tbuckley/cabot-search huggingface dataset:
Racial Disparities in COVID-19 Testing and Outcomes
Authors: Gabriel J. Escobar, Alyce S. Adams, Vincent X. Liu, Lauren Soltesz, Yi-Fen Irene Chen, Stephen M. Parodi, G. Thomas Ray, Laura C. Myers, Charulata M. Ramaprasad, Richard Dlott, Catherine Lee
Journal: Annals of Internal Medicine (2021)

Racial disparities exist in outcomes after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.To evaluate the contribution of race/ethnicity in SARS-CoV-2 testing, infection, and outcomes.Retrospective cohort study (1 February 2020 to 31 May 2020).Integrated health care delivery system in Northern California.Adult health plan members.Age, sex, neighborhood deprivation index, comorbid conditions, acute physiology indices, and race/ethnicity; SARS-CoV-2 testing and incidence of positive test results; and hospitalization, illness severity, and mortality.Among 3 481 716 eligible members, 42.0% were White, 6.4% African American, 19.9% Hispanic, and 18.6% Asian; 13.0% were of other or unknown race. Of eligible members, 91 212 (2.6%) were tested for SARS-CoV-2 infection and 3686 had positive results (overall incidence, 105.9 per 100 000 persons; by racial group, White, 55.1; African American, 123.1; Hispanic, 219.6; Asian, 111.7; other/unknown, 79.3). African American persons had the highest unadjusted testing and mortality rates, White persons had the lowest testing rates, and those with other or unknown race had the lowest mortality rates. Compared with White persons, adjusted testing rates among non-White persons were marginally higher, but infection rates were significantly higher; adjusted odds ratios [aORs] for African American persons, Hispanic persons, Asian persons, and persons of other/unknown race were 2.01 (95% CI, 1.75 to 2.31), 3.93 (CI, 3.59 to 4.30), 2.19 (CI, 1.98 to 2.42), and 1.57 (CI, 1.38 to 1.78), respectively. Geographic analyses showed that infections clustered in areas with higher proportions of non-White persons. Compared with White persons, adjusted hospitalization rates for African American persons, Hispanic persons, Asian persons, and persons of other/unknown race were 1.47 (CI, 1.03 to 2.09), 1.42 (CI, 1.11 to 1.82), 1.47 (CI, 1.13 to 1.92), and 1.03 (CI, 0.72 to 1.46), respectively. Adjusted analyses showed no racial differences in inpatient mortality or total mortality during the study period. For testing, comorbid conditions made the greatest relative contribution to model explanatory power (77.9%); race only accounted for 8.1%. Likelihood of infection was largely due to race (80.3%). For other outcomes, age was most important; race only contributed 4.5% for hospitalization, 12.8% for admission illness severity, 2.3% for in-hospital death, and 0.4% for any death.The study involved an insured population in a highly integrated health system.Race was the most important predictor of SARS-CoV-2 infection. After infection, race was associated with increased hospitalization risk but not mortality.The Permanente Medical Group, Inc.
Understanding the key issues in the treatment of uncontrolled persistent asthma with type 2 inflammation
Authors: William W. Busse, Monica Kraft, Klaus F. Rabe, Yamo Deniz, Paul J. Rowe, Marcella Ruddy, Mario Castro
Journal: European Respiratory Journal (2021)

Asthma is a complex respiratory disease that varies in severity and response to treatment. Several asthma phenotypes with unique clinical and inflammatory characteristics have been identified. Endotypes, based on distinct molecular profiles, help to further elucidate the heterogeneity within asthma. Type 2 inflammation, involving both the innate (type 2 innate lymphoid cell) and adaptive (T-helper type 2 cells) immune systems, underpins the complex pathophysiology of chronic inflammation in asthma, as well as the presence of comorbid disease (
Solving the T-Cell Problem: Generation of Immune Stealth AAV: Conference: 16th Annual Meeting of the American Society of Gene and Cell Therapy (ASGCT) Location: Salt Lake City, UT Date: MAY 15-18, 2013; By: Thierry VandenDriessche, Frederico Mingozzi, Nisha Nair,Jessica Willems, Hanneke Evens, Omid Ghandeharian, Kathy High, Marinee K. Chuah.
Authors: Nisha Nair Shivsankaran Nair
Journal: Molecular Therapy (2013)
Non-coding RNAs regulation of macrophage polarization in cancer
Authors: Swati Mohapatra, Carlotta Pioppini, Bulent Ozpolat, George A. Calin
Journal: Molecular Cancer (2021)

