Medicine and Health Sciences Commons^™

Vulnerable Yet Unprotected: The Hidden Curriculum Of The Care Of The Incarcerated Patient, Michelle Ihn Suh, Marc David Robinson

Faculty, Staff and Students Publications

No abstract provided.

Statin Use And Risk Of Diabetes By Subclinical Atherosclerosis Burden (From A Multi-Ethnic Study Of Atherosclerosis Report), Mahmoud Al Rifai, Moyses Szklo, Jaideep Patel, Michael J Blaha, Christie M Ballantyne, Vera Bittner, Pamela Morris, John W Mcevoy, Michael D Shapiro, Mouaz H Al-Mallah, Philip Greenland, Salim S Virani

Faculty, Staff and Students Publications

Although there is a significant reduction in atherosclerotic cardiovascular disease risk with statins, a higher risk of diabetes mellitus has been demonstrated in randomized clinical trials. The risk of incident diabetes with statins may be heterogeneous by presence of coronary artery calcium (CAC). We evaluated participants without prevalent diabetes at baseline from the MESA (Multi-Ethnic Study of Atherosclerosis), a prospective cohort study of subjects free of clinical cardiovascular disease at baseline. We used multivariable-adjusted Cox proportional hazards models to study the association between statin use and incident diabetes, adjusting for sociodemographic and cardiovascular risk factors, including time-varying statin use and …

A Toddler With New Seizures, Progressive White Matter Lesions, And Multifocal Microhemorrhages, Dana Tlais, Stephanie Fetzko, Nitya Gulati, Huy Brandon D Tran, Sarah Risen, Yi-Chen Lai

Faculty, Staff and Students Publications

A 16-month-old, previously healthy male is hospitalized for new onset seizures. Initial investigation is significant for enterovirus/rhinovirus respiratory infection, abnormal T2 signal predominantly in the white matter and scattered microhemorrhages on brain MRI, transaminitis, and thrombocytopenia. His symptoms initially improve on steroid therapy and he is discharged from the hospital. During the ensuing month with the tapering of the steroids, he develops new motor deficits for which he is rehospitalized. His laboratory investigation on readmission is unremarkable. However, there is significant progression of white matter lesions and microhemorrhages on repeat MRI. While in the hospital, he becomes febrile and has …

Lipid-Lowering Therapy Use And Intensification Among United States Veterans Following Myocardial Infarction Or Coronary Revascularization Between 2015 And 2019, Alexander R Zheutlin, Catherine G Derington, Jennifer S Herrick, Robert S Rosenson, Bharat Poudel, Monika M Safford, Todd M Brown, Elizabeth A Jackson, Mark Woodward, Stephanie Reading, Kate Orroth, Jason Exter, Salim S Virani, Paul Muntner, Adam P Bress

Faculty, Staff and Students Publications

Background: Understanding how statins, ezetimibe, and PCSK9i (proprotein convertase subtilisin/kexin type 9 serine protease inhibitors) are prescribed after a myocardial infarction (MI) or elective coronary revascularization may improve lipid-lowering therapy (LLT) intensification and reduce recurrent atherosclerotic cardiovascular disease events. We described the use and intensification of LLT among US veterans who had a MI or elective coronary revascularization between July 24, 2015, and December 9, 2019, within 12 months of hospital discharge.

Methods: LLT intensification was defined as increasing statin dose, or initiating a statin, ezetimibe, or a PCSK9i, overall and among those with an LDL-C (low-density lipoprotein cholesterol) ≥ …

Loss Of Wnt4 In The Gubernaculum Causes Unilateral Cryptorchidism And Fertility Defects, Abhishek Seth, Juan C Bournat, Olga Medina-Martinez, Armando Rivera, Joshua Moore, Hunter Flores, Jill A Rosenfeld, Liya Hu, Carolina J Jorgez

Faculty, Staff and Students Publications

Undescended testis (UDT) affects 6% of male births. Despite surgical correction, some men with unilateral UDT may experience infertility with the contralateral descended testis (CDT) showing no A-dark spermatogonia. To improve our understanding of the etiology of infertility in UDT, we generated a novel murine model of left unilateral UDT. Gubernaculum-specific Wnt4 knockout (KO) mice (Wnt4-cKO) were generated using retinoic acid receptor β2-cre mice and were found to have a smaller left-unilateral UDT. Wnt4-cKO mice with abdominal UDT had an increase in serum follicle-stimulating hormone and luteinizing hormone and an absence of germ cells in the undescended testicle. Wnt4-cKO mice …

