Digital Commons Network^™

Emerging Options And Future Strategies In Immunotherapy For Advanced Lung Squamous-Cell Carcinoma, Y Wang, R Rosell, F R Hirsch, S Lu, R Govindan, K Park, S Peters, J J Zhang

2020-Current year OA Pubs

Advanced-stage lung squamous-cell carcinoma (LUSC) remains a therapeutic challenge. Although immune checkpoint inhibitors (ICIs) have revolutionized LUSC treatment, only a small subset of LUSC patients can achieve durable clinical benefits, underscoring the need for novel strategies. Emerging immunotherapy strategies have demonstrated early evidence of promise for LUSC patients, particularly multi-specific antibodies and fusion proteins, antibody-drug conjugates, adoptive cell therapies, and cancer vaccines. Additionally, advances in multi-omics and artificial intelligence offer potential for precise immunotherapy by deciphering the complex tumor-immune microenvironment and predicting therapeutic responses. The future of LUSC treatment lies in rational multi-target and biological therapies to boost immune cytotoxicity, …

Finding Significant Hits In Networks: A Network-Based Tool For Analyzing Gene-Level P-Values To Identify Significant Genes Missed By Standard Methods, Sandeep Acharya, Vaha Akbary Moghaddam, Wooseok J Jung, Yu S Kang, Shu Liao, Michael A Province, Michael R Brent

2020-Current year OA Pubs

Finding Significant Hits in Networks (FISHNET) uses prior biological knowledge, represented as gene interaction networks and gene function annotations, to identify genes that do not meet the genome-wide significance threshold but replicate, nonetheless. Its input is gene-level P-values from any source, including omicsWAS, aggregation of genome-wide association studies P-values, CRISPR screens, or differential expression analysis. It is based on the idea that genes whose P-values are low purely by chance are distributed randomly across networks and functions, so genes with suggestive P-values that cluster in densely connected subnetworks and share common functions are less likely to reflect chance and more …

Bach2 Regulates T Cell Lineage State To Enhance Car T Cell Function, Tien-Ching Chang, Amanda Heard, John Lattin, John M Warrington, Amanda Barrett, Jack H Landmann, Yangdon Tenzin, Vishaal Ganesh, Bryant Thompson, Sadia Afrin, Deepesh Kumar Gupta, Ju-Fang Chang, Julie Ritchey, Mehmet Emrah Selli, Yu-Sung Hsu, A J Federico, Avery Horn, Michael P Meers, John F Dipersio, Nathan Singh, Et Al.

2020-Current year OA Pubs

Nearly all chimeric antigen receptors (CARs) signal in the absence of antigen, referred to as 'tonic signaling'. Tonic signaling of CARs containing 41BB domains enhances T cell fitness and function, in contrast to the exhaustion driven by CD28-containing CARs. Here we show that 41BB induces BACH2, a transcriptional regulator that directs stem and memory programs. Overexpression of BACH2 successfully prevented exhaustion but locked CAR T cells in a quiescent state. We linked BACH2 to a degradation domain to tune BACH2, enabling us to prevent exhaustion while enabling potent effector function that broadly enhanced the long-term efficacy of CAR T cells …

Cdk4/6 Inhibition Mitigates Chemotherapy-Induced Expansion Of Tp53-Mutant Clonal Hematopoiesis, Irenaeus C C Chan, Giulia Petrone, J Scott Beeler, Duc Tran, Griffen Mustion, Catrina Fronick, Carlos Cruchaga, Kelly L Bolton, Et Al.

2020-Current year OA Pubs

Therapy-related myeloid neoplasm (tMN) is a fatal consequence of exposure to cytotoxic therapy administered in the treatment of cancer. Individuals with pre-existing TP53 clonal hematopoiesis (CH) are at high risk of tMN, with avoidance of therapy being the only strategy to reduce tMN risk. Here, in four randomized clinical trials, we show that the CDK4/6 inhibitor trilaciclib, given in conjunction with a variety of chemotherapeutic regimens and across diverse populations of patients with cancer, mitigates chemotherapy-related expansion of CH clones with mutations in DNA damage response genes, including TP53. This finding was also observed in a syngeneic mouse model of …

Durability Of Efficacy, Safety, And Quality Of Life 5 Years After Valoctocogene Roxaparvovec Gene Transfer For Severe Hemophilia A: Final Phase 3 Gener8-1 Trial Results, Andrew D Leavitt, Elaine Majerus, Et Al.

