Digital Commons Network^™

Comparison Of Model-Predicted And Observed Evinacumab Pharmacokinetics And Efficacy In Children Aged < 5 Years With Homozygous Familial Hypercholesterolemia., Sébastien Bihorel, Robert Dingman, Jeanne Mendell, Katy C. Norman, Richard T. George, Xue-Qiao Zhao, Robert Pordy, Daniel Garcia, Wendy S. Putnam, Geetha Raghuveer, Brian W. Mccrindle, Elena Fornari, Ivo Baric, Shubha Srinivasan, Melissa Diamond, Eliot A. Brinton, John D. Davis, A Thomas Dicioccio, Lutz Harnisch

Manuscripts, Articles, Book Chapters and Other Papers

Evinacumab, an angiopoietin-like 3 inhibitor, significantly reduces low-density lipoprotein cholesterol (LDL-C) in patients with homozygous familial hypercholesterolemia (HoFH). Herein, we report pharmacokinetic and efficacy analyses of evinacumab in <  5-year-old patients with HoFH. Population pharmacometric models characterizing evinacumab exposure and LDL-C response accounting for lipoprotein apheresis effect in ≥ 5-year-old patients were adapted for growth and maturation to predict and compare evinacumab and LDL-C concentrations across age/weight groups in virtual ≥ 6-month-old patients receiving 15 mg/kg evinacumab intravenous (iv) infusions every 4 weeks (q4w). As expected from allometric theory, weight-based dosing resulted in decreasing evinacumab exposures with declining body weight. Consistent with trends observed in > 5-year-old patients, the predicted percent change from LDL-C baseline (%∆LDL-C) was generally comparable or even higher in <  5-year-old patients (63.0%-68.5%) than in 5- to <  18-year-old patients (61.3%-67.8%) or adults (51.7%), with the predicted percentages of patients achieving %∆LDL-C > 50% also higher in <  5-year-old patients (82.0%-86.9%) versus 5- to <  18-year-old patients (72.0%-84.5%) and adults (54.8%). Through a managed access program, six 1- to <  5-year-old patients received between 5 and 23 iv infusions of 15 mg/kg evinacumab q4w. Rapid and clinically meaningful LDL-C reductions were observed, with %∆LDL-C at the last reported dose ranging from 41.3% to 77.3%. Based on the actual patient dosing and plasmapheresis history, model-predicted evinacumab and LDL-C concentrations were comparable to the observed data collected in the managed access program. Overall, this analysis provides evidence for the use of evinacumab 15 mg/kg iv q4w dosing regimen in 6-month-old to 5-year-old patients.

Modeling Cell Differentiation In Neuroblastoma: Insights Into Development, Malignancy, And Treatment Relapse., Simon F. Martina-Perez, Luke A. Heirene, Jennifer C. Kasemeier, Paul M. Kulesa, Ruth E. Baker

Manuscripts, Articles, Book Chapters and Other Papers

Neuroblastoma is a paediatric extracranial solid cancer that arises from the developing sympathetic nervous system and is characterised by an abnormal distribution of cell types in tumours compared to healthy infant tissues. In this paper, we propose a new mathematical model of cell differentiation during sympathoadrenal development. By performing Bayesian inference of the model parameters using clinical data from patient samples, we show that the model successfully accounts for the observed differences in cell type heterogeneity among healthy adrenal tissues and four common types of neuroblastomas. Using a phenotypically structured model, we show that alterations in healthy differentiation dynamics are …

Exploring Multimodal Large Language Models On Transthoracic Echocardiogram (Tte) Tasks For Cardiovascular Decision Support, Jianfu Li, Yiming Li, Zenan Sun, Evan Yu, Ahmed M Abdelhameed, Weiguo Cao, Haifang Li, Jianping He, Pengze Li, Jingna Feng, Yue Yu, Xinyue Hu, Manqi Li, Rakesh Kumar, Yifang Dang, Fang Li, Shahyar M Gharacholou, Cui Tao

Faculty, Staff and Student Publications

Objective: Multimodal large language models (LLMs) offer new potential for enhancing cardiovascular decision support, particularly in interpreting echocardiographic data. This study systematically evaluates and benchmarks foundation models from diverse domains on echocardiogram-based tasks to assess their effectiveness, limitations and potential in clinical cardiovascular applications.

