Medical Specialties Commons^™

The Respiratory Enzyme Complex Rnf Is Vital For Metabolic Adaptation And Virulence In Fusobacterium Nucleatum, Timmie A Britton, Chenggang Wu, Yi-Wei Chen, Dana Franklin, Yimin Chen, Martha I Camacho, Truc T Luong, Asis Das, Hung Ton-That

Faculty, Staff and Student Publications

The Gram-negative oral pathobiont Fusobacterium nucleatum can traverse to extra-oral sites such as placenta and colon, promoting adverse pregnancy outcomes and colorectal cancer, respectively. How this anaerobe sustains many metabolically changing environments enabling its virulence potential remains unclear. Informed by our genome-wide transposon mutagenesis, we report here that the highly conserved Rhodobacter nitrogen-fixation (Rnf) complex, encoded by the rnfCDGEAB gene cluster, is key to fusobacterial metabolic adaptation and virulence. Genetic disruption of the Rnf complex via non-polar, in-frame deletion of rnfC (ΔrnfC) abrogates polymicrobial interaction (or coaggregation) associated with adhesin RadD and biofilm formation. The defect in coaggregation …

Analysis Of Breast Cancer Mortality In The Us-1975 To 2019, Jennifer L Caswell-Jin, Liyang P Sun, Diego Munoz, Ying Lu, Yisheng Li, Hui Huang, John M Hampton, Juhee Song, Jinani Jayasekera, Clyde Schechter, Oguzhan Alagoz, Natasha K Stout, Amy Trentham-Dietz, Sandra J Lee, Xuelin Huang, Jeanne S Mandelblatt, Donald A Berry, Allison W Kurian, Sylvia K Plevritis

Faculty, Staff and Student Publications

IMPORTANCE: Breast cancer mortality in the US declined between 1975 and 2019. The association of changes in metastatic breast cancer treatment with improved breast cancer mortality is unclear.

OBJECTIVE: To simulate the relative associations of breast cancer screening, treatment of stage I to III breast cancer, and treatment of metastatic breast cancer with improved breast cancer mortality.

DESIGN, SETTING, AND PARTICIPANTS: Using aggregated observational and clinical trial data on the dissemination and effects of screening and treatment, 4 Cancer Intervention and Surveillance Modeling Network (CISNET) models simulated US breast cancer mortality rates. Death due to breast cancer, overall and by …

Perioperative Toripalimab Plus Chemotherapy For Patients With Resectable Non-Small Cell Lung Cancer: The Neotorch Randomized Clinical Trial, Shun Lu, Wei Zhang, Lin Wu, Wenxiang Wang, Peng Zhang, Wentao Fang, Wenqun Xing, Qixun Chen, Lin Yang, Jiandong Mei, Lijie Tan, Xiaohong Sun, Shidong Xu, Xiaohua Hu, Guohua Yu, Dongliang Yu, Nong Yang, Yuping Chen, Jinlu Shan, Ligang Xing, Hui Tian, Xun Zhang, Ming Zhou, Haohui Fang, Guowu Wu, Yunpeng Liu, Minhua Ye, Lejie Cao, Jie Jiang, Xingya Li, Liangming Zhu, Danqing Li, Mingqiang Kang, Aihong Zhong, Keneng Chen, Nan Wu, Qian Sun, Haitao Ma, Kaican Cai, Changli Wang, Gen Lin, Kunshou Zhu, Yu Zhang, Xiaochun Zhang, Hong Hu, Wengang Zhang, Jun Chen, Zhixiong Yang, Xiaosheng Hang, Jian Hu, Yunchao Huang, Zhiye Zhang, Lumin Zhang, Liwei Zhang, Lunxu Liu, Dongmei Lin, Jie Zhang, Gang Chen, Yuan Li, Lei Zhu, Weihua Wang, Wenbo Yu, Dezhen Cao, Patricia Keegan, Sheng Yao

Faculty, Staff and Student Publications

IMPORTANCE: Adjuvant and neoadjuvant immunotherapy have improved clinical outcomes for patients with early-stage non-small cell lung cancer (NSCLC). However, the optimal combination of checkpoint inhibition with chemotherapy remains unknown.

OBJECTIVE: To determine whether toripalimab in combination with platinum-based chemotherapy will improve event-free survival and major pathological response in patients with stage II or III resectable NSCLC compared with chemotherapy alone.

DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial enrolled patients with stage II or III resectable NSCLC (without EGFR or ALK alterations for nonsquamous NSCLC) from March 12, 2020, to June 19, 2023, at 50 participating hospitals in China. The …

Metabolomic Rewiring Promotes Endocrine Therapy Resistance In Breast Cancer, Songyeon Ahn, Jun Hyoung Park, Sandra L Grimm, Danthasinghe Waduge Badrajee Piyarathna, Tagari Samanta, Vasanta Putluri, Dereck Mezquita, Suzanne A W Fuqua, Nagireddy Putluri, Cristian Coarfa, Benny Abraham Kaipparettu

Faculty, Staff and Students Publications

Approximately one-third of endocrine-treated women with estrogen receptor-alpha positive (ER+) breast cancers (BC) are at risk of recurrence due to intrinsic or acquired resistance. Thus, it is vital to understand the mechanisms underlying endocrine therapy resistance in ER+ BC to improve patient treatment. Mitochondrial fatty acid β-oxidation (FAO) has been shown to be a major metabolic pathway in triple-negative BC (TNBC) that can activate Src signaling. Here, we found metabolic reprogramming that increases FAO in ER+ BC as a mechanism of resistance to endocrine therapy. A metabolically relevant, integrated gene signature was derived from transcriptomic, metabolomic, and lipidomic analyses in …

Impact Of Transcatheter Heart Valve Type On Outcomes Of Surgical Explantation After Failed Transcatheter Aortic Valve Replacement: The Explant-Tavr International Registry, Syed Zaid, Neal S Kleiman, Sachin S Goel, Molly I Szerlip, Michael J Mack, Mateo Marin-Cuartas, Siamak Mohammadi, Tamim M Nazif, Axel Unbehaun, Martin Andreas, Derek R Brinster, Newell B Robinson, Lin Wang, Basel Ramlawi, Lenard Conradi, Nimesh D Desai, John K Forrest, Rodrigo Bagur, Tom C Nguyen, Ron Waksman, Lionel Leroux, Eric Van Belle, Kendra J Grubb, Hasan A Ahmad, Paolo Denti, Thomas Modine, Vinayak N Bapat, Tsuyoshi Kaneko, Michael J Reardon, Gilbert H L Tang, On Behalf Of The Explant-Tavr Registry Investigators

Faculty, Staff and Students Publications

Background: There are limited data on the impact of transcatheter heart valve (THV) type on the outcomes of surgical explantation after THV failure.

Aims: We sought to determine the outcomes of transcatheter aortic valve replacement (TAVR) explantation for failed balloon-expandable valves (BEV) versus self-expanding valves (SEV).

Methods: From November 2009 to February 2022, 401 patients across 42 centres in the EXPLANT-TAVR registry underwent TAVR explantation during a separate admission from the initial TAVR. Mechanically expandable valves (N=10, 2.5%) were excluded. The outcomes of TAVR explantation were compared for 202 (51.7%) failed BEV and 189 (48.3%) failed SEV.

Results: Among 391 …

Comparative Transcriptomic Analysis Of Cerebellar Astrocytes Across Developmental Stages And Brain Regions, Wookbong Kwon, Dong-Joo Choi, Kwanha Yu, Michael R Williamson, Sanjana Murali, Yeunjung Ko, Junsung Woo, Benjamin Deneen

Faculty, Staff and Students Publications

Astrocytes are the most abundant glial cell type in the central nervous system, and they play a crucial role in normal brain function. While gliogenesis and glial differentiation occur during perinatal cerebellar development, the processes that occur during early postnatal development remain obscure. In this study, we conducted transcriptomic profiling of postnatal cerebellar astrocytes at postnatal days 1, 7, 14, and 28 (P1, P7, P14, and P28), identifying temporal-specific gene signatures at each specific time point. Comparing these profiles with region-specific astrocyte differentially expressed genes (DEGs) published for the cortex, hippocampus, and olfactory bulb revealed cerebellar-specific gene signature across these …

Chagas Disease Diagnostic Practices At Four Major Hospital Systems In California And Texas, Emily A Kelly, Jose I Echeverri Alegre, Katherine Promer, Jesica Hayon, Roumen Iordanov, Khuzaima Rangwalla, Jerry J Zhang, Zian Fang, Cindy Huang, Cassiana E Bittencourt, Sharon Reed, Rosa M Andrade, Caryn Bern, Eva H Clark, Jeffrey D Whitman

Faculty, Staff and Students Publications

BACKGROUND: Chagas disease (CD) is a parasitic disease that affects ∼300 000 people living in the United States. CD leads to cardiac and/or gastrointestinal disease in up to 30% of untreated people. However, end-organ damage can be prevented with early diagnosis and antiparasitic therapy.

METHODS: We reviewed electronic health records of patients who underwent testing for CD at four hospital systems in California and Texas between 2016 and 2020. Descriptive analyses were performed as a needs assessment for improving CD diagnosis.