Growth Parameters In Children With Achondroplasia: A 7-Year, Prospective, Multinational, Observational Study, Ravi Savarirayan, Melita Irving, Paul Harmatz, Borja Delgado, William R Wilcox, John Philips, Natalie Owen, Carlos A Bacino, Louise Tofts, Joel Charrow, Lynda E Polgreen, Julie Hoover-Fong, Paul Arundel, Ignacio Ginebreda, Howard M Saal, Donald Basel, Rosendo Ullot Font, Keiichi Ozono, Michael B Bober, Valerie Cormier-Daire, Kim-Hanh Le Quan Sang, Genevieve Baujat, Yasemin Alanay, Frank Rutsch, Daniel Hoernschemeyer, Klaus Mohnike, Hiroshi Mochizuki, Asako Tajima, Yumiko Kotani, David D Weaver, Klane K White, Clare Army, Kevin Larrimore, Keith Gregg, George Jeha, Claire Milligan, Elena Fisheleva, Alice Huntsman-Labed, Jonathan Day

Faculty, Staff and Students Publications

Purpose: This study was undertaken to collect baseline growth parameters in children with achondroplasia who might enroll in interventional trials of vosoritide, and to establish a historical control.

Methods: In this prospective, observational study, participants (≤17 years) underwent a detailed medical history and physical examination and were followed every 3 months until they finished participating in the study by enrolling in an interventional trial or withdrawing.

Results: A total of 363 children were enrolled (28 centers, 8 countries). Mean (SD) follow up was 20.4 (15.0) months. In participants < 1 year, mean annualized growth velocity (AGV) was 11.6 cm/year for girls and 14.6 cm/year for boys. By age 1 year, mean AGV decreased to 7.4 cm/year in girls and 7.1 cm/year in boys. By age 10 years, mean AGV decreased to 3.6 cm/year for both sexes. Mean height z-score in participants < 1 year was -2.5 for girls and -3.2 for boys and decreased up to the age 5 years (-5.3 for girls; -4.6 for boys). Girls and boys had a disproportionate upper-to-lower body segment ratio. Mean ratio was highest in participants aged < 1 year (2.9 for girls; 2.8 for boys) and decreased gradually to approximately 2 in both sexes from 4 years of age onward.

Conclusion: This study represents one of the largest datasets of prospectively collected …

A New Chapter In An Evolving Pandemic: Successful Pediatric Liver Transplantation With Sars-Cov-2+ Donors, Matthew Benjamin Goss, Daniel Hao Bin Leung, Stephanie Marie Pouch, Flor M Munoz, Elizabeth Andrea Moulton, Tyler Malcolm Mccann Lambing, Sarah Koohmaraie, Nicolas Fernando Moreno, Christine A O'Mahony, John A Goss, Nhu Thao Nguyen Galván

Faculty, Staff and Students Publications

BACKGROUND: Amid a viral pandemic with poorly understood transmissibility and pathogenicity in the pediatric patient, we report the first pediatric liver transplants utilizing allografts from SARS-CoV-2+ donors.

METHODS: We describe the outcomes of two pediatric liver transplant recipients who received organs from SARS-CoV-2 nucleic acid test-positive (NAT+) donors. Data were obtained through the respective electronic medical record system and UNet DonorNet platform.

RESULTS: The first donor was a 3-year-old boy succumbing to head trauma. One of four nasopharyngeal (NP) swabs and 1 of 3 bronchoalveolar lavage (BAL) NAT tests demonstrated SARS-CoV-2 infection before organ procurement. The second donor was a …

Human Loss-Of-Function Variants In The Serotonin 2c Receptor Associated With Obesity And Maladaptive Behavior, Yang He, Bas Brouwers, Hesong Liu, Hailan Liu, Katherine Lawler, Edson Mendes De Oliveira, Dong-Kee Lee, Yongjie Yang, Aaron R Cox, Julia M Keogh, Elana Henning, Rebecca Bounds, Aliki Perdikari, Vikram Ayinampudi, Chunmei Wang, Meng Yu, Longlong Tu, Nan Zhang, Na Yin, Junying Han, Nikolas A Scarcelli, Zili Yan, Kristine M Conde, Camille Potts, Jonathan C Bean, Mengjie Wang, Sean M Hartig, Lan Liao, Jianming Xu, Inês Barroso, Jacek Mokrosinski, Yong Xu, I Sadaf Farooqi

