Digital Commons Network^™

Association Of Resilience-Related Life Experiences On Variability On Age Of Onset In Dominantly Inherited Alzheimer Disease, Hye Joo Son, Randall J. Bateman, Jorge J. Llibre-Guerra, Richard J. Perrin, John C. Morris, Carlos Cruchaga, Jason Hassenstab, Alisha Daniels, Et Al.

2020-Current year OA Pubs

BACKGROUND AND OBJECTIVES: It remains unknown whether the associations between protective lifestyles and sporadic dementia risk reported in observational studies also affect age at symptom onset (AAO) in autosomal dominant Alzheimer disease (ADAD) with predominant genetic influences. We investigated the associations between resilience-related life experiences and interindividual AAO variability in ADAD.

METHODS: We performed a longitudinal and confirmatory analysis of the Dominantly Inherited Alzheimer Network prospective observational cohort (January 2009-June 2018, follow-up duration 2.13 ± 2.22 years), involving clinical, CSF, and lifestyle/behavioral assessments. We performed a 2-pronged comprehensive resilience assessment in each cohort. Cohort 1, incorporating the general resilience definition …

Impact Of Cancer Therapy On Clonal Hematopoiesis Mutations And Subsequent Clinical Outcomes, Kevin T Nead, Irenaeus C C Chan, Kelly L Bolton, Et Al.

2020-Current year OA Pubs

Exposure to cancer therapies is associated with an increased risk of clonal hematopoiesis (CH). The objective of our study was to investigate the genesis and evolution of CH after cancer therapy. In this prospective study, we undertook error-corrected duplex DNA sequencing in blood samples collected before and at 2 time points after chemoradiation in patients with esophageal or lung cancer recruited from 2013 to 2018. We applied a customized workflow to identify the earliest changes in CH mutation count and clone size and determine their association with clinical outcomes. Our study included 29 patients (87 samples). Their median age was …

Multidimensional Profiling Of Human T Cells Reveals High Cd38 Expression, Marking Recent Thymic Emigrants And Age-Related Naive T Cell Remodeling, Pavla Bohacova, Marina Terekhova, Riley Mullins, Kamila Husarcikova, Irina Shchukina, Alina Ulezko Antonova, Barbora Echalar, Jan Kossl, Adam Saidu, Chelsea Mannie, Laura Arthur, Daniel Kreisel, Philip A Mudd, Marina Cella, Sidharth V Puram, Pirooz Eghtesady, Maxim N Artyomov, Et Al.

2020-Current year OA Pubs

Thymic involution is a key factor in human immune aging, leading to reduced thymic output and a decline in recent thymic emigrant (RTE) naive T cells in circulation. Currently, the precise definition of human RTEs and their corresponding cell surface markers lacks clarity. Analysis of single-cell RNA-seq/ATAC-seq data distinguished RTEs by the expression of SOX4, IKZF2, and TOX and CD38 protein, whereby surface CD38

Implementation Study Of The Carra Uveitis Consensus Treatment Plans: Feasibility For Clinical Practice And Applicability For Research., Margaret H. Chang, Fatima Barbar-Smiley, Shoghik Akoghlanian, Joanne Drew, Sheila T. Angeles-Han, Megan Quinlan-Waters, John F. Bohnsack, Ashley M. Cooper, Barbara Edelheit, Jennifer Twachtman-Bassett, Melissa A. Lerman, Kabita Nanda, C Egla Rabinovich, Mindy S. Lo, Carra Uveitis Workgroup And The Carra Registry Investigators

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Chronic anterior uveitis (CAU) carries a significant risk for eye complications and vision loss. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) introduced consensus treatment plans (CTPs) to standardize treatment for CAU and facilitate future comparative effectiveness studies. Two CTPs were developed to address: 1) initiation of methotrexate (MTX) in patients with CAU naïve to steroid-sparing therapy, and 2) initiation of a TNF inhibitor (TNFi) in patients with severe uveitis or uveitis refractory to MTX. We evaluated implementation of the uveitis CTPs using existing CARRA Registry infrastructure and assessed feasibility of the CTPs for comparative effectiveness research.

