Digital Commons Network^™

Serum Metabolites Associated With Depression And Anxiety In The Hispanic Community Health Study/Study Of Latinos, Xinye Qiu, Yu Zhang, Yogesh Purushotham, Qibin Qi, Bing Yu, Jan Bressler, Krista M Perreira, Humberto Parada, Martha L Daviglus, Alejandra Cid Vega, Carmen R Isasi, Linda C Gallo, Tamar Sofer

Faculty, Staff and Student Publications

Omics signatures for psychiatric conditions have been under-investigated. In this study, we used data from a representative observational cohort study of Hispanic/Latino adults to identify serum metabolites associated with symptoms of depression or anxiety and to develop and assess metabolite risk scores (MRSs) of these phenotypes. We conducted a metabolome-wide association study of 768 metabolites with depression and anxiety symptoms, using two separate assay batches measured from baseline samples collected between June 2008 and July 2011 for discovery (batch 1: n = 4002 adults) and replication (batch 2: n = 2178 adults). We estimated the associations via survey-based generalized linear …

Risk Of Alzheimer Dementia After High-Dose Vs Standard-Dose Influenza Vaccination, Avram Samuel Bukhbinder, Yaobin Ling, Lauren Jhin, Elizabeth He, Kristofer Harris, Mya Rodriguez, Jenna Thomas, Gabriela Cruz, Kamal Phelps, Yejin Kim, Luyao Chen, Xiaoqian Jiang, Paul E Schulz

Faculty, Staff and Student Publications

Background and objectives: Previous studies, including large cohort analyses comparing vaccinated and unvaccinated adults, suggest that routine immunizations such as inactivated influenza vaccines (IIVs) may reduce Alzheimer dementia (AD) risk. Whether AD risk differs after high-dose IIV (H-IIV) vs standard-dose IIV (S-IIV) remains unexamined. We hypothesized that AD risk would be lower among adults ≥65 years after H-IIV compared with S-IIV.

Methods: This retrospective cohort study analyzed data spanning 2014-2019 from IQVIA PharMetrics Plus for Academics, a US health care claims database. Eligible participants were ≥65 years with ≥2 years of continuous medical and pharmaceutical coverage and no previous diagnostic …

High Concordance Of Physician-Attestation With Manual Data Abstraction For Sickle Cell Type: An Ash Rc Data Hub Study, Alexis A Thompson, Ashima Singh, Donna S Neuberg, Amanda M Brandow, Allison A King, Sophie Lanzkron, Emily A Semmel, Sam Walters, Susan Rogers, Kathleen Torres, William A Wood

2020-Current year OA Pubs

Sickle cell disease (SCD) is the most common inherited blood disorder in the United States. The American Society of Hematology Research Collaborative (ASH RC) has built an SCD Data Hub (DH) to facilitate research and quality improvement using real-world data. To our knowledge, we report here the first analyses from the DH, focusing on cohort demographics and accurate identification of SCD diagnosis type. DH sites have data use agreements with ASH RC to extract and transfer electronic health record (EHR) data at least quarterly. Principal investigators (PI) provided additional attestation of SCD diagnosis based on existing local data sources deemed …

Familial Healthy Aging And Longevity: The Role Of Spouses, Søren Netra, Angéline Galvin, Matthew Keys, Katrine Lawaetz Kristensen, Jacob Krabbe Pedersen, Bharat Thyagarajan, Svetlana Ukraintseva, Mary K Wojczynski, Dorret I Boomsma, Kaare Christensen

2020-Current year OA Pubs

BACKGROUND: Families with exceptional longevity often experience delayed onset of age-related diseases and reduced mortality across generations-a pattern influenced by shared genetic and behavioral factors. While several studies have focused on the members of longevity-enriched families (LEF), little is known about the health trajectories of the spouses marrying into these families. Given prior evidence of substantially reduced mortality among spouses of LEF members, determining whether this advantage reflects selection, shared environments, or behavioral convergence is essential for understanding the mechanisms that underlie intergenerational health transmission.

