Medicine and Health Sciences Commons^™

Spatiotemporal Correlation Analysis Of Hydraulic Fracturing And Stroke In The United States, Chuanbo Hu, Bin Liu, Shuo Wang, Zhenduo Zhu, Amelia Adcock, James Simpkins, Xin Li

2020-Current year OA Pubs

Hydraulic fracturing or fracking has led to a rapid growth of oil and gas production in the United States, but the impact of fracking on public health is an important but underresearched topic. We designed a methodology to study spatiotemporal correlations between the risk of fracking and stroke mortality. An annualized loss expectancy (ALE) model is applied to quantify the risk of fracking. The geographically and temporally weighted regression (GTWR) model is used to analyze spatiotemporal correlations of stroke mortality, fracking ALE, and nine other socioeconomic- and health-related factors. The analysis shows that fracking ALE is moderately correlated with stroke …

A Pilot Randomized Trial To Examine Effects Of A Hybrid Closed-Loop Insulin Delivery System On Neurodevelopmental And Cognitive Outcomes In Adolescents With Type 1 Diabetes, Allan L Reiss, Ana Maria Arbelaez, Et Al

2020-Current year OA Pubs

Type 1 diabetes (T1D) is associated with lower scores on tests of cognitive and neuropsychological function and alterations in brain structure and function in children. This proof-of-concept pilot study (ClinicalTrials.gov Identifier NCT03428932) examined whether MRI-derived indices of brain development and function and standardized IQ scores in adolescents with T1D could be improved with better diabetes control using a hybrid closed-loop insulin delivery system. Eligibility criteria for participation in the study included age between 14 and 17 years and a diagnosis of T1D before 8 years of age. Randomization to either a hybrid closed-loop or standard diabetes care group was performed …

Association Between Fall History And Gait, Balance, Physical Activity, Depression, Fear Of Falling, And Motor Capacity: A 6-Month Follow-Up Study, Catherine Park, Md Moin Uddin Atique, Ramkinker Mishra, Bijan Najafi

Center on Aging Staff Publications

Maintaining function in older adults is key to the quality of life and longevity. This study examined the potential impact of falls on accelerating further deterioration over time in gait, balance, physical activity, depression, fear of falling, and motor capacity in older adults. 163 ambulatory older adults (age = 76.5 ± 7.7 years) participated and were followed for 6 months. They were classified into fallers or non-fallers based on a history of falling within the past year. At baseline and 6 months, all participants were objectively assessed for gait, balance, and physical activity using wearable sensors. Additional assessments included psychosocial …

Integrated Relationship Of Nasopharyngeal Airway Host Response And Microbiome Associates With Bronchiolitis Severity, Michimasa Fujiogi, Yoshihiko Raita, Marcos Pérez-Losada, Robert J Freishtat, Juan C Celedón, Jonathan M Mansbach, Pedro A Piedra, Zhaozhong Zhu, Carlos A Camargo, Kohei Hasegawa

Faculty, Staff and Students Publications

Bronchiolitis is a leading cause of infant hospitalizations but its immunopathology remains poorly understood. Here we present data from 244 infants hospitalized with bronchiolitis in a multicenter prospective study, assessing the host response (transcriptome), microbial composition, and microbial function (metatranscriptome) in the nasopharyngeal airway, and associate them with disease severity. We investigate individual associations with disease severity identify host response, microbial taxonomical, and microbial functional modules by network analyses. We also determine the integrated relationship of these modules with severity. Several modules are significantly associated with risks of positive pressure ventilation use, including the host-type I interferon, neutrophil/interleukin-1, T cell …

A Scoping Review Protocol To Elucidate Outcomes Following Abiraterone Versus Enzalutamide For Prostate Cancer, Yash B Shah, Amy L Shaver, William Kevin Kelly, Grace Lu-Yao

Department of Medical Oncology Faculty Papers

INTRODUCTION: Abiraterone acetate and enzalutamide are commonly employed in prostate cancer therapy in an interchangeable manner. These drugs are highly efficacious in androgen antagonism to improve patient outcomes, but they also carry noteworthy risk of adverse effects. Common toxicities vary amongst the two drugs and may have differential interactions with patient co-morbidities, but these patterns are unclear as co-morbidities typically serve as exclusion criteria in clinical trials. Hence, there is no existing guidance on how clinicians may tailor treatment based on patient-specific factors. Analysis of differential patient outcomes between these two drugs can inform future systematic reviews, new clinical studies, …