RESULTS: In total, 470 patients were tested for CD. Cardiac indications made up more than half (60%) of all …

Aging Fly Cell Atlas Identifies Exhaustive Aging Features At Cellular Resolution, Kenneth A Wilson, Sudipta Bar, Eric B Dammer, Enrique M Carrera, Brian A Hodge, Tyler A U Hilsabeck, Joanna Bons, George W Brownridge, Jennifer N Beck, Jacob Rose, Melia Granath-Panelo, Christopher S Nelson, Grace Qi, Akos A Gerencser, Jianfeng Lan, Alexandra Afenjar, Geetanjali Chawla, Rachel B Brem, Philippe M Campeau, Hugo J Bellen, Birgit Schilling, Nicholas T Seyfried, Lisa M Ellerby, Pankaj Kapahi

Faculty, Staff and Students Publications

Dietary restriction (DR) delays aging, but the mechanism remains unclear. We identified polymorphisms in mtd, the fly homolog of OXR1, which influenced lifespan and mtd expression in response to DR. Knockdown in adulthood inhibited DR-mediated lifespan extension in female flies. We found that mtd/OXR1 expression declines with age and it interacts with the retromer, which regulates trafficking of proteins and lipids. Loss of mtd/OXR1 destabilized the retromer, causing improper protein trafficking and endolysosomal defects. Overexpression of retromer genes or pharmacological restabilization with R55 rescued lifespan and neurodegeneration in mtd-deficient flies and endolysosomal defects in fibroblasts from patients with lethal loss-of-function …

Regional Variability In The Prevalence Of Food Insecurity And Diet Quality Among United States Children, Jayna M Dave, Tzuan A Chen, Alexandra N Castro, Mamie White, Elizabeth A Onugha, Sloane Zimmerman, Debbe Thompson

Children’s Nutrition Research Center Staff Publications

Understanding the association between food security status (FSS) and diet quality in children is crucial. This study investigated regional variability in FSS, participation in the federal nutrition assistance program (FNAP), and diet quality among US children. National Health and Nutrition Examination Survey (NHANES) data from 2013 to 2016 were analyzed. The association between FSS, FNAP participation, and diet quality (Healthy Eating Index—HEI-2015) was assessed using multiple linear/logistic regression models. The sample included 6403 children (mean age: 7.5 years; 51% male; 33% Hispanic). Within the sample, 13% reported child food insecurity, and 30% reported household food insecurity. Additionally, 90% participated in …

Delineating The Mechanism Of Fragility At Bcl6 Breakpoint Region Associated With Translocations In Diffuse Large B Cell Lymphoma, Vidya Gopalakrishnan, Urbi Roy, Shikha Srivastava, Khyati M Kariya, Shivangi Sharma, Saniya M Javedakar, Bibha Choudhary, Sathees C Raghavan

Faculty, Staff and Student Publications

BCL6 translocation is one of the most common chromosomal translocations in cancer and results in its enhanced expression in germinal center B cells. It involves the fusion of BCL6 with any of its twenty-six Ig and non-Ig translocation partners associated with diffuse large B cell lymphoma (DLBCL). Despite being discovered long back, the mechanism of BCL6 fragility is largely unknown. Analysis of the translocation breakpoints in 5' UTR of BCL6 reveals the clustering of most of the breakpoints around a region termed Cluster II. In silico analysis of the breakpoint cluster sequence identified sequence motifs that could potentially fold into …

Molecular And Clinical Effects Of Aromatase Inhibitor Therapy On Skeletal Muscle Function In Early-Stage Breast Cancer, Tara A Seibert, Lei Shi, Sandra Althouse, Richard Hoffman, Bryan P Schneider, Kristen A Russ, Cody A Altherr, Stuart J Warden, Theresa A Guise, Andrew R Coggan, Tarah J Ballinger

Faculty, Staff and Student Publications

We evaluated biochemical changes in skeletal muscle of women with breast cancer initiating aromatase inhibitors (AI), including oxidation of ryanodine receptor RyR1 and loss of stabilizing protein calstabin1, and detailed measures of muscle function. Fifteen postmenopausal women with stage I-III breast cancer planning to initiate AI enrolled. Quadriceps muscle biopsy, dual-energy x-ray absorptiometry, isokinetic dynamometry, Short Physical Performance Battery, grip strength, 6-min walk, patient-reported outcomes, and serologic measures of bone turnover were assessed before and after 6 months of AI. Post-AI exposure, oxidation of RyR1 significantly increased (0.23 ± 0.37 vs. 0.88 ± 0.80, p <  0.001) and RyR1-bound calstabin1 significantly decreased (1.69 ± 1.53 vs. 0.74 ± 0.85, p <  0.001), consistent with dysfunctional calcium channels in skeletal muscle. Grip strength significantly decreased at 6 months. No significant differences were seen in isokinetic dynamometry measures of muscle contractility, fatigue resistance, or muscle recovery post-AI exposure. However, there was significant correlation between oxidation of RyR1 with muscle power (r = 0.60, p = 0.02) and muscle fatigue (r = 0.57, p = 0.03). Estrogen deprivation therapy for breast cancer resulted in maladaptive changes in skeletal muscle, consistent with the biochemical signature of dysfunctional RyR1 calcium channels. Future studies will evaluate longer trajectories of muscle function change and include other high bone turnover states, such as bone metastases.

