tbuckley/cabot-search huggingface dataset:
Can clinical benefits of modulators effectively ‘modulate’ adherence in people with CF?
Authors: Chelsea S Davis, Jonathan D Cogen
Journal: Thorax (2021)

Cystic fibrosis (CF) is a progressive, life-limiting genetic disease caused by a dysfunctional CF transmembrane conductance regulator (CFTR) protein that leads to mucus clearance abnormalities, the development of chronic endobronchial infections and progressive, irreversible lung damage. Historically, treatments for CF have largely been supportive in nature and have focused on symptomatic improvement from the many CF-related disease manifestations, including pulmonary, gastrointestinal and sinus-related morbidities. The use of acute and chronic medications to address these disease-related complications has undoubtedly improved the lives of people with CF (PwCF) and extended life expectancy.

The approval of ivacaftor by the US Food and Drug Administration on 31 January 2012 for PwCF 6 years and older with a G551D mutation has heralded in a new era of CF care. For the first time, a CF therapy (termed CFTR modulator) was developed to target the underlying CFTR protein defect itself. Since its approval, several other CFTR modulators have been deployed in the clinical arena; the most recent (and arguably the most effective) of which is elexacaftor/tezacaftor/ivacaftor, a CFTR modulator currently approved for all PwCF 12 years and older with at least once copy of the Phe508del mutation.

While the approval of CFTR modulators has revolutionised the care of PwCF and might even improve life expectancy, there remains a number of potential barriers to CFTR modulator adherence, including cost, perceived medication benefit, delays in prior authorisations, decreased access to care and individual factors …
Suppression of mTOR Signaling Attenuates Apoptotic Effects Induced By the NEDD8-Activating Enzyme Inhibitor Pevonedistat (MLN4924) in Acute Myeloid Leukemia Cells
Authors: Naxin Guo, Mary Nemer, Subanky Sivagnanalingam, Mitra Azadniv, Jason H. Mendler, Michael W. Becker, Jane L. Liesveld
Journal: Blood (2017)
Association of Age, Antipsychotic Medication, and Symptom Severity in Schizophrenia With Proton Magnetic Resonance Spectroscopy Brain Glutamate Level
Authors: Kate Merritt, Philip K. McGuire, Alice Egerton, André Aleman, Wolfgang Block, Oswald J. N. Bloemen, Faith Borgan, Juan R. Bustillo, Aristides A. Capizzano, Jennifer Marie Coughlin, Camilo De la Fuente-Sandoval, Arsime Demjaha, Kara Dempster, Kim Q. Do, Fei Du, Peter Falkai, Beata Galinska-Skok, Jurgen Gallinat, Charles Gasparovic, Cedric E. Ginestet, Naoki Goto, Ariel Graff-Guerrero, Beng Choon Ho, Oliver D. Howes, Sameer Jauhar, Peter Jeon, Tadafumi Kato, Charles A. Kaufmann, Lawrence S. Kegeles, Matcheri Keshavan, Sang-Young Kim, Hiroshi Kunugi, John Lauriello, Edith Jantine Liemburg, Meghan E. Mcilwain, Gemma Modinos, Elias D. Mouchlianitis, Jun Nakamura, Igor Nenadic, Dost Öngür, Miho Ota, Lena Palaniyappan, Christos Pantelis, Eric Plitman, Sotirios Posporelis, Scot E. Purdon, Jürgen R. Reichenbach, Perry F. Renshaw, Bruce R. Russell, Akira Sawa, Martin Schaefer, Dikoma C. Shungu, Stefan Smesny, Jeffrey A. Stanley, James M. Stone, Agata Szulc, Reggie Taylor, Katy Thakkar, Jean Théberge, Philip G. Tibbo, Therese van Amelsvoort, Jerzy Walecki, Peter C. Williamson, Stephen James Wood, Lijing Xin, Hidenori Yamasue
Journal: JAMA Psychiatry (2021)

Proton magnetic resonance spectroscopy (1H-MRS) studies indicate that altered brain glutamatergic function may be associated with the pathophysiology of schizophrenia and the response to antipsychotic treatment. However, the association of altered glutamatergic function with clinical and demographic factors is unclear.
Functional interpretation of ATAD3A variants in neuro-mitochondrial phenotypes
Authors: Zheng Yie Yap, Yo Han Park, Saskia B. Wortmann, Adam C. Gunning, Shlomit Ezer, Sukyeong Lee, Lita Duraine, Ekkehard Wilichowski, Kate Wilson, Johannes A. Mayr, Matias Wagner, Hong Li, Usha Kini, Emily Davis Black, Kristin G. Monaghan, James R. Lupski, Sian Ellard, Dominik S. Westphal, Tamar Harel, Wan Hee Yoon
Journal: Genome Medicine (2021)

