Medical Specialties Commons^™

Nih Funding For Vaccine Readiness Before The Covid-19 Pandemic, Anthony E. Kiszewski, Ekaterina Galkina Cleary, Matthew J. Jackson, Fred D. Ledley

Natural & Applied Sciences Faculty Publications

Rapid development of vaccines for COVID-19 has relied on the application of existing vaccine technologies. This work examines the maturity of ten technologies employed in candidate vaccines (as of July 2020) and NIH funding for published research on these technologies from 2000–2019. These technologies vary from established platforms, which have been used successfully in approved products, to emerging technologies with no prior clinical validation. A robust body of published research on vaccine technologies was supported by 16,358 fiscal years of NIH funding totaling $17.2 billion from 2000–2019. During this period, NIH funding for published vaccine research against specific pandemic threats …

Role Of Awake Prone Positioning In Patients With Moderate-To-Severe Covid-19: An Experience From A Developing Country, Iffat Khanum, Fatima Samar, Fatimah Yousuf, Safia Awan, Adil Aziz, Kiren Habib, Nosheen Nasir, Syed Faisal Mahmood, Bushra Jamil

Department of Medicine

There is limited evidence on the efficacy of awake prone positioning (PP) in non-ventilated patients with COVID-19 who have hypoxemia. We, therefore, aim to describe our experience with the use of early proning in awake, non-intubated patients with confirmed COVID-19. In our retrospective observational study, 23 patients with confirmed positive PCR test results for Severe Acute respiratory Syndrome Coronavirus-2 (SARS-CoV-2) and hypoxemia that required oxygen therapy with or without non-invasive ventilation were treated with PP. Patients were classified into mild, moderate and severe COVID-19 disease. There were no targeted number of hours for proning per day and patients were kept …

Structural And Functional Properties Of Subsidiary Atrial Pacemakers In A Goat Model Of Sinus Node Disease, Luca Soattin, Zoltan Borbas, Jane Caldwell, Brian Prendergast, Akbar Vohra, Yawer Saeed, Andreas Hoschtitzky, Joseph Yanni, Andrew Atkinson, Sunil Jit Logantha

Section of Cardiology

Background: The sinoatrial/sinus node (SAN) is the primary pacemaker of the heart. In humans, SAN is surrounded by the paranodal area (PNA). Although the PNA function remains debated, it is thought to act as a subsidiary atrial pacemaker (SAP) tissue and become the dominant pacemaker in the setting of sinus node disease (SND). Large animal models of SND allow characterization of SAP, which might be a target for novel treatment strategies for SAN diseases.
Methods: A goat model of SND was developed (n = 10) by epicardially ablating the SAN and validated by mapping of emergent SAP locations through …

Patterns Of Left Ventricular Hypertrophy And Late Gadolinium Enhancement On Cardiac Mri In Patients With Hypertrophic Cardiomyopathy And Their Prognostic Significance - An Experience From A South Asian Country, Fateh Ali Tipoo Sultan, Sheema Saadia

Section of Cardiology

Objectives: Cardiac magnetic resonance (CMR) imaging is very pertinent in the diagnosis and risk stratification of patients with hypertrophic cardiomyopathy (HCM). We aimed to assess the patterns of left ventricular (LV) hypertrophy, late gadolinium enhancement (LGE), and their prognostic significance in HCM patients in Pakistani population, as no such data are available from Pakistan.
Material and methods: This was a retrospective, single center study. All patients who had confirmed diagnosis of HCM on CMR at Aga Khan University Hospital during the period of 2011-2019 were identified and included in the study.
Results: A total of 74 patients were included with …

Effectiveness Of Transcutaneous Bilirubin Measurement In High-Risk Neonates And To Evaluate Validity Of Transcutaneous Bilirubin With Total Serum Bilirubin Levels In Both Low And High-Risk Neonates At A Tertiary Care Center In A Developing Country, Durre Shahwar Khan, Adnan Mirza, Areesh Bhatti, Ali Shabbir Hussain, Batha Tariq, Arjumand Rizvi

Department of Paediatrics and Child Health

Objectives: To evaluate the usefulness of transcutaneous bilirubin (TcBR) nomogram in high-risk neonates and to identify the validity of TcBR and total serum bilirubin (TsBR) in both low and high-risk neonates to guide management in under-resourced settings.
Methodology: A cross-sectional study was conducted at the well-baby nursery of a tertiary care center in Karachi, Pakistan. All neonates admitted in the well-baby nursery with jaundice were stratified into high and low-risk groups. Eighty-seven neonates were included in the low-risk group and 121 neonates in the high-risk group. The usefulness of the TcBR nomogram in high-risk neonates and the validity of TcBR …

