tbuckley/cabot-search huggingface dataset:
Dual Functional States of R406W-Desmin Assembly Complexes Cause Cardiomyopathy With Severe Intercalated Disc Derangement in Humans and in Knock-In Mice
Authors: Harald Herrmann, Eva Cabet, Nicolas R. Chevalier, Julia Moosmann, Dorothea Schultheis, Jan Haas, Mirjam Schowalter, Carolin Berwanger, Veronika Weyerer, Abbas Agaimy, Benjamin Meder, Oliver J. Müller, Hugo A. Katus, Ursula Schlötzer-Schrehardt, Patrick Vicart, Ana Ferreiro, Sven Dittrich, Christoph S. Clemen, Alain Lilienbaum, Rolf Schröder
Journal: Circulation (2020)

Mutations in the human desmin gene cause myopathies and cardiomyopathies. This study aimed to elucidate molecular mechanisms initiated by the heterozygous R406W-desmin mutation in the development of a severe and early-onset cardiac phenotype.We report an adolescent patient who underwent cardiac transplantation as a result of restrictive cardiomyopathy caused by a heterozygous R406W-desmin mutation. Sections of the explanted heart were analyzed with antibodies specific to 406W-desmin and to intercalated disc proteins. Effects of the R406W mutation on the molecular properties of desmin were addressed by cell transfection and in vitro assembly experiments. To prove the genuine deleterious effect of the mutation on heart tissue, we further generated and analyzed R405W-desmin knock-in mice harboring the orthologous form of the human R406W-desmin.Microscopic analysis of the explanted heart revealed desmin aggregates and the absence of desmin filaments at intercalated discs. Structural changes within intercalated discs were revealed by the abnormal organization of desmoplakin, plectin, N-cadherin, and connexin-43. Next-generation sequencing confirmed the DES variant c.1216C>T (p.R406W) as the sole disease-causing mutation. Cell transfection studies disclosed a dual behavior of R406W-desmin with both its integration into the endogenous intermediate filament system and segregation into protein aggregates. In vitro, R406W-desmin formed unusually thick filaments that organized into complex filament aggregates and fibrillar sheets. In contrast, assembly of equimolar mixtures of mutant and wild-type desmin generated chimeric filaments of seemingly normal morphology but with occasional prominent irregularities. Heterozygous and homozygous R405W-desmin knock-in mice develop both a myopathy and a cardiomyopathy. In particular, the main histopathologic results from the patient are recapitulated in the hearts from R405W-desmin knock-in mice of both genotypes. Moreover, whereas heterozygous knock-in mice have a normal life span, homozygous animals die at 3 months of age because of a smooth muscle-related gastrointestinal phenotype.We demonstrate that R406W-desmin provokes its severe cardiotoxic potential by a novel pathomechanism, where the concurrent dual functional states of mutant desmin assembly complexes underlie the uncoupling of desmin filaments from intercalated discs and their structural disorganization.
Emricasan to prevent new decompensation in patients with NASH-related decompensated cirrhosis
Authors: Catherine Frenette, Zeid Kayali, Edward Mena, Parvez S. Mantry, Kathryn J. Lucas, Guy Neff, Miguel Rodriguez, Paul J. Thuluvath, Ethan Weinberg, Bal R. Bhandari, James Robinson, Nicole Wedick, Jean L. Chan, David T. Hagerty, Kris V. Kowdley, Kathleen Corey, David Bernstein, Mazen Noureddin, Nyingi Kemmer, Andrew DeLemos, Nikolaos Pyrsopoulos, William Lee, Marwan Ghabril, Andrew Scanga, Mark McKenzie, Eric Lawitz, Viviana Figueroa-Diaz, Douglas Simonetto, Richard Frederick, Kimberly Brown, George Therapondos, Aasim Sheikh, Danielle Brandman, Lance Stein, Victor Ankoma-Sey, Kalyan Bhamidimarri, Charles Landis, Brett Fortune, Hugo Vargas, Manal Abdelmalek, Bradley Freilich, Don Rockey, John Vierling, Harvey Tatum, Michael Curry, Mitchell Shiffman, Kiran Bambha, Reem Ghalib, Amy Stratton, Nadeem Anwar, Stephen Caldwell, Ayman Koteish, Mohammad Siddiqui, Sammy Saab, Nikunj Shah, Anita Kohli, Mary Rinella, Souvik Sarkar, Dawn Torres, Elizabeth Verna, Ravi Ravendhran, Justin Reynolds, Ray Thomason, Ray Kim, Fernando Membreno, Sofia Jakab, Stevan Gonzalez, Andrew Keaveny, Jen-Jung Pan, Satinder Gill, Jonathan Huang, James Strobel, Amanda Wieland, Giuseppe Morelli, Thomas Amankonah, Marina Roytman, Warren Schmidt, Gary Abrams, Bhaktasharan Patel
Journal: Journal of Hepatology (2020)
Sustained Remission of Granulomatosis With Polyangiitis After Discontinuation of Glucocorticoids and Immunosuppressant Therapy: Data From the French Vasculitis Study Group Registry
Authors: Xavier Puéchal, Michele Iudici, Christian Pagnoux, Alexandre Karras, Pascal Cohen, François Maurier, Thomas Quéméneur, François Lifermann, Mohamed Hamidou, Luc Mouthon, Benjamin Terrier, Loïc Guillevin
Journal: Arthritis & Rheumatology (2020)

