Digital Commons Network^™

Dcis Knowledge Of Women Choosing Between Active Surveillance And Surgery For Low-Risk Dcis, E G Engelhardt, R S J M Schmitz, M A Gerritsma, C M T Sondermeijer, E Verschuur, J H E Houtzager, R Griffioen, N Bijker, R M Mann, V Retèl, F H Van Duijnhoven, J Wesseling, E M A Bleiker

Faculty, Staff and Student Publications

BACKGROUND: Ductal carcinoma in situ (DCIS) can progress to invasive breast cancer (IBC), but often never will. As we cannot predict accurately which DCIS-lesions will or will not progress to IBC, almost all women with DCIS undergo breast-conserving surgery supplemented with radiotherapy, or even mastectomy. In some countries, endocrine treatment is prescribed as well. This implies many women with non-progressive DCIS undergo overtreatment. To reduce this, the LORD patient preference trial (LORD-PPT) tests whether mammographic active surveillance (AS) is safe by giving women with low-risk DCIS a choice between treatment and AS. For this, sufficient knowledge about DCIS is crucial. …

Communities That Heal Intervention And Mortality Including Polysubstance Overdose Deaths: A Randomized Clinical Trial, Bridget Freisthler, Rouba A. Chahine, Jennifer Villani, Redonna Chandler, Daniel J. Feaster, Svetla Slavova, Jolene Defiore-Hyrmer, Alexander Y. Walley, Sarah Kosakowski, Arnie Aldridge, Carolina Barbosa, Sabana Bhatta, Candace Brancato, Carly Bridden, Mia Christopher, Tom Clarke, James David, Lauren D'Costa, Irene Ewing, Soledad Fernandez, Erin Gibson, Louisa Gilbert, Megan E. Hall, Sarah Hargrove, Timothy Hunt, Elizabeth N. Kinnard, Lauren Larochelle, Aaron Macoubray, Shawn R. Nigam, Edward V. Nunes, Carrie B. Oser, Sharon Pagnano, Peter J. Rock, Pamela Salsberry, Aimee Shadwick, Thomas J. Stopka, Sylvia Tan, Jessica L. Taylor, Philip M. Westgate, Elwin Wu, Gary A. Zarkin, Sharon L. Walsh, Nabila El-Bassel, T. John Winhusen, Jeffrey H. Samet, Emmanuel A. Oga

Biostatistics Faculty Publications

IMPORTANCE: The HEALing Communities Study (HCS) evaluated the effectiveness of the Communities That HEAL (CTH) intervention in preventing fatal overdoses amidst the US opioid epidemic.

OBJECTIVE: To evaluate the impact of the CTH intervention on total drug overdose deaths and overdose deaths involving combinations of opioids with psychostimulants or benzodiazepines.

DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial was a parallel-arm, multisite, community-randomized, open, and waitlisted controlled comparison trial of communities in 4 US states between 2020 and 2023. Eligible communities were those reporting high opioid overdose fatality rates in Kentucky, Massachusetts, New York, and Ohio. Covariate constrained randomization stratified …

Hippocampal Gray Matter Volume In Young Adulthood Varies With Adolescent Alcohol Use, Juliann B Purcell, Nathaniel G Harnett, Sylvie Mrug, Marc N Elliott, Susan Tortolero Emery, Mark A Schuster, David C Knight

Faculty, Staff and Student Publications

Adolescent substance use is linked with negative future outcomes (e.g., depression, anxiety, substance use disorder). Given that the brain undergoes significant maturation during adolescence, this developmental period may represent a time of particular vulnerability to substance use. Neuroimaging research has largely focused on heavy or binge patterns of substance use; thus, relatively less is known about the neural impact of a broader range of adolescent substance use. Characterizing the neural impact of a broader range of adolescent substance use may inform prevention and treatment efforts. The present study investigated relationships between adolescent substance use trajectories (i.e., alcohol, tobacco, and cannabis) …

Genomic Biomarkers To Predict Response To Atezolizumab Plus Bevacizumab Immunotherapy In Hepatocellular Carcinoma: Insights From The Imbrave150 Trial, Sun Young Yim, Sung Hwan Lee, Seung-Woo Baek, Bohwa Sohn, Yun Seong Jeong, Sang-Hee Kang, Kena Park, Hyewon Park, Sunyoung S Lee, Ahmed O Kaseb, Young Nyun Park, Sun-Hee Leem, Michael A Curran, Ji Hoon Kim, Ju-Seog Lee

Faculty, Staff and Student Publications

Background/aims: Combination immunotherapy, exemplified by atezolizumab plus bevacizumab, has become the standard of care for inoperable hepatocellular carcinoma (HCC). However, the lack of predictive biomarkers and limited understanding of response mechanisms remain a challenge.

