Digital Commons Network^™

Secondary Cytogenetic Abnormalities In Core-Binding Factor Aml Harboring Inv(16) Vs T(8;21), Se Young Han, Krzysztof Mrózek, Jenna Voutsinas, Qian Wu, Elizabeth A. Morgan, Hanne Vestergaard, Robert Ohgami, Philip M. Kluin, Thomas Kielsgaard Kristensen, Sheeja Pullarkat, Michael Boe Møller, Ana-Iris Schiefer, Linda B. Baughn, Young Kim, David Czuchlewski, Jacobien R. Hilberink, Hans-Peter Horny, Tracy I. George, Michelle Dolan, Nam K. Ku, Cecilia Arana Yi, Vinod Pullarkat, Jessica Kohlschmidt, Amandeep Salhotra, Lori Soma, Clara D. Bloomfield, Dong Chen, Wolfgang R. Sperr, Guido Marcucci, Christina Cho, Cem Akin, Jason Gotlib, Sigurd Broesby-Olsen, Melissa Larson, Michael A. Linden, H Joachim Deeg, Gregor Hoermann, Miguel-Angel Perales, Jason L. Hornick, Mark R. Litzow, Ryotaro Nakamura, Daniel Weisdorf, Gautam Borthakur, Gerwin Huls, Peter Valent, Celalettin Ustun, Cecilia C S Yeung

Pathology Research and Scholarship

Patients with core-binding factor (CBF) acute myeloid leukemia (AML), caused by either t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22), have higher complete remission rates and longer survival than patients with other subtypes of AML. However, ∼40% of patients relapse, and the literature suggests that patients with inv(16) fare differently from those with t(8;21). We retrospectively analyzed 537 patients with CBF-AML, focusing on additional cytogenetic aberrations to examine their impact on clinical outcomes. Trisomies of chromosomes 8, 21, or 22 were significantly more common in patients with inv(16)/t(16;16): 16% vs 7%, 6% vs 0%, and 17% vs 0%, respectively. In contrast, del(9q) and loss of …

Cell Lineage Tracing Links Erα Loss In Erbb2-Positive Breast Cancers To The Arising Of A Highly Aggressive Breast Cancer Subtype, Yunfeng Ding, Yonghong Liu, Dong-Kee Lee, Zhangwei Tong, Xiaobin Yu, Yi Li, Yong Xu, Rainer B Lanz, Bert W O'Malley, Jianming Xu

Children’s Nutrition Research Center Staff Publications

HER2-positive (HER2+) breast cancers (BrCs) contain approximately equal numbers of ERα+HER2+ and ERα−HER2+ cases. An enduring obstacle is the unclear cell lineage-related characteristics of these BrCs. Although ERα+HER2+ BrCs could lose ERα to become ERα−HER2+ BrCs, direct evidence is missing. To investigate ERα dependencies and their implications during BrC growth and metastasis, we generated ERαCreRFP-T mice that produce an RFP-marked ERα+ mammary gland epithelial cell (MGEC) lineage. RCAS virus-mediated expression of Erbb2, a rodent Her2 homolog, first produced comparable numbers of ERα+RFP+Erbb2+ and ERα−RFP−Erbb2+ MGECs. Early hyperplasia developed mostly from ERα+RFP+Erbb2+ cells and ERα−RFP−Erbb2+ cells in these lesions were rare. …

Novel Autosegmentation Spatial Similarity Metrics Capture The Time Required To Correct Segmentations Better Than Traditional Metrics In A Thoracic Cavity Segmentation Workflow, Kendall J Kiser, Arko Barman, Sonja Stieb, Clifton D Fuller, Luca Giancardo

2020-Current year OA Pubs

Automated segmentation templates can save clinicians time compared to de novo segmentation but may still take substantial time to review and correct. It has not been thoroughly investigated which automated segmentation-corrected segmentation similarity metrics best predict clinician correction time. Bilateral thoracic cavity volumes in 329 CT scans were segmented by a UNet-inspired deep learning segmentation tool and subsequently corrected by a fourth-year medical student. Eight spatial similarity metrics were calculated between the automated and corrected segmentations and associated with correction times using Spearman's rank correlation coefficients. Nine clinical variables were also associated with metrics and correction times using Spearman's rank …

Common Dna Methylation Dynamics In Endometriod Adenocarcinoma And Glioblastoma Suggest Universal Epigenomic Alterations In Tumorigenesis, Jennifer A Karlow, Benpeng Miao, Xiaoyun Xing, Ting Wang, Bo Zhang