Association Of Blood Pressure Variability And Diuretics With Cardiovascular Events In Patients With Chronic Kidney Disease Stages 1-5, L Parker Gregg, S Susan Hedayati, Hui Yang, Peter N Van Buren, Subhash Banerjee, Sankar D Navaneethan, Salim S Virani, Wolfgang C Winkelmayer, Carlos A Alvarez

Faculty, Staff and Students Publications

Visit-to-visit blood pressure variability (BPV) is associated with cardiovascular events in the general population. Data are scarce in chronic kidney disease (CKD). We hypothesized that BPV would be associated with cardiovascular outcomes, death, and end-stage kidney disease (ESKD) and that diuretics would modify these associations in patients with CKD.

We studied U.S. Veterans with non-dialysis CKD stages 1-5 and hypertension on non-diuretic antihypertensive monotherapy. At the time of second antihypertensive agent prescription, we propensity-matched for exposure to a loop or thiazide diuretic vs. any other antihypertensive. BPV was defined as the coefficient of variation of systolic blood pressure over …

Guideline-Directed Heart Failure Therapy In Patients After Left Ventricular Assist Device Implantation, Bailey M. Colvin, James C. Coons, Craig J. Beavers

The VAD Journal

Background: Left ventricular assist devices (LVADs) are used as an advanced therapy option for patients with stage D heart failure. These devices provide mechanical unloading of the heart as either a bridge to transplant or recovery, or as destination therapy. In patients with LVADs, there are emerging data on the use of heart failure guideline-directed medical therapy (GDMT) to improve outcomes. This review describes the current evidence available for the use of neurohormonal blocking agents in patients with LVADs.

Methods: Articles were found using PubMed and web searches for heart failure therapies/neurohormonal blockade and LVADs. Studies were included if they …

Glucagon Blockade Restores Functional Β-Cell Mass In Type 1 Diabetic Mice And Enhances Function Of Human Islets, May-Yun Wang, E Danielle Dean, Ezekiel Quittner-Strom, Yi Zhu, Kamrul H Chowdhury, Zhuzhen Zhang, Shangang Zhao, Na Li, Reshing Ye, Young Lee, Yiyi Zhang, Shiuhwei Chen, Xinxin Yu, Derek C Leonard, Greg Poffenberger, Alison Von Deylen, S Kay Mccorkle, Amnon Schlegel, Kyle W Sloop, Alexander M Efanov, Ruth E Gimeno, Philipp E Scherer, Alvin C Powers, Roger H Unger, William L Holland

Faculty, Staff and Students Publications

We evaluated the potential for a monoclonal antibody antagonist of the glucagon receptor (Ab-4) to maintain glucose homeostasis in type 1 diabetic rodents. We noted durable and sustained improvements in glycemia which persist long after treatment withdrawal. Ab-4 promoted β-cell survival and enhanced the recovery of insulin+ islet mass with concomitant increases in circulating insulin and C peptide. In PANIC-ATTAC mice, an inducible model of β-cell apoptosis which allows for robust assessment of β-cell regeneration following caspase-8–induced diabetes, Ab-4 drove a 6.7-fold increase in β-cell mass. Lineage tracing suggests that this restoration of functional insulin-producing cells was at least partially …

Management Of Intracranial Haemangiopericytomas, Noman Ahmad, Saqib Kamran Bakhshi, Muhammad Shahzad Shamim

Section of Neurosurgery

Haemangiopericytomas are rare tumours, commonly mistaken as meningiomas on radiology. These tumours are considered malignant and treatment involves aggressive surgery, followed by adjuvant radiation therapy, and close radiological and clinical follow ups. Herein the authors have reviewed the recent literature on the management of these tumours.

Pregnancy After Embolization For Arteriovenous Malformation: An Uncommon Successful Outcome, Arshia Javed, Sana Sheikh

Department of Obstetrics & Gynaecology

Uterine arteriovenous malformation (AVM) is an uncommon but fatal condition and can cause bleeding from abnormal connection between artery and vein. Pregnancy after embolization of uterine AVM is very uncommon, and there are increased risks of spontaneous abortion and growth retardation. We report a case of pregnancy after bilateral uterine artery embolization for AVM and its successful outcome..

