Digital Commons Network^™

Distress Related To Psychotic Experiences: Enhancing The World Health Organization Composite International Diagnostic Interview Psychosis Screen, Hans Oh, Nicole R Karcher, Nirit Soffer-Dudek, Ai Koyanagi, Megan Besecker, Jordan E Devylder

2020-Current year OA Pubs

BACKGROUND: The abbreviated version of the World Health Organization (WHO) Composite International Diagnostic Interview (CIDI) psychosis screen tends to yield high prevalence in online samples. Psychotic Experiences (PE) may not necessarily indicate current or imminent psychopathology; however, distressing PE appear to be more clinically informative.

METHODS: We analyzed data collected from an online survey administered to a Qualtrics panel (N = 2522 adults). Using multivariable logistic regression, we examined the association between PE (with and without associated distress) and several mental health outcomes, adjusting for age, gender, and race/ethnicity.

RESULTS: Individuals with distressing PE had greater odds of most mental …

The Evolution Of Primary Care Telehealth Disparities During Covid-19: Retrospective Cohort Study, Rachel D'Amico, Patrick M Schnell, Randi Foraker, J Nwando Olayiwola, Daniel E Jonas, Seuli Bose Brill

2020-Current year OA Pubs

BACKGROUND: Telehealth has become widely used as a novel way to provide outpatient care during the COVID-19 pandemic, but data about telehealth use in primary care remain limited. Studies in other specialties raise concerns that telehealth may be widening existing health care disparities, requiring further scrutiny of trends in telehealth use.

OBJECTIVE: Our study aims to further characterize sociodemographic differences in primary care via telehealth compared to in-person office visits before and during the COVID-19 pandemic and determine if these disparities changed throughout 2020.

METHODS: We conducted a retrospective cohort study in a large US academic center with 46 primary …

Choroid Plexus-Targeted Nkcc1 Overexpression To Treat Post-Hemorrhagic Hydrocephalus, Cameron Sadegh, Yong Zhang, Michael J Holtzman, Et Al.

2020-Current year OA Pubs

Post-hemorrhagic hydrocephalus (PHH) refers to a life-threatening accumulation of cerebrospinal fluid (CSF) that occurs following intraventricular hemorrhage (IVH). An incomplete understanding of this variably progressive condition has hampered the development of new therapies beyond serial neurosurgical interventions. Here, we show a key role for the bidirectional Na-K-Cl cotransporter, NKCC1, in the choroid plexus (ChP) to mitigate PHH. Mimicking IVH with intraventricular blood led to increased CSF [K

Genome-Wide Association Study Of Breast Density Among Women Of African Ancestry, Shefali Setia Verma, Lindsay Guare, Sarah Ehsan, Aimilia Gastounioti, Gabrielle Scales, Marylyn D Ritchie, Despina Kontos, Anne Marie Mccarthy, Penn Medicine Biobank

2020-Current year OA Pubs

Breast density, the amount of fibroglandular versus fatty tissue in the breast, is a strong breast cancer risk factor. Understanding genetic factors associated with breast density may help in clarifying mechanisms by which breast density increases cancer risk. To date, 50 genetic loci have been associated with breast density, however, these studies were performed among predominantly European ancestry populations. We utilized a cohort of women aged 40-85 years who underwent screening mammography and had genetic information available from the Penn Medicine BioBank to conduct a Genome-Wide Association Study (GWAS) of breast density among 1323 women of African ancestry. For each …

A Single-Cell Multiomic Analysis Of Kidney Organoid Differentiation, Yasuhiro Yoshimura, Yoshiharu Muto, Nicolas Ledru, Haojia Wu, Kohei Omachi, Jeffrey H Miner, Benjamin D Humphreys

2020-Current year OA Pubs

Kidney organoids differentiated from pluripotent stem cells are powerful models of kidney development and disease but are characterized by cell immaturity and off-target cell fates. Comparing the cell-specific gene regulatory landscape during organoid differentiation with human adult kidney can serve to benchmark progress in differentiation at the epigenome and transcriptome level for individual organoid cell types. Using single-cell multiome and histone modification analysis, we report more broadly open chromatin in organoid cell types compared to the human adult kidney. We infer enhancer dynamics by cis-coaccessibility analysis and validate an enhancer driving transcription of

