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Cd5 Expression In Ctcl And Its Implications For Anti-Cd5 Car T-Cell Therapy, Leena Wardeh, Madeline Williams, Courtney Prestwood, Zachary Wolner, Neda Nikbakht

Department of Dermatology and Cutaneous Biology Faculty Papers

Cutaneous T-Cell Lymphomas (CTCL) are a heterogenous group of T-cell malignancies in the skin and have poor treatment outcomes in advanced stages. CD5, a surface glycoprotein expressed on most mature T cells, has emerged as a promising target for chimeric antigen receptor (CAR) T-cell therapy in systemic T-cell lymphomas. However, its expression profile in CTCL and relevance for targeted therapy remain unclear. Notably, in CTCL, the cell surface expression of receptors, such as CD7 and CD26, tends to become downregulated on the surfaces of malignant T cells In this study, we analyzed single-cell RNA sequencing (scRNA-seq) data from patients at …

Signs, Symptoms, And Health-Related Quality Of Life In Melas: Measuring What’S Important From The Patient And Clinician Perspectives, Paolo Medrano, Benjamin Banderas, Marisa Brimmer, Lily Settel, Sari Berger, Alan Shields, Amy Goldstein, Amel Karaa, Austin Larson, Sumit Parikh, Fernando Scaglia, Karra Danyelle Harrington, Chris James Edgar, Pamela Ventola, Matthew Webster, Jennifer Chickering, Chad Gwaltney, Phebe Wilson, Chad Glasser

Faculty, Staff and Students Publications

Background and objectives: Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) is a rare genetic syndrome mostly associated with pathogenic variants in mitochondrial DNA. As there is limited research on the life experience of patients with MELAS, this study aimed to develop an understanding of the patient experience of MELAS through qualitative interviews to identify, describe, and substantiate important and relevant signs, symptoms, and health-related quality-of-life (HRQoL) impact (S/S/I) concepts.

Methods: Clinician and patient interviews were conducted virtually using semi-structured interview guides. During 60-minute interviews with five experts in the United States, clinicians were asked for their perspective on …

Correcting For The Inflated Adult Population Denominator In An English Nationwide Health Care Cohort: Database Analysis Study, Sudhir Venkatesan, Mark Joy, Gavin Jamie, Debasish Kar, Robert Williams, Xuejuan Fan, Wilhelmine Meeraus, Ruby S.M. Tsang, Kathryn S. Taylor, Sylvia Taylor, F. D. Richard Hobbs, Sneha N. Anand, Chris Robertson, Simon De Lusignan

Peninsula Medical School

Background:Electronic health care databases are widely used for epidemiological studies. However, they may contain inactive records of individuals no longer participating in the health care system. These inactive records create a methodological challenge as they systematically appear as unexposed with no recorded outcomes. Given the widespread health care system engagement during the COVID-19 pandemic, the English National Health Service (NHS), which hosts a national pandemic planning and research dataset with linkage to COVID-19 vaccination and emergency care data, makes it an ideal setting to identify the extent of overrepresentation due to inactive health care records and assess ways to mitigate …

Positron Emission Tomography Reveals Increased Myocardial Glucose Uptake In A Subset Of Friedreich Ataxia Patients, R Mark Payne, Thomas M O'Connell, P Melanie Pride, Gregg R Wagner, George J Eckert, Tiffany R Johnson, Weinian Shou, Gary D Hutchins

Faculty, Staff and Student Publications

Why some but not all patients with the rare disease Friedreich ataxia (FRDA) are at increased risk of poor cardiovascular outcome and death is unclear and unpredictable. We investigated the hypothesis that mitochondrial dysfunction in FRDA leads to altered patterns of myocardial metabolic substrate utilization. We recruited 5 healthy controls (Ctl) and 11 FRDA participants. All underwent fasting myocardial positron emission tomography (PET scan) with 15O–H2O, 18F-FDG, and 11C-Palmitate. We conducted cardiac transcriptomics on mice with ablation of the Frda gene in heart to explore mechanisms of fuel substrate utilization. Five (45%) FRDA participants had an LV mass index (LVMi) …

