Digital Commons Network^™

Disease Activity Of Rheumatoid Arthritis And Kidney Function Decline: A Large Prospective Registry Study, Sho Fukui, Wolfgang C Winkelmayer, Sara K Tedeschi, Javier Marrugo, Hongshu Guan, Leslie Harrold, Heather J Litman, Tomohiro Shinozaki, Daniel H Solomon

Faculty, Staff and Students Publications

Introduction: Chronic kidney disease (CKD) is a common comorbidity of rheumatoid arthritis (RA). The association of longitudinal RA disease activity with long-term kidney function has remained uncertain.

Method: We analysed a multicentre prospective RA registry in the USA from 2001 to 2022. The exposure was updated time-averaged Clinical Disease Activity Index (TA-CDAI) categories from study enrolment. The primary outcome was a longitudinal estimated glomerular filtration rate (eGFR) change. Secondary outcomes included developments of CKD stage G3a (eGFR< 60 mL/min/1.73 m2) and stage G3b (eGFR< 45 mL/min/1.73 m2). Results were adjusted for relevant time-fixed and time-varying covariates.

Results: 31 129 patients (median age: 58.0 years, female: 76.3%, median eGFR: 90.7 mL/min/1.73 m2) contributed 234 973 visits and 146 778 person-years …

Benefits And Harms Of Hepatocellular Carcinoma Screening Outreach In Patients With Cirrhosis: A Multicenter Randomized Clinical Trial, Amit G Singal, Darine Daher, Manasa Narasimman, Sruthi Yekkaluri, Yan Liu, Vanessa Cerda, Chaitra Banala, Aisha Khan, Minjae Lee, Karim Seif El Dahan, Caitlin C Murphy, Jennifer R Kramer, Ruben Hernaez

Faculty, Staff and Students Publications

Background: The value of hepatocellular carcinoma screening is defined by the balance of benefits from early tumor detection vs harms because of false-positive results. We evaluated the value of a mailed outreach strategy for hepatocellular carcinoma screening in patients with cirrhosis.

Methods: We conducted a multicenter pragmatic randomized clinical trial comparing mailed outreach for hepatocellular carcinoma screening (n = 1436) and usual care with visit-based screening (n = 1436) among patients with cirrhosis at 3 health systems from March 2018 to September 2021. Outcomes of interest were early stage hepatocellular carcinoma detection (ie, screening benefit) and diagnostic evaluation for false-positive …

Parasite-Microbiota Interactions: A Pathway To Innovative Interventions For Chagas Disease, Leishmaniasis, And Ascariasis, Juan David Ramírez, Sergio Castañeda, Jill Weatherhead, Cristina Poveda

Faculty, Staff and Students Publications

Parasitic infections are a major global health challenge, driven in part by complex interactions between parasites, host microbiota, and immune responses. Recent advances in microbiome research highlight the critical role of microbiota in influencing disease outcomes and treatment effectiveness. This review examines how changes in the microbiota impact parasite transmission, disease progression, and responses to treatment, focusing on key parasitic diseases such as Chagas disease, leishmaniasis, and ascariasis. The microbiota can either exacerbate or mitigate disease severity, depending on its composition, providing critical insights for novel therapeutic strategies. Emerging approaches discussed include the use of targeted probiotics, prebiotics, and microbiota-modulating …

Magnesium Sulfate In The Management Of Acute Ischemic Stroke: A Review Of The Literature And Future Directions, Maximillian S Feygin, Alex Brenner, Omar Tanweer

Faculty, Staff and Students Publications

Background: The management of acute ischemic stroke (AIS) was revolutionized within the last 15 years with the introduction of mechanical thrombectomy (MT) to standard of care. Despite the success of mechanical thrombectomy (MT) in achieving high recanalization rates for large vessel occlusion, functional independence post-treatment remains suboptimal. The current limitations of MT prompt evaluation of the role of adjunctive pharmacologic neuroprotective therapies to prevent excitotoxicity, cellular apoptosis, and inflammation that cause irreversible neuronal damage during AIS. Magnesium (MgSO4) provides an attractive neuroprotectant profile, having many different effects, and is inexpensive, readily available, and has a long-established safety and tolerability profile …

Exploring Individual Differences In Amygdala-Mediated Memory Modulation, Martina K Hollearn, Joseph R Manns, Lou T Blanpain, Stephan B Hamann, Kelly Bijanki, Robert E Gross, Daniel L Drane, Justin M Campbell, Krista L Wahlstrom, Griffin F Light, Aydin Tasevac, Phillip Demarest, Peter Brunner, Jon T Willie, Cory S Inman