Methods: We curated three cardiovascular imaging datasets-EchoNet-Dynamic, TMED2, and an expert-annotated echocardiogram (TTE) dataset-to evaluate performance on four critical tasks: (1) cardiac function evaluation through ejection fraction (EF) prediction, (2) cardiac view classification, (3) aortic stenosis (AS) severity assessment, and (4) cardiovascular disease classification. We evaluated six multimodal LLMs: EchoClip (cardiovascular-specific), BiomedGPT and LLaVA-Med (medical-domain), and …

Scaling Up Biomedical Vision-Language Models: Fine-Tuning, Instruction Tuning, And Multi-Modal Learning, Cheng Peng, Kai Zhang, Mengxian Lyu, Hongfang Liu, Lichao Sun, Yonghui Wu

Faculty, Staff and Student Publications

Objective: To advance biomedical vision language model capabilities through scaling up, fine-tuning, and instruction tuning, develop vision-language models with improved performance in handling long text, explore strategies to efficiently adopt vision language models for diverse multi-modal biomedical tasks, and examine the zero-shot learning performance.

Methods: We developed two biomedical vision language models, BiomedGPT-Large and BiomedGPT-XLarge, based on an encoder-decoder-based transformer architecture. We fine-tuned the two models on 23 benchmark datasets from 6 multi-modal biomedical tasks, including one image-only task (image classification), three language-only tasks (text understanding, text summarization, and question answering), and two vision-language tasks (visual question answering and image …

Colorectal-Specific Radiation Dose And Chemotherapy Risk For Subsequent Colorectal Malignancies In Childhood Cancer Survivors: A Childhood Cancer Survivor Study (Ccss) Report, Constance A Owens, Ethan B Ludmir, Qi Liu, Weiyu Qiu, Aashish C Gupta, Susan A Smith, Bastien Rigaud, Kristy K Brock, James E Bates, Taylor G Meyers, Arnold C Paulino, Christine B Peterson, Stephen F Kry, Jop C Teepen, Cécile M Ronckers, Joseph P Neglia, Wendy M Leisenring, Kevin C Oeffinger, Paul C Nathan, Lucie M Turcotte, David C Hodgson, Melissa M Hudson, Leslie L Robison, Chaya S Moskowitz, Gregory T Armstrong, Tara O Henderson, Yutaka Yasui, Rebecca M Howell

Faculty, Staff and Student Publications

Purpose: Among childhood cancer survivors, we evaluated not previously explored relationships between colorectal subsequent malignant neoplasm (SMN) incidence and colorectum-specific radiation dose metrics currently used in radiation therapy (RT) planning and expanded upon previously reported chemotherapy associations.

Methods: The Childhood Cancer Survivor Study (CCSS) includes 5-year survivors of childhood cancer diagnosed between 1970 and 1999. RT was assessed as mean colorectal dose (MCD) and the percent volume (VX Gy) receiving ≥5, 10, 20, 30, and 40 Gy. Chemotherapy was assessed as cumulative doses for procarbazine and platinum agents, cyclophosphamide-equivalent doses for alkylating agents, and doxorubicin-equivalent doses for anthracyclines. Piecewise-exponential models …

Intentional Creation Of Suboptimal, Realistic Dose Distributions, Skylar S Gay, Mary P Gronberg, Raymond Mumme, Beth M Beadle, Anuja Jhingran, Tze Yee Lim, Zhiqian H Yu, Christine Chung, Meena Khan, Chelsea Pinnix, Sanjay Shete, Brent Parker, Tucker J Netherton, Carlos E Cardenas, Laurence E Court

Faculty, Staff and Student Publications

Background: Radiation oncology residents report a lack of understanding and confidence in assessing radiotherapy plan quality. A contributing factor is the environment in which plan review is taught during residency, that is, routine clinical practice, which does not provide ample time for self-guided practice in a low-stakes setting. Expertise in plan review requires diverse case presentation and many examples, which are often not achievable in smaller programs and for less common cancer types. As plan quality affects patient outcomes, it is important to address these pitfalls in the education of residents on plan review.

Purpose: To address the identified pitfalls …

Probabilistic Template Matching For Detecting Resting-State Functional Mri Language Network In Brain Tumor Patients, Jian Ming Teo, Vinodh A Kumar, Alexander M Khalaf, Kyle R Noll, Sherise D Ferguson, Chibawanye I Ene, Sujit S Prabhu, Max Wintermark, Ho-Ling Liu

Faculty, Staff and Student Publications

Background: Intersubject variation among patients with brain tumors complicates the template matching process for detecting the resting-state (rs) functional MRI (fMRI) language network when using independent component analysis (ICA).

Purpose: This study aimed to develop methods that use a probabilistic language atlas to incorporate intersubject variation in brain tumor patients into the template matching process.