METHODS: This …

Immunologic Signatures Of Response And Resistance To Nivolumab With Ipilimumab In Advanced Metastatic Cancer, Apostolia M Tsimberidou, Farah A Alayli, Kwame Okrah, Alexandra Drakaki, Danny N Khalil, Shivaani Kummar, Saad A Khan, F Stephen Hodi, David Y Oh, Christopher R Cabanski, Shikha Gautam, Stefanie L Meier, Meelad Amouzgar, Shannon M Pfeiffer, Robin Kageyama, Enjun Yang, Marko Spasic, Michael T Tetzlaff, Wai Chin Foo, Travis J Hollmann, Yanyun Li, Matthew Adamow, Phillip Wong, Jonni S Moore, Sharlene Velichko, Richard O Chen, Dinesh Kumar, Samantha Bucktrout, Ramy Ibrahim, Ute Dugan, Lisa Salvador, Vanessa M Hubbard-Lucey, Jill O'Donnell-Tormey, Sandra Santulli-Marotto, Lisa H Butterfield, Diane M Da Silva, Justin Fairchild, Theresa M Lavallee, Lacey J Padrón, Padmanee Sharma

Faculty, Staff and Student Publications

Identifying pan-tumor biomarkers that predict responses to immune checkpoint inhibitors (ICI) is critically needed. In the AMADEUS clinical trial (NCT03651271), patients with various advanced solid tumors were assessed for changes in intratumoral CD8 percentages and their response to ICI. Patients were grouped based on tumoral CD8 levels: those with CD8 <15% (CD8-low) received nivolumab (anti-PD-1) plus ipilimumab (anti-CTLA4) and those with CD8 ≥15% (CD8-high) received nivolumab monotherapy. 79 patients (72 CD8-low and 7 CD8-high) were treated. The disease control rate was 25.0% (18/72; 95% CI: 15.8–35.2) in CD8-low and 14.3% (1/7; 95% CI: 1.1–43.8) in CD8-high. Tumors from 35.9% (14/39; 95% CI: 21.8–51.4) of patients converted from CD8 <15% pretreatment to ≥15% after treatment. Multiomic analyses showed that CD8-low responders had an inflammatory tumor microenvironment pretreatment, enhanced by an influx of CD8 T cells, CD4 T cells, B cells, and macrophages upon treatment. These findings reveal crucial pan-cancer immunological features for ICI response in patients with metastatic disease.

Dna Methylation Near Mad1l1, Kdm2b, And Socs3 Mediates The Effect Of Socioeconomic Status On Elevated Body Mass Index In African American Adults, Láshauntá Glover, Adam G Lilly, Anne E Justice, Annie Green Howard, Brooke S Staley, Yujie Wang, Helen M Kamens, Kendra Ferrier, Jan Bressler, Laura Loehr, Laura M Raffield, Mario Sims, Kari E North, Lindsay Fernández-Rhodes

Faculty, Staff and Student Publications

Obesity and poverty disproportionally affect African American persons. Epigenetic mechanisms could partially explain the association between socioeconomic disadvantage and body mass index (BMI). We examined the extent to which epigenetic mechanisms mediate the effect of socioeconomic status (SES) on BMI. Using data from African American adults from the Atherosclerosis Risk in Communities (ARIC) Study (n = 2664, mean age = 57 years), education, income, and occupation were used to create a composite SES score at visit 1 (1987-1989). We conducted two methylation-wide association analyses to identify associations between SES (visit 1), BMI and cytosine-phosphate-guanine (CpG) sites measured at a subsequent …

Primary Care Experiences Of Adults Reporting Learning Disability: A Probability Sample Survey, Rohit Shankar

Peninsula Medical School

BACKGROUND: Adults with learning disability face multiple adversities, but evidence on their needs and primary care experiences is limited.

AIM: To compare the characteristics and primary care experiences of adults reporting learning disability with those who did not.

DESIGN AND SETTING: This was an analysis of the 2022 General Practice Patient Survey, a national probability sample survey conducted in 2022 with people registered with NHS primary care in England.

METHOD: This analysis reports descriptive profiles, weighted and with 95% confidence intervals. Logistic regression models adjusting for gender, age, ethnicity, and area-level deprivation compared experiences of adults reporting learning disability with …

Alzheimer’S Disease Risk Gene Cd2ap Is A Dose-Sensitive Determinant Of Synaptic Structure And Plasticity, Matea Pavešković, Ruth B De-Paula, Shamsideen A Ojelade, Evelyne K Tantry, Mikhail Y Kochukov, Suyang Bao, Surabi Veeraragavan, Alexandra R Garza, Snigdha Srivastava, Si-Yuan Song, Masashi Fujita, Duc M Duong, David A Bennett, Philip L De Jager, Nicholas T Seyfried, Mary E Dickinson, Jason D Heaney, Benjamin R Arenkiel, Joshua M Shulman