Abstract Background ATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane-anchored protein involved in diverse processes including mitochondrial dynamics, mitochondrial DNA organization, and cholesterol metabolism. Biallelic deletions (null), recessive missense variants (hypomorph), and heterozygous missense variants or duplications (antimorph) in ATAD3A lead to neurological syndromes in humans. Methods To expand the mutational spectrum of ATAD3A variants and to provide functional interpretation of missense alleles in trans to deletion alleles, we performed exome sequencing for identification of single nucleotide variants (SNVs) and copy number variants (CNVs) in ATAD3A in individuals with neurological and mitochondrial phenotypes. A Drosophila Atad3a Gal4 knockin-null allele was generated using CRISPR-Cas9 genome editing technology to aid the interpretation of variants. Results We report 13 individuals from 8 unrelated families with biallelic ATAD3A variants. The variants included four missense variants inherited in trans to loss-of-function alleles (p.(Leu77Val), p.(Phe50Leu), p.(Arg170Trp), p.(Gly236Val)), a homozygous missense variant p.(Arg327Pro), and a heterozygous non-frameshift indel p.(Lys568del). Affected individuals exhibited findings previously associated with ATAD3A pathogenic variation, including developmental delay, hypotonia, congenital cataracts, hypertrophic cardiomyopathy, and cerebellar atrophy. Drosophila studies indicated that Phe50Leu, Gly236Val, Arg327Pro, and Lys568del are severe loss-of-function alleles leading to early developmental lethality. Further, we showed that Phe50Leu, Gly236Val, and Arg327Pro cause neurogenesis defects. On the contrary, Leu77Val and Arg170Trp are partial loss-of-function alleles that cause progressive locomotion defects and whose expression leads to an increase in autophagy and mitophagy in adult muscles. Conclusion Our findings expand the allelic spectrum of ATAD3A variants and exemplify the use of a functional assay in Drosophila to aid variant interpretation.
In Situ Programming of CAR T Cells
Authors: Neha N. Parayath, Matthias T. Stephan
Journal: Annual Review of Biomedical Engineering (2021)

Gene therapy makes it possible to engineer chimeric antigen receptors (CARs) to create T cells that target specific diseases. However, current approaches require elaborate and expensive protocols to manufacture engineered T cells ex vivo, putting this therapy beyond the reach of many patients who might benefit. A solution could be to program T cells in vivo. Here, we evaluate the clinical need for in situ CAR T cell programming, compare competing technologies, review current progress, and provide a perspective on the long-term impact of this emerging and rapidly flourishing biotechnology field.
Endoscopic complete closure of duodenal mucosal defects using a clip with a looped thread after endoscopic resection
Authors: Kengo Kasuga, Ichiro Oda, Satoru Nonaka, Seiichiro Abe, Haruhisa Suzuki, Toshio Uraoka, Yutaka Saito
Journal: Endoscopy (2021)

Closure of mucosal defects after endoscopic resection of superficial nonampullary duodenal tumors is important to reduce the risk of delayed bleeding and perforation [1]. Therefore, we developed a new closure method using a clip with a looped thread ([Video 1]).
Abstract 14845: Remnant Cholesterol and Incident Atherosclerotic Cardiovascular Disease: A Pooled Cohort Primary Prevention Study
Authors: Renato Quispe, Seth S Martin, Erin D Michos, Isha Lamba, Roger S Blumenthal, Anum Saeed, Joao Ac Lima, Rishi Puri, Sarah Nomura, Michael Y Tsai, John T Wilkins, Christie M Ballantyne, Stephen J Nicholls, Steven R Jones, Mohamed B Elshazly
Journal: Circulation (2020)

