Digital Commons Network^™

Improving The Diagnostic Process For Patients With Possible Bladder And Kidney Cancer: A Mixed-Methods Study To Identify Potential Missed Diagnostic Opportunities, Yin Zhou, Hardeep Singh, Willie Hamilton, Stephanie Archer, Sapphire Tan, James Brimicombe, Georgios Lyratzopoulos, Fiona M Walter

Faculty, Staff and Students Publications

Background: Patients with bladder and kidney cancer may experience diagnostic delays.

Aim: To identify patterns of suboptimal care and contributors of potential missed diagnostic opportunities (MDOs).

Design and setting: Prospective, mixed-methods study recruiting participants from nine general practices in Eastern England between June 2018 and October 2019.

Method: Patients with possible bladder and kidney cancer were identified using eligibility criteria based on National Institute for Health and Care Excellence (NICE) guidelines for suspected cancer. Primary care records were reviewed at recruitment and at 1 year for data on symptoms, tests, referrals, and diagnosis. Referral predictors were examined using logistic regression. …

Meld 3.0 Adequately Predicts Mortality And Renal Replacement Therapy Requirements In Patients With Alcohol-Associated Hepatitis, Luis Antonio Díaz, Eduardo Fuentes-López, Gustavo Ayares, Francisco Idalsoaga, Jorge Arnold, María Ayala Valverde, Diego Perez, Jaime Gómez, Rodrigo Escarate, Alejandro Villalón, Carolina A Ramírez, Maria Hernandez-Tejero, Wei Zhang, Steve Qian, Douglas A Simonetto, Joseph C Ahn, Seth Buryska, Winston Dunn, Heer Mehta, Rohit Agrawal, Joaquín Cabezas, Inés García-Carrera, Berta Cuyàs, Maria Poca, German Soriano, Shiv K Sarin, Rakhi Maiwall, Prasun K Jalal, Saba Abdulsada, Fátima Higuera-De-La-Tijera, Anand V Kulkarni, P Nagaraja Rao, Patricia Guerra Salazar, Lubomir Skladaný, Natália Bystrianska, Ana Clemente-Sanchez, Clara Villaseca-Gómez, Tehseen Haider, Kristina R Chacko, Gustavo A Romero, Florencia D Pollarsky, Juan Carlos Restrepo, Susana Castro-Sanchez, Luis G Toro, Pamela Yaquich, Manuel Mendizabal, Maria Laura Garrido, Sebastián Marciano, Melisa Dirchwolf, Victor Vargas, César Jiménez, Alexandre Louvet, Guadalupe García-Tsao, Juan Pablo Roblero, Juan G Abraldes, Vijay H Shah, Patrick S Kamath, Marco Arrese, Ashwani K Singal, Ramon Bataller, Juan Pablo Arab

Faculty, Staff and Students Publications

Background & aims: Model for End-Stage Liver Disease (MELD) score better predicts mortality in alcohol-associated hepatitis (AH) but could underestimate severity in women and malnourished patients. Using a global cohort, we assessed the ability of the MELD 3.0 score to predict short-term mortality in AH.

Methods: This was a retrospective cohort study of patients admitted to hospital with AH from 2009 to 2019. The main outcome was all-cause 30-day mortality. We compared the AUC using DeLong's method and also performed a time-dependent AUC with competing risks analysis.

Results: A total of 2,124 patients were included from 28 centres from 10 …

Health Information Seeking In The Digital Age: A National Survey Of Women With Disabilities, Susan Robinson-Whelen, Rosemary B Hughes, Jeanne L Alhusen, Leanne Beers, Charles G Minard, David Davidson

Faculty, Staff and Students Publications

PURPOSE: Access to high quality and accessible online health information (OHI) is critical for reducing disparities, overcoming barriers, and improving the health of women with disabilities. This study aimed to understand women with physical disabilities' use of the Internet to access OHI, most often searched health topics, perceived usefulness of OHI, and self-reported eHealth literacy and challenges in OHI seeking.

METHODS: We conducted a national online survey with 508 women with physical disabilities who used the Internet.