Faculty, Staff and Students Publications

Amygdala activation by emotional arousal during memory formation can prioritize events for long-term memory. Building upon our prior demonstration that brief electrical stimulation to the human amygdala reliably improved long-term recognition memory for images of neutral objects without eliciting an emotional response, our study aims to explore and describe individual differences and stimulation-related factors in amygdala-mediated memory modulation. Thirty-one patients undergoing intracranial monitoring for intractable epilepsy were shown neutral object images paired with direct amygdala stimulation during encoding with recognition memory tested immediately and one day later. Adding to our prior sample, we found an overall memory enhancement effect without …

Oxidative Stress Promotes Lipid-Laden Macrophage Formation Via Cyp1b1, Yin Zhu, Saugata Dutta, Yohan Han, Dooyoung Choi, Francesca Polverino, Caroline A Owen, Payaningal R Somanath, Xiaoyun Wang, Duo Zhang

Faculty, Staff and Students Publications

Emerging evidence suggests that lipid-laden macrophages (LLM) participate in lung damage in various clinical conditions. However, the mechanisms involved in LLM formation are not fully understood. In this study, we aimed to investigate the link between reactive oxygen species (ROS) and LLM formation. We found that ROS triggered by cigarette smoke extract (CSE) or H2O2 significantly promoted LLM formation. Given the key role of ROS in LLM formation, we further demonstrated that LLM formation is induced by various ROS-producing stimuli, including bacteria, oxidized low-density lipoprotein (OxLDL), hyperoxia, and E-cigarette vapor extract (EVE). Meanwhile, cytochrome P450 family-1 subfamily B member 1 …

Testosterone Modulation Of Muscle Transcriptomic Profile During Lifestyle Therapy In Older Men With Obesity And Hypogonadism, Viola Viola, Tagari Samanta, Maria Liza Duremdes Nava, Alessandra Celli, Reina Armamento-Villareal, Ngoc Ho Lam Nguyen, Georgia Colleluori, Yoann Barnouin, Nicola Napoli, Clifford Qualls, Benny Abraham Kaipparettu, Dennis T Villareal

Faculty, Staff and Students Publications

Background: Testosterone replacement therapy (TRT) added to lifestyle therapy can mitigate weight-loss-induced reduction of muscle mass and bone mineral density (BMD) in older men with obesity and hypogonadism.

Objective: To investigate the molecular mechanisms underlying the attenuation of muscle and BMD loss in response to TRT during intensive lifestyle intervention in this high-risk older population.

Methods: Among 83 older (≥ 65 years) men with obesity (BMI ≥ 30 kg/m2) and hypogonadism (early AM testosterone persistently < 300 ng/dL) associated with frailty (Modified Physical Performance Test score ≤ 31) randomized into 26-week lifestyle therapy plus testosterone (LT+TRT) or placebo (LT+Pbo) in the LITROS trial, 38 underwent serial muscle biopsies for the muscle transcriptomics substudy.

Results: Despite similar ~10% weight loss, lean body mass and thigh muscle volume decreased less in LT+TRT than LT+Pbo (-2% vs. -4%, respectively; p = …

Hospital Commitments To Address Diagnostic Errors: An Assessment Of 95 Us Hospitals, Alexandra Campione Russo, Jean-Luc Tilly, Leah Kaufman, Melissa Danforth, Mark L Graber, J Matthew Austin, Hardeep Singh

Faculty, Staff and Students Publications

Background: Diagnostic errors are a leading cause of patient harm. In 2022, the Leapfrog Group published a report containing 29 evidence-based practices that hospitals can adopt to reduce diagnostic errors.

Objectives: To understand the extent to which US hospitals have already implemented these practices, we conducted a national pilot survey of Leapfrog-participating hospitals.

Methods: To reduce respondent burden, we divided the 29 practices across two surveys: one focused on organizational culture and structure (Domain 1), and the second focused on the diagnostic process itself (Domain 2).

Results: A total of 95 hospitals from 23 states responded to one or both …

Advance: A Biomedical Informatics Approach To Investigate Acute Kidney Injury In Infants, Jennifer A Rumpel, Sofia Perazzo, Jonathan Bona, Andrew M South, Matthew W Harer, Daniel Liu, Michelle C Starr, Mona Khattab, Rachel Han, Cara Slagle, Eileen Ciccia, Tasnim Najaf, Matthew Gillen, Mimily Harsono, Arwa Nada, Kiran Dwarakanath, Semsa Gogcu, Tahagod Mohamed, Christine Stoops, Elizabeth Bonachea, Mary Revenis, Jessica Roberts, Robert Michael Lenzini, Anne Debuyserie, Catherine Joseph, Karna Murthy, Patricio Ray, Mario Schootman, Corey Nagel

Faculty, Staff and Students Publications

Background: Acute kidney injury (AKI) occurs in up to half of infants admitted to the neonatal intensive care unit (NICU) and is associated with increased risks of death and more days of mechanical ventilation, hospitalization, and vasopressor drug support. Our objective was to build a granular relational database to study the impact that AKI has on infants admitted to Level-IV NICUs.

