tbuckley/cabot-search huggingface dataset:
Lymphatic drainage from bronchus-associated lymphoid tissue in tolerant lung allografts promotes peripheral tolerance
Authors: Wenjun Li, Jason M. Gauthier, Alice Y. Tong, Yuriko Terada, Ryuji Higashikubo, Christian C. Frye, Margaret S. Harrison, Kohei Hashimoto, Amit I. Bery, Jon H. Ritter, Ruben G. Nava, Varun Puri, Brian W. Wong, Kory J. Lavine, Ankit Bharat, Alexander S. Krupnick, Andrew E. Gelman, Daniel Kreisel
Journal: Journal of Clinical Investigation (2020)

Tertiary lymphoid organs are aggregates of immune and stromal cells including high endothelial venules and lymphatic vessels that resemble secondary lymphoid organs and can be induced at nonlymphoid sites during inflammation. The function of lymphatic vessels within tertiary lymphoid organs remains poorly understood. During lung transplant tolerance, Foxp3+ cells accumulate in tertiary lymphoid organs that are induced within the pulmonary grafts and are critical for the local downregulation of alloimmune responses. Here, we showed that tolerant lung allografts could induce and maintain tolerance of heterotopic donor-matched hearts through pathways that were dependent on the continued presence of the transplanted lung. Using lung retransplantation, we showed that Foxp3+ cells egressed from tolerant lung allografts via lymphatics and were recruited into donor-matched heart allografts. Indeed, survival of the heart allografts was dependent on lymphatic drainage from the tolerant lung allograft to the periphery. Thus, our work indicates that cellular trafficking from tertiary lymphoid organs regulates immune responses in the periphery. We propose that these findings have important implications for a variety of disease processes that are associated with the induction of tertiary lymphoid organs.
Abstract 15305: Gastric Ulcer Perforation Mimicking Inferoposterior ST Elevation Myocardial Infarction on Electrocardiogram
Authors: Amar Doshi, Sumon Roy, Zackary Tushak, Bharadhwaj Kolipakkam, Zachary Gertz, Richard K Shepard
Journal: Circulation (2020)

Introduction: ST elevation myocardial infarction (STEMI) and gastric perforation are emergencies with progressively higher mortality without emergent intervention. Here we present a case of gastric ulcer perforation presenting as an apparent inferoposterior STEMI. Case: A 63-year-old male with hypertension presented with two days of intermittent abdominal pain. While awaiting imaging, the patient developed acute inferoposterior STEMI (figure 1). In route to the cardiac catheterization lab, abdominal CT was emergently reported as gastric ulcer perforation (figure 2). Incorporating multidisciplinary discussions with the cardiac critical care attending, interventionalist, and surgeon, exploratory laparotomy was pursued instead of cardiac catheterization, and the perforation was repaired. Repeat EKG after surgery showed resolution of ST elevations (figure 3) and serial troponins were negative. With no evidence of coronary ischemia, further workup was deferred. Conclusion: The unique aspects of this case include how an acute intra-abdominal process can mimic an inferoposterior STEMI and a rapid multidisciplinary approach to decision-making facing two potential concurrent emergencies that was potentially life-saving.
Mitigating toxic stress in children affected by conflict and displacement
Authors: Anushka Ataullahjan, Muthanna Samara, Theresa S Betancourt, Zulfiqar A Bhutta
Journal: BMJ (2020)