METHODS: We conducted a multigenerational, retrospective matched cohort study using nationwide Danish civil and health …

A Novel Approach To Defining Progression In Mds And Precursor Myeloid Conditions In The Mds Natural History Study, Amy E Dezern, Matthew Walter, Et Al.

2020-Current year OA Pubs

Patients at risk for progression from myeloid precursor states (idiopathic cytopenia of undetermined significance [ICUS] and clonal cytopenia of undetermined significance [CCUS]) to myelodysplastic syndrome (MDS) are not well defined. Epidemiologic risk factors, clonal changes for MDS development, and evolution from one MDS state to another were available in the MDS Natural History Study (NHS), a prospective cohort enrolled at diverse US sites. Extensive clinical data and biospecimens were collected at baseline and follow-up. A total of 1177 (56%) individuals with MDS or MDS-related precursor conditions (ICUS/idiopathic dysplasia of undetermined significance [IDUS], CCUS, and MDS/myeloproliferative neoplasm overlap) were enrolled and …

How Survivors Of Exploitation Who Use Drugs Navigate Systems Of Care: An Analysis Of Survivor Insights Using The Intersectional Risk Environment, Theresa Anasti, Hilary Thibodeau, Nathaniel A Dell, Kathleen Preble, Lauren Grimes, Lindsay B Gezinski

2020-Current year OA Pubs

BACKGROUND: Drug-related risks such as adverse health outcomes, overdose, and violent victimization vary across populations due to the marginalization of identities, structural inequities, and differing environments. Discrimination and criminalization exacerbate drug-related risks specifically for survivors of sexual exploitation who use drugs. This study aims to understand how survivors who are not currently utilizing intensive treatment services perceive their risk environment, including available resources, and identify possible mechanisms to address health equity. Emphasizing the role of harm reduction and the expertise of lived experience, this paper encourages innovative approaches to supporting survivors.

METHODS: A research team conducted seventeen semi-structured interviews with …

Sex-Aware Genome-Wide Assessment Of De Novo Variants In Autism Across Coding And Noncoding Regions, Tychele N Turner

2020-Current year OA Pubs

BACKGROUND: Autism spectrum disorder (ASD) shows a consistent sex bias, yet how sex shapes de novo variant (DNV) risk across coding and noncoding sequence remains unclear. I analyzed DNVs in > 41,000 parent–child sequenced trios from three ASD family-based cohorts and compared DNV characteristics and enrichment patterns in males and females. Notably, these trios included individuals with ASD as well as those without ASD. I developed a new sex-aware DNV caller (HAT-FLEX) and thoroughly evaluated each candidate DNV using an additional tool introduced in this study, SNOW, to generate a high-confidence callset. RESULTS: I identified enrichment of missense and loss-of-function (LOF) …

Identifying Delays Impacting Maternal And Perinatal Deaths Using A Facility-Based Death Audit Review System Integrated With Community Engagement: A Mixed Methods Study, Zahid Memon, Wardah Ahmed, Shah Muhammad, Sajid Soofi, Shanti Chouhan, Arjumad Rizvi, Paul Barach, Zulfiqar A. Bhutta

College of Population Health Faculty Papers

BACKGROUND: Pakistan's persistently high maternal (178 per 100 000 livebirths) and neonatal (41 per 1000 livebirths) mortality ratios are compounded by lack of reliable data on the root causes and preventable risk factors, which hinders their effective use in improving care and progress toward safe, high-quality services. We sought to identify system delays impacting maternal and perinatal deaths using a facility-based death audit review system integrated with community engagement for implementing actionable solutions.

METHODS: We used a mixed methods, concurrent parallel study design at three secondary level healthcare facilities in District Matiari, Sindh, Pakistan. We reviewed 319 cases that included …

Pediatric Thyroid Cancer Lung Metastases And Rai: Long-Term Results, Ryan C Mueller, Nikhil Rammohan, Anthony J Apicelli, Ana Maria Arbelaez, Farrokh Dehdashti, Barry A Siegel, Vikas Prasad, Perry W Grigsby, Stephanie Markovina

2020-Current year OA Pubs

OBJECTIVES: Children with differentiated thyroid cancer (DTC) often present with lung metastases but historically have good outcomes. Radioactive iodine (RAI) is commonly used to treat these children. Given the rarity of this condition, little evidence detailing long-term outcomes and risk of radiation pneumonitis exists.

