tbuckley/cabot-search huggingface dataset:
Metoprolol in Critically Ill Patients With COVID-19
Authors: Agustín Clemente-Moragón, Juan Martínez-Milla, Eduardo Oliver, Arnoldo Santos, Javier Flandes, Iker Fernández, Lorena Rodríguez-González, Cristina Serrano del Castillo, Ana-María Ioan, María López-Álvarez, Sandra Gómez-Talavera, Carlos Galán-Arriola, Valentín Fuster, César Pérez-Calvo, Borja Ibáñez
Journal: Journal of the American College of Cardiology (2021)

Severe coronavirus disease-2019 (COVID-19) can progress to an acute respiratory distress syndrome (ARDS), which involves alveolar infiltration by activated neutrophils. The beta-blocker metoprolol has been shown to ameliorate exacerbated inflammation in the myocardial infarction setting. The purpose of this study was to evaluate the effects of metoprolol on alveolar inflammation and on respiratory function in patients with COVID-19–associated ARDS. A total of 20 COVID-19 patients with ARDS on invasive mechanical ventilation were randomized to metoprolol (15 mg daily for 3 days) or control (no treatment). All patients underwent bronchoalveolar lavage (BAL) before and after metoprolol/control. The safety of metoprolol administration was evaluated by invasive hemodynamic and electrocardiogram monitoring and echocardiography. Metoprolol administration was without side effects. At baseline, neutrophil content in BAL did not differ between groups. Conversely, patients randomized to metoprolol had significantly fewer neutrophils in BAL on day 4 (median: 14.3 neutrophils/µl [Q1, Q3: 4.63, 265 neutrophils/µl] vs median: 397 neutrophils/µl [Q1, Q3: 222, 1,346 neutrophils/µl] in the metoprolol and control groups, respectively; P = 0.016). Metoprolol also reduced neutrophil extracellular traps content and other markers of lung inflammation. Oxygenation (PaO2:FiO2) significantly improved after 3 days of metoprolol treatment (median: 130 [Q1, Q3: 110, 162] vs median: 267 [Q1, Q3: 199, 298] at baseline and day 4, respectively; P = 0.003), whereas it remained unchanged in control subjects. Metoprolol-treated patients spent fewer days on invasive mechanical ventilation than those in the control group (15.5 ± 7.6 vs 21.9 ± 12.6 days; P = 0.17). In this pilot trial, intravenous metoprolol administration to patients with COVID-19–associated ARDS was safe, reduced exacerbated lung inflammation, and improved oxygenation. Repurposing metoprolol for COVID-19–associated ARDS appears to be a safe and inexpensive strategy that can alleviate the burden of the COVID-19 pandemic.
Utilizing machine learning to improve clinical trial design for acute respiratory distress syndrome
Authors: E. Schwager, K. Jansson, A. Rahman, S. Schiffer, Y. Chang, G. Boverman, B. Gross, M. Xu-Wilson, P. Boehme, H. Truebel, J. J. Frassica
Journal: npj Digital Medicine (2021)

