tbuckley/cabot-search huggingface dataset:
A Novel “Cut and Paste” Method for In Situ Replacement of cMyBP-C Reveals a New Role for cMyBP-C in the Regulation of Contractile Oscillations
Authors: Nathaniel C. Napierski, Kevin Granger, Paul R. Langlais, Hannah R. Moran, Joshua Strom, Katia Touma, Samantha P. Harris
Journal: Circulation Research (2020)

cMyBP-C (cardiac myosin-binding protein-C) is a critical regulator of heart contraction, but the mechanisms by which cMyBP-C affects actin and myosin are only partly understood. A primary obstacle is that cMyBP-C localization on thick filaments may be a key factor defining its interactions, but most in vitro studies cannot duplicate the unique spatial arrangement of cMyBP-C within the sarcomere.The goal of this study was to validate a novel hybrid genetic/protein engineering approach for rapid manipulation of cMyBP-C in sarcomeres in situ.We designed a novel cut and paste approach for removal and replacement of cMyBP-C N'-terminal domains (C0-C7) in detergent-permeabilized cardiomyocytes from gene-edited Spy-C mice. Spy-C mice express a TEVp (tobacco etch virus protease) cleavage site and a SpyTag (st) between cMyBP-C domains C7 and C8. A cut is achieved using TEVp which cleaves cMyBP-C to create a soluble N'-terminal γC0C7 (endogenous [genetically encoded] N'-terminal domains C0 to C7 of cardiac myosin binding protein-C) fragment and an insoluble C'-terminal SpyTag-C8-C10 fragment that remains associated with thick filaments. Paste of new recombinant (r)C0C7 domains is achieved by a covalent bond formed between SpyCatcher (-sc; encoded at the C'-termini of recombinant proteins) and SpyTag. Results show that loss of γC0C7 reduced myofilament Ca2+ sensitivity and increased cross-bridge cycling (ktr) at submaximal [Ca2+]. Acute loss of γC0C7 also induced auto-oscillatory contractions at submaximal [Ca2+]. Ligation of rC0C7 (exogenous [recombinant] N'-terminal domains C0 to C7 of cardiac myosin binding protein-C)-sc returned pCa50 and ktr to control values and abolished oscillations, but phosphorylated (p)-rC0C7-sc did not completely rescue these effects.We describe a robust new approach for acute removal and replacement of cMyBP-C in situ. The method revealed a novel role for cMyBP-C N'-terminal domains to damp sarcomere-driven contractile waves (so-called spontaneous oscillatory contractions). Because phosphorylated (p)-rC0C7-sc was less effective at damping contractile oscillations, results suggest that spontaneous oscillatory contractions may contribute to enhanced contractility in response to inotropic stimuli.
Research on Improving Outcomes and Reducing Costs of Psychological Interventions: Toward Delivering the Best to the Most for the Least
Authors: Brian T. Yates
Journal: Annual Review of Clinical Psychology (2020)

Treatment and prevention efforts guided by psychological theory, research, and practice can have outcomes of greater value than the resources consumed by those efforts-and outcomes superior to those attainable by other means, often at lower costs. How can we make this hope true more often, for more of the clients who need our services, despite severe resource constraints? Routinely reporting the costs, effectiveness, and benefits of psychological interventions from client, practitioner, and societal perspectives is only a beginning. We also need to use descriptive and inferential statistics to measure, report, and analyze the cost-effectiveness and cost-benefit of our interventions to discover the strongest determinants of intervention costs and outcomes. The emerging literature on cost-inclusive research in psychology suggests that delivery systems are one primary determinant of costs and outcomes of most interventions, as are the psychological techniques applied.
Impact of left ventricular ejection fraction on clinical outcomes after left main coronary artery revascularization: results from the randomized EXCEL trial
Authors: Daniel J.F.M. Thuijs, Milan Milojevic, Gregg W. Stone, John D. Puskas, Patrick W. Serruys, Joseph F. Sabik, Ovidiu Dressler, Aaron Crowley, Stuart J. Head, A. Pieter Kappetein
Journal: European Journal of Heart Failure (2020)

