tbuckley/cabot-search huggingface dataset:
COVID-19 infection in kidney transplant recipients
Authors: Debasish Banerjee, Joyce Popoola, Sapna Shah, Irina Chis Ster, Virginia Quan, Mysore Phanish
Journal: Kidney International (2020)

By 21 March 2020 infections related to the novel coronavirus SARS-CoV-2 had affected people from 177 countries and caused 11,252 reported deaths worldwide. Little is known about risk, presentation and outcomes of SARS-CoV-2 (COVID-19) infection in kidney transplantation recipients, who may be at high-risk due to long-term immunosuppression, comorbidity and residual chronic kidney disease. Whilst COVID-19 is predominantly a respiratory disease, in severe cases it can cause kidney and multi-organ failure. It is unknown if immunocompromised hosts are at higher risk of more severe systemic disease. Therefore, we report on seven cases of COVID-19 in kidney transplant recipients (median age 54 (range 45-69), three females, from a cohort of 2082 managed transplant follow-up patients) over a six-week period in three south London hospitals. Two of seven patients presented within three months of transplantation. Overall, two were managed on an out-patient basis, but the remaining five required hospital admission, four in intensive care units. All patients displayed respiratory symptoms and fever. Other common clinical features included hypoxia, chest crepitation, lymphopenia and high C-reactive protein. Very high D dimer, ferritin and troponin levels occurred in severe cases and likely prognostic. Immunosuppression was modified in six of seven patients. Three patients with severe disease were diabetic. During a three week follow up one patient recovered, and one patient died. Thus, our findings suggest COVID-19 infection in kidney transplant patients may be severe, requiring intensive care admission. The symptoms are predominantly respiratory and associated with fever. Most patients had their immunosuppression reduced and were treated with supportive therapy.
Poor functional performance 1 year after ACL reconstruction increases the risk of early osteoarthritis progression
Authors: Brooke Patterson, Adam Geoffrey Culvenor, Christian J Barton, Ali Guermazi, Joshua Stefanik, Hayden G Morris, Timothy S Whitehead, Kay M Crossley
Journal: British Journal of Sports Medicine (2020)

Background Not meeting functional performance criteria increases reinjury risk after ACL reconstruction (ACLR), but the implications for osteoarthritis are not well known. Objective To determine if poor functional performance post-ACLR is associated with risk of worsening early osteoarthritis features, knee symptoms, function and quality of life (QoL). Methods Seventy-eight participants (48 men) aged 28±15 years completed a functional performance test battery (three hop tests, one-leg-rise) 1 year post-ACLR. Poor functional performance was defined as &lt;90% limb symmetry index (LSI) on each test. At 1 and 5 years, MRI, Knee injury Osteoarthritis Outcome Score (KOOS) and International Knee Documentation Committee (IKDC) subjective form were completed. Primary outcomes were: (i) worsening patellofemoral and tibiofemoral MRI-osteoarthritis features (cartilage, bone marrow lesions (BMLs) and meniscus) and (ii) change in KOOS and IKDC scores, between 1 and 5 years. Results Only 14 (18%) passed (≥90% LSI on all tests) the functional test battery. Poor functional performance on the battery (all four tests &lt;90% LSI) 1 year post-ACLR was associated with 3.66 times (95% CI 1.12 to 12.01) greater risk of worsening patellofemoral BMLs. A triple-crossover hop &lt;90% LSI was associated with 2.09 (95% CI 1.15 to 3.81) times greater risk of worsening patellofemoral cartilage. There was generally no association between functional performance and tibiofemoral MRI-osteoarthritis features, or KOOS/IKDC scores. Conclusion Only one in five participants met common functional performance criteria (≥90% LSI all four tests) 1 year post-ACLR. Poor function on all four tests was associated with a 3.66 times increased risk of worsening patellofemoral BMLs, and generally not associated with decline in self-reported outcomes.
The dilemma of differentiating between acute hepatitis B and chronic hepatitis B with acute exacerbation: Is quantitative serology the answer?
Authors: Sujata Lall, Pragya Agarwala, Guresh Kumar, Manoj Kumar Sharma, Ekta Gupta
Journal: Clinical and Molecular Hepatology (2020)

