Medicine and Health Sciences Commons^™

Junctional Ectopic Tachycardia Caused By Junctophilin-2 Expression Silencing Is Selectively Sensitive To Ryanodine Receptor Blockade, Qixin Yang, Hanna J Tadros, Bo Sun, Minu-Tshyeto Bidzimou, Jordan E Ezekian, Feng Li, Andreas Ludwig, Xander H T Wehrens, Andrew P Landstrom

Faculty, Staff and Students Publications

Junctional ectopic tachycardia (JET) is a potentially fatal cardiac arrhythmia. Hcn4:shJph2 mice serve as a model of nodal arrhythmias driven by ryanodine type 2 receptor (RyR2)–mediated Ca2+ leak. EL20 is a small molecule that blocks RyR2 Ca2+ leak. In a novel in vivo model of JET, Hcn4:shJph2 mice demonstrated rapid conversion of JET to sinus rhythm with infusion of EL20. Primary atrioventricular nodal cells demonstrated increased Ca2+ transient oscillation frequency and increased RyR2-mediated stored Ca2+ leak which was normalized by EL20. EL20 was found to be rapidly degraded in mouse and human plasma, making it a potential novel therapy for …

Trajectories Of Egfr And Risk Of Albuminuria In Youth With Type 2 Diabetes: Results From The Today Cohort Study, Laure El Ghormli, Hui Wen, Diane Uschner, Morey W Haymond, Kara S Hughan, Katherine Kutney, Lori Laffel, Sherida E Tollefsen, Elia N Escaname, Jane Lynch, Petter Bjornstad, Today Study Group

Faculty, Staff and Students Publications

BACKGROUND: We conducted exploratory analyses to identify distinct trajectories of estimated glomerular filtration rate (eGFR) and their relationship with hyperfiltration, subsequent rapid eGFR decline, and albuminuria in participants with youth-onset type 2 diabetes enrolled in the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study.

METHODS: Annual serum creatinine, cystatin C, urine albumin, and creatinine measurements were obtained from 377 participants followed for ≥ 10 years. Albuminuria and eGFR were calculated. Hyperfiltration peak is the greatest eGFR inflection point during follow-up. Latent class modeling was applied to identify distinct eGFR trajectories.

RESULTS: At baseline, participants' mean age …

Socioeconomic Disparities In Procedural Choice And Outcomes After Aortic Valve Replacement, Paige E Brlecic, Katie J Hogan, John A Treffalls, Christopher B Sylvester, Joseph S Coselli, Marc R Moon, Todd K Rosengart, Subhasis Chatterjee, Ravi K Ghanta

Faculty, Staff and Students Publications

OBJECTIVE: To identify potential socioeconomic disparities in the procedural choice of patients undergoing surgical aortic valve replacement (SAVR) versus transcatheter aortic valve replacement (TAVR) and in readmission outcomes after SAVR or TAVR.

METHODS: The Nationwide Readmissions Database was queried to identify a total of 243,691 patients who underwent isolated SAVR and TAVR between January 2016 and December 2018. Patients were stratified according to a tiered socioeconomic status (SES) metric comprising patient factors including education, literacy, housing, employment, insurance status, and neighborhood median income. Multivariable analyses were used to assess the effect of SES on procedural choice and risk-adjusted readmission outcomes. …

Machine Learning For Dynamic And Early Prediction Of Acute Kidney Injury After Cardiac Surgery, Christopher T Ryan, Zijian Zeng, Subhasis Chatterjee, Matthew J Wall, Marc R Moon, Joseph S Coselli, Todd K Rosengart, Meng Li, Ravi K Ghanta

Faculty, Staff and Students Publications

OBJECTIVE: Acute kidney injury after cardiac surgery increases morbidity and mortality. Diagnosis relies on oliguria or increased serum creatinine, which develop 48 to 72 hours after injury. We hypothesized machine learning incorporating preoperative, operative, and intensive care unit data could dynamically predict acute kidney injury before conventional identification.