RESULTS: Respondents utilized a wide variety of OHI resources. They searched a broad array of health and disability-related topics, with bowel/bladder and finding …

Anesthetic Management Of Renal Cell Carcinoma With Level 3 Inferior Vena Cava Extension In A Patient With Severe Coronary Artery Disease, Kyle R Gashler, Alan K Ritchie, Ryan Hood, Stephanie O Ibekwe

Faculty, Staff and Students Publications

A 49-year-old male with untreated type 2 diabetes and a family history of coronary artery disease (CAD) presented with right flank pain and profound progressive dyspnea on exertion to the emergency department of Ben Taub Hospital, a tertiary county hospital. Workup revealed right renal cell carcinoma with metastatic extension into the inferior vena cava (IVC). In addition, the patient had significant CAD with 95% occlusion of the proximal left anterior descending coronary artery amenable to percutaneous coronary intervention (PCI). After multidisciplinary discussions involving cardiovascular anesthesiology, cardiology, urology, and cardiothoracic surgery, it was estimated that the mortality benefit of immediate tumor …

Disparities In Antifibrotic Medication Utilization Among Veterans With Idiopathic Pulmonary Fibrosis, Bhavika Kaul, Joyce S Lee, Laura A Petersen, Charles Mcculloch, Ivan O Rosas, Venkata D Bandi, Ning Zhang, Alison M Dedent, Harold R Collard, Mary A Whooley

Faculty, Staff and Students Publications

Background: Two antifibrotic medications, pirfenidone and nintedanib, are approved for the treatment of idiopathic pulmonary fibrosis (IPF). Little is known about their real-world adoption.

Research question: What are the real-world antifibrotic utilization rates and factors associated with uptake among a national cohort of veterans with IPF?

Study design and methods: This study identified veterans with IPF who received care either provided by the Veterans Affairs (VA) Healthcare System or non-VA care paid for by the VA. Patients who had filled at least one antifibrotic prescription through the VA pharmacy or Medicare Part D between October 15, 2014, and December 31, …

Hunger Extends Lifespan By Modulating Histone Proteins, Hailan Liu, Hongjie Li, Yong Xu

Faculty, Staff and Students Publications

No abstract provided.

Utilization Rates Of Sglt2 Inhibitors Among Patients With Type 2 Diabetes, Heart Failure, And Atherosclerotic Cardiovascular Disease: Insights From The Department Of Veterans Affairs, Aliza Hussain, David Ramsey, Michelle Lee, Dhruv Mahtta, Muhammad Shahzeb Khan, Vijay Nambi, Christie M Ballantyne, Laura A Petersen, Adrienne D Walker, Waleed T Kayani, Javed Butler, Leandro Slipczuk, Joseph G Rogers, Biykem Bozkurt, Sankar D Navaneethan, Salim S Virani

Faculty, Staff and Students Publications

Background: Multiple clinical trials have demonstrated significant cardiovascular benefit with use of sodium-glucose cotransporter-2 (SGLT2) inhibitors in patients with type 2 diabetes (T2DM) and heart failure (HF) irrespective of ejection fraction. There are limited data evaluating real-world prescription and practice patterns of SGLT2 inhibitors.

Objectives: The authors sought to assess utilization rates and facility-level variation in the use among patients with established atherosclerotic cardiovascular disease (ASCVD), HF, and T2DM using data from the nationwide Veterans Affairs health care system.

Methods: The authors included patients with established ASCVD, HF, and T2DM seen by a primary care provider between January 1, 2020, …

Noncanonical Binding Of Transcription Factors: Time To Revisit Specificity?, Md Abul Hassan Samee

Faculty, Staff and Students Publications

Transcription factors (TFs) are one of the most studied classes of DNA-binding proteins that have a direct functional impact on gene transcription and thus, on human physiology and disease. The mechanisms that TFs use for recognizing target DNA binding sites have been studied for nearly five decades, yet they remain poorly understood. It is classically assumed that a TF recognizes a specific sequence pattern, or motif, as its binding sites. However, recent studies are consistently finding examples of noncanonical binding, that is, TFs binding at sites that do not resemble their sequence motifs. Here we review the current literature on …

Disparities In Antifibrotic Medication Utilization Among Veterans With Idiopathic Pulmonary Fibrosis, Bhavika Kaul, Joyce S Lee, Laura A Petersen, Charles Mcculloch, Ivan O Rosas, Venkata D Bandi, Ning Zhang, Alison M Dedent, Harold R Collard, Mary A Whooley

Faculty, Staff and Students Publications

BACKGROUND: Two antifibrotic medications, pirfenidone and nintedanib, are approved for the treatment of idiopathic pulmonary fibrosis (IPF). Little is known about their real-world adoption.

