Digital Commons Network^™

Lifestyle Intervention Therapy Modulates Global Dna Methylation And Adipogenic Gene Expression In Severely Obese Hypogonadal Men, Siresha Bathina, Virginia Fuenmayor Lopez, Mia Prado, Salina Biene Teo, Dennis T Villareal, Rui Chen, Clifford Qualls, Reina Armamento-Villareal

Faculty, Staff and Students Publications

Background/Objectives: Previous studies have suggested that lifestyle intervention (LSI) therapies involving diet and exercise can modulate DNA methylation; however, whether this occurs in severely obese hypogonadal men undergoing weight loss from diet and exercise remains unclear.

Methods: In this study, we investigated the effects of weight loss from diet and exercise on global DNA methylation as well as on the mRNA expression of specific demethylation enzymes, DNMT1, DNMT3A, and DNMT3B—in peripheral blood mononuclear cells (PBMCs) and DNA methylation markers in DNA of severely obese hypogonadal men. This is a secondary analysis of samples of severely obese (body …

Incidence Of Venous Thromboembolism In Women Receiving Transdermal Oestradiol/Testosterone With Micronised Progesterone In Accordance With Nice Guidelines, Amy Neville, Dan Reisel, John Benton, Mohit Khera, Louise Newson

Faculty, Staff and Students Publications

Background: Despite growing evidence supporting the long-term safety of hormone replacement therapy (HRT), concerns persist about certain adverse health outcomes, including venous thromboembolism (VTE). The aim of the study is to evaluate the risk of VTE in peri- and postmenopausal women treated with transdermal 17β-oestradiol with micronised progesterone or intrauterine progesterone (levonorgestrel) via the Mirena coil, in a real-world clinical setting.

Methods: The study included peri- and postmenopausal women attending a private menopause clinic between January 1, 2023, and December 31, 2023. Patients were actively undergoing treatment with transdermal oestradiol and progesterone in the form of micronised oral progesterone or …

Gut Microbiota Modulation Via Repeated Donor Fecal Transplantation Improves Motor And Gastrointestinal Symptoms In Drug-Naïve Parkinson’S Disease: A Randomized Phase 2 Trial, Rui Zhang, Renyi Feng, Jiuqi Wang, Yongkang Chen, Han Liu, Qingyong Zhu, Haiyan Tian, Chi Qin, Junfang Teng, Beisha Tang, Min Wu, Jinsheng Zeng, Erxi Wu, Xuebing Ding, Xuejing Wang

Faculty, Staff and Students Publications

The gut-brain axis is increasingly recognized as a critical contributor to Parkinson's disease (PD) pathogenesis, yet the therapeutic impact of microbiota modulation remains unclear due to lack of clinical trials in drug-naïve patients. We conducted a randomized, double-blind, placebo-controlled phase 2 trial to evaluate the safety, tolerability, and efficacy of repeated donor fecal microbiota transplantation (dFMT) in de novo PD. FMT was administered for seven days (200 mL on days 1-3; 50 mL on days 4-7) per 4-week cycle. Seventy-two patients were randomized 1:1 to receive dFMT or autologous FMT (aFMT), and 66 completed the trial. At 35 weeks, the …

In Vivo Hsc Gene Therapy Enables Sustained Ecd4-Ig Expression For Siv Prevention, Chang Li, Anna K Anderson, Anne-Sophie Kuhlmann, Veronica Nelson, Audrey Germond, Hongjie Wang, Aphrodite Georgakopoulou, Sucheol Gil, Jasmin Martinez-Reyes, Andrew Riker, Shruthi Shankar Raman, Jiho Kim, Philip Ng, Donna Palmer, Michael D Alpert, Nickolas Skamangas, Charles Bailey, Tianling Ou, Christine M Fennessey, Michael Farzan, Keith R Jerome, Brandon F Keele, Hans-Peter Kiem, André Lieber, John K Bui

Faculty, Staff and Students Publications

We aim to develop an in vivo hematopoietic stem cell (HSC) gene therapy approach for the prevention and control of HIV-1 infection. Toward this goal, we engineered helper-dependent adenovirus (HDAd) 6/3+ vectors to directly transduce HSCs in vivo, enabling progeny cells to secrete eCD4-Ig, a decoy protein that broadly neutralizes HIV/simian immunodeficiency virus (SIV) isolates by mimicking the primary viral receptor CD4 and coreceptors such as CCR5. In rhesus macaques, the HDAd 6/3+ platform achieved long-term expression of an enhanced eCD4-Ig variant (“eCD4-Ig-Emm06”) that retained potent neutralization efficacy in vivo. Transduced HSCs differentiated into lymphoid and myeloid lineages …