Circadian Clock Protein Bmal1 Broadly Influences Autophagy And Endolysosomal Function In Astrocytes, Celia A Mckee, Alexander J Polino, Melvin W King, Erik S Musiek

2020-Current year OA Pubs

An emerging role for the circadian clock in autophagy and lysosome function has opened new avenues for exploration in the field of neurodegeneration. The daily rhythms of circadian clock proteins may coordinate gene expression programs involved not only in daily rhythms but in many cellular processes. In the brain, astrocytes are critical for sensing and responding to extracellular cues to support neurons. The core clock protein BMAL1 serves as the primary positive circadian transcriptional regulator and its depletion in astrocytes not only disrupts circadian function but also leads to a unique cell-autonomous activation phenotype. We report here that astrocyte-specific deletion …

How Does Facilitation In Healthcare Work? Using Mechanism Mapping To Illuminate The Black Box Of A Meta-Implementation Strategy, Amy M Kilbourne, Elvin Geng, Ingrid Eshun-Wilson, Shannon Sweeney, Donna Shelley, Deborah J Cohen, Joann E Kirchner, Maria E Fernandez, Michael L Parchman

2020-Current year OA Pubs

BACKGROUND: Healthcare facilitation, an implementation strategy designed to improve the uptake of effective clinical innovations in routine practice, has produced promising yet mixed results in randomized implementation trials and has not been fully researched across different contexts.

OBJECTIVE: Using mechanism mapping, which applies directed acyclic graphs that decompose an effect of interest into hypothesized causal steps and mechanisms, we propose a more concrete description of how healthcare facilitation works to inform its further study as a meta-implementation strategy.

METHODS: Using a modified Delphi consensus process, co-authors developed the mechanistic map based on a three-step process. First, they developed an initial …

Biomechanical Models And Mechanisms Of Cellular Morphogenesis And Cerebral Cortical Expansion And Folding, David C Van Essen

2020-Current year OA Pubs

Morphogenesis of the nervous system involves a highly complex spatio-temporal pattern of physical forces (mainly tension and pressure) acting on cells and tissues that are pliable but have an intricately organized cytoskeletal infrastructure. This review begins by covering basic principles of biomechanics and the core cytoskeletal toolkit used to regulate the shapes of cells and tissues during embryogenesis and neural development. It illustrates how the principle of 'tensegrity' provides a useful conceptual framework for understanding how cells dynamically respond to forces that are generated internally or applied externally. The latter part of the review builds on this foundation in considering …

Modulating Fast Skeletal Muscle Contraction Protects Skeletal Muscle In Animal Models Of Duchenne Muscular Dystrophy, Alan J. Russell, Twlya I. Juehne, Jinsheng Yu, Et Al.

2020-Current year OA Pubs

Duchenne muscular dystrophy (DMD) is a lethal muscle disease caused by absence of the protein dystrophin, which acts as a structural link between the basal lamina and contractile machinery to stabilize muscle membranes in response to mechanical stress. In DMD, mechanical stress leads to exaggerated membrane injury and fiber breakdown, with fast fibers being the most susceptible to damage. A major contributor to this injury is muscle contraction, controlled by the motor protein myosin. However, how muscle contraction and fast muscle fiber damage contribute to the pathophysiology of DMD has not been well characterized. We explored the role of fast …

Strategies To Bridge Equitable Implementation Of Telehealth, Allison M Gustavson, Allison A Lewinski, Ellen E Fitzsimmons-Craft, Gloria D Coronado, Sarah E Linke, Denalee M O'Malley, Alyce S Adams, Russell E Glasgow, Lisa M Klesges

2020-Current year OA Pubs

During the COVID-19 pandemic, the rapid scaling of telehealth limited the extent to which proactive planning for equitable implementation was possible. The deployment of telehealth will persist in the postpandemic era, given patient preferences, advances in technologies, growing acceptance of telehealth, and the potential to overcome barriers to serve populations with limited access to high-quality in-person care. However, aspects and unintended consequences of telehealth may leave some groups underserved or unserved, and corrective implementation plans that address equitable access will be needed. The purposes of this paper are to (1) describe equitable implementation in telehealth and (2) integrate an equity …

Safety And Efficacy Of Axicabtagene Ciloleucel Versus Standard Of Care In Patients 65 Years Of Age Or Older With Relapsed/Refractory Large B-Cell Lymphoma, Jason R Westin, Armin Ghobadi, Et Al.