Methods: Using data from the IMbrave150plus cohort, we applied an immune signature score (ISS) predictor to stratify HCC patients treated with atezolizumab plus bevacizumab or with sorafenib alone into potential high and low response groups. By applying multiple statistical approaches including a Bayesian covariate prediction algorithm, we refined the signature to 10 key genes (ISS10) for clinical use while maintaining similar predictive power to the full …

Multifocal, Multiphenotypic Tumours Arising From An Mtor Mutation Acquired In Early Embryogenesis, Clarissa N Pacyna, Madhanagopal Anandapadamanaban, Kevin W Loudon, Iain M Hay, Olga Perisic, Ruoyan Li, Matthew Byrne, Laura Allen, Kirsty Roberts, Yvette Hooks, Anne Y Warren, Grant D Stewart, Menna R Clatworthy, Sarah A Teichmann, Sam Behjati, Peter J Campbell, Roger L Williams, Thomas J Mitchell

Faculty, Staff and Student Publications

Embryogenesis is a vulnerable time. Mutations in developmental cells can result in the wide dissemination of cells predisposed to disease within mature organs. We characterised the evolutionary history of four synchronous renal tumours from a 14-year-old girl using whole genome sequencing alongside single cell and bulk transcriptomic sequencing. Phylogenetic reconstruction timed the origin of all tumours to a multipotent embryonic cell committed to the right kidney, around 4 weeks post-conception. Biochemical and structural analysis of their shared MTOR mutation, absent from normal tissues, demonstrates enhanced protein flexibility, enabling a FAT domain hinge to dramatically increase activity of mTORC1 and mTORC2. …

Drug-Resistant Epilepsy In Tuberous Sclerosis Complex Is Associated With Tsc2 Genotype: More Findings From The Preventing Epilepsy Using Vigatrin (Prevent) Trial, Laura S Farach, Melissa A Richard, Aynara C Wulsin, Elizabeth M Bebin, Darcy A Krueger, Mustafa Sahin, Brenda E Porter, Tarrant O Mcpherson, Jurriaan M Peters, Sarah O'Kelley, Katherine S Taub, Rajsekar Rajaraman, Stephanie C Randle, William M Mcclintock, Mary Kay Koenig, Michael D Frost, Klaus Werner, Danielle A Nolan, Michael Wong, Gary Cutter, Hope Northrup, Kit Sing Au

Faculty, Staff and Student Publications

Background: Children with tuberous sclerosis complex (TSC) are at high risk for drug-resistant epilepsy (DRE). The ability to stratify those at highest risk for DRE is important for counseling and prompt, aggressive management, necessary to optimize neurocognitive outcomes. Using the extensively phenotyped PREVeNT cohort, we aimed to characterize whether the TSC genotype was associated with DRE.

Methods: The study group (N = 70) comprised participants with TSC enrolled at age less than or equal to six months with detailed epilepsy and other phenotypic and genotypic data, prospectively collected as part of the PREVeNT trial. Genotype-phenotype correlations of DRE, time to …

Asxl1/Tet2 Genotype-Based Risk Stratification Outperforms Asxl1 Mutational Impact And Is Independent Of Mutant Variant Allele Fractions In Chronic Myelomonocytic Leukemia, Clifford M Csizmar, Mark Gurney, Rashmi Kanagal-Shamanna, Kelly Chien, Danielle Hammond, Terra L Lasho, Christy M Finke, Christopher Dean, Anuya Natu, Abhishek A Mangaonkar, Aref Al-Kali, Naseema Gangat, Ayalew Tefferi, Hassan Alkhateeb, Guillermo Garcia-Manero, Rami S Komrokji, Najla A Ali, Eric Padron, Guillermo Montalban-Bravo, Mrinal M Patnaik

Faculty, Staff and Student Publications

No abstract provided.