Subcortical-Cortical Dynamical States Of The Human Brain And Their Breakdown In Stroke, Chiara Favaretto, Michele Allegra, Gustavo Deco, Nicholas V Metcalf, Joseph C Griffis, Gordon L Shulman, Andrea Brovelli, Maurizio Corbetta

2020-Current year OA Pubs

The mechanisms controlling dynamical patterns in spontaneous brain activity are poorly understood. Here, we provide evidence that cortical dynamics in the ultra-slow frequency range (<0.01-0.1 Hz) requires intact cortical-subcortical communication. Using functional magnetic resonance imaging (fMRI) at rest, we identify Dynamic Functional States (DFSs), transient but recurrent clusters of cortical and subcortical regions synchronizing at ultra-slow frequencies. We observe that shifts in cortical clusters are temporally coincident with shifts in subcortical clusters, with cortical regions flexibly synchronizing with either limbic regions (hippocampus/amygdala), or subcortical nuclei (thalamus/basal ganglia). Focal lesions induced by stroke, especially those damaging white matter connections between basal ganglia/thalamus and cortex, provoke anomalies in the fraction times, dwell times, and transitions between DFSs, causing a bias toward abnormal network integration. Dynamical anomalies observed 2 weeks after stroke recover in time and contribute to explaining neurological impairment and long-term outcome.

Capg Is Required For Ebola Virus Infection By Controlling Virus Egress From Infected Cells, Hiroyuki Mori, James P Connell, Callie J Donahue, Ruthmabel Boytz, Yen Thi Kim Nguyen, Daisy W Leung, Douglas J Lacount, Robert A Davey

2020-Current year OA Pubs

The replication of Ebola virus (EBOV) is dependent upon actin functionality, especially at cell entry through macropinocytosis and at release of virus from cells. Previously, major actin-regulatory factors involved in actin nucleation, such as Rac1 and Arp2/3, were shown important in both steps. However, downstream of nucleation, many other cell factors are needed to control actin dynamics. How these regulate EBOV infection remains largely unclear. Here, we identified the actin-regulating protein, CAPG, as important for EBOV replication. Notably, knockdown of CAPG specifically inhibited viral infectivity and yield of infectious particles. Cell-based mechanistic analysis revealed a requirement of CAPG for virus …

Assessing Age-Specific Vaccination Strategies And Post-Vaccination Reopening Policies For Covid-19 Control Using Seir Modeling Approach, Xia Wang, Hulin Wu, Sanyi Tang

Faculty, Staff and Student Publications

As the availability of COVID-19 vaccines, it is badly needed to develop vaccination guidelines to prioritize the vaccination delivery in order to effectively stop COVID-19 epidemic and minimize the loss. We evaluated the effect of age-specific vaccination strategies on the number of infections and deaths using an SEIR model, considering the age structure and social contact patterns for different age groups for each of different countries. In general, the vaccination priority should be given to those younger people who are active in social contacts to minimize the number of infections, while the vaccination priority should be given to the elderly …

Phenotypic And Genetic Spectrum Of Atp6v1a Encephalopathy: A Disorder Of Lysosomal Homeostasis, Renzo Guerrini, Davide Mei, Katalin Kerti-Szigeti, Sara Pepe, Mary Kay Koenig, Gretchen Von Allmen, Megan T Cho, Kimberly Mcdonald, Janice Baker, Vikas Bhambhani, Zöe Powis, Lance Rodan, Rima Nabbout, Giulia Barcia, Jill A Rosenfeld, Carlos A Bacino, Cyril Mignot, Lillian H Power, Catharine J Harris, Dragan Marjanovic, Rikke S Møller, Trine B Hammer, Riikka Keski Filppula, Päivi Vieira, Clara Hildebrandt, Stephanie Sacharow, Luca Maragliano, Fabio Benfenati, Katherine Lachlan, Andreas Benneche, Florence Petit, Jean Madeleine De Sainte Agathe, Barbara Hallinan, Yue Si, Ingrid M Wentzensen, Fanggeng Zou, Vinodh Narayanan, Naomichi Matsumoto, Alessandra Boncristiano, Giancarlo La Marca, Mitsuhiro Kato, Kristin Anderson, Carmen Barba, Luisa Sturiale, Domenico Garozzo, Roberto Bei, Laura Masuelli, Valerio Conti, Gaia Novarino, Anna Fassio

