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Correlations Within And Between Highly Multiplexed Proteomic Assays Of Human Plasma, Mary R Rooney, Jingsha Chen, Christie M Ballantyne, Ron C Hoogeveen, Eric Boerwinkle, Bing Yu, Keenan A Walker, Pascal Schlosser, Elizabeth Selvin, Nilanjan Chatterjee, David Couper, Morgan E Grams, Josef Coresh Jun 2025

Correlations Within And Between Highly Multiplexed Proteomic Assays Of Human Plasma, Mary R Rooney, Jingsha Chen, Christie M Ballantyne, Ron C Hoogeveen, Eric Boerwinkle, Bing Yu, Keenan A Walker, Pascal Schlosser, Elizabeth Selvin, Nilanjan Chatterjee, David Couper, Morgan E Grams, Josef Coresh

Faculty, Staff and Students Publications

Introduction: The number of assays on proteomic platforms has grown rapidly. The leading platforms, SomaScan and Olink, have strengths and limitations. Comparisons of precision on the latest platforms-SomaScan 11k and Olink Explore HT-have not yet been established.

Methods: Among 102 participants in the Atherosclerosis Risk in Communities Study (mean age 74 years, 53% women, 47% Black), we used split plasma samples to measure platform precision. CV and Spearman correlations were calculated for each assay. Cross-platform agreement was assessed for overlapping proteins.

Results: SomaScan 11k demonstrated a median correlation of 0.85 for the 10 778 assays and a median CV of …


Oral Pcsk9 Inhibitors: Can Novel Therapies Overcome Barriers To Effective Ldl-Cholesterol Management?, Christie M Ballantyne, Alberico L Catapano, Khurram Nasir Jun 2025

Oral Pcsk9 Inhibitors: Can Novel Therapies Overcome Barriers To Effective Ldl-Cholesterol Management?, Christie M Ballantyne, Alberico L Catapano, Khurram Nasir

Faculty, Staff and Students Publications

No abstract provided.


Posterior Predictive Design For Phase I Clinical Trials, Chenqi Fu, Shouhao Zhou, J Jack Lee Jun 2025

Posterior Predictive Design For Phase I Clinical Trials, Chenqi Fu, Shouhao Zhou, J Jack Lee

Faculty, Staff and Student Publications

Interval-based designs represent cutting-edge adaptive methodologies for phase I clinical trials to identify the maximum tolerated dose (MTD). These designs exhibit robust performance comparable to more intricate, model-based designs, and their pretabulated decision rule enables them to be implemented as simply as the conventional algorithm-based designs. In this paper, we introduce the posterior predictive (PoP) design, a novel interval-based design that leverages advanced Bayesian predictive hypothesis testing techniques for dose escalation and de-escalation. Our work moves beyond the existing model-assisted interval-based designs by achieving global optimality in dose transition. Theoretically, the global optimality ensures that the proposed design can consistently …


Restoration Of The Tumor Suppressor Function Of Y220c-Mutant P53 By Rezatapopt, A Small-Molecule Reactivator, Anna M Puzio-Kuter, Lizhong Xu, Mary Kate Mcbrayer, Romyr Dominique, Hongju H Li, Bruce J Fahr, Alyssa M Brown, Amy E Wiebesiek, Brandon M Russo, Chris L Mulligan, Hong Yang, Josh Battaglia, Kimberly A Robell, Dafydd H Thomas, Kuo-Sen Huang, Alexander Solovyov, Benjamin D Greenbaum, Jonathan D Oliner, Thomas W Davis, Melissa L Dumble, Melissa L Johnson, Shunbin Xiong, Peirong Yang, Guillermina Lozano, Marc M Fellous, Binh T Vu, Alison M Schram, Arnold J Levine, Masha V Poyurovsky Jun 2025

Restoration Of The Tumor Suppressor Function Of Y220c-Mutant P53 By Rezatapopt, A Small-Molecule Reactivator, Anna M Puzio-Kuter, Lizhong Xu, Mary Kate Mcbrayer, Romyr Dominique, Hongju H Li, Bruce J Fahr, Alyssa M Brown, Amy E Wiebesiek, Brandon M Russo, Chris L Mulligan, Hong Yang, Josh Battaglia, Kimberly A Robell, Dafydd H Thomas, Kuo-Sen Huang, Alexander Solovyov, Benjamin D Greenbaum, Jonathan D Oliner, Thomas W Davis, Melissa L Dumble, Melissa L Johnson, Shunbin Xiong, Peirong Yang, Guillermina Lozano, Marc M Fellous, Binh T Vu, Alison M Schram, Arnold J Levine, Masha V Poyurovsky

Faculty, Staff and Student Publications

Restoration of the tumor suppressor function of tumor-associated p53 mutants, including the Y220C substitution, has posed a significant challenge for therapeutic discovery. In this study, we describe rezatapopt (PC14586), part of a series of compounds designed to reactivate the p53 Y220C mutant. These compounds restore p53 tumor suppressor function by correcting its conformation and enabling it to bind DNA and activate downstream target genes, thus inducing antiproliferative changes in tumor cells. Our findings are supported by biochemical and structural analysis, in vitro and in vivo transcriptomics, and functional data, revealing the recovery of multiple aspects of the wild-type p53 program. …


A Novel Cardiomyopathy Phenotype Linked To A Chd7 Missense Variant, In Young Park, Chih-Wei Hsu, Karim Bouazoune, Christina E Espindola, Madeline Hannah Mclaughlin Armond, Cristian Coarfa, Sandra L Grimm, James F Martin, Donna M Martin, Cheryl Lyn Walker Jun 2025

A Novel Cardiomyopathy Phenotype Linked To A Chd7 Missense Variant, In Young Park, Chih-Wei Hsu, Karim Bouazoune, Christina E Espindola, Madeline Hannah Mclaughlin Armond, Cristian Coarfa, Sandra L Grimm, James F Martin, Donna M Martin, Cheryl Lyn Walker

