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  1. Article ; Online: Uncovering interpretable potential confounders in electronic medical records

    Jiaming Zeng / Michael F. Gensheimer / Daniel L. Rubin / Susan Athey / Ross D. Shachter

    Nature Communications, Vol 13, Iss 1, Pp 1-

    2022  Volume 14

    Abstract: Randomized clinical trials are often plagued by selection bias, and expert-selected covariates may insufficiently adjust for confounding factors. Here, the authors develop a framework based on natural language processing to uncover interpretable ... ...

    Abstract Randomized clinical trials are often plagued by selection bias, and expert-selected covariates may insufficiently adjust for confounding factors. Here, the authors develop a framework based on natural language processing to uncover interpretable potential confounders from text.
    Keywords Science ; Q
    Language English
    Publishing date 2022-02-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: The Association Between Alpha-1 Adrenergic Receptor Antagonists and In-Hospital Mortality From COVID-19

    Liam Rose / Laura Graham / Allison Koenecke / Michael Powell / Ruoxuan Xiong / Zhu Shen / Brett Mench / Kenneth W. Kinzler / Chetan Bettegowda / Bert Vogelstein / Susan Athey / Joshua T. Vogelstein / Maximilian F. Konig / Todd H. Wagner

    Frontiers in Medicine, Vol

    2021  Volume 8

    Abstract: Effective therapies for coronavirus disease 2019 (COVID-19) are urgently needed, and pre-clinical data suggest alpha-1 adrenergic receptor antagonists (α1-AR antagonists) may be effective in reducing mortality related to hyperinflammation independent of ... ...

    Abstract Effective therapies for coronavirus disease 2019 (COVID-19) are urgently needed, and pre-clinical data suggest alpha-1 adrenergic receptor antagonists (α1-AR antagonists) may be effective in reducing mortality related to hyperinflammation independent of etiology. Using a retrospective cohort design with patients in the Department of Veterans Affairs healthcare system, we use doubly robust regression and matching to estimate the association between baseline use of α1-AR antagonists and likelihood of death due to COVID-19 during hospitalization. Having an active prescription for any α1-AR antagonist (tamsulosin, silodosin, prazosin, terazosin, doxazosin, or alfuzosin) at the time of admission had a significant negative association with in-hospital mortality (relative risk reduction 18%; odds ratio 0.73; 95% CI 0.63–0.85; p ≤ 0.001) and death within 28 days of admission (relative risk reduction 17%; odds ratio 0.74; 95% CI 0.65–0.84; p ≤ 0.001). In a subset of patients on doxazosin specifically, an inhibitor of all three alpha-1 adrenergic receptors, we observed a relative risk reduction for death of 74% (odds ratio 0.23; 95% CI 0.03–0.94; p = 0.028) compared to matched controls not on any α1-AR antagonist at the time of admission. These findings suggest that use of α1-AR antagonists may reduce mortality in COVID-19, supporting the need for randomized, placebo-controlled clinical trials in patients with early symptomatic infection.
    Keywords COVID-19 ; coronavirus disease ; alpha-1-adrenergic receptor antagonist ; infectious disease ; off-label drug use ; Medicine (General) ; R5-920
    Subject code 610
    Language English
    Publishing date 2021-03-01T00:00:00Z
    Publisher Frontiers Media S.A.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article: Alpha-1 adrenergic receptor antagonists prevent acute respiratory distress syndrome and death: implications for Coronavirus disease 2019

    Joshua Vogelstein T. / Michael Powell / Allison Koenecke / Ruoxuan Xiong / Nicole Fischer / Sakibul Huq / Adham Khalafallah M. / Nickolas Papadopoulos / Kenneth Kinzler W. / Bert Vogelstein / Shibin Zhou / Chetan Bettegowda / Maximilian Konig F. / Brett Mensh / Susan Athey

    Abstract: In Coronavirus disease 2019 (COVID-19), the initial viral replication phase is often followed by a hyperinflammatory reaction in the lungs and other organ systems ('cytokine storm syndrome') that leads to acute respiratory distress syndrome (ARDS), multi- ...

    Abstract In Coronavirus disease 2019 (COVID-19), the initial viral replication phase is often followed by a hyperinflammatory reaction in the lungs and other organ systems ('cytokine storm syndrome') that leads to acute respiratory distress syndrome (ARDS), multi-organ failure, and death - despite maximal supportive care. Preventing hyperinflammation is key to avoiding progression to severe stages of COVID-19. We have previously demonstrated that alpha-1 adrenergic receptor ($\\alpha_1$-AR) antagonists can prevent cytokine storm syndrome and resulting death in mice. Here, we present a retrospective study of outcomes in patients with acute respiratory distress (n = 13,125) or pneumonia (n = 108,956). Patients with acute respiratory distress who were taking $\\alpha_1$-AR antagonists for other conditions had a 35% reduced risk of requiring ventilation, and a 56% reduced risk of ventilation and death, compared to non-users (adjusted OR = 0.41, 95% CI 0.17-0.81, p = 0.01). By contrast, no significant effect was observed for beta-adrenergic receptor ($\\beta$-AR) antagonists. These results support studying $\\alpha_1$-AR antagonists for preventing ARDS and reducing mortality in pneumonia and acute respiratory distress, as well as highlight the need for prospective trials of $\\alpha_1$-AR antagonists to assess their efficacy in preventing cytokine storm syndrome and death in COVID-19.
    Keywords covid19
    Publisher arxiv
    Document type Article
    Database COVID19

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  4. Article ; Online: Targeting the catecholamine-cytokine axis to prevent SARS-CoV-2 cytokine storm syndrome

    Maximilian F Konig / Mike Powell / Verena Staedtke / Ren-Yuan Bai / David L Thomas / Nicole Fischer / Sakibul Huq / Adham M Khalafallah / Allison Koenecke / Nickolas Papadopoulos / Kenneth W Kinzler / Bert Vogelstein / Joshua T Vogelstein / Susan Athey / Shibin Zhou / Chetan Bettegowda

    Abstract: The mortality of Coronavirus disease 2019 (COVID-19) appears to be driven by acute respiratory distress syndrome (ARDS) and a dysregulated immune response to SARS-CoV-2. Emerging evidence suggests that a subset of COVID-19 is characterized by the ... ...