Objective Data on sustained remission of granulomatosis with polyangiitis (GPA) after discontinuation of therapy (referred to as GPA with sustained remission off‐therapy [SROT]) are scarce. In the present study, SROT among GPA patients from the French Vasculitis Study Group Registry was evaluated to identify factors associated with its occurrence and durability. Methods For inclusion of patients in the study, the diagnosis of GPA had to meet the GPA classification criteria defined by the American College of Rheumatology and/or the revised Chapel Hill Consensus Conference nomenclature for vasculitis. SROT was defined as achievement of remission (a Birmingham Vasculitis Activity Score of 0) that was sustained for ≥6 consecutive months after having discontinued glucocorticoid (GC) and immunosuppressant treatments. The characteristics of the patients at baseline and treatments received were compared at 3, 5, and 10 years postdiagnosis according to whether or not SROT had been reached and maintained. Results Among 795 patients with GPA, 92 GPA patients with SROT at 3 years postdiagnosis were compared to 342 control subjects who had experienced disease relapse and/or were still receiving GCs or immunosuppressants. No baseline differences were found, but patients with SROT at 3 years postdiagnosis had more frequently received intravenous cyclophosphamide as induction therapy compared to control subjects ( P = 0.01), with a higher median number of infusions ( P = 0.05). At 5 years postdiagnosis, no baseline differences were observed between groups, but patients with SROT at 5 years postdiagnosis had received more cyclophosphamide infusions compared to control subjects ( P = 0.03). More patients with SROT had received rituximab as maintenance therapy than control subjects at 3 years and 5 years postdiagnosis ( P = 0.09 and P &lt; 0.001, respectively). Of the 74 patients enrolled in the GPA Registry with 10‐year follow‐up data after having received conventional maintenance therapy, 15 (20%) had reached SROT at 3 years, and 5 (7%) maintained SROT at 10 years postdiagnosis. Conclusion After conventional therapies, 7% of GPA patients had reached SROT at 10 years postdiagnosis. No baseline vasculitis characteristics distinguished patients who achieved/maintained SROT from those who experienced disease relapse and/or those who continued to receive GCs or immunosuppressant therapy, but patients with SROT had received more intensive induction therapy and rituximab as maintenance therapy more frequently.
FocusNetv2: Imbalanced large and small organ segmentation with adversarial shape constraint for head and neck CT images
Authors: Yunhe Gao, Rui Huang, Yiwei Yang, Jie Zhang, Kainan Shao, Changjuan Tao, Yuanyuan Chen, Dimitris N. Metaxas, Hongsheng Li, Ming Chen
Journal: Medical Image Analysis (2020)
Assessing disparities in engagement in a post-discharge virtual visit follow-up program.
Authors: Abdullateef Abdulkareem, Nathan Handley, Samantha Burdette, Adam Binder
Journal: Journal of Clinical Oncology (2020)