Quality Of Life In Patients With P16+ Oropharyngeal Cancer Receiving Accelerated Radiation Therapy With Either Cisplatin Or Cetuximab In The Nrg/Rtog 1016 Randomized Controlled Trial, Jolie Ringash, Pedro A Torres-Saavedra, Maura L Gillison, Jimmy J Caudell, David J Adelstein, Paul M Harari, Erich M Sturgis, Ethan Basch, Shlomo A Koyfman, Greg A Krempl, Dukagjin M Blakaj, James Edward Bates, Thomas J Galloway, Christopher U Jones, Beth M Beadle, Jonathan Harris, Quynh-Thu Le, Sue S Yom, Benjamin Movsas

Faculty, Staff and Students Publications

Purpose: NRG/RTOG 1016 was a phase III randomized noninferiority de-escalation trial comparing cetuximab versus cisplatin, concurrent with accelerated radiation 70 Gy/6 weeks, in p16+ oropharyngeal cancer. Quality of life (QOL) was a secondary endpoint.

Methods and materials: Eligible/consenting patients among the first 400 entered completed the EORTC QLQ-C30/H&N35 at baseline, end of treatment, 3, 6, and 12 months posttreatment, to provide 90% power to detect an effect size of 0.5 in the between-arm change in QOL scores from baseline to 6 months. We report completion, responsiveness, and patterns over time across domains between arms, considering a difference of >10 points …

Cilostazol Conduction Effects: A Possible Adjunctive Therapy Option?, Justin Haloot, Yochai Birnbaum

Faculty, Staff and Students Publications

No abstract provided.

Incarcerated Geriatric Patients’ Experiences Of Aging And Healthcare, Michelle I Suh, Stephen Chen, Megan Benavides, Sumin Yoon, Nia Lucas, Josiah D Rich, Marc David Robinson, Anita N Chary

Faculty, Staff and Students Publications

Older adults comprise the fastest growing demographic in correctional facilities in the United States. Studies have shown older adults in prison report difficulty accessing healthcare and navigating the prison environment. Little is known about how older adults navigate aging and access healthcare in the jail setting. We sought to explore experiences of older adults incarcerated in a county jail. We conducted semi-structured qualitative interviews with 20 older adults (> 50 years old) who were incarcerated at a local county jail and were referred to the emergency department for acute care needs. Interviews focused on experiences of aging while incarcerated and …

An Interpretable Machine Learning Model For Predicting Prognosis Of Medulloblastoma Integrating Genetic And Clinical Features, Yu Su, Kaiwen Deng, Xuan Chen, Zhaoyang Feng, Dongyang Wang, Craig Daniels, Hyun Yong Koh, Ricardo Daniel Gonzalez, Hiromichi Suzuki, Tsubasa Miyauchi, Fei Liu, Wei Wang, Jiankang Li, Shuaicheng Li, Rui Chen, Xiaoguang Qiu, Chunde Li, Tao Jiang, Michael D Taylor, Jiao Zhang, Hailong Liu, Yu Tian

Faculty, Staff and Students Publications

Background: Medulloblastoma (MB), the most common malignant pediatric brain tumor, lacks prognostic tools integrating clinical, molecular, and treatment-related characteristics for individualized management.

Methods: We developed machine learning models using multicenter data from 729 Chinese patients (2001-2023), of whom 509 were assigned to the training set and 220 to the testing set, and further validated the models on 201 patients from international MB consortia. To accommodate patients and researchers with varying datatypes, four application scenarios were established, including clinical-molecular-radiotherapy (CMR), clinical-molecular (CM), clinical-radiotherapy (CR), and clinical-only (CO).