2020-Current year OA Pubs

BACKGROUND: Valoctocogene roxaparvovec, a gene therapy for severe hemophilia A, enables endogenous factor VIII (FVIII) expression and confers bleed control.

OBJECTIVES: To present the final 5-year efficacy and safety results from the phase 3 GENEr8-1 trial.

METHODS: Adult men (

RESULTS: Median follow-up was 261.1 weeks; 128 of 134 participants completed the study. For the 112 participants who enrolled from a previous noninterventional study (rollover population), mean ABR for treated bleeds declined by 83.3% (

CONCLUSION: Valoctocogene roxaparvovec provides durable hemostatic efficacy, FVIII activity, and improved health-related quality of life for ≥5 years, with no new safety signals.

Signal Peptidase Complex Mediates Rotavirus Vp7 Processing And Virion Assembly, Xuejiao Zhu, Enkai Li, Liliana Sanchez-Tacuba, Wandy Beatty, Bin Li, Siyuan Ding

2020-Current year OA Pubs

For viruses that replicate in the proximity of or bud at the endoplasmic reticulum (ER) associated membranes, proper processing of their glycoproteins is critical for successful infection. Rotavirus outer capsid protein VP7 is an ER-resident protein. However, its N-terminal signal peptide is removed by an unknown proteolytic mechanism. In this study, we leveraged tandem affinity purification followed by high-resolution mass spectrometry to profile host proteins that interact with VP7. We identified members of the signal peptidase complex (SPC) family as important host factors that facilitate rotavirus infection. CRISPR knockout or siRNA knockdown of distinct SPC subunits resulted in significant decrease …

Improving Vaccination In People With Ckd: Report From A National Kidney Foundation Working Group, Susan F. Massengill, Kenneth A. Andreoni, Keith A. Bellovich, Cheryl Courtlandt, Vimal K. Derebail, David L. Feldman, Gia J. Oh, John W. Sleasman, Kristina A. Bryant, Improving Vaccination In Ckd Working Group

Department of Surgery Faculty Papers

People with chronic kidney disease (CKD) are particularly vulnerable to vaccine-preventable infections. Therefore, the National Kidney Foundation organized a multidisciplinary working group, including people with CKD and family care partners, to develop recommendations to improve vaccination rates, vaccination effectiveness, and health care for the CKD population. A modified Delphi process was used to achieve consensus on the recommendations. Recommendations on vaccination in CKD patients were organized into these categories: (1) patient preferences; (2) assessing the vaccination status of patients with CKD; (3) assessing vaccine response in patients with CKD; (4) vaccination of immunocompromised patients; (5) vaccination in posttransplant patients; (6) …

Apoe And Plasma Ad Biomarkers: The Role Of Genetic Ancestry In Hispanics/Latinos, Caitlin Cheung, Natasha Z Anita, Paola Filigrana, Myriam Fornage, Kevin A Gonzalez, Linda C Gallo, Carmen R Isasi, Robert C Kaplan, Xihao Li, Freddie Márquez, Humberto Parada, Krista M Perreira, Alberto R Ramos, Tatjana Rundek, Wassim Tarraf, Fernando D Testai, Charles Decarli, Hector M González, Tamar Sofer

Faculty, Staff and Student Publications

Background: Apolipoprotein E (APOE) alleles are well-established genetic risk factors for Alzheimer's disease (AD), but their effects on AD biomarkers (amyloid beta [Aβ]42/40, phosphorylated tau [p-tau]181, neurofilament light chain [NfL], and glial fibrillary acidic protein [GFAP]) may vary across populations due to ancestry-, age-, and sex-related differences. We hypothesized that these effects vary across Hispanic/Latino background groups with distinct ancestral admixture.

Methods: We analyzed ε2 and ε4 allele associations with AD biomarkers using survey-weighted linear regression models, adjusting for demographic covariates. Secondary analyses examined genetic analysis group- and ancestry-specific effects.