100 Background: Transitions of care are a frequent focus of quality improvement initiatives. In attempt to improve upon the transitions of care for oncology patients, our institution implemented a post discharge virtual visit follow-up program. Previous studies have suggested that socioeconomic status impacts engagement in technology based interventions. Herein, we report the impact of socio-economic status based on area deprivation index (ADI) on engagement with the program. Methods: All patients admitted to the elective chemotherapy service were included. Retrospective analysis of characteristics of each participant was conducted. Data included eligibility (access to the internet, appropriate device, English language proficiency, ability to set up video visit and a patient portal account) for video visit, interest in participating, completion of the visit and any interventions performed during the visit. In addition, ADI was calculated for each individual. Patients were classified into quartiles based on ADI (quartiles increased with ADI). Chi squared testing was performed to assess whether socioeconomic status affected enrollment in video visits. Simple descriptive analysis was also performed. Results: One hundred seven unique patients were included for review. Of these, 33 (31%), 39 (36%), 16 (15%) and 19 (18%) were in quartile(Q) 1, 2, 3 and 4 respectively. Eligibility per quartile was 29 (88%), 34(87%), 13(81%), and 15(83%). ADI quartile did not significantly affect virtual visit eligibility (p = .50). A total of 91 patients (85%) were eligible for video visits; of these, 46 patients declined. Of the 46 patients that declined 9 (19%), 20 (43%), 8 (17%), and 9 (19%) were in Q1, Q2, Q3 and Q4 respectively. Fifteen patients cited technology issues as reasons for declining telehealth visits - 10 (67%) from Q1 and Q2 and 5 (33%) from Q3 and Q4. The vast majority cited lack of interest as reason for declining. Conclusions: ADI as a measure of socioeconomic status did not significantly affect eligibility for or enrollment in video visits. This may be explained by more ubiquitous access to internet services in a large urban setting. Current research is currently being conducted to understand patient barriers to engagement in virtual visits.
Implementation of care near home model (CNH) for cancer patients in response to COVID-19 pandemic.
Authors: Abdul-Rahman Jazieh, Nashmia Al Mutairi, Abdulrahman Al Hadab, Ashwaq Al Olayan, Ayman Al Hejazi, Abdullah Al Qarni, Mohsen Al Zahrani, Hussam Shehata, Mona Al Shami, Abdulrahman Al Raizah, Azzah Gadallah, Luhanga Musumadi, Fawaz Al Rabeeah, Thamer Alotaibi, Abdulaziz Al Ajlan
Journal: Journal of Clinical Oncology (2020)

32 Background: Cancer care is heavily centered in health care facilities due to the requirements of providing complex multidisciplinary care with multiple testing and interventions. We describe our experience in implementing a new model of care to minimize cancer patients visit to health care facilities and to reduce the risk of infections and to decrease the pressure on the health care system. Methods: In response to the COVID-19 pandemic, we reengineered the cancer care process to reduce patients visit to the hospital by the implementation of a Care Near Home (CNH) Model, which comprises of four components: virtual clinic, laboratory testing near home, shipping medications and supplies, and involving local health care facilities. The effectiveness and acceptance of this new model has been assessed by the delivery of timely care successfully and assessing the satisfaction patients and healthcare providers. Results: On March 18, 2020, we launched the virtual clinics followed by different components of the model. The number of virtual clinic visits has increased significantly from 399 visits in March to 1107 in April 2020. More the 90% of physicians and patients who responded to the survey expressed their acceptance and satisfaction with the virtual clinic services. Medications were shipped to total of 603 patients. Of those, 578 (96%) patients received their medications (378 patients outside city, 200 patients inside city of which, 95% received medications within 24 hours). Only 25 (4%) patients did not receive their medications and we arrange for alternative solutions. Laboratories in various regions were set up to perform the tests for our patients and to communicate the results through our electronic healthcare records system. The process of ordering and performing the test were piloted with success and now we are at the scaling up phase. Conclusions: Although the implementation of CNH Model was driven by COVID-19 pandemic, it will be integrated in our work process and utilized as a long term approach to manage many of our patients because it is more convenient to them and more cost effective to the health care system.
Much to Fear about MUCH
Authors: Rajiv Agarwal
Journal: Journal of the American Society of Nephrology (2020)

