tbuckley/cabot-search huggingface dataset:
Urate-Lowering Therapy and Chronic Kidney Disease Progression
Authors: Daniel I. Feig
Journal: New England Journal of Medicine (2020)

The prevalence and severity of chronic kidney disease (CKD) has been increasing for decades. Because of its tremendous financial and health burden, both to persons and to health systems, mitigation of the progression of CKD is of critical importance. Two articles in this issue of the Journal report the primary results of separate randomized, controlled clinical trials that address the use of urate-lowering therapy for the prevention of kidney disease progression. Doria et al.1 present the results of the Preventing Early Renal Loss in Diabetes (PERL) trial, which investigated the use of a xanthine oxidase inhibitor, allopurinol, in patients with . . .
Learning endometriosis phenotypes from patient-generated data
Authors: Iñigo Urteaga, Mollie McKillop, Noémie Elhadad
Journal: npj Digital Medicine (2020)

Endometriosis is a systemic and chronic condition in women of childbearing age, yet a highly enigmatic disease with unresolved questions: there are no known biomarkers, nor established clinical stages. We here investigate the use of patient-generated health data and data-driven phenotyping to characterize endometriosis patient subtypes, based on their reported signs and symptoms. We aim at unsupervised learning of endometriosis phenotypes using self-tracking data from personal smartphones. We leverage data from an observational research study of over 4000 women with endometriosis that track their condition over more than 2 years. We extend a classical mixed-membership model to accommodate the idiosyncrasies of the data at hand, i.e., the multimodality and uncertainty of the self-tracked variables. The proposed method, by jointly modeling a wide range of observations (i.e., participant symptoms, quality of life, treatments), identifies clinically relevant endometriosis subtypes. Experiments show that our method is robust to different hyperparameter choices and the biases of self-tracking data (e.g., the wide variations in tracking frequency among participants). With this work, we show the promise of unsupervised learning of endometriosis subtypes from self-tracked data, as learned phenotypes align well with what is already known about the disease, but also suggest new clinically actionable findings. More generally, we argue that a continued research effort on unsupervised phenotyping methods with patient-generated health data via new mobile and digital technologies will have significant impact on the study of enigmatic diseases in particular, and health in general.
NAADP/SERCA3-Dependent Ca <sup>2+</sup> Stores Pathway Specifically Controls Early Autocrine ADP Secretion Potentiating Platelet Activation
Authors: Miao Feng, Ziane Elaïb, Delphine Borgel, Cécile V. Denis, Frédéric Adam, Marijke Bryckaert, Jean-Philippe Rosa, Régis Bobe
Journal: Circulation Research (2020)

Ca2+ signaling is a key and ubiquitous actor of cell organization and its modulation controls many cellular responses. SERCAs (sarco-endoplasmic reticulum Ca2+-ATPases) pump Ca2+ into internal stores that play a major role in the cytosolic Ca2+ concentration rise upon cell activation. Platelets exhibit 2 types of SERCAs, SERCA2b and SERCA3 (SERCA3 deficient mice), which may exert specific roles, yet ill-defined. We have recently shown that Ca2+ mobilization from SERCA3-dependent stores was required for full platelet activation in weak stimulation conditions.To uncover the signaling mechanisms associated with Ca2+ mobilization from SERCA3-dependent stores leading to ADP secretion.Using platelets from wild-type or Serca3-deficient mice, we demonstrated that an early (within 5-10 s following stimulation) secretion of ADP specifically dependent on SERCA3 stored Ca2+ is exclusively mobilized by nicotinic acid adenosine dinucleotide-phosphate (NAADP): both Ca2+ mobilization from SERCA3-dependent stores and primary ADP secretion are blocked by the NAADP receptor antagonist Ned-19, and reciprocally both are stimulated by permeant NAADP. In contrast, Ca2+ mobilization from SERCA3-dependent stores and primary ADP secretion were unaffected by inhibition of the production of IP3 (inositol-1,4,5-trisphosphate) by phospholipase-C and accordingly were not stimulated by permeant IP3.Upon activation, an NAADP/SERCA3 Ca2+ mobilization pathway initiates an early ADP secretion, potentiating platelet activation, and a secondary wave of ADP secretion driven by both an IP3/SERCA2b-dependent Ca2+ stores pathway and the NAADP/SERCA3 pathway. This does not exclude that Ca2+ mobilized from SERCA3 stores may also enhance platelet global reactivity to agonists. Because of its modulating effect on platelet activation, this NAADP-SERCA3 pathway may be a relevant target for anti-thrombotic therapy. Graphic Abstract: A graphic abstract is available for this article.
Smartphone Activation of Citizen Responders to Facilitate Defibrillation in Out-of-Hospital Cardiac Arrest
Authors: Linn Andelius, Carolina Malta Hansen, Freddy K. Lippert, Lena Karlsson, Christian Torp-Pedersen, Annette Kjær Ersbøll, Lars Køber, Helle Collatz Christensen, Stig Nikolaj Blomberg, Gunnar H. Gislason, Fredrik Folke
Journal: Journal of the American College of Cardiology (2020)