Transdiagnostic Alterations In White Matter Microstructure Associated With Suicidal Thoughts And Behaviours In The Enigma Suicidal Thoughts And Behaviours Consortium, Laura S Van Velzen, Lejla Colic, Zuriel Ceja, Maria R Dauvermann, Luca M Villa, Hannah S Savage, Yara J Toenders, Niousha Dehestani, Alyssa H Zhu, Adrian I Campos, Lauren E Salminen, Martin Alda, Ingrid Agartz, Nina Alexander, Rosa Ayesa-Arriola, Elizabeth D Ballard, Nerisa Banaj, Carlotta Barkhau, Zeynep Başgöze, Jochen Bauer, Francesco Benedetti, Klaus Berger, Bianca Besteher, Katharina Brosch, Manuel Canal-Rivero, Simon Cervenka, Romain Colle, Colm G Connolly, Emmanuelle Corruble, Philippe Courtet, Baptiste Couvy-Duchesne, Benedicto Crespo-Facorro, Kathryn R Cullen, Udo Dannlowski, Jeremy Deverdun, Ana M Diaz-Zuluaga, Lorielle M F Dietze, Jennifer W Evans, Negar Fani, Kira Flinkenflügel, Naomi P Friedman, Ian H Gotlib, Nynke A Groenewold, Dominik Grotegerd, Tomas Hajek, Alexander S Hatoum, Marco Hermesdorf, Ian B Hickie, Yoshiyuki Hirano, Tiffany C Ho, Yuki Ikemizu, Frank Iorfino, Jonathan C Ipser, Yuko Isobe, Andrea P Jackowski, Fabrice Jollant, Tilo Kircher, Melissa Klug, Sheri-Michelle Koopowitz, Anna Kraus, Axel Krug, Emmanuelle Le Bars, Elisabeth J Leehr, Meng Li, Elizabeth T C Lippard, Carlos Lopez-Jaramillo, Ivan I Maximov, Andrew M Mcintosh, Katie A Mclaughlin, Sean R Mcwhinney, Susanne Meinert, Elisa Melloni, Philip B Mitchell, Benson Mwangi, Igor Nenadić, Stener Nerland, Emilie Olie, Victor Ortiz-García De La Foz, Pedro M Pan, Fabricio Pereira, Fabrizio Piras, Federica Piras, Sara Poletti, Andrew E Reineberg, Gloria Roberts, Rafael Romero-García, Matthew D Sacchet, Giovanni A Salum, Anca-Larisa Sandu, Carl M Sellgren, Eiji Shimizu, Harry R Smolker, Jair C Soares, J Douglas Steele, Frederike Stein, Dan J Stein, Benjamin Straube, Lea Teutenberg, Florian Thomas-Odenthal, Paula Usemann, Romain Valabregue, Johanna Valencia-Echeverry, Gerd Wagner, Gordon Waiter, Martin Walter, Heather C Whalley, Mon-Ju Wu, Tony T Yang, Carlos A Zarate, Andre Zugman, Giovana B Zunta-Soares, Kees Van Heeringen, Sanne J H Van Rooij, Nic Van Der Wee, Steven Van Der Werff, Paul M Thompson, Hilary P Blumberg, Anne-Laura Van Harmelen, Miguel E Rentería, Neda Jahanshad, Enigma Suicidal Thoughts And Behaviours Consortium, Lianne Schmaal

Faculty, Staff and Student Publications

Previous studies have suggested that alterations in white matter (WM) microstructure are implicated in suicidal thoughts and behaviours (STBs). However, findings of diffusion tensor imaging (DTI) studies have been inconsistent. In this large-scale mega-analysis conducted by the ENIGMA Suicidal Thoughts and Behaviours (ENIGMA-STB) consortium, we examined WM alterations associated with STBs. Data processing was standardised across sites, and resulting WM microstructure measures (fractional anisotropy (FA), axial diffusivity (AD), mean diffusivity and radial diffusivity) for 24 WM tracts and one global measure were pooled across 40 cohorts. We compared these measures among individuals with a psychiatric diagnosis and lifetime history of …

Distinct Spatiotemporal Patterns Of White Matter Hyperintensity Progression, Jinyong Chung, Gilsoon Park, Wi-Sun Ryu, Dawid Schellingerhout, Hang-Rai Kim, Dong-Seok Gwak, Elizabeth Haddad, Neda Jahanshad, Beom Joon Kim, Keun-Sik Hong, Hyerin Oh, Sang-Wuk Jeong, Joon-Tae Kim, Man Seok Park, Kang-Ho Choi, Kyungbok Lee, Tai Hwan Park, Sang-Soon Park, Jong-Moo Park, Kyusik Kang, Kyung-Ho Yu, Mi Sun Oh, Soo Joo Lee, Jae Guk Kim, Jae-Kwan Cha, Dae-Hyun Kim, Jun Lee, Moon-Ku Han, Yong-Jin Cho, Byung-Chul Lee, Philip M Bath, Joanna M Wardlaw, Hee-Joon Bae, Hosung Kim, Dong-Eog Kim

