Digital Commons Network^™

Gastroesophageal Reflux And Gastrointestinal Symptoms After Metabolic And Bariatric Surgery In Adolescents: An 8-Year Follow-Up Analysis, John B Rode, Suhail A Zeineddin, Jane C Khoury, Todd M Jenkins, Stephanie R Sisley, Anita P Courcoulas, Justin R Ryder, Marc P Michalsky, Thomas H Inge

Children’s Nutrition Research Center Staff Publications

Importance: Vertical sleeve gastrectomy (VSG) and Roux-en-Y gastric bypass (RYGB) are the most commonly performed metabolic and bariatric surgery (MBS) procedures in adolescents and adults. Despite their safety and effectiveness, there is concern over postoperative gastrointestinal symptoms (GIS), especially gastroesophageal reflux symptoms (GERS), in those undergoing VSG.

Objective: To evaluate the long-term prevalence of GIS in adolescents who underwent RYGB or VSG.

Design, setting, and participants: This is a prospective, multicenter, observational cohort study at five academic referral centers in the United States. Patients were enrolled from February 28, 2007, through December 30, 2011. The analysis included 228 adolescents: 161 …

Linear Growth During Treatment With A Simplified, Combined Protocol: Secondary Analyses Of Severely Wasted Children 6-59 Months In The Compas Cluster Randomized Controlled Trial, Grace Heymsfield, Kevin Stephenson, Zachary Tausanovitch, André Briend, Marko Kerac, Heather Stobaugh, Jeanette Bailey, Suvi T Kangas

2020-Current year OA Pubs

A simplified, combined protocol treats children with moderate acute malnutrition (MAM), defined by mid-upper arm circumference (MUAC) of <  125 and ≥ 115 mm and no oedema, with 1 daily sachet of ready-to-use therapeutic food (RUTF) and those with severe acute malnutrition (SAM), defined by MUAC <  115 mm and/or oedema, with two daily sachets of RUTF. This protocol was previously shown to result in non-inferior recovery compared to standard treatment that used higher, weight-based RUTF dosing among children with SAM and ready-to-use supplementary food (RUSF) for MAM in a cluster-based randomised controlled trial in Kenya and South Sudan. We conducted a secondary analysis of this trial to compare linear growth among children admitted with MUAC <  115 mm. Linear and ponderal growth were calculated from admission to discharge and visualised using aggregate growth curves. HAZ change adjusted for admission characteristics was negative across the course of treatment but similar across arms [-0.21 ± 0.18 SE in the standard arm, -0.24 ± 0.18 SE in simplified; difference (95% confidence interval) 0.03 (-0.12, 0.18)]. The unadjusted mean ± SE linear growth velocity from admission to discharge was 1.8 ± 0.7 mm/week in the standard arm compared to 1.7 ± 0.7 mm/week in the simplified arm [difference = 0.09 (-0.36, 0.53)] and similar in adjusted analysis. MUAC and weight gain velocities were not significantly different by treatment arm. Reducing the RUTF dose prescribed to children during SAM treatment does not appear to affect linear growth or other growth velocities during treatment.

Acute Kidney Injury In Severe Alcohol-Associated Hepatitis Treated With Anakinra Plus Zinc Or Prednisone, Kavish R Patidar, Wanzhu Tu, Thomas G Cotter, Douglas A Simonetto, Amon Asgharpour, Muhammad Y Jan, Qing Tang, Yunpeng Yu, Yang Li, Moyinoluwa Taiwo, Prashanth Thevkar Nagesh, Srinivasan Dasarathy, Patrick S Kamath, Craig J Mcclain, Naga Chalasani, Gyongyi Szabo, Ramon Bataller, Mack Mitchell, Wajahat Z Mehal, Laura E Nagy, Vijay H Shah, Samer Gawrieh, Arun J Sanyal

Faculty, Staff and Students Publications

Background and aims: In a recent trial, patients with severe alcohol-associated hepatitis treated with anakinra plus zinc (A+Z) had lower survival and higher acute kidney injury (AKI) rates versus prednisone (PRED). We characterize the clinical factors and potential mechanisms associated with AKI development in that trial.

Approach and results: Data from 147 participants in a multicenter randomized clinical trial (74 A+Z, 73 PRED) were analyzed. AKI, AKI phenotypes, and kidney injury biomarkers were compared between participants who did/did not develop AKI in the 2 treatment arms. Multivariable competing risk analyses were performed to identify baseline risk factors for incident AKI, …

First-In-Human Phase I Study Of A Cd16a Bispecific Innate Cell Engager, Afm24, Targeting Egfr-Expressing Solid Tumors, Anthony El-Khoueiry, Todd A Fehniger, Mark Foster, Melissa M Berrien-Elliott, Et Al.