Results: We construct four model scenarios and assess their predictive performance in the testing …

Bacterial Fecal Microbiome Composition Associated With Hiv Stage Among Rural And Peri-Urban Adults Living With Hiv In Uganda, Bożena M Morawski, Elise R Morton, Miya Yunus, Claudia Muñoz-Zanzi, Rojelio Mejia, Ran Blekhman, David R Boulware, Sarah M Lofgren

Faculty, Staff and Students Publications

Background

Gut microbiome composition in HIV-infection provides insight into HIV pathogenesis and potentially offers avenues to adjunctive HIV therapies. Although two-thirds of people living with HIV (PLHIV) are in Africa, studies of the gut microbiome PLHIV have focused on non-African populations. Additionally, social, cultural, and environmental factors influence the gut microbiome and differ substantially between African and Western and urban and rural communities. Here, we quantify the relationships between immune status and fecal microbiome composition in 175 rural Ugandan PLHIV.

Methods

In 2013, 175 Ugandan PLHIV contributed a single fecal sample as part of a cohort study of 202 participants. …

Underexplored Maternal Microbiomes: Immune, Metabolic, And Microbial Pathways Shaping Pregnancy Outcomes, Rafael Tomoya Michita, Nicole Jimenez, Melissa M Herbst-Kralovetz, Indira U Mysorekar

Faculty, Staff and Students Publications

Maternal microbial ecosystems play critical roles in shaping reproductive physiology and pregnancy outcomes. During the pre-conception and prenatal periods, these communities modulate maternal physiology by regulating immune tolerance, nutrient metabolism, and susceptibility to pregnancy complications such as preterm birth, hypertensive disorders, and gestational diabetes. While the gut microbiota has been extensively studied, the roles of cervicovaginal, urinary, respiratory, oral, and upper reproductive tract microbiomes remain less clear. In this minireview, we synthesize current knowledge on these underexplored maternal microbiomes, with an emphasis on the cervicovaginal and urinary microbiota and their interactions with the placenta and fetus. We discuss cross-niche microbial …

Hematopoietic Cell Transplantation For Wiskott-Aldrich Syndrome: A Pidtc Report, Jessie L Alexander, Blachy J Dávila Saldaña, Ruta Brazauskas, Sravya Gethika Dammalapati, Linda M Griffith, Ami J Shah, Kristin A Shimano, Hans D Ochs, Jack J Bleesing, Christen L Ebens, Malika Kapadia, Andrea Bauchat, Neena Kapoor, Joseph H Oved, Hesham Eissa, Hannah Lust, Michael D Keller, Hilary Haines, Shanmuganathan Chandrakasan, Julie-An Talano, Ahmad Rayes, Lisa Madden, Evan Shereck, Holly K Miller, Lisa Forbes Satter, Caridad Martinez, Jacob Rozmus, Jeffrey J Bednarski, Lolie C Yu, Deepakbabu Chellapandian, Victor M Aquino, Alan Knutsen, Hey Chong, Ashley Chopek, Alfred P Gillio, Avni Joshi, Hemalatha Rangarajan, Theodore B Moore, Jeffrey R Andolina, Kenneth B Desantes, Mark Vander Lugt, Susan E Prockop, David C Shyr, Kathleen E Sullivan, Suhag Parikh, Katja G Weinacht, Troy R Torgerson, Rebecca Marsh, Christopher C Dvorak, Alice Y Chan, Elie Haddad, Jennifer R Heimall, Michael A Pulsipher, Jennifer W Leiding, Donald B Kohn, Jennifer M Puck, Luigi D Notarangelo, David J Rawlings, Morton J Cowan, Aleksandra Petrovic, Sung-Yun Pai, Lauri M Burroughs

Faculty, Staff and Students Publications

Wiskott-Aldrich syndrome (WAS), an X-linked disorder characterized by immunodeficiency, thrombocytopenia, autoimmunity, and malignancy, can be effectively treated with allogeneic hematopoietic cell transplantation (HCT). Older age at HCT and mismatched donors are known to affect overall survival (OS). However, the influence of specific clinical manifestations or WAS variant class on OS and factors associated with event-free survival (EFS) remain incompletely defined. We analyzed outcomes of 308 patients with WAS who underwent HCT at 37 institutions of the Primary Immune Deficiency Treatment Consortium from 1990 to 2018. With a median follow-up of 5.3 years, the 5-year OS and EFS were 87.2% and …

Association Between Bmi Z-Score And Postoperative Complications In Pediatric Neuromuscular Scoliosis Surgery, Alexander K Mihas, Dion Birhiray, Chun Wai Hung, Lorenzo R Deveza, Dallas Vanorny, Frank Gerow, Darrell Hanson, Benny Dahl

Faculty, Staff and Students Publications

Study Design

Single-center retrospective review.