Faculty, Staff and Student Publications

White matter hyperintensity, a key imaging biomarker for brain health, has prognostic implications for stroke. Using a multicenter MRI dataset of 9179 stroke patients plus the UK Biobank (n = 36,210 low/high risk controls), we employ Subtype and Stage Inference modeling and identify three distinct white matter hyperintensity progression subtypes: fronto-parietal, radial, and temporo-occipital. Longitudinal validation confirms classification stability. The fronto-parietal subtype shows delayed onset and more hypertension, while the temporo-occipital subtype has more atrial fibrillation and coronary heart disease. The fronto-parietal and radial subtypes are linked to small vessel stroke, while the temporo-occipital subtype is linked to cardioembolism. The …

Racial Disparities In Clonal Hematopoiesis And Their Impact On Hematologic Malignancies, Zijian Zhang, Chao Cheng

Faculty, Staff and Students Publications

Clonal hematopoiesis of indeterminate potential (CHIP) is a known risk factor for hematologic malignancies (HM), but its distribution and clinical implications across diverse ancestries remain poorly characterized. In this study, we investigated CHIP and its progression to HM in a large, racially diverse cohort from the All of Us Research Program, comprising 245,388 participants. We identified 10,446 CHIP driver mutations in 9,476 individuals. Our analysis revealed clear racial disparities in CHIP prevalence and mutational profiles: African American (AA) individuals had higher odds of CHIP and exhibited distinct mutation patterns compared to White American (WA) individuals. Consistent with prior studies, CHIP …

Whole-Genome Sequencing Reveals Individual And Cohort Level Insights Into Chromosome 9p Syndromes, Yingxi Wang, Eleanor I Sams, Rachel Slaugh, Sandra Crocker, Emily Cordova Hurtado, Sophia Tracy, Ying-Chen Claire Hou, Christopher Markovic, Kostandin Valle, Victoria Tate, Khadija Belhassan, Elizabeth Appelbaum, Titilope Akinwe, Rodrigo T Starosta, Yang Cao, Amber Neilson, Yu Liu, Nathaniel Jensen, Reza Ghasemi, Tina Lindsay, Juana Manuel, Sophia Couteranis, Milinn Kremitzki, Jack Ustanik, Thomas Antonacci, Jeffrey K Ng, Andrew Emory, Laura Metz, Tracie Deluca, Katherine N Lyons, Toni Sinnwell, Brianne Thomeczek, Kymme Wang, Nick Sisneros, Megha Muraleedharan, Anantha Kethireddy, Marco Corbo, Harsha Gowda, Katherine A King, Christina A Gurnett, Susan K Dutcher, Catherine Gooch, Yang E Li, Matthew W Mitchell, Kevin A Peterson, Amjad Horani, Jill A Rosenfeld, Weimin Bi, Pawel Stankiewicz, Hsiao-Tuan Chao, Jennifer E Posey, Christopher M Grochowski, Zain Dardas, Erik G Puffenberger, Christopher E Pearson, Frank Kooy, Dale Annear, A Micheil Innes, Michael Heinz, Richard Head, Robert Fulton, Stephan Toutain, 9p-Arch, Lucinda Antonacci-Fulton, Xiaoxia Cui, Robi D Mitra, F Sessions Cole, Julie Neidich, Patricia I Dickson, Jeffrey Milbrandt, Tychele N Turner

Faculty, Staff and Students Publications

Background: Previous genomic efforts on chromosome 9p deletion and duplication syndromes have utilized low-resolution strategies (i.e., karyotypes, chromosome microarrays). These studies have provided important initial insights into these syndromes. This current study is the first large-scale whole-genome sequencing (WGS) study of 100 individuals from families with chromosome 9p syndromes.

Methods: Through the newly formed 9P-ARCH (Advanced Research in Chromosomal Health: Genomic, Phenotypic, and Functional Aspects of 9p-Related syndromes) research network, we assembled a cohort of individuals from families with chromosome 9p syndromes. WGS was applied to 100 individuals, and other genomic technologies were applied to a subset of individuals. To …

Increasing Opportunities For Community Input In Harm Reduction Program Development Using Iterative Engagement., Nicole M. Wagner, Jordan A. Carlson, Meagan Bean, Amy Wineland, Joshua Blum, Scott A. Cardona, Sheila Covarrubias, Allison Kempe, Abby C. King, Amy G. Huebschmann

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Incorporating people who use substances into a community-engaged research process can support the implementation and evaluation of evidence-based harm reduction programs. Attending to their voice ensures those who need these programs will use them. Yet, ongoing co-learning with people who use substances, often the ideal for community engaged research, poses a challenge for recruitment, ongoing participation, and obtaining diverse perspectives. We need novel strategies to support flexibility among populations experiencing legal and social instability so that community engaged work includes more diverse perspectives. In this paper, we describe a novel community engagement approach called Effective Adaptable and Sustainable in …