Methods: A relational database was created by linking data from the Children's Hospitals Neonatal Database with AKI-focused data from electronic health records from 9 centers.

Results: The current cohort consists of 24,870 infants with a median (IQR) gestational age …

Forearm Versus Upper Arm Location Of Arteriovenous Access Used At Hemodialysis Initiation: Temporal Trends And Racial Disparities, Melandrea L Worsley, Jingbo Niu, Kevin F Erickson, Neal R Barshes, Wolfgang C Winkelmayer, L Parker Gregg

Faculty, Staff and Students Publications

Rationale & objective: Race and ethnicity differences exist in the type of arteriovenous access (AVA, including fistulas and grafts) used at hemodialysis (HD) initiation. The preferred anatomic location for the creation of an initial HD AVA is typically in the forearm We evaluated race and ethnicity differences in the use of an AVA in the forearm location at HD initiation.

Study design: Retrospective cohort study.

Setting & participants: Using records from DaVita Kidney Care linked to the US Renal Data System (USRDS), we evaluated patients aged≥16 years who initiated in-center HD with an AVA between 2006 and 2019.

Predictor: Race …

Qm107, A Novel Cd148 (Rtp Type J) Activating Peptide Therapy For Treating Neovascular Age-Related Macular Degeneration, Samantha Arokiasamy, Michaela J M Balderstone, Faheem Shaik, Enrico Cristante, Thomas C Moseley, Akshay Madoo, Matteo Rizzi, James W Bainbridge, Konstantin Tsoyi, Ivan O Rosas, James R Whiteford, Giulia De Rossi

Faculty, Staff and Students Publications

Background and purpose: Angiogenesis is a pathological component of neovascular age-related macular degeneration. Current therapies, although successful, are prone to high levels of patient non-response and a loss of efficacy over time, indicating the need to explore other therapeutic avenues. We have shown that an interaction between syndecan-2 and the tyrosine phosphatase receptor CD148 (RTP Type J) results in the ablation of angiogenesis. Here we exploit this pathway to develop a peptide activator of CD148 as a therapy for neovascular age-related macular degeneration.

Experimental approach: We tested a peptide (QM107) derived from syndecan-2 in a variety of angiogenesis models and …

Relationship Between Gestational Weight Gain With Fetal Body Composition And Organ Volumes In The Eunice Kennedy Shriver National Institute Of Child Health And Human Development (Nichd) Fetal Dimensional Study: A Prospective Pregnancy Cohort, Kathryn A Wagner, Zhen Chen, Stefanie N Hinkle, Jessica L Gleason, Wesley Lee, William A Grobman, John Owen, Roger B Newman, Daniel W Skupski, Dian He, Seth Sherman, Robert E Gore-Langton, Cuilin Zhang, Jagteshwar Grewal, Katherine L Grantz

Faculty, Staff and Students Publications

Background: Inadequate and excessive gestational weight gain (GWG) are associated with increased risk of newborn small- and large-for-gestational-age, respectively, and future offspring adiposity. However, the relationship between GWG and three-dimensional (3D) measures of fetal body composition and organ volumes, which may provide greater insight into fetal growth via measurement of soft tissue, remains unknown.

Objectives: The objective of this study was to examine the relationship between trimester-specific GWG and 3D fetal body composition and organ volume measurements.

Methods: In a diverse, US prospective pregnancy cohort, trimester-specific GWG was calculated as difference between maternal weight at beginning and end of each …

Long-Term Fxa Inhibition Attenuates Thromboinflammation After Acute Myocardial Infarction And Stroke By Platelet Proteome Alteration, Amin Polzin, Marcel Benkhoff, Manuela Thienel, Maike Barcik, Philipp Mourikis, Khrystyna Shchurovska, Carolin Helten, Vincent Ehreiser, Zhang Zhe, Franziska Von Wulffen, Alexander Theiss, Sameera Peri, Sophie Cremer, Samantha Ahlbrecht, Saif Zako, Laura Wildeis, Gabrielle Al-Kassis, Daniel Metzen, Amelie Utz, Hao Hu, Lilian Vornholz, Goran Pavic, Enzo Lüsebrink, Jan Strecker, Steffen Tiedt, Mareike Cramer, Michael Gliem, Tobias Ruck, Sven G Meuth, Tobias Zeus, Christoph Mayr, Herbert B Schiller, Lukas Simon, Steffen Massberg, Malte Kelm, Tobias Petzold

Faculty, Staff and Students Publications

Background: Immediate activated factor (F)X (FXa) inhibition exerts direct antiplatelet effects in the context of arterial thrombosis but little is known about the impact of long-term therapy on platelet function in ischemic cardiovascular diseases.