Abstract Aim To evaluate the impact of left ventricular ejection fraction (LVEF) on 3‐year outcomes in patients with left main coronary artery disease (LMCAD) undergoing percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) in the EXCEL trial. Methods and results The EXCEL trial randomized patients with LMCAD to PCI with everolimus‐eluting stents ( n = 948) or CABG ( n = 957). Among 1804 patients with known baseline LVEF, 74 (4.1%) had LVEF &lt;40% [heart failure with reduced ejection fraction (HFrEF)], 152 (8.4%) LVEF 40–49% [heart failure with mid‐range ejection fraction (HFmrEF)] and 1578 (87.5%) LVEF ≥50% (heart failure with preserved ejection fraction). Patients with HFrEF vs. HFmrEF vs. preserved LVEF experienced a longer postoperative hospital stay (9.0 vs. 7.0 vs. 6.0 days, P = 0.02) with greater peri‐procedural complications after CABG, while hospital stay after PCI was unaffected by LVEF (1.5 vs. 2.0 vs. 1.0 days, P = 0.20). The composite primary endpoint of death, stroke, or myocardial infarction at 3 years was 29.3% (PCI) vs. 27.6% (CABG) in patients with HFrEF, 16.2% vs. 15.0% in patients with HFmrEF, and 14.5% vs. 14.6% in those with preserved LVEF, respectively ( P interaction = 0.90). Smoothing spline analysis demonstrated that the 3‐year risk of all‐cause death increased when LVEF decreased, both in patients undergoing CABG and PCI. Conclusion In the EXCEL trial, the composite rate of death, stroke or myocardial infarction at 3 years was significantly higher in patients with HFrEF compared with HFmrEF or preserved LVEF, driven by an increased rate of all‐cause death. No significant differences after PCI vs. CABG were observed among patients with HFrEF, HFmrEF and preserved LVEF. Longer‐term follow‐up could provide important insights on differences in clinical outcomes that might emerge over time. Clinical Trial Registration: ClinicalTrials.gov Identifier NCT01205776 .
Phenome-wide association analysis suggests the APOL1 linked disease spectrum primarily drives kidney-specific pathways
Authors: Archna Bajaj, Andrea Ihegword, Chengxiang Qiu, Aeron M. Small, Wei-Qi Wei, Lisa Bastarache, QiPing Feng, Rachel L. Kember, Marjorie Risman, Roy D. Bloom, David L. Birtwell, Heather Williams, Christian M. Shaffer, Jinbo Chen, Regeneron Genetics Center, Joshua C. Denny, Daniel J. Rader, C. Michael Stein, Scott M. Damrauer, Katalin Susztak
Journal: Kidney International (2020)
Defining Optimal Empirical Antibiotic Regimens in a Rapidly Changing Landscape of Resistance
Authors: Jay J. H. Park, Srinivas Murthy
Journal: JAMA Network Open (2020)

Julia A. Bielicki, MD; Mike Sharland, MD; Paul T. Heath, FRCPCH; A. Sarah Walker, PhD; Ramesh Agarwal, MD; Paul Turner, PhD; David A. Cromwell, PhD
Paediatrician left suicide note suggesting he secretly left patients unvaccinated
Authors: Owen Dyer
Journal: BMJ (2020)

A popular Chicago paediatrician who took his own life left a note suggesting that he falsified medical records for the past decade and may not have immunised his patients.

Van Koinis went missing last August and in September he was found in a forest near Chicago, dead from a self-inflicted gunshot. But with questions still unanswered months later, police have decided to publicise his suicide note. 

Cook County sheriff Tom Dart described it to local media. “The note was very short,” Dart told CBS 2 Chicago. “He expressed a lot of regret, referring to the vaccinations. It was the only thing he mentioned in the suicide note. It was this and only this.”