2020-Current year OA Pubs

PURPOSE: Older patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) may be considered ineligible for curative-intent therapy including high-dose chemotherapy with autologous stem-cell transplantation (HDT-ASCT). Here, we report outcomes of a preplanned subgroup analysis of patients ≥65 years in ZUMA-7.

PATIENTS AND METHODS: Patients with LBCL refractory to or relapsed ≤12 months after first-line chemoimmunotherapy were randomized 1:1 to axicabtagene ciloleucel [axi-cel; autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy] or standard of care (SOC; 2-3 cycles of chemoimmunotherapy followed by HDT-ASCT). The primary endpoint was event-free survival (EFS). Secondary endpoints included safety and patient-reported outcomes (PROs).

RESULTS: Fifty-one and …

Single-Nucleus Multi-Omics Of Human Stem Cell-Derived Islets Identifies Deficiencies In Lineage Specification, Punn Augsornworawat, Nathaniel J Hogrebe, Matthew Ishahak, Mason D Schmidt, Erica Marquez, Marlie M Maestas, Daniel A Veronese-Paniagua, Sarah E Gale, Julia R Miller, Leonardo Velazco-Cruz, Jeffrey R Millman

2020-Current year OA Pubs

Insulin-producing β cells created from human pluripotent stem cells have potential as a therapy for insulin-dependent diabetes, but human pluripotent stem cell-derived islets (SC-islets) still differ from their in vivo counterparts. To better understand the state of cell types within SC-islets and identify lineage specification deficiencies, we used single-nucleus multi-omic sequencing to analyse chromatin accessibility and transcriptional profiles of SC-islets and primary human islets. Here we provide an analysis that enabled the derivation of gene lists and activity for identifying each SC-islet cell type compared with primary islets. Within SC-islets, we found that the difference between β cells and awry …

Cortical Atrophy And Leukoaraiosis, Imaging Markers Of Cerebrovascular Small Vessel Disease, Are Associated With Driving Behavior Changes Among Cognitively Normal Older Adults, Ganesh M Babulal, Ling Chen, David B Carr, Ann M Johnson, Joshua S Shimony, Jason Doherty, Samantha Murphy, Alexis Walker, Hailee Domash, Russ Hornbeck, Sarah Keefe, Shaney Flores, Cyrus A Raji, John C Morris, Beau M Ances, Tammie L S Benzinger

2020-Current year OA Pubs

BACKGROUND: Cerebral small vessel disease (CSVD) as measured by cortical atrophy and white matter hyperintensities [leukoaraiosis], captured via magnetic resonance imaging (MRI) are increasing in prevalence due to the growth of the aging population and an increase in cardiovascular risk factors in the population. CSVD impacts cognitive function and mobility, but it is unclear if it affects complex, functional activities like driving.

METHODS: In a cohort of 163 cognitively normal, community-dwelling older adults (age ≥ 65), we compared naturalistic driving behavior with mild/moderate leukoaraiosis, cortical atrophy, or their combined rating in a clinical composite termed, aging-related changes to those without …

The Influence Of The Built Environment On The Community Participation Of Adults Aging With Long-Term Physical Disabilities: A Mixed Methods Approach, Rachel H. Desai

WUSM Theses and Dissertations – All Programs

Adults living with a long-term physical disability experience difficulties living independently and participating in the community as they age. A combination of personal (e.g., fatigue) and environmental (e.g., transportation accessibility) factors influence these restrictions in participation. The impact of the built environment is a key aspect to consider when understanding community participation restrictions for adults aging with long-term physical disabilities (AAwPD) because these factors are often more modifiable. However, the processes by which the built environment impacts AAwPD are not well understood. Interventions targeting these factors to address the community participation needs of AAwPD are limited.