RESEARCH QUESTION: What are the real-world antifibrotic utilization rates and factors associated with uptake among a national cohort of veterans with IPF?

STUDY DESIGN AND METHODS: This study identified veterans with IPF who received care either provided by the Veterans Affairs (VA) Healthcare System or non-VA care paid for by the VA. Patients who had filled at least one antifibrotic prescription through the VA pharmacy or Medicare Part D between October 15, 2014, and December 31, …

Exploring Gastrointestinal Health In Mecp2 Duplication Syndrome, Davut Pehlivan, Muharrem Ak, Daniel G Glaze, Bernhard Suter, Kathleen J Motil

Faculty, Staff and Students Publications

BACKGROUND: MECP2 duplication syndrome (MDS) is a rare neurogenetic syndrome caused by duplications of MECP2 at the Xq28 region. Although constipation and gastrointestinal reflux are reported in MDS, a comprehensive characterization of gastrointestinal health has not been fully explored.

METHODS: We conducted a parent survey to explore the characteristics of gastrointestinal health in individuals with MDS using a secure online registry and compared differences in gastrointestinal symptoms between individuals with MDS and those with Rett syndrome (RTT).

KEY RESULTS: One hundred six surveys were analyzed. Symptoms commonly associated with constipation occurred in 72% to 89% of MDS individuals. Eleven percent …

Remote Robotic Surgery And Virtual Education Platforms: How Advanced Surgical Technologies Can Increase Access To Surgical Care In Resource-Limited Settings, Youmna A Sherif, Mohammed A Adam, Aimee Imana, Sarnai Erdene, Rachel W Davis

Faculty, Staff and Students Publications

Advanced surgical technologies consist of remote and virtual platforms that facilitate surgical care and education. It also includes the infrastructure necessary to utilize these platforms (e.g., internet access, robotic systems, and simulators). Given that 5 billion people lack access to safe and timely surgical care, the appeal of these technologies to the field of global surgery lies primarily in its ability to eliminate geographical barriers and address surgeon shortages. This article discusses the use of virtual and remote technologies in resource-limited settings, the potential applications of these technologies, the possible barriers to their integration, and the impact these technologies may …

Deployment Of Cisplatin In Veterans With Oropharyngeal Cancer: Toxicity And Impact On Oncologic Outcomes, Ola Soliman, David C Wilde, Jan O Kemnade, Anita L Sabichi, George Chen, Albert Chen, Samantha N Little, Andrew T Huang, David J Hernandez, Vlad C Sandulache

Faculty, Staff and Students Publications

OBJECTIVE: Cisplatin forms the backbone of systemic chemotherapy treatment for oropharyngeal squamous cell carcinoma (OPSCC). The ideal cisplatin dosing regimen remains yet to be fully defined for achieving optimal efficacy and toxicity profiles in patients with comorbidity.

METHODS: We retrospectively reviewed oncologic and toxicity data for patients with OPSCC treated at the Michael E. DeBakey Veterans Affairs Medical Center between 2000 and 2020 who initiated curative intent, definitive chemo-radiation with one of three single agent regimens: high dose (HD) cisplatin, low dose (LD) cisplatin or cetuximab.

RESULTS: Patients with HPV-associated tumors and nonsmokers demonstrated improved overall and disease-free survival along …

Current Practices In Pediatric Continuous Kidney Replacement Therapy: A Systematic Review-Guided Multinational Modified Delphi Consensus Study, Dana Y Fuhrman, Katja M Gist, Ayse Akcan-Arikan

Faculty, Staff and Students Publications

BACKGROUND: Continuous kidney replacement therapy (CKRT) has become an integral part of the care of critically ill children. However, uncertainty exists regarding the current state of how CKRT is prescribed and delivered in children. The main objective of this study was to identify the current practices for pediatric CKRT.