Dispatching citizen responders through a smartphone application (app) holds the potential to increase bystander cardiopulmonary resuscitation (CPR) and defibrillation in out-of-hospital cardiac arrest (OHCA).This study investigated arrival at the OHCA location of app-dispatched citizen responders before the Emergency Medical Services (EMS) and the association with bystander CPR and bystander defibrillation.Suspected OHCAs with alerted citizen responders from September 1, 2017, to August 31, 2018, were included. Citizen responders located 1.8 km (1.1 miles) from the OHCA were dispatched to start CPR or retrieve an automated external defibrillator. OHCAs where at least 1 citizen responder arrived before EMS were compared with OHCAs where EMS arrived first. In both groups, random bystanders could be present before the arrival of citizen responders and the EMS. Primary outcomes were bystander CPR and bystander defibrillation, which included CPR and defibrillation by citizen responders and random bystanders.Citizen responders were alerted in 819 suspected OHCAs, of which 438 (53.5%) were confirmed cardiac arrests eligible for inclusion. At least 1 citizen responder arrived before EMS in 42.0% (n = 184) of all included OHCAs. When citizen responders arrived before EMS, the odds for bystander CPR increased (odds ratio: 1.76; 95% confidence interval: 1.07 to 2.91; p = 0.027) and the odds for bystander defibrillation more than tripled (odds ratio: 3.73; 95% confidence interval: 2.04 to 6.84; p < 0.001) compared with OHCAs in which citizen responders arrived after EMS.Arrival of app-dispatched citizen responders before EMS was associated with increased odds for bystander CPR and a more than 3-fold increase in odds for bystander defibrillation. (The HeartRunner Trial; NCT03835403).
Myocarditis in a 16-year-old boy positive for SARS-CoV-2
Authors: Massimiliano Gnecchi, Francesco Moretti, Emilio Maria Bassi, Sergio Leonardi, Rossana Totaro, Luciano Perotti, Valentina Zuccaro, Stefano Perlini, Lorenzo Preda, Fausto Baldanti, Raffaele Bruno, Luigi Oltrona Visconti
Journal: The Lancet (2020)
Obesity/Metabolic Syndrome and Diabetes Mellitus on Peri-implantitis
Authors: Paula Gabriela Faciola Pessôa de Oliveira, Estevam A. Bonfante, Edmara T.P. Bergamo, Sérgio Luis Scombatti de Souza, Leonardo Riella, Andrea Torroni, Ernesto B. Benalcazar Jalkh, Lukasz Witek, Christopher D. Lopez, Willian Fernando Zambuzzi, Paulo G. Coelho
Journal: Trends in Endocrinology and Metabolism (2020)
Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer’s disease model
Authors: Shoutang Wang, Meer Mustafa, Carla M. Yuede, Santiago Viveros Salazar, Philip Kong, Hua Long, Michael Ward, Omer Siddiqui, Robert Paul, Susan Gilfillan, Adiljan Ibrahim, Hervé Rhinn, Ilaria Tassi, Arnon Rosenthal, Tina Schwabe, Marco Colonna
Journal: The Journal of Experimental Medicine (2020)