Research informing community-based organizations …

Effect Of Obesity And Insulin Resistance On Glucose And Fatty Acid Metabolism, Chao Cao

WUSM Theses and Dissertations – All Programs

In people with obesity, insulin resistance of glucose and fatty acid metabolism is common and it is thought that insulin resistance of fatty acid metabolism is involved in causing insulin resistance of glucose metabolism and subsequently hyperglycemia through a mechanism referred to as “lipotoxicity”. However, in many individuals with obesity and insulin resistance fasting plasma glucose and free fatty acid (FFA) concentrations are not elevated. It is widely believed that pancreatic beta-cells detect the need to increase insulin secretion in order to compensate for the impaired insulin action caused by insulin resistance in these people, whereas beta-cell dysfunction results in …

Developing Tools For The Implementation And Evaluation Of Participatory Worker Health Promotion Interventions, Ryan J. Walsh

WUSM Theses and Dissertations – All Programs

The chronic disease burden among American workers leads to substantial expenditures on healthcare, lost productivity at work, and reduced quality of life. Workers from communities of lower socioeconomic status (SES) shoulder a disproportionate burden of chronic diseases and costs. A promising strategy for addressing this population health burden is to develop and implement participatory worker health promotion interventions in workplaces. Part of this effort to develop and implement these programs entails improving the quality of evaluation tools and approaches. Thus, we completed a series of secondary analyses of a large participatory worker health promotion program trial called Working For You. …

Goal Setting And Goal Management For Chronic Conditions: Intervention And Implementation Strategies, Eunyoung Kang

WUSM Theses and Dissertations – All Programs

Adults with chronic conditions experience limited participation in personally meaningful activities and roles. Chronic conditions can present challenges across personal factors such as cognitive, psychological, physiological, or neurobehavioral functions. These personal factors then dynamically interact with environmental factors, occupation, and performance, ultimately hindering adults with chronic conditions in achieving their goals to fully participate in meaningful activities and roles.

Goal setting and goal management has evolved from diverse theories including Social Cognitive Theory, Self-Determination Theory, and The Theory of Intentional Action Control. These theories emphasize the importance of addressing influential theoretical constructs such as self-efficacy and outcome expectancy but also …

Self-Regulation Processes Of Depressive Symptoms And Participation In Persons With Stroke Using Heart Rate Variability As A Real-Time Biomarker, Yejin Lee

WUSM Theses and Dissertations – All Programs

Depressive symptoms are a key risk factor for restrictions in participation in daily activities in persons with stroke. Thus, many researchers have attempted to develop interventions for relieving depressive symptoms after stroke, however, post-stroke depressive symptoms are still undertreated. To develop evidence-based approaches for reducing depressive symptoms, and thereby ultimately enhancing participation in daily activities, it is important to understand what moderates the associations between depressive symptoms and participation in daily activities in persons with stroke to employ the moderator as an intervention target.

One possible mechanism to moderate such associations is self-regulation – cognitive, behavioral, and emotion regulation. Self-regulation …

Role Of Midkine In Cancer Drug Resistance: Regulators Of Its Expression And Its Molecular Targeting, Minakshi Saikia, Nathan Cheung, Abhay Kumar Singh, Vaishali Kapoor

2020-Current year OA Pubs

Molecules involved in drug resistance can be targeted for better therapeutic efficacies. Research on midkine (MDK) has escalated in the last few decades, which affirms a positive correlation between disease progression and MDK expression in most cancers and indicates its association with multi-drug resistance in cancer. MDK, a secretory cytokine found in blood, can be exploited as a potent biomarker for the non-invasive detection of drug resistance expressed in various cancers and, thereby, can be targeted. We summarize the current information on the involvement of MDK in drug resistance, and transcriptional regulators of its expression and highlight its potential as …

Trem2 Inhibition Triggers Antitumor Cell Activity Of Myeloid Cells In Glioblastoma, Rui Sun, Rowland Han, Colin Mccornack, Saad Khan, G Travis Tabor, Yun Chen, Jinchao Hou, Haowu Jiang, Kathleen M Schoch, Diane D Mao, Ryan Cleary, Alicia Yang, Qin Liu, Jingqin Luo, Allegra Petti, Timothy M Miller, Jason D Ulrich, David M Holtzman, Albert H Kim

2020-Current year OA Pubs

Triggering receptor expressed on myeloid cells 2 (TREM2) plays important roles in brain microglial function in neurodegenerative diseases, but the role of TREM2 in the GBM TME has not been examined. Here, we found that TREM2 is highly expressed in myeloid subsets, including macrophages and microglia in human and mouse GBM tumors and that high TREM2 expression correlates with poor prognosis in patients with GBM. TREM2 loss of function in human macrophages and mouse myeloid cells increased interferon-γ-induced immunoactivation, proinflammatory polarization, and tumoricidal capacity. In orthotopic mouse GBM models, mice with chronic and acute Trem2 loss of function exhibited decreased …

Effects Of A Virtual Voice-Based Coach Delivering Problem-Solving Treatment On Emotional Distress And Brain Function: A Pilot Rct In Depression And Anxiety, Thomas Kannampallil, Et Al.