METHODS: We conducted a systematic review of the literature from 2012 to 2022 to identify data regarding CKRT timing of initiation, dosing, anticoagulation, fluid removal, and quality monitoring. Using this data, we then performed a two-round modified Delphi process using a multinational internet-assisted survey of prescribers of CKRT.

RESULTS: The survey …

Safety And Efficacy Of Underwater Versus Conventional Endoscopic Mucosal Resection For Colorectal Polyps: Systematic Review And Meta-Analysis Of Rcts, Saurabh Chandan, Jay Bapaye, Shahab R Khan, Babu P Mohan, Daryl Ramai, Dushyant S Dahiya, Mohammad Bilal, Peter V Draganov, Mohamed O Othman, Joaquin Rodriguez Sánchez, Gursimran S Kochhar

Faculty, Staff and Students Publications

Background and study aims Conventional endoscopic mucosal resection (C-EMR) is limited by low en-bloc resection rates, especially for large (> 20 mm) lesions. Underwater EMR (U-EMR) has emerged as an alternative for colorectal polyps and is being shown to improve en-bloc resection rates. We conducted a systematic review and meta-analysis comparing the two techniques.

Methods Multiple databases were searched through November 2022 for randomized controlled trials (RCTs) comparing outcomes of U-EMR and C-EMR for colorectal polyps. Meta-analysis was performed to determine pooled proportions and relative risks (RRs) of R0 and en-bloc resection, polyp recurrence, resection time, and adverse events.

Results …

Kinase Inhibitor Pulldown Assay Identifies A Chemotherapy Response Signature In Triple-Negative Breast Cancer Based On Purine-Binding Proteins, Junkai Wang, Alexander B Saltzman, Eric J Jaehnig, Jonathan T Lei, Anna Malovannaya, Matthew V Holt, Meggie N Young, Mothaffar F Rimawi, Foluso O Ademuyiwa, Meenakshi Anurag, Beom-Jun Kim, Matthew J Ellis

Faculty, Staff and Students Publications

Triple-negative breast cancer (TNBC) constitutes 10%–15% of all breast tumors. The current standard of care is multiagent chemotherapy, which is effective in only a subset of patients. The original objective of this study was to deploy a mass spectrometry (MS)-based kinase inhibitor pulldown assay (KIPA) to identify kinases elevated in non-pCR (pathologic complete response) cases for therapeutic targeting. Frozen optimal cutting temperature compound–embedded core needle biopsies were obtained from 43 patients with TNBC before docetaxel- and carboplatin-based neoadjuvant chemotherapy. KIPA was applied to the native tumor lysates that were extracted from samples with high tumor content. Seven percent of all …

Androgen-Regulated Stromal Complement Component 7 (C7) Suppresses Prostate Cancer Growth, Zhicheng Zhou, Deyong Jia, Ohjoon Kwon, Shan Li, Huiyun Sun, Martine P Roudier, Daniel W Lin, Lawrence True, Colm Morrissey, Chad J Creighton, John K Lee, Li Xin

Faculty, Staff and Students Publications

The complement system is a major component of the innate immune system that works through the cytolytic effect of the membrane attack complex (MAC). Complement component 7 (C7) is essential for MAC assembly and its precisely regulated expression level is crucial for the cytolytic activity of MAC. We show that C7 is specifically expressed by the stromal cells in both mouse and human prostates. The expression level of C7 inversely correlates with clinical outcomes in prostate cancer. C7 is positively regulated by androgen signaling in the mouse prostate stromal cells. The androgen receptor directly transcriptionally regulates the mouse and human …

Heterogeneity Of The Group B Streptococcal Type Vii Secretion System And Influence On Colonization Of The Female Genital Tract, Brady L Spencer, Alyx M Job, Clare M Robertson, Zainab A Hameed, Camille Serchejian, Caitlin S Wiafe-Kwakye, Jéssica C Mendonça, Morgan A Apolonio, Prescilla E Nagao, Melody N Neely, Natalia Korotkova, Konstantin V Korotkov, Kathryn A Patras, Kelly S Doran

