Digital Commons Network^™

What Do Cancer Genetic Providers Want Us To Know About Variant Reclassification And Recontact That We Are Not Asking? A Thematic Analysis Of Open-Ended Survey Responses, Kerri Brown, Marisel Ponton, Elenita Davidson, Banu Arun, Robert J Volk, Sanjay Shete, Susan K Peterson, Sukh Makhnoon

Faculty, Staff and Student Publications

BACKGROUND: Accurate variant classification and relaying reclassified results to patients is critical for hereditary cancer care delivery. Over a 5- to 10-year period, 6%-15% of variants undergo reclassification. As the frequency of reclassifications increases, the issue of whether, how, when, and which providers should recontact patients becomes important but remains contentious.

METHODS: The authors used inductive thematic analysis to analyze open-ended comments offered by oncologists and genetic counselors (GCs) from a large national survey.

RESULTS: Of the 634 oncologists and cancer GCs, 126 (20%) offered substantive free-text comments. Four thematic areas emerged: 1) ambiguity over professional responsibility to recontact, 2) …

Lung Tissue Multilayer Network Analysis Uncovers The Molecular Heterogeneity Of Chronic Obstructive Pulmonary Disease, Nuria Olvera, Jon Sánchez-Valle, Iker Núñez-Carpintero, Joselyn Rojas-Quintero, Guillaume Noell, Sandra Casas-Recasens, Alen Faiz, Philip Hansbro, Angela Guirao, Rosalba Lepore, Davide Cirillo, Alvar Agustí, Francesca Polverino, Alfonso Valencia, Rosa Faner

Faculty, Staff and Students Publications

Rationale: Chronic obstructive pulmonary disease (COPD) is a heterogeneous condition. Objectives: We hypothesized that the unbiased integration of different COPD lung omics using a novel multilayer approach might unravel mechanisms associated with clinical characteristics.

Methods: We profiled mRNA, microRNA and methylome in lung tissue samples from 135 former smokers with COPD. For each omic (layer), we built a patient network on the basis of molecular similarity. The three networks were used to build a multilayer network, and optimization of multiplex modularity was used to identify patient communities across the three distinct layers. Uncovered communities were related to clinical features.

Measurements …

Conference Report: Review Of Clinical Implementation Of Advanced Quantitative Imaging Techniques For Personalized Radiotherapy, Yevgeniy Vinogradskiy, Houda Bahig, Nicholas Bucknell, Jeffrey Buchsbaum, Hui-Kuo George Shu

Department of Radiation Oncology Faculty Papers

The topic of quantitative imaging in radiation therapy was presented as a "Masterclass" at the 2023 annual meeting of the American Society of Radiation Oncology (ASTRO). Dual-energy computed tomography (CT) and single-positron computed tomography were reviewed in detail as the first portion of the meeting session, with data showing utility in many aspects of radiation oncology including treatment planning and dose response. Positron emission tomography/CT scans evaluating the functional volume of lung tissue so as to provide optimal avoidance of healthy lungs were presented second. Advanced brain imaging was then discussed in the context of different forms of magnetic resonance …

Dilated Cardiomyopathy-Associated Skeletal Muscle Actin (Acta1) Mutation R256h Disrupts Actin Structure And Function And Causes Cardiomyocyte Hypocontractility, Ankit Garg, Silvia Jansen, Lina Greenberg, Rui Zhang, Kory J Lavine, Michael J Greenberg

2020-Current year OA Pubs

Skeletal muscle actin (ACTA1) mutations are a prevalent cause of skeletal myopathies consistent with ACTA1's high expression in skeletal muscle. Rare de novo mutations in ACTA1 associated with combined cardiac and skeletal myopathies have been reported, but ACTA1 represents only ~20% of the total actin pool in cardiomyocytes, making its role in cardiomyopathy controversial. Here we demonstrate how a mutation in an actin isoform expressed at low levels in cardiomyocytes can cause cardiomyopathy by focusing on a unique ACTA1 variant, R256H. We previously identified this variant in a family with dilated cardiomyopathy, who had reduced systolic function without clinical skeletal …

A Reward Self-Bias Leads To More Optimal Foraging For Ourselves Than Others, Luis Sebastian Contreras-Huerta, M. Andrea Pisauro, Svenja Küchenhoff, Arno Gekiere, Campbell Le Heron, Patricia L. Lockwood, Matthew A.J. Apps