D-Mannose Reduces Cellular Senescence And Nlrp3/Gasdermind/Il-1Β-Driven Pyroptotic Uroepithelial Cell Shedding In The Murine Bladder, Chetanchandra S Joshi, Arnold M Salazar, Caihong Wang, Marianne M Ligon, Rayvanth R Chappidi, Bisiayo E Fashemi, Paul A Felder, Amy Mora, Sandra L Grimm, Cristian Coarfa, Indira U Mysorekar

Faculty, Staff and Students Publications

Aging is a risk factor for disease via increased susceptibility to infection, decreased ability to maintain homeostasis, inefficiency in combating stress, and decreased regenerative capacity. Multiple diseases, including urinary tract infection (UTI), are more prevalent with age; however, the mechanisms underlying the impact of aging on the urinary tract mucosa and the correlation between aging and disease remain poorly understood. Here, we show that, relative to young (8-12 weeks) mice, the urothelium of aged (18-24 months) female mice accumulates large lysosomes with reduced acid phosphatase activity and decreased overall autophagic flux in the aged urothelium, indicative of compromised cellular homeostasis. …

Postprandial Glucose Variability Following Typical Meals In Youth Living With Type 1 Diabetes., Susana R. Patton, Simon Bergford, Jennifer L. Sherr, Robin L. Gal, Peter Calhoun, Mark A. Clements, Michael C. Riddell, Corby K. Martin

Manuscripts, Articles, Book Chapters and Other Papers

We explored the association between macronutrient intake and postprandial glucose variability in a large sample of youth living with T1D and consuming free-living meals. In the Type 1 Diabetes Exercise Initiative Pediatric (T1DEXIP) Study, youth took photographs before and after their meals on 3 days during a 10 day observation period. We used the remote food photograph method to obtain the macronutrient content of youth's meals. We also collected physical activity, continuous glucose monitoring, and insulin use data. We measured glycemic variability using standard deviation (SD) and coefficient of variation (CV) of glucose for up to 3 h after meals. …

Identifying Opportunities For Prevention Of Adverse Outcomes Following Female Genital Fistula Repair: Protocol For A Mixed-Methods Study In Uganda, Alison El Ayadi, Susan Obore, Fred Kirya, Suellen Miller, Abner Korn, Hadija Nalubwama, John Neuhaus, Monica Getahun, Patrick Eyul, Robert Twine, Erin Andrew, Justus Barageine

Department of Obstetrics and Gynecology Faculty Papers

BACKGROUND: Female genital fistula is a traumatic debilitating injury, frequently caused by prolonged obstructed labor, affecting between 500,000-2 million women in lower-resource settings. Vesicovaginal fistula causes urinary incontinence, and other morbidity may occur during fistula development. Women with fistula are stigmatized, limit social and economic engagement, and experience psychiatric morbidity. Improved surgical access has reduced fistula consequences yet post-repair risks impacting quality of life and well-being include fistula repair breakdown or recurrence and ongoing or changing urine leakage or incontinence. Limited evidence on risk factors contributing to adverse outcomes hinders interventions to mitigate adverse events. This study aims to quantify …

Mastitis And Mammary Abscess Management Audit (Mamma) In The Uk And Ireland, Alona Courtney, Jonathon Clymo, Ruth Parks, Alexander Wilkins, Ruth Brown, Rachel O'Connell, Rajiv Dave, Marianne Dillon, Hiba Fatayer, Rachel Gallimore, Ashu Gandhi, Matthew Gardiner, Victoria Harmer, Lyndsey Hookway, Gareth Irwin, Charlotte Ives, Helen Mathers, Juliette Murray, D Peter O'Leary, Neill Patani, Sophie Paterson, Shelley Potter, Ruth Prichard, Giovanni Satta, T G Teoh, Paul Ziprin, Stuart Mcintosh, Michael R Boland, Daniel Richard Leff, Mamma Research Collaborative

Faculty, Staff and Student Publications

BACKGROUND: The aim of this multicentre prospective audit was to describe the current practice in the management of mastitis and breast abscesses in the UK and Ireland, with a specific focus on rates of surgical intervention.

METHODS: This audit was conducted in two phases from August 2020 to August 2021; a phase 1 practice survey and a phase 2 prospective audit. Primary outcome measurements for phase 2 included patient management pathway characteristics and treatment type (medical/radiological/surgical).