Methods: This retrospective study included 79 patients with brain tumors (average age, 50 ± 15 years) who underwent presurgical task-based (tb)-fMRI and rs-fMRI at clinical 3T scanners. At varying template generation thresholds (τ), binary and probabilistic templates were obtained from the language atlas. A binary …

Continuous Androgen Deprivation Therapy With Or Without Metastasis-Directed Therapy For Oligometastatic Prostate Cancer: The Multicenter Phase 2 Randomized Extend Trial, Alexander D Sherry, Bilal A Siddiqui, Cara Haymaker, Bryan M Fellman, Marina N Medina-Rosales, Tharakeswara K Bathala, Shuqi Wang, Suyu Liu, Aaron Seo, Kieko Hara, Hsinyi Lu, Patricia Troncoso, Stephen G Chun, Chul S Ha, Lauren L Mayo, Henry Mok, Ryan J Park, Brian F Chapin, Ryan M Phillips, Matthew P Deek, Craig A Kovitz, Ana Aparicio, Amado J Zurita, Patrick G Pilie, Lorenzo Cohen, Seungtaek L Choi, Alexandre Reuben, Phuoc T Tran, Paul G Corn, Sumit K Subudhi, Chad Tang

Faculty, Staff and Student Publications

Background and objective: Oligometastatic prostate cancer (omPC) is characterized by limited metastases. We hypothesized that metastasis-directed therapy (MDT) to all sites of omPC combined with androgen deprivation therapy (ADT) would improve clinical outcomes.

Methods: In the multicenter phase 2 EXTEND trial, patients with omPC were randomized 1:1 to ADT versus MDT + ADT in two independently powered and randomized baskets, one using intermittent ADT and one using continuous ADT. The primary endpoint was progression-free survival (PFS). The secondary endpoints included radiologic PFS (rPFS) and castration resistance-free survival (CRFS). Here, the primary results of the continuous ADT basket, the combined analysis …

Integration Of Genetic And Imaging Data For Alzheimer's Disease Diagnosis And Interpretation, Yanfei Wang, Qing Wang, Minghao Zhou, Jialu Liang, Lei You, Breton Asken, Xiaobo Zhou, Qianqian Song

Faculty, Staff and Student Publications

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by complex interactions between genetic risk factors and structural brain changes. Traditional diagnostic approaches that rely on single-modality data, such as imaging or genomics alone, often fall short in both predictive accuracy and biological interpretability. To address these limitations, AlzCLIP, a novel contrastive learning framework that integrates single nucleotide polymorphism (SNP) profiles and MRI-derived imaging features into a unified embedding space is introduced. This joint representation captures disease-relevant interactions between genetic variation and brain structure, enabling both accurate diagnosis and mechanistic insight into AD. AlzCLIP is trained and evaluated on two …

Study Of 18 F-Fluciclovine Pet For Serial Assessment Of Glioblastoma Tumor Volumes During Surgery And Radiotherapy, Samir A Dagher, Jason M Johnson, Rania M M Mohamed, Shehbaz Ansari, Osama Mawlawi, Ho-Ling Liu, Max Wintermark, Dawid Schellingerhout, Lesley Flynt, Debra N Yeboa, Jeffrey S Weinberg, Sherise D Ferguson, Maria K Gule-Monroe

Faculty, Staff and Student Publications

PURPOSE: Recent evidence supports incorporating 18 F-Fluciclovine PET for glioblastoma treatment planning and monitoring, as it better captures tumor infiltration compared to conventional MRI. However, the relationship between PET- and MRI-defined tumor volumes remains unclear, particularly in the post-treatment setting. This study prospectively compares tumor volumes on MRI and PET at multiple timepoints throughout the treatment course and evaluates volumetric changes with therapy.

METHODS: We prospectively enrolled 8 adults with IDH-wildtype glioblastoma treated with surgery and chemoradiation between September 2019 and 2021. Participants underwent paired 18 F-Fluciclovine PET/CT and conventional MRI at four timepoints: preoperatively, pre-radiation, and at one- and …

Acute Kidney Injury Is Associated With Elevated Urinary Endotrophin, Amanda J Clark, Brenda Mendoza Flores, Marie Christelle Saade, Kyle Q Vu, Isaac J Pence, Ningyan Zhang, Zhiqiang An, Dawei Bu, Philipp E Scherer, Samir M Parikh