METHODS: Cardiac surgery patients at a tertiary hospital (2008-2019) were identified using electronic medical records in the Medical Information Mart for Intensive Care IV database. Preoperative and intraoperative parameters included demographics, Charlson Comorbidity subcategories, and operative details. Intensive care unit data included hemodynamics, medications, fluid intake/output, and laboratory results. Kidney Disease: Improving …

Influence Of Concomitant Ablation Of Nonparoxysmal Atrial Fibrillation During Coronary Artery Bypass Grafting On Mortality And Readmissions, John A Treffalls, Katie J Hogan, Paige E Brlecic, Christopher B Sylvester, Todd K Rosengart, Joseph S Coselli, Marc R Moon, Ravi K Ghanta, Subhasis Chatterjee

Faculty, Staff and Students Publications

OBJECTIVE: We determined the utilization rate of surgical ablation (SA) during coronary artery bypass grafting (CABG) and compared outcomes between CABG with or without SA in a national cohort.

METHODS: The January 2016 to December 2018 Nationwide Readmissions Database was searched for all patients undergoing isolated CABG with preoperative persistent or chronic atrial fibrillation by using the International Classification of Diseases, 10th Revision classification. Propensity score matching and multivariate logistic regressions were performed to compare outcomes, and Cox proportional hazards model was used to assess risk factors for 1-year readmission.

RESULTS: Of 18,899 patients undergoing CABG with nonparoxysmal atrial fibrillation, …

Development Of Canagliflozin Nanocrystals Sublingual Tablets In The Presence Of Sodium Caprate Permeability Enhancer: Formulation Optimization, Characterization, Sammar Fathy Elhabal, Mohamed A El-Nabarawi, Nashwa Abdelaal, Mohamed Fathi Mohamed Elrefai, Shrouk A Ghaffar, Mohamed Mansour Khalifa, Passant M Mohie, Dania S Waggas, Ahmed Mohsen Elsaid Hamdan, Samar Zuhair Alshawwa, Essa M Saied, Nahla A Elzohairy, Tayseer Elnawawy, Rania A Gad, Nehal Elfar, Hanaa Mohammed, Mohammad Ahmad Khasawneh

Faculty, Staff and Students Publications

Canagliflozin (CFZ) is a sodium-glucose cotransporter-2 inhibitor (SGLT2) that lowers albuminuria in type-2 diabetic patients, cardiovascular, kidney, and liver disease. CFZ is classified as class IV in the Biopharmaceutical Classification System (BCS) and is characterized by low permeability, solubility, and bioavailability, most likely attributed to hepatic first-pass metabolism. Nanocrystal-based sublingual formulations were developed in the presence of sodium caprate, as a wetting agent, and as a permeability enhancer. This formulation is suitable for children and adults and could enhance solubility, permeability, and avoid enterohepatic circulation due to absorption through the sublingual mucosa. In the present study, formulations containing various surfactants …

Blood Test Result Communication In Primary Care: Mixed-Methods Systematic Review Protocol, Helen Nankervis, Alyson Huntley, Penny Whiting, William Hamilton, Hardeep Singh, Sarah Dawson, Jane Sprackman, Anna Ferguson Montague, Jessica Watson

Faculty, Staff and Students Publications

Background: After testing, ensuring test results are communicated and actioned is important for patient safety, with failure or delay in diagnosis the most common cause of malpractice claims in primary care worldwide. Identifying interventions to improve test communication from the decision to test through to sharing of results has important implications for patient safety, GP workload, and patient engagement.

Aim: To assess the factors around communication of blood test results between primary care providers (for example GPs, nurses, reception staff) and their patients and carers.

Design & setting: A mixed methods systematic review including primary studies involving communication of blood …

Global Cardiovascular Research: Gaps And Opportunities, Maha Inam, Zainab Samad, Elizabeth M Vaughan, Aysha Almas, Bashir Hanif, Abdul Mannan Minhas, Zeerak Jarrar, Fatima Zohra Habib, Sana Sheikh, Dongshan Zhu, Salim S Virani

Faculty, Staff and Students Publications

Purpose of review: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide. CVDs contribute to a large health and economic burden on a global scale. We aim to describe the current landscape of global cardiovascular research, highlight significant findings, and identify potential opportunities for further studies.