METHODS: We conducted a retrospective analysis of patients < 20 years old who received RAI for DTC lung metastases between 1973 and 2018. Disease-free survival (DFS) was calculated from diagnosis to last follow-up. Overall survival and rates of acute and late radiation pneumonitis were determined by chart review and obituary searches.

RESULTS: Sixteen patients met eligibility criteria. Fourteen presented with thyroid, nodal, and lung disease; one presented with thyroid and nodal disease with nodal and lung recurrence; and one presented with thyroid-only disease with nodal and lung recurrence. All patients underwent thyroidectomy, 10 underwent neck dissection, and four underwent …

Delivering Safe Sleep And Breastfeeding Education To Pregnant And New Mothers Through Private Facebook Groups: Study Protocol For A 4-Armed Randomized Controlled Trial, Rebecca F Carlin, Margaret G Parker, Ann L Kellams, Fern R Hauck, Stephen Kerr, Benjamin T Cornwell, Marc T Kiviniemi, Nicole Geller, Katherine E Boguszewski, Michael J Corwin, Eve R Colson, Rachel Y Moon

2020-Current year OA Pubs

BACKGROUND: Annually, more than 3500 US infants die suddenly and unexpectedly. Many sudden unexpected infant deaths (SUID) are preventable with greater adherence to safe infant sleep guidelines. There are racial and economic disparities in guideline adherence and SUID rates. Education alone has proven ineffective at altering behavior for many parents, and social networks and social norms regarding infant care have been found to influence rates of unsafe sleep. Using the power of social networks to shape social norms by delivering education through moderated online social media groups provides a unique opportunity to influence these practices in large groups of parents. …

Perceived Inadequate Neighborhood Food Shopping And Cardiovascular Disease Risk: The Multi-Ethnic Study Of Atherosclerosis, Amier Haidar, Ghadi Ghanem, Rishi Rikhi, Karol E Watson, Shreela V Sharma, Michael D Shapiro

Faculty, Staff and Student Publications

Background: Individuals with access to healthy food have healthier diets, improved cardiometabolic risk profiles, and decreased cardiovascular disease (CVD). However, previous studies have focused on the neighborhood food environment as distance to and density of food retailers. Our study examines the association between an individual's perceived adequacy of neighborhood food shopping and incident CVD.

Methods: We analyzed data from 6814 participants in the MESA (Multi-Ethnic Study of Atherosclerosis), a prospective cohort study of individuals aged 45 to 84 who were enrolled in the study between 2000 and 2002 and followed longitudinally. Cox proportional hazards models estimated hazard ratios (HRs) for …

Out-Of-Pocket Costs And Antihypertensive Medication Use Among Veterans: A Natural Experiment, Alexander R. Zheutlin, Alexander Chaitoff, Daniel Addo, Joshua A. Jacobs, Catherine G. Derington, Eric L. Stulberg, Peter A. Glynn, Bernardo Modenesi, Jordana B. Cohen, Adam P. Bress

Department of Neurology Faculty Papers

BACKGROUND: Blood pressure (BP) control remains suboptimal in the United States despite available low-cost antihypertensive medications. Even small out-of-pocket medication costs may contribute to adherence. We determined whether $0 versus >$0 out-of-pocket costs for antihypertensive medications is associated with differences in adherence, discontinuation, BP control, and cardiovascular outcomes.

METHODS: We included veterans with newly diagnosed hypertension who initiated antihypertensive medication in the Veterans Health Administration from 2004 to 2022. A fuzzy regression discontinuity design with 2-stage residual inclusion leveraged differences in medication copay policy at a 50% service-connected disability threshold (≥50% service-connected disability: $0 out-of-pocket cost versus < 50%: $8 monthly cost). Outcomes included 1-year medication nonadherence (proportion of days covered < 80%), 1-year medication discontinuation (no medication in the final 90 days of the study year), 1-year BP control (systolic BP/diastolic BP < 140/90 mm Hg and < 130/80 mm Hg) and cardiovascular disease events (myocardial infarction, coronary revascularization, peripheral artery disease, or stroke).