Racial And Geographic Disparities In Influenza Vaccination In The U.S. Among Individuals With Atherosclerotic Cardiovascular Disease: Renewed Importance In The Setting Of Covid-19, Mahmoud Al Rifai, Umair Khalid, Arunima Misra, Jing Liu, Khurram Nasir, Miguel Cainzos-Achirica, Dhruv Mahtta, Christie M. Ballantyne, Laura A. Petersen, Salim S. Virani

Office of the Provost

Introduction: The importance of receiving an annual influenza vaccine among patients with atherosclerotic cardiovascular disease (ASCVD) is well established. With the rapid community spread and the possibility of another wave of COVID-19 infections in the fall, receiving an influenza vaccine is of particular importance to mitigate the risk associated with overlapping influenza and COVID-19 infections.
Methods: We utilized cross-sectional data from the 2016 to 2019 Behavioral Risk Factor Surveillance System (BRFSS), a nationally representative U.S. telephone-based survey of adults 18 years or older. Race/ethnicity was our exposure of interest. We assessed the relative difference in influenza vaccination by race/ethnicity for …

Is Covid-19 Pushing Us To The Fifth Industrial Revolution (Society 5.0)?, Zouina Sarfraz, Azza Sarfraz, Hamza M. Iftikar, Ramsha Akhund

Department of Paediatrics and Child Health

The coronavirus disease 2019 (COVID-19) pandemic may further promote the development of Industry 4.0 leading to the fifth industrial revolution (Society 5.0). Industry 4.0 technology such as Big Data (BD) and Artificial Intelligence (AI) may lead to a personalized system of healthcare in Pakistan. The final bridge between humans and machines is Society 5.0, also known as the super-smart society that employs AI in healthcare manufacturing and logistics. In this communication, we review various Industry 4.0 and Society 5.0 technologies including robotics and AI being inspected to control the rate of transmission of COVID-19 globally. We demonstrate the applicability of …

Telemedicine: A New Frontier In Clinical Practice, Munazza Asad, Nooresahar, Saniya Sabzwari

Department of Family Medicine

The COVID-19 pandemic has highlighted the important role of telemedicine as a tool for safe healthcare delivery across the world. While its use was more common in the developed world, the developing world has also adopted this strategy. It is important to develop a clear process and contextual guidance for effective use of this strategy for better patient-doctor interaction and its role in teaching/learning of trainees.

Association Of Vitamin D Deficiency And Disease Activity In Systemic Lupus Erythematosus Patients: Two-Year Follow-Up Study, Ainan Arshad, Saad Bin Zafar Mahmood, Ahmed Ayaz, Adil A. Manji, Akash Kumar Ahuja

Section of Internal Medicine

Objectives: This study aims to determine the prevalence of vitamin D deficiency in Pakistani systemic lupus erythematosus (SLE) patients and the effect of vitamin D deficiency on the severity and outcomes of SLE.
Patients and methods: This retrospective study evaluated SLE patients presenting to our hospital between January 2009 and December 2018. A total of 98 patients (13 males, 85 females; mean age 39.8±14.9 years; range, 16 to 73 years) with vitamin D levels available at the time of diagnosis were included in the study. Disease activity was measured using SLE disease activity score at the time of diagnosis and …

Evaluation Of Serum Ferritin For Prediction Of Severity And Mortality In Covid-19- A Cross Sectional Study, Sibtain Ahmed, Zeeshan Ansar Ahmed, Imran Siddiqui, Naveed Haroon Rashid, Maheen Mansoor, Lena Jafri

Department of Pathology and Laboratory Medicine

Background: Ferritin even though widely recognized as a representative of total body iron stores, its prognostic utility is linked with COVID-19. This study was aimed at evaluation of the association of ferritin with severity in Coronavirus disease 2019 (COVID-19), hospitalized patients and to test the hypothesis that it is an independent predictor of mortality.
Material and methods: This study was conducted at Chemical Pathology, Department of Pathology and Laboratory Medicine, Aga Khan University (AKU), Karachi. Medical records of all in-patients including both genders, and all age groups with documented COVID-19 from 1st March to 10^th August 2020 were reviewed. …