Anushka Ataullahjan and colleagues describe the myriad stressors related to conflict and displacement experienced by children and how best to reduce their negative effect Armed conflict and displacement pose a threat to the health and wellbeing of children. As the global community begins to recognize the cumulative effects of conflict and displacement related stressors, our attention has shifted to toxic stress and its short and long term health effects.1 Toxic stress, regarded as the result of prolonged activation of the stress response, can occur before birth and during childhood is known to contribute to epigenetic changes, with health and neurodevelopmental consequences.2 However, various social factors and early and appropriate intervention can help mitigate the negative effects.3 Over 415 million children were living in conflict affected countries in 2018,4 including 33 million displaced children (16 million refugees and asylum seekers, and 17 million internally displaced children).5 Although all children are vulnerable to toxic stress, certain subgroups are particularly vulnerable because of their marginalization—for example, orphaned or unaccompanied children, girls, children with HIV infection, and children with developmental disorders or a disability. These groups may face additional stressors and have reduced access to services. The emergence of covid-19 has also raised concerns about spread in conflict affected populations adding to the risk of toxic stress (box 1). Box 1 ### Covid-19 in humanitarian settings Conflict affected populations are particularly vulnerable to covid-19. Overcrowding and inadequate water and sanitation systems in refugee camps and informal settlements, coupled with previously existing illnesses, may increase the spread and severity of covid-19.67 Moreover, resource and health system constraints may restrict access to adequate and appropriate care.67 Control measures such as physical distancing may be difficult and may also increase economic precarity, intimate partner violence, and food insecurity in populations already vulnerable because of … RETURN TO TEXT
HUMAN PLURIPOTENT STEM CELL DERIVED HEPATIC PLATFORMS TO STUDY SARS-COV-2 INFECTION
Authors: V. Chandar, B. E. Nilsson-Payant, V. Gupta, L. Yang, Y. Bram, D. Nguyen, M. Cioffi, B. R. TenOever, S. Chen, R. E. Schwartz
Journal: Hepatology (2020)

Background: COVID-19 was declared a pandemic by the World Health Organization, caused by severe acute respiratory syndrome corona-virus 2 (SARS-CoV-2) Respiratory failure is the most common mortality outcome in COVID-19 patients, yet serious and even fatal manifestations are seen across multiple organ systems Emerging clinical data from our own hospital revealed a high prevalence of initial presentations with GI manifestations Almost one third of patients presenting to our hospital reported at least one gastrointestinal manifestation including nausea, vomiting, diarrhea, or abdominal pain 62% of patients presented with biochemical evidence of liver injury Moreover, the presence of liver injury on presentation was associated with a significantly higher risk of ICU admission and death As this is a new and novel clinical entity, robust in vitro models that phenocopy SARS-CoV-2 infection and human COVID-19 disease are limited Current in vitro (e g Vero cells) and in vivo models (mouse models engineered with ACE2) are so distinct from human infection that they may not capture key components of viral infection or virus-host interactions Therefore, the development of robust human models of COVID-19 infection will be essential for the study of SARS-Cov-2 viral infection and to identify robust SARS-CoV-2 therapeutics Methods: Human pluripotent stem cells (hPSCs), including human embryonic stem cells hESCs) and induced pluripotent stem cells (hiPSCs), can be used to derive functional human cells/tissues/organoids for modeling human disease and drug discovery, including for infectious diseases Here we leveraged several stem cell platforms (e g endodermal lineages including hepatocyte and cholangiocyte) along with primary human hepatocytes and cholangiocyte organoid systems to study SARS-CoV-2 infection SARS-CoV-2 pseudoparticles were used to study SARS-CoV-2 viral entry SARS-CoV-2 (USA-WA1/2020) was used to validate viral infection and to study cellular response Autopsy liver samples from COVID-19 patients were obtained and compared to SARS-CoV-2 infected liver models Results: Adult hepatocyte and cholangiocyte organoids along with PSC derived hepatocytes and cholangiocytes are Permissive to SARS-CoV-2 virus infection and show similar transcriptome changes and chemokine responses for SARSCoV- 2 infection as seen in autopsy samples from COVID-19 Patients Conclusion: We report here the development of robust models of SARS-CoV-2 infection in primary and PSC derived hepatocyte and cholangiocytes which phenocopy COVID-19 hepatic disease These disease-relevant human cell/organoid-based platforms can be directly applied for drug screening and the evaluation of prospective antiviral therapeutics as well be used to delineate molecular mechanisms underlying COVID-19 disease
The Social Context of Religion in the Jurisdictions of Bioethics
Authors: John H. Evans
Journal: The American Journal of Bioethics (2020)