RESULTS: Among 417 …

Maternal Inflammation Alters Nuclear And Mitochondrial Dna Methylation Patterns In Neonatal Brain Monocytes, Andrew Ebenezer, Jonathan Hicks, Brooke Hollander, Alexander Hone, Mona Batish, Robert Akins, Adam Marsh, Elizabeth Wright-Jin

Department of Medicine Faculty Papers

Neonatal hypoxic ischemic encephalopathy (HIE) is a common birth complication that can cause death or lifelong disabling conditions like cerebral palsy, epilepsy, and autism. It is well established that maternal infection and inflammation are significant risk factors for HIE but reasons for this increase in neurological risk to the offspring remain unknown. Inflammation or infection are associated with epigenetic changes and may contribute to the increased risk of neurodevelopmental disability in exposed offspring. Here, we analyzed and compared DNA methylation patterns in brain monocytes isolated from control, maternal immune activation (MIA), and an inflammation sensitized HIE (IS-HIE) CF-1 mouse model …

Natural History Of 15 Patients With Autosomal Dominant Wfs1 Pathogenic Variants Associated With Sensorineural Hearing Loss And Optic Atrophy, Jessica P Roberts, Abby F Tang, Daniela Hernandez, Brianna Carman, Liam Oiknine, Cris Brown, Stacy Hurst, Yunshuo Tang, Fumihiko Urano

2020-Current year OA Pubs

OBJECTIVE: Autosomal dominant pathogenic variants in WFS1 cause a spectrum of disorders with phenotypic manifestations including low-frequency sensorineural hearing loss, optic nerve atrophy accompanied by low- to mid-frequency sensorineural hearing loss, non-syndromic diabetes mellitus, and early-onset cataracts. These conditions are generally milder than autosomal recessive Wolfram syndrome, except for Hattersley-Urano syndrome. Despite growing recognition of these disorders, data on clinical progression and long-term outcomes remain limited. This study aims to expand knowledge on disease severity and progression in autosomal dominant WFS1-related disorders. APPROACH: Clinical data were obtained from the Washington University International Registry and Clinical Study for Wolfram Syndrome and …

A Digital Diabetes Prevention Program For Hispanic Adolescents (Fit24+): Protocol For A Feasibility Randomized Controlled Trial, Erica G Soltero, Marbelly Partida, Sandra Mihail, Lizette Villanueva, Callie Lopez, Salma M Musaad, Teresia M O'Connor, Maria J Redondo, Matthew Buman, Debbe Thompson

Faculty, Staff and Students Publications

Background: Hispanic youth are disproportionately impacted by obesity and subsequent type 2 diabetes (T2D) yet remain underrepresented in diabetes prevention research. Digital health interventions hold promise for increasing the accessibility to and engagement in disease prevention programming, particularly among high-risk populations. However, there is a significant gap in the literature regarding digital T2D prevention programs for adolescents or Hispanic youth.

Objective: The objective of this article is to describe the protocol for examining the feasibility of a 12-week digital diabetes prevention program among Hispanic adolescents with obesity.

Methods: Participants (N=40; aged 12-16 years) will be randomized (1:1) to a 12-week …

Enhanced Dietary Monitoring Using Fecal Genomics For Childhood Malnutrition Interventions, Ammara Aqeel, Najeeha T Iqbal, Sanam Iram Soomro, Sheraz Ahmed, Teresa K Mcdonald, Olivia Osborne, Sharon Jiang, Nolan Ives, Kazi Ahsan, Fayaz Umrani, Michael J Barratt, Jeffrey I Gordon, Syed Asad Ali, Lawrence A David

2020-Current year OA Pubs

Ready-to-use therapeutic and supplementary foods (RUTF/RUSF) are a primary treatment for childhood malnutrition in Community Management of Acute Malnutrition (CMAM) programs. However, measuring intervention compliance is labor intensive and unreliable. We applied FoodSeq, a fecal genomic dietary assessment biomarker, in malnourished infants (3-15 months) from Matiari, Pakistan. FoodSeq identified a significant increase in the abundance of DNA from chickpea, a primary RUSF ingredient, during RUSF administration and captured region-specific complementary feeding practices, including age-inappropriate feeding practices such as wide-spread tea consumption. Our findings highlight the potential of dietary genomics as an empirical and scalable tool for compliance monitoring and dietary …