Faculty, Staff and Students Publications

Type VIIb secretion systems (T7SSb) in Gram-positive bacteria facilitate physiology, interbacterial competition, and/or virulence via EssC ATPase-driven secretion of small ɑ-helical proteins and toxins. Recently, we characterized T7SSb in group B Streptococcus (GBS), a leading cause of infection in newborns and immunocompromised adults. GBS T7SS comprises four subtypes based on variation in the C-terminus of EssC and the repertoire of downstream effectors; however, the intraspecies diversity of GBS T7SS and impact on GBS-host interactions remains unknown. Bioinformatic analysis indicates that GBS T7SS loci encode subtype-specific putative effectors, which have low interspecies and inter-subtype homology but contain similar domains/motifs and therefore …

A Myofiber-Derived Secreted Factor For Muscle Regeneration, Fang Xiao, Zheng Sun

Faculty, Staff and Students Publications

No abstract provided.

Feasibility Of Delivering A Virtual 1-Day Acceptance And Commitment Therapy Workshop To Rural Veterans Through Community Partnerships, Lilian Dindo, Angelic Chaison, Merlyn Rodrigues, Ken Woods, Alicia Mark, Derrecka Boykin

Faculty, Staff and Students Publications

Background: This single-arm, open pilot study examined the feasibility and initial efficacy of a 1-day virtual Acceptance and Commitment Therapy (ACT) group workshop for distressed veterans.

Methods: We collaborated with veteran-serving community-based organizations to enhance outreach to veterans, especially those in rural areas. Veterans completed a baseline assessment and two follow-up assessments (1 month, 3 months) after workshop participation. Feasibility outcomes included reach (workshop recruitment and completion rates; veteran characteristics) and acceptability (open-ended survey question about satisfaction). Clinical outcomes included psychological distress (Outcome Questionnaire-45), stressor-related distress (PTSD Checklist-5), community reintegration (Military to Civilian Questionnaire), and meaning and purpose (PROMIS Short …

Crat Links Cholesterol Metabolism To Innate Immune Responses In The Heart, Hua Mao, Aude Angelini, Shengyu Li, Guangyu Wang, Luge Li, Cam Patterson, Xinchun Pi, Liang Xie

Faculty, Staff and Students Publications

Chronic inflammation is associated with increased risk and poor prognosis of heart failure; however, the precise mechanism that provokes sustained inflammation in the failing heart remains elusive. Here we report that depletion of carnitine acetyltransferase (CRAT) promotes cholesterol catabolism through bile acid synthesis pathway in cardiomyocytes. Intracellular accumulation of bile acid or intermediate, 7α-hydroxyl-3-oxo-4-cholestenoic acid, induces mitochondrial DNA stress and triggers cGAS-STING-dependent type I interferon responses. Furthermore, type I interferon responses elicited by CRAT deficiency substantially increase AIM2 expression and AIM2-dependent inflammasome activation. Genetic deletion of cardiomyocyte CRAT in mice of both sexes results in myocardial inflammation and dilated cardiomyopathy, …

An Initial Trial Of Opt-In-Early: An Online Training Program For Caregivers Of Autistic Children, Yael G Dai, Rebecca P Thomas, Lynn Brennan, My-Linh Luu, Jamie Hughes-Lika, Molly Reilly, Paula Moreno, Brenda Obe, Kelli B Ahmed, Leandra N Berry, Robin P Goin-Kochel, Molly S Helt, Marianne L Barton, Thyde Dumont-Mathieu, Diana L Robins, Deborah A Fein

Faculty, Staff and Students Publications

Early intervention can help children learn language and improve social communication. However, many barriers, including the expense of services and an insufficient number of providers, prohibit families from accessing services when their children are young. We developed a comprehensive online program for caregivers of autistic children. The program, Online Parent Training in Early Behavioral Intervention (OPT-In-Early), uses text and video demonstrations to teach caregivers effective methods for improving their children's language, social, and adaptive skills (e.g. using utensils, toilet training), and reducing their children's disruptive behavior. Sixty-three parents from three states participated in the study. Half of the parents received …