2020-Current year OA Pubs

Consumer-based voice assistants have the ability to deliver evidence-based treatment, but their therapeutic potential is largely unknown. In a pilot trial of a virtual voice-based coach, Lumen, delivering problem-solving treatment, adults with mild-to-moderate depression and/or anxiety were randomized to the Lumen intervention (n = 42) or waitlist control (n = 21). The main outcomes included changes in neural measures of emotional reactivity and cognitive control, and Hospital Anxiety and Depression Scale [HADS] symptom scores over 16 weeks. Participants were 37.8 years (SD = 12.4), 68% women, 25% Black, 24% Latino, and 11% Asian. Activation of the right dlPFC (neural region …

A Phase 1b Randomized Clinical Trial Of Ct1812 To Measure Aβ Oligomer Displacement In Alzheimer's Disease Using An Indwelling Csf Catheter, Kelsie M Labarbera, Carla M Yuede, Hannah M Edwards, Woodrow D Gardiner, John R Cirrito, Et Al.

2020-Current year OA Pubs

No abstract provided.

Two Forms Of Asynchronous Release With Distinctive Spatiotemporal Dynamics In Central Synapses, Gerardo Malagon, Jongyun Myeong, Vitaly A Klyachko

2020-Current year OA Pubs

Asynchronous release is a ubiquitous form of neurotransmitter release that persists for tens to hundreds of milliseconds after an action potential. How asynchronous release is organized and regulated at the synaptic active zone (AZ) remains debatable. Using nanoscale-precision imaging of individual release events in rat hippocampal synapses, we observed two spatially distinct subpopulations of asynchronous events, ~75% of which occurred inside the AZ and with a bias towards the AZ center, while ~25% occurred outside of the functionally defined AZ, that is, ectopically. The two asynchronous event subpopulations also differed from each other in temporal properties, with ectopic events occurring …

Co-Clinical Imaging Metadata Information (Cimi) For Cancer Research To Promote Open Science, Standardization, And Reproducibility In Preclinical Imaging, Stephen M Moore, James D Quirk, Andrew W Lassiter, Richard Laforest, Kooresh I Shoghi, Et Al.

2020-Current year OA Pubs

Preclinical imaging is a critical component in translational research with significant complexities in workflow and site differences in deployment. Importantly, the National Cancer Institute's (NCI) precision medicine initiative emphasizes the use of translational co-clinical oncology models to address the biological and molecular bases of cancer prevention and treatment. The use of oncology models, such as patient-derived tumor xenografts (PDX) and genetically engineered mouse models (GEMMs), has ushered in an era of co-clinical trials by which preclinical studies can inform clinical trials and protocols, thus bridging the translational divide in cancer research. Similarly, preclinical imaging fills a translational gap as an …

Five-Year Follow-Up Of Zuma-1 Supports The Curative Potential Of Axicabtagene Ciloleucel In Refractory Large B-Cell Lymphoma, Sattva S Neelapu, Armin Ghobadi, Nancy L Bartlett, Et Al.