Duncan NRI Faculty and Staff Publications

CD2-Associated protein (CD2AP) is a candidate susceptibility gene for Alzheimer's disease, but its role in the mammalian central nervous system remains largely unknown. We show that CD2AP protein is broadly expressed in the adult mouse brain, including within cortical and hippocampal neurons, where it is detected at pre-synaptic terminals. Deletion of Cd2ap altered dendritic branching and spine density, and impaired ubiquitin-proteasome system activity. Moreover, in mice harboring either one or two copies of a germline Cd2ap null allele, we noted increased paired-pulse facilitation at hippocampal Schaffer-collateral synapses, consistent with a haploinsufficient requirement for pre-synaptic release. Whereas conditional Cd2ap knockout in …

Trβ Activation Confers At2-To-At1 Cell Differentiation And Anti-Fibrosis During Lung Repair Via Klf2 And Cebpa, Xin Pan, Lan Wang, Juntang Yang, Yingge Li, Min Xu, Chenxi Liang, Lulu Liu, Zhongzheng Li, Cong Xia, Jiaojiao Pang, Mengyuan Wang, Meng Li, Saiya Guo, Peishuo Yan, Chen Ding, Ivan O Rosas, Guoying Yu

Faculty, Staff and Students Publications

Aberrant repair underlies the pathogenesis of pulmonary fibrosis while effective strategies to convert fibrosis to normal regeneration are scarce. Here, we found that thyroid hormone is decreased in multiple models of lung injury but is essential for lung regeneration. Moreover, thyroid hormone receptor α (TRα) promotes cell proliferation, while TRβ fuels cell maturation in lung regeneration. Using a specific TRβ agonist, sobetirome, we demonstrate that the anti-fibrotic effects of thyroid hormone mainly rely on TRβ in mice. Cellularly, TRβ activation enhances alveolar type-2 (AT2) cell differentiation into AT1 cell and constrains AT2 cell hyperplasia. Molecularly, TRβ activation directly regulates the …

Human Epidemiology And Response To Sars-Cov-2 (Heros): Objectives, Design, And Enrollment Results Of A 12-City Remote Observational Surveillance Study Of Households With Children, Using Direct-To-Participant Methods, Patricia C Fulkerson, Katherine Rivera-Spoljaric, Et Al.

2020-Current year OA Pubs

The Human Epidemiology and Response to SARS-CoV-2 (HEROS) Study is a prospective, multicity, 6-month incidence study conducted from May 2020 to February 2021. The objectives were to identify risk factors for SARS-CoV-2 infection and household transmission among children and people with asthma and allergic diseases, and to use the host nasal transcriptome sampled longitudinally to understand infection risk and sequelae at the molecular level. To overcome challenges of clinical study implementation due to the coronavirus pandemic, this surveillance study used direct-to-participant methods to remotely enroll and prospectively follow eligible children who are participants in other National Institutes of Health-funded pediatric …

Xenotransplanted Human Organoids Identify Transepithelial Zinc Transport As A Key Mediator Of Intestinal Adaptation, Maame Efua S Sampah, Vered Gazit, Deborah C Rubin, Et Al.

2020-Current year OA Pubs

Short bowel syndrome (SBS) leads to severe morbidity and mortality. Intestinal adaptation is crucial in improving outcomes. To understand the human gene pathways associated with adaptation, we perform single-cell transcriptomic analysis of human small intestinal organoids explanted from mice with experimental SBS. We show that transmembrane ion pathways, specifically the transepithelial zinc transport pathway genes SLC39A4 and SLC39A5, are upregulated in SBS. This discovery is corroborated by an external dataset, bulk RT-qPCR, and Western blots. Oral zinc supplementation is shown to improve survival and weight gain of SBS mice and increase the proliferation of intestinal crypt cells in vitro. Finally, …

Increased Myositis And Possible Myocarditis In Melanoma Patients Treated With Immune Checkpoint Inhibitors In The Covid-19 Era, Allison L. Gradone, Vincent T Ma, Alexi Vasbinder, Leslie A Fecher, Sarah Yentz, Salim S Hayek, Christopher D Lao

Department of Medical Oncology Faculty Papers

BACKGROUND: Immune checkpoint inhibitor (ICI)-mediated myocarditis results in significant morbidity and mortality. At our institution, we noted an increased incidence of ICI-mediated myocarditis cases, leading to further investigation in our database of advanced melanoma patients treated with ICI therapy.

METHODS: A single-center, retrospective cohort analysis of patients with advanced melanoma identified cases of ICI-mediated myocarditis and myositis.