RESULTS: A total of 69 hospitals participated in phase 2 (1312 patients). The key findings were a high overall rate of incision and drainage …

Global Benchmarks In Primary Robotic Bariatric Surgery Redefine Quality Standards For Roux-En-Y Gastric Bypass And Sleeve Gastrectomy, Guillaume Giudicelli, Daniel Gero, Lind Romulo, Vasu Chirumamilla, Pouya Iranmanesh, Christopher K Owen, Wayne Bauerle, Amador Garcia, Lisa Lucas, Anne-Sophie Mehdorn, Dhananjay Pandey, Abdullah Almuttawa, Francisco Cabral, Abhishek Tiwari, Virginia Lambert, Beniamino Pascotto, Celine De Meyere, Marouan Yahyaoui, Thomas Haist, Oliver Scheffel, Maud Robert, Frederiek Nuytens, Santiago Azagra, Lilian Kow, Arun Prasad, Carlos Vaz, Michel Vix, Vivek Bindal, Jan H Beckmann, David Soussi, Ramon Vilallonga, Maher El Chaar, Erik B Wilson, Arif Ahmad, Andre Teixeira, Monika E Hagen, Christian Toso, Pierre-Alain Clavien, Milo Puhan, Marco Bueter, Minoa K Jung

Faculty, Staff and Student Publications

BACKGROUND: Whether the benefits of the robotic platform in bariatric surgery translate into superior surgical outcomes remains unclear. The aim of this retrospective study was to establish the 'best possible' outcomes for robotic bariatric surgery and compare them with the established laparoscopic benchmarks.

METHODS: Benchmark cut-offs were established for consecutive primary robotic bariatric surgery patients of 17 centres across four continents (13 expert centres and 4 learning phase centres) using the 75th percentile of the median outcome values until 90 days after surgery. The benchmark patients had no previous laparotomy, diabetes, sleep apnoea, cardiopathy, renal insufficiency, inflammatory bowel disease, immunosuppression, …

Biallelic Variants In Rbm42 Cause A Multisystem Disorder With Neurological, Facial, Cardiac, And Musculoskeletal Involvement, Yiyao Chen, Bingxin Yang, Xiaoyu Merlin Zhang, Songchang Chen, Minhui Wang, Liya Hu, Nina Pan, Shuyuan Li, Weihui Shi, Zhenhua Yang, Li Wang, Yajing Tan, Jian Wang, Yanlin Wang, Qinghe Xing, Zhonghua Ma, Jinsong Li, He-Feng Huang, Jinglan Zhang, Chenming Xu

Faculty, Staff and Students Publications

Here, we report a previously unrecognized syndromic neurodevelopmental disorder associated with biallelic loss-of-function variants in the RBM42 gene. The patient is a 2-year-old female with severe central nervous system (CNS) abnormalities, hypotonia, hearing loss, congenital heart defects, and dysmorphic facial features. Familial whole-exome sequencing (WES) reveals that the patient has two compound heterozygous variants, c.304C>T (p.R102*) and c.1312G>A (p.A438T), in the RBM42 gene which encodes an integral component of splicing complex in the RNA-binding motif protein family. The p.A438T variant is in the RRM domain which impairs RBM42 protein stability in vivo. Additionally, p.A438T disrupts the interaction of …

Features Of Acute Covid-19 Associated With Post-Acute Sequelae Of Sars-Cov-2 Phenotypes: Results From The Impacc Study, Al Ozonoff, Naresh Doni Jayavelu, Shanshan Liu, Esther Melamed, Carly E Milliren, Jingjing Qi, Linda N Geng, Grace A Mccomsey, Charles B Cairns, Lindsey R Baden, Joanna Schaenman, Albert C Shaw, Hady Samaha, Vicki Seyfert-Margolis, Florian Krammer, Lindsey B Rosen, Hanno Steen, Caitlin Syphurs, Ravi Dandekar, Casey P Shannon, Rafick P Sekaly, Lauren I R Ehrlich, David B Corry, Farrah Kheradmand, Mark A Atkinson, Scott C Brakenridge, Nelson I Agudelo Higuita, Jordan P Metcalf, Catherine L Hough, William B Messer, Bali Pulendran, Kari C Nadeau, Mark M Davis, Ana Fernandez Sesma, Viviana Simon, Harm Van Bakel, Seunghee Kim-Schulze, David A Hafler, Ofer Levy, Monica Kraft, Chris Bime, Elias K Haddad, Carolyn S Calfee, David J Erle, Charles R Langelier, Walter Eckalbar, Steven E Bosinger, Bjoern Peters, Steven H Kleinstein, Elaine F Reed, Alison D Augustine, Joann Diray-Arce, Holden T Maecker, Matthew C Altman, Ruth R Montgomery, Patrice M Becker, Nadine Rouphael