2020-Current year OA Pubs

PURPOSE: Innate immune cell-based therapies have shown promising antitumor activity against solid and hematologic malignancies. AFM24, a bispecific innate cell engager, binds CD16A on NK cells/macrophages and EGFR on tumor cells, redirecting antitumor activity toward tumors. The safety and tolerability of AFM24 were evaluated in this phase I/IIa dose-escalation/dose-expansion study in patients with recurrent or persistent, advanced solid tumors known to express EGFR.

PATIENTS AND METHODS: The main objective in phase I was to determine the MTD and/or recommended phase II dose. The primary endpoint was the incidence of dose-limiting toxicities during the observation period. Secondary endpoints included the incidence …

Multi-Omic Analysis Of Biological Aging Biomarkers In Long-Term Calorie Restriction And Endurance Exercise Practitioners: A Cross-Sectional Study, Giovanni Fiorito, Valeria Tosti, Silvia Polidoro, Beatrice Bertozzi, Nicola Veronese, Edda Cava, Francesco Spelta, Laura Piccio, Dayna S Early, Daniel Raftery, Paolo Vineis, Luigi Fontana

2020-Current year OA Pubs

Calorie restriction (CR) and physical exercise (EX) are well-established interventions known to extend health span and lifespan in animal models. However, their impact on human biological aging remains unclear. With recent advances in omics technologies and biological age (BioAge) metrics, it is now possible to assess the impact of these lifestyle interventions without the need for long-term follow-up. This study compared BioAge biomarkers in 41 middle-aged and older adult long-term CR practitioners, 41 age- and sex-matched endurance athletes (EX), and 35 sedentary controls consuming Western diets (WD), through PhenoAge: a composite score derived from nine blood-biomarkers. Additionally, a subset of …

Social Determinants Of Health And Health Literacy In Emergency Patients With Diabetic Ketoacidosis, Daniel F Suarez, Ryan M Schneider, Margo Girardi, Gina Larossa, Julianne Yeary, Taylor Kaser, Rachel Ancona, Paulina Cruz Bravo, Richard T Griffey

2020-Current year OA Pubs

INTRODUCTION: Social determinants of health (SDoH) and health literacy have been demonstrated to significantly impact health outcomes. As part of a study of diabetic ketoacidosis (DKA) treatment from the emergency department (ED), we assessed the burden of SDoH and health literacy among patients with DKA to identify potentially modifiable risk factors in the development of DKA.

METHODS: This was an exploratory, prospective, cross-sectional study of adult patients with DKA in a large urban academic ED from March 2023-March 2024. We administered the Centers for Medicare & Medicaid Services Accountable Health Communities Health-Related Social Needs Screening Tool (SNST) and the Brief …

O The Places Rural Children Will Go…To Get Physical Activity: A Cross Sectional Analysis., Bethany Forseth, Jordan A. Carlson, Adrian Ortega, Chelsea Steel, Brittany Lancaster, Lauren Fitzpatrick, Qianxia Jiang, Ann M. Davis

Manuscripts, Articles, Book Chapters and Other Papers

PURPOSE: Youth living in rural areas have higher risk for overweight/obesity. It is important to understand where these children engage in moderate-to-vigorous physical activity (MVPA) and sedentary time to encourage or intervene on activity in specific locations. This study compared MVPA and sedentary time across locations among children with overweight/obesity in the rural Midwest of the U.S.

METHODS: Participants wore an accelerometer and Global Positioning System tracker over 7-days to collect data on MVPA, sedentary time, and location. Locations were categorized as Home, Home Neighborhood, School, School Neighborhood, and 'Other'. Differences based on school and non-school days were examined.

RESULTS: …

Association Of Parental Oral Health Knowledge And Self-Efficacy With Early Childhood Caries And Oral Health Quality Of Life In Texas Schoolchildren, Shreela V Sharma, Jeanette E Deason, Mengxi Wang, Alejandra Garcia-Quintana, Ru-Jye Chuang, Kila Johnson, Shalisa Garner, Steven Kelder, Jose-Miguel Yamal

Faculty, Staff and Student Publications

Improving children's oral health is a national priority. Parental knowledge and self-efficacy influence children's health behaviors; however, the relationship between parental oral health-related knowledge, self-efficacy, child oral health-related quality of life (OHQoL), and dental caries remains unclear, especially among low-income, ethnically diverse U.S. families. This study assesses the relationship between parental oral health-related knowledge, self-efficacy, child dental caries, and OHQoL. This cross-sectional seco ndary analysis uses baseline data from a school-based cluster-randomized controlled trial among children (kindergarten-second grade). Dental assessments were conducted using the International Caries Detection and Assessment System (ICDAS) on site in schools at baseline (n = 34 …

Metagenomic Signatures Of Extraintestinal Bacterial Infection In The Febrile Term Infant Gut Microbiome, Anna L Deveaux, Carla Hall-Moore, Nurmohammad Shaikh, Meghan Wallace, Carey-Ann D Burnham, David Schnadower, Nathan Kuppermann, Prashant Mahajan, Octavio Ramilo, Phillip I Tarr, Gautam Dantas, Drew J Schwartz

2020-Current year OA Pubs

BACKGROUND: Extraintestinal bacterial infections (EBIs), e.g., urinary tract infection, bacteremia, and meningitis, occur in approximately 10% of febrile infants younger than 60 days. Although many EBI-causing species commonly reside in the infant gut, proof that the digestive system is a pre-infection habitat remains unestablished.