Objective

To investigate the association between BMI Z-scores and postoperative complications in pediatric patients with neuromuscular scoliosis undergoing spinal instrumentation.

Methods

Pediatric patients who underwent spinal instrumentation for neuromuscular scoliosis from July 2012 to June 2016 with a minimum 2-year follow-up were included. BMI and BMI Z-scores were calculated, and patients were stratified into CDC-defined BMI-for-age percentiles: underweight (< 5th percentile), normal (5th to < 85th percentile), overweight (85th to < 95th percentile), and obese (≥95th percentile). Logistic regression assessed associations of BMI, BMI Z-score, and BMI groups with postoperative complications.

Results

In total, 147 patients were included. Average follow-up was 3.2 ± 1.4 years. The most common diagnosis was cerebral palsy (39.5%). Complications occurred in 65 (44.2%) patients: 32 (21.8%) had a surgical site infection (SSI), …

Early Camp Signaling Orchestrates Single-Cell Synchronicity Throughout Dictyostelium Development, Mariko Katoh-Kurasawa, Lena Trnovec, Peter Lehmann, Rui Chen, Yumei Li, Blaž Zupan, Gad Shaulsky

Faculty, Staff and Students Publications

Synchronicity is observed in many biological systems, including development, as seen in vertebrate body axis formation, fly eye development, and development of the social amoeba D. discoideum. Despite its prevalence, quantitative analyses of synchronicity at the single-cell level remain rare. Here we show that synchronicity in D. discoideum is mediated by early cAMP signaling. Using single-cell RNA sequencing (scRNA-seq), we quantify transcriptome similarities between individual cells during development. We show that synchronicity first declines upon starvation but then increases with the onset of cAMP-pulse signaling. Synchronicity remains stable throughout development and differs between prespore and prestalk cells. Genetic perturbations of …

Proteomics Analysis Of Plasma For Risk Of Sepsis: Findings From The Atherosclerosis Risk In Communities Study, Junichi Ishigami, Xiao Hu, Pascal Schlosser, Thomas R Austin, Jingsha Chen, Bruce M Psaty, David Dowdy, Christie M Ballantyne, Morgan E Grams, Josef Coresh, James S Floyd, Kunihiro Matsushita

Faculty, Staff and Students Publications

Background: Sepsis is a life-threatening complication of infection with high mortality. A high-throughput analysis of circulating blood proteins may provide mechanistic insight and potent therapeutic targets for the prevention of sepsis.

Methods: We used multivariable Cox regression analysis to examine the association of 4955 plasma proteins, measured by SomaScan, with the risk of incident sepsis among 11 065 participants of the Atherosclerosis Risk in Communities (ARIC) Study (visit 3 in 1993 to 1995; mean age, 60.1 years, 54.4% female, 21.0% Black). Proteins (false discovery rate [FDR] of P < 0.05) discovered at visit 3 were replicated using data at visit 5 (n = 4869 in 2011 to 2013: mean age, 75.5 years) and in the Cardiovascular Health Study (CHS) (n = 3512 in 1992 to 1993; mean age, 74.5 years). Canonical pathways were identified by enrichment analyses.

Results: At ARIC visit three, 669 proteins were associated with the risk …

Bi-Allelic Variants In Nrdc Cause A Neurodevelopmental Disorder Characterized By Neonatal Lethality, Microcephaly, And Brain Abnormalities, Davut Pehlivan, Abigail Sandoval, Reza Maroofian, François Lecoquierre, Aisha M Al Shamsi, Gyu S Lee, Osman Yesilbas, Preston Taylor, Matthew B Mcdougal, Vahid Bahrambeigi, Omid Aryani, Juan Felipe Ramirez, Khalid Hama Salih, Chadi Al Alam, Heba Morsy, Haytham Hussien, Tarek Omar, Ibrahim M Abdelrazek, Anne Claire Brehin, Dana Marafi, Tugba Kalayci, Jubran Abu Rahma, Jawabreh Kassem Talbeya, Husein Dabbah, Eric Verspyck, Toktam Moosavian, Jawid M Fatih, Tadahiro Mitani, Gulsen Akay, Daniel G Calame, Anne-Marie Guerrot, Wendy K Chung, Henry Houlden, James R Lupski, Adel Shalata, Wan Hee Yoon

