tbuckley/cabot-search huggingface dataset:
A randomized controlled study of convalescent plasma for individuals hospitalized with COVID-19 pneumonia
Authors: Katharine J. Bar, Pamela A. Shaw, Grace H. Choi, Nicole Aqui, Andrew Fesnak, Jasper B. Yang, Haideliza Soto-Calderon, Lizette Grajales, Julie Starr, Michelle Andronov, Miranda Mastellone, Chigozie Amonu, Geoff Feret, Maureen DeMarshall, Marie Buchanan, Maria Caturla, James Gordon, Alan Wanicur, M. Alexandra Monroy, Felicity Mampe, Emily Lindemuth, Sigrid Gouma, Anne M. Mullin, Holly Barilla, Anastasiya Pronina, Leah Irwin, Raeann Thomas, Risa A. Eichinger, Faye Demuth, Eline T. Luning Prak, Jose L. Pascual, William R. Short, Michal A. Elovitz, Jillian Baron, Nuala J. Meyer, Kathleen O. Degnan, Ian Frank, Scott E. Hensley, Donald L. Siegel, Pablo Tebas
Journal: Journal of Clinical Investigation (2021)

BackgroundAntibody-based strategies for COVID-19 have shown promise in prevention and treatment of early disease. COVID-19 convalescent plasma (CCP) has been widely used but results from randomized trials supporting its benefit in hospitalized patients with pneumonia are limited. Here, we assess the efficacy of CCP in severely ill, hospitalized adults with COVID-19 pneumonia.MethodsWe performed a randomized control trial (PennCCP2), with 80 adults hospitalized with COVID-19 pneumonia, comparing up to 2 units of locally sourced CCP plus standard care versus standard care alone. The primary efficacy endpoint was comparison of a clinical severity score. Key secondary outcomes include 14- and 28-day mortality, 14- and 28-day maximum 8-point WHO ordinal score (WHO8) score, duration of supplemental oxygenation or mechanical ventilation, respiratory SARS-CoV-2 RNA, and anti-SARS-CoV-2 antibodies.ResultsEighty hospitalized adults with confirmed COVID-19 pneumonia were enrolled at median day 6 of symptoms and day 1 of hospitalization; 60% were anti-SARS-CoV-2 antibody seronegative. Participants had a median of 3 comorbidities, including risk factors for severe COVID-19 and immunosuppression. CCP treatment was safe and conferred significant benefit by clinical severity score (median [MED] and interquartile range [IQR] 10 [5.5-30] vs. 7 [2.75-12.25], P = 0.037) and 28-day mortality (n = 10, 26% vs. n = 2, 5%; P = 0.013). All other prespecified outcome measures showed weak evidence toward benefit of CCP.ConclusionTwo units of locally sourced CCP administered early in hospitalization to majority seronegative participants conferred a significant benefit in clinical severity score and 28-day mortality. Results suggest CCP may benefit select populations, especially those with comorbidities who are treated early.Trial RegistrationClinicalTrials.gov NCT04397757.FundingUniversity of Pennsylvania.
Abstract P197: Heart Failure In A Universally Insured Working Age Population: The Military Community Experience
Authors: Veronique L Roger, Amanda Banaag, Jessica Korona-Bailey, Clesson Turner, Mark C Haigney, Tracey Perez Koehlmoos
Journal: Circulation (2022)