RESULTS: We studied a cohort of febrile term infants <  60 days old who presented to one of thirteen US emergency departments in the Pediatric Emergency Care Applied Research Network from 2016 to 2019. Forty EBI cases and 74 febrile controls matched for age, sex, and race without documented EBIs were selected for analysis. Shotgun sequencing was performed of the gut microbiome and of strains cultured from the gut and extraintestinal site(s) of EBI cases, including blood, urine, and/or cerebrospinal fluid. Using a combination of EBI isolate genomics and fecal metagenomics, we detected an intestinal strain presumptively isogenic to the EBI pathogen (> 99.999% average nucleotide identity) in 63% of infants with EBIs. Although there was no difference in gut microbiome diversity between cases and controls, we observed significantly increased Escherichia coli relative abundance in the gut microbiome of infants with EBIs caused by E. coli. Infants with E. coli …

Adipose Progenitor Cell-Derived Extracellular Vesicles Suppress Macrophage M1 Program To Alleviate Midlife Obesity, Qing Zhou, Jia Gao, Guorao Wu, Chenwei Wang, Yan Yang, Teng Huang, Yi Wang, Tiantian Yue, Zhichao Gao, Hao Xie, Fei Xiong, Ke Xiang, Tuying Yong, Wanguang Zhang, Tongtong Zhang, Wen Kong, Cai Chen, Shu Zhang, Qilin Yu, Xuemei Fan, Shiwei Liu, Yanjun Liu, Cong-Yi Wang

Children’s Nutrition Research Center Staff Publications

Among different age groups, middle-aged individuals are particularly susceptible to obesity, with a 22% higher risk of all-cause mortality. However, the underlying mechanisms remain unclear. In this study, we identify adipose progenitor cells (APCs) in the white adipose tissue (WAT) of middle-aged subjects as potential causes of midlife obesity. Specifically, the extracellular vesicles (EVs) derived from APCs display an impaired ability to mitigate the inflammaging of adipose tissue macrophages (ATMs) in middle-aged individuals. Mechanistically, these EVs, lacking miR-145-5p, fail to suppress the expression of L-selectin in ATMs, thereby facilitating their M1 program via the NF-κB signaling pathway. In contrast, EVs …

Genetic Associations With C-Peptide Levels Before Type 1 Diabetes Diagnosis In At-Risk Relatives, Taylor M Triolo, Hemang M Parikh, Mustafa Tosur, Lauric A Ferrat, Lu You, Peter A Gottlieb, Richard A Oram, Suna Onengut-Gumuscu, Jeffrey P Krischer, Stephen S Rich, Andrea K Steck, Maria J Redondo

Children’s Nutrition Research Center Staff Publications

Objective: We sought to determine whether the type 1 diabetes genetic risk score-2 (T1D-GRS2) and single nucleotide polymorphisms are associated with C-peptide preservation before type 1 diabetes diagnosis.

Methods: We conducted a retrospective analysis of 713 autoantibody-positive participants who developed type 1 diabetes in the TrialNet Pathway to Prevention Study who had T1DExomeChip data. We evaluated the relationships of 16 known single nucleotide polymorphisms and T1D-GRS2 with area under the curve (AUC) C-peptide levels during oral glucose tolerance tests conducted in the 9 months before diagnosis.

Results: Higher T1D-GRS2 was associated with lower C-peptide AUC in the 9 months before …

Exploring Profiles Of Fathers Integrating Food And Physical Activity Parenting Practices, John A Jimenez-Garcia, Louise C Mâsse, Robert L Newton, Salma M Musaad, Alicia Beltran, Teresia M O'Connor

Children’s Nutrition Research Center Staff Publications

Objective: This study aims to identify fathers' profiles integrating food parenting practices (FPP) and physical activity parenting practices (PAPP).

Design: We analysed cross-sectional data. The fathers completed the reduced FPP and PAPP item banks and socio-demographic and family dynamics (co-parenting and household responsibility) questionnaires. We identified fathers' profiles via latent profile analysis. We explored the influence of social determinants, child characteristics and family dynamics on fathers' profiles using multinomial logistic regression.