A Multidomain Peptide Hydrogel-Liposome Composite For Controlled Release Of A Cyclic Dinucleotide In Oral Cancer, Joseph W R Swain, Andrea H Molina, Gemalene M Sunga, Danielle Chew-Martinez, Neeraja Dharmaraj, Alejandra Cobos Perez, Arghadip Dey, Ephraim J Vázquez-Rosado, Simon Young, Jeffrey D Hartgerink

Faculty, Staff and Student Publications

While immunotherapy is a promising treatment strategy for cancer, the majority of head and neck squamous cell carcinoma (HNSCC) patients treated with single-agent immunotherapy do not respond. Therefore, researchers are investigating combination treatments with immunostimulatory molecules that can maximize anti-tumor responses. Cyclic dinucleotides (CDNs) are STING agonists that hold promise in combination approaches, but they require frequent intratumoral administration when used in both preclinical models of HNSCC and clinical trials. To reduce administration frequency, we have created a peptide hydrogel–liposome composite system, K2-Lip(CDN), for local and prolonged availability of CDN. We investigated the loading limits of cationic liposomes in both …

Etalanetug (E2814) In Dominantly Inherited Alzheimer's Disease: An Open-Label Phase 1b/2 Study To Assess Safety And Target Engagement In Participants With Mild To Moderate Cognitive Impairment, Erica Andreozzi, Kanta Horie, Nicolas R Barthélemy, Brian A Gordon, Shaney Flores, Tammie L S Benzinger, Eric Mcdade, Randall J Bateman, Et Al.

2020-Current year OA Pubs

INTRODUCTION: Etalanetug (E2814) is designed to delay the clinical progression of Alzheimer's disease (AD) by binding to the microtubule binding region (MTBR) of tau implicated in seeding and spreading of tau pathology. Dominantly inherited Alzheimer's disease (DIAD) is a rare form of the disease (<  1%), having similar changes in the tau distribution and pathology to sporadic AD. Herein, we report the safety, pharmacology and biomarker results of the etalanetug Study 103 in DIAD patients.

METHODS: Study 103 enrolled participants with mild-to-moderate cognitive impairment due to DIAD who received etalanetug intravenously every 4 weeks escalating from 750 mg, 1500 mg, 3000 mg, to 4500 mg. After ascending to 4500 mg, patients received 4500 mg for up to 108 weeks. Tau pathology biomarkers, ptau217 and MTBR-tau243 were measured in CSF. Additional …

Epigenome-Wide Association Study Of Blood Proteome In The Atherosclerosis Risk In Communities Study, Yang Li, Aditya Surapaneni, Zulema Rodriguez-Hernandez, Pascal Schlosser, Eugene P Rhee, Eric Boerwinkle, Bing Yu, Megan L Grove, Kelly V Ruggles, Josef Coresh, Morgan Grams

Faculty, Staff and Student Publications

Characterizing the relationship between DNA methylation and circulating proteins is critical to understanding the epigenetic regulation of the human plasma proteome. Here, we performed an epigenome-wide association study of 5,032 circulating proteins in 1,449 White and 315 Black participants from the Atherosclerosis Risk in Communities cohort. We identified 12,500 significant protein quantitative trait methylation (pQTM)-protein associations involving 1,647 proteins. Among 7,796 unique pQTMs, 14.7% were classified as cis-pQTMs, which were enriched for fundamental cellular processes, whereas trans-pQTMs were predominantly linked to immune-related functions. Trans-pQTMs also exhibited stronger associations with demographic, lifestyle, and clinical traits as compared with cis-pQTMs. We identified …

An Innovative Curriculum To Empower Trainees And Faculty To Address Patient-Initiated Identity-Based Misconduct In The Clinical Learning Environment, Nkanyezi Ferguson, Lauren E. Hock, Patrick Barlow, Aisha S. Jamison, Marcy E. Rosenbaum, Nicole Del Castillo