Faculty, Staff and Student Publications

Acute kidney injury (AKI) is prevalent among hospitalized patients. Novel biomarkers are needed to diagnose AKI and target therapies. Endotrophin (ETP) is a molecule released during collagen type VI formation that may promote injury and fibrosis. Although serum ETP elevation has been associated with adverse outcomes in AKI, urinary ETP has not been assessed in AKI, nor has ETP been evaluated in a pediatric population. Urine samples were collected from a tertiary children's hospital. Medical records were reviewed, and patients who met criteria were sorted into three categories:

Functional Ability Profiles In Beta-Propeller Protein-Associated Neurodegeneration (Bpan), Francesco Gavazzi, Samuel R Pierce, Vanessa Smith, Eric Yang, Julie Skorup, Kristy Pucci, Emma Kotes, Allan M Glanzman, Stacy V Cusack, Todd Levy, Holly Dubbs, Emma Wiener, Sarah Woidill, Joseph Vithayathil, Abbas Jawad, Nivedita Thakur, Laura A Adang

Faculty, Staff and Student Publications

Background: Beta-propeller Protein-Associated Neurodegeneration (BPAN) is a rare neurodevelopmental degenerative disorder caused by pathogenic variants in WDR45 leading to brain iron accumulation. Its rarity and complex clinical course make it difficult to select appropriate clinical outcome assessments (COAs). This study evaluates established COAs for feasibility and effectiveness in capturing BPAN's functional ability profiles exploring cognitive, motor, and behavioral features.

Methods: We performed an observational study. Children were recruited as part of the Myelin Disorders Biorepository Project at the Children's Hospital of Philadelphia. We administered the Gross Motor Function Measure-88 (GMFM-88), the Leiter International Performance Scale (Leiter-3), and the Vineland Adaptive …

Identifying Performance Differences Between Two Pulse Oximetry Systems In Simulated Critical Neonatal Conditions, Brian King, Jake Dove, Scott J Mcgonigle, Warwick A Ames, Zachary A Vesoulis

2020-Current year OA Pubs

OBJECTIVE: Pulse oximetry is used to guide critical clinical decisions in neonatology. We used a vital signs simulator to compare performance of two pulse oximetry systems in conditions not tested in standardized clinical verification studies.

STUDY DESIGN: We devised a set of simulated tissue translucency, perfusion, peripheral oxygen saturation (SpO

RESULTS: The mean SpO

CONCLUSION: Significant performance differences can be observed when comparing pulse oximeters at low translucency and perfusion conditions. Patient simulators cannot replace clinical testing but provide a safe and cost-effective method for additional performance profiling.

Real-World Impact Of Amiodarone On Apixaban Population Pharmacokinetics In Hospitalized Patients, Samantha Kolowrat, Chazmyn Riley, Kevin Lam, Lynda Thomson, Douglas F. Stickle, Walter K. Kraft

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Despite common coadministration in nonvalvular atrial fibrillation (NVAF), there is minimal evidence regarding the impact of concomitant amiodarone use on apixaban pharmacokinetics (PK). We described the population PK of apixaban (2.5 and 5mg twice daily) in 106 hospitalized patients with and without concomitant amiodarone administration at steady state. Apixaban PK was reasonably described by a one-compartment model with first-order absorption and linear elimination. Aside from the receipt of amiodarone, age was retained as a statistically significant covariate on apparent clearance. Model-based simulations depicted concomitant amiodarone use increasing AUCT for both 2.5mg (1.58, 90% CI [1.28, 1.87]) and 5mg (1.12, 90% …

Two Decades Of Diagnostic Safety Research: Advances, Challenges, And Next Steps, Sundas Khan, Andrea Bradford, Christina L Cifra, Hardeep Singh

Faculty, Staff and Students Publications

Since the National Academies of Sciences, Engineering, and Medicine (NASEM) report Improving Diagnosis in Health Care, various research efforts have accelerated progress to understand and improve diagnostic safety. In this opinion piece, we summarize two decades of progress in methods for identifying and learning from diagnostic errors and provide recommendations for future research. Multiple methods have been used to quantify diagnostic errors in various clinical settings, thereby facilitating a deeper understanding of the nature and magnitude of the problem and enabling studies of contributing factors. However, the use of standardized definitions of a diagnostic error and/or diagnostic safety event, …

Centrally Inserted Central Catheter Placement Using A Novel, Handheld, Image-Guided, Robotic Device: Results Of Initial Feasibility Trial In Patients, James P Herlihy, William E Cohn, Adrian Ebner

Faculty, Staff and Students Publications

Background: Central venous access devices (CVADs) are an essential and widely used tool for the treatment of the critically ill, patients undergoing major surgery, and for many patients requiring hemodialysis. Automation of centrally inserted central catheters (CICCs) could potentially make CVAD placement safer, more effective, and more accessible. A new device that uses ultrasound image-guided, robotic needle placement, in addition to traditional Seldinger technique, to place a CICC is described.