Center for Medical Ethics and Health Policy Staff Publications

Loss of function in the chromatin remodeler CHD7 causes CHARGE syndrome, characterized by variable penetrance and diverse abnormalities. However, establishing genotype-phenotype correlations has been challenging, as most CHD7 inactivating mutations are null alleles. Through CHD7 missense variant analysis at potential phosphorylation sites, we identified T730 (T720 in mice) as a critical residue associated with pathogenesis. Using a CHD7 T730 missense variant (Chd7T720A) and a frameshift null allele (Chd7fs) in a mouse model, we found that Chd7fs/fs mice were non-viable, while Chd7fs/+ mice exhibited haploinsufficiency-related circling behavior. Notably, Chd7fs/T720A mice died before postnatal …


Iron Deficiency Without Anemia And Reduced Basal Ganglia Iron Content In Youths, Dimitri Fiani, Joo-Won Kim, Mianzhi Hu, Ramiro Salas, Sarah Heilbronner, Jacquelyn Powers, Muhammad Haque, Stephanie Dinh, Xiaofan Huang, Darrell Worthy, Sridevi Devaraj, Junqian Xu, Chadi Calarge Jun 2025

Iron Deficiency Without Anemia And Reduced Basal Ganglia Iron Content In Youths, Dimitri Fiani, Joo-Won Kim, Mianzhi Hu, Ramiro Salas, Sarah Heilbronner, Jacquelyn Powers, Muhammad Haque, Stephanie Dinh, Xiaofan Huang, Darrell Worthy, Sridevi Devaraj, Junqian Xu, Chadi Calarge

Faculty, Staff and Students Publications

Importance: Although brain iron is necessary for neurogenesis, myelination, and neurotransmitter synthesis, iron deficiency (ID) is defined solely based on hematological outcomes.

Objective: To examine the association of ID without anemia with basal ganglia (BG) iron content and its structural and functional sequelae in adolescents.

Design, setting, and participants: This cross-sectional study enrolled participants using the electronic medical record system from a large network of pediatrics clinics between December 2020 and April 2024. Otherwise healthy, unmedicated participants aged 10 to 17 years with a depressive or anxiety disorder or with no psychopathology were consecutively enrolled. Anemia and acute inflammation led …


Harnessing Electrophiles In Vivo: A Pilot Study In Swine Using A Hydrophobic Radiopaque Formulation Of 2-Propylpentanoyl Chloride, Erik Cressman, Danielle Stolley, Natalie Fowlkes, Edd Felix, Waldemar Priebe, Steve Parrish, David Fuentes Jun 2025

Harnessing Electrophiles In Vivo: A Pilot Study In Swine Using A Hydrophobic Radiopaque Formulation Of 2-Propylpentanoyl Chloride, Erik Cressman, Danielle Stolley, Natalie Fowlkes, Edd Felix, Waldemar Priebe, Steve Parrish, David Fuentes

Faculty, Staff and Student Publications

Manipulating biology through chemistry is older than the discipline of chemistry itself. Traditionally, selectivity of oral or intravenous drugs relied on preferential drug-receptor binding. A novel approach exploiting image-guided techniques to impart spatial selectivity opens up a wide range of new possibilities for study and manipulation of biology. Motivated initially by the poor prognosis for solid tumors such as liver cancer, we demonstrate the use of an extreme form of in vivo chemistry for targeted delivery of 2-propylpentanoyl chloride in a swine model. The ensuing reaction in tissue devitalizes it by multiple mechanisms with lasting effects and, critically, demonstrates very …


A Comprehensive, Multi-Center, Immunogenomic Analysis Of Melanoma Brain Metastases, Lucy Boyce Kennedy, Amanda E D Van Swearingen, Marissa R Lee, Layne W Rogers, Alexander B Sibley, Jeff Sheng, Dadong Zhang, Xiaodi Qin, Eric S Lipp, Swaminathan Kumar, Aron Joon, Pixu Shi, Michael A Davies, Kouros Owzar, Carey K Anders, April K S Salama Jun 2025

A Comprehensive, Multi-Center, Immunogenomic Analysis Of Melanoma Brain Metastases, Lucy Boyce Kennedy, Amanda E D Van Swearingen, Marissa R Lee, Layne W Rogers, Alexander B Sibley, Jeff Sheng, Dadong Zhang, Xiaodi Qin, Eric S Lipp, Swaminathan Kumar, Aron Joon, Pixu Shi, Michael A Davies, Kouros Owzar, Carey K Anders, April K S Salama

Faculty, Staff and Student Publications

Background: Melanoma brain metastases (MBM) have a unique molecular profile compared to extracranial metastases (ECM). Description of the biological features and clinical outcomes of MBM will facilitate the design of rational therapies.

Methods: We examined the mutational landscape and gene expression profiles of MBM (74 patients) and ECM (34 patients) in paired patient samples from a previously published dataset with whole-exome sequencing (WES) and RNA sequencing (RNAseq) data from MD Anderson Cancer Center (MDACC). We also present findings from MBM from a new cohort of 14 patients from Duke University to strengthen investigation of somatic mutations and gene expression profiles. …


Assessment Of Frailty In Patients With Heart Failure: A New Heart Failure Frailty Score Developed By Delphi Consensus, Cristiana Vitale, Emmanuelle Berthelot, Andrew J S Coats, Hill Loreena, Nancy M Albert, Michal Tkaczyszyn, Stamatis Adamopoulos, Lisa Anderson, Markus S Anker, Stefan D Anker, Derek Bell, Tuvia Ben-Gal, Vasiliki Bistola, Biykem Bozkurt, Poppy Brooks, Miguel Camafort, Juan Jesus Carrero, Ovidiu Chioncel, Dong-Ju Choi, Wook-Jin Chung, Wolfram Doehner, Daniel Fernández-Bergés, Roberto Ferrari, Mona Fiuzat, Juan Esteban Gomez-Mesa, Finn Gustafsson, Ewa Jankowska, Seok-Min Kang, Koichiro Kinugawa, Kamlesh Khunti, F D Richard Hobbs, Christopher Lee, Yuri Lopatin, Matthew Maddocks, Giuseppe Maltese, Elena Marques-Sule, Yuya Matsue, Òscar Miró, Brenda Moura, Massimo Piepoli, Piotr Ponikowski, Giovanni Pulignano, Amina Rakisheva, Robin Ray, Angela Sciacqua, Petar Seferovic, Trinidad Sentandreu-Mañó, Shirley Sze, Alan Sinclair, Anna Strömberg, Olga Theou, Hiroyuki Tsutsui, Izabella Uchmanowicz, Maria Teresa Vidan, Maurizio Volterrani, Stephan Von Haehling, Byungsu Yoo, Jian Zhang, Yuhui Zhang, Marco Metra, Giuseppe Massimo Claudio Rosano Jun 2025