RESULTS: 366 patients with advanced melanoma received a dose of ICI from September 2014 to October 2019. Of these patients, there were 0 cases of ICI-mediated myocarditis (0%, 95% CI 0%-1.0%) and 2 cases of ICI-mediated myositis (0.55%, 95% CI 0.07%-1.96%). From November …

Genetic And Clinical Correlates Of Two Neuroanatomical Ai Dimensions In The Alzheimer's Disease Continuum, Junhao Wen, Aristeidis Sotiras, Daniel S Marcus, Pamela Lamontagne, Tammie L Benzinger, John C Morris, Et Al.

2020-Current year OA Pubs

Alzheimer's disease (AD) is associated with heterogeneous atrophy patterns. We employed a semi-supervised representation learning technique known as Surreal-GAN, through which we identified two latent dimensional representations of brain atrophy in symptomatic mild cognitive impairment (MCI) and AD patients: the "diffuse-AD" (R1) dimension shows widespread brain atrophy, and the "MTL-AD" (R2) dimension displays focal medial temporal lobe (MTL) atrophy. Critically, only R2 was associated with widely known sporadic AD genetic risk factors (e.g., APOE ε4) in MCI and AD patients at baseline. We then independently detected the presence of the two dimensions in the early stages by deploying the trained …

Machine Learning And Bayesian Network Analyses Identifies Associations With Insomnia In A National Sample Of 31,285 Treatment-Seeking College Students, Adam Calderon, Seung Yeon Baik, Matthew H S Ng, Ellen E Fitzsimmons-Craft, Daniel Eisenberg, Denise E Wilfley, C Barr Taylor, Michelle G Newman

2020-Current year OA Pubs

BACKGROUND: A better understanding of the relationships between insomnia and anxiety, mood, eating, and alcohol-use disorders is needed given its prevalence among young adults. Supervised machine learning provides the ability to evaluate which mental disorder is most associated with heightened insomnia among U.S. college students. Combined with Bayesian network analysis, probable directional relationships between insomnia and interacting symptoms may be illuminated.

METHODS: The current exploratory analyses utilized a national sample of college students across 26 U.S. colleges and universities collected during population-level screening before entering a randomized controlled trial. We used a 4-step statistical approach: (1) at the disorder level, …

25-Hydroxycholesterol Promotes Brain Cytokine Production And Leukocyte Infiltration In A Mouse Model Of Lipopolysaccharide-Induced Neuroinflammation, Johnathan Romero, Danira Toral-Rios, Jinsheng Yu, Steven M Paul, Anil G Cashikar

2020-Current year OA Pubs

Neuroinflammation has been implicated in the pathogenesis of several neurologic and psychiatric disorders. Microglia are key drivers of neuroinflammation and, in response to different inflammatory stimuli, overexpress a proinflammatory signature of genes. Among these, Ch25h is a gene overexpressed in brain tissue from Alzheimer's disease as well as various mouse models of neuroinflammation. Ch25h encodes cholesterol 25-hydroxylase, an enzyme upregulated in activated microglia under conditions of neuroinflammation, that hydroxylates cholesterol to form 25-hydroxycholesterol (25HC). 25HC can be further metabolized to 7α,25-dihydroxycholesterol, which is a potent chemoattractant of leukocytes. We have previously shown that 25HC increases the production and secretion of …

Biologic And Clinical Analysis Of Childhood Gamma Delta T-All Identifies Lmo2/Stag2 Rearrangements As Extremely High Risk, Shunsuke Kimura, Chun Shik Park, Lindsey E Montefiori, Ilaria Iacobucci, Petri Pölönen, Qingsong Gao, Elizabeth D Arnold, Andishe Attarbaschi, Anthony Brown, Barbara Buldini, Kenneth J Caldwell, Yunchao Chang, Chelsey Chen, Cheng Cheng, Zhongshan Cheng, John Choi, Valentino Conter, Kristine R Crews, Hester A De Groot-Kruseman, Takao Deguchi, Mariko Eguchi, Hannah E Muhle, Sarah Elitzur, Gabriele Escherich, Burgess B Freeman, Zhaohui Gu, Katie Han, Keizo Horibe, Toshihiko Imamura, Sima Jeha, Motohiro Kato, Kean H Chiew, Tanya Khan, Michal Kicinski, Stefan Köhrer, Steven M Kornblau, Rishi S Kotecha, Chi-Kong Li, Yen-Chun Liu, Franco Locatelli, Selina M Luger, Elisabeth M Paietta, Atsushi Manabe, Hanne V Marquart, Riccardo Masetti, Mellissa Maybury, Pauline Mazilier, Jules P P Meijerink, Sharnise Mitchell, Takako Miyamura, Andrew S Moore, Koichi Oshima, Katarzyna Pawinska-Wasikowska, Rob Pieters, Mollie S Prater, Shondra M Pruett-Miller, Ching-Hon Pui, Chunxu Qu, Michaela Reiterova, Noemi Reyes, Kathryn G Roberts, Jacob M Rowe, Atsushi Sato, Kjeld Schmiegelow, Martin Schrappe, Shuhong Shen, Szymon Skoczeń, Orietta Spinelli, Jan Stary, Michael Svaton, Masatoshi Takagi, Junko Takita, Yanjing Tang, David T Teachey, Paul G Thomas, Daisuke Tomizawa, Jan Trka, Elena Varotto, Tiffaney L Vincent, Jun J Yang, Allen E J Yeoh, Yinmei Zhou, Martin Zimmermann, Hiroto Inaba, Charles G Mullighan