Results: ε4 was associated with lower Aβ42/40 and higher p-tau181and …

The Role Of Top-Down Appetite Self-Regulation In The Development Of Healthy Eating Behaviors Among Children: A Narrative Review And Socialization Framework, David J Bridgett, Sheryl O Hughes, Matthew Broussard, Daniela Mccourt, Christina M Croce, Jennifer O Fisher

Children’s Nutrition Research Center Staff Publications

Appetite self-regulation (ASR) among children is thought to have a fundamental role in shaping the development of healthy eating behaviors, dietary intake, and growth during childhood. Parallel to developmental frameworks for understanding "general" self-regulation among children, ASR has been described as involving children's use of "top-down" cognitive processes to moderate "bottom-up" biological drives around food approach and avoidance in the interest of achieving desired eating behaviors or outcomes. Whereas bottom-up ASR processes during early childhood are well characterized, particularly in the context of dysregulation and obesity risk, the role of top-down ASR processes in the development of healthy eating behaviors …

Perceptions And Use Of Behaviour Change Interventions For Physical Activity In Chronic Respiratory Disease In The Republic Of Ireland, Ciara Hanrahan, Joseph G Mcveigh, Terence M O'Connor, Thierry Troosters, Julie Broderick

Children’s Nutrition Research Center Staff Publications

Objectives: Behaviour change interventions may support physical activity behaviour in people with chronic respiratory disease. The most effective interventions for long-term physical activity behaviour change in this cohort remains unclear. This aim of this study was to explore the use and perceptions of behaviour change interventions by both providers of physical activity programmes for people with chronic respiratory disease and by people living with chronic obstructive pulmonary disease (COPD) in The Republic of Ireland.

Design: Two anonymous online and paper-copy cross-sectional surveys, piloted and mapped to the COM-B model of behaviour change, were distributed via social media and relevant gate-keepers …

Pre- And Postnatal Exposure To Pm2.5 And No2 And Blood Pressure In Children: Results From The Echo Cohort, Yu Ni, Andrew Law, Xingyu Gao, Adam A Szpiro, Christine T Loftus, Miranda Jones, Logan C Dearborn, Marnie F Hazlehurst, Allison R Sherris, Sindana Ilango, Kaja Z Lewinn, Nicole R Bush, Qi Zhao, Leonardo Trasande, Joseph T Flynn, Daniel A Enquobahrie, Ruby H N Nguyen, Tom O'Connor, Arpita K Vyas, Mingyu Zhang, Hooman Mirzakhani, Alison Hipwell, Anne Starling, Alicia K Peterson, Akhgar Ghassabian, Assiamira Ferrara, Judy Aschner, Scott Collingwood, Margaret R Karagas, Michelle Katzow, Annemarie Stroustrup, Mehtap Haktnair, Tina V Hartert, Brittney M Snyder, Sophia Jan, Anne Marie Singh, Dana Dabelea, Angela M Malek, Jennifer K Straughen, Carlos A Camargo, Miatta A Buxton, Rosalind Wright, Kecia Carroll, Keia Sanderson, Daphne Koinis Mitchell, Viren D'Sa, Christine Hockett, Anne L Dunlop, Shohreh F Farzen, Sunni L Mumford, Akram N Alshawabkeh, Hudson P Santos, Xueying Zhang, Zhongzheng Niu, Nan Ji, Carrie Breton, Donghai Liang, Catherine J Karr, Echo Cohort Consortium

Children’s Nutrition Research Center Staff Publications

Background: There is growing interest in understanding the link between early life exposures to ambient air pollution and childhood blood pressure; however, existing findings, largely from single site/cohort studies, are inconclusive.

Methods: We examined the association between exposures to fine particulate matter (PM2.5) and nitrogen dioxide (NO2) and blood pressure measured at age 5-12 years in 4863 U.S. children from 20 pregnancy cohorts of the NIH ECHO cohort. Point-based residential exposures were derived from spatiotemporal models with a biweekly resolution and averaged over each trimester, the whole pregnancy, and child age 0-2 years. We converted systolic (SBP) and diastolic blood …

Comparison Of Variant Callers Using 60 532 Multi-Ancestry Whole Genome Sequences, Hufeng Zhou, Nathan O Stitziel, Et Al.