Setting: Online survey in the USA.

Participants: Fathers of 5-11-year-old children.

Results: We analysed data from 606 fathers (age = 38 ± 8·0; Hispanic = 37·5 %). Most fathers …

Identification Of Lysosomal Lipolysis As An Essential Noncanonical Mediator Of Adipocyte Fasting And Cold-Induced Lipolysis, Yu-Sheng Yeh, Trent D. Evans, Mari Iwase, Se-Jin Jeong, Arick Park, Ali Ghasemian, Borna Dianati, Ali Javaheri, Et Al.

2020-Current year OA Pubs

Adipose tissue lipolysis is the process by which triglycerides in lipid stores are hydrolyzed into free fatty acids (FFAs), serving as fuel during fasting or cold-induced thermogenesis. Although cytosolic lipases are considered the predominant mechanism of liberating FFAs, lipolysis also occurs in lysosomes via lysosomal acid lipase (LIPA), albeit with unclear roles in lipid storage and whole-body metabolism. We found that adipocyte LIPA expression increased in adipose tissue of mice when lipolysis was stimulated during fasting, cold exposure, or β-adrenergic agonism. This was functionally important, as inhibition of LIPA genetically or pharmacologically resulted in lower plasma FFAs under lipolytic conditions. …

Inflammation And Gut Barrier Function-Related Genes And Colorectal Cancer Risk In Western European Populations, Hannah B Mandle, Mazda Jenab, Marc J Gunter, Anne Tjønneland, Anja Olsen, Christina C Dahm, Jie Zhang, Pierre-Emmanuel Sugier, Joseph Rothwell, Gianluca Severi, Rudolf Kaaks, Verena A Katzke, Matthias B Schulze, Giovanna Masala, Sabina Sieri, Salvatore Panico, Carlotta Sacerdote, Catalina Bonet, Maria-Jose Sánchez, Pilar Amiano, José María Huerta, Marcela Guevara, Richard Palmqvist, Thyra Löwenmark, Aurora Perez-Cornago, Elisabete Weiderpass, Alicia K Heath, Amanda J Cross, Paolo Vineis, David J Hughes, Veronika Fedirko

Faculty, Staff and Student Publications

Gut barrier dysfunction and related inflammation are known to be associated with the development and progression of colorectal cancer (CRC). We investigated associations of 292 single-nucleotide polymorphisms (SNPs) from 27 genes related to endotoxins/lipopolysaccharide (LPS) sensing and tolerance, mucin synthesis, inflammation, and Crohn's disease with colon and rectal cancer risks. Incident CRC cases (N = 1374; colon = 871, rectum = 503) were matched 1:1 to controls nested within the European Prospective Investigation into Cancer and Nutrition cohort. Previously measured serum concentrations of gut barrier function and inflammation biomarkers (flagellin/LPS-specific immunoglobulins and C-reactive protein [CRP]) were available for a sub-set …

Precision Phenotyping For Curating Research Cohorts Of Patients With Unexplained Post-Acute Sequelae Of Covid-19, Alaleh Azhir, Jonas Hügel, Jiazi Tian, Jingya Cheng, Ingrid V Bassett, Douglas S Bell, Elmer V Bernstam, Maha R Farhat, Darren W Henderson, Emily S Lau, Michele Morris, Yevgeniy R Semenov, Virginia A Triant, Shyam Visweswaran, Zachary H Strasser, Jeffrey G Klann, Shawn N Murphy, Hossein Estiri

Faculty, Staff and Student Publications

BACKGROUND: Scalable identification of patients with post-acute sequelae of COVID-19 (PASC) is challenging due to a lack of reproducible precision phenotyping algorithms, which has led to suboptimal accuracy, demographic biases, and underestimation of the PASC.

METHODS: In a retrospective case-control study, we developed a precision phenotyping algorithm for identifying cohorts of patients with PASC. We used longitudinal electronic health records data from over 295,000 patients from 14 hospitals and 20 community health centers in Massachusetts. The algorithm employs an attention mechanism to simultaneously exclude sequelae that prior conditions can explain and include infection-associated chronic conditions. We performed independent chart reviews …

Youtube User Traffic To Paired Epilepsy Education Videos In English And Spanish: Comparative Study., Luna Kimahri Varela, Stephanie Horton, Ahmed Abdelmoity, Jean-Baptist Lepichon, Mark A. Hoffman

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Effectively managing epilepsy in children necessitates the active engagement of parents, a factor that is reliant on their understanding of this neurological disorder. Widely available, high-quality, patient-focused, bilingual videos describing topics important for managing epilepsy are limited. YouTube Analytics is a helpful resource for gaining insights into how users of differing backgrounds consume video content.