Seladelpar Efficacy And Safety At 3 Months In Patients With Primary Biliary Cholangitis: Enhance, A Phase 3, Randomized, Placebo-Controlled Study, Gideon M Hirschfield, Mitchell L Shiffman, Aliya Gulamhusein, Kris V Kowdley, John M Vierling, Cynthia Levy, Andreas E Kremer, Ehud Zigmond, Pietro Andreone, Stuart C Gordon, Christopher L Bowlus, Eric J Lawitz, Richard J Aspinall, Daniel S Pratt, Karina Raikhelson, Maria S Gonzalez-Huezo, Michael A Heneghan, Sook-Hyang Jeong, Alma L Ladrón De Guevara, Marlyn J Mayo, George N Dalekos, Joost P H Drenth, Ewa Janczewska, Barbara A Leggett, Frederik Nevens, Victor Vargas, Eli Zuckerman, Christophe Corpechot, Eduardo Fassio, Holger Hinrichsen, Pietro Invernizzi, Palak J Trivedi, Lisa Forman, David E J Jones, Stephen D Ryder, Mark G Swain, Alexandra Steinberg, Pol F Boudes, Yun-Jung Choi, Charles A Mcwherter, Enhance Study Group

Faculty, Staff and Students Publications

BACKGROUND AND AIMS: ENHANCE was a phase 3 study that evaluated efficacy and safety of seladelpar, a selective peroxisome proliferator-activated receptor-δ (PPAR) agonist, versus placebo in patients with primary biliary cholangitis with inadequate response or intolerance to ursodeoxycholic acid (UDCA).

APPROACH AND RESULTS: Patients were randomized 1:1:1 to oral seladelpar 5 mg (n=89), 10 mg (n=89), placebo (n=87) daily (with UDCA, as appropriate). Primary end point was a composite biochemical response [alkaline phosphatase (ALP) < 1.67×upper limit of normal (ULN), ≥15% ALP decrease from baseline, and total bilirubin ≤ ULN] at month 12. Key secondary end points were ALP normalization at month 12 and change in pruritus numerical rating scale (NRS) at month 6 in patients with baseline score ≥4. Aminotransferases were assessed. ENHANCE was terminated early following an erroneous safety signal in a concurrent, NASH trial. While blinded, primary and secondary efficacy end points were amended to month 3. Significantly more patients receiving seladelpar met the primary end point (seladelpar 5 mg: 57.1%, 10 mg: 78.2%) versus placebo (12.5%) ( p < 0.0001). ALP normalization occurred in 5.4% ( p =0.08) and 27.3% ( p < 0.0001) of patients receiving 5 and 10 mg seladelpar, respectively, versus 0% receiving placebo. Seladelpar 10 mg significantly reduced mean pruritus NRS versus placebo [10 mg: -3.14 ( p =0.02); placebo: -1.55]. Alanine aminotransferase decreased significantly with seladelpar versus placebo [5 mg: 23.4% ( p =0.0008); 10 mg: 16.7% ( p =0.03); placebo: 4%]. There were no serious treatment-related adverse events.

CONCLUSIONS: Patients with primary biliary cholangitis (PBC) with inadequate response or intolerance to UDCA who were treated with seladelpar 10 mg had significant improvements in liver …

Clinical And Laboratory Predictors Of Dehydration Severity In Children With Diabetic Ketoacidosis, Jennifer L Trainor, Nicole S Glaser, Leah Tzimenatos, Michael J Stoner, Kathleen M Brown, Julie K Mcmanemy, Jeffrey E Schunk, Kimberly S Quayle, Lise E Nigrovic, Arleta Rewers, Sage R Myers, Jonathan E Bennett, Maria Y Kwok, Cody S Olsen, T Charles Casper, Simona Ghetti, Nathan Kuppermann, Pediatric Emergency Care Applied Research Network (Pecarn) Fluid Study Group

Faculty, Staff and Students Publications

STUDY OBJECTIVE: Our primary objective was to characterize the degree of dehydration in children with diabetic ketoacidosis (DKA) and identify physical examination and biochemical factors associated with dehydration severity. Secondary objectives included describing relationships between dehydration severity and other clinical outcomes.