Subsyndromes And Symptom Clusters: Multilevel Factor Analysis Of Behavioral And Psychological Symptoms Of Dementia With Intensive Longitudinal Data, Carolyn E Z Pickering, Vicki Winstead, Mustafa Yildiz, Danny Wang, Maria Yefimova, Andrew M Pickering

Faculty, Staff and Student Publications

Introduction: Behavioral and psychological symptoms in dementia (BPSD) are dynamic phenomena with a high amount of intraindividual variability. We applied a multilevel framework to identify subsyndromes (between-person factors) that represent clinically relevant profiles of BPSD and identify symptom clusters (within-person factors) that represent contextually driven daily symptom experiences.

Methods: This study used an intensive longitudinal design in which 68 co-residing family caregivers to persons living with dementia were recruited to proxy report on their care recipient's daily symptom experiences of 23 different BPSD for eight consecutive days (n = 443 diaries). A multilevel exploratory/confirmatory factor analysis was used to account …

Impact Of Race And Ethnicity On Outcomes After Umbilical Cord Blood Transplantation, Karen Ballen, Tao Wang, Naya He, Jennifer M Knight, Sanghee Hong, Haydar Frangoul, Leo F Verdonck, Amir Steinberg, Miguel A Diaz, C Fred Lemaistre, Sherif M Badawy, Jeffrey J Pu, Hasan Hashem, Bipin Savani, Akshay Sharma, Hillard M Lazarus, Muhammad Bilal Abid, Jason Tay, Hemalatha G Rangarajan, Tamila Kindwall-Keller, Cesar O Freytes, Amer Beitinjaneh, Lena E Winestone, Usama Gergis, Nosha Farhadfar, Neel S Bhatt, Raquel M Schears, David Gómez-Almaguer, Mahmoud Aljurf, Vaibhav Agrawal, Yachiyo Kuwatsuka, Sachiko Seo, David I Marks, Leslie Lehmann, William A Wood, Shahrukh Hashmi, Wael Saber

Faculty, Staff and Student Publications

Background: Umbilical cord blood transplant (UCBT) improves access to transplant for patients lacking a fully matched donor. Previous Center for International Blood and Marrow Transplant Research (CIBMTR) showed that Black patients had a lower overall survival (OS) than White patients following single UCBT. The current study draws on a larger modern cohort and compares outcomes among White, Latinx, Black, and Asian patients.

Objective: To compare outcomes by social determinants of health.

Study design: We designed a retrospective study using CIBMTR data. US patients were between ages 1 and 80; 983 received single and 1529 double UCBT as reported to CIBMTR, …

The Qiba Profile For Diffusion-Weighted Mri: Apparent Diffusion Coefficient As A Quantitative Imaging Biomarker, Michael A Boss, Dariya Malyarenko, Savannah Partridge, Nancy Obuchowski, Amita Shukla-Dave, Jessica M Winfield, Clifton D Fuller, Kevin Miller, Virendra Mishra, Michael Ohliger, Lisa J Wilmes, Raj Attariwala, Trevor Andrews, Nandita M Desouza, Daniel J Margolis, Thomas L Chenevert

Faculty, Staff and Student Publications

The apparent diffusion coefficient (ADC) provides a quantitative measure of water mobility that can be used to probe alterations in tissue microstructure due to disease or treatment. Establishment of the accepted level of variance in ADC measurements for each clinical application is critical for its successful implementation. The Diffusion-Weighted Imaging Biomarker Committee of the Quantitative Imaging Biomarkers Alliance (QIBA) has recently advanced the ADC Profile from the consensus to clinically feasible stage for the brain, liver, prostate, and breast. This profile distills multiple studies on ADC repeatability and describes detailed procedures to achieve stated performance claims on an observed ADC …

Temporal Recording Of Mammalian Development And Precancer, Mirazul Islam, Yilin Yang, Alan J Simmons, Vishal M Shah, Krushna Pavan Musale, Yanwen Xu, Naila Tasneem, Zhengyi Chen, Linh T Trinh, Paola Molina, Marisol A Ramirez-Solano, Iannish D Sadien, Jinzhuang Dou, Andrea Rolong, Ken Chen, Mark A Magnuson, Jeffrey C Rathmell, Ian G Macara, Douglas J Winton, Qi Liu, Hamim Zafar, Reza Kalhor, George M Church, Martha J Shrubsole, Robert J Coffey, Ken S Lau