Abstract Heterogeneous patient populations, complex pharmacology and low recruitment rates in the Intensive Care Unit (ICU) have led to the failure of many clinical trials. Recently, machine learning (ML) emerged as a new technology to process and identify big data relationships, enabling a new era in clinical trial design. In this study, we designed a ML model for predictively stratifying acute respiratory distress syndrome (ARDS) patients, ultimately reducing the required number of patients by increasing statistical power through cohort homogeneity. From the Philips eICU Research Institute (eRI) database, no less than 51,555 ARDS patients were extracted. We defined three subpopulations by outcome: (1) rapid death, (2) spontaneous recovery, and (3) long-stay patients. A retrospective univariate analysis identified highly predictive variables for each outcome. All 220 variables were used to determine the most accurate and generalizable model to predict long-stay patients. Multiclass gradient boosting was identified as the best-performing ML model. Whereas alterations in pH, bicarbonate or lactate proved to be strong predictors for rapid death in the univariate analysis, only the multivariate ML model was able to reliably differentiate the disease course of the long-stay outcome population (AUC of 0.77). We demonstrate the feasibility of prospective patient stratification using ML algorithms in the by far largest ARDS cohort reported to date. Our algorithm can identify patients with sufficiently long ARDS episodes to allow time for patients to respond to therapy, increasing statistical power. Further, early enrollment alerts may increase recruitment rate.
Long-Term Symptoms Among Adults Tested for SARS-CoV-2 — United States, January 2020–April 2021
Authors: Valentine Wanga, Jennifer R. Chevinsky, Lina V. Dimitrov, Megan E. Gerdes, Geoffrey P. Whitfield, Robert A. Bonacci, Miriam A.M. Nji, Alfonso C. Hernandez-Romieu, Jessica S. Rogers-Brown, Tim McLeod, Julie Rushmore, Caitlyn Lutfy, Dena Bushman, Emilia Koumans, Sharon Saydah, Alyson B. Goodman, Sallyann M. Coleman King, Brendan R. Jackson, Jennifer R. Cope
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

Abbreviations: CI = confidence interval; N/A = not applicable.* p-value for weighted Wald chi-square test; all p-values <0.05 indicate significant differences.† Unweighted number of persons who received positive or negative SARS-CoV-2 test results.§ 189 of 698 respondents who received a positive test result and 961 of 2,437 respondents who received a negative test result reported receiving 1 dose of vaccine.¶ Respondents who ever experienced a long-term symptom and received at least 1 vaccine dose.** Includes those reporting receiving a vaccine made symptoms a lot better, somewhat better, or a little better.† † Includes those reporting receiving a vaccine made symptoms a little worse, somewhat worse, or a lot worse.
Simultaneous targeting of TGF-β/PD-L1 synergizes with radiotherapy by reprogramming the tumor microenvironment to overcome immune evasion
Authors: Yan Lan, Mahmoud Moustafa, Maximilian Knoll, Chunxiao Xu, Jennifer Furkel, Adam Lazorchak, Tsz-Lun Yeung, Sayed-Mohammad Hasheminasab, Molly H. Jenkins, Sarah Meister, Huakui Yu, Julian Schlegel, Bo Marelli, Zili Tang, Guozhong Qin, Carmen Klein, Jin Qi, Cheng Zhou, George Locke, Damir Krunic, Melissa G. Derner, Christian Schwager, Rachel E. Fontana, Katharina Kriegsmann, Feng Jiang, Katrin Rein, Mark Kriegsmann, Juergen Debus, Kin-Ming Lo, Amir Abdollahi
Journal: Cancer Cell (2021)

Localized radiotherapy (RT) induces an immunogenic antitumor response that is in part counterbalanced by activation of immune evasive and tissue remodeling processes, e.g., via upregulation of programmed cell death-ligand 1 (PD-L1) and transforming growth factor β (TGF-β). We report that a bifunctional fusion protein that simultaneously inhibits TGF-β and PD-L1, bintrafusp alfa (BA), effectively synergizes with radiotherapy, leading to superior survival in multiple therapy-resistant murine tumor models with poor immune infiltration. The BA + RT (BART) combination increases tumor-infiltrating leukocytes, reprograms the tumor microenvironment, and attenuates RT-induced fibrosis, leading to reconstitution of tumor immunity and regression of spontaneous lung metastases. Consistently, the beneficial effects of BART are in part reversed by depletion of cytotoxic CD8+ T cells. Intriguingly, targeting of the TGF-β trap to PD-L1+ endothelium and the M2/lipofibroblast-like cell compartment by BA attenuated late-stage RT-induced lung fibrosis. Together, the results suggest that the BART combination has the potential to eradicate therapy-resistant tumors while sparing normal tissue, further supporting its clinical translation.
Authors’ response: Efficacy and effectiveness of COVID-19 vaccines against SARS-CoV-2 infection: More data on asymptomatic SARS-CoV-2 infection
Authors: Thomas Harder, Judith Koch, Sabine Vygen-Bonnet, Wiebe Külper-Schiek, Antonia Pilic, Sarah Reda, Stefan Scholz, Ole Wichmann
Journal: Eurosurveillance (2021)