Introduction: Emerging evidence suggests that remnant cholesterol (RC) promotes future atherosclerotic cardiovascular disease (ASCVD) events. Our aim was to estimate the risk associated with RC beyond low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB). Hypothesis: RC provides incremental prognostic information regarding incident ASCVD, independent of LDL-C and apoB. Methods: We pooled data from 17,532 individuals from Atherosclerosis Risk in Communities study (n=9,748), Multi-Ethnic Study of Atherosclerosis (n=3,049) and Coronary Artery Risk Development in Young Adults (n=4,735), who were ASCVD-free at baseline and had measurements of lipids, apoB and apolipoprotein A1. RC was calculated as non-high-density cholesterol (non-HDL-C) minus LDL-C estimated by the Martin/Hopkins equation. Adjusted Cox models were used to estimate the risk for incident ASCVD associated with log RC levels. We also performed discordance analyses examining relative ASCVD risk in discordant/concordant groups of RC and LDL-C across median cutpoints and cutpoints of percentile equivalence to LDL-C targets (70 and 100 mg/dL). Results: Mean age of participants was 52.3±17.9 years, 56.7% women and 34% black. There were 2,143 ASCVD events over median follow-up of 18.7 years. After multivariable adjustment including apoB and HDL-C, logRC was associated with higher ASCVD risk [HR 1.42, 95% CI (1.23-1.63)]. In discordance analyses, the high RC and low LDL-C group (≥/&lt;median) was associated with increased ASCVD risk compared to the low/low concordant group [1.17, (1.01-1.35)] but the low RC and high LDL-C group was not. Similar results were shown when examining discordance across lower cutpoints. Conclusion: In ASCVD-free individuals, elevated RC levels were associated with ASCVD independent of traditional risk factors and LDL-C and apoB levels. RC assessment and management in primary prevention, beyond LDL-C and apoB, is useful and requires further scrutiny.
Vascular inflammation in moderate‐to‐severe atopic dermatitis is associated with enhanced Th2 response
Authors: Axel P. Villani, Ana B. Pavel, Jianni Wu, Marie Fernandes, Catherine Maari, Etienne Saint‐Cyr Proulx, Carolyn Jack, Jacob Glickman, Seulah Choi, Helen He, Benjamin Ungar, Yeriel Estrada, Naoya Kameyama, Ning Zhang, Juana Gonzales, Jean‐Claude Tardif, James G. Krueger, Robert Bissonnette, Emma Guttman‐Yassky
Journal: Allergy (2021)

Abstract Background In atopic dermatitis (AD), some studies have shown an association with increased cardiovascular disease in certain populations. However, other investigations found modest or no association. Despite conflicting results, molecular profiling studies in both AD skin and blood have demonstrated upregulation of atherosclerosis and cardiovascular risk‐related markers. However, the underlying mechanisms connecting AD to vascular inflammation/atherosclerosis are unknown. In this study, we aim to determine factors associated with vascular inflammation/atherosclerosis in AD patients. Methods We used 18‐FDG PET‐CT to characterize vascular inflammation in AD patients and healthy subjects. In parallel, we assessed their skin and blood immune profiles to determine AD‐related immune biomarkers associated with vascular inflammation. We also assessed levels of circulating microparticles, which are known to be associated with increased cardiovascular risk. Results We found significant correlations between vascular inflammation and Th2‐related products in skin and blood of AD patients as well as atherosclerosis‐related markers that were modulated by dupilumab. Circulating levels of endothelial microparticles were significantly higher in severe AD patients and tended to correlate with vascular inflammation assessed by PET‐CT. Conclusion Vascular inflammation in AD is associated with enhanced Th2 response and clinical severity, which may explain cardiovascular comorbidities observed in select AD populations. Larger prospective studies are needed to further evaluate vascular inflammation and cardiovascular events and mortality in AD patients. Finally, as dupilumab treatment demonstrated significant modulation of atherosclerosis‐related genes in AD patients compared to placebo, these data suggest that modulation of vascular inflammation with systemic treatment should be explored in patients with AD.
Feeding during neonatal therapeutic hypothermia, assessed using routinely collected National Neonatal Research Database data: a retrospective, UK population-based cohort study
Authors: Chris Gale, Nicholas T Longford, Dusha Jeyakumaran, Kayleigh Ougham, Cheryl Battersby, Shalini Ojha, Jon Dorling
Journal: The Lancet Child & Adolescent Health (2021)

Therapeutic hypothermia is standard of care in high-income countries for babies born with signs of hypoxic ischaemic encephalopathy, but optimal feeding during treatment is uncertain and practice is variable. This study aimed to assess the association between feeding during therapeutic hypothermia and clinically important outcomes.
Abstract PO-030: The harmala alkaloid harmine as a novel cancer cell radiosensitizer
Authors: Caleb R.P. Smack, Audrey Lafargue, Christine Lam, Francesca A. Carrieri, Ismaeel Siddiqui, Hailun Wang, Phuoc T. Tran
Journal: Clinical Cancer Research (2021)