Background/Aims: Acute exacerbations of chronic hepatitis B (CHB-AEs) are common in endemic areas and are often presumed to be acute hepatitis B (AHB) due to their similarities in clinical and serological pictures, presenting a major diagnostic dilemma. This study aimed to identify laboratory markers for differentiating between the two groups, and to establish the cut-off value for significant markers.&lt;br/&gt;Methods: A retrospective analysis of records was conducted for patients who presented with clinical features of acute hepatitis along with hepatitis B surface antigen (HBsAg) and IgM antibody to hepatitis B core antigen (IgM anti-HBc) positivity from May 2015 to May 2017. A total of 172 patients were enrolled and grouped as AHB (n=89) and CHB-AE (n=83) based on their history of hepatitis B virus infection and duration of HBsAg persistence. Virological and biochemical parameters were analyzed and compared. Cut-off values, sensitivity, and specificity of the variables were calculated.&lt;br/&gt;Results: The median value of signal by cut-off (S/Co) ratio for IgM anti-HBc was significantly higher in AHB group (30.44) compared to CHB-AE group (8.63) with a sensitivity and specificity of 97% and 84%, respectively, at a cut-off of 20.5 (P&lt;0.01). The mean international normalized ratio (INR) was significantly greater in CHB-AE (1.88±1.24) group compared to AHB group (1.62±0.17) with a sensitivity and specificity of 57.9% and 45.1%, respectively, at a cut-off value of 1.27.&lt;br/&gt;Conclusions: A value of 20.5 S/Co of IgM anti-HBc and 1.27 INR could be helpful in differentiating between AHB and CHB-AE. (Clin Mol Hepatol 2020;26:187-195)
PEX5, a novel target of microRNA-31-5p, increases radioresistance in hepatocellular carcinoma by activating Wnt/β-catenin signaling and homologous recombination
Authors: Jie Wen, Kai Xiong, Abudureyimujiang Aili, Hao Wang, Yuequan Zhu, Zhengquan Yu, Xueyan Yao, Ping Jiang, Lixiang Xue, Junjie Wang
Journal: Theranostics (2020)

Rationale: Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide, with high recurrence and metastasis rates. Although radiation is an effective treatment for tumors, it is often limited by intrinsic radioresistance in HCC. The contributions of dysregulated microRNAs, including miR-31-5p, to HCC progression have been recently reported. However, the role of miR-31-5p in the radiation response of HCC is unknown. In this study, we aimed to investigate the impact of miR-31-5p on HCC radiosensitivity. Methods: miR-31-5p expression in HCC tissues, paired adjacent tissues, and HCC cell lines was measured using quantitative real-time polymerase chain reaction and in situ hybridization. Bioinformatic analyses, gain- and loss-of-function experiments, and luciferase reporter assays were performed to validate peroxisomal biogenesis factor 5 (PEX5) as a direct target of miR-31-5p. The biofunctions of PEX5 and miR-31-5p in HCC were determined by Transwell, wound-healing, and Cell Counting Kit-8 (CCK8) assays. A colony formation assay was used to evaluate the radiosensitivity of HCC cells. The interaction among PEX5, β-catenin, Rac1, and JNK-2 was confirmed by coimmunoprecipitation. A xenograft tumor model was established to validate the effects of miR-31-5p and PEX5 on HCC progression and radiosensitivity in vivo.Results: Low expression of miR-31-5p in HCC specimens, as observed in this study, predicted a poor clinical outcome. However, the expression pattern of PEX5, as a direct target of miR-31-5p, was opposite that of miR-31-5p, and high PEX5 expression indicated poor prognosis in HCC patients. Ectopic expression of PEX5 increased the proliferation, migration, and invasion abilities and enhanced the radioresistance of HCC cells in vitro and in vivo; however, these phenotypes were inhibited by miR-31-5p. Mechanistically, PEX5 stabilized cytoplasmic β-catenin and facilitated β-catenin nuclear translocation to activate Wnt/β-catenin signaling. Moreover, upon radiation exposure, PEX5 reduced excessive reactive oxygen species (ROS) accumulation and activated the homologous recombination (HR) pathway, which protected HCC cells from radiation-induced damage. Conclusions: Our findings demonstrated a novel role for PEX5 as a miR-31-5p target and a mediator of the Wnt/β-catenin signaling and HR pathways, providing new insights into studying HCC radiation responses and implicating PEX5 and miR-31-5p as potential therapeutic targets in HCC.
Health Care Spending by Enrollees With Substance Use and Mental Health Disorders in High-Deductible Health Plans vs Traditional Plans
Authors: Matthew D. Eisenberg, Shawn Du, Aditi P. Sen, Alene Kennedy-Hendricks, Colleen L Barry
Journal: JAMA Psychiatry (2020)