Abstract Noncoding RNA (ncRNA) transcripts that did not code proteins but regulate their functions were extensively studied for the last two decades and the plethora of discoveries have instigated scientists to investigate their dynamic roles in several diseases especially in cancer. However, there is much more to learn about the role of ncRNAs as drivers of malignant cell evolution in relation to macrophage polarization in the tumor microenvironment. At the initial stage of tumor development, macrophages have an important role in directing Go/No-go decisions to the promotion of tumor growth, immunosuppression, and angiogenesis. Tumor-associated macrophages behave differently as they are predominantly induced to be polarized into M2, a pro-tumorigenic type when recruited with the tumor tissue and thereby favoring the tumorigenesis. Polarization of macrophages into M1 or M2 subtypes plays a vital role in regulating tumor progression, metastasis, and clinical outcome, highlighting the importance of studying the factors driving this process. A substantial number of studies have demonstrated that ncRNAs are involved in the macrophage polarization based on their ability to drive M1 or M2 polarization and in this review we have described their functions and categorized them into oncogenes, tumor suppressors, Juggling tumor suppressors, and Juggling oncogenes.
Protein/AS01B vaccination elicits stronger, more Th2-skewed antigen-specific human T follicular helper cell responses than heterologous viral vectors
Authors: Carolyn M. Nielsen, Ane Ogbe, Isabela Pedroza-Pacheco, Susanne E. Doeleman, Yue Chen, Sarah E. Silk, Jordan R. Barrett, Sean C. Elias, Kazutoyo Miura, Ababacar Diouf, Martino Bardelli, Rebecca A. Dabbs, Lea Barfod, Carole A. Long, Barton F. Haynes, Ruth O. Payne, Angela M. Minassian, Todd Bradley, Simon J. Draper, Persephone Borrow
Journal: Cell Reports Medicine (2021)

Interactions between B cells and CD4+ T follicular helper (Tfh) cells are key determinants of humoral responses. Using samples from clinical trials performed with the malaria vaccine candidate antigen Plasmodium falciparum merozoite protein (PfRH5), we compare the frequency, phenotype, and gene expression profiles of PfRH5-specific circulating Tfh (cTfh) cells elicited by two leading human vaccine delivery platforms: heterologous viral vector prime boost and protein with AS01B adjuvant. We demonstrate that the protein/AS01B platform induces a higher-magnitude antigen-specific cTfh cell response and that this correlates with peak anti-PfRH5 IgG concentrations, frequency of PfRH5-specific memory B cells, and antibody functionality. Furthermore, our data indicate a greater Th2/Tfh2 skew within the polyfunctional response elicited following vaccination with protein/AS01B as compared to a Th1/Tfh1 skew with viral vectors. These data highlight the impact of vaccine platform on the cTfh cell response driving humoral immunity, associating a high-magnitude, Th2-biased cTfh response with potent antibody production.
Lessons from intensified surveillance of viral hepatitis A, Israel, 2017 and 2018
Authors: Yael Gozlan, Itay Bar-Or, Hadar Volnowitz, Efrat Asulin, Rivka Rich, Emilia Anis, Yonat Shemer, Moran Szwarcwort Cohen, Etti Levy Dahary, Licita Schreiber, Ilana Goldiner, Orit Rozenberg, Orit Picard, Michal Savion, Inbal Fuchs, Ella Mendelson, Orna Mor
Journal: Eurosurveillance (2021)