Dart added, “He …
CD4+ T Cells Sustain Aggressive Chronic Lymphocytic Leukemia through a CD40L-Independent Mechanism
Authors: Matteo Bellone, Paolo Dellabona, Arianna Calcinotto, Giulia Casorati, Alessandra Rovida, Maria Teresa Sabrina Bertilaccio, Elena Cattaneo, Matteo Grioni, Federico caligaris-Cappio, Paolo Ghia
Journal: Blood (2019)
Don’t call me Bibi—or anybody else, for that matter
Authors: Fizzah Ali
Journal: BMJ (2020)

As medical students, our vocabulary expands exponentially to accommodate written exams and clinical assessments, but nothing prepared me for the slang I encountered on the wards in my foundation years. It was here that I first came across the term “Bibi-itis.” A decade later I found it was still being used.

It happened in the doctors’ office. I was scrolling through a list of patient referrals on my computer wondering out loud what undiagnosed entity awaited me in the emergency department. Beside me, my colleague asserted that the crucial diagnostic clue could be found in the patient’s name. In fact, he went on, that based on my race and my gender, if my name appeared on a list of …
CNTNAP4 deficiency in dopaminergic neurons initiates parkinsonian phenotypes
Authors: Wenlong Zhang, Miaomiao Zhou, Weiye Lu, Junwei Gong, Feng Gao, Yuanquan Li, Xuandong Xu, Yuwan Lin, Xiaokang Zhang, Liuyan Ding, Zhiling Zhang, Guihua Li, Xiang Chen, Xiangdong Sun, Xiaoqin Zhu, Pingyi Xu, Yunlong Zhang
Journal: Theranostics (2020)

Rationale: Contactin-associated protein-like 4 (CNTNAP4) belongs to the neurexin superfamily and has critical functions in neurological development and synaptic function. Loss of CNTNAP4 in interneurons has been linked to autism, schizophrenia, and epilepsy. CNTNAP4 is also highly enriched in dopaminergic (DA) neurons in the substantia nigra (SN), however, few studies have investigated the role of CNTNAP4 in DA neurons, and whether CNTNAP4 deficiency in DA neurons contributes to Parkinson's disease (PD) remains unclear. Methods: Effects of CNTNAP4 knockdown or overexpression on the DA MN9D cell line were assessed via Western blotting, immunocytochemistry, and RNA sequencing. An in vivo animal model, including CNTNAP4 knockout mice and stereotaxic injections of adeno-associated viral short-hairpin RNA with the tyrosine-hydroxylase promotor to silence CNTNAP4 in the SN, as well as the resulting physiological/behavioral effects, were evaluated via behavioral tests, Western blotting, immunohistochemistry, and transmission electron microscopy. Enzyme-linked immunosorbent assays (ELISAs) were performed to examine the cerebrospinal fluid (CSF) and plasma CNTNAP4 concentrations in PD patients. Results: We demonstrated that CNTNAP4 knockdown induced mitophagy and increased α-synuclein expression in MN9D cells. CNTNAP4 knockdown in the SN induced PD-like increases in SN-specific α-synuclein expression, DA neuronal degeneration, and motor dysfunction in mice. In addition, CNTNAP4 knockdown in SN-DA neurons increased autophagosomes and reduced synaptic vesicles in the SN. Furthermore, CNTNAP4 knockout mice showed movement deficits, nigral DA degeneration, and increased autophagy, which were consistent with the SN-specific knockdown model. We also found that CSF and plasma CNTNAP4 expression was increased in PD patients; in particular, plasma CNTNAP4 was increased in male PD patients compared with controls or female PD patients. Conclusion: Our findings suggest that CNTNAP4 deficiency may initiate phenotypes relevant to PD, of which we elucidated some of the underlying mechanisms.
PTH-075 Vaccinations in inflammatory bowel disease patients receiving biologic therapy, are they being considered?
Authors: K Chatten, L Cornthwaite, E Nixon, A Goel
Journal: Gut (2017)