Mir147 Promotes Mucosal Integrity And Healing In Intestinal Inflammation, Agnieszka K Czopik, Arash Dabiri, Chia-Hao Tung, Victoria Vaughn, Xiangsheng Huang, Jinlian Wang, Hui Li, Nicolas F Moreno, Natalia V Piwko, Katherine Figarella, Hongfang Liu, Zhongming Zhao, Xiaoyi Yuan, Holger K Eltzschig

Faculty, Staff and Student Publications

The intestinal mucosal epithelium forms a barrier between luminal contents and the body. MicroRNAs (miRNAs) regulate mucosal homeostasis by controlling inflammatory responses and structural integrity. Here, we discovered a protective role for miR147 in intestinal inflammation using a miR147tdTomato reporter mouse. miR147 was enriched in the intestines, with the highest expression in the colonic epithelial cells at the luminal surface, with prominent expression in differentiated enterocytes. Mice with general or intestinal epithelial deletion of miR147 showed increased intestinal inflammation and diminished mucosal healing during colitis. RNA sequencing of miR147-deficient cells showed dysregulated immune signaling, with upregulated proinflammatory cytokine pathways and …

Lifestyle Data-Based Multiclass Obesity Prediction With Interpretable Ensemble Models Incorporating Shap And Lime Analysis, Shahid Mohammad Ganie, Pijush Kanti Dutta Pramanik, Zhongming Zhao

Faculty, Staff and Student Publications

Obesity is a major public health concern. Predicting obesity risk from lifestyle data can guide targeted interventions, but current models remain limited. This study first evaluates ensemble learning methods and then combines approaches to improve prediction accuracy and generalizability. Four ensemble techniques-boosting, bagging, stacking, and voting-were tested. Five boosting and five bagging models were constructed alongside voting and stacking models. Hyperparameter tuning optimized performance, and feature importance analysis guided potential feature elemination. In phase two, hybrid stacking and voting models integrated the best-performing boosting and bagging models to enhance predictive capability. Model robustness was ensured through k-fold cross-validation and statistical …

Genome-Wide Association Study Of Childhood B-Cell Acute Lymphoblastic Leukemia Reveals Novel African Ancestry-Specific Susceptibility Loci, Cindy Im, Andrew R Raduski, Lauren J Mills, Kashi Raj Bhattarai, Robert J Mobley, Kelly R Barnett, Zhanni Lu, Kenneth Liao, Nathan Anderson, Rebecca A Johnson, Erica Langer, Anthony J Hooten, Alix E Seif, Kathrin M Bernt, Matthew Tsang, Brandon A Mamou, Luis Gil-De-Gómez, Julie A Wolfson, Danielle N Friedman, Neerav Shukla, Laura J Klesse, Erin L Marcotte, Lingyun Ji, Alice Dang, Minjie Luo, Yiming Zhong, Jalen Langie, Charleston W K Chiang, Adam De Smith, Joseph L Wiemels, Andrew Dewan, Xiaomei Ma, Catherine Metayer, Zhaoming Wang, Heather H Nelson, Nathan Pankratz, Tianzhong Yang, Saonli Basu, Lucie M Turcotte, Jun J Yang, Daniel Savic, Michael E Scheurer, Logan G Spector

Faculty, Staff and Students Publications

B-cell acute lymphoblastic leukemia (B-ALL) is the most common pediatric malignancy. Given racial/ethnic differences in incidence and outcomes, B-ALL genome-wide association studies among children of African ancestry are needed. Leveraging multi-institutional datasets with 840 African American children with B-ALL and 3360 controls, nine loci achieved genome-wide significance (P <  5 × 10−8) after meta-analysis. Two loci were established trans-ancestral susceptibility regions (IKZF1, ARID5B), while the remaining novel loci were specific to African populations. Five-year overall survival among children carrying novel risk alleles was significantly worse (83% versus 96% in non-carriers, P = 4.8 × 10−3). Novel risk variants were also associated with subtype-specific disease (P <  0.05), including higher susceptibility for a subtype overrepresented in African American children (TCF3-PBX1) and lower …

Sexually Dimorphic Sail Feathers In The Mandarin Duck As A Model For Lifelong Developmental Modulation, Pin-Chi Tang, Hsu-Chen Cheng, Gee-Way Lin, Yung-Chih Lai, Ya-Chen Liang, Ping Wu, Tzu-Chiao Lin, Chen Siang Ng, Isheng Jason Tsai, Ang Li, Wen Hsiung Li, Chih-Feng Chen, Cheng-Ming Chuong, Randall Widelitz