Faculty, Staff and Student Publications

Temporal ordering of cellular events offers fundamental insights into biological phenomena. Although this is traditionally achieved through continuous direct observations1,2, an alternative solution leverages irreversible genetic changes, such as naturally occurring mutations, to create indelible marks that enables retrospective temporal ordering3–5. Using a multipurpose, single-cell CRISPR platform, we developed a molecular clock approach to record the timing of cellular events and clonality in vivo, with incorporation of cell state and lineage information. Using this approach, we uncovered precise timing of tissue-specific cell expansion during mouse embryonic development, unconventional developmental relationships between cell …

Outcomes In Solid Organ Transplant Recipients Receiving Organs From A Donor With Fusarium Solani Species Complex Meningitis, Isabel S Griffin, Dallas J Smith, Pallavi Annambhotla, Jeremy A W Gold, Luis Ostrosky-Zeichner, Carol A Kauffman, Lalitha Gade, Anastasia Litvintseva, Daniel Zp Friedman, Angie G Nishio Lucar, Tarina C Parpia, Joshua Lieberman, Janet Bujan, Julie Corkrean, Mukul K Divatia, Kevin Grimes, Jiejian Lin, Constance Mobley, Mary R Schwartz, Bashar Hannawi, Anne Malilay, Anne O'Boye, Jeffrey Lysne, Mrinalini Venkata Subramani, Hayley Heckmann, Venice Servellita, Charles Chiu, Sridhar V Basavaraju

Faculty, Staff and Student Publications

Background: Five organs (heart, right lung, liver, right, and left kidneys) from a deceased patient were transplanted into five recipients in four US states; the deceased patient was identified as part of a healthcare-associated fungal meningitis outbreak among patients who underwent epidural anesthesia in Matamoros, Mexico.

Methods: After transplant surgeries occurred, Fusarium solani species complex, a fungal pathogen with a high case-mortality rate, was identified in cerebrospinal fluid from the organ donor by metagenomic next-generation sequencing (mNGS) and fungal-specific polymerase chain reaction and in plasma by mNGS.

Results: Four of five transplant recipients received recommended voriconazole prophylaxis; four were monitored …

The Five Homologous Ciar-Controlled Ccn Srnas Of Streptococcus Pneumoniae Modulate Zn-Resistance, Nicholas R De Lay, Nidhi Verma, Dhriti Sinha, Abigail Garrett, Maximillian K Osterberg, Daisy Porter, Spencer Reiling, David P Giedroc, Malcolm E Winkler

Faculty, Staff and Student Publications

Zinc is a vital transition metal for all bacteria; however, elevated intracellular free Zn levels can result in mis-metalation of Mn-dependent enzymes. For Mn-centric bacteria such as Streptococcus pneumoniae that primarily use Mn instead of Fe as an enzyme cofactor, Zn is particularly toxic at high concentrations. Here, we report our identification and characterization of the function of the five homologous, CiaRH-regulated Ccn sRNAs in controlling S. pneumoniae virulence and metal homeostasis. We show that deletion of all five ccn genes (ccnA, ccnB, ccnC, ccnD, and ccnE) from S. pneumoniae strains D39 (serotype 2) and TIGR4 (serotype 4) causes Zn …

Development Of An Engineered Extracellular Vesicles-Based Vaccine Platform For Combined Delivery Of Mrna And Protein To Induce Functional Immunity, Xin Luo, Kathleen M Mcandrews, Kent A Arian, Sami J Morse, Viktoria Boeker, Shreyasee V Kumbhar, Yingying Hu, Krishnan K Mahadevan, Kaira A Church, Sriram Chitta, Nicolas T Ryujin, Janine Hensel, Jianli Dai, Dara P Dowlatshahi, Hikaru Sugimoto, Michelle L Kirtley, Valerie S Lebleu, Shabnam Shalapour, Joe H Simmons, Raghu Kalluri

Faculty, Staff and Student Publications

mRNA incorporated in lipid nanoparticles (LNPs) became a new class of vaccine modality for induction of immunity against COVID-19 and ushered in a new era in vaccine development. Here, we report a novel, easy-to-execute, and cost effective engineered extracellular vesicles (EVs)-based combined mRNA and protein vaccine platform (EVX-M+P vaccine) and explore its utility in proof-of-concept immunity studies in the settings of cancer and infectious disease. As a first example, we engineered EVs, natural nanoparticle carriers shed by all cells, to contain ovalbumin mRNA and protein (EVOvaM+P vaccine) to serve as cancer vaccine against ovalbumin-expressing melanoma tumors. EVOvaM+P administration to mice …

Social Determinants Of Health And Surgical Desirability Of Outcome Ranking In Older Veterans, Michael A Jacobs, Yubo Gao, Susanne Schmidt, Paula K Shireman, Michael Mader, Carly A Duncan, Leslie R M Hausmann, Karyn B Stitzenberg, Lillian S Kao, Mary Vaughan Sarrazin, Daniel E Hall

Faculty, Staff and Student Publications

Importance: Evaluating how social determinants of health (SDOH) influence veteran outcomes is crucial, particularly for quality improvement.