Introduction  With a recent paradigm shift in IBD management, biologics are being used earlier in disease course, often in combination with immunomodulators. This poses significant immunosuppression and infection risk. Optimised vaccination uptake provides an opportunity to reduce serious infection risk from preventable illness in patients with IBD.  European Crohn’s and Colitis Organisation (ECCO) have produced consensus guidelines on vaccinations for this patient group.1  Method  Our aim was to assess whether patients on biologic treatment (as single or combination therapy with immunomodulators) are receiving vaccinations in line with ECCO guidelines.  We identified patients treated with biologics (adalimumab/infliximab) for IBD at Royal Preston Hospital from an established database. GP Practices were contacted in the Central Lancashire area and asked to complete a cross sectional survey using their electronic records detailing what vaccinations patients had received and whether they were listed for recall.  Results  Out of 100 surveys sent to GP practices, 58 were returned. The average patient age was 41 years. 43 (74.1%) had a diagnosis of Crohn’s and 15 (25.9%) of ulcerative colitis. Influenza vaccine had the highest uptake at 62.1% and 74.1% on recall (3 of these had other medical indications for vaccination). For all other vaccines uptake was low ranging 0% (shingles) to 46.6% (MMR). The data on vaccinations is detailed in the table below:  Conclusion  The uptake of vaccinations among IBD patients on biologics is low. With the use of biologics likely to increase in this patient population, targeted interventions aimed at improving vaccination rates are needed. Recent studies have shown systematic educational initiatives in primary and secondary care can improve vaccination rates(2). Formal annual reviews focusing on health maintenance measures and development of collaborative pathways between primary and secondary care may help remove barriers to implementation of guidelines.  References  . Rahier JF, Magro F, Abreu C, et al.  . Christensen K, Steenholdt C, Buhl S at al. Systematic Information to Health-Care Professionals about Vaccination Guidelines Improves Adherence in Patients With Inflammatory Bowel Disease in Anti-TNFα Therapy. Am J Gastroenterol. 2015;110(11):1526–32.  Disclosure of Interest  None Declared
Hepatitis B-related outcomes following direct-acting antiviral therapy in Taiwanese patients with chronic HBV/HCV co-infection
Authors: Ming-Lun Yeh, Chung-Feng Huang, Ching-I. Huang, Jacinta A. Holmes, Meng-Hsuan Hsieh, Yi-Shan Tsai, Po-Cheng Liang, Pei-Chien Tsai, Ming-Yen Hsieh, Zu-Yau Lin, Shinn-Cherng Chen, Jee-Fu Huang, Chia-Yen Dai, Wan-Long Chuang, Raymond T. Chung, Ming-Lung Yu
Journal: Journal of Hepatology (2020)