2020-Current year OA Pubs

Whole genome sequencing (WGS) studies play a pivotal role in studying the genetic underpinnings of human diseases and traits. High quality and reproducible variant calling is the cornerstone for the success of downstream analyses, including WGS association studies and polygenic risk prediction. This paper compares the data quality, performance, and concordance of two widely used WGS variant callers, the Genome Analysis Toolkit (GATK) and Variant Tool set that discovers short variants (VT), using 60 532 multi-ancestry whole genomes sequenced by the Centers for Common Disease Genomics (CCDGs) of the NHGRI Genome Sequencing Program. Our findings show that both QCed GATK …

Increased Clinical Frailty Is Associated With Aortic-Related Mortality Following Fenestrated And Branched Endovascular Repair For Thoracoabdominal Aortic Aneurysm, Silvia Chen, Elizabeth Ramirez, Blake E Murphy, Anjali Sribalaskandarajah, Martin Bunker, Joel Kruger, Karina A Newhall, Rebecca A Sorber, Sara L Zettervall, Matthew P Sweet

2020-Current year OA Pubs

OBJECTIVE: Clinical frailty is associated with reduced long-term survival after fenestrated and branched endovascular aortic repair (F/BEVAR). This study assesses the impact of phenotypic clinical frailty on perioperative outcomes and cause of death following F/BEVAR for thoracoabdominal aortic aneurysm.

METHODS: Patients who underwent F/BEVAR at a single institution from 2012 to 2024 were identified. The clinical frailty scale (CFS) was used to determine phenotypic frailty. Patients with a preoperative CFS of ≥4 (vulnerable) and a CFS of < 4 were compared. We used χ

RESULTS: We included 233 patients; 60 (25.8%) had a CFS of ≥4 and 173 (74.2%) had a CFS of < 4. Patients with a CFS of ≥4 were more likely to have chronic obstructive pulmonary disease (53% vs 27%) and were treated for slightly larger aneurysms (72 mm vs 68 mm; P = .04). There were no differences in symptomatic presentation, aneurysm extent, or operative complexity between patient groups. Additionally, there were no differences in perioperative complications including 30-day mortality, stroke, and spinal cord ischemia. Patients with a CFS of ≥4 had an increased length of hospitalization (11.3 days vs 6.9 days; P < .01) and were less likely to return to preoperative functional status (62.7% vs 86.1%; P < .01). The 3-year all-cause and aortic-related mortality rates were 35.2% and 5.7%, respectively. Patients with a CFS of ≥4 had a lower survival at 1 year (74% vs 89%), 3 years (39% vs 73%), and 5 years (25% vs 56%), compared with patients with a CFS of < 4 (P < .01). The most common causes of death among both groups were pulmonary comorbidities (14.0%), oncologic conditions (14.0%), cardiovascular comorbidities (11.2%), and procedure-related complications (11.2%). Patients with a CFS of ≥4 were more likely to die from aortic-related mortality (10.3% vs 5.9%; P = .02), pulmonary comorbidities (15.4 vs 13.2%; P = .04), systemic decline (7.7% vs 1.5%; P = .02), and infection (12.8% vs 7.4%; P = .03). Aortic-related mortality for the entire patient cohort was 2.2% and 5.7% at 1 year and 3 years, respectively. Aortic-related deaths among clinically frail patients were often due to an inability to tolerate further aortic operations (eg, arch repair), and secondary to follow-up nonadherence in patients with a CFS of < 4.

CONCLUSIONS: In an expanded …

Parkinson's Disease As A Somato-Cognitive Action Network Disorder, Jianxun Ren, Evan M Gordon, Nico U F Dosenbach, Et Al.