This article refers to:There’s No Harm in Talking: Re-Establishing the Relationship Between Theological and Secular BioethicsPurely Faith-Based vs. Rationally-Informed Theological BioethicsPluralism in the Jewish Ethical TraditionPublic Reason as the Way for Dialogue“‘There’s No Harm in Talking’…True…But It Depends on How We Talk and What We Then Do”Community, Complicity, and Critique: Christian Concepts in Secular BioethicsTalking at Cross Purposes: Why We Shouldn’t Re-Establish the Relationship Between Theological and Secular BioethicsTheorizing Religion in Its Meanings for Bioethics
Abstract 15641: Fever. The True Unmasker of My Disease
Authors: Gerardo Zablah, Rosario A Colombo
Journal: Circulation (2020)

Introduction: The most common etiology of sudden cardiac death (SCD) from ventricular tachyarrhythmias (VTA) is an acute ischemic event from coronary artery disease (CAD; followed by genetic syndromes, including Brugada Syndrome (BS). The presentation of SCD with an ECG showing RBBB pattern with ST segment elevation (STSE) in leads V1-V3 in healthy patients and in the absence electrolyte imbalances, CAD, or structural heart disease is known as BS. It can be triggered by abundant meals, excessive alcohol intake, cocaine, local anesthetics, tricyclic antidepressants, lithium, propofol and fevers. Case Presentation: 29 y/o woman presenting with atypical chest pain, malaise, and a remote history of a syncopal episode. She denied family history of SCD. She was febrile to 100.4 o F, tachycardic, with regular heart sounds and no murmurs. Laboratory work up was normal. ECG from two years ago showed nonspecific interventricular conduction delay. ECG on admission showed STSE in anterior precordial leads which disappeared with resolution of her fever. Due to the Brugada-like pattern in her ECG and remote history of syncope, AICD placement was recommended. Flecainide challenge was not pursued, since the patient was amenable to AICD. Genetic counseling and testing were provided to her family members. Discussion: Most patients with BS are healthy adults between 30-40 y/o without significant medical history. A defect in the sodium channel SCN5A, results in a loss of homogeneity in the myocardial action potential. This mutant channel may be exaggerated when exposed to supraphysiologic temperatures, unmasking BS and elevating the risk of VTA and SCD. BS is carried through generations in an autosomal dominant fashion. Medical management alone is ineffective and not recommended. AICD is the only effective treatment for prevention of SCD. Conclusion: BS is an identifiable and preventable cause of death. In patients presenting with multiple syncopal episodes or aborted VTA’s, in the absence of significant cardiovascular history, and with known or equivocal family history of SCD, the diagnosis of BS must be considered. Health providers across all practice settings should have the skill of identifying its clinical and ECG presentation in order to decrease the rate of SCD.
Deferring a Change in the Standard of Care for Small Cell Lung Cancer Brain Metastases—Reply
Authors: Chad G. Rusthoven, Paul D. Brown, Tyler P. Robin
Journal: JAMA Oncology (2020)

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Mental Health–Related Emergency Department Visits Among Children Aged &lt;18 Years During the COVID-19 Pandemic — United States, January 1–October 17, 2020
Authors: Rebecca T. Leeb, Rebecca H. Bitsko, Lakshmi Radhakrishnan, Pedro Martinez, Rashid Njai, Kristin M. Holland
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