Objectives: Therefore, we analyzed platelet-derived effects of long-term FXa inhibition in the setting of acute myocardial infarction (AMI) and stroke.

Methods: We evaluated the effect of acute versus chronic FXa inhibition on thromboinflammation following AMI and stroke in mice in vivo. Mechanistically, we identified changes in platelet gene expression and proteome under chronic FXa nonvitamin K antagonist oral anticoagulant treatment and characterized its functional consequence on …

A Statistical Framework For Multi-Trait Rare Variant Analysis In Large-Scale Whole-Genome Sequencing Studies, Xihao Li, Han Chen, Margaret Sunitha Selvaraj, Eric Van Buren, Hufeng Zhou, Yuxuan Wang, Ryan Sun, Zachary R Mccaw, Zhi Yu, Min-Zhi Jiang, Daniel Dicorpo, Sheila M Gaynor, Rounak Dey, Donna K Arnett, Emelia J Benjamin, Joshua C Bis, John Blangero, Eric Boerwinkle, Donald W Bowden, Jennifer A Brody, Brian E Cade, April P Carson, Jenna C Carlson, Nathalie Chami, Yii-Der Ida Chen, Joanne E Curran, Paul S De Vries, Myriam Fornage, Nora Franceschini, Barry I Freedman, Charles Gu, Nancy L Heard-Costa, Jiang He, Lifang Hou, Yi-Jen Hung, Marguerite R Irvin, Robert C Kaplan, Sharon L R Kardia, Tanika N Kelly, Iain Konigsberg, Charles Kooperberg, Brian G Kral, Changwei Li, Yun Li, Honghuang Lin, Ching-Ti Liu, Ruth J F Loos, Michael C Mahaney, Lisa W Martin, Rasika A Mathias, Braxton D Mitchell, May E Montasser, Alanna C Morrison, Take Naseri, Kari E North, Nicholette D Palmer, Patricia A Peyser, Bruce M Psaty, Susan Redline, Alexander P Reiner, Stephen S Rich, Colleen M Sitlani, Jennifer A Smith, Kent D Taylor, Hemant K Tiwari, Ramachandran S Vasan, Satupa'itea Viali, Zhe Wang, Jennifer Wessel, Lisa R Yanek, Bing Yu, Nhlbi Trans-Omics For Precision Medicine (Topmed) Consortium, Josée Dupuis, James B Meigs, Paul L Auer, Laura M Raffield, Alisa K Manning, Kenneth M Rice, Jerome I Rotter, Gina M Peloso, Pradeep Natarajan, Zilin Li, Zhonghua Liu, Xihong Lin

Faculty, Staff and Student Publications

Large-scale whole-genome sequencing (WGS) studies have improved our understanding of the contributions of coding and noncoding rare variants to complex human traits. Leveraging association effect sizes across multiple traits in WGS rare variant association analysis can improve statistical power over single-trait analysis, and also detect pleiotropic genes and regions. Existing multi-trait methods have limited ability to perform rare variant analysis of large-scale WGS data. We propose MultiSTAAR, a statistical framework and computationally scalable analytical pipeline for functionally informed multi-trait rare variant analysis in large-scale WGS studies. MultiSTAAR accounts for relatedness, population structure and correlation among phenotypes by jointly analyzing multiple …

American Cochlear Implant Alliance Position Statement On Newborn Congenital Cytomegalovirus Screening, Megan Honor Pesch, Kevin David Brown, Amy L Birath, Gail J Demmler-Harrison, Cailtin Sapp, Anne Morgan Selleck, Alex D Sweeney

Faculty, Staff and Students Publications

It is estimated that 1 in every 200 US newborns has congenital cytomegalovirus (cCMV). Delayed identification of cCMV in newborns precludes timely intervention to mitigate sequelae of the infection such as hearing loss and other neurological complications. Newborn testing for cCMV enables appropriate diagnosis and intervention by multidisciplinary teams to properly manage the immediate sequelae of cCMV, avoid unnecessary additional testing that can result from delayed diagnosis, and monitor for future complications. It is the position of the American Cochlear Implant Alliance, the National CMV Foundation, and the American Academy of Otolaryngology-Head and Neck Surgery that universal newborn cCMV screening …

Gheard: An Open-Access Modular Curriculum To Incorporate Equity, Anti-Racism, And Decolonization Training Into Global Health Education, Amy R L Rule, Heather A Haq, Adelaide Barnes, Demarco Bowen, Msandeni Chiume-Kayuni, Whitney Cameron, S Aya Fanny, Elizabeth Groothuis, Bethany Hodge, Cindy Howard, James C Hudspeth, Sheridan Langford, Megan S Mchenry, Ijeoma Nnodim Opara, Beena D Kamath-Rayne, Parminder S Suchdev, Reena P Tam, Franci Taylor, Victor Musiime

Faculty, Staff and Students Publications

Background Global health (GH) interest is rising among graduate medical education (GME) trainees, yet GH engagement is marred by the impact of colonization or racism, and there remains a lack of training to confront these challenges.