Discussion | This analysis found that FES is associated with reduced criminality.The low overall prevalence of convictions in this sample was reassuring but limited detection of group differences.Nevertheless, allocation to STEP reduced subsequent and first-time convictions and was less than levels in a larger European trial. 3Putative mechanisms include STEP's improvement of vocational functioning, 4 which is associated with reduced youth criminality, 5 and reduction of psychiatric hospitalizations, 4 which disrupt work and school functioning but may also signal reductions in episodes of behavioral dysregulation that can result in arrests. 6However, these speculations need to be tested against more granular information about the circumstances of each arrest.Such replication with a larger sample and more comprehensive (eg, adding juvenile, jail diversion, and department of corrections data) databases is urgently needed to inform service design and policy.
A Humanized Lym-1 CAR with Novel DAP10/DAP12 Signaling Domains Demonstrates Reduced Tonic Signaling and Increased Antitumor Activity in B-Cell Lymphoma Models
Authors: Long Zheng, Luqing Ren, Aida Kouhi, Leslie A. Khawli, Peisheng Hu, Harvey R. Kaslow, Alan L. Epstein
Journal: Clinical Cancer Research (2020)

Abstract Purpose: The murine Lym-1 mAb targets a discontinuous epitope (Lym-1 epitope) on several subtypes of HLA-DR, which is upregulated in a majority of human B-cell lymphomas and leukemias. Unlike CD19, the Lym-1 epitope does not downregulate upon crosslinking, which may provide an advantage as a target for CAR T-cell therapy. Lym-1 CAR T cells with a conventional 4-1BB and CD3ζ (BB3z) signaling domain exhibited impaired ex vivo expansion. This study aimed to identify the underlying mechanisms and develop strategies to overcome this effect. Experimental Design: A functional humanized Lym-1 antibody (huLym-1-B) was identified and its scFv form was used for CAR design. To overcome observed impaired expansion in vitro, a huLym-1-B CAR using DAP10 and DAP12 (DAP) signaling domains was evaluated for ex vivo expansion and in vivo function. Results: Impaired expansion in huLym-1-B-BB3z CAR T cells was shown to be due to ligand-dependent suboptimal CAR signaling caused by interaction of the CAR binding domain and the surface of human T cells. Using the novel DAP signaling domain construct, the effects of suboptimal CAR signaling were overcome to produce huLym-1-B CAR T cells with improved expansion ex vivo and function in vivo. In addition, the Lym-1 epitope does not significantly downregulate in response to huLym-1-B-DAP CAR T cells both ex vivo and in vivo. Conclusions: DAP intracellular domains can serve as signaling motifs for CAR, and this new construct enables nonimpaired production of huLym-1-B CAR T cells with potent in vivo antitumor efficacy.
The Science Underlying COVID-19
Authors: Peter P. Liu, Alice Blet, David Smyth, Hongliang Li
Journal: Circulation (2020)

The coronavirus disease 2019 (COVID-19) pandemic has affected health and economy worldwide on an unprecedented scale. Patients have diverse clinical outcomes, but those with preexisting cardiovascular disease, hypertension, and related conditions incur disproportionately worse outcome. The high infectivity of severe acute respiratory syndrome coronavirus 2 is in part related to new mutations in the receptor binding domain, and acquisition of a furin cleavage site in the S-spike protein. The continued viral shedding in the asymptomatic and presymptomatic individuals enhances its community transmission. The virus uses the angiotensin converting enzyme 2 receptor for internalization, aided by transmembrane protease serine 2 protease. The tissue localization of the receptors correlates with COVID-19 presenting symptoms and organ dysfunction. Virus-induced angiotensin converting enzyme 2 downregulation may attenuate its function, diminish its anti-inflammatory role, and heighten angiotensin II effects in the predisposed patients. Lymphopenia occurs early and is prognostic, potentially associated with reduction of the CD4+ and some CD8+ T cells. This leads to imbalance of the innate/acquired immune response, delayed viral clearance, and hyperstimulated macrophages and neutrophils. Appropriate type I interferon pathway activation is critical for virus attenuation and balanced immune response. Persistent immune activation in predisposed patients, such as elderly adults and those with cardiovascular risk, can lead to hemophagocytosis-like syndrome, with uncontrolled amplification of cytokine production, leading to multiorgan failure and death. In addition to the airways and lungs, the cardiovascular system is often involved in COVID-19 early, reflected in the release of highly sensitive troponin and natriuretic peptides, which are all extremely prognostic, in particular, in those showing continued rise, along with cytokines such as interleukin-6. Inflammation in the vascular system can result in diffuse microangiopathy with thrombosis. Inflammation in the myocardium can result in myocarditis, heart failure, cardiac arrhythmias, acute coronary syndrome, rapid deterioration, and sudden death. Aggressive support based on early prognostic indicators with expectant management can potentially improve recovery. Appropriate treatment for heart failure, arrhythmias, acute coronary syndrome, and thrombosis remain important. Specific evidence-based treatment strategies for COVID-19 will emerge with ongoing global collaboration on multiple approaches being evaluated. To protect the wider population, antibody testing and effective vaccine will be needed to make COVID-19 history.
Abstract 12092: Down-Regulation of the Velosin Containing Protein and Reduced Phosphorylation of Mitofusion-2 Protein Result in Abnormal Mitophagy in Left Ventricular Myocardium of Dogs With Heart Failure
Authors: Ramesh C Gupta, Vinita Singh-Gupta, Kefei Zhang, Hani N Sabbah
Journal: Circulation (2018)