IntroductionUniversal vaccination of toddlers has led to very low hepatitis A (HAV) endemicity in Israel. However, sporadic outbreaks still occur, necessitating better surveillance.AimTo implement a comprehensive HAV surveillance programme.MethodsIn 2017 and 2018, sera from suspected HAV cases that tested positive for anti-HAV IgM antibodies were transferred to the Central Virology Laboratory (CVL) for molecular confirmation and genotyping. Sewage samples were collected in Israel and Palestine* and were molecularly analysed. All molecular (CVL), epidemiological (District Health Offices and Epidemiological Division) and clinical (treating physicians) data were combined and concordantly assessed.ResultsOverall, 146 cases (78 in 2017 and 68 in 2018, median age 34 years, 102 male) and 240 sewage samples were studied. Most cases (96%) were unvaccinated. In 2017, 89% of cases were male, 45% of whom were men who have sex with men (MSM). In 2018, 49% were male, but only 3% of them were MSM (p < 0.01). In 2017, 82% of cases and 63% of sewage samples were genotype 1A, phylogenetically associated with a global MSM-HAV outbreak. In 2018, 80% of cases and 71% of sewage samples were genotype 1B, related to the endemic strain previously identified in Israel and Palestine*. Environmental analysis revealed clustering of sewage and cases' sequences, and country-wide circulation of HAV.ConclusionsMolecular confirmation of HAV infection in cases and analysis of environmental samples, combined with clinical and epidemiological investigation, may improve HAV surveillance. Sequence-based typing of both clinical and sewage-derived samples could assist in understanding viral circulation.
Characterizing tumor shrinkage as a measure of clinical benefit for immune checkpoint inhibitors
Authors: Thomas Kelleher, Junliang Cai, Nicholas AJ Botwood, Dominic F Labriola
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background We explored whether the effectiveness of immune checkpoint inhibitors (ICIs) can be characterized by incorporating a composite of duration of response (DOR) to complement traditional Response Evaluation Criteria in Solid Tumors (RECIST) criteria for objective response rate (ORR) in an intent-to-treat (ITT) population. Furthermore, the correlation of this novel endpoint, characterized by the restricted mean time in response (RMTR), with overall survival (OS) will be examined. Methods We analyzed ORR alone or in combination with DOR (RMTR) in available phase I, II, and III trials evaluating nivolumab monotherapy or in combination with ipilimumab across solid tumor types. ORR was evaluated per RECIST V.1.1. DOR was estimated using individual patient data in ITT populations regardless of RECIST response, with non-responders imputed as zero. Associations between ORR alone or RMTR and OS were evaluated in the ITT population. DOR curves were generated using the Kaplan-Meier product limit method, and 6-month RMTR, a measure of response durability, was derived from the area under the curves. For ORR and RMTR in the ITT population, the strength of association with OS was analyzed using Pearson correlation coefficients ( r ). Results Nivolumab treatment was associated with longer response durations than active control in responder and ITT populations. Similarly, ORR and RMTR were both significantly correlated with OS (ORR vs OS: r =0.684, p=0.02; RMTR vs OS: r =0.695, p=0.018). Conclusions Combining ORR and DOR (RMTR) to objectively characterize tumor shrinkage in an ITT patient population is a novel approach that appears to correlate well with OS in patients treated with nivolumab monotherapy or in combination with ipilimumab. This endpoint may provide a more complete characterization of tumor shrinkage to incorporate into the design of future ICI clinical trials. However, confirmation of this approach will require further research.
Were Ancestral Proteins Less Specific?
Authors: Lucas C Wheeler, Michael J Harms
Journal: Molecular Biology and Evolution (2021)

Some have hypothesized that ancestral proteins were, on average, less specific than their descendants. If true, this would provide a universal axis along which to organize protein evolution and suggests that reconstructed ancestral proteins may be uniquely powerful tools for protein engineering. Ancestral sequence reconstruction studies are one line of evidence used to support this hypothesis. Previously, we performed such a study, investigating the evolution of peptide-binding specificity for the paralogs S100A5 and S100A6. The modern proteins appeared more specific than their last common ancestor (ancA5/A6), as each paralog bound a subset of the peptides bound by ancA5/A6. In this study, we revisit this transition, using quantitative phage display to measure the interactions of 30,533 random peptides with human S100A5, S100A6, and ancA5/A6. This unbiased screen reveals a different picture. While S100A5 and S100A6 do indeed bind to a subset of the peptides recognized by ancA5/A6, they also acquired new peptide partners outside of the set recognized by ancA5/A6. Our previous work showed that ancA5/A6 had lower specificity than its descendants when measured against biological targets; our new work shows that ancA5/A6 has similar specificity to the modern proteins when measured against a random set of peptide targets. This demonstrates that altered biological specificity does not necessarily indicate altered intrinsic specificity, and sounds a cautionary note for using ancestral reconstruction studies with biological targets as a means to infer global evolutionary trends in specificity.
Obesity and risk of catheter-related infections in the ICU. A post hoc analysis of four large randomized controlled trials
Authors: Niccolò Buetti, Bertrand Souweine, Leonard Mermel, Olivier Mimoz, Stéphane Ruckly, Ambre Loiodice, Nicolas Mongardon, Jean-Christophe Lucet, Jean-Jacques Parienti, Jean-François Timsit
Journal: Intensive Care Medicine (2021)
Equity and evidence during vaccine rollout: stepped wedge cluster randomised trials could help
Authors: Katy J L Bell, Paul Glasziou, Fiona Stanaway, Patrick Bossuyt, Les Irwig
Journal: BMJ (2021)