Faculty, Staff and Student Publications

Vacuolar-type H+-ATPase (V-ATPase) is a multimeric complex present in a variety of cellular membranes that acts as an ATP-dependent proton pump and plays a key role in pH homeostasis and intracellular signalling pathways. In humans, 22 autosomal genes encode for a redundant set of subunits allowing the composition of diverse V-ATPase complexes with specific properties and expression. Sixteen subunits have been linked to human disease. Here we describe 26 patients harbouring 20 distinct pathogenic de novo missense ATP6V1A variants, mainly clustering within the ATP synthase α/β family-nucleotide-binding domain. At a mean age of 7 years (extremes: 6 weeks, youngest deceased …

Somatic Variants In Diverse Genes Leads To A Spectrum Of Focal Cortical Malformations, Dulcie Lai, Meethila Gade, Edward Yang, Hyun Yong Koh, Jinfeng Lu, Nicole M Walley, Anne F Buckley, Tristan T Sands, Cigdem I Akman, Mohamad A Mikati, Guy M Mckhann, James E Goldman, Peter Canoll, Allyson L Alexander, Kristen L Park, Gretchen K Von Allmen, Olga Rodziyevska, Meenakshi B Bhattacharjee, Hart G W Lidov, Hannes Vogel, Gerald A Grant, Brenda E Porter, Annapurna H Poduri, Peter B Crino, Erin L Heinzen

Faculty, Staff and Student Publications

Post-zygotically acquired genetic variants, or somatic variants, that arise during cortical development have emerged as important causes of focal epilepsies, particularly those due to malformations of cortical development. Pathogenic somatic variants have been identified in many genes within the PI3K-AKT-mTOR-signalling pathway in individuals with hemimegalencephaly and focal cortical dysplasia (type II), and more recently in SLC35A2 in individuals with focal cortical dysplasia (type I) or non-dysplastic epileptic cortex. Given the expanding role of somatic variants across different brain malformations, we sought to delineate the landscape of somatic variants in a large cohort of patients who underwent epilepsy surgery with hemimegalencephaly …

Disease Burden In Patients With Acute Hepatic Porphyria: Experience From The Phase 3 Envision Study, Bruce Wang, Paolo Ventura, Kei-Ichiro Takase, Manish Thapar, David Cassiman, Ilja Kubisch, Shangbin Liu, Marianne T Sweetser, Manisha Balwani

Division of Gastroenterology and Hepatology Faculty Papers

BACKGROUND: Acute hepatic porphyria (AHP) is a family of four rare genetic diseases, each involving deficiency in a hepatic heme biosynthetic enzyme. Resultant overproduction of the neurotoxic intermediates δ-aminolevulinic acid (ALA) and porphobilinogen (PBG) leads to disabling acute neurovisceral attacks and progressive neuropathy. We evaluated the AHP disease burden in patients aged ≥ 12 years in a post hoc analysis of the Phase 3, randomized, double-blind, placebo-controlled ENVISION trial of givosiran (NCT03338816), an RNA interference (RNAi) therapeutic that targets the enzyme ALAS1 to decrease ALA and PBG production. We analyzed baseline AHP severity via chronic symptoms between attacks, comorbidities, concomitant …

Chap-Child: An Open Source Method For Estimating Sit-To-Stand Transitions And Sedentary Bout Patterns From Hip Accelerometers Among Children., Jordan A. Carlson, Nicola D. Ridgers, Supun Nakandala, Rong Zablocki, Fatima Tuz-Zahra, John Bellettiere, Paul R Hibbing, Chelsea Steel, Marta M. Jankowska, Dori E. Rosenberg, Mikael Anne Greenwood-Hickman, Jingjing Zou, Andrea Z. Lacroix, Arun Kumar, Loki Natarajan

Manuscripts, Articles, Book Chapters and Other Papers

Background: Hip-worn accelerometer cut-points have poor validity for assessing children's sedentary time, which may partly explain the equivocal health associations shown in prior research. Improved processing/classification methods for these monitors would enrich the evidence base and inform the development of more effective public health guidelines. The present study aimed to develop and evaluate a novel computational method (CHAP-child) for classifying sedentary time from hip-worn accelerometer data.