Faculty, Staff and Student Publications

Acute lymphoblastic leukemia expressing the gamma delta T-cell receptor (γδ T-ALL) is a poorly understood disease. We studied 200 children with γδ T-ALL from 13 clinical study groups to understand the clinical and genetic features of this disease. We found age and genetic drivers were significantly associated with outcome. γδ T-ALL diagnosed in children under 3 years of age was extremely high-risk and enriched for genetic alterations that result in both LMO2 activation and STAG2 inactivation. Mechanistically, using patient samples and isogenic cell lines, we show that inactivation of STAG2 profoundly perturbs chromatin organization by altering enhancer-promoter looping, resulting in …

Multi-Ancestry Gwas Meta-Analyses Of Lung Cancer Reveal Susceptibility Loci And Elucidate Smoking-Independent Genetic Risk, Bryan R Gorman, Sun-Gou Ji, Michael Francis, Anoop K Sendamarai, Yunling Shi, Poornima Devineni, Uma Saxena, Elizabeth Partan, Andrea K Devito, Jinyoung Byun, Younghun Han, Xiangjun Xiao, Don D Sin, Wim Timens, Jennifer Moser, Sumitra Muralidhar, Rachel Ramoni, Rayjean J Hung, James D Mckay, Yohan Bossé, Ryan Sun, Christopher I Amos, Va Million Veteran Program, Saiju Pyarajan

Faculty, Staff and Student Publications

Lung cancer remains the leading cause of cancer mortality, despite declining smoking rates. Previous lung cancer GWAS have identified numerous loci, but separating the genetic risks of lung cancer and smoking behavioral susceptibility remains challenging. Here, we perform multi-ancestry GWAS meta-analyses of lung cancer using the Million Veteran Program cohort (approximately 95% male cases) and a previous study of European-ancestry individuals, jointly comprising 42,102 cases and 181,270 controls, followed by replication in an independent cohort of 19,404 cases and 17,378 controls. We then carry out conditional meta-analyses on cigarettes per day and identify two novel, replicated loci, including the 19p13.11 …

2024 Clinical Practice Guideline Update By The Infectious Diseases Society Of America On Complicated Intraabdominal Infections: Diagnostic Imaging Of Suspected Acute Cholecystitis And Acute Cholangitis In Adults, Children, And Pregnant People, Robert A Bonomo, Morven S Edwards, Fredrick M Abrahamian, Mary Bessesen, Anthony W Chow, E Patchen Dellinger, Ellie Goldstein, Mary K Hayden, Romney Humphries, Kaye, Brian A Potoski, Rodríguez-Baño, Robert Sawyer, Marion Skalweit, David R Snydman, Pranita D Tamma, Katelyn Donnelly, Jennifer Loveless

Faculty, Staff and Students Publications

This article is part of a clinical practice guideline update on the risk assessment, diagnostic imaging, and microbiological evaluation of complicated intraabdominal infections in adults, children, and pregnant people, developed by the Infectious Diseases Society of America. In this article, the panel provides recommendations for diagnostic imaging of suspected acute cholecystitis and acute cholangitis. The panel's recommendations are based on evidence derived from systematic literature reviews and adhere to a standardized methodology for rating the certainty of evidence and strength of recommendation according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach.