Children’s Nutrition Research Center Staff Publications

Serotonin reuptake inhibitors and receptor agonists are used to treat obesity, anxiety and depression. Here we studied the role of the serotonin 2C receptor (5-HT2CR) in weight regulation and behavior. Using exome sequencing of 2,548 people with severe obesity and 1,117 control individuals without obesity, we identified 13 rare variants in the gene encoding 5-HT2CR (HTR2C) in 19 unrelated people (3 males and 16 females). Eleven variants caused a loss of function in HEK293 cells. All people who carried variants had hyperphagia and some degree of maladaptive behavior. Knock-in male mice harboring a human loss-of-function HTR2C variant developed …

Derivation And Validation Of A Clinical Prediction Rule For Upper Limb Functional Outcomes After Traumatic Cervical Spinal Cord Injury, Saad Javeed, Jacob K Greenberg, Justin K Zhang, Christopher F Dibble, Jawad M Khalifeh, Ying Liu, Thomas J Wilson, Lynda J Yang, Yikyung Park, Wilson Z Ray

2020-Current year OA Pubs

IMPORTANCE: Traumatic cervical spinal cord injury (SCI) can result in debilitating paralysis. Following cervical SCI, accurate early prediction of upper limb recovery can serve an important role in guiding the appropriateness and timing of reconstructive therapies.

OBJECTIVE: To develop a clinical prediction rule to prognosticate upper limb functional recovery after cervical SCI.

DESIGN, SETTING, AND PARTICIPANTS: This prognostic study was a retrospective review of a longitudinal cohort study including patients enrolled in the National SCI model systems (SCIMS) database in US. Eligible patients were 15 years or older with tetraplegia (neurological level of injury C1-C8, American Spinal Cord Injury Association …

Risk Of Nonalcoholic Fatty Liver Disease And Associations With Gastrointestinal Cancers, Scott Mchenry, Xiaoyu Zong, Mengyao Shi, Cassandra D L Fritz, Katrina S Pedersen, Linda R Peterson, Jeffrey K Lee, Ryan C Fields, Nicholas O Davidson, Yin Cao

2020-Current year OA Pubs

Metabolic syndrome may contribute to the rising incidence of multiple gastrointestinal (GI) cancers in recent birth cohorts. However, other than hepatocellular carcinoma, the association between nonalcoholic fatty liver disease (NAFLD) and risk of non-liver GI cancers is unexplored. We prospectively examined the associations of NAFLD risk with GI cancers among 319,290 participants in the UK Biobank (2006-2019). Baseline risk for NAFLD was estimated using the Dallas Steatosis Index, a validated prediction tool. Multivariable Cox models were used to estimate relative risks (RRs) and 95% confidence intervals (CIs) according to NAFLD risk categories: low (<20%), intermediate (20%-49%), and high (≥50%). We also examined the associations by age of cancer diagnosis (earlier onset [<60] vs. ≥60). A total of 273 incident liver cancer and 4789 non-liver GI cancer cases were diagnosed. Compared with individuals at low risk for NAFLD, those at high risk had 2.41-fold risk of liver cancer (RR = 2.41, 95% CI: 1.73-3.35) and 23% increased risk of non-liver GI cancers (RR = 1.23, 95% CI: 1.14-1.32) (all p

Lifespan Benefits For The Combination Of Rapamycin Plus Acarbose And For Captopril In Genetically Heterogeneous Mice, Randy Strong, Kerry Kornfeld, Et Al.

2020-Current year OA Pubs

Mice bred in 2017 and entered into the C2017 cohort were tested for possible lifespan benefits of (R/S)-1,3-butanediol (BD), captopril (Capt), leucine (Leu), the Nrf2-activating botanical mixture PB125, sulindac, syringaresinol, or the combination of rapamycin and acarbose started at 9 or 16 months of age (RaAc9, RaAc16). In male mice, the combination of Rapa and Aca started at 9 months and led to a longer lifespan than in either of the two prior cohorts of mice treated with Rapa only, suggesting that this drug combination was more potent than either of its components used alone. In females, lifespan in mice …

Impact Of Aortic Valve Effective Height Following Valve-Sparing Root Replacement On Postoperative Insufficiency And Reoperation, Puja Kachroo, Meghan O Kelly, Nadia H Bakir, Catherine Cooper, Alan C Braverman, Nicholas T Kouchoukos, Marc R Moon

2020-Current year OA Pubs

BACKGROUND: This study evaluated the impact of anatomic aortic root parameters during valve-sparing root replacement on the probability of postoperative aortic insufficiency and freedom from aortic valve reoperation.