Methods: Participants were 278, 8-11-year-olds recruited from nine primary schools in Melbourne, Australia with differing socioeconomic status. Participants concurrently wore a thigh-worn activPAL (ground truth) and hip-worn ActiGraph (test measure) during up to 4 …

Location-Specific Psychosocial And Environmental Correlates Of Physical Activity And Sedentary Time In Young Adolescents: Preliminary Evidence For Location-Specific Approaches From A Cross-Sectional Observational Study., Adrian Ortega, Carolina M Bejarano, Christopher C Cushing, Vincent S. Staggs, Amy Papa, Chelsea Steel, Robin P. Shook, Terry L. Conway, Brian E. Saelens, Karen Glanz, Kelli L. Cain, Lawrence D. Frank, Jacqueline Kerr, Jasper Schipperijn, James F. Sallis, Jordan A. Carlson

Manuscripts, Articles, Book Chapters and Other Papers

Background: A better understanding of the extent to which psychosocial and environmental correlates of physical activity are specific to locations would inform intervention optimization.

Purpose: To investigate cross-sectional associations of location-general and location-specific variables with physical activity and sedentary time in three common locations adolescents spend time.

Methods: Adolescents (N = 472,Mage = 14.1,SD = 1.5) wore an accelerometer and global positioning systems (GPS) tracker and self-reported on psychosocial (e.g., self-efficacy) and environmental (e.g., equipment) factors relevant to physical activity and sedentary time. We categorized each survey item based on whether it was specific to a location to generate psychosocial …

Understanding The Feelings And Experiences Of Patients With Periodontal Disease: A Qualitative Meta-Synthesis, Jun Yin, Yan Li, Mingyu Feng, Li Li

Faculty, Staff and Student Publications

BACKGROUND: Patients' experiences, feelings, and perceptions play key roles in quality of life and dental care quality, but they are poorly understood in periodontal disease. Therefore, this meta-synthesis aimed to gain deep insights into the feelings, experiences, and perceptions of people living with periodontal disease.

METHODS: Electronic database searches in PubMed, Cochrane Library, EMBASE, Scopus, Web of Science, PsycINFO, CINAHL, and Open AIRE were conducted up to December 2021 (updated in June 2022). The JBI Critical Appraisal Tool was used for quality assessment. Then reviewers integrated findings from qualitative studies with a thematic synthesis approach.

RESULTS: A total of 567 …

Rna Binding Protein Rbm46 Regulates Mitotic-To-Meiotic Transition In Spermatogenesis, Baomei Qian, Yang Li, Ruoyu Yan, Shenglin Han, Zhiwen Bu, Jie Gong, Bangjin Zheng, Zihan Yuan, Sen Ren, Qing He, Jinwen Zhang, Chen Xu, Ruilin Wang, Zheng Sun, Mingyan Lin, Jian Zhou, Lan Ye

Faculty, Staff and Students Publications

Meiosis entry during spermatogenesis requires reprogramming from mitotic to meiotic gene expression profiles. Transcriptional regulation has been extensively studied in meiosis entry, but gain of function for master transcription factors is insufficient to down-regulate mitotic genes. RNA helicase YTHDC2 and its partner MEIOC emerge as essential posttranscriptional regulators of meiotic entry. However, it is unclear what governs the RNA binding specificity of YTHDC2/MEIOC. Here, we identified RNA binding protein RBM46 as a component of the YTHDC2/MEIOC complex. Testis-specific Rbm46 knockout in mice causes infertility with defective mitotic-to-meiotic transition, phenocopying global Ythdc2 or Meioc knockout. RBM46 binds to 3′ UTR of …