Cell Type-Specific Epigenetic Priming Of Gene Expression In Nucleus Accumbens By Cocaine, Philipp Mews, Yentl Van Der Zee, Ashik Gurung, Molly Estill, Rita Futamura, Hope Kronman, Aarthi Ramakrishnan, Meagan Ryan, Abner A Reyes, Benjamin A Garcia, Caleb J Browne, Simone Sidoli, Li Shen, Eric J Nestler

2020-Current year OA Pubs

A hallmark of addiction is the ability of drugs of abuse to trigger relapse after periods of prolonged abstinence. Here, we describe an epigenetic mechanism whereby chronic cocaine exposure causes lasting chromatin and downstream transcriptional modifications in the nucleus accumbens (NAc), a critical brain region controlling motivation. We link prolonged withdrawal from cocaine to the depletion of the histone variant H2A.Z, coupled with increased genome accessibility and latent priming of gene transcription, in D1 dopamine receptor-expressing medium spiny neurons (D1 MSNs) that relate to aberrant gene expression upon drug relapse. The histone chaperone ANP32E removes H2A.Z from chromatin, and we …

Distinct Visual Processing Networks For Foveal And Peripheral Visual Fields, Jie Zhang, Huihui Zhou, Shuo Wang

2020-Current year OA Pubs

Foveal and peripheral vision are two distinct modes of visual processing essential for navigating the world. However, it remains unclear if they engage different neural mechanisms and circuits within the visual attentional system. Here, we trained macaques to perform a free-gaze visual search task using natural face and object stimuli and recorded a large number of 14588 visually responsive units from a broadly distributed network of brain regions involved in visual attentional processing. Foveal and peripheral units had substantially different proportions across brain regions and exhibited systematic differences in encoding visual information and visual attention. The spike-local field potential (LFP) …

Nationwide Availability Of And Enrollment In Medicare And Medicaid Dual-Eligible Special Needs Plans With Exclusively Aligned Enrollment, Kenton J Johnston, Michelle Hendricks, Megha Dabas, Eliza Macneal, Jeah Jung, David J Meyers, Jose F Figueroa, Eric T Roberts

2020-Current year OA Pubs

IMPORTANCE: In 2021, the Centers for Medicare & Medicaid Services designated a new category of dual-eligible special needs plans (D-SNPs) with exclusively aligned enrollment (receive Medicare and Medicaid benefits through the same plan or affiliated plans within the same organization).

OBJECTIVE: To assess the availability of and enrollment in D-SNPs with exclusively aligned enrollment and to compare the characteristics of beneficiaries enrolled in D-SNPs with exclusively aligned enrollment available vs beneficiaries without such enrollment available.

DESIGN, SETTING, AND PARTICIPANTS: Full-benefit beneficiaries enrolled in D-SNPs for 6 months or longer in 2021 or 2022. Availability of and beneficiary enrollment in D-SNPs …

Whole-Genome Sequencing In 333,100 Individuals Reveals Rare Non-Coding Single Variant And Aggregate Associations With Height, Gareth Hawkes, Robin N Beaumont, Zilin Li, Ravi Mandla, Xihao Li, Christine M Albert, Donna K Arnett, Allison E Ashley-Koch, Aneel A Ashrani, Kathleen C Barnes, Eric Boerwinkle, Jennifer A Brody, April P Carson, Nathalie Chami, Yii-Der Ida Chen, Mina K Chung, Joanne E Curran, Dawood Darbar, Patrick T Ellinor, Myrian Fornage, Victor R Gordeuk, Xiuqing Guo, Jiang He, Chii-Min Hwu, Rita R Kalyani, Robert Kaplan, Sharon L R Kardia, Charles Kooperberg, Ruth J F Loos, Steven A Lubitz, Ryan L Minster, Take Naseri, Satupa'itea Viali, Braxton D Mitchell, Joanne M Murabito, Nicholette D Palmer, Bruce M Psaty, Susan Redline, M Benjamin Shoemaker, Edwin K Silverman, Marilyn J Telen, Scott T Weiss, Lisa R Yanek, Hufeng Zhou, Nhlbi Trans-Omics For Precision Medicine (Topmed) Consortium, Ching-Ti Liu, Kari E North, Anne E Justice, Jonathan M Locke, Nick Owens, Anna Murray, Kashyap Patel, Timothy M Frayling, Caroline F Wright, Andrew R Wood, Xihong Lin, Alisa Manning, Michael N Weedon