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Spatiofunctional Dynamics of NKX3.1 to Safeguard the Prostate from Cancer
Authors: Andrew J. Finch, Esther Baena
Journal: Cancer Discovery (2021)

Abstract Summary: A novel role of NKX3.1 in the mitochondria regulating the transcription of the electron transport chain components is reported. Mechanistically, HSPA9 chaperones NKX3.1 into the mitochondria in response to oxidative stress to regulate reactive oxygen species and suppress tumor initiation. See related article by Papachristodoulou et al., p. 2316.
Associations between exposure to landscape fire smoke and child mortality in low-income and middle-income countries: a matched case-control study
Authors: Tao Xue, Guannan Geng, Jiajianghui Li, Yiqun Han, Qian Guo, Frank J Kelly, Martin J Wooster, Huiyu Wang, Bahabaike Jiangtulu, Xiaoli Duan, Bin Wang, Tong Zhu
Journal: The Lancet Planetary Health (2021)

BackgroundThe prevalence of landscape fires has increased, particularly in low-income and middle-income countries (LMICs). We aimed to assess the impact of exposure to landscape fire smoke (LFS) on the health of children.MethodsWe conducted a sibling-matched case-control study and selected 552 155 children (aged <18 years) from Demographic and Health Surveys in 55 LMICs from 2000 to 2014. Each deceased child was matched with their sibling(s). The exposure indicators were fire-sourced PM2·5 and dry-matter emissions. We associated these exposure indicators with child mortality using conditional regressions, and derived an exposure–response function using a non-linear model. Based on the association, we quantified the global burden of fire-attributable child deaths in LMICs from 2000 to 2014.FindingsEach 1 μg/m3 increment of fire-sourced PM2·5 was associated with a 2·31% (95% CI 1·50–3·13) increased risk of child mortality. The association was robust to different models. The exposure–response function was superlinear and suggested per-unit exposure to larger fires was more toxic. Based on our non-linear exposure–response function, we estimated that between 2000 and 2014, the five countries with the largest number of child deaths associated with fire-sourced PM2·5 were Nigeria (164 000 [126 000 to 209 000] annual deaths), Democratic Republic of the Congo (126 000 [95% CI 114 000 to 139 000] annual deaths), India (65 900 [−22 200 to 147 000] annual deaths), Uganda (30 200 [24 500 to 36 300] annual deaths), and Indonesia (28 900 [19 100 to 38 400]).InterpretationExposure to landscape fire smoke contributes substantially to the global burden of child mortality.FundingNational Natural Science Foundation of China, Ministry of Science and Technology of China, Peking University, UK National Institute for Health Research Health Protection Research Unit, Leverhulme Center for Wildfires, Environment and Society, and National Environment Research Council National Capability funding to National Centre for Earth Observation and Energy Foundation.
Residential exposure to transportation noise in Denmark and incidence of dementia: national cohort study
Authors: Manuella Lech Cantuaria, Frans Boch Waldorff, Lene Wermuth, Ellen Raben Pedersen, Aslak Harbo Poulsen, Jesse Daniel Thacher, Ole Raaschou-Nielsen, Matthias Ketzel, Jibran Khan, Victor H Valencia, Jesper Hvass Schmidt, Mette Sørensen
Journal: BMJ (2021)