Faculty, Staff and Students Publications

Nardilysin (NRDC) plays a role in multiple cellular functions in diverse cellular compartments, including ectodomain shedding in the plasma membrane, as well as chaperoning a key Krebs cycle enzyme in mitochondria. We had previously reported limited clinical information from two individuals with homozygous frameshift variants in NRDC. With inclusion of previously published individuals, here we report 14 individuals (10 females, four males) from nine unrelated families carrying homozygous NRDC pathogenic variants. Common clinical features include severe to profound developmental delay/intellectual disability (12/12), microcephaly (13/13), prematurity (5/13), lethality in the first 3 years of life (9/14), seizures (7/11), joint contractures (4/8), …

Modulating Alternative Splicing Of Mecp2 Is A Potential Therapeutic Strategy For Rett Syndrome, Harini P Tirumala, Li Wang, Yan Li, Sameer S Bajikar, Ashley G Anderson, Wei Wang, Alexander J Trostle, Mahla Zahabiyon, Aleksandar Bajic, Jean J Kim, Hu Chen, Zhandong Liu, Huda Y Zoghbi

Faculty, Staff and Students Publications

Rett syndrome (RTT) is a neurological disorder caused by loss-of-function mutations in methyl CpG binding protein 2 (MECP2), a transcriptional regulator essential for maintenance of normal neuronal function. The current FDA-approved treatment for RTT, Trofinetide, mildly alleviates some symptoms. In contrast, re-introducing MeCP2 or increasing its amount through transgenesis in mouse RTT models improves most neurological phenotypes and enhances survival. Here, we devised a therapeutic strategy to moderately increase MeCP2 protein by modulating the alternative splicing of MECP2 to switch the less efficiently translated e2 to the more efficiently translated e1 isoform. We deleted Mecp2 exon 2 (unique …

Characteristics And Incidence Of Gastric Cancer Among Patients With Autoimmune And Non-Autoimmune Atrophic Gastritis In A U.S. Population, Mimi C Tan, Kadon N Caskey, Irene Jeong-Ah Lee, Yan Liu, Juan Gomez Cifuentes, Shilpa Jain, Hashem B El-Serag

Faculty, Staff and Students Publications

Background: Autoimmune gastritis (AIG) is a risk factor for gastric neuroendocrine tumor (NET). We compared risk factors between AIG cases, non-autoimmune atrophic gastritis (NAIG) cases, and normal controls and determined the incidence of gastric malignancy, including adenocarcinoma and NET.

Methods: We included patients who underwent endoscopy with gastric biopsy between 3/2006 and 9/2021 in Harris Health (Houston, Texas). We identified AIG cases, NAIG cases (gastric atrophy or intestinal metaplasia [GIM] without autoimmune features), and normal controls (without AIG, NIAG, and GIM). A GI pathologist confirmed AIG diagnosis on histopathology report or slide. We determined risk factors of AIG compared to …

Pharmacologic And Oncohistone Inhibition Of Setd2 Converge On Genomic Instability, Alyssa T Paparella, Ashley G Boice, In Young Park, Rajkishor Nishad, Durga Tripathi, Seth A Nelson, Edward W Pietryk, H Josh Jang, Ian J Frew, W Kimryn Rathmell, Frank M Mason, Cristian Coarfa, Ruhee Dere, Cheryl Lyn Walker

Faculty, Staff and Students Publications

Background/objectives: SETD2 is a dual-function methyltransferase important for methylation of histone H3 at lysine 36 and α-tubulin in spindle microtubules. Genetic inactivation of SETD2 during oncogenesis drives loss of H3K36me3, genomic instability, and cancer progression. This study asked if disruption of genomic stability was a canonical feature of SETD2 inactivation via different pathways.

Methods: We evaluated the impact of EPZ-719, a pharmacologic SETD2 inhibitor, and an H3.3K36M mutant histone ("oncohistone") that binds and sequesters SETD2, on methylation activity and genomic stability in human cell lines. SETD2 activity was measured using in vitro methylation assays, H3K36me3 loss confirmed by Western analysis, …

Ten Years Real-World Experience With Sacubitril/Valsartan In Patients With Heart Failure With Reduced Ejection Fraction, Gianluigi Savarese, Christian Basile, Alexandre Mebazaa, Antoni Bayes-Genis, Seok Min Kang, Byung-Su Yoo, Carlos Eid, Biykem Bozkurt, Javed Butler

Faculty, Staff and Students Publications

Introduction: Sacubitril/valsartan (Sac/Val) represents a cornerstone of heart failure (HF) with reduced ejection fraction (HFrEF) management. This systematic review provides a comprehensive overview of real-world evidence (RWE) regarding the implementation, clinical effectiveness, and safety of Sac/Val in patients with HFrEF.