Objective To develop a modular, open-access curriculum that provides training in decolonization for GH GME and evaluate its feasibility and impact on learners’ critical reflection on decolonization.

Methods From 2019 to 2022, 40 GH educators, including international and indigenous scholars from diverse organizations, created the Global Health Education for Equity, Anti-Racism, and Decolonization (GHEARD) curriculum. Using Kern’s 6 steps of curriculum development, critical gaps …

Figg At 5: An Update On Us Public Perspectives On Forensic Investigative Genetic Genealogy Five Years After Its Introduction To Criminal Investigations, Christi J Guerrini, Jill O Robinson, Mohamed I Elsaid, Whitney Bash Brooks, Ariel Levchenko, Stephanie M Fullerton, Sara Huston, Norah L Crossnohere, John F P Bridges, Jacklyn M Dahlquist, Louiza Kalokairinou, Diana Madden, Cece Moore, Amy L Mcguire

Center for Medical Ethics and Health Policy Staff Publications

In 2018, after law enforcement announced it had used a technique called forensic investigative genetic genealogy (FIGG) to identify the Golden State Killer, we conducted a U.S. general population survey and found most respondents supported using FIGG to solve violent crimes. Since then, FIGG has helped close hundreds of criminal cases, but it also has weathered controversies. On FIGG's fifth anniversary, we conducted an expanded, follow-up survey with U.S.-based participants to determine if public opinion had changed and found continued support for FIGG across most applications. The same proportion (91 %) of respondents in the 2018 and 2023 surveys endorsed …

Incidence And Survival Of Children And Adolescents With Wilms Tumor, United States, 2001-2020, Andres F Espinoza, Ekene Onwuka, David A Siegel, Shifan Dai, Sanjeev A Vasudevan, Michael E Scheurer, Philip J Lupo

Center for Medical Ethics and Health Policy Staff Publications

Background: Wilms tumor (WT) is the most common pediatric malignancy of the kidney. Past studies describing WT incidence and survival used surveillance data with < 30% of the US population. We evaluated differences in WT incidence and survival comparing demographic groups and tumor characteristics.

Methods: We analyzed new cases of WT among patients aged < 20 years at diagnosis by using incidence data from US Cancer Statistics (USCS) for 2003-2020 and 5-year relative survival (RS) data from the National Program of Cancer Registries (NPCR) for 2001-2019. To assess incidence trends, average annual percent change (AAPC) was calculated by using joinpoint regression. Relative survival (RS) and all-cause survival were calculated overall and by demographic and clinical variables.

Results: During 2003-2020, 8218 cases of WT were reported in USCS, which represented an age-adjusted incidence rate of 5.7 cases per million. Rates were the highest among females (6.3), children aged 0-4 years (17.2), and non-Hispanic Black patients (7.1). Overall, trends remained stable (AAPC = -0.4, 95% CI: -1.4 to 0.4). Among 7567 cases of WT in NPCR, 5-year RS was 92.6%. Patients with the lowest …

Improving Individualized Rhabdomyosarcoma Prognosis Predictions Using Somatic Molecular Biomarkers, Mark Zobeck, Javed Khan, Rajkumar Venkatramani, M Fatih Okcu, Michael E Scheurer, Philip J Lupo

Center for Medical Ethics and Health Policy Staff Publications

Purpose: Molecular markers increasingly influence risk-stratified treatment selection for pediatric rhabdomyosarcoma (RMS). This study aims to integrate molecular and clinical data to produce individualized prognosis predictions that can further improve treatment selection.

Methods: Clinical variables and somatic mutation data for 20 genes from 641 patients with RMS in the United Kingdom and the United States were used to develop three Cox proportional hazard models for predicting event-free survival (EFS). The Baseline Clinical (BC) model included treatment location, age, fusion status, and risk group. The Gene Enhanced 2 (GE2) model added TP53 and MYOD1 mutations to the BC predictors. The Gene …

Polygenic Score For Clinicopathologic Features And Survival Outcomes In Papillary Thyroid Carcinoma, Sophie Li, Guibin Zheng, Li Xu, Maitrayee Goswami, Mark E Zafereo, Steven I Sherman, Guojun Li, Erich M Sturgis, Jennifer R Wang

Faculty, Staff and Students Publications

Importance: Genome-wide association studies have identified germline variants associated with the development of papillary thyroid carcinoma (PTC) that can be used to construct a polygenic score (PGS). It is important to determine whether patients with higher germline genetic risk, as summarized using PGS, present with more aggressive disease and/or develop worse clinical outcomes.