Background: Heart disease is the leading cause of death in the United States (US) and deaths due to heart failure (HF) are increasing, while disparities are widening. The military community is pertinent to the study of the epidemiology of HF for several reasons: the 9.6 million individuals receiving care through the Military Health System (MHS) are representative of the working age US population and the MHS is the closest model to universal healthcare in the US. Hence, this environment is conducive to evaluate health disparities as access to care is uncoupled from race, sex, and ethnicity. Further, persons who serve have numerous risk factors (hypertension, smoking, PTSD, anxiety), HF is a leading cause of death among veterans and for those on active duty presents challenges to military readiness. Methods: We conducted a cross-sectional study of MHS beneficiaries aged 18 to 64 years to measure the prevalence of HF in 2018-19 overall and by sex, race, and other sociodemographic characteristics. HF was defined by International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes. Results: Among 6,375,086 MHS beneficiaries aged 18 to 64 years, 142,201 (2.23%) were diagnosed with HF. Beneficiaries with HF were mainly men (60%), age 50 to 59 (41%), retired from military service (52%), with a Senior Enlisted rank (proxy for lower socio-economic status based on salary) (79%) and serving in the US Army (39%). In logistic regression, male sex, older age, Black race, and lower rank were associated with higher relative odds of HF. After multivariable adjustment, Black race and lower rank were independently associated with large increases in prevalent HF (Table). Conclusion: Among MHS beneficiaries of working age, the prevalence of HF is high and substantial disparities exist. The large excess odds of HF among Black beneficiaries and among lower rank individuals underscores the urgent need to understand and address the determinants of these disparities.
Concerns over functional experiments, interpretation, and required controls. Reply.
Authors: Wan-Chen Hsieh, Shih-Yu Chen
Journal: Journal of Clinical Investigation (2022)

Wang for their careful reading of our manuscript, especially for their comments on the alterations of the cell surface by SARS-CoV-2 and how these alterations affect NK-related immunosurveillence (1).We agree that a comprehensive profiling of the plasma membrane proteome is essential and that a study similar to that described previously is warranted (2).However, our strategy was to begin by identifying the unique features of NK immunophenotypes that control SARS-CoV-2 and then focus on the relevant ligands.We believe these two directions are complementary and provide different perspectives of how NK cells interact with virus-infected cells.Regarding the upregulation of CD155 by SARS-CoV-2, we were also surprised to observe the upregulation of CD155 by pseudovirus that expressed only the spike protein.However, recent reports demonstrated that the spike protein alone or binding of the spike protein to the receptors can trigger signaling in host cells, which is in agreement with our findings that the spike protein is a stressor even in the absence of other viral components (3-6).That downregulation of CD155 is observed upon infection with other viruses (e.g., HCMV) resulting in evasion of NK cell surveillance is not mutually exclusive with our findings.Instead, it further strengthens the importance of investigating NK cell receptor repertoires in detail at the single-cell level.Since NK cells coexpressing DNAM1 and TIGIT, but not DNAM1 alone, are the subsets correlated with the viral clearance, this implies an inhibitory role of CD155 in the context of SARS-CoV-2 infection.We also agree that the differential expression of CD155 that we observed was the cumulative effect of both virus infection and IFN and other cytokines produced following infection.More comprehensive time-course experiments will be required to better clarify these effects, but are beyond the scope of this study.The histogram of absolute levels (mass cytometry) of CD155 is shown in Figure 1A for reference.To further demonstrate the involvement of DNAM1, we indeed observed a decrease in NK cell killing after incubation with anti-DNAM1 antibody (Figure 1B).The mock-infected controls for the TIGIT-Fc NK experiments are shown in Figure 1C.There were no significant effects of TIGIT-Fc on NK cell killing in mock-infected controls, which demonstrates that the enhancement of NK cell killing efficiency was specific to SARS-CoV-2 virus-infected target cells.
Viral Dynamics of SARS-CoV-2 Variants in Vaccinated and Unvaccinated Persons
Authors: Stephen M Kissler, Joseph R Fauver, Christina Mack, Caroline G Tai, Mallery I Breban, Anne E Watkins, Radhika M Samant, Deverick J Anderson, Jessica Metti, Gaurav Khullar, Rachel Baits, Matthew MacKay, Daisy Salgado, Tim Baker, Joel T Dudley, Christopher E Mason, David D Ho, Nathan D Grubaugh, Yonatan H Grad
Journal: New England Journal of Medicine (2021)
Abstract P063: Socioeconomic Status And Component Of Iatrogenic Obesity In The United States
Authors: Beini Lyu, Morgan Grams, Alex R Chang, Lesley Inker, Elizabeth Selvin, Jung-im Shin
Journal: Circulation (2022)