School of Psychology

People are self-biased for rewards. We place a higher value on rewards if we receive them than if other people do. However, existing work has ignored one of the most powerful theorems from behavioural ecology of how animals seek resources in everyday life, the Marginal Value Theorem (MVT), which accounts for optimal behaviour for maximising resources intake rate. Does this self-bias help humans maximise rewards when foraging for their own benefit compared to foraging for the benefit of others? Participants had to decide when to leave patches where reward intake was gradually depleting, in environments with different average reward rates. …

Dna Methylation Classifier To Diagnose Pancreatic Ductal Adenocarcinoma Metastases From Different Anatomical Sites, Teodor G Calina, Eilís Perez, Elena Grafenhorst, Jamal Benhamida, Simon Schallenberg, Adrian Popescu, Ines Koch, Tobias Janik, Baoqing Chen, Jana Ihlow, Stephanie Roessler, Benjamin Goeppert, Bruno Sinn, Marcus Bahra, George A Calin, Eliane T Taube, Uwe Pelzer, Christopher C M Neumann, David Horst, Erik Knutsen, David Capper, Mihnea P Dragomir

Faculty, Staff and Student Publications

Background: We have recently constructed a DNA methylation classifier that can discriminate between pancreatic ductal adenocarcinoma (PAAD) liver metastasis and intrahepatic cholangiocarcinoma (iCCA) with high accuracy (PAAD-iCCA-Classifier). PAAD is one of the leading causes of cancer of unknown primary and diagnosis is based on exclusion of other malignancies. Therefore, our focus was to investigate whether the PAAD-iCCA-Classifier can be used to diagnose PAAD metastases from other sites.

Methods: For this scope, the anomaly detection filter of the initial classifier was expanded by 8 additional mimicker carcinomas, amounting to a total of 10 carcinomas in the negative class. We validated the …

Polygenic Risk For Alcohol Use Disorder Affects Cellular Responses To Ethanol Exposure In A Human Microglial Cell Model, Xindi Li, Arpana Agrawal, Et Al.

2020-Current year OA Pubs

Polygenic risk scores (PRSs) assess genetic susceptibility to alcohol use disorder (AUD), yet their molecular implications remain underexplored. Neuroimmune interactions, particularly in microglia, are recognized as notable contributors to AUD pathophysiology. We investigated the interplay between AUD PRS and ethanol in human microglia derived from iPSCs from individuals with AUD high-PRS (diagnosed with AUD) or low-PRS (unaffected). Ethanol exposure induced elevated CD68 expression and morphological changes in microglia, with differential responses between high-PRS and low-PRS microglial cells. Transcriptomic analysis revealed expression differences in MHCII complex and phagocytosis-related genes following ethanol exposure; high-PRS microglial cells displayed enhanced phagocytosis and increased

Modeling Antisense Oligonucleotide Therapy In Mecp2 Duplication Syndrome Human Ipsc-Derived Neurons Reveals Gene Expression Programs Responsive To Mecp2 Levels, Sameer S Bajikar, Yehezkel Sztainberg, Alexander J Trostle, Harini P Tirumala, Ying-Wooi Wan, Caroline L Harrop, Jesse D Bengtsson, Claudia M B Carvalho, Davut Pehlivan, Bernhard Suter, Jeffrey L Neul, Zhandong Liu, Paymaan Jafar-Nejad, Frank Rigo, Huda Y Zoghbi

Faculty, Staff and Students Publications

Genomic copy-number variations (CNVs) that can cause neurodevelopmental disorders often encompass many genes, which complicates our understanding of how individual genes within a CNV contribute to pathology. MECP2 duplication syndrome (MDS or MRXSL in OMIM; OMIM#300260) is one such CNV disorder caused by duplications spanning methyl CpG-binding protein 2 (MECP2) and other genes on Xq28. Using an antisense oligonucleotide (ASO) to normalize MECP2 dosage is sufficient to rescue abnormal neurological phenotypes in mouse models overexpressing MECP2 alone, implicating the importance of increased MECP2 dosage within CNVs of Xq28. However, because MDS CNVs span MECP2 and additional genes, we generated human …