Herzog and colleagues raise the thorny issue of allocating scarce vaccines, comparing the proportional allocation model with a fair priority model.1 Regardless of what is used for prioritisation between and within countries, there will be a long period of rollout before most of the world’s population are offered vaccination. For groups of equivalent priority, a fair and equitable way to decide on the order of rollout is to use a lottery, or system of random choice.2 Such randomised …
Hunting for a Diagnosis
Authors: Nathan Houchens, Sarah Hartley, Scott P. Commins, Dru Claar, Sanjay Saint
Journal: New England Journal of Medicine (2021)

A 47-year-old man in Michigan presented to the ED with a 1-day history of presyncope, swelling of the eyelids, and diffuse pruritic rash. He reported a 3-week history of postprandial watery bowel movements and a 5-day history of diffuse, crampy abdominal pain.
Recent advances in proteome‐wide label‐free target deconvolution for bioactive small molecules
Authors: Jichao Sun, Nayana Prabhu, Jun Tang, Fan Yang, Lin Jia, Jinan Guo, Kefeng Xiao, Wai Leong Tam, Pär Nordlund, Lingyun Dai
Journal: Medicinal Research Reviews (2021)

Abstract Small‐molecule drugs modulate biological processes and disease states through engagement of target proteins in cells. Assessing drug–target engagement on a proteome‐wide scale is of utmost importance in better understanding the molecular mechanisms of action of observed beneficial and adverse effects, as well as in developing next generation tool compounds and drugs with better efficacies and specificities. However, systematic assessment of drug–target engagement has been an arduous task. With the continuous development of mass spectrometry‐based proteomics instruments and techniques, various chemical proteomics approaches for drug target deconvolution (i.e., the identification of molecular target for drugs) have emerged. Among these, the label‐free target deconvolution approaches that do not involve the chemical modification of compounds of interest, have gained increased attention in the community. Here we provide an overview of the basic principles and recent biological applications of the most important label‐free methods including the cellular thermal shift assay, pulse proteolysis, chemical denaturant and protein precipitation, stability of proteins from rates of oxidation, drug affinity responsive target stability, limited proteolysis, and solvent‐induced protein precipitation. The state‐of‐the‐art technical implications and future outlook for the label‐free approaches are also discussed.
Genetic Predisposition for Type 2 Diabetes Mellitus in a Cameroonian Population: Contribution of rs4731702(C/T) Polymorphism of Krüppel-Like Factor 14 Gene
Authors: Magellan Guewo-Fokeng, Eugene Sobngwi, Barbara Atogho-Tiedeu, Jean-Claude Mbanya, Wilfred F. Mbacham
Journal: Metabolism (2021)
Immuno-metabolic interfaces in cardiac disease and failure
Authors: Edoardo Bertero, Jan Dudek, Clement Cochain, Murilo Delgobo, Gustavo Ramos, Brenda Gerull, Takahiro Higuchi, Martin Vaeth, Alma Zernecke, Stefan Frantz, Ulrich Hofmann, Christoph Maack
Journal: Cardiovascular Research (2021)