METHODS: From 1995 to 2020, 177 patients underwent valve-sparing root replacement (163 reimplantations, 14 remodeling). Preoperative and postoperative echocardiograms were analyzed to measure annulus and sinus diameters, effective height of leaflet coaptation, and degree of aortic insufficiency. Logistic regression was used to evaluate predictors of 2+ or greater late postoperative aortic insufficiency. Fine-Gray regression determined predictors for aortic valve reintervention.

RESULTS: The study population included 122 (69%) men with a mean age …

Association Of Leukocyte Telomere Length With Perceived Physical Fatigability, Rain Katz, Emma L Gay, Allison L Kuipers, Joseph H Lee, Lawrence S Honig, Kaare Christensen, Mary F Feitosa, Mary K Wojczynski, Nancy W Glynn, Llfs Research Group

2020-Current year OA Pubs

BACKGROUND: Leukocyte telomere length (LTL) is a potential genomic marker of biological aging, but its relation to fatigability, a prognostic indicator of phenotypic aging (e.g., functional decline) is unknown. We hypothesized shorter LTL would predict greater perceived physical fatigability, but that this association would be attenuated by adjusting for chronological age.

METHODS: Two generations of participants (N = 1997; 309 probands, 1688 offspring) were from the Long Life Family Study (age = 73.7 ± 10.4, range 60-108, 54.4 % women), a longitudinal cohort study of aging. LTL was assayed at baseline. Perceived physical fatigability was measured 8.0 ± 1.1 years …

Infections In The First Year Of Life And Development Of Beta Cell Autoimmunity And Clinical Type 1 Diabetes In High-Risk Individuals: The Trigr Cohort, Olga Kordonouri, David Cuthbertson, Malin Belteky, Bärbel Aschemeier-Fuchs, Neil H White, Elisabeth Cummings, Mikael Knip, Johnny Ludvigsson

2020-Current year OA Pubs

AIMS/HYPOTHESIS: Accumulated data suggest that infections in early life contribute to the development of type 1 diabetes. Using data from the Trial to Reduce IDDM in the Genetically at Risk (TRIGR), we set out to assess whether children who later developed diabetes-related autoantibodies and/or clinical type 1 diabetes had different exposure to infections early in life compared with those who did not.

METHODS: A cohort of 2159 children with an affected first-degree relative and HLA-conferred susceptibility to type 1 diabetes were recruited between 2002 and 2007 and followed until 2017. Infections were registered prospectively. The relationship between infections in the …

Macrophage Depletion Blocks Congenital Sarm1-Dependent Neuropathy, Caitlin B Dingwall, Amy Strickland, Sabrina W Yum, Aldrin Ky Yim, Jian Zhu, Peter L. Wang, Yurie Yamada, Robert E. Schmidt, Yo Sasaki, A. Joseph Bloom, Aaron Diantonio, Jeffrey Milbrandt

2020-Current year OA Pubs

Axon loss contributes to many common neurodegenerative disorders. In healthy axons, the axon survival factor NMNAT2 inhibits SARM1, the central executioner of programmed axon degeneration. We identified 2 rare NMNAT2 missense variants in 2 brothers afflicted with a progressive neuropathy syndrome. The polymorphisms resulted in amino acid substitutions V98M and R232Q, which reduced NMNAT2 NAD+-synthetase activity. We generated a mouse model to mirror the human syndrome and found that Nmnat2V98M/R232Q compound-heterozygous CRISPR mice survived to adulthood but developed progressive motor dysfunction, peripheral axon loss, and macrophage infiltration. These disease phenotypes were all SARM1-dependent. Remarkably, macrophage depletion therapy blocked and reversed …