2020-Current year OA Pubs

Parkinson's disease (PD) is an incurable neurological disorder that often begins insidiously with sleep disturbances and somatic symptoms, progressing to whole-body motor and cognitive symptoms

A Quantitative Cell-Based Reporter Links Tdp-43 Aggregation And Dysfunction To Define Pathogenic Mechanisms, Lohany Diax Mamede, Miwei Hu, Jaime Vaquer-Alicea, Amanda R. Titus, Patricia M. Passos, Erica Lantelme, Rachel L French, Paige A. Kirschner, Marc I. Diamond, Timothy M. Miller, Yuna M. Ayala

2020-Current year OA Pubs

TDP-43 pathology is a hallmark of fatal neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and limbic-predominant age-related TDP-43-encephalopathy (LATE). In affected patients, cytoplasmic TDP-43 aggregates are accompanied by disruption of its normal nuclear localization and function. Because TDP-43 is an RNA binding protein that controls transcript processing, including repression of cryptic exon splicing, its loss leads to dysregulation of gene expression. Despite its central significance in disease, the connection between TDP-43 aggregation and dysfunction remains poorly understood, and models to study the underlying mechanisms are limited. Here, we characterize a robust and quantitative cell-based reporter that captures …

Brief Report: Long-Acting Injectable Prep Can Substantially Reduce Hiv Incidence In Los Angeles County: A Simulation Study, Aditya Khanna, Francis Lee, Katrina Schrode, Daniel Sheeler, Anna Hotton, John Schneider, Kayo Fujimoto, Siri Chirumamilla, Ekow Kwa Sey, Nina T Harawa

Faculty, Staff and Student Publications

Background: Although oral pre-exposure prophylaxis (PrEP) has been instrumental in decreasing HIV incidence, its daily dosing regimen poses adherence challenges. Using an agent-based network model informed by empirical data, we simulate the impact of introducing long-acting injectable (LAI) PrEP among young Black men who have sex with men (YBMSM) in Los Angeles County, a group disproportionately affected by HIV.

Setting: Computer simulations using an agent-based network model.

Methods: We modeled HIV transmission among YBMSM over 10 years under scenarios varying the proportion of PrEP users opting for LAI instead of oral medications and adherence levels to LAI retention. The model …

Preferences For Game-Based Elements To Increase Preexposure Prophylaxis And Hiv Prevention Engagement Among Latino Men Who Have Sex With Men: South Florida, 2022, Lacey Despres, Edda Rodriguez, Ross Shegog, Stephanie Diez, Susanne Doblecki-Lewis, Kayo Fujimoto, Suzanne Randolph Cunningham, Mariano Kanamori

Faculty, Staff and Student Publications

We explored gaming elements as a tool to promote engagement in HIV prevention services among Latino men who have sex with men. We conducted thematic content analysis of semistructured interview data that we collected from 12 Latino men who have sex with men (April-August 2022) in South Florida. Themes emerged related to intervention delivery, components, and perceptions. Our findings will guide the development of a game-based intervention to improve preexposure prophylaxis and HIV prevention engagement among Latino men who have sex with men.

Associations Of Moderate-To-Vigorous Physical Activity Timing With Type 2 Diabetes Incidence In Uk Biobank And Prevalent Glycemic Measures In Nhanes, Qiuyu Feng, Gali Albalak, Linjun Ao, Qian Xiao, Heming Wang, Jeroen H P M Van Der Velde, Jessica C Kiefte-De Jong, Martin K Rutter, Charles E Matthews, Joshua R Freeman, Ko Willems Van Dijk, Diana Van Heemst, Raymond Noordam

Faculty, Staff and Student Publications

Objective: We assessed the association between timing of moderate-to-vigorous physical activity (MVPA) with incident type 2 diabetes (T2D) and glycemic measures.

Research design and methods: Regression models were used to assess associations between accelerometer-derived MVPA timing and incident T2D in UK Biobank (UKB) (n = 84,528, prospective), prevalent diabetes, and glycemic measures in the National Health and Nutrition Examination Survey (NHANES) (n = 6,998, cross-sectional).

Results: In UKB, with early morning (0500-0959) MVPA as reference and before adjustment for total MVPA, "variable-timing" MVPA was associated with the lowest incident T2D risk; while after adjustment, afternoon-evening MVPA (1500-2400) showed the lowest …

Hyperpolypharmacy And Readmission Risk Among Medicare Beneficiaries: The Role Of Postdischarge Care, Maria Ukhanova, Linda D Highfield, Trudy M Krause, Gayla M Ferguson, Robert O Morgan

Faculty, Staff and Student Publications

Objectives: Medication reconciliation post discharge may reduce readmission risk in populations with multimorbidity and polypharmacy. We aimed to evaluate the association between hyperpolypharmacy and 30-day readmissions; determine the impact of postdischarge care on 30-day readmissions; and identify interactions among hyperpolypharmacy, postdischarge care, and 30-day readmissions in 2 Medicare populations: individuals 65 years and older and individuals of any age with a qualifying disability.