Methods: A systematic literature search of PubMed was conducted through March 2024 following PRISMA guidelines.

Results: The review included 45 manuscripts from 30 different studies, primarily from Europe (44%) and the US (30%). RWE confirmed that Sac/Val was associated with a lower risk of cardiovascular mortality (10%-16%), HF hospitalization (10%-38%), and all-cause mortality (10%-25%). Sac/Val was significantly associated with cardiac …

Activin A Secretion By Muscle-Repairing Macrophages Induces Heterotopic Ossification In Mice, Wenqiang Yin, Kazuo Okamoto, Asuka Terashima, Warunee Pluemsakunthai, Takehito Ono, Taku Ito-Kureha, Shizuo Akira, Yoshinobu Hashizume, Roland Baron, Satoshi Ueha, Kouji Matsushima, Martin M Matzuk, Yuji Mishina, Hiroshi Takayanagi

Faculty, Staff and Students Publications

The immune system is not only essential for host defense, but it is also involved in tissue maintenance and disease pathogenesis. Macrophages play a key role in tissue repair, fibrosis, and tumorigenesis, but the mechanisms underlying their multifunctionality have not been fully explored. Here, we identified Mrep (Ly6ChiCX3CR1loPDPN+CD9+) as a crucial subset of macrophages for muscle regeneration after muscle injury. Muscle regeneration required Mrep-derived activin A, which was produced via the TLR4/TIR domain-containing adapter-inducing interferon-β/TANK-binding kinase 1/interferon regulatory factor 3/7 signaling pathway in response to muscle injury. Mrep exerted pathological effects by secreting activin A in a model of genetically …

Regulating Ai In Pediatrics-Is Transparency Enough?, R Brandon Hunter, Kolaleh Eskandanian, Chester J Koh

Faculty, Staff and Students Publications

No abstract provided.

Rounding Styles On Inpatient Infectious Disease Consult Services: Impact On Education And Patient-Care Delivery, Melanie Kiener, Vanessa Ku, Prathit A Kulkarni

Faculty, Staff and Students Publications

Inpatient infectious disease (ID) consult services have recently been experiencing increased patient volumes due to a variety of factors, including higher patient complexity, increased patient turnover, growing rates of antimicrobial resistant infections, population aging, and ID outbreaks. As a result, increased time and resources have been required to continue to deliver high-quality medical care to patients. At academic teaching hospitals, providing patient care in the context of increased volumes must be balanced with the educational mission for trainees. Rounding is a central component of ID clinical work which brings together patient care and education. In this narrative review, we aim …

Validation And Longitudinal Trajectory Analysis Of An Ai-Based Ecg Model For Aortic Stenosis: From Community Screening To Pre-Ta\Vr Risk Stratification, Matthew W Segar, Kaleb D Lambeth, Alexander Postalian, Stephanie Coulter, Jasen Gilge, Naveed Razvi, Mohammad Saeed, Robert D Paisley, Ambarish Pandey, Mehdi Razavi

Faculty, Staff and Students Publications

Aims: Early aortic stenosis (AS) detection remains challenging, with many patients presenting late when left ventricular dysfunction may be irreversible. We evaluated whether longitudinal AI-enhanced ECG patterns can predict outcomes years before intervention and assessed the community screening potential of the AK-AVS model.