Introduction: Overweight and obesity are more prevalent in people with lower socioeconomic status (SES). Use of obesogenic prescription medications such as certain anticonvulsants, antidepressants, beta-blockers, and antidiabetic medications may contribute to the disparities in obesity by SES in US adults. Methods Using data from the 2009-2018 National Health and Nutrition Examination Survey (NHANES), we assessed the use of obesogenic medication by SES among overweight and obese adults aged ≥20 years taking ≥1 prescription medication. Based on low SES indicator – &lt;high school education, household income &lt;federal poverty level, and having public health insurance only, we categorized participants into 3 SES groups (0, 1, and ≥2 low SES indicators as high, intermediate, and low SES). We used logistic regression to examine the association between SES and obesogenic medication use. All analyses accounted for the complex NHANES survey design. Results Among 11,796 participants (mean age 54.6, 54.1% female), the mean body mass index (SE) was 32.5 (0.1) kg/m 2 . Use of obesogenic medication was more common among people with lower SES in all survey years, with a trend toward increased prevalence over time among people with low SES ( Figure ). Lower SES was associated with obesogenic medication use in demographic-adjusted models (OR 1.4 [95%CI 1.2-1.5] for intermediate SES and 1.9 [1.7-2.1] for low SES, compared to high SES). The associations remained significant after further accounting for number of medications (OR [95% CI] =1.1 [1.0-1.3] for intermediate SES and 1.2 [1.0-1.4] for low SES). Results were consistent when assessed by individual SES indicators. Conclusions: Use of obesogenic medication is common in the US. Lower SES was associated with more frequent use of obesogenic medication even after controlling for medication burden. These results suggest that disparities in obesogenic medication use may contribute to the higher obesity prevalence among people with lower SES.
miRNA signatures associated with vulnerability to food addiction in mice and humans
Authors: Alejandra García-Blanco, Laura Domingo-Rodriguez, Judit Cabana-Domínguez, Noèlia Fernández-Castillo, Laura Pineda-Cirera, Jordi Mayneris-Perxachs, Aurelijus Burokas, Jose Espinosa-Carrasco, Silvia Arboleya, Jessica Latorre, Catherine Stanton, Bru Cormand, Jose-Manuel Fernández-Real, Elena Martín-García, Rafael Maldonado
Journal: Journal of Clinical Investigation (2022)

Food addiction is characterized by a loss of behavioral control over food intake and is associated with obesity and other eating disorders. The mechanisms underlying this behavioral disorder are largely unknown. We aimed to investigate the changes in miRNA expression promoted by food addiction in animals and humans and their involvement in the mechanisms underlying the behavioral hallmarks of this disorder. We found sharp similitudes between miRNA signatures in the medial prefrontal cortex (mPFC) of our animal cohort and circulating miRNA levels in our human cohort, which allowed us to identify several miRNAs of potential interest in the development of this disorder. Tough decoy (TuD) inhibition of miRNA-29c-3p in the mouse mPFC promoted persistence of the response and enhanced vulnerability to developing food addiction, whereas miRNA-665-3p inhibition promoted compulsion-like behavior and also enhanced food addiction vulnerability. In contrast, we found that miRNA-137-3p inhibition in the mPFC did not lead to the development of food addiction. Therefore, miRNA-29c-3p and miRNA-665-3p could be acting as protective factors with regard to food addiction. We believe the elucidation of these epigenetic mechanisms will lead to advances toward identifying innovative biomarkers and possible future interventions for food addiction and related disorders based on the strategies now available to modify miRNA activity and expression.
Computational Analysis of Cholangiocarcinoma Phosphoproteomes Identifies Patient-Specific Drug Targets
Authors: Shirin Elizabeth Khorsandi, Arran D. Dokal, Vinothini Rajeeve, David J. Britton, Megan S. Illingworth, Nigel Heaton, Pedro R. Cutillas
Journal: Cancer Research (2021)