The outcome of HBV infection, including the dynamics of HBsAg and HBV virological reactivation, among patients coinfected with HCV receiving direct-acting antivirals (DAAs) remains unclear. Thus, we aimed to analyze HBV-related outcomes in these patients.Serial HBsAg and HBV DNA levels were measured in 79 HBV/HCV-coinfected patients receiving DAAs (13 receiving anti-HBV nucleot(s)ide analog [NUC] therapy simultaneously). The endpoints included HBsAg dynamics and seroclearance, HBV reactivation (HBV DNA >1 log increase or >100 IU/ml if undetectable at baseline) and HBV-related clinical reactivation.HBsAg levels declined from a median of 73.3 IU/ml at baseline to 16.2 IU/ml at the end-of-DAA treatment and increased to 94.1 IU/ml at 12 months post-treatment. During a mean 11.1-months of follow-up, 8 (10.1%) patients experienced HBsAg seroclearance and 30 (38.0%) HBV reactivation (12-month cumulative incidence, 10.3% and 40.4%, respectively). Patients with pre-treatment HBsAg ≤10 IU/ml had a significantly higher rate of HBsAg seroclearance (hazard ratio [HR] 8.52; 95% CI 1.048-69.312) and lower risk of HBV reactivation than those with pre-treatment HBsAg >10 IU/ml (HR 2.88; 95% CI 1.057-7.844) in multivariate analyses. Six patients (4 cirrhotics) not receiving NUC therapy experienced HBV-related clinical reactivation; 3 of the 4 cirrhotics developed liver failure and 2 died despite immediate NUC therapy. Compared to untreated HBV-monoinfected patients, HBV/HCV-coinfected patients without NUC prophylaxis had a similar rate of HBsAg seroclearance, but a significantly higher risk of HBV reactivation following DAA therapy (HR 6.59; 95% CI 2.488-17.432).DAA-treated HBV/HCV-coinfected patients had significantly higher rates of HBV seroclearance, particularly among those with low pre-treatment HBsAg titer, but were at higher risk of HBV reactivation, particularly among those with higher pre-treatment HBsAg titer. Prophylactic anti-HBV therapy is essential for cirrhotic patients, irrespective of baseline HBV DNA levels.We studied outcomes relating to hepatitis B virus (HBV) in patients coinfected with both hepatitis B and C. Patients receiving direct-acting antiviral treatment for hepatitis C were more likely to experience seroclearance (or functional cure of HBV), but were also more likely to experience HBV reactivation, which can lead to hepatitis, liver failure and death. In coinfected cirrhotic patients being treated for HCV, prophylactic treatment for HBV is mandatory.
Prevalence of sarcoidosis-associated pulmonary hypertension: cumulative analysis of two PULSAR studies
Authors: Stefan Pabst, Christian Grohé, Dirk Skowasch
Journal: European Respiratory Journal (2020)

<b>A cumulative analysis of both PULSAR trials would demonstrate sarcoidosis-associated pulmonary hypertension proven by right heart catheter in 15/510 patients and precapillary PH in 13/510 patients</b>http://bit.ly/34VGWbv
CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors
Authors: Haiping Wang, Fabien Franco, Yao-Chen Tsui, Xin Xie, Marcel P. Trefny, Roberta Zappasodi, Syed Raza Mohmood, Juan Fernández-García, Chin-Hsien Tsai, Isabell Schulze, Florence Picard, Etienne Meylan, Roy Silverstein, Ira Goldberg, Sarah-Maria Fendt, Jedd D. Wolchok, Taha Merghoub, Camilla Jandus, Alfred Zippelius, Ping-Chih Ho
Journal: Nature Immunology (2020)
Targeting DNA Repair to Drive Immune Responses: It's Time to Reconsider the Strategy for Clinical Translation
Authors: Nobuyuki Takahashi, Ira Surolia, Anish Thomas
Journal: Clinical Cancer Research (2020)

PARP inhibition induces robust local and systemic antitumor immune responses and curative responses when combined with immune checkpoint blockade in many preclinical studies. However, the combination has not markedly improved antitumor effect compared with individual agents in clinical trials to date. We propose that the data from these trials indicate a lack of synergistic interaction of PARP inhibition and immune checkpoint blockade, with implications for reexamining our current strategies for clinical translation. As current mouse models do not recapitulate the genomic heterogeneity or tumor microenvironment of human cancers, better models are urgently needed. Tumor-extrinsic factors modulate immune checkpoint blockade response and they may be better assessed in early-phase clinical trials with frequent tissue and blood sampling. Further work is also needed to uncover the dose and schedule dependency of DNA repair modulation on the immune system. In homologous recombination repair-deficient tumors, randomized trials should be prioritized to address whether the benefit is superior to that of PARP inhibitor monotherapy. In tumors that are not homologous recombination repair deficient, research biopsies should be integrated to early-phase clinical trials to discover biomarkers that can predict clinical benefit. These considerations are relevant to the variety of adjunctive therapeutics being combined with immune checkpoint blockade to improve probability, duration, and potency of antitumor activity.
Quality and Safety in Healthcare, Part LXV
Authors: Jay A. Harolds
Journal: Clinical Nuclear Medicine (2020)