OBJECTIVE: This study analyzes traffic to paired educational videos of English and Spanish versions of the same content. By examining the use patterns and preferences of individuals seeking information in different languages, we gained valuable insights into how language influences the use of clinical …

Developing A Novel Index For Individual-Level Social Determinants And Cardiovascular Diseases In The Coronary Artery Risk Development In Young Adults (Cardia) Study, Tao Gao, Yinan Zheng, Brian Joyce, Lei Liu, Lili Liu, Catarina Kiefe, Sarah Forrester, Bing Yu, Ankeet Bhatt, Penny Gordon-Larsen, Donald Lloyd-Jones, Kai Zhang, Lifang Hou

Faculty, Staff and Student Publications

Background: Social determinants of health (SDH) have been found to contribute to cardiovascular risk and the development of cardiovascular disease (CVD). However, few studies have examined early-life exposure to SDH and the combined effect of multiple SDH measures on CVD. There is an urgent need to develop an SDH index for use in practice and clinical settings.

Methods: A total of 3189 participants from the CARDIA Study who had chest CT scans at the year-25 (Y25) visit were included in this study. Personal and parental SDH measures, including education, occupation, income, financial strain, and childhood family environment, were obtained through …

Developing A Novel Index For Individual-Level Social Determinants And Cardiovascular Diseases In The Coronary Artery Risk Development In Young Adults (Cardia) Study, Tao Gao, Yinan Zheng, Brian Joyce, Lei Liu, Lili Liu, Catarina Kiefe, Sarah Forrester, Bing Yu, Ankeet Bhatt, Penny Gordon-Larsen, Donald Lloyd-Jones, Kai Zhang, Lifang Hou

2020-Current year OA Pubs

BACKGROUND: Social determinants of health (SDH) have been found to contribute to cardiovascular risk and the development of cardiovascular disease (CVD). However, few studies have examined early-life exposure to SDH and the combined effect of multiple SDH measures on CVD. There is an urgent need to develop an SDH index for use in practice and clinical settings.

METHODS: A total of 3189 participants from the CARDIA Study who had chest CT scans at the year-25 (Y25) visit were included in this study. Personal and parental SDH measures, including education, occupation, income, financial strain, and childhood family environment, were obtained through …

Simvastatin And Rifaximin In Decompensated Cirrhosis: A Randomized Clinical Trial, Elisa Pose, César Jiménez, Giacomo Zaccherini, Daniela Campion, Salvatore Piano, Frank Erhard Uschner, Koos De Wit, Olivier Roux, Kohilan Gananandan, Wim Laleman, Cristina Solé, Sonia Alonso, Berta Cuyàs, Xavier Ariza, Adrià Juanola, Ann T Ma, Laura Napoleone, Jordi Gratacós-Ginès, Marta Tonon, Enrico Pompili, Jordi Sánchez-Delgado, Andrew S Allegretti, Manuel Morales-Ruiz, Marta Carol, Martina Pérez-Guasch, Núria Fabrellas, Judit Pich, Claudia Martell, María Joyera, Gemma Domenech, José Ríos, Ferrán Torres, Miquel Serra-Burriel, Rubén Hernáez, Elsa Solà, Isabel Graupera, Hugh Watson, Germán Soriano, Rafael Bañares, Rajeshwar P Mookerjee, Claire Francoz, Ulrich Beuers, Jonel Trebicka, Paolo Angeli, Carlo Alessandria, Paolo Caraceni, Víctor M Vargas, Juan G Abraldes, Patrick S Kamath, Pere Ginès

Faculty, Staff and Students Publications

Importance: There are no useful treatments to prevent the development of severe complications of liver cirrhosis. Simvastatin and rifaximin have shown beneficial effects in liver cirrhosis.

Objective: To assess whether simvastatin combined with rifaximin improves outcomes in patients with decompensated cirrhosis.

Design, setting, and participants: Double-blind, placebo-controlled, phase 3 trial conducted among patients with decompensated cirrhosis in 14 European hospitals between January 2019 and December 2022. The last date of follow-up was December 2022.

Interventions: Patients were randomly assigned to receive simvastatin, 20 mg/d, plus rifaximin, 1200 mg/d (n = 117), or identical-appearing placebo (n = 120) for 12 months …

Metabolic Signatures In Adipose Tissue Linking Lipophilic Persistent Organic Pollutant Mixtures To Blood Pressure Five Years After Bariatric Surgery Among Adolescents, Shudi Pan, Zhenjiang Li, Douglas I Walker, Brittney O Baumert, Hongxu Wang, Jesse A Goodrich, Sarah Rock, Thomas H Inge, Todd M Jenkins, Stephanie Sisley, Scott M Bartell, Stavra Xanthakos, Xiangping Lin, Brooklynn Mcneil, Anna R Robuck, Catherine E Mullins, Michele A La Merill, Erika Garcia, Max T Aung, Sandrah P Eckel, Rob Mcconnell, David V Conti, Justin R Ryder, Lida Chatzi