Open Access Publications

Trends in altered DNA methylation have been defined across human cancers, revealing global loss of methylation (hypomethylation) and focal gain of methylation (hypermethylation) as frequent cancer hallmarks. Although many cancers share these trends, little is known about the specific differences in DNA methylation changes across cancer types, particularly outside of promoters. Here, we present a comprehensive comparison of DNA methylation changes between two distinct cancers, endometrioid adenocarcinoma (EAC) and glioblastoma multiforme (GBM), to elucidate common rules of methylation dysregulation and changes unique to cancers derived from specific cells. Both cancers exhibit significant changes in methylation over regulatory elements. Notably, hypermethylated …

Keap1 Cancer Mutants: A Large-Scale Molecular Dynamics Study Of Protein Stability., Carter J Wilson, Megan Chang, Mikko Karttunen, Wing-Yiu Choy

Chemistry Publications

We have performed 280 μs of unbiased molecular dynamics (MD) simulations to investigate the effects of 12 different cancer mutations on Kelch-like ECH-associated protein 1 (KEAP1) (G333C, G350S, G364C, G379D, R413L, R415G, A427V, G430C, R470C, R470H, R470S and G476R), one of the frequently mutated proteins in lung cancer. The aim was to provide structural insight into the effects of these mutants, including a new class of ANCHOR (additionally NRF2-complexed hypomorph) mutant variants. Our work provides additional insight into the structural dynamics of mutants that could not be analyzed experimentally, painting a more complete picture of their mutagenic effects. Notably, blade-wise …

Efficacy Of As04-Adjuvanted Vaccine Against Human Papillomavirus (Hpv) Types 16 And 18 In Clearing Incident Hpv Infections: Pooled Analysis Of Data From The Costa Rica Vaccine Trial And The Patricia Study, Joseph E. Tota, Frank Struyf, Allan Hildesheim, Paula Gonzalez, Martin Ryser, Rolando Herrero, John Schussler, Naveen Karkada, Ana Cecilia Rodriguez, Nicolas Folschweiller, Carolina Porras, Mark Schiffman, John T. Schiller, Wim Quint, Aimée R. Kreimer, Matti Lehtinen, Cosette M. Wheeler, Joshua N Sampson

Pathology Research and Scholarship

Clinical trial data and real-world evidence suggest that the AS04-adjuvanted vaccine targeting human papillomavirus types 16 and 18 (AS04-HPV-16/18) vaccine provides nearly 90% protection against cervical intraepithelial neoplasia grade 3 or higher irrespective of type, among women vaccinated before sexual debut. This high efficacy is not fully explained by cross-protection. Although AS04-HPV-16/18 vaccination does not affect clearance of prevalent infections, it may accelerate clearance of newly acquired infections. We pooled data from 2 large-scale randomized controlled trials to evaluate efficacy of the AS04-HPV-16/18 vaccine against clearance of nontargeted incident infections. Results of our analysis do not suggest an effect in …

Phenotypic And Genomic Profiling Of Staphylococcus Argenteus In Canada And The United States And Recommendations For Clinical Result Reporting, Alireza Eshaghi, Carl Bommersbach, Sandra Zittermann, C A Burnham, Robin Patel, Audrey N Schuetz, Samir N Patel, Julianne V Kus

Open Access Publications

No abstract provided.

A Method To Delineate De Novo Missense Variants Across Pathways Prioritizes Genes Linked To Autism, Amanda Koire, Panagiotis Katsonis, Young Won Kim, Christie Buchovecky, Stephen J Wilson, Olivier Lichtarge

Faculty, Staff and Students Publications

Genotype-phenotype relationships shape health and population fitness but remain difficult to predict and interpret. Here, we apply an evolutionary action method in mutational landscapes to unravel genes and pathways connected to autism spectrum disorder (ASD). Evolutionary action predicts the impact of missense variants on protein function by measuring motions in fitness landscapes, based on phylogenetic distances and substitution odds in homologous sequences. By examining 368 pathways across 2,384 individuals with ASD (probands), we found that 23 pathways, a total of 398 genes, had de novo missense variants biased to higher evolutionary action scores than expected by random chance, including axonogenesis, …

Electronic Clinical Decision Support For Children With Minor Head Trauma And Intracranial Injuries: A Sociotechnical Analysis, Jacob K Greenberg, Ayodamola Otun, Azzah Nasraddin, Ross C Brownson, Nathan Kuppermann, David D Limbrick, Po-Yin Yen, Randi E Foraker

2020-Current year OA Pubs

BACKGROUND: Current management of children with minor head trauma (MHT) and intracranial injuries is not evidence-based and may place some children at risk of harm. Evidence-based electronic clinical decision support (CDS) for management of these children may improve patient safety and decrease resource use. To guide these efforts, we evaluated the sociotechnical environment impacting the implementation of electronic CDS, including workflow and communication, institutional culture, and hardware and software infrastructure, among other factors.