Objective: To assess whether germline risk defined by PGS is associated with clinicopathologic features and survival outcomes for patients with PTC.

Design, setting, and participants: This retrospective cohort study included patients with newly diagnosed PTC who presented to The University of Texas MD Anderson Cancer Center for …

Effectiveness Of The Primary Bacillus Calmette-Guérin Vaccine Against The Risk Of Mycobacterium Tuberculosis Infection And Tuberculosis Disease: A Meta-Analysis Of Individual Participant Data, Puck T Pelzer, Logan Stuck, Leonardo Martinez, Alexandra S Richards, Carlos Acuña-Villaorduña, Naomi E Aronson, Maryline Bonnet, Anna C Carvalho, Pei-Chun Chan, Li-Min Huang, Chi-Tai Fang, Gavin Churchyard, Helena Del Corral-Londoño, Manjula Datta, Marcos A Espinal, Katherine Fielding, Andrew J Fiore-Gartland, Alberto Garcia-Basteiro, Willem Hanekom, Mark Hatherill, Phillip C Hill, Helena Huerga, Edward C Jones-López, Afranio Kritski, Anna M Mandalakas, Punam Mangtani, Eduardo Martins Netto, Harriet Mayanja, Rufaida Mazahir, Megan Murray, Molebogeng Rangaka, Thomas Scriba, Jitendra Singh, Sarman Singh, Catherine M Stein, Johan Vekemans, Lilly M Verhagen, Julian A Villalba, Anne Wajja, Basilea Watson, Richard G White, Frank G J Cobelens

Faculty, Staff and Students Publications

Background: Tuberculosis vaccine trials using disease as the primary endpoint are large, time consuming, and expensive. An earlier immunological measure of the protection against disease would accelerate tuberculosis vaccine development. We aimed to assess whether the effectiveness of the Bacillus Calmette-Guérin (BCG) vaccine for prevention of Mycobacterium tuberculosis infection was consistent with that for prevention of tuberculosis disease.

Methods: We conducted an individual participant data (IPD) meta-analysis on experimental and observational longitudinal studies before April 6, 2018, identified through systematic reviews, known to us through expert knowledge in the field, reporting on BCG vaccination status, M tuberculosis infection test (QuantiFERON …

Spock2 Controls The Proliferation And Function Of Immature Pancreatic Β-Cells Through Mmp2, Katarzyna Blaszczyk, Anna P Jedrzejak, Natalia Ziojla, Ekaterina Shcheglova, Karolina Szarafin, Artur Jankowski, Christine A Beamish, Jolanta Chmielowiec, Omaima M Sabek, Ashok Balasubramanyam, Sanjeet Patel, Malgorzata Borowiak

Faculty, Staff and Students Publications

Human pluripotent stem cell-derived β-cells (SC-β-cells) represent an alternative cell source for transplantation in diabetic patients. Although mitogens could in theory be used to expand β-cells, adult β-cells very rarely replicate. In contrast, newly formed β-cells, including SC-β-cells, display higher proliferative capacity and distinct transcriptional and functional profiles. Through bidirectional expression modulation and single-cell RNA-seq, we identified SPOCK2, an ECM protein, as an inhibitor of immature β-cell proliferation. Human β-cells lacking SPOCK2 presented elevated MMP2 expression and activity, leading to β-integrin-FAK-c-JUN pathway activation. Treatment with the MMP2 protein resulted in pronounced short- and long-term SC-β-cell expansion, significantly increasing glucose-stimulated insulin …

Wonoep Appraisal: Targeted Therapy Development For Early Onset Epilepsies, Pablo M Casillas-Espinosa, Jennifer C Wong, Wanda Grabon, Ana Gonzalez-Ramos, Massimo Mantegazza, Nihan Carcak Yilmaz, Manisha Patel, Kevin Staley, Raman Sankar, Terence J O'Brien, Özlem Akman, Ganna Balagura, Adam L Numis, Jeffrey L Noebels, Stéphanie Baulac, Stéphane Auvin, David C Henshall, Aristea S Galanopoulou

Faculty, Staff and Students Publications

The early onset epilepsies encompass a heterogeneous group of disorders, some of which result in drug-resistant seizures, developmental delay, psychiatric comorbidities, and sudden death. Advancement in the widespread use of targeted gene panels as well as genome and exome sequencing has facilitated the identification of different causative genes in a subset of these patients. The ability to recognize the genetic basis of early onset epilepsies continues to improve, with de novo coding variants accounting for most of the genetic etiologies identified. Although current disease-specific and disease-modifying therapies remain limited, novel precision medicine approaches, such as small molecules, cell therapy, and …