Mark2 Variants Cause Autism Spectrum Disorder Via The Downregulation Of Wnt/Β-Catenin Signaling Pathway., Maolei Gong, Jiayi Li, Zailong Qin, Matheus Vernet Machado Bressan Wilke, Yijun Liu, Qian Li, Haoran Liu, Chen Liang, Joel A. Morales-Rosado, Ana S A Cohen, Susan S. Hughes, Bonnie Sullivan, Valerie A. Waddell, Marie-José H. Van Den Boogaard, Richard H. Van Jaarsveld, Ellen Van Binsbergen, Koen L. Van Gassen, Tianyun Wang, Susan M. Hiatt, Michelle D. Amaral, Whitley V. Kelley, Jianbo Zhao, Weixing Feng, Changhong Ren, Yazhen Yu, Nicole J. Boczek, Matthew J. Ferber, Carrie Lahner, Sherr Elliott, Yiyan Ruan, Cyril Mignot, Boris Keren, Hua Xie, Xiaoyan Wang, Bernt Popp, Christiane Zweier, Juliette Piard, Christine Coubes, Frederic Tran Mau-Them, Hana Safraou, A Micheil Innes, Julie Gauthier, Jacques L. Michaud, Daniel C. Koboldt, Odent Sylvie, Marjolaine Willems, Wen-Hann Tan, Benjamin Cogne, Claudine Rieubland, Dominique Braun, Scott Douglas Mclean, Konrad Platzer, Pia Zacher, Henry Oppermann, Lucie Evenepoel, Pierre Blanc, Laïla El Khattabi, Neshatul Haque, Nikita R. Dsouza, Michael T. Zimmermann, Raul Urrutia, Eric W. Klee, Yiping Shen, Hongzhen Du, Leonard Rappaport, Chang-Mei Liu, Xiaoli Chen

Manuscripts, Articles, Book Chapters and Other Papers

Microtubule affinity-regulating kinase 2 (MARK2) contributes to establishing neuronal polarity and developing dendritic spines. Although large-scale sequencing studies have associated MARK2 variants with autism spectrum disorder (ASD), the clinical features and variant spectrum in affected individuals with MARK2 variants, early developmental phenotypes in mutant human neurons, and the pathogenic mechanism underlying effects on neuronal development have remained unclear. Here, we report 31 individuals with MARK2 variants and presenting with ASD, other neurodevelopmental disorders, and distinctive facial features. Loss-of-function (LoF) variants predominate (81%) in affected individuals, while computational analysis and in vitro expression assay of missense variants supported the effect of …

Estimating The Number Of Polygenic Diseases Among Six Mutually Exclusive Entities Of Non-Tumors And Cancer, C I Edvard Smith, Jan A Burger, Rula Zain

Faculty, Staff and Student Publications

In the era of precision medicine with increasing amounts of sequenced cancer and non-cancer genomes of different ancestries, we here enumerate the resulting polygenic disease entities. Based on the cell number status, we first identified six fundamental types of polygenic illnesses, five of which are non-cancerous. Like complex, non-tumor disorders, neoplasms normally carry alterations in multiple genes, including in 'Drivers' and 'Passengers'. However, tumors also lack certain genetic alterations/epigenetic changes, recently named 'Goners', which are toxic for the neoplasm and potentially constitute therapeutic targets. Drivers are considered essential for malignant transformation, whereas environmental influences vary considerably among both types of …

Probabilistic Presurgical Language Fmri Atlas Of Patients With Brain Tumors, Jian Ming Teo, Vinodh A Kumar, Jina Lee, Rami W Eldaya, Ping Hou, Mu-Lan Jen, Kyle R Noll, Peng Wei, Sherise D Ferguson, Sujit S Prabhu, Max Wintermark, Ho-Ling Liu

Faculty, Staff and Student Publications

Background and purpose: Patients with brain tumors have high intersubject variation in putative language regions, which may limit the utility of straightforward application of healthy subject brain atlases in clinical scenarios. The purpose of this study was to develop a probabilistic functional brain atlas that consolidates language functional activations of sentence completion and Silent Word Generation language paradigms using a large sample of patients with brain tumors.

Materials and methods: The atlas was developed using retrospectively collected fMRI data from patients with brain tumors who underwent their first standard-of-care presurgical language fMRI scan at our institution between July 18, 2015, …

Racial Disparity In Mortality From Tuberculosis In The Us Between States With And Without A History Of Jim-Crow Laws: An Analysis Of The Global Burden Of Disease (Gbd) And Risk Factors Study, 1990 To 2019, Philimon N Gona, Lorena M Estrada-Martinez, Lingling Zhang, Clara M Gona, Aaloke Mody, Sowmya R Rao, Joseph Cooper, Kibibi Mack-Shelton, Ping Chen, Suzanne G Leveille, Ali H Mokdad, G. B. D. 2019 T. B. Racial Disparity

2020-Current year OA Pubs

BACKGROUND: While TB-related mortality in the US declined four-fold from 1990 to 2019, country-level estimates of TB burden obscure within-state racial heterogeneity and changes in TB burden over time. In sixteen US Southern States and Washington DC, the effects of health inequities engendered by Jim-Crow laws enacted from the late 1800s to the 1960s have not been evaluated for TB-related mortality. We, therefore, sought to compare TB mortality rates and annualized rate of change (AROC) between 1990 and 2019 in former Jim-Crow vs. non-Jim-Crow states to help guide response efforts and inform resource prioritization to improve racial equity.