Hypertension is the most common cardiovascular and kidney risk factor yet one that is the least well measured. For nearly 50 years, we have been able to record BP noninvasively over 24 hours, therefore better describe the true mean and define its circadian profile.[1][1] This has led to the
Biomarker testing patterns and use of targeted therapy in Medicare Fee-for-Service (FFS) beneficiaries newly diagnosed with metastatic non-small cell lung cancer (mNSCLC).
Authors: Anik Patel, Aurelien Jamotte, Tara Matsuda, Partha Manas Das, Ehab Elkhouly, Ann Xi, Barton Jones, Anne Murunga, Allison Petrilla, Nathan Markward, Kendall Lee Stevinson
Journal: Journal of Clinical Oncology (2020)

278 Background: The number of targeted therapies approved for treatment of mNSCLC has increased over the past 5 years. Strategies to identify eligible patients with actionable mutations for targeted therapy include simultaneous testing of ≥ 2 genes via next generation sequencing (NGS) or multiple simultaneous gene testing (MSGT) and sequential single gene testing (SSGT). Current clinical practice guidelines strongly recommend broad molecular profiling in all patients for the simultaneous assessment of multiple genes, including EGFR, ALK and ROS1, that may have potential roles in cancer development. Limited real-world (RW) evidence is available describing the uptake of these strategies and receipt of targeted therapy. Methods: Medicare beneficiaries age 65 years or older, newly diagnosed with mNSCLC and tested for mutations of interest in mNSCLC (ALK, EGFR, ROS1, BRAF, HER2, KRAS, MET, NTRK, RET) from July 2014 - June 2018 were identified using Medicare FFS claims (100% sample) linked to biomarker results in PROGNOS NSCLC Explorer. Patients were followed from date of first metastatic diagnosis and stratified by line of therapy, testing strategy, and year of mNSCLC diagnosis. Those testing positive for an actionable biomarker were identified and then segmented by timing of receipt of a subsequent targeted therapy. Results: 12,272 beneficiaries met inclusion criteria: median age: 75 years, 51% were female, 86% white. Among mNSCLC patients with at least one biomarker test result, EGFR and ALK mutation status were the most commonly tested and reported in 85% and 63% respectively. Overall, 1540 (12.5%) tested positive for EGFR, ALK or ROS1. The relative use of NGS or MSGT vs. SSGT for biomarker testing increased over time, from 63% in 2014 to 80% in 2018. During this period, 789 patients were identified as having at least one positive biomarker test result prior to initiating 1L therapy: 635 were identified via NGS or MSGT while 154 were identified via SSGT. Despite a positive test for mutations of interest, only 292 patients received a targeted drug at 1L. Conclusions: This RW study of mNSCLC patients demonstrates an increasing trend to test patients for multiple biomarkers at once via NGS or other MSGT methods. The number of patients receiving appropriate targeted therapies was low, suggesting the need to address the barriers to administration of guideline-recommended therapy.
Anti‐VEGF DNA‐based aptamers in cancer therapeutics and diagnostics
Authors: Claudia Riccardi, Ettore Napolitano, Chiara Platella, Domenica Musumeci, Mariarosa A. B. Melone, Daniela Montesarchio
Journal: Medicinal Research Reviews (2020)

Abstract The vascular endothelial growth factor (VEGF) family and its receptors play fundamental roles not only in physiological but also in pathological angiogenesis, characteristic of cancer progression. Aiming at finding putative treatments for several malignancies, various small molecules, antibodies, or protein‐based drugs have been evaluated in vitro and in vivo as VEGF inhibitors, providing efficient agents approved for clinical use. Due to the high clinical importance of VEGF, also a great number of anti‐VEGF nucleic acid‐based aptamers—that is, oligonucleotides able to bind with high affinity and specificity a selected biological target—have been developed as promising agents in anticancer strategies. Notable research efforts have been made in optimization processes of the identified aptamers, searching for increased target affinity and/or bioactivity by exploring structural analogues of the lead compounds. This review is focused on recent studies devoted to the development of DNA‐based aptamers designed to target VEGF. Their therapeutic potential as well as their significance in the construction of highly selective biosensors is here discussed.
Long non-coding RNAs: From disease code to drug role
Authors: Yuanyuan Chen, Zhaojun Li, Xiaoguang Chen, Sen Zhang
Journal: Acta Pharmaceutica Sinica B (2020)