TREM2 is a receptor for lipids expressed in microglia. The R47H variant of human TREM2 impairs ligand binding and increases Alzheimer's disease (AD) risk. In mouse models of amyloid β (Aβ) accumulation, defective TREM2 function affects microglial response to Aβ plaques, exacerbating tissue damage, whereas TREM2 overexpression attenuates pathology. Thus, AD may benefit from TREM2 activation. Here, we examined the impact of an anti-human TREM2 agonistic mAb, AL002c, in a mouse AD model expressing either the common variant (CV) or the R47H variant of TREM2. Single-cell RNA-seq of microglia after acute systemic administration of AL002c showed induction of proliferation in both CV- and R47H-transgenic mice. Prolonged administration of AL002c reduced filamentous plaques and neurite dystrophy, impacted behavior, and tempered microglial inflammatory response. We further showed that a variant of AL002c is safe and well tolerated in a first-in-human phase I clinical trial and engages TREM2 based on cerebrospinal fluid biomarkers. We conclude that AL002 is a promising candidate for AD therapy.
Interspecific Gene Flow and the Evolution of Specialization in Black and White Rhinoceros
Authors: Yoshan Moodley, Michael V Westbury, Isa-Rita M Russo, Shyam Gopalakrishnan, Andrinajoro Rakotoarivelo, Remi-Andre Olsen, Stefan Prost, Tate Tunstall, Oliver A Ryder, Love Dalén, Michael W Bruford
Journal: Molecular Biology and Evolution (2020)

Abstract Africa’s black (Diceros bicornis) and white (Ceratotherium simum) rhinoceros are closely related sister-taxa that evolved highly divergent obligate browsing and grazing feeding strategies. Although their precursor species Diceros praecox and Ceratotherium mauritanicum appear in the fossil record ∼5.2 Ma, by 4 Ma both were still mixed feeders, and were even spatiotemporally sympatric at several Pliocene sites in what is today Africa’s Rift Valley. Here, we ask whether or not D. praecox and C. mauritanicum were reproductively isolated when they came into Pliocene secondary contact. We sequenced and de novo assembled the first annotated black rhinoceros reference genome and compared it with available genomes of other black and white rhinoceros. We show that ancestral gene flow between D. praecox and C. mauritanicum ceased sometime between 3.3 and 4.1 Ma, despite conventional methods for the detection of gene flow from whole genome data returning false positive signatures of recent interspecific migration due to incomplete lineage sorting. We propose that ongoing Pliocene genetic exchange, for up to 2 My after initial divergence, could have potentially hindered the development of obligate feeding strategies until both species were fully reproductively isolated, but that the more severe and shifting paleoclimate of the early Pleistocene was likely the ultimate driver of ecological specialization in African rhinoceros.
Patient-centred care: the cornerstone for high-value musculoskeletal pain management
Authors: Ivan Lin, Louise Wiles, Rob Waller, JP Caneiro, Yusuf Nagree, Leon Straker, Chris G Maher, Peter P B O'Sullivan
Journal: British Journal of Sports Medicine (2020)

We identified 11 common recommendations to deliver best care for musculoskeletal (MSK) pain.1 Recommendation 1, that MSK pain care is patient centred, is the cornerstone for best care. Yet patient-centred care is often undervalued, under-recognised, undertrained and considered less important than technical skills/knowledge. Greater attention to patient-centredness improves patient and practitioner outcomes and reduces costs.2 3 A paradigm shift is needed in which patient-centred skills are learnt with the same rigour as technical skills (eg, patient physical examination procedures). However, clinicians and high-performance professionals are often unsure of how the patient centredness of their practice can be improved. The simplest step is for clinicians to improve the effectiveness of their communication.

Patient-centred care incorporates each individual’s context, knowledge, needs, values, goals and preferences into shared decision-making about management.4 Achieving this relies on effective communication,4 which elicits the patient’s concerns, within their unique context, leading to a partnership in management. This process is individualised, interactive, dynamic and evolves over the patient’s journey.