Recent findings: There has been remarkable research output regarding cardiovascular health in recent decades. Large-scale collaborative studies have made impactful strides in identifying modifiable risk factors and forming evidence-based guidelines to facilitate improved cardiovascular care and outcomes. However, there are significant CVD disparities between high- and low- income countries which require …

Closing The Gaps In Care Of Dyslipidemia: Revolutionizing Management With Digital Health And Innovative Care Models, Samuel J Apple, Rachel Clark, Jonathan Daich, Macarena Lopez Gonzalez, Robert J Ostfeld, Peter P Toth, Vera Bittner, Seth S Martin, Jamal S Rana, Khurram Nasir, Michael D Shapiro, Salim S Virani, Leandro Slipczuk

Faculty, Staff and Students Publications

Although great progress has been made in the diagnostic and treatment options for dyslipidemias, unawareness, underdiagnosis and undertreatment of these disorders remain a significant global health concern. Growth in digital applications and newer models of care provide novel tools to improve the management of chronic conditions such as dyslipidemia. In this review, we discuss the evolving landscape of lipid management in the 21st century, current treatment gaps and possible solutions through digital health and new models of care. Our discussion begins with the history and development of value-based care and the national establishment of quality metrics for various chronic conditions. …

Prevalence, Awareness, And Treatment Of Elevated Ldl Cholesterol In Us Adults, 1999-2020, Ahmed Sayed, Ann Marie Navar, Leandro Slipczuk, Christie M Ballantyne, Zainab Samad, Carl J Lavie, Salim S Virani

Faculty, Staff and Students Publications

This cross-sectional study compares the prevalence, awareness, and treatment of elevated low-density lipoprotein (LDL) cholesterol in US adults in 1999-2000 vs 2017-2020.

Providers’ Perspectives On The Impact Of Culture In The Recognition And Diagnosis Of Anxiety, Darius B Dawson, Christie G-J Tsao, Patricia Chen, Traber D Giardina, Terri L Fletcher

Faculty, Staff and Students Publications

Objectives: We examined providers' perspectives about how culture affects diagnosing and recognizing anxiety.

Methods: We interviewed providers about diagnosing anxiety ("How do you think culture impacts expression and diagnosis of anxiety?") and used inductive analysis, with open coding, to allow themes to emerge organically.

Results: We identified three themes: (1) Impartiality toward Culture: downplaying culture in recognizing or diagnosing anxiety and not acknowledging necessary cultural diagnostic considerations; (2) Acknowledgment of Cultural Impact: detailed variations across different cultural communities in how patients present with and describe anxiety, with differing levels of stigma associated with expressing and treating anxiety; (3) Culturally Integrated …

Corrigendum To “Phenotypes Of Disease Severity In A Cohort Of Hospitalized Covid-19 Patients: Results From The Impacc Study” [Ebiomedicine 83 (2022) 104208], Al Ozonoff, Joanna Schaenman, Naresh Doni Jayavelu, Carly E Milliren, Carolyn S Calfee, Charles B Cairns, Monica Kraft, Lindsey R Baden, Albert C Shaw, Florian Krammer, Harm Van Bakel, Denise A Esserman, Shanshan Liu, Ana Fernandez Sesma, Viviana Simon, David A Hafler, Ruth R Montgomery, Steven H Kleinstein, Ofer Levy, Chris Bime, Elias K Haddad, David J Erle, Bali Pulendran, Kari C Nadeau, Mark M Davis, Catherine L Hough, William B Messer, Nelson I Agudelo Higuita, Jordan P Metcalf, Mark A Atkinson, Scott C Brakenridge, David Corry, Farrah Kheradmand, Lauren I R Ehrlich, Esther Melamed, Grace A Mccomsey, Rafick Sekaly, Joann Diray-Arce, Bjoern Peters, Alison D Augustine, Elaine F Reed, Matthew C Altman, Patrice M Becker, Nadine Rouphael, Impacc Study Group Members

Faculty, Staff and Students Publications

No abstract provided.