METHODS: In this cohort study, we analyzed data from 753 children with 811 episodes of DKA in the Pediatric Emergency Care Applied Research Network Fluid Therapies Under Investigation Study, a randomized clinical trial of fluid resuscitation protocols for children with DKA. We used multivariable regression analyses to identify physical examination and biochemical factors associated with dehydration severity, and we …

Variation In Early Anakinra Use And Short-Term Outcomes In Multisystem Inflammatory Syndrome In Children, Joyce C Chang, Cameron C Young, Eyal Muscal, Sara K Sexson Tejtel, Margaret M Newhams, Suden Kucukak, Hillary Crandall, Aline B Maddux, Courtney M Rowan, Natasha B Halasa, Helen A Harvey, Charlotte V Hobbs, Mark W Hall, Michele Kong, Cassyanne L Aguiar, Jennifer E Schuster, Julie C Fitzgerald, Aalok R Singh, Kari Wellnitz, Ryan A Nofziger, Natalie Z Cvijanovich, Elizabeth H Mack, Adam J Schwarz, Sabrina M Heidemann, Jane W Newburger, Laura D Zambrano, Angela P Campbell, Manish M Patel, Adrienne G Randolph, Mary Beth F Son, Overcoming Covid Investigators

Faculty, Staff and Students Publications

OBJECTIVE: Evidence regarding effectiveness of interleukin-1 receptor antagonism in multisystem inflammatory syndrome in children (MIS-C) is lacking. We characterized variation in initial treatment with anakinra and evaluated cardiovascular outcomes associated with adding anakinra to standard initial therapy.

METHODS: We conducted a retrospective cohort study of MIS-C cases in a US surveillance registry from November 2020 to December 2021. Day 0 was the first calendar day of immunomodulatory treatment. Factors associated with initial anakinra use (days 0-1) were identified. We compared cases in patients ages 2-20 years receiving intravenous immunoglobulin (IVIG) and glucocorticoids versus anakinra plus IVIG and/or glucocorticoids on days …

Effect Of Exogenous L-Carnitine On Aortic Stiffness In Dyslipidemic Adolescents: Design Of A Quadruple-Blind, Randomized, Controlled Interventional Trial, Justin P Zachariah, Sandra Pena, Philip J Lupo, Nagireddy Putluri, Daniel J Penny, Melissa A Richard

Faculty, Staff and Students Publications

BACKGROUND: Atherosclerotic cardiovascular disease (ASCVD) risk factors including vascular remodeling leading to hypertension and dyslipidemia are prevalent among children and adolescents. Conflicting observational and Mendelian randomization data suggest endogenous carnitine may affect arterial stiffness and lipid traits. Because of this, we developed a study to evaluate the causal role for carnitine in arterial stiffness at a point when the lifecourse trajectory to hypertension can be modified.

METHODS: This study is a mechanistic, double-blinded, randomized control trial (RCT) in 166 adolescents with dyslipidemia for the effect of 6 months of maximum dose 3 g daily oral l-carnitine supplementation (CS+) versus placebo …

Spatial Mapping Of The Dna Adducts In Cancer, Kimiko L Krieger, Elise K Mann, Kevin J Lee, Elyse Bolterstein, Deborah Jebakumar, Michael M Ittmann, Valeria L Dal Zotto, Mohamed Shaban, Arun Sreekumar, Natalie R Gassman

Faculty, Staff and Students Publications

DNA adducts and strand breaks are induced by various exogenous and endogenous agents. Accumulation of DNA damage is implicated in many disease processes, including cancer, aging, and neurodegeneration. The continuous acquisition of DNA damage from exogenous and endogenous stressors coupled with defects in DNA repair pathways contribute to the accumulation of DNA damage within the genome and genomic instability. While mutational burden offers some insight into the level of DNA damage a cell may have experienced and subsequently repaired, it does not quantify DNA adducts and strand breaks. Mutational burden also infers the identity of the DNA damage. With advances …

Delayed Skeletal Development And Igf-1 Deficiency In A Mouse Model Of Lysinuric Protein Intolerance, Bridget M Stroup, Xiaohui Li, Sara Ho, Haonan Zhouyao, Yuqing Chen, Safa Ani, Brian Dawson, Zixue Jin, Ronit Marom, Ming-Ming Jiang, Isabel Lorenzo, Daniel Rosen, Denise Lanza, Nathalie Aceves, Sara Koh, John R Seavitt, Jason D Heaney, Brendan Lee, Lindsay C Burrage