Faculty, Staff and Students Publications

Persistent organic pollutants (POPs) are lipophilic environmental contaminants accumulated in the adipose tissue. Weight loss interventions, such as bariatric surgery, can mobilize POPs from adipose tissue into the bloodstream. We hypothesized that this mobilization could contribute to increases in blood pressure among 57 adolescents with severe obesity undergoing bariatric surgery. POPs and metabolic features were measured from visceral adipose tissue collected during surgery using gas and liquid chromatography, coupled with high-resolution mass spectrometry. Blood pressure was assessed at baseline, 6 months, and 5 years post-surgery. We used quantile g-computation to estimate associations of POP mixtures with blood pressure changes. With …

Improved Patient-Reported Outcomes With Post-Transplant Cyclophosphamide: A Quality-Of-Life Evaluation And 2-Year Outcomes Of Bmt Ctn 1703., Shernan G Holtan, Javier Bolaños-Meade, Monzr M Al Malki, Juan Wu, Carrie L Kitko, Ran Reshef, Andrew R Rezvani, Brian C Shaffer, Melhem M Solh, Janny M Yao, Lyndsey Runaas, Hany Elmariah, Karilyn T Larkin, Najla El Jurdi, Mahasweta Gooptu, Alison W Loren, Aric C Hall, Amin M Alousi, Omer Jamy, William Clark, Leslie Kean, Ami S Bhatt, Miguel-Angel Perales, Kristy Applegate, Yvonne Adeduni Efebera, Eric Leifer, Richard J Jones, Mary M Horowitz, Deborah Mattila, Wael Saber, Mehdi Hamadani, Michael J Martens

Oncology Articles

The BMT CTN 1703 phase III trial confirmed that graft-versus-host disease (GVHD) prophylaxis with post-transplantation cyclophosphamide (PTCy), tacrolimus (Tac), and mycophenolate mofetil (MMF) results in superior GVHD-free, relapse-free survival (GRFS) compared with Tac/methotrexate (MTX) prophylaxis. This companion study assesses the effect of these regimens on patient-reported outcomes (PROs). Using the Lee Chronic GVHD Symptom Score and PROMIS subscales (physical function, GI symptoms, social role satisfaction) as primary end points and hemorrhagic cystitis symptoms and Lee subscales as secondary end points, responses from English and Spanish speakers were analyzed at baseline and days 100, 180, and 365 after transplant. PRO scores …

A Phase I/Ii Trial Of Avelumab Combinations With Ivuxolimab, Utomilumab, And Radiation Therapy In Patients With Advanced Gastrointestinal Malignancies, Jibran Ahmed, Anne Knisely, Carlos Torrado, Bettzy Stephen, Yali Yang, Juhee Song, Anas Alshawa, Abdulrazzak Zarifa, Anuja Jhingran, Eugene J Koay, Van Karlyle Morris, Milind Javle, Robert A Wolff, Funda Meric-Bernstam, Shubham Pant, Jordi Rodon, Aung Naing

Faculty, Staff and Student Publications

Background: Checkpoint agonists utomilumab (4-1BB agonist) and ivuxolimab (OX40 agonist) enhance Teffector cell function. Preclinical studies suggest that combining these drugs with avelumab (anti-PD-L1 antibody) can potentially synergize this effect. In addition, tissue abscopal effects of radiation therapy may improve antigen presentation, complementing PD-L1 blockade. We conducted a single institution, open-label, multi-arm, non-randomized, phase 1/2 clinical trial of avelumab in combination with ivuxolimab, with or without utomilumab, and radiation therapy in patients with advanced solid tumors. Herein, we present a subgroup analysis in patients with gastrointestinal (GI) tumors (pancreatic, colon, gastric, and hepatocellular).

Methods: The primary objectives of this study …

Factors Driving Adolescent Tuberculosis Incidence By Age And Sex In 30 High-Tuberculosis Burden Countries: A Mathematical Modelling Study, Silvia S Chiang, Megan B Murray, Alexander W Kay, Peter J Dodd

Faculty, Staff and Students Publications

INTRODUCTION: During adolescence, tuberculosis incidence rises, with a greater increase in males compared with females. Tuberculosis notifications and estimates infrequently disaggregate adolescent age groups. Moreover, the factors that drive the increases in overall incidence and the male-to-female (MF) ratio remain unclear.