Introduction: We previously showed that structural abnormalities of mitochondria (MITO) occur in cardiomyocytes of the failing human and canine heart and include hyperplasia, reduced organelle size...
Transcriptional Patterning of the Ventricular Cardiac Conduction System
Authors: Ozanna Burnicka-Turek, Michael T. Broman, Jeffrey D. Steimle, Bastiaan J. Boukens, Nataliya B. Petrenko, Kohta Ikegami, Rangarajan D. Nadadur, Yun Qiao, David E. Arnolds, Xinan H. Yang, Vickas V. Patel, Marcelo A. Nobrega, Igor R. Efimov, Ivan P. Moskowitz
Journal: Circulation Research (2020)

Rationale: The heartbeat is organized by the cardiac conduction system (CCS), a specialized network of cardiomyocytes. Patterning of the CCS into atrial node versus ventricular conduction system (VCS) components with distinct physiology is essential for the normal heartbeat. Distinct node versus VCS physiology has been recognized for more than a century, but the molecular basis of this regional patterning is not well understood. Objective: To study the genetic and genomic mechanisms underlying node versus VCS distinction and investigate rhythm consequences of failed VCS patterning. Methods and Results: Using mouse genetics, we found that the balance between T-box transcriptional activator, Tbx5 , and T-box transcriptional repressor, Tbx3 , determined the molecular and functional output of VCS myocytes. Adult VCS-specific removal of Tbx5 or overexpression of Tbx3 re-patterned the fast VCS into slow, nodal-like cells based on molecular and functional criteria. In these cases, gene expression profiling showed diminished expression of genes required for VCS-specific fast conduction but maintenance of expression of genes required for nodal slow conduction physiology. Action potentials of Tbx5 -deficient VCS myocytes adopted nodal-specific characteristics, including increased action potential duration and cellular automaticity. Removal of Tbx5 in vivo precipitated inappropriate depolarizations in the atrioventricular (His)-bundle associated with lethal ventricular arrhythmias. TBX5 bound and directly activated cis -regulatory elements at fast conduction channel genes required for fast physiological characteristics of the VCS action potential, defining the identity of the adult VCS. Conclusions: The CCS is patterned entirely as a slow, nodal ground state, with a T-box dependent, physiologically dominant, fast conduction network driven specifically in the VCS. Disruption of the fast VCS gene regulatory network allowed nodal physiology to emerge, providing a plausible molecular mechanism for some lethal ventricular arrhythmias.
Utility, Appropriateness, and Content of Electronic Consultations Across Medical Subspecialties
Authors: Salman Ahmed, Yvelynne P. Kelly, Tapas R. Behera, Michelle H. Zelen, Ifedayo Kuye, Ryan Blakey, Susan A. Goldstein, Jason H. Wasfy, Alistair Erskine, Adam Licurse, Mallika L. Mendu
Journal: Annals of Internal Medicine (2020)