Cancer-Driving Mutations Are Enriched In Genic Regions Intolerant To Germline Variation, Dimitrios Vitsios, Ryan S Dhindsa, Dorota Matelska, Jonathan Mitchell, Xuequing Zou, Joshua Armenia, Fengyuan Hu, Quanli Wang, Ben Sidders, Andrew R Harper, Slavé Petrovski

Duncan NRI Faculty and Staff Publications

Large reference datasets of protein-coding variation in human populations have allowed us to determine which genes and genic subregions are intolerant to germline genetic variation. There is also a growing number of genes implicated in severe Mendelian diseases that overlap with genes implicated in cancer. We hypothesized that cancer-driving mutations might be enriched in genic subregions that are depleted of germline variation relative to somatic variation. We introduce a new metric, OncMTR (oncology missense tolerance ratio), which uses 125,748 exomes in the Genome Aggregation Database (gnomAD) to identify these genic subregions. We demonstrate that OncMTR can significantly predict driver mutations …

Continuous Glucose Monitoring Metrics For Earlier Identification Of Pre-Diabetes: Protocol For A Systematic Review And Meta-Analysis, Sara Gottfried, Laura Pontiggia, Andrew B. Newberg, Gregory Laynor, Daniel A. Monti

Institute of Emerging Health Professions Faculty Papers

Introduction: Glycaemic variability and other metrics are not well characterised in subjects without diabetes. More comprehensive sampling as obtained with continuous glucose monitoring (CGM) may improve diagnostic accuracy of the transition from health to pre-diabetes. Our goal is to investigate the glycaemic system as it shifts from health to pre-disease in adult patients without diabetes using CGM metrics. New insights may offer therapeutic promise for reversing dysglycaemia more successfully with dietary, nutritional and lifestyle change before progression occurs to pre-diabetes and diabetes.

Methods and analysis: This systematic review will include comprehensive searches of the PubMed, Scopus, Cochrane Library and ClinicalTrials.gov …

Controlling Multiple Covid-19 Epidemic Waves: An Insight From A Multi-Scale Model Linking The Behaviour Change Dynamics To The Disease Transmission Dynamics, Biao Tang, Weike Zhou, Xia Wang, Hulin Wu, Yanni Xiao

Faculty, Staff and Student Publications

COVID-19 epidemics exhibited multiple waves regionally and globally since 2020. It is important to understand the insight and underlying mechanisms of the multiple waves of COVID-19 epidemics in order to design more efficient non-pharmaceutical interventions (NPIs) and vaccination strategies to prevent future waves. We propose a multi-scale model by linking the behaviour change dynamics to the disease transmission dynamics to investigate the effect of behaviour dynamics on COVID-19 epidemics using game theory. The proposed multi-scale models are calibrated and key parameters related to disease transmission dynamics and behavioural dynamics with/without vaccination are estimated based on COVID-19 epidemic data (daily reported …

The Pro-Fibrotic Response To Lens Injury Is Signaled In A Pi3k Isoform-Specific Manner, A. Sue Menko, Janice L. Walker

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The signaling inputs that function to integrate biochemical and mechanical cues from the extracellular environment to alter the wound-repair outcome to a fibrotic response remain poorly understood. Here, using a clinically relevant post-cataract surgery wound healing/fibrosis model, we investigated the role of Phosphoinositide-3-kinase (PI3K) class I isoforms as potential signaling integrators to promote the proliferation, emergence and persistence of collagen I-producing alpha smooth muscle actin (αSMA+) myofibroblasts that cause organ fibrosis. Using PI3K isoform specific small molecule inhibitors, our studies revealed a requisite role for PI3K p110α in signaling the CD44+ mesenchymal leader cell population that we previously identified as …

Modelling Neurological Diseases In Large Animals: Criteria For Model Selection And Clinical Assessment, Samantha L Eaton, Jonathan D Cooper, Et Al.

2020-Current year OA Pubs

No abstract provided.