Abstract Cholangiocarcinoma is a form of hepatobiliary cancer with an abysmal prognosis. Despite advances in our understanding of cholangiocarcinoma pathophysiology and its genomic landscape, targeted therapies have not yet made a significant impact on its clinical management. The low response rates of targeted therapies in cholangiocarcinoma suggest that patient heterogeneity contributes to poor clinical outcome. Here we used mass spectrometry–based phosphoproteomics and computational methods to identify patient-specific drug targets in patient tumors and cholangiocarcinoma-derived cell lines. We analyzed 13 primary tumors of patients with cholangiocarcinoma with matched nonmalignant tissue and 7 different cholangiocarcinoma cell lines, leading to the identification and quantification of more than 13,000 phosphorylation sites. The phosphoproteomes of cholangiocarcinoma cell lines and patient tumors were significantly correlated. MEK1, KIT, ERK1/2, and several cyclin-dependent kinases were among the protein kinases most frequently showing increased activity in cholangiocarcinoma relative to nonmalignant tissue. Application of the Drug Ranking Using Machine Learning (DRUML) algorithm selected inhibitors of histone deacetylase (HDAC; belinostat and CAY10603) and PI3K pathway members as high-ranking therapies to use in primary cholangiocarcinoma. The accuracy of the computational drug rankings based on predicted responses was confirmed in cell-line models of cholangiocarcinoma. Together, this study uncovers frequently activated biochemical pathways in cholangiocarcinoma and provides a proof of concept for the application of computational methodology to rank drugs based on efficacy in individual patients. Significance: Phosphoproteomic and computational analyses identify patient-specific drug targets in cholangiocarcinoma, supporting the potential of a machine learning method to predict personalized therapies.
Aggressive intraoperative warming versus routine thermal management during non-cardiac surgery (PROTECT): a multicentre, parallel group, superiority trial
Authors: Daniel I Sessler, Lijian Pei, Kai Li, Shusen Cui, Matthew T V Chan, Yuguang Huang, Jingxiang Wu, Xuemei He, Gausan R Bajracharya, Eva Rivas, Carmen K M Lam, Kai Li, Shusen Cui, Yaozhong Zhang, Hai Sun, Zhouting Hu, Wangyu Li, Yangdong Han, Wei Han, Pengcheng Zhao, Hong Ye, Peng Chen, Zhihua Zhu, Weisong Dai, Lei Jin, Wenchao Bian, Yan Liu, Matthew T V Chan, Beaker B Y Fung, Eva Lee, Ka Yan Hui, Gordon Y S Choi, Wai Tat Wong, Chee Sam Chan, Lijian Pei, Yuguang Huang, Yi Xiao, Bin Wu, Weiming Kang, Ling Lan, Chen Sun, Jingxiang Wu, Yuwei Qiu, Wei Tang, Yunyun Zhang, Qi Huang, Xiaofei Lu, Tingting Li, Qimeng Yu, Jie Yu, Xuemei He, Rurong Wang, Hong Chang, Yunxia Zuo, Zhirong Sun, Wenting Hou, Congxia Pan, Xi Liu, Xue Zhang, Sheng Wang, Yin Kang, Zhengliang Ma, Xiaoping Gu, Changhong Miao, Daniel I Sessler, Eva Rivas, Gausan R Bajracharya, Mauro Bravo, Andrea Kurz, Alparslan Turan, Kurt Ruetzler, Kamal Maheshwari, Guangmei Mao, Yanyan Han, Ece Yamak Altinpulluk, Mateo Montalvo Compana, Federico Almonacid-Cardenas, Steve M Leung, CeCelia K Hanline, David M Chelnick, Marianne Tanios, Michael Walters, Michael J Rosen, Stephanie Ezoke, Edward J Mascha, Carmen K M Lam, Benny C P Cheng, Renee P L Yip, P J Devereaux
Journal: The Lancet (2022)
Duodenal Ulcer-Induced Gastric Outlet Obstruction Showing Pyloric Wall Thickening and Abnormal FDG Uptake Mimicking Malignancy
Authors: Xia Ji, Aisheng Dong
Journal: Clinical Nuclear Medicine (2022)