METHODS: We …

Large-Scale Application Of Clingen-Insight Apc-Specific Acmg/Amp Variant Classification Criteria Leads To Substantial Reduction In Vus, Xiaoyu Yin, Marcy Richardson, Andreas Laner, Xuemei Shi, Elisabet Ognedal, Valeria Vasta, Thomas V O Hansen, Marta Pineda, Deborah Ritter, Johan De Dunnen, Emadeldin Hassanin, Wencong Lyman Lin, Ester Borras, Karl Krahn, Margareta Nordling, Alexandra Martins, Khalid Mahmood, Emily Nadeau, Victoria Beshay, Carli Tops, Maurizio Genuardi, Tina Pesaran, Ian M Frayling, Gabriel Capellá, Andrew Latchford, Sean V Tavtigian, Carlo Maj, Sharon E Plon, Marc S Greenblatt, Finlay A Macrae, Isabel Spier, Stefan Aretz

Faculty, Staff and Students Publications

Pathogenic constitutional APC variants underlie familial adenomatous polyposis, the most common hereditary gastrointestinal polyposis syndrome. To improve variant classification and resolve the interpretative challenges of variants of uncertain significance (VUSs), APC-specific variant classification criteria were developed by the ClinGen-InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (VCEP) based on the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP). A streamlined algorithm using the APC-specific criteria was developed and applied to assess all APC variants in ClinVar and the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) international reference APC Leiden Open Variation …

High Incidence And Geographic Distribution Of Cleft Palate In Finland Are Associated With The Irf6 Gene, Fedik Rahimov, Pekka Nieminen, Priyanka Kumari, Emma Juuri, Tiit Nikopensius, Kitt Paraiso, Jakob German, Antti Karvanen, Mart Kals, Abdelrahman G Elnahas, Juha Karjalainen, Mitja Kurki, Aarno Palotie, Estonian Biobank Research Team, Finngen, Arja Heliövaara, Tõnu Esko, Sakari Jukarainen, Priit Palta, Andrea Ganna, Anjali P Patni, Daniel Mar, Karol Bomsztyk, Julie Mathieu, Hannele Ruohola-Baker, Axel Visel, Walid D Fakhouri, Brian C Schutte, Robert A Cornell, David P Rice

Faculty, Staff and Student Publications

In Finland, the frequency of isolated cleft palate (CP) is higher than that of isolated cleft lip with or without cleft palate (CL/P). This trend contrasts to that in other European countries but its genetic underpinnings are unknown. We conducted a genome-wide association study in the Finnish population and identified rs570516915, a single nucleotide polymorphism highly enriched in Finns, as strongly associated with CP (P = 5.25 × 10-34, OR = 8.65, 95% CI 6.11-12.25), but not with CL/P (P = 7.2 × 10-5), with genome-wide significance. The risk allele frequency of rs570516915 parallels the regional variation of CP prevalence …

Mitral Annular Disjunction In Heritable Thoracic Aortic Disease: Insights From The Montalcino Aortic Consortium, Kishan L Asokan, Jennifer R Landes, Wannes Renders, Laura Muiño Mosquera, Julie De Backer, David W Jantzen, Anji T Yetman, Gisela Teixido-Tura, Arturo Evangelista, Richmond Jeremy, Edward G Jones, Shaine Morris, Tam Doan, Maral Ouzonian, Alan Braverman, Guillaume Jondeau, Olivier Milleron, Dianna M Milewicz, Siddharth K Prakash

Faculty, Staff and Student Publications

Background: Mitral annular disjunction (MAD), posterior displacement of the mitral valve leaflet hinge point, predisposes to arrhythmias or sudden cardiac death. We evaluated the burden of MAD, mitral valve prolapse (MVP), and mitral regurgitation (MR) by heritable thoracic aortic disease gene in a cross-sectional analysis of 2014-2023 data in the Montalcino Aortic Consortium registry.