Abstract Radiation therapy resistance remains a persistent clinical challenge in the treatment of multiple different cancer types. Better appreciation of novel molecular targets to improve radiation therapy efficacy is needed. TWIST1 is an epithelial-mesenchymal transcription factor whose expression is linked to therapy resistance, including radioresistance, in cancer. We have shown previously that the harmala alkaloid harmine degrades TWIST1 and possess anti-tumor activity. We hypothesized that harmine may radiosensitize cancer cells via downregulation of TWIST1. We examined the effects of harmine combined with radiation (RT) on two TWIST1 overexpressing tumor cell lines, A549 human non-small cell lung cancer (NSCLC) cells and the LMT mouse-derived hepatocellular cancer cell line (HCC), both with doxycycline-inducible Twist1 expression. We also used the LM mouse-derived HCC cell line without Twist1 expression as a control. In vitro assays for clonogenic survival, apoptosis, cell cycle distribution, γH2AX foci kinetics, and protein expression in pathways important for cancer cell survival and radioresistance were performed. Harmine alone exhibited anti-cancer activity irrespective of Twist1 expression as shown by decreased clonogenic survival. Harmine caused a supra-additive radiosensitization in all cancer cell lines with radiation enhancement ratios between 1.05 – 3.04. In vivo we are evaluating tumor growth delay and effects of combined harmine and RT treatment in a NSCLC hind-flank tumor growth model. Mechanistic elucidation of these results, studies on normal cells, and in vivo validation are ongoing. Citation Format: Caleb R.P. Smack, Audrey Lafargue, Christine Lam, Francesca A. Carrieri, Ismaeel Siddiqui, Hailun Wang, Phuoc T. Tran. The harmala alkaloid harmine as a novel cancer cell radiosensitizer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-030.
Functional respiratory assessment: some key misconceptions and their clinical implications
Authors: José Alberto Neder
Journal: Thorax (2021)

Dear editors,

There are few specialties in which the functional evaluation assumes the same pivotal role as in respiratory medicine. Although the patterns of abnormalities exposed by pulmonary function tests are not pathognomonic, they are frequently helpful to narrow the diagnostic alternatives. In the right clinical context, the absence of functional abnormality might be reassuring. Testing results can provide useful information for the longitudinal assessment of patients with known respiratory diseases; moreover, they might have an auxiliary role on risk stratification and prognosis estimation. Unfortunately, there has been a progressive abandonment of applied respiratory physiology in favour of basic sciences and molecular medicine. Accordingly, controversial issues on pulmonary function tests interpretation are much less discussed nowadays compared with a few decades ago. It should also be recognised that some key concepts in the interpretation of spirometry, ‘static’ lung volumes and cardiopulmonary exercise testing are still based on physiological constructs rather than evidence from prospective trials. With the intent of igniting some critical reflections on the current role of the laboratory of lung function tests on clinical decision making in our field, I herein challenge some deeply entrenched interpretative beliefs. They have been selected based on our long-standing interaction with learners and seasoned pulmonologists. In each scenario, I discuss the reasons why a given statement might be misleading, and the potential clinical consequences of testing misinterpretation. If feasible, I suggest some strategies to avoid the underlying pitfalls.

There is little disagreement that, in the right clinical context, a FEV1/FVC ratio <the lower limit of normal (LLN) rules in obstruction (though, by definition, 5% of normal subjects have an FEV1/FVC ratio <LLN). However, if the small airways close precociously during the forced expiratory manoeuvre in a subject with airway disease, FVC might decrease more (or to the same …
A deep-learning pipeline for the diagnosis and discrimination of viral, non-viral and COVID-19 pneumonia from chest X-ray images
Authors: Guangyu Wang, Xiaohong Liu, Jun Shen, Chengdi Wang, Zhihuan Li, Linsen Ye, Xingwang Wu, Ting Chen, Kai Wang, Xuan Zhang, Zhongguo Zhou, Jian Yang, Ye Sang, Ruiyun Deng, Wenhua Liang, Tao Yu, Ming Gao, Jin Wang, Zehong Yang, Huimin Cai, Guangming Lu, Lingyan Zhang, Lei Yang, Wenqin Xu, Winston Wang, Andrea Olvera, Ian Ziyar, Charlotte Zhang, Oulan Li, Weihua Liao, Jun Liu, Wen Chen, Wei Chen, Jichan Shi, Lianghong Zheng, Longjiang Zhang, Zhihan Yan, Xiaoguang Zou, Guiping Lin, Guiqun Cao, Laurance L. Lau, Long Mo, Yong Liang, Michael Roberts, Evis Sala, Carola-Bibiane Schönlieb, Manson Fok, Johnson Yiu-Nam Lau, Tao Xu, Jianxing He, Kang Zhang, Weimin Li, Tianxin Lin
Journal: Nature Biomedical Engineering (2021)
Regulatory concepts to guide and promote the accelerated but safe clinical development and licensure of COVID‐19 vaccines in Europe
Authors: Ralf Wagner, Juliane Meißner, Elena Grabski, Yuansheng Sun, Stefan Vieths, Eberhard Hildt
Journal: Allergy (2021)