Abstract Objective To investigate the association between long term residential exposure to road traffic and railway noise and risk of incident dementia. Design Nationwide prospective register based cohort study. Setting Denmark. Participants 1 938 994 adults aged ≥60 years living in Denmark between 1 January 2004 and 31 December 2017. Main outcome measures Incident cases of all cause dementia and dementia subtypes (Alzheimer’s disease, vascular dementia, and Parkinson’s disease related dementia), identified from national hospital and prescription registries. Results The study population included 103 500 participants with incident dementia, and of those, 31 219 received a diagnosis of Alzheimer’s disease, 8664 of vascular dementia, and 2192 of Parkinson’s disease related dementia. Using Cox regression models, 10 year mean exposure to road traffic and railway noise at the most (L den max) and least (L den min) exposed façades of buildings were associated with a higher risk of all cause dementia. These associations showed a general pattern of higher hazard ratios with higher noise exposure, but with a levelling off or even small declines in risk at higher noise levels. In subtype analyses, both road traffic noise and railway noise were associated with a higher risk of Alzheimer’s disease, with hazard ratios of 1.16 (95% confidence interval 1.11 to 1.22) for road L den max ≥65 dB compared with &lt;45 dB, 1.27 (1.22 to 1.34) for road L den min ≥55 dB compared with &lt;40 dB, 1.16 (1.10 to 1.23) for railway L den max ≥60 dB compared with &lt;40 dB, and 1.24 (1.17 to 1.30) for railway L den min ≥50 dB compared with &lt;40 dB. Road traffic, but not railway, noise was associated with an increased risk of vascular dementia. Results indicated associations between road traffic L den min and Parkinson’s disease related dementia. Conclusions This nationwide cohort study found transportation noise to be associated with a higher risk of all cause dementia and dementia subtypes, especially Alzheimer’s disease.
Simultaneous inhibition of breast cancer and its liver and lung metastasis by blocking inflammatory feed-forward loops
Authors: Zhengze Lu, Yang Long, Jiaxin Li, Jiaxin Li, Kebai Ren, Wei Zhao, Xuhui Wang, Chunyu Xia, Yashi Wang, Man Li, Zhirong Zhang, Qin He
Journal: Journal of Controlled Release (2021)
Clinical Activity of Ripretinib in Patients with Advanced Gastrointestinal Stromal Tumor Harboring Heterogeneous <i>KIT/PDGFRA</i> Mutations in the Phase III INVICTUS Study
Authors: Sebastian Bauer, Michael C. Heinrich, Suzanne George, John R. Zalcberg, César Serrano, Hans Gelderblom, Robin L. Jones, Steven Attia, Gina D'Amato, Ping Chi, Peter Reichardt, Julie Meade, Ying Su, Rodrigo Ruiz-Soto, Jean-Yves Blay, Margaret von Mehren, Patrick Schöffski
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Most patients with gastrointestinal stromal tumor (GIST) have activating mutations in KIT/PDGFRA and are initially responsive to tyrosine kinase inhibitors (TKI). The acquisition of secondary mutations leads to refractory/relapsed disease. This study reports the results of an analysis from the phase III INVICTUS study (NCT03353753) characterizing the genomic heterogeneity of tumors from patients with advanced GIST and evaluating ripretinib efficacy across KIT/PDGFRA mutation subgroups. Patients and Methods: Tumor tissue and liquid biopsy samples that captured circulating tumor DNA were collected prior to study enrollment and sequenced using next-generation sequencing. Subgroups were determined by KIT/PDGFRA mutations and correlation of clinical outcomes and KIT/PDGFRA mutational status was assessed. Results: Overall, 129 patients enrolled (ripretinib 150 mg once daily, n = 85; placebo, n = 44). The most common primary mutation subgroup detected by combined tissue and liquid biopsies were in KIT exon 11 (ripretinib, 61.2%; placebo, 77.3%) and KIT exon 9 (ripretinib, 18.8%; placebo, 15.9%). Patients receiving ripretinib demonstrated progression-free survival (PFS) benefit versus placebo regardless of mutation status (HR 0.16) and in all assessed subgroups in Kaplan–Meier PFS analysis (exon 11, P &amp;lt; 0.0001; exon 9, P = 0.0023; exon 13, P &amp;lt; 0.0001; exon 17, P &amp;lt; 0.0001). Among patients with wild-type KIT/PDGFRA by tumor tissue, PFS ranged from 2 to 23 months for ripretinib versus 0.9 to 10.1 months for placebo. Conclusions: Ripretinib provided clinically meaningful activity across mutation subgroups in patients with advanced GIST, demonstrating that ripretinib inhibits a broad range of KIT/PDGFRA mutations in patients with advanced GIST who were previously treated with three or more TKIs.
Exogenous inter-α inhibitor proteins prevent cell death and improve ischemic stroke outcomes in mice
Authors: Louise D. McCullough, Meaghan Roy-O’Reilly, Yun-Ju Lai, Anthony Patrizz, Yan Xu, Juneyoung Lee, Aleah Holmes, Daniel C. Kraushaar, Anjali Chauhan, Lauren H. Sansing, Barbara S. Stonestreet, Liang Zhu, Julia Kofler, Yow-Pin Lim, Venugopal Reddy Venna
Journal: Journal of Clinical Investigation (2021)