Communication is also not just about the patient interview. It includes how clinicians approach the physical examination, how they engage and empower the patient in shared decision-making and arrive …
Risk of bias in studies investigating novel diagnostic biomarkers for heart failure with preserved ejection fraction. A systematic review
Authors: Michiel T.H.M. Henkens, Sharon Remmelzwaal, Emma L. Robinson, Adriana J. van Ballegooijen, Arantxa Barandiarán Aizpurua, Job A.J. Verdonschot, Anne G. Raafs, Jerremy Weerts, Mark R. Hazebroek, Sandra Sanders‐van Wijk, M. Louis Handoko, Hester M. den Ruijter, Carolyn S.P. Lam, Rudolf A. de Boer, Walter J. Paulus, Vanessa P.M. van Empel, Rein Vos, Hans‐Peter Brunner‐La Rocca, Joline W.J. Beulens, Stephane R.B. Heymans
Journal: European Journal of Heart Failure (2020)
A Randomized, Placebo-Controlled Trial of Pembrolizumab Plus Chemotherapy in Patients With Metastatic Squamous NSCLC: Protocol-Specified Final Analysis of KEYNOTE-407
Authors: Luis Paz-Ares, David Vicente, Ali Tafreshi, Andrew Robinson, Hector Soto Parra, Julien Mazières, Barbara Hermes, Irfan Cicin, Balazs Medgyasszay, Jerónimo Rodríguez-Cid, Isamu Okamoto, SungSook Lee, Rodryg Ramlau, Vladimir Vladimirov, Ying Cheng, Xuan Deng, Ying Zhang, Tuba Bas, Bilal Piperdi, Balazs Halmos
Journal: Journal of Thoracic Oncology (2020)
A new gene associated with a β-thalassemia phenotype: the observation of variants in SUPT5H
Authors: Ahlem Achour, Tamara Koopmann, Rob Castel, Gijs W. E. Santen, Nicolette den Hollander, Jeroen Knijnenburg, Claudia A. L. Ruivenkamp, Sandra G. J. Arkesteijn, Jeanet ter Huurne, Sharda Bisoen, Maaike Verschuren, Linda Vijfhuizen, Rianne Schaap, Anneliese Grimbergen, Jennichjen Slomp, Joanne Traeger-Synodinos, Christina Vrettou, Serge Pissard, Frederic Galacteros, Frank Baas, Cornelis L. Harteveld
Journal: Blood (2020)
Comparative Effectiveness of Glucose-Lowering Drugs for Type 2 Diabetes
Authors: Apostolos Tsapas, Ioannis Avgerinos, Thomas Karagiannis, Konstantinos Malandris, Apostolos Manolopoulos, Panagiotis Andreadis, Aris Liakos, David R. Matthews, Eleni Bekiari
Journal: Annals of Internal Medicine (2020)

Background: Several pharmacologic options for type 2 diabetes are available. Purpose: To compare benefits and harms of glucose-lowering drugs in adults with type 2 diabetes. Data Sources: Several databases from inception through 18 December 2019 and ClinicalTrials.gov on 10 April 2020. Study Selection: English-language randomized trials that had at least 24 weeks of intervention and assessed the effects of glucose-lowering drugs on mortality, glycemic, and vascular outcomes. Data Extraction: Pairs of reviewers extracted data and appraised risk of bias. Data Synthesis: 453 trials assessing 21 antidiabetic interventions from 9 drug classes were included. Interventions included monotherapies (134 trials), add-on to metformin-based therapies (296 trials), and monotherapies versus add-on to metformin therapies (23 trials). There were no differences between treatments in drug-naive patients at low cardiovascular risk. Insulin regimens and specific glucagon-like peptide-1 receptor agonists (GLP-1 RAs) added to metformin-based background therapy produced the greatest reductions in hemoglobin A1c level. In patients at low cardiovascular risk receiving metformin-based background treatment (298 trials), there were no clinically meaningful differences between treatments for mortality and vascular outcomes. In patients at increased cardiovascular risk receiving metformin-based background treatment (21 trials), oral semaglutide, empagliflozin, liraglutide, extended-release exenatide, and dapagliflozin reduced all-cause mortality. Oral semaglutide, empagliflozin, and liraglutide also reduced cardiovascular death. Odds of stroke were lower with subcutaneous semaglutide and dulaglutide. Sodium–glucose cotransporter-2 (SGLT-2) inhibitors reduced heart failure hospitalization and end-stage renal disease. Subcutaneous semaglutide and canagliflozin increased diabetic retinopathy and amputation, respectively. Limitation: Inconsistent definitions of cardiovascular risk and low-level confidence in some estimates for patients at low cardiovascular risk. Conclusion: In diabetic patients at low cardiovascular risk, no treatment differs from placebo for vascular outcomes. In patients at increased cardiovascular risk receiving metformin-based background therapy, specific GLP-1 RAs and SGLT-2 inhibitors have a favorable effect on certain cardiovascular outcomes. Primary Funding Source: European Foundation for the Study of Diabetes, supported by an unrestricted educational grant from AstraZeneca. (PROSPERO: CRD42019122043)
Patient acceptance of using telemedicine for follow-up of lupus nephritis in the COVID-19 outbreak
Authors: Ho So, Cheuk-Chun Szeto, Lai-Shan Tam
Journal: Annals of the Rheumatic Diseases (2020)