Faculty, Staff and Student Publications

The role of rare non-coding variation in complex human phenotypes is still largely unknown. To elucidate the impact of rare variants in regulatory elements, we performed a whole-genome sequencing association analysis for height using 333,100 individuals from three datasets: UK Biobank (N = 200,003), TOPMed (N = 87,652) and All of Us (N = 45,445). We performed rare ( < 0.1% minor-allele-frequency) single-variant and aggregate testing of non-coding variants in regulatory regions based on proximal-regulatory, intergenic-regulatory and deep-intronic annotation. We observed 29 independent variants associated with height at P < 6×10-10" role="presentation" style="box-sizing: inherit; display: inline-block; line-height: 0; font-size: 18.08px; font-size-adjust: none; overflow-wrap: normal; text-wrap-mode: nowrap; float: none; direction: ltr; max-width: none; max-height: none; min-width: 0px; min-height: 0px; border: 0px; margin: 0px; padding: 1px 0px; color: rgb(33, 33, 33); font-family: BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif; position: relative;">6×10−106×10-10 after conditioning on previously reported variants, with effect sizes ranging from -7cm to +4.7 cm. We also identified and replicated non-coding aggregate-based associations proximal to HMGA1 containing variants associated with a 5 cm taller height and of highly-conserved variants in …

Whole-Exome Sequencing Uncovers The Genetic Complexity Of Bicuspid Aortic Valve In Families With Early-Onset Complications, Sara Mansoorshahi, Anji T Yetman, Malenka M Bissell, Yuli Y Kim, Hector I Michelena, Julie De Backer, Laura Muiño Mosquera, Dawn S Hui, Anthony Caffarelli, Maria G Andreassi, Ilenia Foffa, Dongchuan Guo, Rodolfo Citro, Margot De Marco, Justin T Tretter, Shaine A Morris, Simon C Body, Jessica X Chong, Michael J Bamshad, Dianna M Milewicz, Siddharth K Prakash

Faculty, Staff and Student Publications

Bicuspid aortic valve (BAV) is the most common congenital heart lesion with an estimated population prevalence of 1%. We hypothesize that specific gene variants predispose to early-onset complications of BAV (EBAV). We analyzed whole-exome sequences (WESs) to identify rare coding variants that contribute to BAV disease in 215 EBAV-affected families. Predicted damaging variants in candidate genes with moderate or strong supportive evidence to cause developmental cardiac phenotypes were present in 107 EBAV-affected families (50% of total), including genes that cause BAV (9%) or heritable thoracic aortic disease (HTAD, 19%). After appropriate filtration, we also identified 129 variants in 54 candidate …

The Cochlear Dose And The Age At Radiotherapy Predict Severe Hearing Loss After Passive Scattering Proton Therapy And Cisplatin In Children With Medulloblastoma, Mohammad H Abu-Arja, Austin L Brown, Jack M Su, M Fatih Okcu, Holly B Lindsay, Susan L Mcgovern, Mary Frances Mcaleer, David R Grosshans, Murali M Chintagumpala, Arnold C Paulino

Faculty, Staff and Student Publications

Background: Hearing loss (HL) is associated with worse neurocognitive outcomes among patients with medulloblastoma. We aimed to identify risk factors associated with severe HL and to evaluate the generalizability of a published HL calculator among patients treated with passive scattering proton therapy (PSPT) and cisplatin.

Methods: We identified patients aged 3-21 years who were treated at our centers between 2007 and 2022. Audiograms were graded using the International Society of Pediatric Oncology (SIOP) Boston scale. Time to grades 3-4 HL was evaluated using Kaplan-Meier and multivariable Cox models to estimate hazard ratios and 95% confidence intervals (CI).

Results: Seventy-nine patients …

Identification Of A Single-Dose, Low-Flip-Angle-Based Cbv Threshold For Fractional Tumor Burden Mapping In Recurrent Glioblastoma, Aliya Anil, Ashley M Stokes, John P Karis, Laura C Bell, Jennifer Eschbacher, Kristofer Jennings, Melissa A Prah, Leland S Hu, Jerrold L Boxerman, Kathleen M Schmainda, C Chad Quarles

Faculty, Staff and Student Publications

Background and purpose: DSC-MR imaging can be used to generate fractional tumor burden (FTB) maps via application of relative CBV thresholds to spatially differentiate glioblastoma recurrence from posttreatment radiation effects (PTRE). Image-localized histopathology was previously used to validate FTB maps derived from a reference DSC-MR imaging protocol by using preload, a moderate flip angle (MFA, 60°), and postprocessing leakage correction. Recently, a DSC-MR imaging protocol with a low flip angle (LFA, 30°) with no preload was shown to provide leakage-corrected relative CBV (rCBV) equivalent to the reference protocol. This study aimed to identify the rCBV thresholds for the LFA protocol …