Study design: Retrospective observational study using the 5% national sample Medicare fee-for-service claims data from 2016 to 2019.

Methods: We used descriptive statistics and generalized estimating equation models adjusted for covariates to assess the relationships among hyperpolypharmacy, …

Intraoperative Blood Pressure Management In Noncardiac Surgery: A Narrative Review Based On Current Evidence, Alexandre Joosten, Michelle S Chew, Emmanuel Futier, Anatole Harrois, Matthias Jacquet-Lagreze, Matthieu Legrand, Antonio Messina, Paul S Myles, Bernd Saugel, Daniel I Sessler, Denise P Veelo, Jean-Luc Fellahi

Faculty, Staff and Student Publications

Purpose: Blood pressure is closely monitored during anaesthesia, yet the optimal intraoperative target remains uncertain. This narrative review synthesizes contemporary observational and randomized evidence and explores emerging strategies for individualized haemodynamic management.

Methods: We reviewed major observational cohort studies, randomized controlled trials (RCTs), consensus statements, and recent technological developments addressing intraoperative hypotension, MAP thresholds, and strategies to prevent perioperative organ injury in adult noncardiac surgery.

Results: Large observational datasets consistently demonstrate graded, duration-dependent associations between intraoperative MAP 60-70 mmHg and postoperative myocardial injury, acute kidney injury, and mortality . These findings have informed international recommendations to avoid MAP below 60-65 …

Barriers To Occupational And Physical Therapy Utilization For Children With Cancer, Maria C Swartz, Shiming Zhang, Donna Kelly, Clark R Andersen, Keri Schadler, Alakh P Rajan, Eduardo Gonzalez Villarreal, Stephanie J Wells, Amy Heaton, Karen Moody

Faculty, Staff and Student Publications

Introduction: Occupational and physical therapy (OT/PT) referrals and utilization barriers for childhood cancer patients have not been adequately examined. The current study investigated factors influencing referrals to and utilization of OT/PT services among children with cancer at an NIH-designated cancer center.

Methods: This retrospective cohort study included pediatric cancer patients (up to 18.99 years) presenting to the center over a 33.5-month period. Variables that could influence referrals to OT/PT were extracted from the electronic medical record (EMR) including OT and PT referrals (inpatient and outpatient), OT and PT consult completion, age at diagnosis, cancer type, sex, race/ethnicity, insurance, cancer treatment, …

Physical Activity In Osteosarcoma Patients During And Post Therapy: A Single Site Prospective Observational Study, Elysia R Cohen, Clark Andersen, Karen Moody, Maria C Swartz, Michael C Robertson, Alakh Rajan, Theresa Honey, Sandra Lugo, Grace Waterman, Keri Schadler

Faculty, Staff and Student Publications

PURPOSE: Osteosarcoma is the most common primary bone tumor in childhood and adolescence. Many patients face long-term impairments in their mobility and function after treatment, leading to a decrease in their quality of life. Exercise has been shown to improve functional recovery and improve quality of life in patients with cancer, though data specific to children with osteosarcoma are sparse. Exercise has also been shown to be feasible in patients undergoing chemotherapy, with numerous potential benefits to health and quality of life. To design the most effective exercise interventions for children and adolescents with osteosarcoma, we must first understand the …

Estimating Population Structure Using Epigenome-Wide Methylation Data, Ziqing Wang, Kent D Taylor, Jerome I Rotter, Stephen S Rich, Yinan Zheng, Lifang Hou, Xiuqing Guo, Jan Bressler, Laura M Raffield, Yongmei Liu, Robert Kaplan, Donald M Lloyd-Jones, Alanna C Morrison, Myriam Fornage, Bruce M Psaty, Jennifer A Brody, Tamar Sofer