Methods and results: MAD was determined by direct measurement of echocardiographic images. MR and MVP were defined according to current clinical guidelines. Associations were evaluated using χ2 or Fisher exact tests. MR and MVP were enriched in Montalcino Aortic Consortium participants (672) with pathogenic variants (PV) …

Trends In Transcatheter Versus Surgical Aortic Valve Replacement Outcomes In Patients With Low-Surgical Risk: A Systematic Review And Meta-Analysis Of Randomized Trials, Sina Kazemian, Parisa Fallahtafti, Mohammad Sharifi, Negin Sadat Hosseini Mohammadi, Hamidreza Soleimani, Arman Soltani Moghadam, Elaheh Karimi, Yaser Sattar, Yaser Jenab, Mehdi Mehrani, Alimohammad Hajizeinali, Mina Iskander, Mehrshad Fathian Sabet, Negar Salehi, Karim Al-Azizi, Diaa Hakim, Mahboob Alam, Kaveh Hosseini

Faculty, Staff and Students Publications

Background: Limited data exist on long-term outcomes after transcatheter aortic valve replacement (TAVR) and surgical aortic valve replacement (SAVR). This meta-analysis aims to elucidate outcome trends following TAVR versus SAVR in patients with severe aortic stenosis and low-surgical risk.

Methods and results: A systematic search was conducted in PubMed, Embase, Scopus, and the Cochrane Library databases from inception until May 2024, to identify studies comparing TAVR versus SAVR in patients with low-surgical risk (Society of Thoracic Surgeons predicted risk of mortality score < 4%). The primary outcome was all-cause mortality. Secondary outcomes included cardiovascular mortality, stroke, disabling stroke, rehospitalization, myocardial infarction, aortic valve reintervention, permanent pacemaker implantation, and new-onset atrial fibrillation. Binary random-effects models were used to compare the risk of each outcome across various follow-up intervals and the risk of bias was assessed using the Cochrane Collaboration's Risk of Bias-2 tool. The meta-analysis included 6 randomized trials including 4682 patients. TAVR was associated with a lower risk of all-cause mortality than SAVR in the 30-day (hazard ratio [HR: 0.45] [95% CI: 0.26-0.77], I2: 0%) and 30-day to 1-year (HR: 0.55 [95% CI: 0.37-0.81], I2: 16%) follow-ups. However, the …

Nepali Oral Microbiomes Reflect A Gradient Of Lifestyles From Traditional To Industrialized, Erica Ryu, Yoshina Gautam, Diana Proctor, Dinesh Bhandari, Sarmila Tandukar, Meera Gupta, Guru Prasad Gautam, David Relman, Ahmed Shibl, Jeevan Bahadur Sherchand, Aashish Jha, Emily Davenport

SKMC Student Presentations and Publications

BACKGROUND: Lifestyle plays an important role in shaping the gut microbiome. However, its contributions to the oral microbiome remain less clear, due to the confounding effects of geography and methodology in investigations of populations studied to date. Furthermore, while the oral microbiome seems to differ between foraging and industrialized populations, we lack insight into whether transitions to and away from agrarian lifestyles shape the oral microbiota. Given the growing interest in so-called "vanishing microbiomes" potentially being a risk factor for increased disease prevalence in industrialized populations, it is important that we distinguish lifestyle from geography in the study of microbiomes …

Nepali Oral Microbiomes Reflect A Gradient Of Lifestyles From Traditional To Industrialized, Erica P Ryu, Yoshina Gautam, Diana M Proctor, Dinesh Bhandari, Sarmila Tandukar, Meera Gupta, Guru Prasad Gautam, David A Relman, Ahmed A Shibl, Jeevan Bahadur Sherchand, Aashish R Jha, Emily R Davenport

Faculty, Staff and Student Publications

Background: Lifestyle plays an important role in shaping the gut microbiome. However, its contributions to the oral microbiome remain less clear, due to the confounding effects of geography and methodology in investigations of populations studied to date. Furthermore, while the oral microbiome seems to differ between foraging and industrialized populations, we lack insight into whether transitions to and away from agrarian lifestyles shape the oral microbiota. Given the growing interest in so-called "vanishing microbiomes" potentially being a risk factor for increased disease prevalence in industrialized populations, it is important that we distinguish lifestyle from geography in the study of microbiomes …