Faculty, Staff and Student Publications

Developmental processes extend beyond embryogenesis to support lifelong tissue adaptations. Avian feather follicles, with their resident stem cells and capacity for cyclic regeneration, provide a dynamic model for postnatal tissue remodeling. Here, we propose the Mandarin duck (Aix galericulata) as an ideal model to study lifelong developmental modulation, focusing on the sexually dimorphic "sail feather"-a secondary flight feather in males that undergoes seasonal transformation into a strikingly asymmetric, ornamented phenotype during the breeding season. We identified asymmetric morphogen expression in regenerating male sail feathers and used transcriptome and H3K27ac ChIP-seq to uncover male and female signaling pathways and regulatory elements. …

Everolimus And Low-Dose Tacrolimus After Heart Transplant In Children: A Randomized Clinical Trial, Christopher S Almond, Kevin P Daly, Erin L Albers, Juan C Alejos, Rebecca Ameduri, Scott R Auerbach, Lynsey Barkoff, Aliessa P Barnes, Matthew J Bock, Arene Butto, Waldemar F Carlo, Chesney D Castleberry, Maryanne R Chrisant, Shriprasad R Deshpande, William J Dreyer, Melanie D Everitt, Brian Feingold, Selena Gonzales, Seth A Hollander, Steven J Kindel, Gloria L Klein, Ashwin K Lal, Jacqueline M Lamour, Joanne Lee, Minmin Lu, Irene D Lytrivi, Shelley D Miyamoto, Elfriede Pahl, David M Peng, Thomas D Ryan, Tajinder P Singh, Jennifer A Su, David L Sutcliffe, A Marian Ybarra, Steven Zangwill, Joseph W Rossano, Lynn A Sleeper

Faculty, Staff and Students Publications

Importance: Studies suggest that everolimus may reduce the risk of rejection, cardiac allograft vasculopathy (CAV), chronic kidney disease (CKD), and cytomegalovirus (CMV) after heart transplant. Everolimus use is controversial because of data demonstrating higher infection deaths when everolimus is introduced de novo after transplant. It is unclear whether everolimus is safe and effective when initiated at 6 months posttransplant in children, a population in which median graft survival is limited to 15 years and randomized clinical trials are lacking.

Objective: To evaluate the safety and efficacy of everolimus combined with low-dose tacrolimus to prevent major adverse transplant events (MATEs) in …

Sperm And Offspring Production In A Nonobstructive Azoospermia Mouse Model Via Testicular Mrna Delivery Using Lipid Nanoparticles, Daisuke Mashiko, Chihiro Emori, Yuki Hatanaka, Daisuke Motooka, Chen Pan, Yuki Kaneda, Martin M Matzuk, Masahito Ikawa

Faculty, Staff and Students Publications

Microsurgical testicular sperm extraction (microTESE) with intracytoplasmic sperm injection (ICSI) represents the current standard treatment for nonobstructive azoospermia (NOA). However, cures remain unavailable for NOA patients lacking retrievable haploid cells. mRNA supplementation could be a potential treatment for genetic defects leading to impaired spermatogenesis. Lipid nanoparticles (LNPs) have emerged as mRNA delivery vehicles with minimal risk of genome integration; however, their ability to selectively deliver mRNA to specific cell types remains limited. To overcome this, microRNA (miRNA) target sequences were incorporated into mRNA constructs to restrict expression specifically to germ cells. Using pyruvate dehydrogenase E1 subunit alpha 2 (PDHA2) knockout …

Influences On Emergency Clinician Use Of Health Information Exchange: Interview Study, Brian E. Dixon, Umesh Ghimire, Benjamin Richter, Corinne Bowditch, Saurabh Rahurkar, John T. Finnell, Joshua R. Vest

Division of Internal Medicine Faculty Papers & Presentations

BACKGROUND: Health information exchange (HIE) supports clinical decision-making in emergency medicine settings. Despite evidence and policies that encourage the adoption of HIE, use by clinicians is limited. Moreover, few studies examine HIE use years after adoption by hospitals or clinics.

OBJECTIVE: This study aims to examine the perceptions and use of a mature, operational HIE system by emergency department clinicians years after its implementation.

METHODS: We interviewed 21 clinicians in various roles (eg, attending physician and nurse practitioner) across multiple health systems that participate in a statewide HIE network. We asked questions about their use of the HIE system and …

Biallelic Loss-Of-Function Variants In C19orf44 Lead To Retinal Degeneration, Hafiz Muhammad Jafar Hussain, Wang Meng, Yumei Li, Sabika Firasat, Mark E Pennesi, Michael B Gorin, Bin Guan, Rebecca Lynn Clark, Emma Fale-Olsen, Ranya Al Rawi, Aime Agather, Laryssa A Huryn, Paul Yang, Anna Matynia, Rui Chen

Faculty, Staff and Students Publications

Background: Inherited retinal diseases (IRDs) are a group of disorders often resulting in progressive vision loss, ultimately leading to blindness. A significant portion of their genetic causes remain unresolved, partly due to undiscovered disease-associated genes or variants. This study aimed to identify novel genetic links to IRDs.