The Microrna Processor Drosha Is A Candidate Gene For A Severe Progressive Neurological Disorder, Scott Barish, Mumine Senturk, Kelly Schoch, Amanda L Minogue, Diego Lopergolo, Chiara Fallerini, Jake Harland, Jacob H Seemann, Nicholas Stong, Peter G Kranz, Sujay Kansagra, Mohamad A Mikati, Joan Jasien, Mays El-Dairi, Paolo Galluzzi, Francesca Ariani, Alessandra Renieri, Francesca Mari, Michael F Wangler, Swathi Arur, Yong-Hui Jiang, Shinya Yamamoto, Vandana Shashi, Hugo J Bellen

Faculty, Staff and Students Publications

DROSHA encodes a ribonuclease that is a subunit of the Microprocessor complex and is involved in the first step of microRNA (miRNA) biogenesis. To date, DROSHA has not yet been associated with a Mendelian disease. Here, we describe two individuals with profound intellectual disability, epilepsy, white matter atrophy, microcephaly and dysmorphic features, who carry damaging de novo heterozygous variants in DROSHA. DROSHA is constrained for missense variants and moderately intolerant to loss-of-function (o/e = 0.24). The loss of the fruit fly ortholog drosha causes developmental arrest and death in third instar larvae, a severe reduction in brain size and loss …

Years Of Life Lost Associated With Covid-19 Deaths In The Usa During The First 2 Years Of The Pandemic, Troy Quast, Ross Andel, Sean Gregory, Eric A Storch

Center for Medical Ethics and Health Policy Staff Publications

Background: Prior estimates of the years of life lost (YLLs) in the USA associated with coronavirus disease 2019 (COVID-19) were 1.2 million through 11 July 2020 and 3.9 million through 31 January 2021 (which roughly coincides with the first full year of the pandemic). The aim of this study is to update YLL estimates through the first 2 years of the pandemic.

Methods: We employed data regarding COVID-19 deaths through 5 February 2022 by jurisdiction, gender and age group. We used actuarial life expectancy tables by gender and age to estimate YLLs.

Results: We estimated roughly 9.7 million YLLs due …

A Sparse Representation Strategy To Eliminate Pseudo-Hfo Events From Intracranial Eeg For Seizure Onset Zone Localization, Behrang Fazli Besheli, Zhiyi Sha, Jay R Gavvala, Candan Gurses, Sacit Karamursel, Michael M Quach, Daniel J Curry, Sameer A Sheth, David J Francis, Thomas R Henry, Nuri F Ince

Faculty, Staff and Student Publications

Objective.

High-frequency oscillations (HFOs) are considered a biomarker of the epileptogenic zone in intracranial EEG recordings. However, automated HFO detectors confound true oscillations with spurious events caused by the presence of artifacts.

Approach.

We hypothesized that, unlike pseudo-HFOs with sharp transients or arbitrary shapes, real HFOs have a signal characteristic that can be represented using a small number of oscillatory bases. Based on this hypothesis using a sparse representation framework, this study introduces a new classification approach to distinguish true HFOs from the pseudo-events that mislead seizure onset zone (SOZ) localization. Moreover, we further classified the HFOs into ripples and …

Heavy Metals In Breast Implant Capsules And Breast Tissue: Findings From The Systemic Symptoms In Women-Biospecimen Analysis Study: Part 2, Roger Wixtrom, Caroline Glicksman, Marshall Kadin, Marisa Lawrence, Melinda Haws, Sarah Ferenz, James Sung, Patricia Mcguire

2020-Current year OA Pubs

BACKGROUND: Breast Implant Illness (BII), as described in recent medical literature and by social media, describes a range of symptoms in patients with breast implants for which there are no physical findings or laboratory results that explain their symptoms.

OBJECTIVES: Part 2 of this study aims to determine whether heavy metals are present in the capsules around saline and silicone implants and if there are statistical differences in the type or level of these metals between women with or without symptoms. Demographic data was collected to investigate potential alternate sources of metals: inhaled, absorbed, or ingested.