Genetic Risk Factors Underlying White Matter Hyperintensities And Cortical Atrophy, Yash Patel, Jean Shin, Eeva Sliz, Ariana Tang, Aniket Mishra, Rui Xia, Edith Hofer, Hema Sekhar Reddy Rajula, Ruiqi Wang, Frauke Beyer, Katrin Horn, Max Riedl, Jing Yu, Henry Völzke, Robin Bülow, Uwe Völker, Stefan Frenzel, Katharina Wittfeld, Sandra Van Der Auwera, Thomas H Mosley, Vincent Bouteloup, Jean-Charles Lambert, Geneviève Chêne, Carole Dufouil, Christophe Tzourio, Jean-François Mangin, Rebecca F Gottesman, Myriam Fornage, Reinhold Schmidt, Qiong Yang, Veronica Witte, Markus Scholz, Markus Loeffler, Gennady V Roshchupkin, M Arfan Ikram, Hans J Grabe, Sudha Seshadri, Stephanie Debette, Tomas Paus, Zdenka Pausova

Faculty, Staff and Student Publications

White matter hyperintensities index structural abnormalities in the cerebral white matter, including axonal damage. The latter may promote atrophy of the cerebral cortex, a key feature of dementia. Here, we report a study of 51,065 individuals from 10 cohorts demonstrating that higher white matter hyperintensity volume associates with lower cortical thickness. The meta-GWAS of white matter hyperintensities-associated cortical 'atrophy' identifies 20 genome-wide significant loci, and enrichment in genes specific to vascular cell types, astrocytes, and oligodendrocytes. White matter hyperintensities-associated cortical 'atrophy' showed positive genetic correlations with vascular-risk traits and plasma biomarkers of neurodegeneration, and negative genetic correlations with cognitive functioning. …

Transcranial Direct Current Stimulation Combined With Repetitive Transcranial Magnetic Stimulation For Depression: A Randomized Clinical Trial, Dongsheng Zhou, Xingxing Li, Shuochi Wei, Chang Yu, Dongmei Wang, Yuchen Li, Jiaxin Li, Junyao Liu, Shen Li, Wenhao Zhuang, Yanli Li, Ruichenxi Luo, Zhiwang Liu, Jimeng Liu, Yongming Xu, Jialin Fan, Guidong Zhu, Weiqian Xu, Yiping Tang, Raymond Y Cho, Thomas R Kosten, Xiang-Yang Zhang

Staff and Researcher Publications

IMPORTANCE: Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are both recognized as effective treatments for depression when applied individually. However, it is unknown whether rTMS combined with tDCS has better efficacy in the treatment of major depressive disorder (MDD).

OBJECTIVE: To investigate the clinical effectiveness and safety of rTMS, tDCS, tDCS + rTMS, and sham tDCS + sham rTMS after 2 weeks of treatment in patients with MDD.

DESIGN, SETTING, AND PARTICIPANTS: This double-blind, sham-controlled randomized clinical trial was conducted from November 2021 to April 2023 at 3 hospitals in China (Kangning Hospital affiliated with Ningbo …

Age-Related Decline In Blood-Brain Barrier Function Is More Pronounced In Males Than Females In Parietal And Temporal Regions, Xingfeng Shao, Qinyang Shou, Kimberly Felix, Brandon Ojogho, Xuejuan Jiang, Brian T Gold, Megan M Herting, Eric L Goldwaser, Peter Kochunov, Elliot Hong, Ioannis Pappas, Meredith Braskie, Hosung Kim, Steven Cen, Kay Jann, Danny J J Wang

Faculty, Staff and Student Publications

The blood-brain barrier (BBB) plays a pivotal role in protecting the central nervous system (CNS), and shielding it from potential harmful entities. A natural decline of BBB function with aging has been reported in both animal and human studies, which may contribute to cognitive decline and neurodegenerative disorders. Limited data also suggest that being female may be associated with protective effects on BBB function. Here, we investigated age and sex-dependent trajectories of perfusion and BBB water exchange rate (kw) across the lifespan in 186 cognitively normal participants spanning the ages of 8-92 years old, using a non-invasive diffusion-prepared pseudo-continuous arterial …

Differences In Brain Volume In Military Service Members And Veterans After Blast-Related Mild Tbi: A Limbic-Cenc Study, Emily L Dennis, Jared A Rowland, Carrie Esopenko, Nicholas J Tustison, Mary R Newsome, Elizabeth S Hovenden, Brian B Avants, Jessica Gill, Sidney R Hinds, Kimbra Kenney, Hannah M Lindsey, Sarah L Martindale, Mary Jo Pugh, Randall S Scheibel, Pashtun-Poh Shahim, Robert Shih, James R Stone, Maya Troyanskaya, William C Walker, Kent Werner, Gerald E York, David X Cifu, David F Tate, Elisabeth A Wilde

Faculty, Staff and Students Publications

Importance: Blast-related mild traumatic brain injuries (TBIs), the "signature injury" of post-9/11 conflicts, are associated with clinically relevant, long-term cognitive, psychological, and behavioral dysfunction and disability; however, the underlying neural mechanisms remain unclear.