Objective: The device was used in a small, first-in-human, trial for placing non-tunneled hemodialysis catheters (NTHDCs), in order to determine feasibility of clinical use.

Methods: Consecutive patients requiring a NTHDC, …

Physician Perceptions Of The Evaluation And Management Of Incarcerated Patients In The Emergency Department, Michelle Suh, Anita N Chary, Melanie F Molina, Caitlin M Farrell, Mark B Mycyk, Vidya Eswaran

Faculty, Staff and Students Publications

Background: Incarcerated patients in the United States are frequently seen in the emergency department. Although other specialties have reported differential care for patients who are incarcerated, little is known about the emergency physicians' evaluation and management of patients who are incarcerated.

Objective: The aim of our study was to characterize emergency physician (EP) perceptions of the emergency department (ED) care of incarcerated patients.

Methods: We surveyed emergency medicine resident and attending physicians at three academic safety-net EDs that regularly treat incarcerated patients from May to June 2023. We conducted thematic analysis of responses about perceptions of ED evaluation and management …

From Pachymeningitis Hemorrhagica To Abusive Head Trauma: A Journey Through The Centuries, Oliver Berthold, Flora Blangis, Christopher Spencer Greeley

Faculty, Staff and Students Publications

The development of medical knowledge follows specific principles. These also apply to abusive head trauma. The seminal literature from the early 20th century is based on earlier research from Europe, which is fundamental to understand the evolution of understanding and nomenclature of abusive head trauma. A review of original medical literature on intracranial injuries in children, published in German, English, and French, was conducted using PubMed and Google Scholar for articles before 1950. The primary search focused on subdural hemorrhages and pachymeningitis in children, followed by a snowball search of references. Full texts of available manuscripts were reviewed. Primary literature …

A Rare Molecular Diagnosis In A Patient With Hepatocerebral Syndrome Contributes To The Expansion Of The Phenotypic Spectrum Of Polg2 -Related Mitochondrial Disorder, Vittoria Rossi, Dan Brooks, Hongzheng Dai, Elizabeth Mizerik, Karla Salazar, Daniel Davila-Williams, Yishay Ben-Moshe, Seema R Lalani, Sarah H Elsea, Charul Gijavanekar, Daryl A Scott, Keren Machol, Mir Reza Bekheirnia, Fernando Scaglia

Faculty, Staff and Students Publications

POLG2 encodes an accessory subunit in DNA polymerase gamma that is required for mitochondrial DNA synthesis. Monoallelic pathogenic variants in POLG2 are associated primarily with progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant type 4 (PEOA4, MIM #610131). We report a rare case of severe infantile hepatocerebral syndrome associated with biallelic variants in POLG2. The proband, a 5-week-old female infant, presented with seizures and acute liver failure. Extensive metabolic workup, including untargeted metabolomics analysis and elevated plasma growth differentiation factor 15, was suggestive of mitochondrial dysfunction. Rapid trio genome sequencing identified compound heterozygous variants, a likely pathogenic variant and …

A Computer Vision And Machine Learning Approach To Classify Views In Distal Radius Radiographs, Rohan Vemu, Dion Birhiray, Bassem Darwish, Raven Hollis, Sai Unnam, Srikhar Chilukuri, Lorenzo Deveza

Faculty, Staff and Students Publications

Advances in computer vision and machine learning have augmented the ability to analyze orthopedic radiographs. A critical but underexplored component of this process is the accurate classification of radiographic views and localization of relevant anatomical regions, both of which can impact the performance of downstream diagnostic models. This study presents a deep learning object detection model and mobile application designed to classify distal radius radiographs into standard views-anterior-posterior (AP), lateral (LAT), and oblique (OB)- while localizing the anatomical region most relevant to distal radius fractures. A total of 1593 deidentified radiographs were collected from a single institution between 2021 and …

Management Of Patients With Heart Failure At High Risk Of Hyperkalaemia: The Care-Hk In Hf Registry, Stephen J Greene, Andrew J Sauer, Michael Böhm, Biykem Bozkurt, Javed Butler, John G F Cleland, Andrew J S Coats, Nihar R Desai, Diederick E Grobbee, Ellie Kelepouris, Fausto Pinto, Giuseppe Rosano, Victoria Donachie, Solenn Fabien, Sandra Waechter, Maria G Crespo-Leiro, Martin Hülsmann, Tibor Kempf, Otmar Pfister, Anne-Catherine Pouleur, Manish Saxena, Martin Schulz, Maurizio Volterrani, Stefan D Anker, Mikhail N Kosiborod

Faculty, Staff and Students Publications

Aims: Patients with heart failure (HF) at high risk for hyperkalaemia are underrepresented in prospective HF registries. The CARE-HK in HF registry sought to characterize prospectively the clinical profile, management, and outcomes for patients with HF at high risk of hyperkalaemia.

