT and younger than 60 years old. Taken together, our data demonstrate that the enrichment of senescent Vδ2<sup>pos</sup> T cells in CLM patients is not only induced by patients' aging but also by the toxicity of CHT that further accelerates the accumulation of CD57<sup>pos</sup> T<sub>EMRA</sub> cells highly dysfunctional in their anti-tumor activities. These results are important to both predict the clinical outcome of CLM and to optimize those protocols of cell cancer immunotherapy employing unconventional Vδ2<sup>pos</sup> T cells.
Problems with the dual-systems approach to temporal cognition
Authors: David E Melnikoff, John A Bargh
Journal: Behavioral and Brain Sciences (2019)

Abstract Contrary to Hoerl &amp; McCormack (H&amp;M), we argue that the best account of temporal cognition in humans is one in which a single system becomes capable of representing time. We suggest that H&amp;M's own evidence for dual systems of temporal cognition – simultaneous contradictory beliefs – does not recommend dual systems, and that the single system approach is more plausible.