Methods and results: We conducted two complementary analyses: (1) community validation of the AK-AVS model in 3632 cardiovascular disease-free ARIC participants, and (2) longitudinal trajectory analysis of 7860 ECGs from 2040 TAVR recipients collected up to 10 years pre-procedure. Unsupervised clustering identified distinct AK-AVS trajectories, with mortality associations assessed using Cox regression and net reclassification improvement. In …

Comparison Of Opioid Utilization In Older Adults With Rheumatoid Arthritis Before And After Initiating Biological Or Targeted Synthetic Disease-Modifying Antirheumatic Drugs, Yinan Huang, Shadi Bazzazzadehgan, Liang-Yuan Lin, Omkar Ghodke, Sebastian Bruera, Kaustuv Bhattacharya, Sujith Ramachandran, John P Bentley, Sandeep K Agarwal, Yi Yang

Faculty, Staff and Students Publications

Introduction: Opioid use is common in rheumatoid arthritis (RA) for pain management; however, evidence of opioid-associated adverse events is increasing. While biological (b) or targeted synthetic (ts) disease-modifying antirheumatic drugs (DMARDs) improve functional outcomes such as pain, little is known about their impact on opioid utilization patterns. This study investigated opioid utilization before and after b/tsDMARD initiation and assessed effect modification by sex.

Methods: Using 5% Medicare claims data from 2012 to 2020, this cohort study included older adults (≥ 65 years) with RA who initiated b/tsDMARDs (first prescription = index date), and had continuous Medicare Parts A, B, and …

Sex Differences In Hospitalizations In The 6 Months Before A Diagnosis Of Transthyretin Amyloid Cardiomyopathy, Chun Shing Kwok, Adnan I Qureshi, Richard P Steeds, Gregg C Fonarow, Biykem Bozkurt, Marianna Fontana, Julian D Gillmore, William E Moody

Faculty, Staff and Students Publications

Background: The influence of sex on the extent of missed opportunities for early diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CM) has not been characterized.

Objectives: The objective of the study was to determine the rate and causes of hospitalization preceding the index admission with ATTR-CM, stratifying analyses according to sex.

Methods: We conducted a retrospective cohort study of the National Readmissions Database to evaluate the 6-month hospitalizations preceding an index admission with a diagnosis of ATTR-CM.

Results: Between 2018 and 2020, there were 10,975 patients hospitalized with ATTR-CM of whom 4,545 (41.1%) had 1 or more hospital admission within the preceding …

Nasopharyngeal Microbiome-Epigenome-Wide Association Analysis In Infants With Severe Bronchiolitis, Ryohei Shibata, Yijun Li, Anat Yaskolka Meir, Sara Javornik Cregeen, Matthew Clayton Ross, Janice A Espinola, Ashley F Sullivan, Liming Liang, Kohei Hasegawa, Carlos A Camargo, Zhaozhong Zhu

Faculty, Staff and Students Publications

Background: Bronchiolitis exposes infants to both acute burdens (e.g., hospitalization in cases of severe bronchiolitis) and increased risks for chronic respiratory sequelae (e.g., asthma). In severe bronchiolitis, recent evidence suggests distinct pathobiological roles of microbiota (e.g., viruses, bacteria) and host responses influenced by genetic and epigenetic factors. However, the relationship of airway microbiota with host DNA methylation (DNAm) in infants with severe bronchiolitis remains unknown.

Methods: In a multi-center prospective cohort of 504 multi-ethnic infants with severe bronchiolitis (age < 1 year), using nasopharyngeal microbiome (exposure) and blood DNAm (outcome, Infinium MethylationEPIC BeadChip, Illumina) data within 24 h of the hospitalization, we conducted microbiome-epigenome-wide association studies (mbEWAS). We examined microbiota-associated differentially methylated CpGs (mbDMCs, false discovery rate [FDR] < 0.05), regions (mbDMRs, FDR < 0.05), and DNAm age acceleration. We also determined the associations of DNAm age acceleration with asthma development by age 6 years. Furthermore, we focused on asthma-related pathogenic bacteria-Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae-for functional analyses by examining serum mbDMR-related proteins (Proseek Multiplex, Olink) and their enriched pathways (FDR < 0.10).

Results: Across 23 common taxa-observed at least in 25% of the infants, we identified 1 mbDMC (S. pneumoniae, cg16594639, chr20: 39528675) …

Histone Demethylase Jmjd1a Protects Mice From Enteric Bacterial Infection By Upregulating Ccl8 Expression To Recruit Macrophages And Cd4+ T Cells, Guifang Lin, Lichun Yang, Shuyan Jiang, Yong Zhang, Ping Luo, Weihua Li, Jianming Xu, Gongpeng Xiong, Chundong Yu, Wenbo Chen