Hypoglossal Nerve Paraganglioma Depicting As Glomus Tumor Of Neck, Zaid Ahmed Shamsi, Fareed Ahmed Shaikh, Muhammad Wasif, Mustafa Belal Hafeez Chaudhry, Nadeem Ahmed Siddiqui, Ziad Sophie

Department of Surgery Docs

Introduction: Paraganglioma are infrequent neuroendocrine tumors that are most commonly found in the carotid body, ganglia of the vagus, jugular and tympanic nerve. Very rarely they can involve other cranial nerves outside the cranial cavity, we present one such case of hypoglossal nerve paraganglioma in neck.
Case report: A 48 years old male presented with 1-month history of right sided stroke and aphasia. Ultrasonography of neck revealed a highly vascular mass on the right side of the neck. CT angiogram confirmed a highly vascular mass arising above the carotid bifurcation. With the working diagnosis of Glomus tumor, he underwent right …

Proximal Subclavian Artery Injury Managed Without Performing Median Sternotomy: A Case Report, Zia Ur Rehman

Department of Surgery Docs

No abstract provided.

Role Of Contrast Enhanced Computed Tomography In Assessing Cervical Lymph Node Metastases In Oral Cavity Squamous Cell Carcinoma, Talha Ahmed Qureshi, Muhammad Wasif, Mohammad Sohail Awan, Adnan Yar Muhammad, Ainulakbar Mughal, Abdullah Ameen

Section of Otolaryngology, Head & Neck Surgery

Objective: To evaluate the diagnostic accuracy of contrast-enhanced computed tomography scan in detecting cervical nodal metastasis in oral cavity squamous cell carcinoma.
Methods: The retrospective cross-sectional study was conducted at Aga Khan University Hospital, Karachi, Pakistan. and comprised records from January 1, 2015, to October 31, 2016, of patients diagnosed with oral cavity squamous cell carcinoma and who underwent surgical resection of primary tumour along with neck dissection after having a contrast-enhanced computed tomography scan of head and neck. Diagnostic accuracy of the scans was calculated using final histopathology as the gold standard. All scans were reviewed by a consultant …

Female Genital Tuberculosis In Pakistan - A Retrospective Review Of 10-Year Laboratory Data And Analysis Of 32 Cases, Tazeen Fatima, Rumina Hasan, Faisal Malik, Imran Ahmed, Linda Alice Bartlett, Michael G. Gravett, Sadia Shakoor

Department of Pathology and Laboratory Medicine

Background: Female genital tuberculosis (FGTB) is an underobserved clinical entity owing to diagnostic challenges stemming from difficulty of obtaining diagnostic specimens and paucibacillary nature of the disease. Yet, FGTB is a cause of infertility, pelvic pain, or menstrual irregularities in high-burden countries. To assess laboratory and microbiology diagnostic utilization for FGTB in Pakistan, we have collected data from 2007 to 2016 to inform the need for improved laboratory diagnostics. The objectives of this study were to determine the proportion of FGTB as culture-confirmed extrapulmonary tuberculosis (EPTB) and to describe the characteristics of women with culture-confirmed FGTB in a nationwide laboratory …

Mental Health Disorders Among Patients With Acute Myocardial Infarction In The United States, Jayakumar Sreenivasan, Muhammad Shahzeb Khan, Safi U Khan, Urvashi Hooda, Wilbert S Aronow, Julio A Panza, Glenn N Levine, Yvonne Commodore-Mensah, Roger S Blumenthal, Erin D Michos

Faculty, Staff and Students Publications

OBJECTIVE: To assess the prevalence, temporal trends and sex- and racial/ethnic differences in the burden of mental health disorders (MHD) and outcomes among patients with myocardial infarction (MI) in the United States.

METHODS: Using the National Inpatient Sample Database, we evaluated a contemporary cohort of patients hospitalized for acute MI in the United States over 10 years period from 2008 to 2017. We used multivariable logistic regression analysis for in-hospital outcomes, yearly trends and estimated annual percent change (APC) in odds of MHD among MI patients.

RESULTS: We included a total sample of 6,117,804 hospitalizations for MI (ST elevation MI …

Off-Label Use Of Direct Oral Anticoagulants In Patients Receiving Surgical Mechanical And Bioprosthetic Heart Valves, Ankur Kalra, Sajjad Raza, Baqir Hasan Jafry, Harley E. King, Joseph A. Lahorra, Lars G. Svensson, Samir R. Kapadia

Medical College Documents

This cohort study assesses direct oral anticoagulant use in patients with surgical prosthetic heart valves in the United States and evaluates differences in preoperative and postoperative profiles in patients discharged while receiving direct oral anticoagulant vs warfarin.