METHODS: Between March and May, 2020 semi-structured qualitative focus group interviews were conducted to identify sociotechnical influences on CDS implementation. Physicians from neurosurgery, emergency medicine, critical care, …

Experience With Liposomal Amphotericin B In Outpatient Parenteral Antimicrobial Therapy, Yvonne J Burnett, Andrej Spec, Mohamed M Ahmed, William G Powderly, Yasir Hamad

Open Access Publications

Outpatient parenteral antimicrobial therapy (OPAT) is a safe, effective, and convenient treatment strategy for patients receiving intravenous antimicrobials in the outpatient setting; however, data are limited describing the use and safety of liposomal amphotericin B (L-AMB). Records of patients receiving L-AMB OPAT between 1/1/2015 and 7/31/2018 were retrospectively reviewed. The primary objective was to describe the OPAT patient population discharged on L-AMB and evaluate factors associated with readmission and adverse events (AEs). Analysis was performed to evaluate for predictors of worse outcomes. Forty-two patients (67% male, median age 50 years) were identified, most of whom were treated for histoplasmosis. The …

Community Support Model On Breastfeeding And Complementary Feeding Practices In Remote Areas In Vietnam: Implementation, Cost, And Effectiveness, Tuan T. Nguyen, Nemat Hajeebhoy, Jia Li, Chung T. Do, Roger Mathisen, Edward A. Frongillo Jr.

Faculty Publications

Background

Poor access to healthcare facilities and consequently nutrition counseling services hinders the uptake of recommended infant and young child feeding (IYCF) practices. To address these barriers and improve IYCF practices, Alive & Thrive (A&T) initiated community support groups in remote villages across nine provinces in Vietnam.

Objective

This study examines the effectiveness of the support group model and related project costs for reaching underserved areas to improve IYCF practices.

Methods

To evaluate the model’s implementation and project costs, we reviewed implementation guidelines, expenditure and coverage reports, monitoring data, and budgets for the nine provinces. To evaluate the model’s effectiveness, …

Models Of Care For Patients With Hypertension And Diabetes In Humanitarian Crises: A Systematic Review, Michael S Jaung, Ruth Willis, Piyu Sharma, Sigiriya Aebischer Perone, Signe Frederiksen, Claudia Truppa, Bayard Roberts, Pablo Perel, Karl Blanchet, Éimhín Ansbro

Faculty, Staff and Students Publications

Care for non-communicable diseases, including hypertension and diabetes (HTN/DM), is recognized as a growing challenge in humanitarian crises, particularly in low- and middle-income countries (LMICs) where most crises occur. There is little evidence to support humanitarian actors and governments in designing efficient, effective, and context-adapted models of care for HTN/DM in such settings. This article aimed to systematically review the evidence on models of care targeting people with HTN/DM affected by humanitarian crises in LMICs. A search of the MEDLINE, Embase, Global Health, Global Indexus Medicus, Web of Science, and EconLit bibliographic databases and grey literature sources was performed. Studies …

Long Term Safety, Tolerability, And Efficacy Of Intracutaneous Zolmitriptan (M207) In The Acute Treatment Of Migraine., Stephanie J. Nahas, Nada Hindiyeh, Deborah I. Friedman, Nada Elbuluk, Donald J. Kellerman, Pamela K. Foreman, Peter Schmidt

Department of Neurology Faculty Papers

OBJECTIVE: To determine the long-term safety and tolerability profile of M207 in the acute treatment of migraine.

BACKGROUND: M207 is an investigational microneedle-based system for intracutaneous delivery of zolmitriptan for the treatment of migraine attacks. Following on the positive results of a Phase 2/3 placebo-controlled efficacy study (ZOTRIP), this study was designed to evaluate the safety of this novel product during repeated use for the treatment of migraine attacks.