The Brown Foundation: Institute of Molecular Medicine

Population stratification is one of the source of inflation in epigenome-wide association studies (EWAS) when not properly accounted for. To address this, we developed methylation population scores (MPSs) to predict genetic principal components (GPCs) using a feature selection approach. We used multi-ethnic DNA methylation data from Illumina EPIC arrays across five cohorts, including MESA (n = 929), CARDIA (n = 1123), JHS (n = 1365), ARIC (n = 2338), and HCHS/SOL (n = 1475), randomly splitting participants into training (85%) and test (15%) sets. Within each cohort, associations between GPCs and CpG sites were estimated using linear regression adjusting for …

Human-Centered Design Of Patient Interviews: Capturing The Experiences Of Patients Recovering From Emergency Abdominal Surgery, Jenna L Marquard, Christie L Martin, Elizabeth C Wick, Amanda C Trofholz, Matthew S Loth, Suhyun Park, Genevieve B Melton

The Brown Foundation: Institute of Molecular Medicine

Objectives: Recognizing the challenges of at-home recovery following a truncated presurgical pathway for emergency laparotomy (EL) patients, we sought to identify barriers and facilitators to optimal recovery. This study aimed to develop a human-centered interview guide to capture the experiences of patients recovering at home after EL.

Methods: We employed an iterative human-centered design (HCD) approach to interview guide development, structured across 3 cycles. Each cycle refined the interview guide based on mock interviews and feedback from an interdisciplinary team. In cycle 1, we focused on creating a patient-centered, understandable guide. In cycle 2, we introduced a preinterview survey to …

Diversity And Immune Dynamics Of Choroid Plexus Macrophages Are Shaped By Distinct Developmental Origins, Siling Du, Khai M Nguyen, Alina Ulezko Antonova, Jose L Fachi, Patrick Fernandes Rodrigues, Alice Verdiani, Martina Molgora, Igor Smirnov, Jasmin Herz, Tornike Mamuladze, Jennifer Ponce, Amanda Swain, Mattia Bugatti, Susan Gilfillan, Marina Cella, William Vermi, Jonathan Kipnis, Marco Colonna, Simone Brioschi

The Brown Foundation: Institute of Molecular Medicine

The choroid plexus forms a key barrier and signaling interface between the brain and peripheral circulation, yet its immune landscape remains incompletely understood. Using single-cell transcriptomics combined with lineage and spatial tracing methods, we identified three biologically distinct populations of choroid plexus macrophages, defined by differential expression of CD163, MHCII or CD9. These subsets arise from separate hematopoietic waves, occupy distinct anatomical niches and differentially rely on CSF1 and IL-34 for survival. We found that TGFβ signaling is essential to maintain their tissue-specific identities, and deletion of Tgfbr2 in these cells induces broad phenotypic reprogramming. During neuroinflammation, choroid plexus macrophages …

Lipids Grease The Chain Of Cancer Progression, Joseph Rupert, Pham Hong Anh Cao, Daniel E Frigo, Mikhail G Kolonin

The Brown Foundation: Institute of Molecular Medicine

The role of lipids in cancer progression has become a fervent area of exploration. The crosstalk of tumors with adipose tissue is a complex but well-regulated orchestration of signaling pathways, lipid transporters, and enzymes. They regulate fatty acid synthesis, their deposition into lipid droplets (LDs) as triglycerides, induction of lipolysis, shuttling lipids across cells, and their systemic trafficking, modification, and catabolism. For the latter, lipid oxidation has emerged as a metabolic process of particular clinical importance. Products of lipid processing can become secondary messengers, contribute to reactive oxygen species (ROS) generation, stimulate the production of antioxidants, and, if left unchecked, …

Neutralization Of Sars-Cov-2 By Igm-14 Via Engagement Of Two Distinct Spike Epitopes, Yan Wang, Yanping Hu, Zhiqiang Ku, Jason Yeung, Jing Zou, Michael Woodson, Nikolai S Prokhorov, Ekaterina S Knyazhanskaya, Haiqing Zhao, Michael B Sherman, Zhiqiang An, Stephen F Carroll, Pei-Yong Shi, Petr G Leiman, Xuping Xie