Methods: All patients underwent comprehensive ophthalmological evaluation, including retinal imaging (fundus autofluorescence and macular optical coherence tomography) and electroretinogram testing. Whole exome sequencing and whole genome sequencing were performed on patients with clinically unsolved IRD, and data were analysed using an in-house pipeline to identify causal variants. Subsequently, Sanger sequencing was performed to …

Global Age-Sex-Specific All-Cause Mortality And Life Expectancy Estimates For 204 Countries And Territories And 660 Subnational Locations, 1950–2023: A Demographic Analysis For The Global Burden Of Disease Study 2023, Gbd 2023 Demographics Collaborators

Faculty, Staff and Students Publications

BACKGROUND: Comprehensive, comparable, and timely estimates of demographic metrics-including life expectancy and age-specific mortality-are essential for evaluating, understanding, and addressing trends in population health. The COVID-19 pandemic highlighted the importance of timely and all-cause mortality estimates for being able to respond to changing trends in health outcomes, showing a strong need for demographic analysis tools that can produce all-cause mortality estimates more rapidly with more readily available all-age vital registration (VR) data. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) is an ongoing research effort that quantifies human health by estimating a range of epidemiological quantities of …

Global Burden Of 292 Causes Of Death In 204 Countries And Territories And 660 Subnational Locations, 1990–2023: A Systematic Analysis For The Global Burden Of Disease Study 2023, Gbd 2023 Causes Of Death Collaborators

Faculty, Staff and Students Publications

Background: Timely and comprehensive analyses of causes of death stratified by age, sex, and location are essential for shaping effective health policies aimed at reducing global mortality. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023 provides cause-specific mortality estimates measured in counts, rates, and years of life lost (YLLs). GBD 2023 aimed to enhance our understanding of the relationship between age and cause of death by quantifying the probability of dying before age 70 years (70q0) and the mean age at death by cause and sex. This study enables comparisons of the impact of causes of …

Cep76 Impairment At The Centrosome-Cilium Interface Contributes To A Spectrum Of Ciliopathies, Kamal Khan, Erika Tavares, Katherine Bishara, Aysegul Ozanturk, Leila Qebibo, Stephan Frangakis, Daniel G Calame, Isabelle Meunier, Béatrice Bocquet, Rafal Ploski, Mohammad Ayman Al Khateeb, Dana Marafi, Luke Mansard, Lena Damaj, Richard A Lewis, Farid Ullah, Thomas Arbogast, Jackson P Ogden, Madeleine Harion, Marjolaine Willems, Maha S Zaki, Tobias Bartolomaeus, Anne-Françoise Roux, James R Lupski, Malgorzata Rydzanicz, Rami Abou Jamra, Francis Ramond, Elise Heon, Lydie Burglen, Erica E Davis

Faculty, Staff and Students Publications

Dysfunction at the centrosome-cilium interface underlies a broad range of ciliopathies. Here, we identify biallelic variants in CEP76, encoding a centrosomal protein, in eight unrelated individuals presenting with neurodevelopmental, ocular, and variable additional multisystem features. Proband-derived fibroblasts and CEP76-depleted RPE1 cells display ciliary deficits, including impaired cilium formation and length, disrupted transition zone architecture, and impaired IFT88-mediated anterograde intraflagellar transport. Zebrafish cep76 mutants recapitulate key clinical phenotypes, and in vitro complementation assays confirm pathogenicity for all tested human disease-associated variants. Proteomics analysis identifies CEP76 interactors, including known partners CCP110 and CEP97, and highlights clinically and functionally relevant candidates, including …

Metabolic Impact Of Dietary Glycine Supplementation In Individuals With Severe Obesity, Hong Chang Tan, Jean W Hsu, E Shyong Tai, Shaji Chacko, Vieon Wu, Paul M Yen, Jean-Paul Kovalik, Farook Jahoor

Faculty, Staff and Students Publications

Glycine plays a central role in human metabolism, and an adequate supply is required for synthesizing glutathione (GSH), eliminating excess metabolites as acylglycine via the glycine conjugation detoxification pathway, and maintaining 1-carbon cycle activity. However, glycine is deficient in individuals with severe obesity, which may compromise these pathways and metabolic health. This exploratory study examines whether dietary glycine supplementation could correct glycine deficiency and impairments in glycine-dependent metabolic pathways. 19 participants with severe obesity (BMI 38.3 ± 5.3 kg/m2) were treated with dietary glycine (100 mg/kg/day) for two weeks. We found that treatment significantly increased the plasma concentration of glycine …