Avpcancerfree: Impact Of A Digital Behavior Change Intervention On Parental Hpv Vaccine –Related Perceptions And Behaviors, Ross Shegog, Lara S Savas, C Mary Healy, Erica L Frost, Sharon P Coan, Efrat K Gabay, Sharice M Preston, Stanley W Spinner, Mathew Wilbur, Elisabeth Becker, Travis Teague, Sally W Vernon

Faculty, Staff and Student Publications

Parent hesitancy contributes to reduced HPV vaccination rates. The HPVcancerfree app (HPVCF) was designed to assist parents in making evidence-based decisions regarding HPV vaccination. This study examined if parents of vaccine-eligible youth (11-12 yrs.) who use HPVCF in addition to usual care demonstrate significantly more positive intentions and attitudes toward HPV vaccination and greater HPV vaccination rates compared to those not using HPVCF. Clinics (n = 51) within a large urban pediatric network were randomly assigned to treatment (HPVCF + usual care) or comparison (usual care only) conditions in a RCT conducted between September 2017 and February 2019. Parents completed …

Hdac2 In Primary Sensory Neurons Constitutively Restrains Chronic Pain By Repressing Α2Δ-1 Expression And Associated Nmda Receptor Activity, Jixiang Zhang, Shao-Rui Chen, Meng-Hua Zhou, Daozhong Jin, Hong Chen, Li Wang, Ronald A Depinho, Hui-Lin Pan

Faculty, Staff and Student Publications

α2δ-1 (encoded by the Cacna2d1 gene) is a newly discovered NMDA receptor-interacting protein and is the therapeutic target of gabapentinoids (e.g., gabapentin and pregabalin) frequently used for treating patients with neuropathic pain. Nerve injury causes sustained α2δ-1 upregulation in the dorsal root ganglion (DRG), which promotes NMDA receptor synaptic trafficking and activation in the spinal dorsal horn, a hallmark of chronic neuropathic pain. However, little is known about how nerve injury initiates and maintains the high expression level of α2δ-1 to sustain chronic pain. Here, we show that nerve injury caused histone hyperacetylation and diminished enrichment of histone deacetylase-2 (HDAC2), …

Synaptic Development In Diverse Olfactory Neuron Classes Uses Distinct Temporal And Activity-Related Programs, Michael A. Aimino, Alison T. Depew, Lucas Restrepo, Timothy J. Mosca

Farber Institute for Neuroscience Faculty Papers

Developing neurons must meet core molecular, cellular, and temporal requirements to ensure the correct formation of synapses, resulting in functional circuits. However, because of the vast diversity in neuronal class and function, it is unclear whether or not all neurons use the same organizational mechanisms to form synaptic connections and achieve functional and morphologic maturation. Moreover, it remains unknown whether neurons united in a common goal and comprising the same sensory circuit develop on similar timescales and use identical molecular approaches to ensure the formation of the correct number of synapses. To begin to answer these questions, we took advantage …

Criterion Validity Of A Short Food Frequency Questionnaire For Mexican American Adults, Natalia I Heredia, Deanna M Hoelscher, Vanessa Vega, Belinda M Reininger

Faculty, Staff and Student Publications

Background: The purpose of this study was to validate the School Physical Activity and Nutrition (SPAN) Food Frequency Questionnaire (FFQ) for Mexican American adults (SPAN MAA). Methods: A sample of 100 Mexican American adult participants was drawn from the Cameron County Hispanic Cohort (on the Texas–Mexico border). We used Spearman rank order correlation coefficients, kappa statistics, and percent agreement to compare the SPAN MAA questionnaire to a 24 h recall collected on the same day. Results: Of 100 participants, 93 were included in the analyses. One item showed substantial (>0.6), five items moderate (>0.4), five items fair ( …

Methylone And Mdma Pharmacokinetics Following Controlled Administration In Humans, Lourdes Poyatos, Alfredo Fabrizio Lo Faro, Diletta Berardinelli, Giorgia Sprega, Sara Malaca, Simona Pichini, Marilyn A. Huestis, Esther Papaseit, Clara Pérez-Mañá, Francesco Paolo Busardò, Magí Farré

Institute of Emerging Health Professions Faculty Papers

The aim of this study is to define, for the first time, human methylone and HMMC plasma pharmacokinetics following controlled administration of 50–200 mg methylone to 12 male volunteers. A new LC-MS/MS method was validated to quantify methylone, MDMA, and their metabolites in plasma. The study was a randomized, cross-over, double-blinded and placebo-controlled study, with a total of 468 plasma samples collected. First, 10 µL of MDMA-d5, MDA-d5 and methylone-d3 internal standards were added to 100 µL of plasma. Two mL of chloroform and ethyl acetate 9:1 (v/v) were then added, mixed well and centrifuged. The supernatant was fortified with …

Multilevel Correlates Of Domain-Specific Physical Activity Among Rural Adults - A Cross-Sectional Study, Alan M Beck, Natalicio H Serrano, Audrey Toler, Ross C Brownson

2020-Current year OA Pubs

BACKGROUND: Increasing physical activity (PA) in rural communities is a vital prevention tactic in multiple chronic diseases; however, little is known on the multilevel correlates of PA rural areas. A better understanding of domain-specific PA adds context for promoting PA in rural communities. The current study sought to determine factors associated with domain-specific and overall moderate-vigorous physical activity (MVPA) in rural communities.

METHODS: Surveys were conducted across 14 rural mid-Western communities, with the final analytical sample including 1241 adults (ages 19-96, M = 57.0 [SD = 16.7], 67.8% female, 83.8% white). Generalized linear models with negative binomial distributions examined the …

Oleuropein Suppresses Endometriosis Progression And Improves The Fertility Of Mice With Endometriosis, Yuri Park, Yeon Jean Cho, Nuri Sung, Mi Jin Park, Xiaoming Guan, William E Gibbons, Bert W O'Malley, Sang Jun Han

Faculty, Staff and Students Publications

BACKGROUND: Endometriosis is an estrogen-dependent inflammatory reproductive disease. Therefore, systematic estrogen depletion and anti-inflammatory drugs are the current treatment for endometriosis. However, current endometriosis treatments have low efficacy and cause adverse effects in endometriosis patients. Consequently, alternative endometriosis treatments targeting endometriosis-specific factors are in demand. In this context, ERβ was selected as a druggable target for endometriosis due to its critical role in progression. Therefore, selective targeting of ERβ without inhibiting ERα activity would be a new paradigm for endometriosis treatment to overcome the low efficacy and adverse effects of hormonal endometriosis therapy.

METHODS: Cell-based ERβ and ERα activity assay …

Let's Talk About Antibiotics: A Randomised Trial Of Two Interventions To Reduce Antibiotic Misuse, Kathy Goggin, Emily A. Hurley, Brian R. Lee, Andrea Bradley-Ewing, Carey Bickford, Kimberly Pina, Evelyn Donis De Miranda, David Yu, Kirsten Weltmer, Sebastian Linnemayr, Christopher C. Butler, Jason G. Newland, Angela L Myers

2020-Current year OA Pubs

BACKGROUND: Children with acute respiratory tract infections (ARTIs) receive ≈11.4 million unnecessary antibiotic prescriptions annually. A noted contributor is inadequate parent-clinician communication, however, efforts to reduce overprescribing have only indirectly targeted communication or been impractical.

OBJECTIVES: Compare two feasible (higher vs lower intensity) interventions for enhancing parent-clinician communication on the rate of inappropriate antibiotic prescribing.

DESIGN: Multisite, parallel group, cluster randomised comparative effectiveness trial. Data collected between March 2017 and March 2019.

SETTING: Academic and private practice outpatient clinics.

PARTICIPANTS: Clinicians (n=41, 85% of eligible approached) and 1599 parent-child dyads (ages 1-5 years with ARTI symptoms, 71% of eligible approached). …

Effect Of Selective Decontamination Of The Digestive Tract On Hospital Mortality In Critically Ill Patients Receiving Mechanical Ventilation: A Randomized Clinical Trial, The Suddicu Investigators For The Australian And New Zealand Intensive Care Society Clinical Trials Group, John A Myburgh, Ian M Seppelt, Fiona Goodman, Laurent Billot, Maryam Correa, Joshua S Davis, Anthony C Gordon, Naomi E Hammond, Jon Iredell, Qiang Li, Sharon Micallef, Jennene Miller, Jayanthi Mysore, Colman Taylor, Paul J Young, Brian H Cuthbertson, Simon R Finfer

Faculty, Staff and Student Publications

IMPORTANCE: Whether selective decontamination of the digestive tract (SDD) reduces mortality in critically ill patients remains uncertain.

OBJECTIVE: To determine whether SDD reduces in-hospital mortality in critically ill adults.

DESIGN, SETTING, AND PARTICIPANTS: A cluster, crossover, randomized clinical trial that recruited 5982 mechanically ventilated adults from 19 intensive care units (ICUs) in Australia between April 2018 and May 2021 (final follow-up, August 2021). A contemporaneous ecological assessment recruited 8599 patients from participating ICUs between May 2017 and August 2021.

INTERVENTIONS: ICUs were randomly assigned to adopt or not adopt a SDD strategy for 2 alternating 12-month periods, separated by a …

Human Dectin-1 Deficiency Impairs Macrophage-Mediated Defense Against Phaeohyphomycosis, Rebecca A. Drummond, Jigar V. Desai, Amy P. Hsu, Vasileios Oikonomou, Donald C. Vinh, Joshua A. Acklin, Michael S. Abers, Magdalena A. Walkiewicz, Sarah L. Anzick, Muthulekha Swamydas, Simon Vautier, Mukil Natarajan, Andrew J. Oler, Daisuke Yamanaka, Katrin D. Mayer-Barber, Yoichiro Iwakura, David Bianchi, Brian Driscoll, Ken Hauck, Ahnika Kline, Nicholas S.P. Viall, Christa S. Zerbe, Elise M.N. Ferré, Monica M. Schmitt, Tom Dimaggio, Stefania Pittaluga, John A. Butman, Adrian M. Zelazny, Yvonne R. Shea, Cesar A. Arias, Cameron Ashbaugh, Maryam Mahmood, Zelalem Temesgen, Alexander G. Theofiles, Masayuki Nigo, Varsha Moudgal, Karen C. Bloch, Sean G. Kelly, M. Suzanne Whitworth, Ganesh Rao, Cindy J. Whitener, Neema Mafi, Juan Gea-Banacloche, Lawrence C. Kenyon, William R. Miller, Katia Boggian, Andrea Gilbert, Matthew Sincock, Alexandra F. Freeman, John E. Bennett, Rodrigo Hasbun, Constantinos M. Mikelis, Kyung J. Kwon-Chung, Yasmine Belkaid, Gordon D. Brown, Jean K. Lim, Douglas B. Kuhns, Steven M. Holland, Michail S. Lionakis

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Subcutaneous phaeohyphomycosis typically affects immunocompetent individuals following traumatic inoculation. Severe or disseminated infection can occur in CARD9 deficiency or after transplantation, but the mechanisms protecting against phaeohyphomycosis remain unclear. We evaluated a patient with progressive, refractory Corynespora cassiicola phaeohyphomycosis and found that he carried biallelic deleterious mutations in CLEC7A encoding the CARD9-coupled, β-glucan-binding receptor, Dectin-1. The patient's PBMCs failed to produce TNF-α and IL-1β in response to β-glucan and/or C. cassiicola. To confirm the cellular and molecular requirements for immunity against C. cassiicola, we developed a mouse model of this infection. Mouse macrophages required Dectin-1 and CARD9 for IL-1β and …

Inhibiting Ack1-Mediated Phosphorylation Of C-Terminal Src Kinase Counteracts Prostate Cancer Immune Checkpoint Blockade Resistance, Dhivya Sridaran, Surbhi Chouhan, Kiran Mahajan, Arun Renganathan, Cody Weimholt, Shambhavi Bhagwat, Melissa Reimers, Eric H Kim, Manish K Thakur, Muhammad A Saeed, Russell K Pachynski, Markus A Seeliger, W Todd Miller, Felix Y Feng, Nupam P Mahajan

2020-Current year OA Pubs

Solid tumours are highly refractory to immune checkpoint blockade (ICB) therapies due to the functional impairment of effector T cells and their inefficient trafficking to tumours. T-cell activation is negatively regulated by C-terminal Src kinase (CSK); however, the exact mechanism remains unknown. Here we show that the conserved oncogenic tyrosine kinase Activated CDC42 kinase 1 (ACK1) is able to phosphorylate CSK at Tyrosine 18 (pY18), which enhances CSK function, constraining T-cell activation. Mice deficient in the Tnk2 gene encoding Ack1, are characterized by diminished CSK Y18-phosphorylation and spontaneous activation of CD8

Sex Differences In Brain Tumor Glutamine Metabolism Reveal Sex-Specific Vulnerabilities To Treatment, Jasmin Sponagel, Jill K Jones, Cheryl Frankfater, Shanshan Zhang, Olivia Tung, Kevin Cho, Kelsey L Tinkum, Hannah Gass, Elena Nunez, Gary J Patti, Jingqin Luo, Joshua B Rubin, Joseph E Ippolito, Et Al.

2020-Current year OA Pubs

BACKGROUND: Brain cancer incidence and mortality rates are greater in males. Understanding the molecular mechanisms that underlie those sex differences could improve treatment strategies. Although sex differences in normal metabolism are well described, it is currently unknown whether they persist in cancerous tissue.

METHODS: Using positron emission tomography (PET) imaging and mass spectrometry, we assessed sex differences in glioma metabolism in samples from affected individuals. We assessed the role of glutamine metabolism in male and female murine transformed astrocytes using isotope labeling, metabolic rescue experiments, and pharmacological and genetic perturbations to modulate pathway activity.

FINDINGS: We found that male glioblastoma …

Acute And Postacute Sequelae Associated With Sars-Cov-2 Reinfection, Benjamin Bowe, Yan Xie, Ziyad Al-Aly

2020-Current year OA Pubs

First infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with increased risk of acute and postacute death and sequelae in various organ systems. Whether reinfection adds to risks incurred after first infection is unclear. Here we used the US Department of Veterans Affairs' national healthcare database to build a cohort of individuals with one SARS-CoV-2 infection (n = 443,588), reinfection (two or more infections, n = 40,947) and a noninfected control (n = 5,334,729). We used inverse probability-weighted survival models to estimate risks and 6-month burdens of death, hospitalization and incident sequelae. Compared to no reinfection, reinfection …

A Randomized Pilot Study Of Oncology Massage To Treat Chemotherapy-Induced Peripheral Neuropathy, Gabriel Lopez, Cathy Eng, Michael Overman, David Ramirez, Wenli Liu, Curtiss Beinhorn, Pamela Sumler, Sarah Prinsloo, Yisheng Li, Minxing Chen, Eduardo Bruera, Lorenzo Cohen

Faculty, Staff and Student Publications

This pilot randomized controlled trial investigated massage therapy for symptomatic relief of chemotherapy-induced peripheral neuropathy (CIPN) to determine the ideal weekly frequency and number of weeks of providing massage. We evaluated the feasibility and initial efficacy of a Swedish massage protocol to treat lower extremity (LE) CIPN. Inclusion criteria: LE neuropathy attributed to oxaliplatin, paclitaxel, or docetaxel, with no other attributable causes; ≥ 6 months since last chemotherapy; self-reported neuropathy score ≥ 3, 0-10 scale; age ≥ 18. Participant randomization (2:2:1:1) to one of four groups: LE (2) or head/neck/shoulder (control; 1) massage 3 times (3X) a week for 4 …

Prevalence Of Sleep-Related Problems And Risks In A Community-Dwelling Older Adult Population: A Cross-Sectional Survey-Based Study, Nancy P Gordon, Jimmy H Yao, Leslea A Brickner, Joan C Lo

Faculty, Staff and Student Publications

BACKGROUND: Despite evidence of adverse health consequences of inadequate restorative sleep for older adults, assessment of sleep quantity, quality, and use of sleep aids is not routinely done. We aimed to characterize sleep problems, sleep risks, and advice received about sleep in a community-dwelling older adult population, overall and in subgroups with health conditions and functional difficulties.

METHODS: This cross-sectional study used weighted self-report data for 5074 Kaiser Permanente Northern California members aged 65-79y who responded to a 2017 or 2020 Member Health Survey. We estimated usual amount of sleep (< 6, 6 to < 7, ≥7 hours) and prevalence of sleep problems (frequent insomnia, frequent daytime fatigue, poor quality sleep, and potential sleep apnea (OSA) symptoms (frequent very loud snoring, apnea episodes)) for older adults overall, by self-rated health, and in subgroups reporting hypertension, diabetes, heart disease, frequent problems with balance/walking, and frequent memory problems. We also estimated percentages who regularly used sleep aids and had discussed sleep adequacy with a healthcare professional in the past year.

RESULTS: Approximately 30% of older adults usually got less …