Prostate Safety Events During Testosterone Replacement Therapy In Men With Hypogonadism: A Randomized Clinical Trial, Shalender Bhasin, Thomas G Travison, Karol M Pencina, Michael O'Leary, Glenn R Cunningham, A Michael Lincoff, Steven E Nissen, M Scott Lucia, Mark A Preston, Mohit Khera, Nader Khan, Michael C Snabes, Xue Li, Catherine M Tangen, Kevin A Buhr, Ian M Thompson

Faculty, Staff and Students Publications

IMPORTANCE: The effect of testosterone replacement therapy (TRT) on the risk of prostate cancer and other adverse prostate events is unknown.

OBJECTIVE: To compare the effect of TRT vs placebo on the incidences of high-grade prostate cancers (Gleason score ≥4 + 3), any prostate cancer, acute urinary retention, invasive prostate procedures, and pharmacologic treatment for lower urinary tract symptoms in men with hypogonadism.

DESIGN, SETTING, AND PARTICIPANTS: This placebo-controlled, double-blind randomized clinical trial enrolled 5246 men (aged 45-80 years) from 316 US trial sites who had 2 testosterone concentrations less than 300 ng/dL, hypogonadal symptoms, and cardiovascular disease (CVD) or …

First-Time Orgasm In A Young Man With Lifelong Anorgasmia After Flibanserin Use: A Case Report, Gal Saffati, Taher Naeem, Basil Kaaki, Mohit Khera

Faculty, Staff and Students Publications

INTRODUCTION: Anorgasmia is a poorly understood phenomenon defined as either a lifelong or acquired consistent inability to achieve ejaculation. Despite the prevalence of anorgasmia, there is currently no established treatment for the condition.

AIMS: To report a unique case of a patient with lifelong anorgasmia who was able to achieve his first orgasm with off-label use of flibanserin.

METHODS: The present case study relies on the patient's self-report and a review of the relevant literature. The patient provided written informed consent.

RESULTS: A 28-year-old male presented to our office with complaints of lifelong anorgasmia, without any signs of erectile dysfunction. …

Assessment And Prevention Of Hypoglycaemia In Primary Care Among Us Veterans: A Mixed Methods Study, Scott J Pilla, Kayla A Meza, Mary Catherine Beach, Judith A Long, Howard S Gordon, Jeffrey T Bates, Donna L Washington, Barbara G Bokhour, Anais Tuepker, Somnath Saha, Nisa M Maruthur

Faculty, Staff and Students Publications

BACKGROUND: Hypoglycaemia from diabetes treatment causes morbidity and lower quality of life, and prevention should be routinely addressed in clinical visits.

METHODS: This mixed methods study evaluated how primary care providers (PCPs) assess for and prevent hypoglycaemia by analyzing audio-recorded visits from five Veterans Affairs medical centres in the US. Two investigators independently coded visit dialogue to classify discussions of hypoglycaemia history, anticipatory guidance, and adjustments to hypoglycaemia-causing medications according to diabetes guidelines.

FINDINGS: There were 242 patients (one PCP visit per patient) and 49 PCPs. Two thirds of patients were treated with insulin and 40% with sulfonylureas. Hypoglycaemia history …

Rehydration Rates And Outcomes In Overweight Children With Diabetic Ketoacidosis, Kathleen M Brown, Nicole S Glaser, Julie K Mcmanemy, Andrew Depiero, Lise E Nigrovic, Kimberly S Quayle, Michael J Stoner, Jeff E Schunk, Jennifer L Trainor, Leah Tzimenatos, Arleta Rewers, Sage R Myers, Maria Y Kwok, Simona Ghetti, T Charles Casper, Cody S Olsen, Nathan Kuppermann, Pediatric Emergency Care Applied Research Network Diabetic Ketoacidosis Fluid Study Group

Faculty, Staff and Students Publications

BACKGROUND AND OBJECTIVES: The Pediatric Emergency Care Applied Research Network Fluid Therapies Under Investigation in Diabetic Ketoacidosis (DKA) (FLUID) Trial found that rapid fluid infusion does not increase the risk of cerebral injury. Concern persists, however, whether fluid rates should be adjusted for overweight or obese patients. We used the FLUID Trial database to evaluate associations between fluid infusion rate and outcomes in these patients.