Competition Between Tool And Hand Motion Impairs Movement Planning In Limb Apraxia, Simon Thibault, John B. Yates, Laurel J. Buxbaum, Aaron L. Wong

Moss-Magee Rehabilitation Papers

Tool use is a complex motor planning problem. Prior research suggests that planning to use tools involves resolving competition between different tool-related action representations. We therefore reasoned that competition may also be exacerbated with tools for which the motions of the tool and the hand are incongruent (e.g., pinching the fingers to open a clothespin). If this hypothesis is correct, we should observe marked deficits in planning the use of incongruent as compared with congruent tools in individuals with limb apraxia following left hemisphere stroke (LCVA), a disorder associated with abnormal action competition. We asked 34 individuals with chronic LCVA …

Estrogen-Related Receptor Alpha Promotes Skeletal Muscle Regeneration And Mitigates Muscular Dystrophy, Thi Thu Hao Nguyen, Ya Xiang Huang, Svitlana Poliakova, Citu Citu, Eira Mann, Danesh H Sopariwala, Zhongming Zhao, Ashok Kumar, Vihang A Narkar

The Brown Foundation: Institute of Molecular Medicine

Skeletal muscle regeneration in chronic muscle diseases such as Duchenne Muscular Dystrophy (DMD) has remained clinically unsurmountable. Estrogen‐related receptor alpha (ERRα) plays a critical role in adult skeletal muscle metabolism and exercise fitness. Whether ERRα activation can drive muscle regeneration and mitigate dystrophy in DMD is not known. We have investigated ERRα signaling in pre‐clinical models of acute muscle injury and DMD. ERRα is induced in differentiating C2C12 myoblast and regenerating muscle. ERRα silencing suppressed proliferation and differentiation in C2C12 myoblasts. RNA sequencing revealed that angiogenic factor and proliferation genes were downregulated by ERRα knockdown in proliferating cells, whereas oxidative …

Conversion Of Failed Anatomic Total Shoulder Arthroplasty To Reverse Shoulder Arthroplasty Yields Similar Pain And Functional Outcomes To Primary Reverse Shoulder Arthroplasty But Has A Higher Baseplate Failure Rate: A Matched Cohort Study., Kevin A Hao, Trevor G Simcox, Keegan M Hones, Jonathan O Wright, Thomas W Wright, Tyler Lamonica, Bradley S Schoch, Joseph J King

Faculty, Staff and Student Publications

Background: To investigate whether patients who initially underwent anatomic total shoulder arthroplasty (aTSA) for glenohumeral osteoarthritis and were subsequently revised to reverse TSA (rTSA) due to rotator cuff failure or glenoid loosening ultimately attained a similar clinical outcome compared with those who underwent primary rTSA and identify predictors of poor outcomes in the former population.

Methods: We did a single-center retrospective review of 63 shoulders who underwent revision rTSA after primary aTSA that failed due to glenoid component loosening (n = 32), rotator cuff failure (n = 24), or recurrent instability (n = 7). Pain and functional outcomes at minimum …

Preoperative Brain Mapping Predicts Language Outcomes After Eloquent Tumor Resection, Matthew T Muir, Kyle Noll, Sarah Prinsloo, Hayley Michener, Jeffrey I Traylor, Vinodh A Kumar, Chibawanye I Ene, Sherise Ferguson, Ho-Ling Liu, Jeffrey S Weinberg, Frederick Lang, Brian A Taylor, Stephanie J Forkel, Sujit S Prabhu

Faculty, Staff and Student Publications

When operating on gliomas near critical language regions, surgeons risk either leaving residual tumor or inducing permanent postoperative language deficits (PLDs). Despite the advent of intraoperative mapping techniques, subjective judgments frequently determine important surgical decisions. We aim to inform data-driven surgery by constructing a non-invasive mapping approach that quantitatively predicts the impact of individual surgical decisions on long-term language function. This study included 79 consecutive patients undergoing resection of language-eloquent gliomas. Patients underwent preoperative navigated transcranial magnetic stimulation (TMS) language mapping to identify language-positive sites ("TMS points") and their associated white matter tracts ("TMS tracts") as well as formal language …

Alterations Of The Upper Respiratory Microbiome Among Children Living With Hiv Infection In Botswana, Sweta M Patel, John Farirai, Mohamed Z Patel, Sifelane Boiditswe, Leabaneng Tawe, Shimane Lekalake, Mogomotsi Matshaba, Andrew P Steenhoff, Tonya Arscott-Mills, Kristen A Feemster, Samir S Shah, Nathan Thielman, Coleen K Cunningham, Lawrence A David, David M Murdoch, Matthew S Kelly