Abstract Peptic ulcer disease is the most common benign cause of gastric outlet obstruction, in which mechanical obstruction occurs in the distal stomach, pylorus, or duodenum. We describe a case of gastric outlet obstruction induced by duodenal ulcer showing irregular pyloric wall thickening with marked enhancement on contras-enhanced CT and increased FDG uptake of the pyloric wall on FDG PET/CT mimicking malignancy.
Biologic Therapies for Severe Asthma
Authors: Guy G. Brusselle, Gerard H. Koppelman
Journal: New England Journal of Medicine (2022)

Patients with severe asthma are at increased risk for a decreased quality of life, fixed airway obstruction, hospitalization, and death. Biologics may be required to reduce the disease burden. This review discusses the mechanisms, efficacy, and safety of biologics for severe asthma.
The Peptide–Drug Conjugate Melflufen Modulates the Unfolded Protein Response of Multiple Myeloma and Amyloidogenic Plasma Cells and Induces Cell Death
Authors: Ken Flanagan, Romika Kumari, Juho J. Miettinen, Staci L. Haney, Michelle L. Varney, Jacob T. Williams, Muntasir M. Majumder, Minna Suvela, Ana Slipicevic, Fredrik Lehmann, Nina N. Nupponen, Sarah A. Holstein, Caroline A. Heckman
Journal: HemaSphere (2022)

Immunoglobulin light-chain (AL) amyloidosis is a rare disease caused by clonal plasma cell secretion of misfolded light chains that assemble as toxic amyloid fibrils, depositing in vital organs including the heart and kidneys, causing organ dysfunction. Plasma cell-directed therapeutics are expected to reduce production of toxic light chain by eliminating amyloidogenic cells in bone marrow, thereby diminishing amyloid fibril deposition and providing the potential for organ recovery. Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly releases alkylating agents inside tumor cells. Melflufen is highly lipophilic, permitting rapid uptake by cells, where it is enzymatically hydrolyzed by aminopeptidases, resulting in intracellular accumulation of the alkylating agents, including melphalan. Previous data demonstrating sensitivity of myeloma cells to melflufen suggest that the drug might be useful in AL amyloidosis. We describe the effects of melflufen on amyloidogenic plasma cells in vitro and ex vivo, demonstrating enhanced cytotoxic effects in comparison to melphalan, as well as novel mechanisms of action through the unfolded protein response (UPR) pathway. These findings provide evidence that melflufen-mediated cytotoxicity extends to amyloidogenic plasma cells, and support the rationale for the evaluation of melflufen in patients with AL amyloidosis.
Avoidable research waste in dermatology: what are the solutions?
Authors: H.C. Williams
Journal: British Journal of Dermatology (2022)