METHODS: We constructed a mechanistic model to estimate cumulative Mycobacterium tuberculosis infection and tuberculosis disease incidence in the WHO’s 30 high-tuberculosis burden countries (HBCs), which represent 86%–90% of global tuberculosis incidence. We derived infection risk from tuberculosis prevalence and assortative social mixing based on sex and age (10–14 years vs 15–19 years old). We adjusted age subgroup-specific risks of …

Clinical Performance Of An N-Terminal Pro-B-Type Natriuretic Peptide Assay In Acute Heart Failure Diagnosis, Lori B Daniels, Patience Ajongwen, Robert H Christenson, Carol L Clark, Deborah B Diercks, Gregory J Fermann, Sharon E Mace, Simon A Mahler, Peter S Pang, Zubaid Rafique, Michael S Runyon, James Tauras, Christopher R Defilippi

Faculty, Staff and Students Publications

Background: We evaluated the Vitros® Immunodiagnostic Products N-terminal pro B-type natriuretic peptide (NT-proBNP) II assay for aiding in diagnosis of heart failure (HF) in patients with acute dyspnea.

Methods: Serum concentrations of NT-proBNP were measured in patient samples from 20 emergency departments across the United States. Study endpoints included sensitivity, specificity, likelihood ratios, and predictive values for diagnosis of acute HF according to age-stratified cutoffs (450, 900, and 1800 pg/mL), and a rule-out age-independent cutoff (300 pg/mL). Additional measures were area under the curve (AUC) for receiver operating characteristic (ROC) curves. Results were also interpreted in patient subgroups with relevant …

Safety And Efficacy Of Dtx401, An Aav8-Mediated Liver-Directed Gene Therapy, In Adults With Glycogen Storage Disease Type I A (Gsdia), David A Weinstein, Terry G Derks, David F Rodriguez-Buritica, Ayesha Ahmad, María-Luz Couce, John J Mitchell, Rebecca Riba-Wolman, Malaya Mount, Julieta Bonvin Sallago, Katalin M Ross, Melanie M Van Der Klauw, Foekje De Boer, Caroline Van Der Schaaf, Heather Saavedra, Miguel Martínez-Olmos, Elvis Atanga, Asad Hosseini, Deepali Mitragotri, Eric Crombez

Faculty, Staff and Student Publications

Glycogen storage disease type Ia (GSDIa) is a rare, life‐threatening, inherited carbohydrate metabolism disorder caused by glucose‐6‐phosphatase (G6Pase) deficiency, which is essential for glycogenolysis and gluconeogenesis. GSDIa management includes a strict medically prescribed diet that typically includes daily uncooked cornstarch doses, including overnight, to maintain euglycemia. DTX401 is an investigational adeno‐associated virus serotype 8 vector expressing the human G6PC1 gene that encodes G6Pase. This open‐label, phase 1/2, dose‐escalation, 52‐week gene therapy trial evaluated the safety and efficacy of a single DTX401 infusion in 12 adults with GSDIa (ClinicalTrials.gov Identifier: NCT03517085). Three participants in Cohort 1 received DTX401 2.0 × …

Caloric Restriction And Telomere Preservation In Tert Knockout Adipocyte Progenitors Does Not Rescue Mice From Metabolic Dysfunction Due To A Tert Function In Adipocyte Mitochondria, Zhanguo Gao, Yongmei Yu, Kristin Eckel-Mahan, Mikhail G Kolonin

The Brown Foundation: Institute of Molecular Medicine

Inactivation of telomerase (TERT) in adipocyte progenitor cells (APC) expedites telomere attrition, and the onset of diabetes in mice fed high-fat diet (HFD), which promotes APC over-proliferation and replicative senescence. Here, we show that time-restricted feeding or caloric restriction in the postnatal development of mice subsequently subjected to HFD prevents telomere attrition but not glucose intolerance. This metabolic effect of dietary intervention was not observed for mice with TERT KO in endothelial or myeloid cells. To characterize the telomere-independent effects of TERT in the APC lineage, we analyzed mice with TERT knockout in mature adipocytes (AD-TERT-KO), which do not proliferate …

Liver Involvement In A Large Cohort Of Patients With Erythropoietic Protoporphyria Or X-Linked Protoporphyria, Cynthia Levy, Hetanshi Naik, Jessica Overbey, Karli Hedstrom, Kelly Wang, Catherine Mcdonough, Mary Freeman, Siobán B Keel, Angelika L Erwin, Amy K Dickey, Rebecca K Leaf, John Quigley, Marshall Mazepa, Bruce Wang, John Phillips, Charles Parker, Brendan Mcguire, Mohamed Kazamel, Herbert Bonkovsky, Sean Rudnick, Karl E Anderson, Akshata Moghe, Manish Thapar, Behnam Saberi, Kristen Wheeden, Robert Desnick, Manisha Balwani, Porphyrias Consortium Of The Rare Diseases Clinical Research Network

Faculty, Staff and Student Publications

Background: Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are characterized by the accumulation of protoporphyrin in the marrow, erythrocytes, plasma, skin, and liver, and present clinically with painful cutaneous phototoxicity. Liver abnormalities have been reported in over 25% of patients with EPP. Further characterization of liver involvement in protoporphyria is needed.