Inter-α inhibitor proteins (IAIPs) are a family of endogenous plasma and extracellular matrix molecules. IAIPs suppress proinflammatory cytokines, limit excess complement activation, and bind extracellular histones to form IAIP-histone complexes, leading to neutralization of histone-associated cytotoxicity in models of sepsis. Many of these detrimental processes also play critical roles in the pathophysiology of ischemic stroke. In this study, we first assessed the clinical relevance of IAIPs in stroke and then tested the therapeutic efficacy of exogenous IAIPs in several experimental stroke models. IAIP levels were reduced in both ischemic stroke patients and in mice subjected to experimental ischemic stroke when compared with controls. Post-stroke administration of IAIP significantly improved stroke outcomes across multiple stroke models, even when given 6 hours after stroke onset. Importantly, the beneficial effects of delayed IAIP treatment were observed in both young and aged mice. Using targeted gene expression analysis, we identified a receptor for complement activation, C5aR1, that was highly suppressed in both the blood and brain of IAIP-treated animals. Subsequent experiments using C5aR1-knockout mice demonstrated that the beneficial effects of IAIPs are mediated in part by C5aR1. These results indicate that IAIP is a potential therapeutic candidate for the treatment of ischemic stroke.
P-128 Influence of anti-diabetic medications on the outcomes of patients with pancreatic ductal adenocarcinoma and type 2 diabetes mellitus
Authors: A. Pretta, G. Pinna, C. Donisi, M. Persano, E. Cimbro, A. Parrino, M. Migliari, M. Dubois, N. Liscia, S. Mariani, E. Lai, V. Pusceddu, M. Puzzoni, P. Ziranu, M. Scartozzi
Journal: Annals of Oncology (2021)
Effective tools for RNA-derived therapeutics: siRNA interference or miRNA mimicry
Authors: Peipei Wang, Yue Zhou, Arthur M Richards
Journal: Theranostics (2021)

The approval of the first small interfering RNA (siRNA) drug Patisiran by FDA in 2018 marks a new era of RNA interference (RNAi) therapeutics. MicroRNAs (miRNA), an important post-transcriptional gene regulator, are also the subject of both basic research and clinical trials. Both siRNA and miRNA mimics are ~21 nucleotides RNA duplexes inducing mRNA silencing. Given the well performance of siRNA, researchers ask whether miRNA mimics are unnecessary or developed siRNA technology can pave the way for the emergence of miRNA mimic drugs. Through comprehensive comparison of siRNA and miRNA, we focus on (1) the common features and lessons learnt from the success of siRNAs; (2) the unique characteristics of miRNA that potentially offer additional therapeutic advantages and opportunities; (3) key areas of ongoing research that will contribute to clinical application of miRNA mimics. In conclusion, miRNA mimics have unique properties and advantages which cannot be fully matched by siRNA in clinical applications. MiRNAs are endogenous molecules and the gene silencing effects of miRNA mimics can be regulated or buffered to ameliorate or eliminate off-target effects. An in-depth understanding of the differences between siRNA and miRNA mimics will facilitate the development of miRNA mimic drugs.
BI08: Remote management of immunotherapy‐induced bullous pemphigoid during the COVID‐19 pandemic
Journal: British Journal of Dermatology (2021)