We read with interest the preliminary German Society of Rheumatology recommendations for the management of patients with autoimmune inflammatory rheumatic diseases during the COVID-19 pandemic, which highlighted the importance of weighing the infection risk of doctor visits against the risk of missing disease controls in individual cases.1 Indeed, the attendance of our lupus nephritis clinic dropped by 14.4% in the 8-week period after the outbreak compared with the same time last year based on the citywide computerised Clinical Management System (So H, 2020). Those unattended patients were at risk of disease flares, which would lead to damage accrual, but at the same time, the rest were exposed to the threat of COVID-19.2 As the other national body suggested, the use of telemedicine (TM), also known as telehealth, to reduce potential exposure to severe acute respiratory syndrome coronavirus 2 might be a reasonable option in these patients.3 Since this is a shared decision-making process between patients and rheumatology healthcare providers, we conducted an online survey to analyse the patient acceptance and perceptions regarding …
Small cell transformation of non-small cell lung cancer on immune checkpoint inhibitors: uncommon or under-recognized?
Authors: Kartik Sehgal, Andreas Varkaris, Hollis Viray, Paul A VanderLaan, Deepa Rangachari, Daniel B Costa
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Histological transformation of oncogene-driven lung adenocarcinoma to small cell lung cancer (SCLC) following treatment with tyrosine kinase inhibitors (TKIs) is a well-described phenomenon. Whether a similar transformation may drive acquired resistance to immune checkpoint inhibitors (ICPIs) in non-SCLC (NSCLC) is uncertain. Hence, tissue biopsies are not universally recommended at progression of NSCLC on ICPIs, unlike TKIs. Case presentation We report a case of a woman in her mid-60s with a 35 pack-years tobacco history and stage IV squamous cell lung carcinoma with no targetable genomic alterations, whose disease progressed within 4 months of first line carboplatin/gemcitabine therapy. Her treatment was switched to second line nivolumab monotherapy which resulted in sustained partial response lasting 21 months. She subsequently developed rapid, bulky progression of mediastinal disease. Biopsy showed transformation to SCLC. Comparison of genomic profiling results from the initial NSCLC diagnosis and SCLC transformation revealed near-identical tumor profiles. Her disease responded to next line carboplatin/etoposide, though lasting for only 10 months. She died 14 months after detection of neuroendocrine transformation of her NSCLC. Systematic review We performed a systematic review of the literature to identify similar cases of NSCLC-to-small cell transformation on ICPIs. Nine patients, including our index case, were identified, with seven (77.8%) on nivolumab and two (22.2%) on pembrolizumab monotherapy. Median survival time since small cell transformation was 13.0 months (95% CI 2.0 to 16.0). Using our patient case as a framework, we further discuss the lack of consensus criteria to distinguish small cell transformation from de novo metachronous SCLC. Conclusions Histological transformation to SCLC is a potential mechanism of acquired resistance to ICPIs in NSCLC. Repeat tissue biopsies should be considered at the time of progression, similar to oncogene-directed therapies. Prospective larger studies are warranted to further characterize NSCLC-to-small cell transformation on ICPIs using molecular fingerprinting with paired tumor genomic profiles, evaluation of neuroendocrine features at baseline and consideration of initial response.
Publisher Correction: Cxcl10+ monocytes define a pathogenic subset in the central nervous system during autoimmune neuroinflammation
Authors: Amir Giladi, Lisa Katharina Wagner, Hanjie Li, Dorothea Dörr, Chiara Medaglia, Franziska Paul, Anat Shemer, Steffen Jung, Simon Yona, Matthias Mack, Achim Leutz, Ido Amit, Alexander Mildner
Journal: Nature Immunology (2020)