Methods: Patients with EPP or XLP enrolled in the longitudinal studies of the NIH-supported Porphyrias Consortium were included. Medical history, laboratory, and liver histology data were abstracted and described.

Results: A total of 322 patients were enrolled; 28 (8.7%) had XLP, 52% were female, and the median age at …

Oxidized Carbon Nanoparticles Enhance Cellular Energetics With Application To Injured Brain, Karthik Mouli, Anton V Liopo, Emily A Mchugh, Erica Underwood, Jing Zhao, Pramod K Dash, Anh T T Vo, Vikas H Malojirao, Muralidhar L Hegde, James M Tour, Paul J Derry, Thomas A Kent

Faculty, Staff and Student Publications

Pro-energetic effects of functionalized, oxidized carbon nanozymes (OCNs) are reported. OCNs, derived from harsh acid oxidation of single-wall carbon nanotubes or activated charcoal are previously shown to possess multiple nanozymatic activities including mimicking superoxide dismutase and catalyzing the oxidation of reduced nicotinamide adenine dinucleotide (NADH) to NAD+. These actions are predicted to generate a glycolytic shift and enhance mitochondrial energetics under impaired conditions. Impaired mitochondrial energy metabolism is increasingly recognized as an important facet of traumatic brain injury (TBI) pathophysiology and decreases the efficiency of electron transport chain (ETC)-coupled adenosine triphosphate (ATP) and NAD+ regeneration. In vitro, OCNs promote a …

Safety And Antitumor Activity Of A Novel Acd25 Treg Depleter Rg6292 As A Single Agent And In Combination With Atezolizumab In Patients With Solid Tumors, Valentina Gambardella, Michael Ong, Maria E Rodriguez-Ruiz, Jean-Pascal Machiels, Miguel F Sanmamed, Vladimir Galvao, Anna Spreafico, Daniel J Renouf, Stephen J Luen, Rachel Galot, Bernard Doger De Spéville, Emiliano Calvo, Aung Naing, Samira Curdt, Theresa Maria Kolben, Eva Rossmann, Tamara Tanos, Kevin Smart, Maria Amann, Yuying Xie, Linxinyu Xu, Enrique Gomez Alcaide, Nicolas Städler, Nicole Justies, Christophe Boetsch, Vaios Karanikas, Gabriel Schnetzler, Kristoffer S Rohrberg

Faculty, Staff and Student Publications

Purpose: Therapeutic depletion of immunosuppressive regulatory T cells (Treg) may overcome resistance to cancer immunotherapies. RG6292 is an anti-CD25 antibody that preferentially depletes Tregs while preserving effector T-cell functions in preclinical models. The safety, pharmacokinetics, pharmacodynamics, and antitumor efficacy of selective Treg depletion by RG6292 administered as monotherapy or in combination with atezolizumab were evaluated in two phase I studies.

Patients and methods: Adult patients with advanced solid tumors were administered intravenous RG6292, given every 3 weeks alone (study 1: NCT04158583, n = 76) or with 1,200 mg atezolizumab every 3 weeks (study 2: NCT04642365, n = 49). …

High-Dose Methotrexate Usage Without Drug-Level Monitoring In Advanced Pediatric Mature B-Cell Non-Hodgkin Lymphoma In A Resource-Limited Setting In Malawi, Rizine R Mzikamanda, Loviisa Mulanje, Casey L Mcatee, Apatsa Matatiyo, Zoe Mwale, Grace Chirwa, Watipaso Wanda, Atupele Miranda Mpasa, Stella Wachepa, Minke H W Huibers, Steve Martin, Tamiwe Tomoka, Maurice Mulenga, Yuri Fedoriw, Gugulethu Mapurisa, Julie M Gastier Foster, Nader El-Mallawany, Katherine D Westmoreland, Peter Wasswa, Carl E Allen, Nmazuo Ozuah

Faculty, Staff and Students Publications

Purpose: Excellent survival for advanced (stages II with high lactate dehydrogenase, III, and IV) pediatric mature B-cell non-Hodgkin lymphoma (MB-NHL) has been achieved with intensive regimens, but adoption in sub-Saharan Africa is limited by inadequate supportive care. We provide real-world data on treating advanced MB-NHL with high-dose methotrexate (HD-MTX; ≥1,000 mg/m2/cycle) where real-time serum MTX monitoring is unavailable.

Methods: We identified two cohorts-a retrospective (January 2017-December 2020) cohort treated with 1,000 or 3,000 mg/m2/cycle of HD-MTX and a prospective (July 2022-July 2023) cohort-with a modified LMB96 protocol containing 3,000 mg/m2/cycle of HD-MTX. All doses of HD-MTX were given over 3 …