Methods and results: CARE-HK in HF was a multinational prospective registry of outpatients with HF (regardless of left ventricular ejection fraction [LVEF]) treated with an angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker/angiotensin receptor-neprilysin inhibitor (ACEI/ARB/ARNI) and either receiving or potential candidate for a mineralocorticoid receptor antagonist (MRA). All patients were at increased risk of hyperkalaemia, defined as hyperkalaemia at baseline, …

Coco-St Detects Global And Local Biological Structures In Spatial Transcriptomics Datasets, Muhammad Aminu, Bo Zhu, Natalie Vokes, Hong Chen, Lingzhi Hong, Jianrong Li, Junya Fujimoto, Mehdi Chaib, Yuqiu Yang, Bo Wang, Alissa Poteete, Monique B Nilsson, Xiuning Le, Tina Cascone, David Jaffray, Nicholas Navin, Tao Wang, Lauren A Byers, Don L Gibbons, John Heymach, Ken Chen, Chao Cheng, Jianjun Zhang, Jia Wu

Faculty, Staff and Students Publications

Spatial domain detection methods often focus on high-variance structures, such as tumour-adjacent regions with sharp gene expression changes, while missing low-variance structures with subtle gene expression shifts, like those between adjacent normal and early adenoma regions. Here, to address this, we introduce ‘compare and contrast spatial transcriptomics’ (CoCo-ST), a graph contrastive feature representation framework. By comparing a target sample with a background sample, CoCo-ST detects both high-variance, broadly shared structures and low-variance, tissue-specific features. It offers technical advantages, including multisample integration, batch-effect correction and scalability across technologies from spot-level Visium data to single-cell Xenium Prime 5K and subcellular Visium HD …

Mutations In The Key Autophagy Tethering Factor Epg5 Link Neurodevelopmental And Neurodegenerative Disorders Including Early-Onset Parkinsonism, Hormos Salimi Dafsari, Celine Deneubourg, Kritarth Singh, Reza Maroofian, Zita Suprenant, Ay Lin Kho, Neil J Ingham, Karen P Steel, Preethi Sheshadri, Franciska Baur, Lea Hentrich, Birgit Gerisch, Mina Zamani, Cesar Alves, Ata Siddiqui, Haidar S Dafsari, Mehri Salari, Anthony E Lang, Michael Harris, Alice Abdelaleem, Saeid Sadeghian, Reza Azizimalamiri, Hamid Galehdari, Gholamreza Shariati, Alireza Sedaghat, Jawaher Zeighami, Daniel Calame, Dana Marafi, Ruizhi Duan, Adrian Boehnke, Gary D Clark, Jill A Rosenfeld, Carrie A Mohila, Dora Steel, Saurabh Chopra, Suvasini Sharma, Nicolai Kohlschmidt, Steffi Patzer, Afshin Saffari, Darius Ebrahimi-Fakhari, Büşra Eser Çavdartepe, Irene J Chang, Erika Beckman, Renate Peters, Andrew Paul Fennell, Bernice Lo, Luisa Averdunk, Felix Distelmaier, Martina Baethmann, Frances Elmslie, Kairit Joost, Sheela Nampoothiri, Dhanya Yesodharan, Hanna Mandel, Amy Kimball, Antonie D Kline, Cyril Mignot, Boris Keren, Vincent Laugel, Katrin Õunap, Kalpana Devadathan, Frederique M C Van Berkestijn, Arpana Silwal, Saskia Koene, Sumit Verma, Mohammed Yousuf Karim, Chahynez Boubidi, Majid Aziz, Gehad Elghazali, Lauren Mattas, Mohammad Miryounesi, Farzad Hashemi-Gorji, Shahryar Alavi, Nayereh Nouri, Mehrdad Noruzinia, Saeideh Kavousi, Arveen Kamath, Sandeep Jayawant, Russell Saneto, Nourelhoda A Haridy, Pinar Ozkan Kart, Ali Cansu, Madeleine Joubert, Claire Beneteau, Kyra E Stuurman, Martina Wilke, Tahsin Stefan Barakat, Homa Tajsharghi, Annarita Scardamaglia, Sadeq Vallian, Semra Hız, Ali Shoeibi, Reza Boostani, Narges Hashemi, Meisam Babaei, Norah Saleh Alsaleh, Julie Porter, Tania Attié-Bitach, Pauline Marzin, Dorota Wicher, Jessica I Gold, Elisabeth Schuler, Amna Kashgari, Rakan F Alanazi, Wafaa Eyaid, Marc Engelen, Mirjam Langeveld, Burkhard Stüve, Yun Li, Gökhan Yigit, Bernd Wollnik, Mariana H G Monje, Dimitri Krainc, Niccolò E Mencacci, Somayeh Bakhtiari, Michael Kruer, Emanuela Argilli, Elliott Sherr, Yalda Jamshidi, Ehsan Ghayoor Karimiani, Yiu Wing Sunny Cheung, Ivan Karin, Giovanni Zifarelli, Peter Bauer, Wendy K Chung, James R Lupski, Manju A Kurian, Jörg Dötsch, Jürgen-Christoph Von Kleist-Retzow, Thomas Klopstock, Matias Wagner, Calvin Yip, Andreas Roos, Rita Carsetti, Carlo Dionisi-Vici, Mathias Gautel, Michael R Duchen, Adam Antebi, Henry Houlden, Manolis Fanto, Heinz Jungbluth