Faculty, Staff and Students Publications

Children living with HIV (CLWH) are at high risk of colonization and infection by respiratory pathogens, though this risk can be reduced by other microbes in the upper respiratory microbiome. The impact of HIV infection on the pediatric upper respiratory microbiome is poorly understood, and we sought to address this knowledge gap by identifying associations between HIV infection and the nasopharyngeal microbiomes of Batswana children. We enrolled Batswana CLWH (< 5 years) and age- and sex-matched HIV-exposed, uninfected and HIV-unexposed, uninfected children in a cross-sectional study. We used shotgun metagenomic sequencing to compare nasopharyngeal microbiomes by HIV status. Among the 143 children in this study, HIV and HIV-associated immunosuppression were associated with alterations in nasopharyngeal microbiome composition, including lower abundances of Corynebacterium species associated with resistance to bacterial pathogen colonization. These findings suggest that the upper respiratory microbiome may contribute to the high risk of respiratory infections among CLWH.

Stereoelectroencephalography Reveals Neural Signatures Of Multisensory Integration In The Human Superior Temporal Sulcus During Audiovisual Speech Perception, Yue Zhang, John F Magnotti, Xiang Zhang, Zhengjia Wang, Yingjia Yu, Kathryn A Davis, Sameer A Sheth, H Isaac Chen, Daniel Yoshor, Michael S Beauchamp

Faculty, Staff and Students Publications

Human speech perception is multisensory, integrating auditory information from the talker's voice with visual information from the talker's face. BOLD fMRI studies have implicated the superior temporal gyrus (STG) in processing auditory speech and the superior temporal sulcus (STS) in integrating auditory and visual speech, but as an indirect hemodynamic measure, fMRI is limited in its ability to track the rapid neural computations underlying speech perception. Using stereoelectroencephalography (sEEG) electrodes, we directly recorded from the STG and STS in 42 epilepsy patients (25F, 17M). Participants identified single words presented in auditory, visual, and audiovisual formats with and without added auditory …

Resilience And Vulnerabilities Of Tumor Cells Under Purine Shortage Stress, Jianpeng Yu, Chen Jin, Cheng Su, David Moon, Michael A Sun, Hong Zhang, Xue Jiang, Fan Zhang, Nomi Tserentsoodol, Michelle L Bowie, Christopher J Pirozzi, Daniel J George, Robert Wild, Xia Gao, David M Ashley, Yiping He, Jiaoti Huang

Faculty, Staff and Students Publications

Purpose: Purine metabolism is a promising therapeutic target in cancer; however, how cancer cells respond to purine shortage, particularly their adaptation and vulnerabilities, remains unclear.

Experimental design: Using the recently developed purine shortage-inducing prodrug DRP-104 and genetic approaches, we investigated the responses in prostate, lung, and glioma cancer models.

Results: We demonstrate that when de novo purine biosynthesis is compromised, cancer cells employ microtubules to assemble purinosomes, multiprotein complexes of de novo purine biosynthesis enzymes that enhance purine biosynthesis efficiency. Although this process enables tumor cells to adapt to purine shortage stress, it also renders them more susceptible to the …

Addressing Barriers To Care For African American Men Facing Prostate Cancer: A Scoping Review Of Navigation Programs, Ashley Nicole Smith, Brittany A. Campbell, Ghilamichael Andemeskel, Peggy Tahir, Joseph Egbunikeokye, Tisha M. Felder Phd, Msw, Barbara Cicerelli, Nynikka R. Palmer

Publications

PURPOSE

African American/Black men are disproportionately impacted by prostate cancer (PCa). Patient navigation is an evidence-based approach to address barriers to care, improve access to care and health outcomes, and reduce disparities. This scoping review provides an in-depth examination of navigation programs in PCa care across the cancer continuum, with a focus on African American/Black men in the United States.

METHODS

We conducted a comprehensive literature search through September 1st, 2023, in PubMed, Embase, Web of Science, and CINAHL Complete, using keywords and index terms within three main themes: PCa, patient navigation, and African American/Black men. We included studies that …

A Social Media Campaign And Web-Based Survey About Prostate Cancer Genetics: Mixed Methods Study, Amy Leader, Stacy Loeb, Preethi Selvan, Ashley Hunter, Rebecca Hartman, Scott Keith, Veda Giri

Department of Medical Oncology Faculty Papers

BACKGROUND: Germline genetic variants are important for prostate cancer (PCa) management and hereditary cancer risk assessment, but testing is underused. Furthermore, patients are often unaware of the genetic connections to PCa. Social media is increasingly serving as a source of awareness for health information and a method to gather data from a large population.

OBJECTIVE: There were three objectives: to (1) create and test social media messages related to PCa genetics and genetic testing, (2) determine which social media message was most engaging, and (3) assess knowledge of and attitudes toward PCa genetic testing through an online survey using the …