Assessment Of Frailty In Patients With Heart Failure: A New Heart Failure Frailty Score Developed By Delphi Consensus, Cristiana Vitale, Emmanuelle Berthelot, Andrew J S Coats, Hill Loreena, Nancy M Albert, Michal Tkaczyszyn, Stamatis Adamopoulos, Lisa Anderson, Markus S Anker, Stefan D Anker, Derek Bell, Tuvia Ben-Gal, Vasiliki Bistola, Biykem Bozkurt, Poppy Brooks, Miguel Camafort, Juan Jesus Carrero, Ovidiu Chioncel, Dong-Ju Choi, Wook-Jin Chung, Wolfram Doehner, Daniel Fernández-Bergés, Roberto Ferrari, Mona Fiuzat, Juan Esteban Gomez-Mesa, Finn Gustafsson, Ewa Jankowska, Seok-Min Kang, Koichiro Kinugawa, Kamlesh Khunti, F D Richard Hobbs, Christopher Lee, Yuri Lopatin, Matthew Maddocks, Giuseppe Maltese, Elena Marques-Sule, Yuya Matsue, Òscar Miró, Brenda Moura, Massimo Piepoli, Piotr Ponikowski, Giovanni Pulignano, Amina Rakisheva, Robin Ray, Angela Sciacqua, Petar Seferovic, Trinidad Sentandreu-Mañó, Shirley Sze, Alan Sinclair, Anna Strömberg, Olga Theou, Hiroyuki Tsutsui, Izabella Uchmanowicz, Maria Teresa Vidan, Maurizio Volterrani, Stephan Von Haehling, Byungsu Yoo, Jian Zhang, Yuhui Zhang, Marco Metra, Giuseppe Massimo Claudio Rosano

Faculty, Staff and Students Publications

Aims: The Heart Failure Frailty Score (HFFS) is a novel, multidimensional tool to assess frailty in patients with heart failure (HF). It has been developed to overcome limitations of existing frailty assessment tools while being practical for clinical use. The HFFS reflects the concept of frailty as a multidimensional, dynamic and potentially reversible state, which increases vulnerability to stressors and risk of poor outcomes in patients with HF.

Methods and results: The HFFS was developed through a Delphi consensus process involving 54 international experts. This approach involved iterative rounds of questionnaires and interviews, where a panel of experts provided their …


Insights On Human Papillomavirus Among Medical Students And Professionals, Fathima Thansiha, Amogha Shree, Rashmi S Jun 2025

Insights On Human Papillomavirus Among Medical Students And Professionals, Fathima Thansiha, Amogha Shree, Rashmi S

Digital Journal of Clinical Medicine

Background: As per World Health Organization, in 2022, 660000 women were diagnosed with cervical cancer worldwide and 350000 women died from the disease. Sexual behaviour is the major risk factor and exposure to Human Papillomavirus has been established as a causative agent in 70-80% of the cases for development of cervical cancer. Most infections with HPV resolve spontaneously and cause no symptoms, persistent infection can cause cervical cancer in women. Effective primary (HPV vaccination) and secondary prevention approaches (screening and treating precancerous lesions) will prevent most cervical cancer cases. Thus, study was conducted with the objective of assessing the knowledge …


Whole-Exome Sequencing Identified Molecular Variants Linked To The Progression Of Gastric Precancerous Lesions In Patients From Southwestern Colombia—An Exploratory Approach., Lizeth Mejia-Ortiz, Jovanny Zabaleta, Jone Garai, Luis Eduardo Bravo, Andres Castillo Jun 2025

Whole-Exome Sequencing Identified Molecular Variants Linked To The Progression Of Gastric Precancerous Lesions In Patients From Southwestern Colombia—An Exploratory Approach., Lizeth Mejia-Ortiz, Jovanny Zabaleta, Jone Garai, Luis Eduardo Bravo, Andres Castillo

School of Graduate Studies Faculty Publications

No abstract provided.


Irnet: Immunotherapy Response Prediction Using Pathway Knowledge-Informed Graph Neural Network, Yuexu Jiang, Manish Sridhar Immadia, Duolin Wang, Shuai Zeng, Yen On Chan, Jing Zhou, Dong Xu, Trupti Joshi Jun 2025

Irnet: Immunotherapy Response Prediction Using Pathway Knowledge-Informed Graph Neural Network, Yuexu Jiang, Manish Sridhar Immadia, Duolin Wang, Shuai Zeng, Yen On Chan, Jing Zhou, Dong Xu, Trupti Joshi

Biomedical Sciences

Introduction: Immune checkpoint inhibitors (ICIs) are potent and precise therapies for various cancer types, significantly improving survival rates in patients who respond positively to them. However, only a minority of patients benefit from ICI treatments.

Objectives: Identifying ICI responders before treatment could greatly conserve medical resources, minimize potential drug side effects, and expedite the search for alternative therapies. Our goal is to introduce a novel deep-learning method to predict ICI treatment responses in cancer patients.