Objective: To measure associations between SDOH, care fragmentation, and surgical outcomes using a Desirability of Outcome Ranking (DOOR).

Design, setting, and participants: This was a cohort study of US veterans using data from the Veterans Affairs (VA) Surgical Quality Improvement Program (VASQIP; 2013-2019) limited to patients aged 65 years or older with inpatient stays between 2 and 30 days, merged with multiple data sources, including Medicare. Race and ethnicity data were retrieved from VASQIP, Medicare and Medicaid beneficiary summary files, the Veterans Health …

Intimate Partner Violence And Parenting, Jeff R Temple, Elizabeth Baumler, Leila Wood

Faculty, Staff and Student Publications

This cohort study evaluates parental stress and protective factors mitigating risks for child maltreatment in the context of intimate partner violence.

Disruption Of Neural Periodicity Predicts Clinical Response After Deep Brain Stimulation For Obsessive-Compulsive Disorder, Nicole R Provenza, Sandesh Reddy, Anthony K Allam, Sameer V Rajesh, Nabeel Diab, Gabriel Reyes, Rose M Caston, Kalman A Katlowitz, Ajay D Gandhi, Raphael A Bechtold, Huy Q Dang, Ricardo A Najera, Nisha Giridharan, Katherine E Kabotyanski, Faiza Momin, Mohammed Hasen, Garrett P Banks, Brian J Mickey, Brent M Kious, Ben Shofty, Benjamin Y Hayden, Jeffrey A Herron, Eric A Storch, Ankit B Patel, Wayne K Goodman, Sameer A Sheth

Faculty, Staff and Students Publications

Recent advances in surgical neuromodulation have enabled chronic and continuous intracranial monitoring during everyday life. We used this opportunity to identify neural predictors of clinical state in 12 individuals with treatment-resistant obsessive-compulsive disorder (OCD) receiving deep brain stimulation (DBS) therapy ( NCT05915741 ). We developed our neurobehavioral models based on continuous neural recordings in the region of the ventral striatum in an initial cohort of five patients and tested and validated them in a held-out cohort of seven additional patients. Before DBS activation, in the most symptomatic state, theta/alpha (9 Hz) power evidenced a prominent circadian pattern and a high …

Dna Methylation-Derived Immune Cell Proportions And Cancer Risk In Black Participants, Christopher S Semancik, Naisi Zhao, Devin C Koestler, Eric Boerwinkle, Jan Bressler, Rachel J Buchsbaum, Karl T Kelsey, Elizabeth A Platz, Dominique S Michaud

Faculty, Staff and Student Publications

Prior cohort studies assessing cancer risk based on immune cell subtype profiles have predominantly focused on White populations. This limitation obscures vital insights into how cancer risk varies across race. Immune cell subtype proportions were estimated using deconvolution based on leukocyte DNA methylation markers from blood samples collected at baseline on participants without cancer in the Atherosclerosis Risk in Communities Study. During a mean of 17.5 years of follow-up, 668 incident cancers were diagnosed in 2,467 Black participants. Cox proportional hazards regression was used to examine immune cell subtype proportions and overall cancer incidence and site-specific incidence (lung, breast, and …

Oligodendroglial Fatty Acid Metabolism As A Central Nervous System Energy Reserve, Ebrahim Asadollahi, Andrea Trevisiol, Aiman S Saab, Zoe J Looser, Payam Dibaj, Reyhane Ebrahimi, Kathrin Kusch, Torben Ruhwedel, Wiebke Möbius, Olaf Jahn, Jun Yup Lee, Anthony S Don, Michelle-Amirah Khalil, Karsten Hiller, Myriam Baes, Bruno Weber, E Dale Abel, Andrea Ballabio, Brian Popko, Celia M Kassmann, Hannelore Ehrenreich, Johannes Hirrlinger, Klaus-Armin Nave