The Brown Foundation: Institute of Molecular Medicine

Engineered immunoglobulin M (IgM) antibodies typically exhibit superior neutralization potency and avidity compared to their parental IgG counterparts, primarily due to multivalent binding to repeated epitopes on a targeting antigen. In this study, we characterize the neutralization breadth and mechanism of action of IgM-14, a previously reported intranasally deliverable antibody targeting SARS-CoV-2. IgM-14 demonstrates remarkably potent antiviral activity against all pre-Omicron variants but significantly reduced efficacy against Omicron BA.1, and complete loss of activity against the later subvariant JN.1. Resistance selection identified two key mutations in the receptor-binding domain (RBD), G476D and F486P, which disrupt IgM-14 binding and confer strong …

Risk Factors For Early-Onset And Late-Onset Dementia: A Prospective Cohort Study, Katherine Giorgio, John J Stephen, Maxwell Mansolf, Elizabeth A Peterson, Alden L Gross, Emily M Briceño, Deborah A Levine, Catherine Helmer, Stéphanie Debette, Aïcha Soumaré, M Arfan Ikram, Frank J Wolters, Sudha Seshadri, Claudia L Satizabal, Jayandra Jung Himali, Lenore J Launer, David Li, Djass Mbangdadji, Donald M Lloyd-Jones, Farzaneh A Sorond, Lihui Zhao, Oscar L Lopez, Suzanne E Judd, Timothy M Hughes, Vilmundur Guðnason, Allison E Aiello, Alison Fohner, Archana Singh-Manoux, Behnam Sabayan, James S Pankow, Paul S De Vries, Kristine Yaffe, Alexa Beiser, Abbas Dehghan, Rachel Zmora, Denise Scholtens, Pamela L Lutsey, Norrina B Allen, Richard Maclehose, Sanaz Sedaghat

Faculty, Staff and Student Publications

Background: Early-onset dementia (onset before age 65 years) is an important health concern, but much of our understanding of its risk factors is inferred from studies of late-onset dementia (onset after age 65 years). We investigated associations between several demographic, clinical, and lifestyle factors with early-onset dementia and compared those estimates against their associations with late-onset dementia.

Methods: Data from five community-based longitudinal cohort studies from the UK and USA were pooled and rigorously harmonised: UK Biobank, Atherosclerosis Risk in Communities Study, Framingham Heart Study, Multi-Ethnic Study of Atherosclerosis, and Whitehall II Study. Dementia was ascertained via hospitalisation and death …

Marginal Dispositions And Shared Decision-Making Among Older Adults In The Ed: A Prospective Cohort Study, Adrian D Haimovich, Anita Chary, Laura Burke, Alexander T Janke, Adam Rodman, Bruce Landon, Nathan I Shapiro, Aanand D Naik, Elizabeth Schoenfeld, Kei Ouchi, Mara A Schonberg

Faculty, Staff and Student Publications

Background: ED disposition decisions for older adults are complex and often uncertain, yet studies rarely capture emergency physicians' real-time perspectives.

Objective: To assess patient outcomes based on emergency physician-perceived need for admission.

Design: Single-site prospective cohort study conducted between July and November 2024.

Setting: A Boston-area academic tertiary care ED.

Participants: Patients aged 65 and older dispositioned by attending physicians, excluding patients who were handed off, left without being seen, or eloped.

Measurements: Physicians rated admission need using a 5-point Likert scale (2-4 considered marginal). Primary outcome was ED disposition stratified by rating. Secondary outcomes were hospital length-of-stay (LOS), 7-day …

Evaluating The Health Economic Impacts Of Baloxavir Marboxil And Oseltamivir For The Treatment Of Influenza In Adult Outpatients In Hong Kong: A Cost-Effectiveness Analysis, Ruohan Chen, Zengyang Shao, Kaiming Bi, Benjamin John Cowling, Zhanwei Du

Faculty, Staff and Student Publications

Background: Baloxavir marboxil, an antiviral used only in private hospitals in Hong Kong since February 2019 for treating influenza, is recognized for its efficacy against strains resistant to standard antiviral agents, providing an alternative to neuraminidase inhibitors such as oseltamivir.

Methods: This study compares the cost-effectiveness of baloxavir and oseltamivir for influenza treatment in otherwise healthy (OwH) and high-risk (HR) adult outpatients in Hong Kong from the healthcare-payer's perspective. A decision tree was utilized to study the progression of influenza and estimate associated costs and quality-adjusted life-years (QALYs) over 14 days for each antiviral.

Findings: In the general population, the …