In the last editorial, I provided examples of research waste in dermatology and suggested that it was due to a system failure rather than just a few "bad apples". Here, I focus on possible solutions, mainly in relation to clinical trials, building on examples from work at the Centre of Evidence-Based Dermatology (CEBD) and other research groups.
Efficacy and safety of oral immunotherapy in children aged 1–3 years with peanut allergy (the Immune Tolerance Network IMPACT trial): a randomised placebo-controlled study
Authors: Stacie M Jones, Edwin H Kim, Kari C Nadeau, Anna Nowak-Wegrzyn, Robert A Wood, Hugh A Sampson, Amy M Scurlock, Sharon Chinthrajah, Julie Wang, Robert D Pesek, Sayantani B Sindher, Mike Kulis, Jacqueline Johnson, Katharine Spain, Denise C Babineau, Hyunsook Chin, Joy Laurienzo-Panza, Rachel Yan, David Larson, Tielin Qin, Don Whitehouse, Michelle L Sever, Srinath Sanda, Marshall Plaut, Lisa M Wheatley, A Wesley Burks
Journal: The Lancet (2022)
Regulation of feeding and therapeutic application of bioactive peptides
Authors: Hiroaki Ueno, Weidong Zhang, Masamitsu Nakazato
Journal: Pharmacology & Therapeutics (2022)

Obesity and obesity-related diseases, such as diabetes mellitus and dyslipidemia, are worldwide pandemics; therefore, studies have been conducted energetically to elucidate the mechanism of obesity and develop anti-obesity drugs. Robust progress in the peptide chemistry and molecular biology has identified many peptides that regulate appetite and energy metabolism over the past dozen years. Several drugs, such as analogs or receptor agonists of anorectic peptides, have been developed. Overall, peptide-related drugs have powerful anti-obesity effects with fewer adverse effects than previous anti-obesity drugs. Liraglutide, a glucagon-like peptide-1 receptor agonist, was first used as an antidiabetic drug, and then high-dose liraglutide was used as an anti-obesity drug. Several candidates have been developed to explore their anti-obesity effects. Additionally, hybrid peptides consisting of two or more peptide sequences with strong anorectic effects have been designed. Here, we review peptides that are important for feeding regulation in terms of their mechanisms of action, interactions, and clinical application as anti-obesity drugs.
Abstract P011: Blood Pressure Postural Changes Variability Is Associated With Cognitive Decline: The S.ages Cohort
Authors: Strumia Mathilde, Jean-Sébastien Vidal, Olivier Hanon, Laure Rouch
Journal: Circulation (2022)

Introduction: Over the past decade, higher blood pressure (BP) variability has been associated with cognitive decline (CD). To date, only one study investigated the specific impact of visit-to-visit BP postural changes variability on dementia but its association with cognition is still unknown. We aimed to investigate the association between BP postural changes variability and cognitive function in noninstitutionalized subjects aged ≥ 65 years. Methods: The S.AGES (Sujets Å;gés) cohort followed for three years noninstitutionalized subjects aged ≥ 65 years without major neurocognitive impairment at inclusion. At each visit, an orthostatic systolic BP (SBP) ratio was calculated using the formula (sitting SBP/standing SBP) x 100. An orthostatic diastolic BP ratio was computed using the same method. Subjects with a SBP ratio &gt; 100% had sitting SBP &gt; standing SBP. We assessed the visit-to-visit BP postural changes variability according to several indicators: standard deviation, coefficient of variation (CV), variation independent of mean, residual standard deviation, average real variability, and successive variation. Cognitive performances were evaluated using the Mini-Mental State Examination. Linear mixed models were used for the analyses. Results: We included 2,974 subjects (mean age 78 years, women 56%). After adjustment for age, sex, education, baseline body mass index, smoking, alcohol intake, atrial fibrillation, congestive heart failure, transient ischemic attack or stroke, coronary artery disease, type 2 diabetes, dyslipidemia, seated SBP/DBP and antihypertensive treatment, greater visit-to-visit systolic BP postural changes variability was significantly associated with CD over time (adjusted β [95% CI] = -0.17 [-0.29; -0.06], p= 0.004 for CV). Similar results were found for visit-to-visit diastolic BP postural changes variability (adjusted β [95% CI] = -0.14 [-0.25; -0.03], p= 0.017 for CV). Conclusion: Greater visit-to-visit BP postural changes variability was associated with CD. Further studies are needed to assess whether controlling orthostatic BP instability over time could be a promising interventional target to preserve cognition among older adults.