    Abstract The mortality of Coronavirus disease 2019 (COVID-19) appears to be driven by acute respiratory distress syndrome (ARDS) and a dysregulated immune response to SARS-CoV-2. Emerging evidence suggests that a subset of COVID-19 is characterized by the development of a cytokine storm syndrome (CSS), and interleukin (IL)-6 levels are predictors of COVID-19 severity and in-hospital mortality. Targeting hyper-inflammation in COVID-19 may be critical for reducing mortality. Catecholamines enhance inflammatory injury by augmenting the production of IL-6 and other cytokines through a self-amplifying feed-forward loop in immune cells that requires alpha-1 adrenergic receptor (α1-AR) signaling. Prophylactic inhibition of catecholamine synthesis with the α1-AR antagonist prazosin reduced catecholamines and cytokine responses in mice, and resulted in markedly increased survival following various hyper-inflammatory stimuli. These findings offer a rationale for studying α1-AR antagonists in the prophylaxis of patients with COVID-19-CSS and ARDS. As high infection rates threaten to overwhelm hospital capacity during this pandemic, preventative approaches that ameliorate COVID-19 severity and reduce excessive mortality are desperately needed. We hypothesize that treatment with prazosin of individuals who test positive for SARS-CoV-2 could reduce catecholamine surges, secondary cytokine dysregulation, and mortality. To investigate a potential role for α1-AR antagonists in preventing poor outcomes in ARDS, we conducted a retrospective analysis of hospitalized patients diagnosed with ARDS. Using data from the Truven Health MarketScan Research Database (2010-2017), we identified 12,673 men (age 45-64) with ARDS, of whom 1,189 patients (9.4%) were prescribed α1-AR antagonists in the previous year. Applying logistic regression models, we found that patients with prior use of α1-AR antagonists had lower odds of the composite of need for invasive mechanical ventilation and mortality compared to non-users (AOR 0.80, 95% CI 0.69-0.94, p=0.008). Mirroring findings from pre-clinical models, these data support a clinical rationale to study α1-AR antagonists in the prophylaxis of ARDS and states of local and systemic immune dysregulation. Prospective, randomized clinical trials of alpha-1 receptor antagonists (e.g. prazosin) administered prior to the onset of severe symptoms are needed to assess their efficacy in preventing CSS and reducing mortality in COVID-19.
    Keywords covid19
    Publisher medrxiv
    Document type Article ; Online
    DOI 10.1101/2020.04.02.20051565
    Database COVID19

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  5. Article ; Online: Alpha-1 adrenergic receptor antagonists to prevent hyperinflammation and death from lower respiratory tract infection

    Allison Koenecke / Michael Powell / Ruoxuan Xiong / Zhu Shen / Nicole Fischer / Sakibul Huq / Adham M Khalafallah / Marco Trevisan / Pär Sparen / Juan J Carrero / Akihiko Nishimura / Brian Caffo / Elizabeth A Stuart / Renyuan Bai / Verena Staedtke / David L Thomas / Nickolas Papadopoulos / Ken W Kinzler / Bert Vogelstein /
    Shibin Zhou / Chetan Bettegowda / Maximilian F Konig / Brett D Mensh / Joshua T Vogelstein / Susan Athey

    eLife, Vol

    2021  Volume 10

    Abstract: In severe viral pneumonia, including Coronavirus disease 2019 (COVID-19), the viral replication phase is often followed by hyperinflammation, which can lead to acute respiratory distress syndrome, multi-organ failure, and death. We previously ... ...

    Abstract In severe viral pneumonia, including Coronavirus disease 2019 (COVID-19), the viral replication phase is often followed by hyperinflammation, which can lead to acute respiratory distress syndrome, multi-organ failure, and death. We previously demonstrated that alpha-1 adrenergic receptor (⍺1-AR) antagonists can prevent hyperinflammation and death in mice. Here, we conducted retrospective analyses in two cohorts of patients with acute respiratory distress (ARD, n = 18,547) and three cohorts with pneumonia (n = 400,907). Federated across two ARD cohorts, we find that patients exposed to ⍺1-AR antagonists, as compared to unexposed patients, had a 34% relative risk reduction for mechanical ventilation and death (OR = 0.70, p = 0.021). We replicated these methods on three pneumonia cohorts, all with similar effects on both outcomes. All results were robust to sensitivity analyses. These results highlight the urgent need for prospective trials testing whether prophylactic use of ⍺1-AR antagonists ameliorates lower respiratory tract infection-associated hyperinflammation and death, as observed in COVID-19.
    Keywords observational study ; causal inference ; respiratory disease ; infectious disease ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Subject code 610
    Language English
    Publishing date 2021-06-01T00:00:00Z
    Publisher eLife Sciences Publications Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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