The Crosstalk Between Cardiomyocyte Calcium And Inflammasome Signaling Pathways In Atrial Fibrillation, Xiaolei Wang, Xiaohui Chen, Dobromir Dobrev, Na Li

Faculty, Staff and Students Publications

Atrial fibrillation (AF) is the most frequent arrhythmia in adults. The prevalence and incidence of AF is going to increase substantially over the next a few decades. Because AF increases the risk of stroke, heart failure, dementia, and others, it severely impacts the quality of life, morbidity and mortality. Although the pathogenesis of AF is multifaceted and complex, focal ectopic activity and reentry are considered as the fundamental proarrhythmic mechanisms underlying AF development. Over the past 2 decades, large amount of evidence points to the key role of intracellular Ca2+ dysregulation in both initiation and maintenance of AF. More recently, …

Deficiency Of Stat1 In Cd11c+ Cells Alters Adipose Tissue Inflammation And Improves Metabolic Dysfunctions In Mice Fed A High-Fat Diet, Antu Antony, Zeqin Lian, Xiaoyuan Dai Perrard, Jerry Perrard, Hua Liu, Aaron R Cox, Pradip Saha, Lothar Hennighausen, Sean M Hartig, Christie M Ballantyne, Huaizhu Wu

Faculty, Staff and Students Publications

CD11c+ macrophages/dendritic cells (MDCs) are increased and display the classically activated M1-like phenotype in obese adipose tissue (AT) and may contribute to AT inflammation and insulin resistance. Stat1 is a key transcription factor for MDC polarization into the M1-like phenotype. Here, we examined the role of Stat1 in obesity-induced AT MDC polarization and inflammation and insulin resistance using mice with specific knockout of Stat1 in MDCs (cKO). Stat1 was upregulated and phosphorylated, indicating activation, early and persistently in AT and AT MDCs of wild-type mice fed a high-fat diet (HFD). Compared with littermate controls, cKO mice fed an HFD (16 …

Is Covid-19-Induced Platelet Activation A Cause Of Concern For Patients With Cancer?, Lenard M Lichtenberger, K Vinod Vijayan

Faculty, Staff and Students Publications

Patients with cancer are more susceptible to be infected by SARS-CoV-2 and develop severe outcomes including ICU admittance, mechanical ventilator support, and a high rate of mortality. Like mid-to late-stage cancer, SARS-CoV-2 infection is associated with platelet hyperactivity, systemic inflammation, thrombotic complications, and coagulopathy. Platelets also promote cancer cell growth, survival in circulation, and angiogenesis at sites of metastases. In this article, we will discuss the potential for platelets in the development of systemic inflammation and thrombosis in SARS-CoV-2-infected patients with cancer, with the concern that the platelet-induced pathogenic events are likely magnified in cancer patients with COVID-19.

Evaluating The Revised American Society For Gastrointestinal Endoscopy Guidelines For Common Bile Duct Stone Diagnosis, Jake S Jacob, Michelle E Lee, Erin Y Chew, Aaron P Thrift, Robert J Sealock

Faculty, Staff and Students Publications

BACKGROUND/AIMS: The American Society for Gastrointestinal Endoscopy (ASGE) revised its guidelines for risk stratification of patients with suspected choledocholithiasis. This study aimed to assess the diagnostic performance of the revision and to compare it to the previous guidelines.

METHODS: We conducted a retrospective cohort study of 267 patients with suspected choledocholithiasis. We identified high-risk patients according to the original and revised guidelines and examined the diagnostic accuracy of both guidelines. We measured the association between individual criteria and choledocholithiasis.