Exome Sequencing In Asian Populations Identifies Low-Frequency And Rare Coding Variation Influencing Parkinson’S Disease Risk, Elaine Gy Chew, Zhehao Liu, Zheng Li, Sun Ju Chung, Michelle M Lian, Moses Tandiono, Yue Jing Heng, Ebonne Y Ng, Louis Cs Tan, Wee Ling Chng, Tiak Ju Tan, Esther Kl Peh, Ying Swan Ho, Xiao Yin Chen, Erin Yt Lim, Chu Hua Chang, Jonavan J Leong, Ting Xuan Peh, Ling Ling Chan, Yinxia Chao, Wing-Lok Au, Kumar M Prakash, Jia Lun Lim, Yi Wen Tay, Vincent Mok, Anne Yy Chan, Juei-Jueng Lin, Beom S Jeon, Kyuyoung Song, Clement C Tham, Chi Pui Pang, Jeeyun Ahn, Kyu Hyung Park, Janey L Wiggs, Tin Aung, Ai Huey Tan, Azlina Ahmad Annuar, Mary B Makarious, Cornelis Blauwendraat, Mike A Nalls, Laurie A Robak, Roy N Alcalay, Ziv Gan-Or, Richard Reynolds, Shen-Yang Lim, Yun Xia, Chiea Chuen Khor, Eng-King Tan, Zhenxun Wang, Jia Nee Foo

Faculty, Staff and Students Publications

Parkinson’s disease (PD) is an incurable, progressive and common movement disorder that is increasing in incidence globally because of population aging. We hypothesized that the landscape of rare, protein-altering variants could provide further insights into disease pathogenesis. Here we performed whole-exome sequencing followed by gene-based tests on 4,298 PD cases and 5,512 controls of Asian ancestry. We showed that GBA1 and SMPD1 were significantly associated with PD risk, with replication in a further 5,585 PD cases and 5,642 controls. We further refined variant classification using in vitro assays and showed that SMPD1 variants with reduced enzymatic activity display the strongest …

Diagnostic Performance Of Contrast-Enhanced Ultrasound In Traumatic Solid Organ Injuries In Children: A Systematic Review And Meta-Analysis, Payam Jannatdoust, Parya Valizadeh, Amir Hassankhani, Melika Amoukhteh, Delaram J Ghadimi, Mahsa Heidari-Foroozan, Paniz Sabeghi, Paniz Adli, Jennifer H Johnston, Pauravi S Vasavada, Ali Gholamrezanezhad

Faculty, Staff and Student Publications

Background: Blunt abdominal trauma (BAT) is a significant contributor to pediatric mortality, often causing liver and spleen injuries. Contrast-enhanced computed tomography (CT), the gold standard for diagnosing solid organ injury, poses radiation risks to children. Contrast-enhanced ultrasound (CEUS) may be a promising alternative imaging modality.

Objectives: To evaluate the diagnostic utility of CEUS for detecting solid organ injuries following BAT in the pediatric population.

Methods: A systematic review and meta-analysis were conducted through a thorough literature search in PubMed, Scopus, Web of Science, and Embase databases up to October 1, 2023. Diagnostic accuracy metrics were aggregated using a bivariate model, …

The Cost Of Inflammatory Bowel Disease Care: How To Make It Sustainable, Johan Burisch, Jennifer Claytor, Inmaculada Hernandez, Jason Ken Hou, Gilaad G Kaplan

Faculty, Staff and Students Publications

The rising global prevalence of inflammatory bowel diseases (IBDs), such as Crohn's disease and ulcerative colitis, underscores the need to examine current and future IBD care costs. Direct health care expenses, including ambulatory visits, hospitalizations, and medications, are substantial, averaging $9,000 to $12,000 per person annually in high-income regions. However, these estimates do not fully account for factors such as disease severity, accessibility, and variability in health care infrastructure among regions. Indirect costs, predominantly stemming from loss in productivity due to absenteeism, presenteeism, and other intangible costs, further contribute to the financial burden of IBD. Despite efforts to quantify indirect …

Diagnoses Supported By A Computerised Diagnostic Decision Support System Versus Conventional Diagnoses In Emergency Patients (Ddx-Bro): A Multicentre, Multiple-Period, Double-Blind, Cluster-Randomised, Crossover Superiority Trial, Wolf E Hautz, Thimo Marcin, Stefanie C Hautz, Stefan K Schauber, Gert Krummrey, Martin Müller, Thomas C Sauter, Cornelia Lambrigger, David Schwappach, Mathieu Nendaz, Gregor Lindner, Simon Bosbach, Ines Griesshammer, Philipp Schönberg, Emanuel Plüss, Valerie Romann, Svenja Ravioli, Nadine Werthmüller, Fabian Kölbener, Aristomenis K Exadaktylos, Hardeep Singh, Laura Zwaan

Faculty, Staff and Students Publications

Background: Diagnostic error is a frequent and clinically relevant health-care problem. Whether computerised diagnostic decision support systems (CDDSSs) improve diagnoses is controversial, and prospective randomised trials investigating their effectiveness in routine clinical practice are scarce. We hypothesised that diagnoses made with a CDDSS in the emergency department setting would be superior to unsupported diagnoses.