Methods: The proposed deep-learning framework leverages graph neural network and biological pathway knowledge. We trained and tested our method using ICI-treated patients’ data from several …


Impact Of Length Of Stay On Diagnostic Yield In The Epilepsy Monitoring Unit: A Multi-Center Retrospective 12-Year Veterans Health Administration Study, Maximillian S Feygin, Autumn Smith, Sruthi Gopinath Karicheri, Khadar Haroun, Omar Khan, Maria R Lopez, Stephan Eisenschenk, John Jones, Stephanie Reeder, Alan R Towne, Christopher Ransom, Karen Medin, James Chen, Tung Tran, Nina I Garga, Noemi Rincon-Flores, Marissa Kellogg, Steven Tobochnik, Zulfi Haneef Jun 2025

Impact Of Length Of Stay On Diagnostic Yield In The Epilepsy Monitoring Unit: A Multi-Center Retrospective 12-Year Veterans Health Administration Study, Maximillian S Feygin, Autumn Smith, Sruthi Gopinath Karicheri, Khadar Haroun, Omar Khan, Maria R Lopez, Stephan Eisenschenk, John Jones, Stephanie Reeder, Alan R Towne, Christopher Ransom, Karen Medin, James Chen, Tung Tran, Nina I Garga, Noemi Rincon-Flores, Marissa Kellogg, Steven Tobochnik, Zulfi Haneef

Faculty, Staff and Students Publications

Objective: Epilepsy Monitoring Units (EMUs) in Veterans Health Administration (VHA) Epilepsy Centers of Excellence (ECoE) are critical for the diagnosis and management of seizure disorders. Whether a shorter length of stay (LOS) in the EMU due to scheduling impacts diagnostic yield is unclear.

Methods: Data from 7074 EMU visits across 15 VHA EMUs (2012-2024) were analyzed. Based on usual admission schedules, EMUs were divided into "fixed" (typically Monday-Friday) or "flexible" subgroups. Diagnostic outcomes were classified as epileptic seizures (ES), psychogenic non-epileptic seizures (PNES), other non-epileptic events, and inconclusive. Diagnostic rates were compared between fixed and flexible sites using cumulative distribution …


Baseline Characteristics Of The Us Study To Protect Brain Health Through Lifestyle Intervention To Reduce Risk (Us Pointer): Successful Enrollment Of A Diverse Clinical Trial Cohort At Risk For Cognitive Decline, Rachel A Whitmer, Laura D Baker, Maria C Carrillo, Heather M Snyder, Maryjo L Cleveland, Darren R Gitelman, Miia Kivipelto, Xiaoyan I Leng, Laura Lovato, Kathryn V Papp, Valory N Pavlik, Stephen P Salloway, Christy C Tangney, Sarah Tomaszewski Farias, Jeff D Williamson, Sharon Wilmoth, Nancy Woolard, Melissa Yu, Mark Andrew Espeland, U.S. Pointer Study Group Jun 2025

Baseline Characteristics Of The Us Study To Protect Brain Health Through Lifestyle Intervention To Reduce Risk (Us Pointer): Successful Enrollment Of A Diverse Clinical Trial Cohort At Risk For Cognitive Decline, Rachel A Whitmer, Laura D Baker, Maria C Carrillo, Heather M Snyder, Maryjo L Cleveland, Darren R Gitelman, Miia Kivipelto, Xiaoyan I Leng, Laura Lovato, Kathryn V Papp, Valory N Pavlik, Stephen P Salloway, Christy C Tangney, Sarah Tomaszewski Farias, Jeff D Williamson, Sharon Wilmoth, Nancy Woolard, Melissa Yu, Mark Andrew Espeland, U.S. Pointer Study Group

Faculty, Staff and Students Publications

Introduction: The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) is a 2-year randomized controlled trial of two lifestyle interventions in 2111 older adults at increased risk for cognitive decline.

Methods: Sociodemographic and clinical characteristics and rates of ancillary study participation were described with means and frequencies.

Results: U.S. POINTER successfully enrolled a cohort, ages 60-79 years, which was ethno-racially inclusive (>30% individuals from groups often under-represented in clinical trials with cognitive outcomes) and 18% residing in neighborhoods with moderate or high levels of socioeconomic deprivation. Enrollees were cognitively intact but at increased …


Author Correction: Inhibitory Specificity From A Connectomic Census Of Mouse Visual Cortex, Casey M Schneider-Mizell, Agnes L Bodor, Derrick Brittain, Joann Buchanan, Daniel J Bumbarger, Leila Elabbady, Clare Gamlin, Daniel Kapner, Sam Kinn, Gayathri Mahalingam, Sharmishtaa Seshamani, Shelby Suckow, Marc Takeno, Russel Torres, Wenjing Yin, Sven Dorkenwald, J Alexander Bae, Manuel A Castro, Akhilesh Halageri, Zhen Jia, Chris Jordan, Nico Kemnitz, Kisuk Lee, Kai Li, Ran Lu, Thomas Macrina, Eric Mitchell, Shanka Subhra Mondal, Shang Mu, Barak Nehoran, Sergiy Popovych, William Silversmith, Nicholas L Turner, William Wong, Jingpeng Wu, Jacob Reimer, Andreas S Tolias, H Sebastian Seung, R Clay Reid, Forrest Collman, Nuno Maçarico Da Costa Jun 2025

Author Correction: Inhibitory Specificity From A Connectomic Census Of Mouse Visual Cortex, Casey M Schneider-Mizell, Agnes L Bodor, Derrick Brittain, Joann Buchanan, Daniel J Bumbarger, Leila Elabbady, Clare Gamlin, Daniel Kapner, Sam Kinn, Gayathri Mahalingam, Sharmishtaa Seshamani, Shelby Suckow, Marc Takeno, Russel Torres, Wenjing Yin, Sven Dorkenwald, J Alexander Bae, Manuel A Castro, Akhilesh Halageri, Zhen Jia, Chris Jordan, Nico Kemnitz, Kisuk Lee, Kai Li, Ran Lu, Thomas Macrina, Eric Mitchell, Shanka Subhra Mondal, Shang Mu, Barak Nehoran, Sergiy Popovych, William Silversmith, Nicholas L Turner, William Wong, Jingpeng Wu, Jacob Reimer, Andreas S Tolias, H Sebastian Seung, R Clay Reid, Forrest Collman, Nuno Maçarico Da Costa

Faculty, Staff and Students Publications

No abstract provided.