2020-Current year OA Pubs

In phase 2 of ZUMA-1, a single-arm, multicenter, registrational trial, axicabtagene ciloleucel (axi-cel) autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy demonstrated durable responses at 2 years in patients with refractory large B-cell lymphoma (LBCL). Here, we assessed outcomes in ZUMA-1 after 5 years of follow-up. Eligible adults received lymphodepleting chemotherapy followed by axi-cel (2 × 106 cells per kg). Investigator-assessed response, survival, safety, and pharmacokinetics were assessed in patients who had received treatment. The objective response rate in these 101 patients was 83% (58% complete response rate); with a median follow-up of 63.1 months, responses were ongoing in 31% …

Protocol For A Scoping Review Of Health Equity Frameworks And Models Applied In Empirical Studies Of Chronic Disease Prevention And Control, Callie Walsh-Bailey, Amanda Gilbert, Thembekile Shato, Brittney Sandler, Ana A Baumann, Cory D Bradley, Gabriella M Mcloughlin, F Hunter Mcguire, Meredith P Fort, Rachel G Tabak

2020-Current year OA Pubs

BACKGROUND: Chronic diseases, such as cancers and cardiovascular diseases, present the greatest burden of morbidity and mortality worldwide. This burden disproportionately affects historically marginalized populations. Health equity is rapidly gaining increased attention in public health, health services, and implementation research, though many health inequities persist. Health equity frameworks and models (FM) have been called upon to guide equity-focused chronic disease and implementation research. However, there is no clear synthesis of the health equity FM used in chronic disease research or how these are applied in empirical studies. This scoping review seeks to fill this gap by identifying and characterizing health …

Data Envelopment Analysis To Evaluate The Efficiency Of Tobacco Treatment Programs In The Nci Moonshot Cancer Center Cessation Initiative, Kathryn Pluta, Li-Shiun Chen, Et Al.

2020-Current year OA Pubs

BACKGROUND: The Cancer Center Cessation Initiative (C3I) is a National Cancer Institute (NCI) Cancer Moonshot Program that supports NCI-designated cancer centers developing tobacco treatment programs for oncology patients who smoke. C3I-funded centers implement evidence-based programs that offer various smoking cessation treatment components (e.g., counseling, Quitline referrals, access to medications). While evaluation of implementation outcomes in C3I is guided by evaluation of reach and effectiveness (via RE-AIM), little is known about technical efficiency-i.e., how inputs (e.g., program costs, staff time) influence implementation outcomes (e.g., reach, effectiveness). This study demonstrates the application of data envelopment analysis (DEA) as an implementation science tool …

Bronchoscopic Evaluation Of A Steerable Needle For Simulated Tumor Targets In The Lung Periphery: A Feasibility Study (Bullseye), Alexander C. Chen, Michael Machuzak, George Cheng, Momen M. Wahidi

2020-Current year OA Pubs

BACKGROUND: Peripheral bronchoscopy is often performed to biopsy peripheral pulmonary lesions. Despite technological advancements to improve reach and access to the lung periphery, the diagnostic yield of peripheral bronchoscopy has been inconsistent, and challenging, particularly for lesions that are adjacent to peripheral bronchi. Current biopsy instruments are reliant on the catheter or scope to align properly with targeted lesions.

OBJECTIVES: This study evaluates the feasibility of using a steerable biopsy needle to gain access to peripheral tumor targets in a cadaveric model.

METHODS: Simulated tumor targets 10-30 mm in axial diameter were placed into human cadavers. Bronchoscopy was performed using …

Diagnosis And Treatment Of Fungal Infections In Lung Transplant Recipients, Jesus E Escamilla, Spenser E January, Rodrigo Vazquez Guillamet

2020-Current year OA Pubs

Fungal infections are a significant source of morbidity in the lung transplant population via direct allograft damage and predisposing patients to the development of chronic lung allograft dysfunction. Prompt diagnosis and treatment are imperative to limit allograft damage. This review article discusses incidence, risk factors, and symptoms with a specific focus on diagnostic and treatment strategies in the lung transplant population for fungal infections caused by

Dynamic Frailty Risk Assessment Among Older Adults With Multiple Myeloma: A Population-Based Cohort Study, Hira Mian, Tanya M Wildes, Ravi Vij, Matthew J Pianko, Ajay Major, Mark A Fiala

2020-Current year OA Pubs

Multiple myeloma (MM) is a cancer of older adults and those who are more frail are at high risk of poor outcomes. Current tools for identifying and categorizing frail patients are often static and measured only at the time of diagnosis. The concept of dynamic frailty (i.e. frailty changing over time) is largely unexplored in MM. In our study, adults with newly-diagnosed MM who received novel drugs between the years 2007-2014 were identified in the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked databases. Using a previously published cumulative deficit approach, a frailty index score was calculated at diagnosis and each …