Published reports suggest that the coronavirus disease 2019 (COVID-19) pandemic has had a negative effect on children's mental health (1,2). Emergency departments (EDs) are often the first point of care for children experiencing mental health emergencies, particularly when other services are inaccessible or unavailable (3). During March 29-April 25, 2020, when widespread shelter-in-place orders were in effect, ED visits for persons of all ages declined 42% compared with the same period in 2019; during this time, ED visits for injury and non-COVID-19-related diagnoses decreased, while ED visits for psychosocial factors increased (4). To assess changes in mental health-related ED visits among U.S. children aged <18 years, data from CDC's National Syndromic Surveillance Program (NSSP) from January 1 through October 17, 2020, were compared with those collected during the same period in 2019. During weeks 1-11 (January 1-March 15, 2020), the average reported number of children's mental health-related ED visits overall was higher in 2020 than in 2019, whereas the proportion of children's mental health-related visits was similar. Beginning in week 12 (March 16) the number of mental health-related ED visits among children decreased 43% concurrent with the widespread implementation of COVID-19 mitigation measures; simultaneously, the proportion of mental health-related ED visits increased sharply beginning in mid-March 2020 (week 12) and continued into October (week 42) with increases of 24% among children aged 5-11 years and 31% among adolescents aged 12-17 years, compared with the same period in 2019. The increased proportion of children's mental health-related ED visits during March-October 2020 might be artefactually inflated as a consequence of the substantial decrease in overall ED visits during the same period and variation in the number of EDs reporting to NSSP. However, these findings provide initial insight into children's mental health in the context of the COVID-19 pandemic and highlight the importance of continued monitoring of children's mental health throughout the pandemic, ensuring access to care during public health crises, and improving healthy coping strategies and resiliency among children and families.
Abstract 15390: Outcomes in Patients Hospitalized With Influenza-related Myocarditis in the United States: A Nationwide Study
Authors: Uwajachukwumma A Uzomah, Pegah Khaloo, Ayman Shaqdan, Pablo A Ledesma, Jennifer Galvin, Leon Ptaszek, Jeremy N Ruskin
Journal: Circulation (2020)

Introduction: Acute myocarditis is a serious complication of influenza. While current reports suggest that subclinical cardiac involvement may be transient, myocarditis has been implicated in up to a third of sudden deaths in patients with influenza. Methods: Patients hospitalized with influenza in the US between 2003 and 2017 were identified using the Nationwide Inpatients Sample. They were subsequently classified to specify those with and without a diagnosis of myocarditis and specific outcomes of interest were compared between these subgroups. Results: : Between 2003 and 2017, 1,187,615 patients were hospitalized with influenza in the US. Of these, 2,430 patients (0.2%) were diagnosed with myocarditis while 1,185,185 patients (99.8%) did not have myocarditis. Patient characteristics and outcomes are shown in the table below. Independent predictors of myocarditis were: age (adjusted odds ratio [aOR]:0.98; 95% CI:0.98-0.99), male sex (aOR:1.21 ; 95% CI:1.01-1.46), Elixhauser score ≥3 (aOR:1.34; 95% CI:1.07-1.7), coagulopathy (aOR:1.67; 95% CI:1.29-2.17), valvular disease (aOR:1.5; 95% CI:1.07-2.1), abnormal weight loss (aOR:1.7; 95% CI:1.23-2.35), and a diagnosis of the 2009 H1N1 influenza virus (aOR:4.79; 95% CI:1.51-15.24). Independent predictors of death in patients hospitalized with influenza myocarditis were: age (aOR:1.04; 95% CI:1.01-1.06), stroke (aOR:11.16; 95% CI:1.57-79.49), shock (aOR:61.1; 95% CI:11.88-314.3), renal failure (aOR:3.56; 95% CI:1.2 -10.55), coagulopathy (aOR:2.62; 95% CI:1.04-6.6), and electrolyte disorders (aOR:3.19; 95% CI:1.07-9.47). Conclusions: Patients with influenza who develop myocarditis are younger than those without myocarditis and have more interventions, longer LOS and worse outcomes including a four-fold higher risk of cardiac arrest and a two-fold higher mortality rate. The strongest independent predictor of developing myocarditis was having the 2009 H1N1 influenza virus infection.
Abstract PO-063: Regulatory T cells regulate fibroblast differentiation during pancreatic carcinogenesis
Authors: Yaqing Zhang, Katelyn L. Donahue, Wei Yan, Zeribe C. Nwosu, Kristee L. Brown, Sion Yang, Howard C. Crawford, Costas A. Lyssiotis, Timothy L. Frankel, Filip Bednar, Marina Pasca di Magliano
Journal: Cancer Research (2020)