Duncan NRI Faculty and Staff Publications

Brain function requires a constant supply of glucose. However, the brain has no known energy stores, except for glycogen granules in astrocytes. In the present study, we report that continuous oligodendroglial lipid metabolism provides an energy reserve in white matter tracts. In the isolated optic nerve from young adult mice of both sexes, oligodendrocytes survive glucose deprivation better than astrocytes. Under low glucose, both axonal ATP levels and action potentials become dependent on fatty acid β-oxidation. Importantly, ongoing oligodendroglial lipid degradation feeds rapidly into white matter energy metabolism. Although not supporting high-frequency spiking, fatty acid β-oxidation in mitochondria and oligodendroglial …

Psychological Distress Among Ethnically Diverse Participants From Eastern And Southern Africa, Kester B B Tindi, Allan Kalungi, Eugene Kinyanda, Bizu Gelaye, Alicia R Martin, Ronald Galiwango, Wilber Ssembajjwe, Fred Kirumira, Adele Pretorius, Anne Stevenson, Charles R J C Newton, Dan J Stein, Elizabeth G Atkinson, Emanuel K Mwesiga, Joseph Kyebuzibwa, Lori B Chibnik, Lukoye Atwoli, Mark Baker, Melkam Alemayehu, Rehema M Mwende, Rocky E Stroud, Solomon Teferra, Stella Gichuru, Symon M Kariuki, Zukiswa Zingela, Moffat Nyirenda, Segun Fatumo, Dickens H Akena

Faculty, Staff and Students Publications

IMPORTANCE: Psychological distress is characterized by anxiety and depressive symptoms. Although prior research has investigated the occurrence and factors associated with psychological distress in low- and middle-income countries, including those in Africa, these studies' findings are not very generalizable and have focused on different kinds of population groups.

OBJECTIVE: To investigate the prevalence and characteristics (sociodemographic, psychosocial, and clinical) associated with psychological distress among African participants.

DESIGN, SETTING, AND PARTICIPANTS: This case-control study analyzed data of participants in the Neuropsychiatric Genetics in African Populations-Psychosis (NeuroGAP-Psychosis) study, which recruited from general outpatient clinics in Eastern (Uganda, Kenya, and Ethiopia) and Southern …

Evaluation Of Vancomycin Dose Needed To Achieve 24-Hour Area Under The Concentration-Time Curve To Minimum Inhibitory Concentration Ratio Greater Than Or Equal To 400 Using Pharmacometric Approaches In Pediatric Intensive Care Patients, Dawoon Jung, Omayma A Kishk, Adnan T Bhutta, Ginny E Cummings, Hana M El Sahly, Manpreet K Virk, Brady S Moffett, Jennifer L Morris Daniel, Amy Watanabe, Nicholas Fishbane, Karen L Kotloff, Kenan Gu, Varduhi Ghazaryan, Jogarao V S Gobburu, Ayse Akcan-Arikan, James D Campbell

Faculty, Staff and Students Publications

OBJECTIVES: To investigate which independent factor(s) have an impact on the pharmacokinetics of vancomycin in critically ill children, develop an equation to predict the 24-hour area under the concentration-time curve from a trough concentration, and evaluate dosing regimens likely to achieve a 24-hour area under the concentration-time curve to minimum inhibitory concentration ratio (AUC24/MIC) greater than or equal to 400.

DESIGN: Prospective population pharmacokinetic study of vancomycin.

SETTING: Critically ill patients in quaternary care PICUs.

PATIENTS: Children 90 days old or older to younger than 18 years who received IV vancomycin treatment, irrespective of the indication for use, in the …

Dsm-5 Criterion-A-Based Trauma Types In Service Members And Veterans Seeking Treatment For Posttraumatic Stress Disorder, Natasha Benfer, Breanna Grunthal, Katherine A Dondanville, Stacey Young-Mccaughan, Abby Blankenship, Chadi G Abdallah, Sudie E Back, Julianne Flanagan, Edna B Foa, Peter T Fox, John H Krystal, Brian P Marx, Donald D Mcgeary, Carmen P Mclean, Kristi E Pruiksma, Patricia A Resick, John D Roache, Paulo Shiroma, Denise M Sloan, Daniel J Taylor, Jennifer Schuster Wachen, Argelio L López-Roca, Karin L Nicholson, Richard P Schobitz, Christian C Schrader, Allah-Fard M Sharrieff, Jeffrey S Yarvis, Jim Mintz, Terence M Keane, Alan L Peterson, Brett T Litz