METHODS: In this 6-12 month open-label, multicenter observational study, participants used an eDiary to record headache symptoms and adverse events at specified intervals up to 48 h following treatment of a …

Ranking Methodology To Evaluate The Severity Of A Quality Gap Using A National Ehr Database., Shivani Sivasankar, An-Lin Cheng, Mark A. Hoffman

Manuscripts, Articles, Book Chapters and Other Papers

Selecting quality improvement projects can often be a reactive process. In order to demonstrate a data-driven strategy, we used multi-site, de-identified electronic health record (EHR) data to prioritize the severity of a quality concern: inappropriate A1c test orders for sickle cell disease patients in two randomly chosen facilities (Facility A & B). The best linear unbiased predictions (BLUP) generated from Generalized Linear Mixed Model (GLMM) was estimated for all 393 facilities with 37,151 SCD patients in the Cerner Health FactsTM (HF) data warehouse based on the ratio of inappropriate A1c orders. Ranking the BLUP after applying the GLMM indicates that …

One-Year Urinary And Sexual Outcome Trajectories Among Prostate Cancer Patients Treated By Radical Prostatectomy: A Prospective Study, Lin Yang, Jung Ae Lee, Emily Heer, Claire Pernar, Graham A Colditz, Ratna Pakpahan, Kellie R Imm, Eric H Kim, Robert L Grubb 3rd, Kathleen Y Wolin, Adam S Kibel, Siobhan Sutcliffe

2020-Current year OA Pubs

BACKGROUND: To examine one-year trajectories of urinary and sexual outcomes, and correlates of these trajectories, among prostate cancer patients treated by radical prostatectomy (RP).

METHODS: Study participants were recruited from 2011 to 2014 at two US institutions. Self-reported urinary and sexual outcomes were measured at baseline before surgery, and 5 weeks, 6 months and 12 months after surgery, using the modified Expanded Prostate Cancer Index Composite-50 (EPIC-50). Changes in EPIC-50 scores from baseline were categorized as improved (beyond baseline), maintained, or impaired (below baseline), using previously-reported minimum clinically important differences.

RESULTS: Of the 426 eligible participants who completed the baseline …

Tofacitinib, An Oral Janus Kinase Inhibitor: Analysis Of Malignancy (Excluding Nonmelanoma Skin Cancer) Events Across The Ulcerative Colitis Clinical Program, Gary R Lichtenstein, Gerhard Rogler, Matthew A Ciorba, Chinyu Su, Gary Chan, Ronald D Pedersen, Nervin Lawendy, Daniel Quirk, Chudy I Nduaka, Andrew J Thorpe, Julian Panés

2020-Current year OA Pubs

BACKGROUND: Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Here, we performed an integrated analysis of malignancy events from the tofacitinib phase 3 UC clinical development program (excluding nonmelanoma skin cancer [NMSC]).

METHODS: Data (up to May 2019) were pooled from two phase 3 induction studies, a phase 3 maintenance study, and an ongoing, open-label, long-term extension (OLE) study, and analyzed as 3 cohorts: induction (N = 1139), maintenance (N = 592), and overall (induction, maintenance, and ongoing OLE study; N = 1124). Proportions and incidence rates (IRs; unique patients with events …

Opportunities And Challenges In Developing A Cryptosporidium Controlled Human Infection Model For Testing Antiparasitic Agents, Rajiv S Jumani, Johanne Blais, Hanns-Christian Tillmann, Florencia Segal, Dean Wetty, Christian Ostermeier, Natko Nuber, Jay Lakshman, Natasha Aziz, Richa Chandra, Wilbur H Chen, Cynthia L Chappell, Thierry T Diagana, Ujjini H Manjunatha

Faculty, Staff and Student Publications

Cryptosporidiosis is a leading cause of moderate-to-severe diarrhea in low- and middle-income countries, responsible for high mortality in children younger than two years of age, and it is also strongly associated with childhood malnutrition and growth stunting. There is no vaccine for cryptosporidiosis and existing therapeutic options are suboptimal to prevent morbidity and mortality in young children. Recently, novel therapeutic agents have been discovered through high-throughput phenotypic and target-based screening strategies, repurposing malaria hits, etc., and these agents have a promising preclinical in vitro and in vivo anti-

Stroma-Targeting Strategies In Pancreatic Cancer: Past Lessons, Challenges And Prospects, Faran Polani, Patrick M Grierson, Kian-Huat Lim

2020-Current year OA Pubs

Pancreatic ductal adenocarcinoma (PDAC) is projected to emerge as the second leading cause of cancer-related death after 2030. Extreme treatment resistance is perhaps the most significant factor that underlies the poor prognosis of PDAC. To date, combination chemotherapy remains the mainstay of treatment for most PDAC patients. Compared to other cancer types, treatment response of PDAC tumors to similar chemotherapy regimens is clearly much lower and shorter-lived. Aside from typically harboring genetic alterations that to date remain un-druggable and are drivers of treatment resistance, PDAC tumors are uniquely characterized by a densely fibrotic stroma that has well-established roles in promoting …