Abstract Pancreatic ductal adenocarcinoma (PDA) is characterized by an extensive fibrotic stroma, which includes vascular elements, infiltrating immune cells, extracellular matrix and a large number of fibroblasts. The tumor microenvironment as a whole has been believed to be immunosuppressive. However, how different cell populations within the stroma contribute to the establishment of the immunosuppression is not fully understood. We sought to investigate the crosstalk between cancer cells, fibroblasts and immune cells within pancreatic cancer with the goal to identify novel targets for PDA treatment. Targeting regulatory T cell (Treg), which acts to suppress immune responses, is considered as one potential approach to relieve the immunosuppression of pancreatic cancer. However, we previously showed that Treg depletion in a genetically engineered mouse model of pancreatic cancer (KC;Foxp3DTR) failed to relieve immunosuppression and led to accelerated tumor progression. We discovered that Treg depletion reprogramed the fibroblast population, with loss of tumor-restraining, smooth muscle actin-expressing fibroblasts. Conversely, Treg depletion resulted in differentiation of inflammatory fibroblast subsets with an increase in chemokines Ccl3, Ccl6, and Ccl8. To fully understand the contribution of Tregs to pancreatic carcinogenesis, we performed single-cell RNA-sequencing (scRNA-seq) with Pancreatic intraepithelial neoplasia (PanIN) from KC mouse and Treg depleted PanIN lesions from KC;Foxp3DTR mouse. scRNA-seq allows us to address cell type identification and heterogeneity of cell responses by unsupervised clustering, which uncovered dramatic differences in several stromal cell populations including fibroblast, CD4 T cell and macrophage subsets between the KC and KC;Foxp3DTR pancreata. We have expanded list of genes that are regulated in tumor associated fibroblasts upon Treg depletion through scRNA-seq. For example, Il33 was one of down-regulated genes in fibroblasts upon Treg depletion. We also obtained potential ligands/receptors interactions between tumor cells, fibroblasts and immune cells through interactome analysis. Our data describe an unexpected crosstalk between Tregs and fibroblasts and point to new mechanisms regulating fibroblast differentiation in pancreatic cancer. Citation Format: Yaqing Zhang, Katelyn L. Donahue, Wei Yan, Zeribe C. Nwosu, Kristee L. Brown, Sion Yang, Howard C. Crawford, Costas A. Lyssiotis, Timothy L. Frankel, Filip Bednar, Marina Pasca di Magliano. Regulatory T cells regulate fibroblast differentiation during pancreatic carcinogenesis [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-063.
Reducing bias and improving transparency in medical research: a critical overview of the problems, progress and suggested next steps
Authors: Stephen H Bradley, Nicholas J DeVito, Kelly E Lloyd, Georgia C Richards, Tanja Rombey, Cole Wayant, Peter J Gill
Journal: Journal of the Royal Society of Medicine (2020)

In recent years there has been increasing awareness of problems that have undermined trust in medical research. This review outlines some of the most important issues including research culture, reporting biases, and statistical and methodological issues. It examines measures that have been instituted to address these problems and explores the success and limitations of these measures. The paper concludes by proposing three achievable actions which could be implemented to deliver significantly improved transparency and mitigation of bias. These measures are as follows: (1) mandatory registration of interests by those involved in research; (2) that journals support the ‘registered reports’ publication format; and (3) that comprehensive study documentation for all publicly funded research be made available on a World Health Organization research repository. We suggest that achieving such measures requires a broad-based campaign which mobilises public opinion. We invite readers to feedback on the proposed actions and to join us in calling for their implementation.