Airway Immune Signatures In Severe And Fatal Infection With Covid-19, Naresh Doni Jayavelu, Jing Jing Qi, Slim Fourati, Farrah Kheradmand, Charles R Langelier, Lauren I R Ehrlich, Joann Diray-Arce, Annmarie Hoch, Monica Kraft, Patrice M Becker, Matthew C Altman, Ruth R Montgomery Jun 2025

Airway Immune Signatures In Severe And Fatal Infection With Covid-19, Naresh Doni Jayavelu, Jing Jing Qi, Slim Fourati, Farrah Kheradmand, Charles R Langelier, Lauren I R Ehrlich, Joann Diray-Arce, Annmarie Hoch, Monica Kraft, Patrice M Becker, Matthew C Altman, Ruth R Montgomery

Faculty, Staff and Students Publications

No abstract provided.


Perioperative Fluid Therapy Impairs Lymphatic Pump Function In Male Rats, Rebecca C Harlow-Adamek, Reetu Singh, Randolph H Stewart, Cristine L Heaps, Glen A Laine, Charles S Cox, Ranjeet M Dongaonkar Jun 2025

Perioperative Fluid Therapy Impairs Lymphatic Pump Function In Male Rats, Rebecca C Harlow-Adamek, Reetu Singh, Randolph H Stewart, Cristine L Heaps, Glen A Laine, Charles S Cox, Ranjeet M Dongaonkar

The Brown Foundation: Institute of Molecular Medicine

Because of its life-saving benefits, perioperative IV fluid therapy remains a cornerstone of medical treatment. However, it also induces sustained edemagenic stress. The resulting persistent interstitial edema-excessive fluid accumulation in the interstitium-significantly delays recovery and worsens patient outcomes. Therefore, to gain a detailed understanding of the lymphatic functional consequences of perioperative fluid therapy, this study aimed to test the hypothesis that perioperative IV fluid therapy compromises lymphatic pump function within 3 days after major surgery. Following a midline laparotomy, animals received IV fluid therapy over 48 h during recovery (FLTP). Three days post-surgery, mesenteric lymphatic vessels from FLTP and sham …


Identification And Functional Assessment Of Candidate Causal Cis-Regulatory Variants Underlying Electrocardiographic Qt Interval Gwas Loci, Supraja Kadagandla, Lavanya Gunamalai, Dongwon Lee, Ashish Kapoor Jun 2025

Identification And Functional Assessment Of Candidate Causal Cis-Regulatory Variants Underlying Electrocardiographic Qt Interval Gwas Loci, Supraja Kadagandla, Lavanya Gunamalai, Dongwon Lee, Ashish Kapoor

The Brown Foundation: Institute of Molecular Medicine

Background: Identifying causal variants among tens or hundreds of associated variants at each locus in genome-wide association studies is challenging. As the vast majority of genome-wide association studies variants are noncoding, sequence variation at cis-regulatory elements (CREs) affecting transcriptional expression of specific genes is a widely accepted molecular hypothesis. Following this hypothesis, combined with the observation that open chromatin is a universal hallmark of all types of CREs, we aimed to identify candidate causal cis-regulatory variants underlying QT interval genome-wide association studies loci.

Methods: Common variants in high linkage disequilibrium with genome-wide significant variants were identified using variant …


Time To Weight Plateau With Tirzepatide Treatment In The Surmount-1 And Surmount-4 Clinical Trials, Deborah B Horn, Scott Kahan, Rachel L Batterham, Dachuang Cao, Clare J Lee, Madhumita Murphy, Sylvia Gonsahn-Bollie, Farai Chigutsa, Adam Stefanski, Julia P Dunn Jun 2025

Time To Weight Plateau With Tirzepatide Treatment In The Surmount-1 And Surmount-4 Clinical Trials, Deborah B Horn, Scott Kahan, Rachel L Batterham, Dachuang Cao, Clare J Lee, Madhumita Murphy, Sylvia Gonsahn-Bollie, Farai Chigutsa, Adam Stefanski, Julia P Dunn

Faculty, Staff and Student Publications

The rate of weight reduction during obesity treatment declines over time and eventually reaches a weight plateau. We investigated factors associated with time to weight plateau (TTWP) in tirzepatide-treated participants with obesity or overweight in a post-hoc analysis of SURMOUNT-1 and SURMOUNT-4 trials. Participants adherent to tirzepatide treatment and achieving ≥5% weight loss by primary endpoint (week 72 SURMOUNT-1; week 88 SURMOUNT-4) were included. Weight plateau was defined as a weight change < 5% over a 12-week interval and all subsequent 12-week intervals. TTWP was time from randomization to the start of the first 12-week interval. Association between baseline characteristics and TTWP was assessed. Overall, 1438 participants in SURMOUNT-1 and 259 in SURMOUNT-4 were included. Across BMI categories (overweight, class I, II, and III), median TTWP in SURMOUNT-1 was 24.3, 26.0, 36.1, and 36.1 weeks, respectively (p < .05, class II and III vs. overweight). By week 72, 90.2%, 88.9%, 87.6%, and 87.8% of participants in SURMOUNT-1 had reached a weight plateau across respective BMI categories [Correction added on 22 January 2025, after first online publication: The "72%" has been changed to "72" in this version.]. Higher doses of tirzepatide (10/15 mg), younger age, and female sex were more likely to reach a weight plateau later. Results in SURMOUNT-4 were similar. In this post-hoc analysis, most participants reached a weight plateau by week 72. Higher doses of tirzepatide, younger age, and female sex were associated with a longer TTWP. Further research into modifiers of weight reduction phases with tirzepatide may inform treatment decisions for its use in chronic weight management. Clinical Trial Registration: ClinicalTrials.gov, identifiers NCT04184622 (SURMOUNT-1) and NCT04660643 (SURMOUNT-4), available at http://www.clinicaltrials.gov/.