METHODS: We compared children and youth who were overweight, obese, or normal weight, in regard to protocol adherence, mental status changes, time to DKA resolution, and electrolyte abnormalities. We investigated associations between outcomes and the …

Re: Incidence Of Sars-Cov-2 Breakthrough Infections After Vaccination In Adults: A Population-Based Survey Through 1 March 2023, Stacia M. Desantis, Ashraf Yaseen, Tianyao Hao, Luis Leon-Novelo, Yashar Talebi, Melissa A. Valerio-Shewmaker, Cesar L. Pinzon Gomez, Sarah E. Messiah, Harold W. Kohl, Steven H. Kelder, Jessica A. Ross, Lindsay N. Padilla, Mark Silberman, Samantha Wylie, David Lakey, Jennifer A. Shuford, Stephen J. Pont, Eric Boerwinkle, Michael D. Swartz

School of Medicine Faculty Publications and Presentations

Mycobacterium tuberculosis (Mtb) has latently infected over two billion people worldwide (LTBI) and caused ~1.6 million deaths in 2021. Human immunodeficiency virus (HIV) co-infection with Mtb will affect the Mtb progression and increase the risk of devel

Contemporary Use Of Coronary Physiology In Cardiology, Ayman Elbadawi, Ramy Sedhom, Mohamed Ghoweba, Abdelazeem Mohamed Etewa, Waleed Kayani, Faisal Rahman

Faculty, Staff and Students Publications

Coronary angiography has a limited ability to predict the functional significance of intermediate coronary lesions. Hence, physiological assessment of coronary lesions, via fractional flow reserve (FFR) or instantaneous wave-free ratio (iFR), has been introduced to determine their functional significance. An accumulating body of evidence has consolidated the role of physiology-guided revascularization, particularly among patients with stable ischemic heart disease. The use of FFR or iFR to guide decision-making in patients with stable ischemic heart disease and intermediate coronary lesions received a class I recommendation from major societal guidelines. Nevertheless, the role of coronary physiology testing is less clear among certain …

Responsibility Gaps And Black Box Healthcare Ai: Shared Responsibilization As A Solution, Benjamin H Lang, Sven Nyholm, Jennifer Blumenthal-Barby

Center for Medical Ethics and Health Policy Staff Publications

As sophisticated artificial intelligence software becomes more ubiquitously and more intimately integrated within domains of traditionally human endeavor, many are raising questions over how responsibility (be it moral, legal, or causal) can be understood for an AI’s actions or influence on an outcome. So called “responsibility gaps” occur whenever there exists an apparent chasm in the ordinary attribution of moral blame or responsibility when an AI automates physical or cognitive labor otherwise performed by human beings and commits an error. Healthcare administration is an industry ripe for responsibility gaps produced by these kinds of AI. The moral stakes of healthcare …

How Should Technology-Dependent Patients' Care Be Managed Collaboratively To Avoid Turfing?, Emma Cooke, Holland Kaplan

Center for Medical Ethics and Health Policy Staff Publications

Technology-dependent patients require interventions (eg, tracheostomies, gastrostomy tubes, or total parenteral nutrition) to survive. Such patients are commonly "turfed" between general services or from subspecialty to general services within the hospital. This case commentary proposes several explanations for why technology-dependent patients are particularly susceptible to turfing, including clinicians' lack of familiarity with managing patients' technology, bias and ableism, and quality-of-life quandaries. It also addresses ways to combat turfing of technology-dependent patients and proposes educational strategies for managing common problems in the care of technology-dependent patients.