Department of Medicine Faculty Papers

Introduction: Training residents and attending physicians on effective communication strategies to manage biased patient and visitor comments is lacking. The I-RESPOND toolkit curriculum provides strategies for addressing identity-based misconduct in the clinical setting. Methods: Resident physicians and faculty in 12 departments at a single academic center participated in the workshop between June 2021 and February 2022. The workshop consisted of interactive didactics, an introduction to the I-RESPOND toolkit, and opportunities to practice communication strategies with formative feedback. Retrospective pre/postworkshop survey instruments and a follow-up survey were used to evaluate the workshop and subsequent experiences. Results: Sixty-six (32%) of 204 participants …

Cerebellar Oligodendrocytic Α-Synuclein Pathology And Dentate Nucleus Neuronal Hypertrophy In Parkinson’S Disease, Diego Iacono, Hui Peng, John Paul Bouffard, Roger Kurlan

Department of Neurology Faculty Papers

Idiopathic Parkinson's disease (iPD) research has historically prioritized basal ganglia dysfunction and neuronal Lewy body pathology, often overlooking cerebellar and non-neuronal cells contributions. This study investigates cerebellar neuropathology in iPD, specifically focusing on neuronal and non-neuronal cells of the dentate nucleus (DN) and its adjacent white matter (DN-WM). We systematically assessed autopsy-confirmed iPD brains vs. age-matched controls using immunohistochemistry and stereology-based morphometry methods. The study evaluated α-synuclein pathology, other common age-related co-occurring pathologies (β-amyloid, Tau, neuroinflammation), myelin integrity (Luxol-Fast-Blue), and neuronal volumetric changes in the DN of the cerebellum. In iPD brains, we identified intracytoplasmic α-synuclein inclusions within oligodendrocytes across …

Trajectories Of Plasma And Csf Mtbr-Tau243 And Phosphorylated-Tau Species Across The Alzheimer's Disease Continuum, Lyduine E Collij, Gemma Salvadó, Kanta Horie, Nicolas R Barthélemy, Tobey J Betthauser, Olof Strandberg, Ruben Smith, Sebastian Palmqvist, Suzanne E Schindler, Rik Ossenkoppele, Shorena Janelidze, Niklas Mattsson-Carlgren, Randall J Bateman, Oskar Hansson

2020-Current year OA Pubs

To efficiently implement plasma and cerebrospinal fluid (CSF) biomarkers for staging and prognosis of Alzheimer disease (AD), we must understand their dynamics across disease progression. We analyzed participants from the Swedish BioFINDER-2 study with mass spectrometry measurements of plasma and CSF tau species, including eMTBR-tau243/MTBR-tau243 and phosphorylation occupancies (%p-tau). Disease duration was estimated using Aβ-PET and tau-PET with the SILA algorithm. Bootstrapped LOESS models showed that %p-tau217 changes earliest, increasing just before Aβ-PET positivity. Other p-tau species changed later, with smaller dynamic ranges and earlier ceiling effects. %p-tau205 and MTBR-tau243 changes aligned with tau-PET positivity onset, while MTBR-tau243-especially plasma eMTBR-tau243-tracked …

High-Throughput Multiplex Detection Of Respiratory Pathogens: Multicenter Evaluation Of The Nxtag Respiratory Pathogen Panel V2 Assay., Marisa C. Nielsen, Ping Ren, Sri Bharathi Kavuri, Karissa Culbreath, Rangaraj Selvarangan, Dithi Banerjee, Blake W. Buchan, Rachel Behounek, Janet Farhang

Manuscripts, Articles, Book Chapters and Other Papers

Respiratory tract infections remain a major cause of global morbidity, highlighting the need for rapid and accurate diagnostic testing. This multicenter study evaluated the clinical and analytical performance of the updated NxTAG Respiratory Pathogen Panel v2 (RPPv2), a high-throughput multiplex molecular assay designed to detect 21 viral and bacterial respiratory pathogens. A total of 2,145 nasopharyngeal swab specimens, including both prospectively enrolled and archived specimens, were analyzed across five U.S. clinical sites. The NxTAG RPPv2 was assessed against FDA-cleared molecular assays and bi-directional sequencing, with contrived specimens used to supplement low-prevalence targets. Valid results were obtained for 99.7% of specimens …