Expanding The Clinical Spectrum Of Porokeratosis Ptychotropica, Brooke R Bartley, Dylan R Maldonado, Steven Mays, Ronald P Rapini Jun 2025

Expanding The Clinical Spectrum Of Porokeratosis Ptychotropica, Brooke R Bartley, Dylan R Maldonado, Steven Mays, Ronald P Rapini

Faculty, Staff and Student Publications

Porokeratosis ptychotropica (PP) is a rare variant of porokeratosis, typically presenting as pink to brown hyperkeratotic plaques in the gluteal cleft and buttocks, defined histologically by multiple cornoid lamellae. Diagnosis of PP is challenging due to its clinical overlap with other dermatologic conditions and inconsistent terminology in the literature. This case report describes a 47-year-old woman exhibiting clinical and pathological features of PP but with a more diffuse presentation than previously documented. The case emphasizes the diagnostic complexities of PP, particularly in atypical presentations, and highlights the critical role of histological examination in distinguishing it from other porokeratoses.


Assessment Of Contextualized Reinforcement Pathology In A Community Sample Of Young Adult Substance Users, Ángel García-Pérez, Alba González-Roz, Roberto Secades-Villa, Gema Aonso-Diego, Sara Weidberg, Jin H Yoon Jun 2025

Assessment Of Contextualized Reinforcement Pathology In A Community Sample Of Young Adult Substance Users, Ángel García-Pérez, Alba González-Roz, Roberto Secades-Villa, Gema Aonso-Diego, Sara Weidberg, Jin H Yoon

Faculty, Staff and Student Publications

Background: Alcohol, tobacco, and cannabis are the most commonly used substances among young populations, often leading to polysubstance use, which correlates with problematic consumption and adverse health outcomes. The contextualized reinforcer pathology (CRP) model explains addictive behaviors through several constructs, including the following: drug demand, delay discounting (DD), and substance-free and substance-related reinforcement. Most previous studies have focused on a single CRP construct and the couse of only two substances. This study aimed to characterize three subgroups of young adults reporting past month use of alcohol only, alcohol + tobacco or cannabis, and alcohol + tobacco + cannabis, in terms …


An Enzyme-Linked Immunosorbent Assay (Elisa)-Based Activity Assay For Amp-Activated Protein Kinase (Ampk), Trezze P Nguyen, Shangze Lyu, Yang Liu Jun 2025

An Enzyme-Linked Immunosorbent Assay (Elisa)-Based Activity Assay For Amp-Activated Protein Kinase (Ampk), Trezze P Nguyen, Shangze Lyu, Yang Liu

Faculty, Staff and Student Publications

AMP-activated protein kinase (AMPK) is the master regulator of cellular and organismal energy homeostasis, playing an essential role in modulating metabolism and other cellular processes. Substantial efforts have been made to develop pharmacological modulators of AMPK activity due to their therapeutic potential against various diseases. Measuring AMPK activity in vitro is a fundamental step for testing AMPK activators and inhibitors. Here, we report an enzyme-linked immunosorbent assay (ELISA)-based AMPK activity assay with simple steps and high sensitivity. This assay offers a robust, in-house alternative to the traditional radioactive methods and other approaches that rely on specialized reagents or commercial kits.


Pharmacogenetics Of Plasma Dolutegravir Exposure During 1-Month Rifapentine/Isoniazid Treatment Of Latent Tuberculosis, Nia Covington, Anne F Luetkemeyer, Marjorie Z Imperial, Rodney Dawson, Yoninah Cramer, Sue Rosenkranz, Susan Swindells, Irina Gelmanova, Anchalee Avihingsanon, Roberto C Arduino, Wadzanai Samaneka, Kelly E Dooley, Rada Savic, Anthony T Podany, David W Haas Jun 2025

Pharmacogenetics Of Plasma Dolutegravir Exposure During 1-Month Rifapentine/Isoniazid Treatment Of Latent Tuberculosis, Nia Covington, Anne F Luetkemeyer, Marjorie Z Imperial, Rodney Dawson, Yoninah Cramer, Sue Rosenkranz, Susan Swindells, Irina Gelmanova, Anchalee Avihingsanon, Roberto C Arduino, Wadzanai Samaneka, Kelly E Dooley, Rada Savic, Anthony T Podany, David W Haas

Faculty, Staff and Student Publications

In Advancing Clinical Therapeutics Globally protocol A5372, a pharmacokinetic study of dolutegravir with 1-month of daily rifapentine/isoniazid, twice-daily dolutegravir offset the induction effects of rifapentine on plasma dolutegravir trough concentrations (C trough ). Here, we characterize the impact on dolutegravir C trough of UGT1A1 , AADAC , and NAT2 polymorphisms that affect dolutegravir, rifapentine, and isoniazid, respectively. People with HIV receiving dolutegravir-based antiretroviral therapy with an indication to treat latent tuberculosis underwent pharmacokinetic sampling during dolutegravir 50 mg once daily alone, and on day 28 of dolutegravir 50 mg twice daily with rifapentine/isoniazid. Multivariable linear regression models characterized genetic associations …


Endovascular Repair Of Type A Dissection Using Thoracic Stent Graft With Innominate Artery Flaring To Correct For Length Mismatch, Aidin Baghbani-Oskouei, Lucas Ruiter Kanamori, Safa Savadi, Steven Maximus, Thanila A Macedo, Anthony Estrera, Salman A Arain, Gustavo S Oderich Jun 2025

Endovascular Repair Of Type A Dissection Using Thoracic Stent Graft With Innominate Artery Flaring To Correct For Length Mismatch, Aidin Baghbani-Oskouei, Lucas Ruiter Kanamori, Safa Savadi, Steven Maximus, Thanila A Macedo, Anthony Estrera, Salman A Arain, Gustavo S Oderich

Faculty, Staff and Student Publications

Type A aortic dissection is the most common aortic catastrophe posing challenges for endovascular repair owing to the fragile aortic wall, proximity to the aortic valve, coronaries, and supra-aortic trunks. While open surgical repair remains the gold standard, endovascular repair is considered in select high-risk patients who meet anatomical criteria, including more than 10 mm length between sinotubular junction to primary tear, aortic diameter of less than 40 mm, and suitable length between sinotubular junction and innominate artery. This illustrated video and case presentation address a modified technique using stent graft flaring of the innominate artery to adjust for length …