Faculty, Staff and Students Publications

Post-acute sequelae of SARS-CoV-2 (PASC) is a significant public health concern. We describe Patient Reported Outcomes (PROs) on 590 participants prospectively assessed from hospital admission for COVID-19 through one year after discharge. Modeling identified 4 PRO clusters based on reported deficits (minimal, physical, mental/cognitive, and multidomain), supporting heterogenous clinical presentations in PASC, with sub-phenotypes associated with female sex and distinctive comorbidities. During the acute phase of disease, a higher respiratory SARS-CoV-2 viral burden and lower Receptor Binding Domain and Spike antibody titers were associated with both the physical predominant and the multidomain deficit clusters. A lower frequency of circulating B …

Cell State Of Origin Impacts Development Of Distinct Endometriosis-Related Ovarian Carcinoma Histotypes, Ian Beddows, Huihui Fan, Karolin Heinze, Benjamin K Johnson, Anna Leonova, Janine Senz, Svetlana Djirackor, Kathleen R Cho, Celeste Leigh Pearce, David G Huntsman, Michael S Anglesio, Hui Shen

Faculty, Staff and Student Publications

Clear cell ovarian carcinoma (CCOC) and endometrioid ovarian carcinoma (ENOC) are ovarian carcinoma histotypes, which are both thought to arise from ectopic endometrial (or endometrial-like) cells through an endometriosis intermediate. How the same cell type of origin gives rise to two morphologically and biologically different histotypes has been perplexing, particularly given that recurrent genetic mutations are common to both and present in nonmalignant precursors. We used RNA transcription analysis to show that the expression profiles of CCOC and ENOC resemble those of normal endometrium at secretory and proliferative phases of the menstrual cycle, respectively. DNA methylation at the promoter of …

Continued Treatment With Tirzepatide For Maintenance Of Weight Reduction In Adults With Obesity: The Surmount-4 Randomized Clinical Trial, Louis J Aronne, Naveed Sattar, Deborah B Horn, Harold E Bays, Sean Wharton, Wen-Yuan Lin, Nadia N Ahmad, Shuyu Zhang, Ran Liao, Mathijs C Bunck, Irina Jouravskaya, Madhumita A Murphy, Surmount-4 Investigators

Faculty, Staff and Student Publications

IMPORTANCE: The effect of continued treatment with tirzepatide on maintaining initial weight reduction is unknown.

OBJECTIVE: To assess the effect of tirzepatide, with diet and physical activity, on the maintenance of weight reduction.

DESIGN, SETTING, AND PARTICIPANTS: This phase 3, randomized withdrawal clinical trial conducted at 70 sites in 4 countries with a 36-week, open-label tirzepatide lead-in period followed by a 52-week, double-blind, placebo-controlled period included adults with a body mass index greater than or equal to 30 or greater than or equal to 27 and a weight-related complication, excluding diabetes.

INTERVENTIONS: Participants (n = 783) enrolled in an open-label …

Pediatric Medical Subspecialist Use In Outpatient Settings, Christopher B Forrest, Candice P Chen, Eliana M Perrin, Christopher J Stille, Ruth Cooper, Katherine Harris, Qian Luo, Mitchell G Maltenfort, Lauren E Parlett

Faculty, Staff and Student Publications

Importance

A first step toward understanding whether pediatric medical subspecialists are meeting the needs of the nation’s children is describing rates of use and trends over time.

Objectives

To quantify rates of outpatient pediatric medical subspecialty use.

Design, Setting, and Participants

This repeated cross-sectional study of annual subspecialist use examined 3 complementary data sources: electronic health records from PEDSnet (8 large academic medical centers [January 1, 2010, to December 31, 2021]); administrative data from the Healthcare Integrated Research Database (HIRD) (14 commercial health plans [January 1, 2011, to December 31, 2021]); and administrative data from the Transformed Medicaid Statistical Information …

Clonal Hematopoiesis And Incident Heart Failure With Preserved Ejection Fraction, Art Schuermans, Michael C Honigberg, Laura M Raffield, Bing Yu, Mary B Roberts, Charles Kooperberg, Pinkal Desai, April P Carson, Amil M Shah, Christie M Ballantyne, Alexander G Bick, Pradeep Natarajan, Joann E Manson, Eric A Whitsel, Charles B Eaton, Alexander P Reiner

Faculty, Staff and Student Publications

IMPORTANCE: Clonal hematopoiesis of indeterminate potential (CHIP), the age-related clonal expansion of hematopoietic stem cells with leukemogenic acquired genetic variants, is associated with incident heart failure (HF).

OBJECTIVE: To evaluate the associations of CHIP and key gene-specific CHIP subtypes with incident HF with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF).