RESULTS: Under the original guidelines, 165 (62%) patients met the criteria for high risk, of whom 79% had confirmed choledocholithiasis. The …

On The Application, Reporting, And Sharing Of In Silico Simulations For Genetic Studies, Kaleigh Riggs, Huann-Sheng Chen, Melissa Rotunno, Bing Li, Naoko I Simonds, Leah E Mechanic, Bo Peng

Faculty, Staff and Students Publications

In silico simulations play an indispensable role in the development and application of statistical models and methods for genetic studies. Simulation tools allow for the evaluation of methods and investigation of models in a controlled manner. With the growing popularity of evolutionary models and simulation-based statistical methods, genetic simulations have been applied to a wide variety of research disciplines such as population genetics, evolutionary genetics, genetic epidemiology, ecology, and conservation biology. In this review, we surveyed 1409 articles from five journals that publish on major application areas of genetic simulations. We identified 432 papers in which genetic simulations were used …

Fusobacteriumnucleatum Adheres To Clostridioides Difficile Via The Radd Adhesin To Enhance Biofilm Formation In Intestinal Mucus, Melinda A Engevik, Heather A Danhof, Jennifer Auchtung, Bradley T Endres, Wenly Ruan, Eugénie Bassères, Amy C Engevik, Qinglong Wu, Maribeth Nicholson, Ruth Ann Luna, Kevin W Garey, Sue E Crawford, Mary K Estes, Renate Lux, Mary Beth Yacyshyn, Bruce Yacyshyn, Tor Savidge, Robert A Britton, James Versalovic

Faculty, Staff and Students Publications

Background:

Although Clostridioides difficile infection (CDI) is known to involve the disruption of the gut microbiota, little is understood regarding how mucus-associated microbes interact with C. difficile. We hypothesized that select mucus-associated bacteria would promote C. difficile colonization and biofilm formation.

Methods/Results:

To create a model of the human intestinal mucus layer and gut microbiota, we used bioreactors inoculated with healthy human feces, treated with clindamycin and infected with C. difficile with the addition of human MUC2-coated coverslips. C. difficile was found to colonize and form biofilms on MUC2-coated coverslips and 16S rRNA sequencing revealed a unique biofilm profile …

Testosterone Therapy And Bone Quality In Men With Diabetes And Hypogonadism: Study Design And Protocol, Vittoria Russo, Georgia Colleluori, Rui Chen, Sanjay Mediwala, Clifford Qualls, Michael Liebschner, Dennis T Villareal, Reina Armamento-Villareal

Faculty, Staff and Students Publications

CONTEXT: Type 2 diabetes mellitus (T2D) is often accompanied by male hypogonadism and both conditions are associated with increased risk for fractures. Testosterone (T) has been shown to improve the bone health of hypogonadal men but has not been tested in patients who also have T2D in addition to low T. To date, there is no treatment that is specifically recommended for bone disease among patients with T2D. This study will evaluate the effect of T therapy on the bone health of male veterans with low T who also have T2D.

METHODS: This is a randomized double-blind placebo-controlled trial of …

Pegylated Arginine Deiminase Depletes Plasma Arginine But Maintains Tissue Arginine Availability In Young Pigs, Mahmoud A Mohammad, Inka C Didelija, Barbara Stoll, Trung C Nguyen, Juan C Marini

Faculty, Staff and Students Publications

Pegylated arginine deiminase (ADI-PEG20) results in the depletion of arginine with the production of isomolar amounts of citrulline. This citrulline has the potential to be utilized by the citrulline recycling pathway regenerating arginine and sustaining tissue arginine availability. The goal of this research was to test the hypothesis that ADI-PEG20 depletes circulating arginine in pigs but maintains tissue arginine concentration and function, and to characterize the kinetics of citrulline and arginine. Two multitracer approaches (bolus dose and primed-continuous infusion) were used to investigate the metabolism of arginine and citrulline in Control (

Tbx5-Encoded T-Box Transcription Factor 5 Variant T223m Is Associated With Long Qt Syndrome And Pediatric Sudden Cardiac Death, Alexandra M Markunas, Perathu K R Manivannan, Jordan E Ezekian, Agnim Agarwal, William Eisner, Katherina Alsina, Hugh D Allen, Gregory A Wray, Jeffrey J Kim, Xander H T Wehrens, Andrew P Landstrom

Faculty, Staff and Students Publications

Long QT syndrome (LQTS) is a genetic disease resulting in a prolonged QT interval on a resting electrocardiogram, predisposing affected individuals to polymorphic ventricular tachycardia and sudden death. Although a number of genes have been implicated in this disease, nearly one in four individuals exhibiting the LQTS phenotype are genotype-negative. Whole-exome sequencing identified a missense T223M variant in TBX5 that cosegregates with prolonged QT interval in a family with otherwise genotype-negative LQTS and sudden death. The TBX5-T223M variant was absent among large ostensibly healthy populations (gnomAD) and predicted to be pathogenic by in silico modeling based on Panther, PolyPhen-2, Provean, …