Big Advocacy, Little Recognition: The Hidden Work Of Black Patients In Precision Medicine, Lynette Hammond Gerido, Kenneth Resnicow, Elena M Stoffel, Tiah Tomlin, Robert Cook-Deegan, Melissa Cline, Amy Coffin, Jill Holdren, Mary Anderlik Majumder, Zhe He

Center for Medical Ethics and Health Policy Staff Publications

As cost-effective next-generation genome sequencing rapidly develops, calls for greater inclusion of Black people in genomic research, policy, and practice are necessary for effective translation of genomic science into precision population health and medicine. Employing a community-based participatory mixed methods research design, we developed a semi-structured survey that was disseminated to three cancer advocacy organizations. Of the 81 survey respondents 49 (60%) self-identified as Black, and 26 (32%) indicated a prior breast cancer diagnosis. Black participants' expressed concerns about genetic testing were evenly distributed between concerns that could be addressed through genetic counseling (24%) and concerns about subsequent use of …

Depressive Symptoms In Autistic Youth With Anxiety Disorders, Rebecca L Greenberg, Andrew G Guzick, Sophie C Schneider, Saira A Weinzimmer, Minjee Kook, Amanda B Perozo Garcia, Eric A Storch

Center for Medical Ethics and Health Policy Staff Publications

Objective: Anxiety and depression often coexist in youth and share overlapping symptomatology; however, little is known about the comorbidity of anxiety and depression in autistic youth. This study explores (1) the frequency of depressive symptoms among autistic children with clinically significant anxiety, (2) clinical variables that may be associated with elevated depressive symptoms, and (3) whether pretreatment depressive symptoms predict cognitive behavioral therapy (CBT) outcomes for anxiety.

Method: Children aged 7 to 13 years (N = 87) and their parents participated in a randomized controlled trial comparing 2 versions of a parent-led, telehealth-delivered CBT program. Parents and children completed a …

Recommendations To Improve Quality Of Probiotic Systematic Reviews With Meta-Analyses, Lynne V Mcfarland, Gail Hecht, Mary E Sanders, Debra A Goff, Ellie J C Goldstein, Colin Hill, Stuart Johnson, Maryam R Kashi, Ravina Kullar, Maria L Marco, Daniel J Merenstein, Mathieu Millette, Geoffrey A Preidis, Eamonn M M Quigley, Gregor Reid, Seppo Salminen, Jason C Sniffen, Harry Sokol, Hania Szajewska, Daniel J Tancredi, Kristin Woolard

Faculty, Staff and Students Publications

Importance: Systematic reviews and meta-analyses often report conflicting results when assessing evidence for probiotic efficacy, partially because of the lack of understanding of the unique features of probiotic trials. As a consequence, clinical decisions on the use of probiotics have been confusing.

Objective: To provide recommendations to improve the quality and consistency of systematic reviews with meta-analyses on probiotics, so evidence-based clinical decisions can be made with more clarity.

Evidence review: For this consensus statement, an updated literature review was conducted (January 1, 2020, to June 30, 2022) to supplement a previously published 2018 literature search to identify areas where …

Will You Go The Distance? A Satisfaction Survey Of Telemedicine In Sexual Medicine, Gal Saffati, Taher Naeem, Jordan Kassab, Daniela Orozco Rendon, Charles Green, Larry I Liphsultz, Mohit Khera

Faculty, Staff and Student Publications

BACKGROUND: The success of telemedicine depends on patient satisfaction with the care that they receive, which is impacted by the ease of use of the technology, quality of the connection, and perceived effectiveness of care.

AIM: The study sought to evaluate patient satisfaction with telemedicine services in a high-volume andrology clinic.

METHODS: We included all patients who had a telemedicine appointment between January 1, 2020, and August 22, 2022. Demographic information was gathered, and a satisfaction survey was conducted using REDCap software. Data were grouped into 2 age categories, with ≥50 years as the cutoff (19-50 years; >50 years). The …

Unmasking And Addressing Burnout In The Mental Health Profession, Sara Edwards

University Honors Theses

Burnout poses a significant challenge among mental health workers, impacting both the well-being of practitioners and the outcomes for their patients. The key inquiries guiding this literature review are: what factors contribute to burnout, and what interventions are essential for treating and preventing burnout in mental health professionals? The findings reveal that factors such as level of experience, lack of quality supervision, vicarious trauma, working conditions, and personal beliefs significantly contribute to burnout. Effective prevention and treatment measures for mental health workers vulnerable to burnout encompass self-monitoring, participation in support groups, additional training, and organizational interventions. These insights could serve …

Greater Socioenvironmental Risk Factors And Higher Chronic Pain Stage Are Associated With Thinner Bilateral Temporal Lobes, Lisa H Antoine, Burel R Goodin, Et Al.