Objective: To investigate associations between a history of remote blast-related mild TBI and regional brain volume in a sample of US veterans and active duty service members.

Design, setting, and participants: Prospective cohort study of US veterans and active duty service members from the Long-Term Impact of Military-Relevant Brain Injury Consortium-Chronic Effects of Neurotrauma Consortium (LIMBIC-CENC), which enrolled more than 1500 participants at 5 sites used in …

Performance Of Risk Models For Antimicrobial Resistance In Adult Patients With Sepsis, M Cristina Vazquez Guillamet, Hanyang Liu, Andrew Atkinson, Victoria J Fraser, Chenyang Lu, Marin H Kollef

2020-Current year OA Pubs

IMPORTANCE: The results of prediction models that stratify patients with sepsis and risk of resistant gram-negative bacilli (GNB) infections inform treatment guidelines. However, these models do not extrapolate well across hospitals.

OBJECTIVE: To assess whether patient case mix and local prevalence rates of resistance contributed to the variable performance of a general risk stratification GNB sepsis model for community-onset and hospital-onset sepsis across hospitals.

DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective cohort study conducted from January 2016 and October 2021. Adult patients with sepsis at 10 acute-care hospitals in rural and urban areas across Missouri and Illinois were included. …

Mutation In Prkra Results In Cerebellar Abnormality And Reduced Eif2Α Phosphorylation In A Model Of Dyt-Prkra., Samuel B Burnett, Allison M Culver, Tricia A Simon, Taylor Rowson, Kenneth Frederick, Kristina Palmer, Stephen A Murray, Shannon W Davis, Rekha C Patel

Faculty Research 2024

Variants in the PRKRA gene, which encodes PACT, cause the early-onset primary dystonia DYT-PRKRA, a movement disorder associated with disruption of coordinated muscle movements. PACT and its murine homolog RAX activate protein kinase R (PKR; also known as EIF2AK2) by a direct interaction in response to cellular stressors to mediate phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2α). Mice homozygous for a naturally arisen, recessively inherited frameshift mutation, Prkralear-5J, exhibit progressive dystonia. In the present study, we investigated the biochemical and developmental consequences of the Prkralear-5J mutation. Our results indicated that the truncated PACT/RAX protein retains …

Acute Kidney Injury Associated With Anticancer Therapies: Small Molecules And Targeted Therapies, Jaya Kala, Teresa Joseph, Marta Pirovano, Roberta Fenoglio, Laura Cosmai

Faculty, Staff and Student Publications

Molecular targeted therapy has revolutionized cancer treatment by significantly improving patient survival compared with standard conventional chemotherapies. The use of these drugs targets specific molecules or targets, which block growth and spread of cancer cells. Many of these therapies have been approved for use with remarkable success in breast, blood, colorectal, lung, and ovarian cancers. The advantage over conventional chemotherapy is its ability to deliver drugs effectively with high specificity while being less toxic. Although known as "targeted," many of these agents lack specificity and selectivity, and they tend to inhibit multiple targets, including those in the kidneys. The side …

Roflumilast Cream, 015%, For Atopic Dermatitis In Adults And Children: Integument-1 And Integument-2 Randomized Clinical Trials, Eric L Simpson, Lawrence F Eichenfield, Javier Alonso-Llamazares, Zoe D Draelos, Laura K Ferris, Seth B Forman, Melinda Gooderham, Mercedes E Gonzalez, Adelaide A Hebert, Leon H Kircik, Mark Lomaga, Angela Moore, Kim A Papp, Vimal H Prajapati, Diane Hanna, Scott Snyder, David Krupa, Patrick Burnett, Erin Almaraz, Robert C Higham, David H Chu, David R Berk

Faculty, Staff and Student Publications

Importance: Safe, effective, and well-tolerated topical treatment options available for long-term use in patients with atopic dermatitis (AD) are limited and associated with low adherence rates.

Objective: To evaluate efficacy and safety of once-daily roflumilast cream, 0.15%, vs vehicle cream in patients with AD.