Corrigendum To “Cardiac Manifestations And Outcomes Of Covid-19 Vaccine-Associated Myocarditis In The Young In The Usa: Longitudinal Results From The Myocarditis After Covid Vaccination (Maciv) Multicenter Study”, Supriya S Jain, Steven A Anderson, Jeremy M Steele, Hunter C Wilson, Juan Carlos Muniz, Jonathan H Soslow, Rebecca S Beroukhim, Victoria Maksymiuk, Xander Jacquemyn, Olivia H Frosch, Brian Fonseca, Ashraf S Harahsheh, Sujatha Buddhe, Ravi C Ashwath, Deepika Thacker, Shiraz A Maskatia, Nilanjana Misra, Jennifer A Su, Saira Siddiqui, Danish Vaiyani, Aswathy K Vaikom-House, M Jay Campbell, Jared Klein, Sihong Huang, Christopher Mathis, Matthew D Cornicelli, Madhu Sharma, Lakshmi Nagaraju, Jocelyn Y Ang, Santosh C Uppu, Preeti Ramachandran, Jyoti K Patel, Frank Han, Jason G Mandell, Jyothsna Akam-Venkata, Michael P Dilorenzo, Michael Brumund, Puneet Bhatla, Parham Eshtehardi, Karina Mehta, Katherine Glover, Matthew L Dove, Khalifah A Aldawsari, Anupam Kumar, Spencer B Barfuss, Adam L Dorfman, Prashant K Minocha, Alexandra B Yonts, Jenna Schauer, Andrew L Cheng, Joshua D Robinson, Zachary Powell, Shubhika Srivastava, Anjali Chelliah, Yamuna Sanil, Lazaro E Hernandez, Lasya Gaur, Michael Antonchak, Marla Johnston, Jonathan D Reich, Narayan Nair, Elizabeth D Drugge, Lars Grosse-Wortmann Jun 2025

Corrigendum To “Cardiac Manifestations And Outcomes Of Covid-19 Vaccine-Associated Myocarditis In The Young In The Usa: Longitudinal Results From The Myocarditis After Covid Vaccination (Maciv) Multicenter Study”, Supriya S Jain, Steven A Anderson, Jeremy M Steele, Hunter C Wilson, Juan Carlos Muniz, Jonathan H Soslow, Rebecca S Beroukhim, Victoria Maksymiuk, Xander Jacquemyn, Olivia H Frosch, Brian Fonseca, Ashraf S Harahsheh, Sujatha Buddhe, Ravi C Ashwath, Deepika Thacker, Shiraz A Maskatia, Nilanjana Misra, Jennifer A Su, Saira Siddiqui, Danish Vaiyani, Aswathy K Vaikom-House, M Jay Campbell, Jared Klein, Sihong Huang, Christopher Mathis, Matthew D Cornicelli, Madhu Sharma, Lakshmi Nagaraju, Jocelyn Y Ang, Santosh C Uppu, Preeti Ramachandran, Jyoti K Patel, Frank Han, Jason G Mandell, Jyothsna Akam-Venkata, Michael P Dilorenzo, Michael Brumund, Puneet Bhatla, Parham Eshtehardi, Karina Mehta, Katherine Glover, Matthew L Dove, Khalifah A Aldawsari, Anupam Kumar, Spencer B Barfuss, Adam L Dorfman, Prashant K Minocha, Alexandra B Yonts, Jenna Schauer, Andrew L Cheng, Joshua D Robinson, Zachary Powell, Shubhika Srivastava, Anjali Chelliah, Yamuna Sanil, Lazaro E Hernandez, Lasya Gaur, Michael Antonchak, Marla Johnston, Jonathan D Reich, Narayan Nair, Elizabeth D Drugge, Lars Grosse-Wortmann

Faculty, Staff and Student Publications

This corrects the article "Cardiac manifestations and outcomes of COVID-19 vaccine-associated myocarditis in the young in the USA: longitudinal results from the Myocarditis After COVID Vaccination (MACiV) multicenter study" in volume 76, 102809.


International Multidisciplinary Consensus Recommendations On Clinical Application Of Three-Dimensional Visualization In Precision Surgery For Pediatric Liver Tumors, Qian Dong, Wenli Xiu, Benjie Tang, Eiso Hiyama, Mary T Austin, Yeming Wu, Xiaojun Yuan, Chengzhan Zhu, Chengli Liu, Hiroki Ishibashi, Karthik K Tappa, Huanmin Wang, Chuandong Sun, Yuntao Ma, Hongwei Xi, Jian Wang, Jianghua Zhan, Kyong Ihn, Mitsuo Shimada, Mingman Zhang, Mary E Brindle, Patrick B Thomas, Shigehisa Fumino, Tao Liu, Thom Lobe, Udo Rolle, Shan Wang, Xiaowen Zhai, Yoshinori Koga, Yoshiaki Kinoshita, Yuzuo Bai, Zhaozhu Li, Zhe Wen, Weikang Pan, Krysta M Sutyak, Pier C Giulianotti Jun 2025

International Multidisciplinary Consensus Recommendations On Clinical Application Of Three-Dimensional Visualization In Precision Surgery For Pediatric Liver Tumors, Qian Dong, Wenli Xiu, Benjie Tang, Eiso Hiyama, Mary T Austin, Yeming Wu, Xiaojun Yuan, Chengzhan Zhu, Chengli Liu, Hiroki Ishibashi, Karthik K Tappa, Huanmin Wang, Chuandong Sun, Yuntao Ma, Hongwei Xi, Jian Wang, Jianghua Zhan, Kyong Ihn, Mitsuo Shimada, Mingman Zhang, Mary E Brindle, Patrick B Thomas, Shigehisa Fumino, Tao Liu, Thom Lobe, Udo Rolle, Shan Wang, Xiaowen Zhai, Yoshinori Koga, Yoshiaki Kinoshita, Yuzuo Bai, Zhaozhu Li, Zhe Wen, Weikang Pan, Krysta M Sutyak, Pier C Giulianotti

Faculty, Staff and Student Publications

Background: Pediatric liver tumors are predominantly primary malignant tumors, and complete tumor resection with sufficient preservation of liver tissue is crucial for improving prognosis. However, due to the delicate anatomical structure of the pediatric liver and the relatively large size of the tumors, especially in difficult cases, the surgical challenges are substantial. While precision liver surgery are widely applied in clinical practice, pediatric cases require more customized approaches. The application of three-dimensional (3D) visualization technology is crucial for enhancing surgical accuracy, allowing for precise preoperative planning and intraoperative guidance.