Faculty, Staff and Students Publications

Objective: Autophagy is a fundamental biological pathway with vital roles in intracellular homeostasis. During autophagy, defective cargoes including mitochondria are targeted to lysosomes for clearance and recycling. Recessive truncating variants in the autophagy gene EPG5 have been associated with Vici syndrome, a severe early-onset neurodevelopmental disorder with extensive multisystem involvement. Here, we aimed to delineate the extended, age-dependent EPG5-related disease spectrum.

Methods: We investigated clinical, radiological, and molecular features from the largest cohort of EPG5-related patients identified to date, complemented by experimental investigation of cellular and animal models of EPG5 defects.

Results: Through worldwide collaboration, we identified 211 patients, 97 …

Information Theory Analysis Of Ctx Shows Consistent Clinical Presentation, Jennifer Hanson, Penelope E Bonnen

Faculty, Staff and Students Publications

Cerebrotendinous xanthomatosis (CTX) is a rare, metabolic disorder caused by pathogenic variants in CYP27A1. The classic clinical presentation includes infantile-onset chronic diarrhea, juvenile-onset bilateral cataracts, with development of tendon xanthomas and progressive neurological dysfunction. These multisystem clinical features typically appear in different decades of life often confounding diagnosis of CTX. Further complicating diagnosis is the generally held belief that the clinical presentation of CTX varies highly between individuals and even within families. We applied information theory analyses to CTX patient data to quantitatively assess clinical variability in CTX. We conducted a systematic review of the literature to identify all CTX …

Molecular Mechanisms In Masld/Mash-Related Hcc, Xiaobo Wang, Liang Zhang, Bingning Dong

Faculty, Staff and Students Publications

Liver cancer is the third leading cause of cancer-related deaths and ranks as the sixth most prevalent cancer type globally. NAFLD or metabolic dysfunction-associated steatotic liver disease, and its more severe manifestation, NASH or metabolic dysfunction-associated steatohepatitis (MASH), pose a significant global health concern, affecting approximately 20%-25% of the population. The increased prevalence of metabolic dysfunction-associated steatotic liver disease and MASH is parallel to the increasing rates of obesity-associated metabolic diseases, including type 2 diabetes, insulin resistance, and fatty liver diseases. MASH can progress to MASH-related HCC (MASH-HCC) in about 2% of cases each year, influenced by various factors such …

Inhibition Of Bmper Mitigates Pulmonary Hypertension By Modulating Lrp1-Yap Interaction In Smooth Muscle Cells, Hua Mao, Claire M Li, Bing Sun, Christopher S Ward, Alan R Waich-Cohen, Ivan O Rosas, Howard J Huang, Harry Karmouty-Quintana, Liang Xie, Lavannya M Pandit, Xinchun Pi

Faculty, Staff and Students Publications

Background: BMPER (bone morphogenetic protein-binding endothelial regulator) is a secreted protein that is highly expressed in endothelial cells. It regulates the BMP (bone morphogenetic protein) pathway during vascular development and adulthood. Mutations in the BMP pathway are recognized as risk factors for pulmonary arterial hypertension group 1 pulmonary hypertension (PH). However, the roles of BMPER in pulmonary arterial hypertension remain unknown.