Faculty, Staff and Students Publications

Jumonji domain-containing 1A (JMJD1A, also known as KDM3A) is a histone demethylase that specifically demethylates H3K9me1/2 to enhance gene expression. The roles of JMJD1A in many physiological and pathological processes have been revealed. However, it is unclear whether JMJD1A is involved in host defense against enteric pathogen infection. In this study, we found that enteric infection with C. rodentium induced JMJD1A expression in colonic epithelial cells at the transcriptional level partly mediated by IRF1. After C. rodentium infection, JMJD1A-/- mice exhibited increased mortality, colonic injury, and C. rodentium load and systemic spread, suggesting that JMJD1A protects host against C. rodentium …

Online Tutorial On Survival Analysis For Biomarker Discovery, Jaka Kokošar, Ela Praznik, Martin Špendl, Nancy P Moreno, Alana Newell, Gad Shaulsky, Blaž Zupan

Faculty, Staff and Students Publications

In biomedicine, survival analysis addresses time-to-event data to study outcomes like patient survival and treatment response, and supports biomarker discovery. Yet, teaching this analysis is often hindered by mathematical and programming barriers. We present a structured, hands-on tutorial that goes beyond a typical online guide-offering integrated video lectures, literature, quizzes, and practical exercises. Built around Orange Data Mining, an open and free no-code visual analytics platform, the tutorial covers key concepts such as censoring, Kaplan-Meier curves, group comparisons, and biomarker discovery through real-world datasets. Organized in four pedagogical units, it progresses from basic survival data analysis to gene and gene-set …

Comparison Of Variant Callers Using 60 532 Multi-Ancestry Whole Genome Sequences, Hufeng Zhou, Zilin Li, Derek Shyr, Xihao Li, Haoyu Yang, Rounak Dey, Yushi Tang, Robert Maier, Eric Boerwinkle, Steve Buyske, Mark Daly, Adam Felsenfeld, Richard A Gibbs, Namrata Gupta, Ira M Hall, Tara Matise, Ginger A Metcalf, Albert Smith, Catherine Reeves, Heidi J Sofia, Nathan O Stitziel, Michael C Zody, Nhgri Genome Sequencing Program (Gsp) Consortium, Benjamin Neale, Xihong Lin

Faculty, Staff and Students Publications

Whole genome sequencing (WGS) studies play a pivotal role in studying the genetic underpinnings of human diseases and traits. High quality and reproducible variant calling is the cornerstone for the success of downstream analyses, including WGS association studies and polygenic risk prediction. This paper compares the data quality, performance, and concordance of two widely used WGS variant callers, the Genome Analysis Toolkit (GATK) and Variant Tool set that discovers short variants (VT), using 60 532 multi-ancestry whole genomes sequenced by the Centers for Common Disease Genomics (CCDGs) of the NHGRI Genome Sequencing Program. Our findings show that both QCed GATK …

Segmental And Multifocal Isolated Dystonias: Similarities And Differences, Hyder A Jinnah, Vittorio Velucci, Daniele Belvisi, Gamze Kilic-Berkmen, Joel S Perlmutter, Laura J Wright, Christine Klein, Jeanne S Feuerstein, Steven Bellows, Joseph Jankovic, Cynthia Comella, Richard L Barbano, Aparna Wagle Shukla, Stephen G Reich, Mark S Ledoux, Alberto J Espay, Kevin R Duque, Florence C F Chang, Victor S C Fung, Sarah Pirio-Richardson, Carmen Terranova, Emile S Moukheiber, Sarah Idrissi, Barbara Vitucci, Susan H Fox, Samuel Frank, Natividad Stover, Brian D Berman, Rachel Saunders-Pullman, William G Ondo, Christopher L Groth, Marcello Esposito, Laura Avanzino, Francesco Bono, Roberto Erro, Marcello Mario Mascia, Antonella Muroni, Alfredo Berardelli, Giovanni Defazio

Faculty, Staff and Students Publications

Background: Whether the traditional distinction between segmental and multifocal dystonia is clinically or scientifically useful remains unclear.

Objective: To evaluate whether idiopathic isolated adult-onset segmental and multifocal dystonia can be differentiated based on clinical features other than the contiguity of affected body regions.

Methods: We compared data on segmental and multifocal dystonia from two large dystonia databases established in the USA and Italy that used similar criteria for patient recruitment and assessment.

Results: Compared to segmental dystonia, multifocal dystonia was characterized by a higher proportion of men, a younger age at dystonia onset, a greater frequency of upper limb dystonia, …