Increased Complement Activation Is A Distinctive Feature Of Severe Sars-Cov-2 Infection, Lina Ma, Sanjaya K. Sahu, Marlene Cano, Vasanthan Kuppuswamy, Jamal Bajwa, Ja’Nia Mcphatter, Tingting Lei, Aaron Day, Daniel Reynolds, Xiaobo Wu, Rebecca Schriefer, Adriana M. Rauseo, Charles W. Goss, Jane A. O’Halloran, Rachel M. Presti, Alfred H. Kim, Andrew E. Gelman, Philip A. Mudd, John P. Atkinson, Hrishikesh S. Kulkarni, Et Al.

2020-Current year OA Pubs

Complement activation has been implicated in the pathogenesis of severe SARS-CoV-2 infection. However, it remains to be determined whether increased complement activation is a broad indicator of critical illness (and thus, no different in COVID-19). It is also unclear which pathways are contributing to complement activation in COVID-19, and if complement activation is associated with certain features of severe SARS-CoV-2 infection, such as endothelial injury and hypercoagulability. To address these questions, we investigated complement activation in the plasma from patients with COVID-19 prospectively enrolled at two tertiary care centers: Washington University School of Medicine (n=134) and Yale School of Medicine …

Cancer-Associated Mutations Reveal A Novel Role For Epcam As An Inhibitor Of Cathepsin-L And Tumor Cell Invasion, Narendra V Sankpal, Taylor C Brown, Timothy P Fleming, John M Herndon, Anusha A Amaravati, Allison N Loynd, William E Gillanders

2020-Current year OA Pubs

BACKGROUND: EpCAM (Epithelial cell adhesion molecule) is often dysregulated in epithelial cancers. Prior studies implicate EpCAM in the regulation of oncogenic signaling pathways and epithelial-to-mesenchymal transition. It was recently demonstrated that EpCAM contains a thyroglobulin type-1 (TY-1) domain. Multiple proteins with TY-1 domains are known to inhibit cathepsin-L (CTSL), a cysteine protease that promotes tumor cell invasion and metastasis. Analysis of human cancer sequencing studies reveals that somatic EpCAM mutations are present in up to 5.1% of tested tumors.

METHODS: The Catalogue of Somatic Mutations in Cancer (COSMIC) database was queried to tabulate the position and amino acid changes of …

Implementation And Sustainability Factors Of Two Early-Stage Breast Cancer Conversation Aids In Diverse Practices, Danielle Schubbe, Mary C Politi, Julie Margenthaler, Courtney Goodwin, Et Al

2020-Current year OA Pubs

BACKGROUND: Conversation aids can facilitate shared decision-making and improve patient-centered outcomes. However, few examples exist of sustained use of conversation aids in routine care due to numerous barriers at clinical and organizational levels. We explored factors that will promote the sustained use of two early-stage breast cancer conversation aids. We examined differences in opinions between the two conversation aids and across socioeconomic strata.

METHODS: We nested this study within a randomized controlled trial that demonstrated the effectiveness of two early-stage breast cancer surgery conversation aids, one text-based and one picture-based. These conversation aids facilitated more shared decision-making and improved the …

Hbme1 And Ck19 Expression In Non-Invasive Follicular Thyroid Neoplasm With Papillary-Like Nuclear Features (Niftp) Vs Other Follicular Patterned Thyroid Lesions, Qandeel Sadiq, Radhika Sekhri, Daniel T Dibaba, Qi Zhao, Shweta Agarwal

Pathology Research and Scholarship

BACKGROUND: Thyroid neoplasms with follicular architecture can have overlapping morphologic features and pose diagnostic confusion among pathologists. Various immunohistochemical stains have been investigated as potential diagnostic markers for PTC, among which HBME1 and CK19 have gained popularity. Non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) poses similar diagnostic challenges with interobserver variability and is often misdiagnosed as adenomatoid nodule or follicular adenoma. This study aims to evaluate expression of HBME1 and CK19 in NIFTPs in comparison to other well-differentiated thyroid neoplasms and benign mimickers.

METHOD: Seventy-three thyroid cases diagnosed over a period of 3 years at Methodist University Hospital, …

Neurocognitive Empowerment For Addiction Treatment (Neat): Study Protocol For A Randomized Controlled Trial., Hamed Ekhtiari, Tara Rezapour, Brionne Sawyer, Hung-Wen Yeh, Rayus Kuplicki, Mimi Tarrasch, Martin P. Paulus, