Digital Commons Network^™

Circadian Regulation Of Gene Expression And Metabolism In The Liver, Dongyin Guan, Mitchell A Lazar

Faculty, Staff and Students Publications

Circadian rhythms are approximately 24-hour cycles of variation in physiological processes, gene expression, and behavior. They result from the interplay of internal biological clocks with daily environmental rhythms, including light/dark and feeding/fasting. Note that 24-hour rhythms of liver metabolic processes have been known for almost 100 years. Modern studies reveal that, like metabolism, hepatic gene expression is highly rhythmic. Genetic or environmental changes can disrupt the circadian rhythms of the liver, leading to metabolic disorders and hepatocellular carcinoma. In this review, we summarize the current understanding of mechanisms regulating rhythmic gene expression in the liver, highlighting the roles of transcription …

Primer For Development Of Guidelines For Helicobacter Pylori Therapy Using Antimicrobial Stewardship, David Y Graham, Jyh-Ming Liou

Faculty, Staff and Students Publications

We provide a primer to assist in the difficult transition of Helicobacter pylori therapy guidelines to those that adhere to the principles of antimicrobial stewardship. This transition will entail abandonment of many of the principles that heretofore formed the basis of treatment guidelines and recommendations. The goals of antimicrobial stewardship include optimization of the use of antibiotics while reducing antimicrobial resistance. The critical outcome measure is absolute cure rate which largely restricts comparative trials to those which reliably produce high cure rates (eg, ∼95%). Therapies that fail to achieve at least a 90% cure rate should be abandoned as unacceptable. …

Efficacy And Safety Of Larotrectinib In Patients With Trk Fusion-Positive Thyroid Carcinoma, Steven G Waguespack, Alexander Drilon, Jessica J Lin, Marcia S Brose, Ray Mcdermott, Mohammed Almubarak, Jessica Bauman, Michela Casanova, Anuradha Krishnamurthy, Shivaani Kummar, Serge Leyvraz, Do-Youn Oh, Keunchil Park, Davendra Sohal, Eric Sherman, Ricarda Norenberg, Josh D Silvertown, Nicoletta Brega, David S Hong, Maria E Cabanillas

Kimmel Cancer Center Faculty Papers

Objective: Larotrectinib is a highly selective tropomyosin receptor kinase (TRK) inhibitor with demonstrated efficacy across various TRK fusion-positive solid tumours. We assessed the efficacy and safety of larotrectinib in patients with TRK fusion-positive thyroid carcinoma (TC).

Methods: We pooled data from three phase I/II larotrectinib clinical trials (NCT02576431, NCT02122913, and NCT02637687). The primary endpoint was the investigator-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors v1.1. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Data cut-off: July 2020.

Results: Twenty-nine patients (median age: 60; range: 6-80) …

Heterozygous Frameshift Variants In Hnrnpa2b1 Cause Early-Onset Oculopharyngeal Muscular Dystrophy, Hong Joo Kim, Payam Mohassel, Sandra Donkervoort, Lin Guo, Kevin O'Donovan, Maura Coughlin, Xaviere Lornage, Nicola Foulds, Simon R Hammans, A Reghan Foley, Charlotte M Fare, Alice F Ford, Masashi Ogasawara, Aki Sato, Aritoshi Iida, Pinki Munot, Gautam Ambegaonkar, Rahul Phadke, Dominic G O'Donovan, Rebecca Buchert, Mona Grimmel, Ana Töpf, Irina T Zaharieva, Lauren Brady, Ying Hu, Thomas E Lloyd, Andrea Klein, Maja Steinlin, Alice Kuster, Sandra Mercier, Pascale Marcorelles, Yann Péréon, Emmanuelle Fleurence, Adnan Manzur, Sarah Ennis, Rosanna Upstill-Goddard, Luca Bello, Cinzia Bertolin, Elena Pegoraro, Leonardo Salviati, Courtney E French, Andriy Shatillo, F Lucy Raymond, Tobias B Haack, Susana Quijano-Roy, Johann Böhm, Isabelle Nelson, Tanya Stojkovic, Teresinha Evangelista, Volker Straub, Norma B Romero, Jocelyn Laporte, Francesco Muntoni, Ichizo Nishino, Mark A Tarnopolsky, James Shorter, Carsten G Bönnemann, J Paul Taylor

Department of Biochemistry and Molecular Biology Faculty Papers

Missense variants in RNA-binding proteins (RBPs) underlie a spectrum of disease phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, and inclusion body myopathy. Here, we present ten independent families with a severe, progressive muscular dystrophy, reminiscent of oculopharyngeal muscular dystrophy (OPMD) but of much earlier onset, caused by heterozygous frameshift variants in the RBP hnRNPA2/B1. All disease-causing frameshift mutations abolish the native stop codon and extend the reading frame, creating novel transcripts that escape nonsense-mediated decay and are translated to produce hnRNPA2/B1 protein with the same neomorphic C-terminal sequence. In contrast to previously reported disease-causing missense variants in HNRNPA2B1, these frameshift …

Thermodynamically Coupled Biosensors For Detecting Neutralizing Antibodies Against Sars-Cov-2 Variants, Jason Z Zhang, Laura A Vanblargan, Michael S Diamond, Et Al.

2020-Current year OA Pubs

We designed a protein biosensor that uses thermodynamic coupling for sensitive and rapid detection of neutralizing antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants in serum. The biosensor is a switchable, caged luciferase-receptor-binding domain (RBD) construct that detects serum-antibody interference with the binding of virus RBD to angiotensin-converting enzyme 2 (ACE-2) as a proxy for neutralization. Our coupling approach does not require target modification and can better distinguish sample-to-sample differences in analyte binding affinity and abundance than traditional competition-based assays.

Targeting Cd123 In Blastic Plasmacytoid Dendritic Cell Neoplasm Using Allogeneic Anti-Cd123 Car T Cells, Tianyu Cai, Agnès Gouble, Kathryn L Black, Anna Skwarska, Ammar S Naqvi, Deanne Taylor, Ming Zhao, Qi Yuan, Mayumi Sugita, Qi Zhang, Roman Galetto, Stéphanie Filipe, Antonio Cavazos, Lina Han, Vinitha Kuruvilla, Helen Ma, Connie Weng, Chang-Gong Liu, Xiuping Liu, Sergej Konoplev, Jun Gu, Guilin Tang, Xiaoping Su, Gheath Al-Atrash, Stefan Ciurea, Sattva S Neelapu, Andrew A Lane, Hagop Kantarjian, Monica L Guzman, Naveen Pemmaraju, Julianne Smith, Andrei Thomas-Tikhonenko, Marina Konopleva

Faculty, Staff and Student Publications

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with poor outcomes with conventional therapy. Nearly 100% of BPDCNs overexpress interleukin 3 receptor subunit alpha (CD123). Given that CD123 is differentially expressed on the surface of BPDCN cells, it has emerged as an attractive therapeutic target. UCART123 is an investigational product consisting of allogeneic T cells expressing an anti-CD123 chimeric antigen receptor (CAR), edited with TALEN

Perceived Roles, Benefits And Barriers Of Virtual Global Health Partnership Initiatives: A Cross-Sectional Exploratory Study, Lisa Umphrey, George Paasi, William Windsor, Grace Abongo, Jessica Evert, Heather Haq, Elizabeth M Keating, Suet Kam Lam, Megan S Mchenry, Carolyne Ndila, Charles Nwobu, Amy Rule, Reena P Tam, Daniel Olson, Peter Olupot-Olupot

Faculty, Staff and Students Publications

BACKGROUND: Virtual global health partnership initiatives (VGHPIs) evolved rapidly during the COVID-19 pandemic to ensure partnership continuity. However the current landscape for VGHPI use and preference is unknown. This study aimed to increase understanding of GH partners' perspectives on VGHPIs.

METHODS: From 15 October to 30 November 2020, An online, international survey was conducted using snowball sampling to document pandemic-related changes in partnership activities, preferences for VGHPIs, and perceived acceptability and barriers. The survey underwent iterative development within a diverse author group, representing academic and clinical institutions, and the non-profit sector. Participants from their professional global health networks were invited, …

Bilateral, Full-Thickness Macular Holes While Undergoing Chemotherapy, Sarah Dieter Od, Brett Garee Od Ms, Susan Zacatelco Od, Julie Henry Od

Optometric Clinical Practice

Background: Bilateral, full-thickness macular holes are a rare condition that can substantially affect quality of life. Macular hole diagnosis and treatment is key for these patients.

Case Report: A 71 year old Caucasian male presented with a chief complaint of distance blur in both eyes, worsening over the past 1-2 weeks. He had no diagnosis of diabetes. He added that his prostate cancer had spread and that his last treatment ended 9 days ago. He was ultimately diagnosed with bilateral, full-thickness macular holes. Referral to a retinal specialist for surgical management yielded good results.

Conclusion: This is …

Cefuroxime-Induced Toxic Maculopathy: A Cataract Co-Management Conundrum, Leonid Skorin Jr., Do, Od, Ms

Optometric Clinical Practice

Background: Cefuroxime-induced toxic maculopathy can occur when an incorrect dilution is injected intracamerally after cataract surgery. This results in a guarded visual prognosis. Cefuroxime-induced toxic maculopathy can also occur sporadically even when the medication dilution is the standard correct dosage. These patients usually recover their vision by the first postoperative week.

Case Report: A 72-year-old Caucasian female developed cefuroxime-induced toxic maculopathy after uneventful cataract surgery. Investigation of the case confirmed that she had a sporadic response to the cefuroxime. It was verified that she received the standard correct dilution of cefuroxime intracamerally. The patient showed a significant improvement in her …

A Cryptic Pocket In Ebola Vp35 Allosterically Controls Rna Binding, Matthew A Cruz, Thomas E Frederick, Upasana L Mallimadugula, Sukrit Singh, Neha Vithani, Maxwell I Zimmerman, Justin R Porter, Katelyn E Moeder, Gaya K Amarasinghe, Gregory R Bowman

Open Access Publications

Protein-protein and protein-nucleic acid interactions are often considered difficult drug targets because the surfaces involved lack obvious druggable pockets. Cryptic pockets could present opportunities for targeting these interactions, but identifying and exploiting these pockets remains challenging. Here, we apply a general pipeline for identifying cryptic pockets to the interferon inhibitory domain (IID) of Ebola virus viral protein 35 (VP35). VP35 plays multiple essential roles in Ebola's replication cycle but lacks pockets that present obvious utility for drug design. Using adaptive sampling simulations and machine learning algorithms, we predict VP35 harbors a cryptic pocket that is allosterically coupled to a key …

Home-Grown School Feeding: Implementation Lessons From A Pilot In A Poor Ethnic Minority Community In Vietnam, Sabina Di Prima, Dai Nguyen Dinh, Demi D. Reurings, E Pamela Wright Phd, Ms, Med, Rn, Cen, Dirk Essink, Jacqueline E. Broerse

Publications

BACKGROUND:

Undernutrition threatens the health and future of preschool children in disadvantaged remote communities. Home-grown school feeding (HGSF) in nursery schools could positively impact children's nutrition while creating multiple benefits for the whole community. However, evidence is lacking on implementation of HGSF within multi-sectoral programs in remote areas.

OBJECTIVE:

This study assessed an HGSF pilot intervention, part of a nutrition-sensitive agriculture (NSA) program, in a mountain ethnic minority community in Vietnam. It aimed to identify the changes brought about by the intervention, in particular diversity of children's food, food sources, barriers and facilitators to change, and future challenges and strategies. …

Barriers And Motivations To Provide Dental Care To Adult Patients With Movement Disorders, Natalia S Rozas, Hillary D Strassner, June M Sadowsky, Cameron B Jeter

Faculty, Staff and Student Publications

Patients with movement disorders, like Parkinson's and Huntington's diseases, tend to have poor oral health. Although contributing factors have been proposed, the willingness and ability of dentists to treat this patient population are still unknown. Our objective is to understand the current barriers and motivations of dentists to treat this patient population as a path to improved care and quality of life. A total of 176 dentists in Texas were surveyed through a structured questionnaire which contained both closed and open-ended questions. Nearly 30% of participants reported having no barriers to treating these patients and 26.7% reported that no such …

Odach: A One-Shot Distributed Algorithm For Cox Model With Heterogeneous Multi-Center Data, Chongliang Luo, Rui Duan, Adam C Naj, Henry R Kranzler, Jiang Bian, Yong Chen

Open Access Publications

We developed a One-shot Distributed Algorithm for Cox proportional-hazards model to analyze Heterogeneous multi-center time-to-event data (ODACH) circumventing the need for sharing patient-level information across sites. This algorithm implements a surrogate likelihood function to approximate the Cox log-partial likelihood function that is stratified by site using patient-level data from a lead site and aggregated information from other sites, allowing the baseline hazard functions and the distribution of covariates to vary across sites. Simulation studies and application to a real-world opioid use disorder study showed that ODACH provides estimates close to the pooled estimator, which analyzes patient-level data directly from all …

The Geriatric Emergency Care Applied Research (Gear) Network Approach: A Protocol To Advance Stakeholder Consensus And Research Priorities In Geriatrics And Dementia Care In The Emergency Department, Ula Hwang, Christopher Carpenter, Scott Dresden, Jeffrey Dussetschleger, Angela Gifford, Ly Hoang, Jesseca Leggett, Armin Nowroozpoor, Zachary Taylor, Manish Shah, The Gear And Gear 2.0 Networks

Open Access Publications

INTRODUCTION: Increasingly, older adults are turning to emergency departments (EDs) to address healthcare needs. To achieve these research demands, infrastructure is needed to both generate evidence of intervention impact and advance the development of implementation science, pragmatic trials evaluation and dissemination of findings from studies addressing the emergency care needs of older adults. The Geriatric Emergency Care Applied Research Network (https://gearnetwork.org) has been created in response to these scientific needs-to build a transdisciplinary infrastructure to support the research that will optimise emergency care for older adults and persons living with dementia.

METHODS AND ANALYSIS: In this paper, we describe our …

Meal Timing, Meal Frequency And Metabolic Syndrome, Fatema Alkhulaifi, Charles Darkoh

Faculty, Staff and Student Publications

Individuals with metabolic syndrome have increased risk for developing health conditions, including cardiovascular diseases and stroke. Modifiable risk factors, such as exercise and diet, are key components in the prevention and control of metabolic syndrome. Specifically, dietary patterns and habits are extremely successful in controlling more than one of the metabolic syndrome risk factors. Meal timing and frequency have been associated with type 2 diabetes, cardiovascular diseases, and other chronic conditions. However, there is limited evidence linking metabolic syndrome to meal timing and meal frequency. This review summarizes and discusses how meal timing and frequency impact metabolic outcomes in adults.

Reduced Er-Mitochondria Connectivity Promotes Neuroblastoma Multidrug Resistance., Jorida Çoku, David M. Booth, Jan Skoda, Madison C Pedrotty, Jennifer Vogel, Kangning Liu, Annette Vu, Erica L Carpenter, Jamie C Ye, Michelle A Chen, Peter Dunbar, Elizabeth Scadden, Taekyung D Yun, Eiko Nakamaru-Ogiso, Estela Area-Gomez, Yimei Li, Kelly C Goldsmith, C Patrick Reynolds, György Hajnóczky, Michael D Hogarty

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Most cancer deaths result from progression of therapy resistant disease, yet our understanding of this phenotype is limited. Cancer therapies generate stress signals that act upon mitochondria to initiate apoptosis. Mitochondria isolated from neuroblastoma cells were exposed to tBid or Bim, death effectors activated by therapeutic stress. Multidrug-resistant tumor cells obtained from children at relapse had markedly attenuated Bak and Bax oligomerization and cytochrome c release (surrogates for apoptotic commitment) in comparison with patient-matched tumor cells obtained at diagnosis. Electron microscopy identified reduced ER-mitochondria-associated membranes (MAMs; ER-mitochondria contacts, ERMCs) in therapy-resistant cells, and genetically or biochemically reducing MAMs in therapy-sensitive …

Applying Systems Thinking To Identify Enablers And Challenges To Scale-Up Interventions For Hypertension And Diabetes In Low-Income And Middle-Income Countries: Protocol For A Longitudinal Mixed-Methods Study, Anusha Ramani-Chander, Mark D Huffman, Et Al

Open Access Publications

INTRODUCTION: There is an urgent need to reduce the burden of non-communicable diseases (NCDs), particularly in low-and middle-income countries, where the greatest burden lies. Yet, there is little research concerning the specific issues involved in scaling up NCD interventions targeting low-resource settings. We propose to examine this gap in up to 27 collaborative projects, which were funded by the Global Alliance for Chronic Diseases (GACD) 2019 Scale Up Call, reflecting a total funding investment of approximately US$50 million. These projects represent diverse countries, contexts and adopt varied approaches and study designs to scale-up complex, evidence-based interventions to improve hypertension and …

Emergency Department Antimicrobial Use In A Low-Resource Setting: Results From A Retrospective Observational Study At A Referral Hospital In Liberia, Sojung Yi, Anu Ramachandran, Lane Epps, Alex Mayah, Taylor W Burkholder, Michael Senyu Jaung, Ahson Haider, Paul Whesseh, John Shakpeh, Kayla Enriquez, Corey Bills

Faculty, Staff and Students Publications

OBJECTIVE: Data on antimicrobial use in low-income and middle-income countries (LMICs) remain limited. In Liberia, the absence of local data impedes surveillance and may lead to suboptimal treatment, injudicious use and resistance against antimicrobials. This study aims to examine antimicrobial prescribing patterns for patients in the emergency department (ED) of a large Liberian public hospital. Secondarily, this prescribing was compared with WHO prescribing indicators.

DESIGN: Retrospective observational study.

SETTING: An adult ED of a large public hospital in Monrovia, Liberia.

PARTICIPANTS: A total of 1082 adult patients (>18 years of age) were recorded in the ED, from 1 January …

Associations Of Steps Per Day And Step Intensity With The Risk Of Diabetes: The Hispanic Community Health Study / Study Of Latinos (Hchs/Sol)., Carmen C. Cuthbertson, Christopher C. Moore, Daniela Sotres-Alvarez, Gerardo Heiss, Carmen R. Isasi, Yasmin Mossavar-Rahmani, Jordan A. Carlson, Linda C. Gallo, Maria M. Llabre, Olga L. Garcia-Bedoya, David Goldsztajn Farelo, Kelly R. Evenson

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Higher levels of moderate-to-vigorous physical activity have been associated with a lower risk of diabetes, but less is known about how daily step counts (steps/day) are associated with diabetes risk. Therefore, we examined the association of steps/day and step intensity with incident diabetes.

METHODS: We included 6634 adults from the population-based prospective cohort Hispanic Community Health Study/Study of Latinos (HCHS/SOL) (2008-2017). Cox proportional hazard models that accounted for complex survey design and sampling weights were used to estimate the association of baseline accelerometer-assessed steps/day and step intensity with 6-year risk of incident diabetes as hazard ratios (HR) and 95% …

Daratumumab Plus Lenalidomide/Bortezomib/Dexamethasone In Black Patients With Transplant-Eligible Newly Diagnosed Multiple Myeloma In Griffin., Ajay K Nooka, Jonathan L Kaufman, Cesar Rodriguez, Andrzej Jakubowiak, Yvonne Efebera, Brandi Reeves, Tanya Wildes, Sarah A Holstein, Larry D Anderson, Ashraf Badros, Leyla Shune, Ajai Chari, Huiling Pei, Annelore Cortoos, Sharmila Patel, J Blake Bartlett, Jessica Vermeulen, Thomas S Lin, Paul G Richardson, Peter Voorhees

Oncology Articles

No abstract provided.

Targeting Non-Coding Rnas To Overcome Cancer Therapy Resistance, Baoqing Chen, Mihnea P Dragomir, Chen Yang, Qiaoqiao Li, David Horst, George A Calin

Faculty, Staff and Student Publications

It is now well known that non-coding RNAs (ncRNAs), rather than protein-coding transcripts, are the preponderant RNA transcripts. NcRNAs, particularly microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are widely appreciated as pervasive regulators of multiple cancer hallmarks such as proliferation, apoptosis, invasion, metastasis, and genomic instability. Despite recent discoveries in cancer therapy, resistance to chemotherapy, radiotherapy, targeted therapy, and immunotherapy continue to be a major setback. Recent studies have shown that ncRNAs also play a major role in resistance to different cancer therapies by rewiring essential signaling pathways. In this review, we present the intricate mechanisms through …

From Self-Efficacy To Imposter Syndrome: The Intrapersonal Traits Of Surgeons, Alexandra Medline, Helyn Grissom, Ndéye F Guissé, Victoria Kravets, Sandra Hobson, Julie Balch Samora, Mara Schenker

Open Access Publications

BACKGROUND: Demographic differences among surgical trainees regarding intrapersonal traits, such as imposter syndrome and assertiveness, have become widely acknowledged. However, many of these characteristics have not been examined in tandem, nor among both trainees and surgeons in practice. This study aimed to address these knowledge gaps.

METHODS: This was an anonymous, voluntary survey study comprised of validated measures of (1) self-efficacy, (2) imposter syndrome, (3) assertiveness, (4) perfectionism, and (5) self-rated likeability. A multimodal recruitment strategy was used and surgeons across all subspecialties were eligible for inclusion.

RESULTS: A total of 296 participants were included, with 54% identifying as female …

Distinct Molecular And Immune Hallmarks Of Inflammatory Arthritis Induced By Immune Checkpoint Inhibitors For Cancer Therapy, Sang T Kim, Yanshuo Chu, Mercy Misoi, Maria E Suarez-Almazor, Jean H Tayar, Huifang Lu, Maryam Buni, Jordan Kramer, Emma Rodriguez, Zulekha Hussain, Sattva S Neelapu, Jennifer Wang, Amishi Y Shah, Nizar M Tannir, Matthew T Campbell, Don L Gibbons, Tina Cascone, Charles Lu, George R Blumenschein, Mehmet Altan, Bora Lim, Vincente Valero, Monica E Loghin, Janet Tu, Shannon N Westin, Aung Naing, Guillermo Garcia-Manero, Noha Abdel-Wahab, Hussein A Tawbi, Patrick Hwu, Isabella C Glitza Oliva, Michael A Davies, Sapna P Patel, Jun Zou, Andrew Futreal, Adi Diab, Linghua Wang, Roza Nurieva

Faculty, Staff and Student Publications

Immune checkpoint inhibitors are associated with immune-related adverse events (irAEs), including arthritis (arthritis-irAE). Management of arthritis-irAE is challenging because immunomodulatory therapy for arthritis should not impede antitumor immunity. Understanding of the mechanisms of arthritis-irAE is critical to overcome this challenge, but the pathophysiology remains unknown. Here, we comprehensively analyze peripheral blood and/or synovial fluid samples from 20 patients with arthritis-irAE, and unmask a prominent Th1-CD8

Human Pancreatic Microenvironment Promotes Β-Cell Differentiation Via Non-Canonical Wnt5a/Jnk And Bmp Signaling, Jolanta Chmielowiec, Wojciech J Szlachcic, Diane Yang, Marissa A Scavuzzo, Katrina Wamble, Alejandro Sarrion-Perdigones, Omaima M Sabek, Koen J T Venken, Malgorzata Borowiak

Faculty, Staff and Students Publications

In vitro derivation of pancreatic β-cells from human pluripotent stem cells holds promise as diabetes treatment. Despite recent progress, efforts to generate physiologically competent β-cells are still hindered by incomplete understanding of the microenvironment's role in β-cell development and maturation. Here, we analyze the human mesenchymal and endothelial primary cells from weeks 9-20 fetal pancreas and identify a time point-specific microenvironment that permits β-cell differentiation. Further, we uncover unique factors that guide in vitro development of endocrine progenitors, with WNT5A markedly improving human β-cell differentiation. WNT5A initially acts through the non-canonical (JNK/c-JUN) WNT signaling and cooperates with Gremlin1 to inhibit …

Connectomic Profiling And Vagus Nerve Stimulation Outcomes Study (Connectivos): A Prospective Observational Protocol To Identify Biomarkers Of Seizure Response In Children And Youth, Lauren Siegel, Matthew D Smyth, Et Al

Open Access Publications

INTRODUCTION: Vagus nerve stimulation (VNS) is a neuromodulation therapy that can reduce the seizure burden of children with medically intractable epilepsy. Despite the widespread use of VNS to treat epilepsy, there are currently no means to preoperatively identify patients who will benefit from treatment. The objective of the present study is to determine clinical and neural network-based correlates of treatment outcome to better identify candidates for VNS therapy.

METHODS AND ANALYSIS: In this multi-institutional North American study, children undergoing VNS and their caregivers will be prospectively recruited. All patients will have documentation of clinical history, physical and neurological examination and …

Meta-Analysis Of Genome-Wide Association Studies Identifies Ancestry-Specific Associations Underlying Circulating Total Tau Levels, Chloé Sarnowski, Mohsen Ghanbari, Joshua C Bis, Mark Logue, Myriam Fornage, Aniket Mishra, Shahzad Ahmad, Alexa S Beiser, Eric Boerwinkle, Vincent Bouteloup, Vincent Chouraki, L Adrienne Cupples, Vincent Damotte, Charles S Decarli, Anita L Destefano, Luc Djoussé, Alison E Fohner, Carol E Franz, Tiffany F Kautz, Jean-Charles Lambert, Michael J Lyons, Thomas H Mosley, Kenneth J Mukamal, Matthew P Pase, Eliana C Portilla Fernandez, Robert A Rissman, Claudia L Satizabal, Ramachandran S Vasan, Amber Yaqub, Stephanie Debette, Carole Dufouil, Lenore J Launer, William S Kremen, William T Longstreth, M Arfan Ikram, Sudha Seshadri

Faculty, Staff and Student Publications

Circulating total-tau levels can be used as an endophenotype to identify genetic risk factors for tauopathies and related neurological disorders. Here, we confirmed and better characterized the association of the 17q21 MAPT locus with circulating total-tau in 14,721 European participants and identified three novel loci in 953 African American participants (4q31, 5p13, and 6q25) at P < 5 × 10-8. We additionally detected 14 novel loci at P < 5 × 10-7, specific to either Europeans or African Americans. Using whole-exome sequence data in 2,279 European participants, we identified ten genes associated with circulating total-tau when aggregating rare variants. Our genetic study sheds light on genes reported to be associated with neurological diseases including stroke, Alzheimer's, and Parkinson's (F5, MAP1B, and BCAS3), with Alzheimer's pathological hallmarks (ADAMTS12, IL15, and FHIT), or with an important function in the brain (PARD3, ELFN2, UBASH3B, SLIT3, and NSD3), and suggests that the genetic architecture of circulating total-tau may differ according to ancestry.

Repurposing Probenecid For The Treatment Of Heart Failure (Re-Prosper-Hf): A Study Protocol For A Randomized Placebo-Controlled Clinical Trial, Jack Rubinstein, Nathan Robbins, Karen Evans, Gabrielle Foster, Kevin Mcconeghy, Toluwalope Onadeko, Julie Bunke, Melanie Parent, Xi Luo, Jacob Joseph, Wen-Chih Wu

Faculty, Staff and Student Publications

BACKGROUND: Improving contractility in heart failure with reduced ejection fraction (HFrEF) has resurfaced as a potential treatment goal. Inotropic therapy is now better understood through its underlying mechanism as opposed to the observed effect of increasing contractility. Calcitropes are a subgroup of inotropes that largely depend on the stimulation of adenylyl cyclase to transform ATP into cyclic adenosine monophosphate (cAMP). At least two clinically relevant calcitropes-istaroxime and probenecid-improve contractility through an increase in systolic intracellular calcium without activating cAMP production. Probenecid, which has been safely used clinically for decades in non-cardiac conditions, has recently been identified as an agonist of …

Overcrowded Housing Increases Risk For Covid-19 Mortality: An Ecological Study, Karan Varshney, Talia Glodjo, Jenna R Adalbert

College of Population Health Faculty Papers

Objectives: Overcrowded housing is a sociodemographic variable associated with increased infection and mortality rates from communicable diseases. It is not well understood if this association exists for COVID-19. Our objective was hence to determine the association between household overcrowding and risk of mortality from COVID-19, and this was done by performing bivariable and multivariable analyses using COVID-19 data from cities in Los Angeles County.

Results: Bivariate regression revealed that overcrowded households were positively associated with COVID-19 deaths (standardized β = 0.863, p < 0.001). COVID-19 case totals, people aged 60+, and the number of overcrowded households met conditions for inclusion in the backwards stepwise linear regression model. Analysis revealed all independent variables were positively associated with mortality rates, primarily for individuals 60 + (standardized β1 = 0.375, p = 0.001), followed by overcrowded households (standardized β2 = 0.346, p = 0.014), and total COVID-19 cases (standardized β3 = 0.311, p < 0.001). Our findings highlight that residing in overcrowded households may be an important risk factor for COVID-19 mortality. Public health entities should consider this population when allocating resources for prevention and control of COVID-19 mortality and future disease outbreaks.

Overcrowded Housing Increases Risk For Covid-19 Mortality: An Ecological Study., Karan Varshney, Talia Glodjo, Jenna Adalbert

College of Population Health Faculty Papers

OBJECTIVES: Overcrowded housing is a sociodemographic variable associated with increased infection and mortality rates from communicable diseases. It is not well understood if this association exists for COVID-19. Our objective was hence to determine the association between household overcrowding and risk of mortality from COVID-19, and this was done by performing bivariable and multivariable analyses using COVID-19 data from cities in Los Angeles County.

RESULTS: Bivariate regression revealed that overcrowded households were positively associated with COVID-19 deaths (standardized β = 0.863, p < 0.001). COVID-19 case totals, people aged 60+, and the number of overcrowded households met conditions for inclusion in the backwards stepwise linear regression model. Analysis revealed all independent variables were positively associated with mortality rates, primarily for individuals 60 + (standardized β

Genetic Evaluation For Hereditary Cancer Syndromes Among African Americans: A Critical Review, Ambreen Khan, Charles R Rogers, Carson D Kennedy, Ana Maria Lopez, Joanne Jeter

Department of Medical Oncology Faculty Papers

While hereditary cancer syndromes have been described and studied for centuries, the completion of the human genome project fueled accelerated progress in precision medicine due to the introduction of genetic testing in the 1990s, creating avenues for tailored treatments and medical management options. However, genetic testing has not benefited everyone equitably, with nearly all of the published work based on individuals of non-Hispanic White/European ancestry. There remains a gap in knowledge regarding the prevalence, penetrance, and manifestations of common hereditary cancer syndromes in the African-American population due to significant disparities in access and uptake of genetic testing. This review summarizes …