DESIGN, SETTING, AND PARTICIPANTS: This population-based cohort study included participants from 2 racially diverse prospective cohort studies with uniform HF subtype adjudication: the Jackson Heart Study (JHS) and Women's Health Initiative (WHI). JHS participants were enrolled during 2000 to 2004 and followed up through 2016. WHI participants were …

Clonal Hematopoiesis Risk Score And All-Cause And Cardiovascular Mortality In Older Adults, Seyedmohammad Saadatagah, Md Mesbah Uddin, Lachelle D Weeks, Abhishek Niroula, Meng Ru, Koichi Takahashi, Lukasz Gondek, Bing Yu, Alexander G Bick, Benjamin L Ebert, Elizabeth A Platz, Pradeep Natarajan, Christie M Ballantyne

Faculty, Staff and Student Publications

IMPORTANCE: Clonal hematopoiesis (CH) with acquired pathogenic variants in myeloid leukemia driver genes is common in older adults but of unknown prognostic value.

OBJECTIVE: To investigate the prevalence of CH and the utility of the CH risk score (CHRS) in estimating all-cause and disease-specific mortality in older adults with CH.

DESIGN, SETTING, AND PARTICIPANTS: This population-based prospective cohort study involved community-dwelling older adults (aged 67-90 years) without hematologic malignant neoplasms (HMs) who were participants in the Atherosclerosis Risk in Communities Visit 5 at 4 US centers: Forsyth County, North Carolina; Jackson, Mississippi; Minneapolis, Minnesota; and Washington County, Maryland. Samples were …

Time To Continuous Renal Replacement Therapy Initiation And 90-Day Major Adverse Kidney Events In Children And Young Adults, Katja M Gist, Shina Menon, Pilar Anton-Martin, Amee M Bigelow, Gerard Cortina, Akash Deep, Sara De La Mata-Navazo, Ben Gelbart, Stephen Gorga, Isabella Guzzo, Kenneth E Mah, Nicholas J Ollberding, H Stella Shin, Sameer Thadani, Amanda Uber, Huaiyu Zang, Michael Zappitelli, David T Selewski, We-Rock Investigators

Faculty, Staff and Students Publications

IMPORTANCE: In clinical trials, the early or accelerated continuous renal replacement therapy (CRRT) initiation strategy among adults with acute kidney injury or volume overload has not demonstrated a survival benefit. Whether the timing of initiation of CRRT is associated with outcomes among children and young adults is unknown.

OBJECTIVE: To determine whether timing of CRRT initiation, with and without consideration of volume overload (VO;

DESIGN, SETTING, AND PARTICIPANTS: This multinational retrospective cohort study was conducted using data from the Worldwide Exploration of Renal Replacement Outcome Collaborative in Kidney Disease (WE-ROCK) registry from 2015 to 2021. Participants included children and young …

C1q Is Elevated During Chronic Staphylococcus Epidermidis Central Nervous System Catheter Infection, Matthew K. Beaver, Lara Bergdolt, Anna Dunaevsky, Tammy Kielian, Gwenn Skar

Journal Articles: Pathology and Microbiology

INTRODUCTION: Significant neurologic morbidity is caused by pediatric cerebrospinal fluid (CSF) shunt infections. The underlying mechanisms leading to impaired school performance and increased risk of seizures are unknown, however, a better understanding of these mechanisms may allow us to temper their consequences. Recent evidence has demonstrated important roles for complement proteins in neurodevelopment and neuroinflammation.

METHODS: We examined complement activation throughout

RESULTS: We found that MASP2 predominated early in catheter infection, but that Factor B was elevated at intermediate time points. Unexpectedly C1q was elevated at late timepoints when bacterial burdens were low or undetectable. Based on these findings and …

Potential Prognostic Determinants For Fet::Creb Fusion-Positive Intracranial Mesenchymal Tumor, Frank M. Mezzacappa, Frankie K. Smith, Weiwei Zhang, Andrew Gard, Fatmagul Kusku Cabuk, Ignancio Gonzalez-Gomez, Hector L. Monforte, Jiancong Liang, Omkar Singh, Martha M. Quezado, Kenneth D. Aldape, Murat Gokden, Julia A. Bridge, Jie Chen

Journal Articles: Pathology and Microbiology

Intracranial mesenchymal tumor (IMT), FET::CREB fusion-positive is a provisional tumor type in the 2021 WHO classification of central nervous system tumors with limited information available. Herein, we describe five new IMT cases from four females and one male with three harboring an EWSR1::CREM fusion and two featuring an EWSR1::ATF1 fusion. Uniform manifold approximation and projection of DNA methylation array data placed two cases to the methylation class "IMT, subclass B", one to "meningioma-benign" and one to "meningioma-intermediate". A literature review identified 74 cases of IMTs (current five cases included) with a median age of 23 years (range 4-79 years) and …