Abstract Matriculating medical students have a low degree of psychological distress. Yet, over time burnout, suicidal ideation, and evidence of depression become quite prevalent among medical students. Often, approximately 50% of the students and sometimes more suffer from burnout. The prevalence of depression in different studies varied but was often approximately 20%. Suicidal ideation in medical students in various articles had a prevalence of approximately 6% to 11%.
Abstract 13892: Purified Eicosapentaenoic Acid Ameliorates Cardiac Fibrosis and Tissue Inflammation in Spontaneously Hypertensive Rats
Authors: Giselle C Melendez, Danielle Medina-Hernandez, Adam W Pflum, Vivian Xu, David M Herrington
Journal: Circulation (2019)

Introduction: We have previously shown that eicosapentaenoic acid (EPA) treatment decreases left ventricular (LV) diastolic dysfunction and interstitial cardiac fibrosis in rats with established hy...
Oncogenic KRAS-Driven Metabolic Reprogramming in Pancreatic Cancer Cells Utilizes Cytokines from the Tumor Microenvironment
Authors: Prasenjit Dey, Jun Li, Jianhua Zhang, Surendra Chaurasiya, Anders Strom, Huamin Wang, Wen-Ting Liao, Frederick Cavallaro, Parker Denz, Vincent Bernard, Er-Yen Yen, Giannicola Genovese, Pat Gulhati, Jielin Liu, Deepavali Chakravarti, Pingna Deng, Tingxin Zhang, Federica Carbone, Qing Chang, Haoqiang Ying, Xiaoying Shang, Denise J. Spring, Bidyut Ghosh, Nagireddy Putluri, Anirban Maitra, Y. Alan Wang, Ronald A. DePinho
Journal: Cancer Discovery (2020)

Abstract A hallmark of pancreatic ductal adenocarcinoma (PDAC) is an exuberant stroma comprised of diverse cell types that enable or suppress tumor progression. Here, we explored the role of oncogenic KRAS in protumorigenic signaling interactions between cancer cells and host cells. We show that KRAS mutation (KRAS*) drives cell-autonomous expression of type I cytokine receptor complexes (IL2rγ–IL4rα and IL2rγ–IL13rα1) in cancer cells that in turn are capable of receiving cytokine growth signals (IL4 or IL13) provided by invading Th2 cells in the microenvironment. Early neoplastic lesions show close proximity of cancer cells harboring KRAS* and Th2 cells producing IL4 and IL13. Activated IL2rγ–IL4rα and IL2rγ–IL13rα1 receptors signal primarily via JAK1–STAT6. Integrated transcriptomic, chromatin occupancy, and metabolomic studies identified MYC as a direct target of activated STAT6 and that MYC drives glycolysis. Thus, paracrine signaling in the tumor microenvironment plays a key role in the KRAS*-driven metabolic reprogramming of PDAC. Significance: Type II cytokines, secreted by Th2 cells in the tumor microenvironment, can stimulate cancer cell–intrinsic MYC transcriptional upregulation to drive glycolysis. This KRAS*-driven heterotypic signaling circuit in the early and advanced tumor microenvironment enables cooperative protumorigenic interactions, providing candidate therapeutic targets in the KRAS* pathway for this intractable disease.
Removal of a gastric wall lesion with a new technique: direct intragastric hybrid resection
Authors: Fernando González-Panizo, David Fernández Luengas, Enrique Vázquez Sequeiros, Jesús Merello Godino, Álvaro Rojas Sánchez, Diego Juzgado Lucas
Journal: Endoscopy (2020)

We performed an upper endoscopy in a 46-year-old woman in an outpatient setting for dyspeptic symptoms. Endoscopy revealed a 25-mm subepithelial lesion in the subcardial area, which was not identified during an endoscopy performed 1 year previously. As endoscopic biopsies were nondiagnostic (normal gastric mucosa), we decided to perform positron emission tomography/computed tomography, which revealed a positive uptake by the lesion.