Multi-Trait Polygenic Scores For Copd And Copd Exacerbations Implicate Druggable Proteins, Chengyue Zhang, Iain R Konigsberg, Yixuan He, Jingzhou Zhang, Tinashe Chikowore, William B Feldman, Xiaowei Hu, Yi Ding, Bogdan Pasaniuc, Diana Chang, Qingwen Chen, Jessica A Lasky-Su, Julian Hecker, Martin D Tobin, Jing Chen, Sean Kalra, Katherine A Pratte, Hae Kyung Im, Emily S Wan, Ani Manichaikul, Edwin K Silverman, Russell P Bowler, Leslie A Lange, Victor E Ortega, Alicia R Martin, Michael H Cho, Matthew R Moll

Faculty, Staff and Student Publications

BACKGROUND

We constructed multi-trait polygenic risk scores (PRSs) predicting chronic obstructive pulmonary disease (COPD) and exacerbations, validated their performance in diverse cohorts, and identified PRS-related proteins for potential therapeutic targeting.

METHODS

PRSmix+, a multi-trait PRS framework, is used to train a composite PRS (PRSmulti) in COPDGene non-Hispanic White participants (n = 6,647). Associations of PRSmulti with COPD status (GOLD 2–4 vs. GOLD 0 or ICD) and exacerbation frequency were tested in COPDGene African American (n = 2,466), ECLIPSE (n = 1,858), Mass General Brigham Biobank (n = 15,152), and All of Us (n = 118,566). …

The Effects Of Orexin Receptor Antagonism During Early Withdrawal In Stimulant Use Disorder: Protocol For A Proof-Of-Concept Study, Heather Webber, Nikky Tran, Rita Blake, Sarah Goldman, Trevor George, Bill Bailey, Robert Suchting, Jin Yoon, Jessica Vincent, Michael Weaver, Joy Schmitz, Scott Lane

Faculty, Staff and Student Publications

Background: Stimulant use disorders (StimUDs), including cocaine and methamphetamine use disorders, remain a major public health concern in the United States with no US Food and Drug Administration (FDA)-approved pharmacological treatments. The early recovery period following stimulant use is marked by sleep disturbances, heightened stress reactivity, and dysregulated reward processing, contributing to high rates of resumption of use. Evidence from animal and human studies supports the orexin neuropeptide system as a promising therapeutic target for minimizing these disruptive mechanisms. Suvorexant, an FDA-approved dual orexin receptor antagonist for insomnia, has previously been shown to improve sleep, reduce stress, and attenuate craving …

Contraception In The Ed: Understanding Education And Opportunities For Clinicians To Advise Patients, Hannah B. Lewis, Teagan R. Mccarthy, Dara Kass, Jennifer L. Kahoud

Department of Emergency Medicine Faculty Papers

Introduction: The United States faces a high rate of unwanted pregnancies. Despite this, many people continue to face barriers to accessing contraception. The emergency department (ED) can help bridge these gaps, but emergency clinicians must first feel comfortable offering contraceptive services. In this study, we sought to determine emergency clinician comfort in prescribing contraceptives and educating patients on their use. We also gauged clinician interest in receiving education specifically geared toward contraceptive care.

Methods: We conducted an online survey of ED residents, attendings, and advanced practice clinicians at Thomas Jefferson Univerity Hospital and affiliates in both the urban and suburban …

Versatile Smad2 And Smad3 Epitope-Tagged Mouse Models For Genomic Profiling Of Tgfβ Signaling: Uncovering Gdf9-Smad2/3 Targets, Zian Liao, Qian Zhang, Keisuke Shimada, Kaori Nozawa, Suni Tang, Masahito Ikawa, Diana Monsivais, Martin M Matzuk