2020-Current year OA Pubs

INTRODUCTION: Previous research indicates ethnic/race group differences in pain and neurodegenerative diseases. Accounting for socioenvironmental factors reduces ethnic/race group differences in clinical and experimental pain. In the current study sample, we previously reported that in individuals with knee pain, ethnic/race group differences were observed in bilateral temporal lobe thickness, areas of the brain associated with risk for Alzheimer's disease, and related dementias. The purpose of the study was to determine if socioenvironmental factors reduce or account for previously observed ethnic/race group differences and explore if a combined effect of socioenvironmental risk and chronic pain severity on temporal lobe cortices is …

Myeloid Lineage Switch Following Cd7-Targeted Chimeric Antigen Receptor T-Cell Therapy In Relapsed/Refractory T-Cell Acute Lymphoblastic Leukemia, Ibrahim Aldoss, David Spencer, Et Al.

2020-Current year OA Pubs

No abstract provided.

Neurofibromin 1 Mutations Impair The Function Of Human Induced Pluripotent Stem Cell-Derived Microglia, Leonard D Kuhrt, Edyta Motta, Nirmeen Elmadany, Hannah Weidling, Raphaela Fritsche-Guenther, Ibrahim E Efe, Olivia Cobb, Jit Chatterjee, Lucy G Boggs, Marina Schnauß, Sebastian Diecke, Marcus Semtner, Corina Anastasaki, David H Gutmann, Helmut Kettenmann

2020-Current year OA Pubs

Neurofibromatosis type 1 (NF1) is an autosomal dominant condition caused by germline mutations in the neurofibromin 1 (NF1) gene. Children with NF1 are prone to the development of multiple nervous system abnormalities, including autism and brain tumors, which could reflect the effect of NF1 mutation on microglia function. Using heterozygous Nf1-mutant mice, we previously demonstrated that impaired purinergic signaling underlies deficits in microglia process extension and phagocytosis in situ. To determine whether these abnormalities are also observed in human microglia in the setting of NF1, we leveraged an engineered isogenic series of human induced pluripotent stem cells to generate human …

Multi-Ancestry Study Of The Genetics Of Problematic Alcohol Use In Over 1 Million Individuals, Hang Zhou, Emma C Johnson, Pamela A F Madden, Andrew C Heath, Arpana Agrawal, Et Al.

2020-Current year OA Pubs

Problematic alcohol use (PAU), a trait that combines alcohol use disorder and alcohol-related problems assessed with a questionnaire, is a leading cause of death and morbidity worldwide. Here we conducted a large cross-ancestry meta-analysis of PAU in 1,079,947 individuals (European, N = 903,147; African, N = 122,571; Latin American, N = 38,962; East Asian, N = 13,551; and South Asian, N = 1,716 ancestries). We observed a high degree of cross-ancestral similarity in the genetic architecture of PAU and identified 110 independent risk variants in within- and cross-ancestry analyses. Cross-ancestry fine mapping improved the identification of likely causal variants. Prioritizing …

Idasanutlin And Navitoclax Induce Synergistic Apoptotic Cell Death In T-Cell Acute Lymphoblastic Leukemia, Kimberly B Johansson, Megan S Zimmerman, Iryna V Dmytrenko, Feng Gao, Daniel C Link

2020-Current year OA Pubs

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy in which activating mutations in the Notch pathway are thought to contribute to transformation, in part, by activating c-Myc. Increased c-Myc expression induces oncogenic stress that can trigger apoptosis through the MDM2-p53 tumor suppressor pathway. Since the great majority of T-ALL cases carry inactivating mutations upstream in this pathway but maintain wildtype MDM2 and TP53, we hypothesized that T-ALL would be selectively sensitive to MDM2 inhibition. Treatment with idasanutlin, an MDM2 inhibitor, induced only modest apoptosis in T-ALL cells but upregulated the pro-apoptotic BH3 domain genes BAX and BBC3, prompting …