The Babyseq Project: A Clinical Trial Of Genome Sequencing In A Diverse Cohort Of Infants, Hadley Stevens Smith, Bethany Zettler, Casie A Genetti, Madison R Hickingbotham, Tanner F Coleman, Matthew Lebo, Anna Nagy, Hana Zouk, Lisa Mahanta, Kurt D Christensen, Stacey Pereira, Nidhi D Shah, Nina B Gold, Sheyenne Walmsley, Sarita Edwards, Ramin Homayouni, Graham P Krasan, Hakon Hakonarson, Carol R Horowitz, Bruce D Gelb, Bruce R Korf, Amy L Mcguire, Ingrid A Holm, Robert C Green

Center for Medical Ethics and Health Policy Staff Publications

Efforts to implement and evaluate genome sequencing (GS) as a screening tool for newborns and infants are expanding worldwide. The first iteration of the BabySeq Project (2015-2019), a randomized controlled trial of newborn sequencing, produced novel evidence on medical, behavioral, and economic outcomes. The second iteration of BabySeq, which began participant recruitment in January 2023, examines GS outcomes in a larger, more diverse cohort of more than 500 infants up to one year of age recruited from pediatric clinics at several sites across the United States. The trial aims for families who self-identify as Black/African American or Hispanic/Latino to make …

Default Mode Network Electrophysiological Dynamics And Causal Role In Creative Thinking, Eleonora Bartoli, Ethan Devara, Huy Q Dang, Rikki Rabinovich, Raissa K Mathura, Adrish Anand, Bailey R Pascuzzi, Joshua Adkinson, Yoed N Kenett, Kelly R Bijanki, Sameer A Sheth, Ben Shofty

Faculty, Staff and Students Publications

The default mode network (DMN) is a widely distributed, intrinsic brain network thought to play a crucial role in internally directed cognition. The present study employs stereo-EEG in 13 human patients, obtaining high resolution neural recordings across multiple canonical DMN regions during two processes that have been associated with creative thinking: spontaneous and divergent thought. We probe these two DMN-associated higher cognitive functions through mind wandering and alternate uses tasks, respectively. Our results reveal DMN recruitment during both tasks, as well as a task-specific dissociation in spatiotemporal response dynamics. When compared to the fronto-parietal network, DMN activity was characterized by …

Penicillin Susceptibility Among Staphylococcus Aureus Skin And Soft Tissue Infections At A Children’S Hospital, J Chase Mcneil, Lauren M Sommer, Marritta Joseph, Kristina G Hulten, Sheldon L Kaplan

Faculty, Staff and Students Publications

Shortly after its introduction into clinical practice, Staphylococcus aureus isolates gained resistance to penicillin via the acquisition of β-lactamases. A number of centers have recently described an increase in the proportion of invasive methicillin-susceptible S. aureus (MSSA), which are also susceptible to penicillin (PSSA). Little data are available regarding the prevalence or impact of PSSA in skin and soft tissue infections (SSTI). Community-acquired MSSA SSTI isolates were obtained through a surveillance study at Texas Children’s Hospital from January 2017 to December 2021. A total of 200 random isolates underwent PCR for blaZ β-lactamase; blaZ-negative isolates then underwent penicillin susceptibility …

In Acute Severe Ulcerative Colitis Patients Who Receive Rescue Therapy, Prior Maintenance Therapy And Day 3 C-Reactive Protein After Rescue Therapy Are Associated With 12-Month Colectomy Risk, Jared A Sninsky, Ana-Maria Staicu, Edward L Barnes

Faculty, Staff and Students Publications

No abstract provided.

How Do Parents Decide On Genetic Testing In Pediatrics? A Systematic Review, Hadley Stevens Smith, Bethany Zettler, Casie A Genetti, Madison R Hickingbotham, Tanner F Coleman, Matthew Lebo, Anna Nagy, Hana Zouk, Lisa Mahanta, Kurt D Christensen, Stacey Pereira, Nidhi D Shah, Nina B Gold, Sheyenne Walmsley, Sarita Edwards, Ramin Homayouni, Graham P Krasan, Hakon Hakonarson, Carol R Horowitz, Bruce D Gelb, Bruce R Korf, Amy L Mcguire, Ingrid A Holm, Robert C Green

Center for Medical Ethics and Health Policy Staff Publications

Efforts to implement and evaluate genome sequencing (GS) as a screening tool for newborns and infants are expanding worldwide. The first iteration of the BabySeq Project (2015-2019), a randomized controlled trial of newborn sequencing, produced novel evidence on medical, behavioral, and economic outcomes. The second iteration of BabySeq, which began participant recruitment in January 2023, examines GS outcomes in a larger, more diverse cohort of more than 500 infants up to one year of age recruited from pediatric clinics at several sites across the United States. The trial aims for families who self-identify as Black/African American or Hispanic/Latino to make …