Sj€ ogren syndrome (OR 0Á39, 95% CI 0Á22-0Á71) and AIDS was associated with lower odds of mixed connective tissue disorder (OR 0Á12, 95% CI 0Á05-0Á28).While the association between other systemic diseases and HIV/AIDS is well established, there is a lack of large studies investigating RSSs in HIV/AIDS.Our study provides data regarding the prevalence of RSSs in HIV/AIDS and identifies lower odds for multiple RSSs in PLWHA.Future studies are needed to investigate the mechanisms underlying these findings, as well as to establish the role of factors such as CD4 count and HAART in favouring or preventing the development of RSS in HIV/AIDS.
Pregnancy, delivery and neonatal complications in women with schizophrenia: a national population-based cohort study
Authors: Cyprien FABRE, Vanessa PAULY, Karine BAUMSTARCK, Damien ETCHECOPAR-ETCHART, Veronica ORLEANS, Pierre-Michel LLORCA, Julie BLANC, Christophe LANCON, Pascal AUQUIER, Laurent BOYER, Guillaume FOND
Journal: The Lancet Regional Health - Europe (2021)

Existing studies evaluating the association between schizophrenia and complications associated with pregnancy, delivery and neonatal outcomes are based on data prior to 2014 and have reported heterogeneous results. The objective of our study was to determine whether pregnant women with schizophrenia were at increased risk of pregnancy, delivery and neonatal complications compared with women without severe mental disorders. We performed a population-based cohort study of all singleton deliveries in France between Jan. 1, 2015, and Dec. 31, 2019. We divided this population into cases (i.e., women with schizophrenia) and controls (i.e., women without a diagnosis of severe mental disorder). Cases and controls were matched (1:4) inside the same hospital and the same year by age, social deprivation, parity, smoking, alcohol and substance addictions, malnutrition, obesity, and comorbidities. Univariate and multivariate models with odds ratios and 95% confidence intervals (ORs [95% CIs]) were used to estimate the association between schizophrenia and 24 pregnancy, delivery and neonatal outcomes. Over 5 years, 3,667,461 singleton deliveries were identified, of which 3,108 occurred in women with schizophrenia. Compared to controls, women with schizophrenia were found to be older; have more frequent smoking, alcohol and substance addictions; suffer from obesity, diabetes and chronic obstructive pulmonary disease; and often be hospitalized in tertiary maternity hospitals. Compared to matched controls, women with schizophrenia had more pregnancy complications (adjusted OR=1.41[95%CI 1.31-1.51]) (i.e., gestational diabetes, gestational hypertension, genito-urinary infection, intrauterine growth retardation and threatened preterm labour). They had more delivery complications (aOR=1.18[95%CI 1.09 1.29]) with more still births/medical abortions (aOR=2.17[95%CI 1.62-2.90]) and caesarean sections (aOR=1.15[95%CI 1.05-1.25]). Newborns of women with schizophrenia had more neonatal complications (aOR=1.38[95%CI 1.27-1.50]) with more born preterm (aOR=1.64[95%CI1.42 -1.90]), small for gestational age (aOR=1.34[95%CI 1.19-1.50]) and low birth weight (aOR=1.75[95%CI 1.53-2.00]). Our results highlight the importance of health disparities between pregnant women with and without schizophrenia, as well as in their newborns. Our study calls for health policy interventions during and before pregnancy, including proportionate intensified care to the level of needs, effective case management and preventive and social determinant approaches. No funding.