Pharmacokinetic-Pharmacodynamic Evidence From A Phase 3 Trial To Support Flat-Dosing Of Rifampicin For Tuberculosis, Huy X. Ngo, Ava Y. Xu, Gustavo E. Velásquez, Nan Zhang, Vincent K. Chang, Ekaterina V. Kurbatova, William C. Whitworth, Erin Sizemore, Kia Bryant, Wendy Carr, Marc Weiner, Kelly E. Dooley, Melissa Engle, Susan E. Dorman, Payam Nahid, Susan Swindells, Richard E. Chaisson, Pheona Nsubuga, Madeleine Lourens, Rodney Dawson, Radojka M. Savic

Journal Articles: Infectious Diseases

BACKGROUND: The optimal dosing strategy for rifampicin in treating drug-susceptible tuberculosis (TB) is still highly debated. In the phase 3 clinical trial Study 31/ACTG 5349 (NCT02410772), all participants in the control regimen arm received 600 mg rifampicin daily as a flat dose. Here, we evaluated relationships between rifampicin exposure and efficacy and safety outcomes.

METHODS: We analyzed rifampicin concentration time profiles using population nonlinear mixed-effects models. We compared simulated rifampicin exposure from flat- and weight-banded dosing. We evaluated the effect of rifampicin exposure on stable culture conversion at 6 months; TB-related unfavorable outcomes at 9, 12, and 18 months using …

Digital Clock Drawing As An Alzheimer's Disease Susceptibility Biomarker: Associations With Genetic Risk Score And Apoe In Older Adults, L I Thompson, M Cummings, S Emrani, David J. Libon, A Ang, C Karjadi, R Au, C Liu

Rowan-Virtua School of Osteopathic Medicine Departmental Research

BACKGROUND: Alzheimer's disease (AD) is the leading cause of dementia in older adults, but most people are not diagnosed until significant neuronal loss has likely occurred along with a decline in cognition. Non-invasive and cost-effective digital biomarkers for AD have the potential to improve early detection.

OBJECTIVE: We examined the validity of DCTclockTM (a digitized clock drawing task) as an AD susceptibility biomarker.

DESIGN: We used two primary independent variables, Apolipoprotein E (APOE) ε4 allele carrier status and polygenic risk score (PRS). We examined APOE and PRS associations with DCTclockTM composite scores as dependent measures.

SETTING: We used existing data …

Safety And Efficacy Of Peptide Receptor Radionuclide Therapy In Neuroendocrine Tumors: A Single Center Experience., Vineeth Sukrithan, Heather Armbruster, Sherise Rogers, Sherry Mori Vogt, Cassandra Grenade, Claire Verschraegen, Ye Zhou, Ashima Goyal, Mona Natwa, Akram Hussein, Hallie Barr, Dramane Konate, Rochelle Batdorf, Andrew Brown, Bonnie Williams, Songzhu Zhao, Lai Wei, Menglin Xu, Manisha H Shah, Bhavana Konda

Oncology Articles

Peptide receptor radionucleotide therapy (PRRT) with 177Lu-dotatate is widely used for the treatment of patients with neuroendocrine tumors (NETs). We analyzed data from 104 patients with NETs treated with 177Lu -dotatate at a US academic center between December 2017 and October 2020 to better understand patterns of long-term efficacy, safety, and toxicity in the real-world setting. 177Lu-dotatate (200 mCi) was administered every eight weeks for four doses. The most common sites of primary disease were small intestine NETs (n = 49, 47%), pancreatic NETs (n = 32, 31%), and lung NETs (n = 7, 7%). Twenty-seven percent had Ki-6720%. The …

Polygenic And Transcriptional Risk Scores Identify Chronic Obstructive Pulmonary Disease Subtypes In The Copdgene And Eclipse Cohort Studies, Matthew Moll, Julian Hecker, John Platig, Jingzhou Zhang, Auyon J. Ghosh, Katherine A. Pratte, Rui-Sheng Wang, Davin Hill, Iain R. Konigsberg, Joe W. Chiles, Craig P. Hersh, Peter J. Castaldi, Kimberly Glass, Jennifer G. Dy, Don D. Sin, Ruth Tal-Singer, Majd Mouded, Stephen I. Rennard, Gary P. Anderson, Gregory L. Kinney, Russell P. Bowler, Jeffrey L. Curtis, Merry-Lynn Mcdonald, Edwin K. Silverman, Brian D. Hobbs, Michael H. Cho

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: Genetic variants and gene expression predict risk of chronic obstructive pulmonary disease (COPD), but their effect on COPD heterogeneity is unclear. We aimed to define high-risk COPD subtypes using genetics (polygenic risk score, PRS) and blood gene expression (transcriptional risk score, TRS) and assess differences in clinical and molecular characteristics.

METHODS: We defined high-risk groups based on PRS and TRS quantiles by maximising differences in protein biomarkers in a COPDGene training set and identified these groups in COPDGene and ECLIPSE test sets. We tested multivariable associations of subgroups with clinical outcomes and compared protein-protein interaction networks and drug repurposing …