Methods: This multicentre, multiple-period, double-blind, cluster-randomised, crossover superiority trial was done in four emergency departments in Switzerland. Eligible patients were adults (aged ≥18 years) presenting with abdominal pain, fever of unknown origin, syncope, or non-specific symptoms. Emergency departments were randomly assigned (1:1) to one of two …

Tuning A Secondary Dose Verification Software For A Ct-Guided Online Adaptive Delivery System, Xiaodong Zhao, Markus Baur, Phillip D H Wall, Eric Laugeman

2020-Current year OA Pubs

BACKGROUND: Quality assurance (QA) remains unstandardized for CT-guided online adaptive radiotherapy (CTgART) platforms (Ethos, Varian Medical Systems, Inc., Palo Alto, CA), as they become more clinically prevalent. A secondary dose calculation software (Mobius3D, Varian Medical Systems, Inc., Palo Alto, CA) is provided for this closed CTgART system. However, the clinical impact of tuning dosimetric leaf gap (DLG) correction values for specific delivery techniques for CTgART secondary dose calculations remains uninvestigated.

PURPOSE: Tuning the DLG correction value for different delivery techniques of the independent secondary dose verification software for adaptive online QA.

METHODS: A total of 31 volumetric arc therapy (VMAT) …

Respiratory Syncytial Virus Disease Burden And Nirsevimab Effectiveness In Young Children From 2023-2024, Heidi L Moline, Ariana P Toepfer, Ayzsa Tannis, Geoffrey A Weinberg, Mary A Staat, Natasha B Halasa, Julie A Boom, Eileen J Klein, John V Williams, Jennifer E Schuster, Leah Goldstein, Erin R Mckeever, Casey Kalman, Clinton Paden, Lydia Atherton, Megha Aggarwal, Pavitra Roychoudhury, Pedro A Piedra, Leila C Sahni, Laura S Stewart, Rangaraj Selvarangan, Marian G Michaels, Elizabeth P Schlaudecker, Peter G Szilagyi, Janet A Englund, Benjamin R Clopper, Natalie J Thornburg, Gordana Derado, Meredith L Mcmorrow, Fatimah S Dawood, New Vaccine Surveillance Network Collaborators

Faculty, Staff and Students Publications

Importance: During the 2023-2024 respiratory syncytial virus (RSV) season in the United States, 2 new RSV prevention products were recommended to protect infants in their first RSV season: nirsevimab and Pfizer's maternal RSV vaccine. Postlicensure studies are needed to assess prevention product impact and effectiveness.

Objective: To compare the epidemiology and disease burden of medically attended RSV-associated acute respiratory illness (ARI) among children younger than 5 years during the 2023-2024 RSV season with 3 prepandemic RSV seasons (2017-2020), estimate nirsevimab effectiveness against medically attended RSV-associated ARI, and compare nirsevimab binding site mutations among circulating RSV in infants with and without …

Emapalumab Treatment In Patients With Rheumatologic Disease-Associated Hemophagocytic Lymphohistiocytosis In The United States: A Retrospective Medical Chart Review Study, Shanmuganathan Chandrakasan, Carl E Allen, Deepika Bhatla, John Carter, May Chien, Robert Cooper, Lauren Draper, Olive S Eckstein, Rabi Hanna, J Allyson Hays, Michelle L Hermiston, Ashley P Hinson, Patricia M Hobday, Michael S Isakoff, Michael B Jordan, Jennifer W Leiding, Renee Modica, Taizo A Nakano, Abiola Oladapo, Sachit A Patel, Priti Pednekar, Mona Riskalla, Susmita N Sarangi, Prakash Satwani, Anand Tandra, Kelly J Walkovich, John D Yee, Adi Zoref-Lorenz, Edward M Behrens

Faculty, Staff and Students Publications

Objective: Rheumatologic disease-associated hemophagocytic lymphohistiocytosis (HLH), a rare, life-threatening, systemic hyperinflammatory syndrome, occurs as a complication of underlying rheumatologic disease. Real-world evidence is lacking on emapalumab, a fully human monoclonal antibody that neutralizes the proinflammatory cytokine interferon-γ, approved for treating patients with primary HLH.

Methods: REAL-HLH, a retrospective medical chart review study conducted across 33 US hospitals, assessed real-world treatment patterns and outcomes in patients with HLH treated with one or more dose of emapalumab between November 20, 2018, and October 31, 2021. Data are presented for the subset of patients with rheumatologic disease-associated HLH.

Results: Fifteen of 105 patients …