The ongoing COVID-19 pandemic caused by the SARS-CoV-2 coronavirus has affected the health of tens of millions of people worldwide. In particular, in elderly and frail individuals the infection can lead to severe disease and even fatal outcomes. Although the pandemic is primarily a human health crisis its consequences are much broader with a tremendous impact on global economics and social systems. Vaccines are considered the most powerful measure to fight the pandemic and protect people from COVID-19. Based on the concerted activities of scientists, manufacturers and regulators, the urgent need for effective countermeasures has provoked the development and licensure of novel COVID-19 vaccines in an unprecedentedly fast and flexible manner within <1 year. To ensure the safety and efficacy of these novel vaccines during the clinical development and the routine use in post-licensure vaccination campaigns existing regulatory requirements and procedures had to be wisely and carefully adapted to allow for an expedited evaluation without compromising the thoroughness of the regulatory and scientific assessment. In this review, we describe the regulatory procedures, concepts and requirements applied to guide and promote the highly accelerated development and licensure of safe and efficacious COVID-19 vaccines in Europe.
Microswimmer Combing: Controlling Interfacial Dynamics for Open‐Surface Multifunctional Screening of Small Animals
Authors: Gongchen Sun, Cassidy‐Arielle Manning, Ga Hyun Lee, Maryam Majeed, Hang Lu
Journal: Advanced Healthcare Materials (2021)

Abstract Image‐based screening of multicellular model organisms is critical for both investigating fundamental biology and drug development. Current microfluidic techniques for high‐throughput manipulation of small model organisms, although useful, are generally complicated to operate, which impedes their widespread adoption by biology laboratories. To address this challenge, this paper presents an ultrasimple and yet effective approach, “microswimmer combing,” to rapidly isolate live small animals on an open‐surface array. This approach exploits a dynamic contact line‐combing mechanism designed to handle highly active microswimmers. The isolation method is robust, and the device operation is simple for users without a priori experience. The versatile open‐surface device enables multiple screening applications, including high‐resolution imaging of multicellular organisms, on‐demand mutant selection, and multiplexed chemical screening. The simplicity and versatility of this method provide broad access to high‐throughput experimentation for biologists and open up new opportunities to study active microswimmers by different scientific communities.
Is Shelter-in-Place Policy Related to Mail Order Pharmacy Use and Racial/Ethnic Disparities for Patients With Diabetes?
Authors: Tainayah W. Thomas, Wendy T. Dyer, Maher Yassin, Romain Neugebauer, Andrew J. Karter, Julie A. Schmittdiel
Journal: Diabetes Care (2021)

Effective management of diabetes during the coronavirus disease 2019 (COVID-19) pandemic is critical given that hyperglycemia is both a risk factor for infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has been associated with poorer outcomes for those infected (1). Unfortunately, inadequate diabetes self-management due to medication nonadherence is prevalent among patients with diabetes and is a major contributor to poor diabetes outcomes (2,3). Research suggests that mail order pharmacy (MOP) use can improve medication adherence (3). However, there is little data on how the COVID-19 pandemic is related to MOP use. Regrettably, racial/ethnic minority patients with diabetes have poorer medication adherence than White patients, and research shows marked disparities among racial/ethnic minorities in SARS-CoV-2 infection rates and outcomes, but little is known about racial/ethnic differences in MOP use during the COVID-19 pandemic (3,4). The objectives of our study were to 1 ) assess the association between the COVID-19 pandemic shelter-in-place order and MOP use and 2 ) examine these associations by patient race/ethnicity.

We conducted a retrospective cohort study using a cohort from a randomized encouragement trial conducted in 2017–2018 at Kaiser Permanente Northern California (KPNC), the Encouraging Mail Order Pharmacy Use to Improve Outcomes and Reduce Disparities …
Association of Adenoma Detection Rate and Adenoma Characteristics With Colorectal Cancer Mortality After Screening Colonoscopy
Authors: Elisabeth Waldmann, Andreas A. Kammerlander, Irina Gessl, Daniela Penz, Barbara Majcher, Anna Hinterberger, Michael Bretthauer, Michael H. Trauner, Monika Ferlitsch
Journal: Clinical Gastroenterology and Hepatology (2021)