The interplay between the cardiovascular system, metabolism, and inflammation plays a central role in the pathophysiology of a wide spectrum of cardiovascular diseases, including heart failure. Here, we provide an overview of the fundamental aspects of the interrelation between inflammation and metabolism, ranging from the role of metabolism in immune cell function to the processes how inflammation modulates systemic and cardiac metabolism. Furthermore, we discuss how disruption of this immuno-metabolic interface is involved in the development and progression of cardiovascular disease, with a special focus on heart failure. Finally, we present new technologies and therapeutic approaches that have recently emerged and hold promise for the future of cardiovascular medicine.
NEDD9 Is a Novel and Modifiable Mediator of Platelet–Endothelial Adhesion in the Pulmonary Circulation
Authors: George A. Alba, Andriy O. Samokhin, Rui-Sheng Wang, Ying-Yi Zhang, Bradley M. Wertheim, Elena Arons, Edward A. Greenfield, Martina H. Lundberg Slingsby, Julia R. Ceglowski, Kathleen J. Haley, Frederick P. Bowman, Yen-Rei Yu, John. C. Haney, George Eng, Richard N. Mitchell, Anthony Sheets, Sara O. Vargas, Sachiko Seo, Richard N. Channick, Peter J. Leary, Sudarshan Rajagopal, Joseph Loscalzo, Elisabeth M. Battinelli, Bradley A. Maron
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Rationale: Data on the molecular mechanisms that regulate platelet-pulmonary endothelial adhesion under conditions of hypoxia are lacking, but may have important therapeutic implications. Objectives: To identify a hypoxia-sensitive, modifiable mediator of platelet-pulmonary artery endothelial cell adhesion and thrombotic remodeling. Methods: Network medicine was used to profile protein-protein interactions in hypoxia-treated human pulmonary artery endothelial cells. Data from liquid chromatography-mass spectrometry and microscale thermophoresis informed the development of a novel antibody (Ab) to inhibit platelet-endothelial adhesion, which was tested in cells from patients with chronic thromboembolic pulmonary hypertension (CTEPH) and three animal models in vivo. Measurements and Main Results: The protein NEDD9 was identified in the hypoxia thrombosome network in silico. Compared with normoxia, hypoxia (0.2% O2) for 24 hours increased HIF-1α (hypoxia-inducible factor-1α)-dependent NEDD9 upregulation in vitro. Increased NEDD9 was localized to the plasma-membrane surface of cells from control donors and patients with CTEPH. In endarterectomy specimens, NEDD9 colocalized with the platelet surface adhesion molecule P-selectin. Our custom-made anti-NEDD9 Ab targeted the NEDD9-P-selectin interaction and inhibited the adhesion of activated platelets to pulmonary artery endothelial cells from control donors in vitro and from patients with CTEPH ex vivo. Compared with control mice, platelet-pulmonary endothelial aggregates and pulmonary hypertension induced by ADP were decreased in NEDD9-/- mice or wild-type mice treated with the anti-NEDD9 Ab, which also decreased chronic pulmonary thromboembolic remodeling in vivo. Conclusions: The NEDD9-P-selectin protein-protein interaction is a modifiable target with which to inhibit platelet-pulmonary endothelial adhesion and thromboembolic vascular remodeling, with potential therapeutic implications for patients with disorders of increased hypoxia signaling pathways, including CTEPH.
Interpreting the Findings of a Meta-analysis of Psychosocial Interventions in Bipolar Disorder
Authors: Co Co Tong, Rebecca Strawbridge, Sameer Jauhar
Journal: JAMA Psychiatry (2021)

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Joseph Sonnabend: the first AIDS doctor
Authors: Bob Roehr
Journal: BMJ (2021)

Photo credit: Simon Watney

Joseph Sonnabend was the world’s first AIDS doctor. He never made that claim, and perhaps it wasn’t quite literally true, but fate placed him in New York City immediately before the start of the epidemic, where his training as a researcher gave him tools that others lacked, and his compassion created a loyal patient following. He was a bit of a curmudgeon, familiar with but not dependent on the hidebound strictures of the medical establishment, comfortable in the role of an outsider.

He was born in Johannesburg when racial discrimination had not yet been codified into the laws of apartheid (1948), and grew up in colonial Rhodesia (now Zimbabwe), where his mother was a physician and his father a university professor of psychology and sociology. He returned to Johannesburg for education at the University of the Witwatersrand (1956), then on to the Royal College of Physicians in Edinburgh (1961), where he trained in infectious diseases.

Sonnabend pursued research rather than clinical care, working at the National Institute of Medical Research in the laboratory of Alick Isaacs, the co-discoverer of interferon. Isaacs’s unexpected death from a brain haemorrhage at age 45 probably contributed to Sonnabend’s decision to accept a research position at Mount Sinai School of Medicine and move to New York City in 1969. The city was at its gritty nadir; homosexual activity was still illegal and discrimination rampant. But the Stonewall riots that year marked the start of a modern gay era and drew many young men who wished to live as …
Pooled Analysis of PFO Occluder Device Trials in Patients With PFO and Migraine
Authors: Mohammad K. Mojadidi, Preetham Kumar, Ahmed N. Mahmoud, Islam Y. Elgendy, Hilary Shapiro, Brian West, Andrew C. Charles, Heinrich P. Mattle, Sherman Sorensen, Bernhard Meier, Stephen D. Silberstein, Jonathan M. Tobis
Journal: Journal of the American College of Cardiology (2021)