Faculty, Staff and Students Publications

Objective: In posttraumatic stress disorder (PTSD), the assumption of the equipotentiality of traumas ignores potentially unique contexts and consequences of different traumas. Accordingly, Stein et al. (2012) developed a reliable typing scheme in which assessors categorized descriptions of traumatic events into six "types": life threat to self (LTS), life threat to other, aftermath of violence (AV), traumatic loss, moral injury by self (MIS), and moral injury by other (MIO). We extended this research by validating the typing scheme using participant endorsements of type, rather than assesor-based types. We examined the concordance of participant and assesor types, frequency, and validity …

Deletion Of Tissue Factor Pathway Inhibitor Isoform Beta Or Gamma, But Not Alpha, Improves Clotting In Hemophilic Mice, Irem Eldem, Lilian Antunes-Heck, Renumathi Subramanian, Nina M Lasky, Katrina Ashworth, Jorge Di Paola, Thomas J Girard

2020-Current year OA Pubs

BACKGROUND: Tissue factor pathway inhibitor (TFPI) regulates tissue factor-triggered coagulation. Humans and mice express transcripts encoding for multidistributed (endothelial, platelet, and plasma) 3-Kunitz domain TFPIα and endothelial membrane-anchored 2-Kunitz TFPIβ. Mice express a third transcript, γ, that encodes plasma lipoprotein-associated 2-Kunitz TFPI. In humans, proteolysis of α and/or β produces plasma lipoprotein-associated 2-Kunitz TFPI at lower levels. In clinical trials, monoclonal antibodies that target all TFPI isoforms extend coagulation and correct bleeding in hemophilic patients but with some thrombosis risks.

OBJECTIVES: To determine the impact of TFPI isoform-specific deletions on promoting clotting in hemophilic mice.

METHODS: Engineered TFPI isoform-specific, hemophilic …

Peripartum Prediction Of Fetal Weight In Gravidas With Obesity, Katherine H Bligard, Jeannie C Kelly, Antonina I Frolova, Anthony O Odibo, Nandini Raghuraman

2020-Current year OA Pubs

OBJECTIVES: Estimated fetal weight (EFW) is an important metric at delivery as neonates with abnormal birthweight and their mothers are at higher risk of birth complications. Data regarding optimal EFW assessment in gravidas with obesity is inconsistent, and with the increasing incidence of obesity, clarification of this question is crucial. We aimed to compare accuracy of ultrasound (US)-derived EFW and clinical assessments of EFW in predicting neonatal birthweight among gravidas with obesity.

METHODS: This prospective cohort study enrolled gravidas with obesity and a singleton pregnancy admitted for delivery at term. EFW was determined using either US biometry or clinical assessment …

Adherence To Hygiene Protocols And Doxycycline Therapy In Ameliorating Lymphatic Filariasis Morbidity In An Endemic Area Post-Interruption Of Disease Transmission In Ghana, Linda Batsa Debrah, Philip J Budge, Et Al.

2020-Current year OA Pubs

Filarial lymphedema (LE) remains a significant global problem despite the progress made toward elimination of lymphatic filariasis (LF). In Ghana, the main approach to LF is preventive chemotherapy, but this has minimal impact on individuals who have already developed LE. In 2018-2020, a 24-month randomized, double-blind, placebo-controlled trial was conducted to evaluate the efficacy of stringent hygiene measures using the Essential Package of Care with or without additional administration of doxycycline (DOX) to improve filarial leg LE. This study enrolled 356 participants with LE stages 1-3 from two districts in the Upper East Region of Ghana. In addition to regular …

Metagenomic Study Of The Mesa: Detection Of Gemella Morbillorum And Association With Coronary Heart Disease, Kent D Taylor, Alexis C Wood, Jerome I Rotter, Xiuqing Guo, David M Herrington, W Craig Johnson, Wendy S Post, Russell P Tracy, Stephen S Rich, Shaista Malik

Faculty, Staff and Students Publications

BACKGROUND: Inflammation is a feature of coronary heart disease (CHD), but the role of proinflammatory microbial infection in CHD remains understudied.