Faculty, Staff and Students Publications

Transforming growth factor β (TGFβ) signaling pathways are integral for a plethora of biological processes. SMAD2 and SMAD3 are the principal transcriptional effectors of TGFβ superfamily ligands, yet quantitative, genome-wide mapping of their DNA-associated complexes under physiological contexts has remained limited due to the lack of specific, robust models. Here, we generated two versatile epitope-tagged mouse models in which endogenous SMAD2 and SMAD3 proteins are globally tagged with hemagglutinin (HA) and podoplanin (PA) sequences, respectively, enabling high-fidelity profiling of SMAD2 and SMAD3 binding across tissues. To demonstrate the broad application of our models, we exemplified the usage of our lines …

Relative Impact Of Multidomain Lifestyle Interventions On Deficit Accumulation Frailty Over 24 Months In The U.S. Pointer Trial, Mark A Espeland, Kayloni Olson, Christy C Tangney, Darren R Gitelman, Maryjo Cleveland, Amber A Thro, Yitbarek N Demesie, Heather M Snyder, Rachel A Whitmer, Pankaja Desai, Rifat Alam, Lucia Crivelli, Thomas M Holland, Olivia Preissle, Rema Raman, Michele K York, Laura D Baker

Faculty, Staff and Students Publications

Background: Multidomain lifestyle interventions hold promise as approaches to slow aging. Deficit accumulation frailty indices (FIs) are increasingly used to capture aging processes. Frailty is highly associated with increased mortality and chronic disease risk, but the degree to which multidomain lifestyle changes impact frailty is not clear.

Methods: The U.S. Study to Protect Brain Health through Lifestyle Intervention to Reduce Risk (U.S. POINTER) was a 2-year randomized clinical trial to compare two multidomain lifestyle interventions designed to increase exercise, improve diet, and promote social and cognitive stimulating activities and health monitoring. The Structured intervention incorporated greater structure, intensity, and accountability …

Reference Proteins To Improve Core 1 And Core 2 Alzheimer's Disease Csf And Plasma Biomarkers, Linda Karlsson, Nicolas R Barthélemy, Kanta Horie, Suzanne E Schindler, Brian A Gordon, Cyrus A Raji, Tammie L S Benzinger, John C Morris, Randall J Bateman, Et Al.

2020-Current year OA Pubs

Concentration-based fluid biomarkers represent an informative and cost-effective way to detect and monitor Alzheimer's disease (AD) pathology. However, non-AD-related interindividual variation in biofluids can also affect biomarker concentrations. Here, we investigated whether normalization of CSF and plasma biomarkers to reference proteins, such as amyloid-β40 (Aβ40) and non-phosphorylated mid-region tau (np-tau), improves their robustness and reliability of representing AD pathology load. Using the Swedish BioFINDER-2 cohort [n = 1702, 50.7% male, mean (standard deviation) age 68.4 (12.2) years], we compared the associations between tau/Aβ-PET load and fluid biomarkers alone versus biomarkers in a ratio with a reference protein (Aβ40 or np-tau) …

Ex Vivo Effect Of Apixaban On Hemostatic Biomarkers In Children With Heart Disease: A Saxophone Trial Substudy, Ghada A Aborkhees, Amy J Barr, Kevin Dietrich, Christoph Male, Zhaoqing Wang, Chen Yao, R Mark Payne, Andrew C Glatz, Paul Monagle, Kristin M Burns, Alison M Reedy, Joshua L Dyme, Peter H Schafer, Antoinette Ajavon-Hartmann, Lesley G Mitchell

2020-Current year OA Pubs

BACKGROUND: The SAXOPHONE (Safety of Apixaban on Pediatric Heart Disease on the Prevention of Embolism) trial demonstrated the safety of apixaban for thromboprophylaxis in children with heart disease. Included a priori in the trial design was an exploratory biomarker substudy to evaluate the effects of apixaban on surrogate biomarkers of efficacy, thrombin generation capacity, and hemostatic proteins. The study assessed changes in d-dimer, thrombin generation assay parameters, factor VIII, fibrinogen, protein C, and protein S in children receiving apixaban compared with standard-of-care vitamin K antagonists (VKAs) or low-molecular-weight heparin.

METHODS: SAXOPHONE participants aged >1 year (n=182) had blood samples for …