Design, setting, and participants: Two phase 3, randomized, double-blind, vehicle-controlled trials (Interventional Trial Evaluating Roflumilast Cream for the Treatment of Atopic Dermatitis 1 and 2 [INTEGUMENT-1 and INTEGUMENT-2]), included patients from sites in the US, Canada, and Poland. Participants were 6 years or older with mild to moderate AD based on Validated Global Assessment for Atopic …

Prediction Of Individual Weight Loss Using Supervised Learning: Findings From The CalerieTm 2 Study, Christina Glasbrenner, Christoph Höchsmann, Carl F. Pieper, Paulina Wasserfurth, James L. Dorling, Corby K. Martin, Leanne M. Redman, Karsten Koehler

Clinical Research Faculty Publications

Background: Predicting individual weight loss (WL) responses to lifestyle interventions is challenging but might help practitioners and clinicians select the most promising approach for each individual. Objective: The primary aim of this study was to develop machine learning (ML) models to predict individual WL responses using only variables known before starting the intervention. In addition, we used ML to identify pre-intervention variables influencing the individual WL response. Methods: We used 12-mo data from the comprehensive assessment of long-term effects of reducing intake of energy (CALERIETM) phase 2 study, which aimed to analyze the long-term effects of caloric restriction on human …

Toward A Responsible Future: Recommendations For Ai-Enabled Clinical Decision Support, Steven Labkoff, Bilikis Oladimeji, Joseph Kannry, Anthony Solomonides, Russell Leftwich, Eileen Koski, Amanda L Joseph, Monica Lopez-Gonzalez, Lee A Fleisher, Kimberly Nolen, Sayon Dutta, Deborah R Levy, Amy Price, Paul J Barr, Jonathan D Hron, Baihan Lin, Gyana Srivastava, Nuria Pastor, Unai Sanchez Luque, Tien Thi Thuy Bui, Reva Singh, Tayler Williams, Mark G Weiner, Tristan Naumann, Dean F Sittig, Gretchen Purcell Jackson, Yuri Quintana

Faculty, Staff and Student Publications

BACKGROUND: Integrating artificial intelligence (AI) in healthcare settings has the potential to benefit clinical decision-making. Addressing challenges such as ensuring trustworthiness, mitigating bias, and maintaining safety is paramount. The lack of established methodologies for pre- and post-deployment evaluation of AI tools regarding crucial attributes such as transparency, performance monitoring, and adverse event reporting makes this situation challenging.

OBJECTIVES: This paper aims to make practical suggestions for creating methods, rules, and guidelines to ensure that the development, testing, supervision, and use of AI in clinical decision support (CDS) systems are done well and safely for patients.

MATERIALS AND METHODS: In May …

Diverse Pathways In Gpcr-Mediated Activation Of Ca2+ Mobilization In Hek293 Cells, Francesco De Pascali, Asuka Inoue, Jeffrey L. Benovic

Department of Biochemistry and Molecular Biology Faculty Papers

G protein-coupled receptors transduce extracellular stimuli into intracellular signaling. Ca²⁺ is a well-known second messenger that can be induced by G protein-coupled receptor activation through the primary canonical pathways involving Gα_q- and Gβγ-mediated activation of phospholipase C-β (PLCβ). While some G_s-coupled receptors are shown to trigger Ca²⁺ mobilization, underlying mechanisms remain elusive. Here, we evaluated whether G_s-coupled receptors including the β₂-adrenergic receptor (β₂AR) and the prostaglandin EP₂ and EP₄ receptors (EP₂R and EP₄R) that are endogenously expressed in human embryonic kidney 293 …

History Of Incarceration And Dental Care Use Among Older Adults In The United States, Alexander Testa, Dylan B Jackson, Carmen Gutierrez, Chantal Fahmy, Vahed Maroufy, Rafael Samper-Ternent, Ana C Neumann

Faculty, Staff and Student Publications

INTRODUCTION: Dental care is a critical component of healthy aging; however, emerging evidence suggests that having been previously incarcerated is a risk factor for not using dental care services. This study investigates the relationship between prior incarceration and dental care among older adults and assesses whether wealth and dental insurance explain this relationship.

METHODS: Data are from the Health and Retirement Study, a nationally representative sample of community-dwelling older adults in the United States, collected in 2012 and 2014. Multivariable logistic regression is used to assess the relationship between a history of incarceration and dental care. Mediation analyses were conducted …