Enormous studies have corroborated that long non-coding RNAs (lncRNAs) extensively participate in crucial physiological processes such as metabolism and immunity, and are closely related to the occurrence and development of tumors, cardiovascular diseases, nervous system disorders, nephropathy, and other diseases. The application of lncRNAs as biomarkers or intervention targets can provide new insights into the diagnosis and treatment of diseases. This paper has focused on the emerging research into lncRNAs as pharmacological targets and has reviewed the transition of lncRNAs from the role of disease coding to acting as drug candidates, including the current status and progress in preclinical research. Cutting-edge strategies for lncRNA modulation have been summarized, including the sources of lncRNA-related drugs, such as genetic technology and small-molecule compounds, and related delivery methods. The current progress of clinical trials of lncRNA-targeting drugs is also discussed. This information will form a latest updated reference for research and development of lncRNA-based drugs.
Addressing Violence and Overdose Among Women Who Use Drugs—Need for Structural Interventions
Authors: Shira M. Goldenberg
Journal: JAMA Network Open (2020)

Nabila El-Bassel, PhD; Andrea Norcini Pala, PhD; Trena I. Mukherjee, MPH; Tara McCrimmon, MPH, MIA; Gaukhar Mergenova, MD, MS; Assel Terlikbayeva, MSW, MD; Sholpan Primbetova, MS, MSW; Susan S. Witte, PhD
Personalising exercise recommendations for healthy cognition and mobility in ageing: time to consider one’s pre-existing function and genotype (Part 2)
Authors: Cindy K Barha, Ryan S Falck, Søren T Skou, Teresa Liu-Ambrose
Journal: British Journal of Sports Medicine (2020)

As we outlined in Part 1, precise exercise recommendations remain elusive and effects of current recommendations are small to moderate. Increased precision of exercise prescriptions may greatly promote adoption, adherence and maximise benefits. Current scientific efforts seek to delineate what (e.g., type, duration, frequency and intensity) exercise should be recommended, when (e.g., midlife vs late life) it is most effective for cognition and for whom and how does exercise benefit cognition and mobility. Identifying moderators (e.g., who, when)—factors that either attenuate or amplify the effects of exercise—will enable precise recommendations for individuals with similar characteristics (i.e., subgroups).

In this two-part editorial series, we focus on for whom factors that may moderate the effect of exercise on cognitive function and mobility (figure 1). In Part 1, we discussed biological sex and gender. Here in Part 2, we focus on the impact of pre-existing physical and cognitive health as well as genetic polymorphisms.



Figure 1 
Proposed moderators of exercise for brain health. Key moderators of the relationship between different types of exercise (e.g., resistance training, aerobic exercise) and brain health are genetics, sex and gender, frailty and lifestage. Please refer to Parts 1 and 2 commentary for more details.



Pre-existing (i.e., baseline) physical function impacts the efficacy of exercise interventions on health outcomes. Exercise prevents a greater number of falls in older adults with a previous fall than those with no such history.1 Among older adults with limited mobility, increasing physical activity of moderate intensity by at least 43 min per week—or ~6 min per day—had significant and clinically meaningful effects on mobility and the risk of major mobility disability,2 highlighting that ‘ a little can do a lot ’ for those at risk for functional decline.

In a 24-month randomised controlled trial (RCT) that compared a home-based and centre-based exercise programme …
Is It Time to Abandon Textured Breast Implants for Breast Cancer Reconstruction?
Authors: Michael R. Cassidy, Daniel S. Roh
Journal: JAMA Surgery (2020)

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The Risk of Contracting COVID-19 Is Not Increased in Patients With Celiac Disease
Authors: Jamie Zhen, Juan Pablo Stefanolo, Maria de la Paz Temprano, Sebastian Tedesco, Caroline Seiler, Alberto Fernandez Caminero, Enrique de-Madaria, Miguel Montoro Huguet, Santiago Vivas, Sonia Isabel Niveloni, Premysl Bercik, Edgardo Smecuol, Luis Uscanga, Elena Trucco, Virginia Lopez, Carolina Olano, Pasquale Mansueto, Antonio Carroccio, Peter H.R. Green, Andrew Day, Jason Tye-Din, Julio Cesar Bai, Carolina Ciacci, Elena F. Verdu, Benjamin Lebwohl, Maria Ines Pinto-Sanchez
Journal: Clinical Gastroenterology and Hepatology (2020)