METHODS: A prospective, blinded …

Grk3 Is A Poor Prognosticator And Serves As A Therapeutic Target In Advanced Gastric Adenocarcinoma, Yuan Li, Yibo Fan, Jinbang Xu, Longfei Huo, Ailing W Scott, Jiankang Jin, Boxuan Yang, Shan Shao, Lang Ma, Ying Wang, Xiaodan Yao, Melissa Pool Pizzi, Matheus Sewastjanow Da Silva, Guoliang Zhang, Lijuan Zhuo, Eun Jeong Cho, Kevin N Dalby, Namita D Shanbhag, Zhenning Wang, Wenliang Li, Shumei Song, Jaffer A Ajani

Faculty, Staff and Student Publications

Background: G protein-coupled receptor (GPCR) is the most targeted protein family by the FDA-approved drugs. GPCR-kinase 3 (GRK3) is critical for GPCR signaling. Our genomic analysis showed that GRK3 expression correlated with poor prognosis of gastric adenocarcinoma (GAC) patients. However, GRK3's functions and clinical utility in GAC progression and metastases are unknown.

Methods: We studied GRK3 expression in normal, primary, and metastatic GAC tissues. We identified a novel GRK3 inhibitor, LD2, through a chemical-library screen. Through genetic and pharmacologic modulations of GRK3, a series of functional and molecular studies were performed in vitro and in vivo. Impact of GRK3 on …

Perioperative Mental Health Intervention Bundle For Older Surgical Patients: Protocol For An Intervention Development And Feasibility Study, Joanna Abraham, Katherine J Holzer, Emily M Lenard, Kenneth E Freedland, Bethany R Tellor Pennington, Rachel C Wolfe, Theresa A Cordner, Ana A Baumann, Mary Politi, Michael Simon Avidan, Eric Lenze

2020-Current year OA Pubs

INTRODUCTION: The perioperative period is high risk for older adults. Depression and anxiety are common perioperative problems, frequently coexisting with cognitive impairment. Older patients with these conditions are more likely than younger patients to experience postoperative delirium, long hospital stays, poor quality of life and rehospitalisation. These experiences can, in turn, exacerbate anxiety and depressive symptoms. Despite these risks, little is known about how to treat perioperative anxiety and depression among older adults.

METHODS AND ANALYSIS: We designed a feasibility study of a perioperative mental health intervention bundle to improve perioperative mental health, specifically depression and anxiety. The overarching goals …

Genome-Wide Interaction Analysis Identified Low-Frequency Variants With Sex Disparity In Lung Cancer Risk, Yafang Li, Xiangjun Xiao, Jianrong Li, Jinyoung Byun, Chao Cheng, Yohan Bossé, James Mckay, Demetrios Albanes, Stephen Lam, Adonina Tardon, Chu Chen, Stig E Bojesen, Maria T Landi, Mattias Johansson, Angela Risch, Heike Bickeböller, H-Erich Wichmann, David C Christiani, Gad Rennert, Susanne Arnold, Gary Goodman, John K Field, Michael P A Davies, Sanjay S Shete, Loic Le Marchand, Olle Melander, Hans Brunnström, Geoffrey Liu, Rayjean J Hung, Angeline S Andrew, Lambertus A Kiemeney, Hongbing Shen, Ryan Sun, Shan Zienolddiny, Kjell Grankvist, Mikael Johansson, Neil Caporaso, Dawn M Teare, Yun-Chul Hong, Philip Lazarus, Matthew B Schabath, Melinda C Aldrich, Ann G Schwartz, Ivan Gorlov, Kristen Purrington, Ping Yang, Yanhong Liu, Younghun Han, Joan E Bailey-Wilson, Susan M Pinney, Diptasri Mandal, James C Willey, Colette Gaba, Paul Brennan, Christopher I Amos, Integral-Ilcco Lung Cancer Consortium

Faculty, Staff and Students Publications

Differences by sex in lung cancer incidence and mortality have been reported which cannot be fully explained by sex differences in smoking behavior, implying existence of genetic and molecular basis for sex disparity in lung cancer development. However, the information about sex dimorphism in lung cancer risk is quite limited despite the great success in lung cancer association studies. By adopting a stringent two-stage analysis strategy, we performed a genome-wide gene-sex interaction analysis using genotypes from a lung cancer cohort including ~ 47 000 individuals with European ancestry. Three low-frequency variants (minor allele frequency < 0.05), rs17662871 [odds ratio (OR) = 0.71, P = 4.29×10-8); rs79942605 (OR = 2.17, P = 2.81×10-8) and rs208908 (OR = 0.70, P = 4.54×10-8) were identified with different risk effect of lung cancer between men and women. Further expression quantitative trait loci and functional annotation analysis suggested rs208908 affects lung cancer risk through differential regulation of Coxsackie virus and adenovirus receptor gene expression in lung tissues between men and women. Our study is one of the first studies to provide novel insights about the genetic and molecular basis for sex disparity in lung cancer development.