Electronic consultations (e-consults) can facilitate patient access to specialists, minimize travel, and reduce unnecessary in-person visits. However, metrics to enable study of e-consults and their effect on processes and patient care are lacking.To assess novel metrics of e-consult appropriateness and utility.Retrospective cohort study.Primary and specialty care practices at 2 large academic and 2 community hospitals of an integrated health system.Patients with e-consult requests to 5 specialties-hematology, infectious disease, dermatology, rheumatology, and psychiatry-between October 2017 and November 2018.The appropriateness of e-consult inquiries was assessed by review of medical records and defined as meeting the following 4 criteria: not answerable by reviewing evidence-based summary sources ("point-of-care resource test"), not merely requesting logistic information, having appropriate clinical urgency, and having appropriate patient complexity. Interrater agreement in assessments of e-consult appropriateness was assessed by the κ statistic. Utility of e-consults was assessed by the rate of avoided visits (AVs), defined by the absence of an in-person visit to the same specialty within 120 days.Overall, 6512 eligible e-consults were made by 1096 referring providers to 121 specialist consultants. Inquiries were characterized as diagnostic, therapeutic, for provider education, or at the request of the patient. Most consultations were answered within 1 day, with variation across specialties (73.1% for psychiatry to 87.8% for infectious disease). Overall, 70.2% of e-consults met all 4 criteria for appropriateness; the frequency of unmet criteria varied among specialties. Raters agreed on the appropriateness of 94% of e-consults (κ = 0.57 [95% CI, 0.36 to 0.79]), indicating moderate agreement. The overall rate of AVs across the 5 specialties was 81.2%; the highest rate was in psychiatry (92.6%) and the lowest in dermatology (61.9%).Generalizability is unknown outside a single integrated health system, where requesting and consulting providers share a common electronic health record.Novel metrics to assess the appropriateness and utility of e-consults provide meaningful insight into practice, provide a rubric for comparison in future studies in additional settings, and suggest areas to improve resource use and patient care.None.
Associative and plastic thalamic signaling to the lateral amygdala controls fear behavior
Authors: Boglárka Barsy, Kinga Kocsis, Aletta Magyar, Ákos Babiczky, Mónika Szabó, Judit M. Veres, Dániel Hillier, István Ulbert, Ofer Yizhar, Ferenc Mátyás
Journal: Nature Neuroscience (2020)
Neuroinflammatory and Behavioral Outcomes Measured in Adult Offspring of Mice Exposed Prenatally to E-Cigarette Aerosols
Authors: Jamie S. Church, Fiona Chace-Donahue, Jason L. Blum, Jill R. Ratner, Judith T. Zelikoff, Jared J. Schwartzer
Journal: Environmental Health Perspectives (2020)

Background: In an effort to decrease the rates of smoking conventional tobacco cigarettes, electronic cigarettes (e-cigarettes) have been proposed as an effective smoking cessation tool. However, little is known about their toxicological impacts. This is concerning given that e-cigarette use is perceived as less harmful than conventional tobacco cigarettes during pregnancy for both the mother and fetus. Objective: The goal of this study was to test the neurodevelopmental consequences of maternal e-cigarette use on adult offspring behavior and neuroimmune outcomes. Methods: Pregnant female CD-1 mice were randomly assigned to one of three treatment groups (n=8–10 per group) and exposed daily to either filtered air, propylene glycol and vegetable glycerol (50:50 PG/VG vehicle), or to PG/VG with 16mg/mL nicotine (+Nic). Whole-body exposures were carried out for 3 h/d, 7 d/week, from gestational day (GD)0.5 until GD17.5. Adult male and female offspring (8 weeks old) were assessed across a battery of behavioral assessments followed by region-specific quantification of brain cytokines using multiplex immunoassays. Results: Adult offspring of both sexes exposed to +Nic exhibited elevated locomotor activity in the elevated plus maze and altered stress-coping strategies in the forced swim task. Moreover, male and female offspring exposed to PG/VG with and without nicotine had a 5.2% lower object discrimination score in the novel object recognition task. In addition to differences in offspring behavior, maternal e-cigarette exposure with nicotine led to a reduction in interleukin (IL)-4 and interferon-gamma (IFNγ) in the diencephalon, as well as lower levels of hippocampal IFNγ (females only). E-cigarette exposure without nicotine resulted in a 2-fold increase of IL-6 in the cerebellum. Discussion: These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067
Integrated Molecular and Clinical Analysis of 1,000 Pediatric Low-Grade Gliomas
Authors: Scott Ryall, Michal Zapotocky, Kohei Fukuoka, Liana Nobre, Ana Guerreiro Stucklin, Julie Bennett, Robert Siddaway, Christopher Li, Sanja Pajovic, Anthony Arnoldo, Paul E. Kowalski, Monique Johnson, Javal Sheth, Alvaro Lassaletta, Ruth G. Tatevossian, Wilda Orisme, Ibrahim Qaddoumi, Lea F. Surrey, Marilyn M. Li, Angela J. Waanders, Stephen Gilheeney, Marc Rosenblum, Tejus Bale, Derek S. Tsang, Normand Laperriere, Abhaya Kulkarni, George M. Ibrahim, James Drake, Peter Dirks, Michael D. Taylor, James T. Rutka, Suzanne Laughlin, Manohar Shroff, Mary Shago, Lili-Naz Hazrati, Colleen D'Arcy, Vijay Ramaswamy, Ute Bartels, Annie Huang, Eric Bouffet, Matthias A. Karajannis, Mariarita Santi, David W. Ellison, Uri Tabori, Cynthia Hawkins
Journal: Cancer Cell (2020)