Faculty, Staff and Students Publications

SLC7A7 deficiency, or lysinuric protein intolerance (LPI), causes loss of function of the y+LAT1 transporter critical for efflux of arginine, lysine and ornithine in certain cells. LPI is characterized by urea cycle dysfunction, renal disease, immune dysregulation, growth failure, delayed bone age and osteoporosis. We previously reported that Slc7a7 knockout mice (C57BL/6×129/SvEv F2) recapitulate LPI phenotypes, including growth failure. Our main objective in this study was to characterize the skeletal phenotype in these mice. Compared to wild-type littermates, juvenile Slc7a7 knockout mice demonstrated 70% lower body weights, 87% lower plasma IGF-1 concentrations and delayed skeletal development. Because poor survival prevents …

Shinybioheat: An Interactive Shiny App To Identify Phenotype Driver Genes In Ecoli And Bsubtilis, Chen Wang, Harikumar Govindarajan, Panagiotis Katsonis, Olivier Lichtarge

Faculty, Staff and Students Publications

SUMMARY: In any population under selective pressure, a central challenge is to distinguish the genes that drive adaptation from others which, subject to population variation, harbor many neutral mutations de novo. We recently showed that such genes could be identified by supplementing information on mutational frequency with an evolutionary analysis of the likely functional impact of coding variants. This approach improved the discovery of driver genes in both lab-evolved and environmental Escherichia coli strains. To facilitate general adoption, we now developed ShinyBioHEAT, an R Shiny web-based application that enables identification of phenotype driving gene in two commonly used model bacteria, …

Cation Leak Through The Atp1a3 Pump Causes Spasticity And Intellectual Disability, Daniel G Calame, Cristina Moreno Vadillo, Seth Berger, Timothy Lotze, Marwan Shinawi, Javaher Poupak, Corina Heller, Julie Cohen, Richard Person, Aida Telegrafi, Chalongchai Phitsanuwong, Kaylene Fiala, Isabelle Thiffault, Florencia Del Viso, Dihong Zhou, Emily A Fleming, Tomi Pastinen, Ali Fatemi, Sruthi Thomas, Samuel I Pascual, Rosa J Torres, Carmen Prior, Clara Gómez-González, Saskia Biskup, James R Lupski, Dragan Maric, Miguel Holmgren, Debra Regier, Sho T Yano

Faculty, Staff and Students Publications

ATP1A3 encodes the α3 subunit of the sodium-potassium ATPase, one of two isoforms responsible for powering electrochemical gradients in neurons. Heterozygous pathogenic ATP1A3 variants produce several distinct neurological syndromes, yet the molecular basis for phenotypic variability is unclear.

We report a novel recurrent variant, ATP1A3(NM_152296.5):c.2324C>T; p.(Pro775Leu), in nine individuals associated with the primary clinical features of progressive or non-progressive spasticity and developmental delay/intellectual disability. No patients fulfil diagnostic criteria for ATP1A3-associated syndromes, including alternating hemiplegia of childhood, rapid-onset dystonia-parkinsonism or cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss (CAPOS), and none were suspected of having an ATP1A3 …

Cellular And Extracellular Vaginal Changes Following Murine Ovarian Removal, Jennifer M Mccracken, Gisele A Calderon, Quynh N Le, Natasha M Faruqui, Swathi Balaji, Julie C E Hakim

Faculty, Staff and Students Publications

Loss of estrogen as a result of aging, pelvic cancer therapy, genetics, or eating disorders affects numerous body systems including the reproductive tract. Specifically, a chronic hypoestrogenic state fosters debilitating vaginal symptoms like atrophy, dryness, and dyspareunia. Current treatment options, including vaginal estrogen and hyaluronan (HA), anecdotally improve symptoms, but rectifying mechanisms are largely understudied. In order to study the hypoestrogenic vaginal environment, in particular the extracellular matrix (ECM), as well as understand the mechanisms behind current treatments and develop new therapies, we characterized a reliable and reproducible animal model. Bilateral ovariectomies (OVX) were performed on 9‐week‐old CD1 mice. After …