Methods: This consensus was collaboratively developed by 36 experts from eight …


Alterations In Gut Microbiome Composition And Increased Inflammatory Markers In Post-Covid-19 Individuals, Tatiana Barichello, Bruno Kluwe-Schiavon, Laura A Borba, Lucas C Pedro, Flávia S Niero, Laísa N Dos Santos, Letícia M Leonardo, Zuleide M Ignácio, Rodrigo Morales, Luciane B Ceretta, Gislaine Z Reus Jun 2025

Alterations In Gut Microbiome Composition And Increased Inflammatory Markers In Post-Covid-19 Individuals, Tatiana Barichello, Bruno Kluwe-Schiavon, Laura A Borba, Lucas C Pedro, Flávia S Niero, Laísa N Dos Santos, Letícia M Leonardo, Zuleide M Ignácio, Rodrigo Morales, Luciane B Ceretta, Gislaine Z Reus

Faculty, Staff and Student Publications

Dysfunctions in the immune system and alterations in the microbiome composition following SARS-CoV-2 infection contribute to persistent neurological issues observed in long COVID-19 survivors. We hypothesize that alterations in the gut microbiome composition and peripheral inflammatory profile following COVID-19 may play pivotal roles in behavior changes among individuals experiencing long-term illness. This cross-sectional study included a sample of post-COVID-19 and non-COVID-19 subjects. We assessed the presence of psychiatric conditions utilizing standardized diagnostic criteria, Hamilton Rating Scale for Anxiety (HAM-A), Hamilton Rating Scale for Depression (HAM-D), Biological Rhythms in Neuropsychiatry Assessment Interview (BRIAN), and Functional Assessment Short Test (FAST). Plasma samples …


Exploring Potential Ethnic Bias Among Mmpi-3 Scales In Assessing Personality Psychopathology, Nicole Shumaker, Tessa Long, Andy Torres, Alfonso Mercado, Ryan J Marek, Jaime L Anderson Jun 2025

Exploring Potential Ethnic Bias Among Mmpi-3 Scales In Assessing Personality Psychopathology, Nicole Shumaker, Tessa Long, Andy Torres, Alfonso Mercado, Ryan J Marek, Jaime L Anderson

Faculty, Staff and Student Publications

This study examined statistical bias in the measurement of personality psychopathology in the Latinx population using the Minnesota Multiphasic Personality Inventory-3 (MMPI-3). Data were extracted from two studies that yielded a composite data set of 103 White individuals and 250 Latinx individuals. All participants were administered the MMPI-2-Restructured Form-Extended Battery (MMPI-2-RF-EX) or MMPI-3 and the Personality Inventory for the DSM-5 Short Form (PID-5-SF). First, we conducted correlation analyses between theoretically overlapping scales of the PID-5-SF and the MMPI-3 among White and Latinx individuals. The majority of theoretically associated scales were found to be at least moderately associated in the …


Association Between Timing Of Angiotensin Ii Administration And Outcomes In Vasoplegia After Cardiac Surgery, Travis J Miles, Michael T Guinn, Orlando R Suero, Todd K Rosengart, Marc R Moon, Joseph S Coselli, Ravi K Ghanta, Subhasis Chatterjee Jun 2025

Association Between Timing Of Angiotensin Ii Administration And Outcomes In Vasoplegia After Cardiac Surgery, Travis J Miles, Michael T Guinn, Orlando R Suero, Todd K Rosengart, Marc R Moon, Joseph S Coselli, Ravi K Ghanta, Subhasis Chatterjee

Faculty, Staff and Students Publications

Objective: Vasoplegic shock after cardiopulmonary bypass (CPB) is a highly morbid condition. The novel vasopressor angiotensin II is increasingly being used for catecholamine-resistant vasoplegia. Although early intervention with adjunctive therapies such as methylene blue can improve outcomes of vasoplegia, the optimal timing for escalation with angiotensin II is unknown.

Methods: Pharmacologic data were extracted from electronic health records for patients who underwent surgery with CPB during 2017-2022. Patients were identified who received angiotensin II intraoperatively or postoperatively (ie, early or late). Multivariable logistic regression was used to determine the risk-adjusted effects of earlier angiotensin II administration on postoperative major adverse …


Norovirus Replication, Host Interactions And Vaccine Advances, B V Venkataram Prasad, Robert L Atmar, Sasirekha Ramani, Timothy Palzkill, Yongcheng Song, Sue E Crawford, Mary K Estes Jun 2025

Norovirus Replication, Host Interactions And Vaccine Advances, B V Venkataram Prasad, Robert L Atmar, Sasirekha Ramani, Timothy Palzkill, Yongcheng Song, Sue E Crawford, Mary K Estes

Faculty, Staff and Students Publications

Human noroviruses (HuNoVs) are the leading cause of acute gastroenteritis worldwide in all age groups and cause significant disease and economic burden globally. To date, no approved vaccines or antiviral therapies are available to treat or prevent HuNoV illness. Several candidate vaccines are in clinical trials, although potential barriers to successful development must be overcome. Recently, significant advances have been made in understanding HuNoV biology owing to breakthroughs in virus cultivation using human intestinal tissue-derived organoid (or enteroid) cultures, advances in structural biology technology combined with epitope mapping and increased metagenomic sequencing. New and unexpected strain-specific differences in pandemic versus …