METHODS AND RESULTS: CHD was defined in the MESA (Multi-Ethnic Study of Atherosclerosis) as myocardial infarction (251 participants), resuscitated arrest (2 participants), and CHD death (80 participants). We analyzed sequencing reads from 4421 MESA participants in the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine program using the PathSeq workflow of the Genome Analysis Tool Kit and a 65-gigabase microbial reference. Paired reads aligning to 840 microbes were detected in >1% of participants. The association of the …

Body Mass Index And Postacute Sequelae Of Sars-Cov-2 Infection In Children And Young Adults, Ting Zhou, Chongliang Luo, Et Al.

2020-Current year OA Pubs

IMPORTANCE: Obesity is associated with increased severity of COVID-19. Whether obesity is associated with an increased risk of post-acute sequelae of SARS-CoV-2 infection (PASC) among pediatric populations, independent of its association with acute infection severity, is unclear.

OBJECTIVE: To quantify the association of body mass index (BMI) status before SARS-CoV-2 infection with pediatric PASC risk, controlling for acute infection severity.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study occurred at 26 US children's hospitals from March 2020 to May 2023 with a minimum follow-up of 179 days. Eligible participants included children and young adults aged 5 to 20 years with …

Changes In Conjunctival Mononuclear Phagocytes And Suppressive Activity Of Regulatory Macrophages In Desiccation Induced Dry Eye, Jehan Alam, Ebru Yaman, Cintia S De Paiva, De-Quan Li, Gerda Cristal Villalba Silva, Zhen Zuo, Stephen C Pflugfelder

Faculty, Staff and Students Publications

Purpose: To evaluate the effects of dry eye on conjunctival immune cell number and transcriptional profiles with attention to mononuclear phagocytes.

Methods: Expression profiling was performed by single-cell RNA sequencing on sorted conjunctival immune cells from non-stressed and C57BL/6 mice subjected to desiccating stress (DS). Monocle 3 modeled cell trajectory, scATAC-seq assessed chromatin accessibility and IPA identified canonical pathways. Inflammation and goblet cells were measured after depletion of MRC1+ MΦs with mannosylated clodronate liposomes.

Results: Mononuclear phagocytes (monocytes, MΦs, DCs) comprised 72 % of immune cells and showed the greatest changes with DS. Distinct DS induced gene expression patterns were …

Polycaprolactone-Based Shape Memory Foams As Self-Fitting Vaginal Stents, Ashley J Hicks, Courteney Roberts, Andrew Robinson, Kailey Wilson, Varsha Kotamreddy, Trace Larue, Arian Veyssi, Felipe Beltran, Julie Hakim, Manuel K Rausch, Melissa Grunlan, Elizabeth Cosgriff-Hernandez

Faculty, Staff and Students Publications

There is an urgent critical need for a patient-forward vaginal stent that can prevent debilitating vaginal stenosis that occurs after pelvic radiation treatments and vaginal reconstruction. To this end, we developed a self-fitting vaginal stent based on a shape-memory polymer (SMP) foam that can assume a secondary, compressed shape for ease of deployment. Upon insertion, the change in temperature and hydration initiates foam expansion to shape fit to the individual patient and restore the lumen of the stent to allow egress of vaginal secretions. To achieve rapid actuation at physiological temperature, we investigated the effect of architecture of two photocurable, …

Discovery Of Genomic And Transcriptomic Pleiotropy Between Kidney Function And Soluble Receptor For Advanced Glycation End Products Using Correlated Meta-Analyses: The Long Life Family Study, Mary F Feitosa, Shiow J Lin, Sandeep Acharya, Bharat Thyagarajan, Mary K Wojczynski, Allison L Kuipers, Alexander Kulminski, Kaare Christensen, Joseph M Zmuda, Michael R Brent, Michael A Province

2020-Current year OA Pubs

Patients with chronic kidney disease (CKD) have increased oxidative stress and chronic inflammation, which may escalate the production of advanced glycation end-products (AGEs). High soluble receptor for AGE (sRAGE) and low estimated glomerular filtration rate (eGFR) levels are associated with CKD and aging. We evaluated whether eGFR calculated from creatinine and cystatin C share pleiotropic genetic factors with sRAGE. We employed whole-genome sequencing and correlated meta-analyses on combined genome-wide association study (GWAS) p-values in 4182 individuals (age range: 24-110) from the Long Life Family Study (LLFS). We also conducted transcriptome-wide association studies (TWAS) on whole blood in a subset of …