Novel Dominant And Recessive Variants In Human Robo1 Cause Distinct Neurodevelopmental Defects Through Different Mechanisms, Yan Huang, Mengqi Ma, Xiao Mao, Davut Pehlivan, Oguz Kanca, Feride Un-Candan, Li Shu, Gulsen Akay, Tadahiro Mitani, Shenzhao Lu, Sukru Candan, Hua Wang, Bo Xiao, James R Lupski, Hugo J Bellen

Duncan NRI Faculty and Staff Publications

The Roundabout (Robo) receptors, located on growth cones of neurons, induce axon repulsion in response to the extracellular ligand Slit. The Robo family of proteins controls midline crossing of commissural neurons during development in flies. Mono- and bi-allelic variants in human ROBO1 (HGNC: 10249) have been associated with incomplete penetrance and variable expressivity for a breath of phenotypes, including neurodevelopmental defects such as strabismus, pituitary defects, intellectual impairment, as well as defects in heart and kidney. Here, we report two novel ROBO1 variants associated with very distinct phenotypes. A homozygous missense p.S1522L variant in three affected siblings with nystagmus; and …

Non-Linear Machine Learning Models Incorporating Snps And Prs Improve Polygenic Prediction In Diverse Human Populations, Michael Elgart, Genevieve Lyons, Santiago Romero-Brufau, Nuzulul Kurniansyah, Jennifer A Brody, Xiuqing Guo, Henry J Lin, Laura Raffield, Yan Gao, Han Chen, Paul De Vries, Donald M Lloyd-Jones, Leslie A Lange, Gina M Peloso, Myriam Fornage, Jerome I Rotter, Stephen S Rich, Alanna C Morrison, Bruce M Psaty, Daniel Levy, Susan Redline, Nhlbi’S Trans-Omics In Precision Medicine (Topmed) Consortium, Tamar Sofer

Faculty, Staff and Student Publications

Polygenic risk scores (PRS) are commonly used to quantify the inherited susceptibility for a trait, yet they fail to account for non-linear and interaction effects between single nucleotide polymorphisms (SNPs). We address this via a machine learning approach, validated in nine complex phenotypes in a multi-ancestry population. We use an ensemble method of SNP selection followed by gradient boosted trees (XGBoost) to allow for non-linearities and interaction effects. We compare our results to the standard, linear PRS model developed using PRSice, LDpred2, and lassosum2. Combining a PRS as a feature in an XGBoost model results in a relative increase in …

High-Resolution Imaging Of Protein Secretion At The Single-Cell Level Using Plasmon-Enhanced Fluorodot Assay, Anushree Seth, Ekansh Mittal, Jingyi Luan, Samhitha Kolla, Monty B Mazer, Hemant Joshi, Rohit Gupta, Priya Rathi, Zheyu Wang, Jeremiah J Morrissey, Joel D Ernst, Cynthia Portal-Celhay, Sharon Celeste Morley, Jennifer A Philips, Srikanth Singamaneni

2020-Current year OA Pubs

Secreted proteins mediate essential physiological processes. With conventional assays, it is challenging to map the spatial distribution of proteins secreted by single cells, to study cell-to-cell heterogeneity in secretion, or to detect proteins of low abundance or incipient secretion. Here, we introduce the "FluoroDOT assay," which uses an ultrabright nanoparticle plasmonic-fluor that enables high-resolution imaging of protein secretion. We find that plasmonic-fluors are 16,000-fold brighter, with nearly 30-fold higher signal-to-noise compared with conventional fluorescence labels. We demonstrate high-resolution imaging of different secreted cytokines in the single-plexed and spectrally multiplexed FluoroDOT assay that revealed cellular heterogeneity in secretion of multiple proteins …