Methods: We assessed BMPER expression in Group 1 pulmonary arterial hypertension patient samples and examined its role in vascular remodeling using in vivo and in vitro approaches.

Results: BMPER level was elevated in pulmonary arterial hypertension lungs and significantly …

Restricting Metabolic Plasticity Enhances Stress Adaptation Through The Modulation Of Pdh And Hif1a In Trap1-Depleted Colon Cancer, Hong-Yuan Tsai, Miao-Hsueh Chen, Jihye Yun, Lisa A Lai, John F Valentine, Mary P Bronner, Teresa A Brentnall, Sheng Pan, Ru Chen

Faculty, Staff and Student Publications

Metabolic plasticity allows cancer cells to survive under adverse conditions. To investigate the role of mitochondrial chaperone tumor necrosis factor receptor-associated protein 1 (TRAP1) in this process, we used CRISPR/Cas9 mediated genetic deletion to knock out (KO) TRAP1 in colon cancer cells. Depletion of TRAP1 triggered a series of events: induced metabolic reprogramming, increased glycolytic flux, downregulation of mitochondrial complex I, and elevated ROS generation. TRAP1-deficient cells showed tolerance to Oxidative Phosphorylation (OXPHOS) inhibitors and exhibited a higher extracellular acidification rate (ECAR). Additionally, TRAP1 depletion activated hypoxia response elements (HREs) and upregulated HIF1A target genes such as GLUT1 and MCT1. …

The Multilevel Limb-Loss And Preservation Rehabilitation Continuum Model (Mlprc): An Evidence-Based Implementation Model Integrating Multiple Perspectives To Improve Outcomes For People Facing Limb Loss, Prateek Grover, Elvin Geng, Rachel G Tabak

2020-Current year OA Pubs

BACKGROUND: The patient journey from threatened to actual limb loss, subsequent rehabilitation, and limb preservation through the health system is complicated and prone to delays, attrition, and inequities. A shared multi(socioecological)-level conceptualization of this journey among the multiple stakeholders is the first step for systematically improving limb care through identification of bottlenecks and gaps, contributory factors, and responsive interventions and implementation strategies.

OBJECTIVE: To meet this knowledge gap by presenting a novel implementation model, the Multilevel Limb-loss and Preservation Rehabilitation Continuum (MLPRC), that can be used to develop multilevel applications.

METHODS: MLPRC was developed in three overlapping steps: (1) design …

Comparing Effectiveness And Safety Of Left Atrial Appendage Closure Devices: A Network Meta-Analysis Of Randomized Controlled Trials, John W Davis, Steven L Mai, Wissam Harmouch, Jenna Reisler, Micaela Mackay, Elizabeth Davis, Pavel Osmancik, Michael W Rich

2020-Current year OA Pubs

INTRODUCTION: Atrial fibrillation-related stroke is a leading cause of morbidity and mortality. The comparative effectiveness and safety of left atrial appendage closure (LAAC) devices, compared with one another and with anticoagulation, is unclear.

METHODS: We conducted a systematic review and network meta-analysis (NMA) of all clinical trials comparing the Watchman and Amplatzer Amulet LAAC devices with each other or with warfarin or direct oral anticoagulants (DOACs). The primary comparison was between LAAC devices with secondary comparisons to anticoagulation. The primary effectiveness outcomes were any stroke and all-cause death. Safety outcomes included any thromboembolism, device embolization, and pericardial effusion.

RESULTS: There …

Moderators Of Antidepressant Augmentation Versus Switch In The Optimum Randomised Controlled Trial, Helena K Kim, Jordan F Karp, Helen Lavretsky, Daniel M Blumberger, Patrick J Brown, Alastair J Flint, Emily Lenard, J Philip Miller, Charles F Reynolds, Steven P Roose, Eric J Lenze, Benoit H Mulsant

2020-Current year OA Pubs

BACKGROUND: Older adults with treatment-resistant depression (TRD) benefit more from treatment augmentation than switching. It is useful to identify moderators that influence these treatment strategies for personalised medicine.

AIMS: Our objective was to test whether age, executive dysfunction, comorbid medical burden, comorbid anxiety or the number of previous adequate antidepressant trials could moderate the superiority of augmentation over switching. A significant moderator would influence the differential effect of augmentation versus switching on treatment outcomes.

METHOD: We performed a preplanned moderation analysis of data from the Optimizing Outcomes of Treatment-Resistant Depression in Older Adults (OPTIMUM) randomised controlled trial (

RESULTS: Of …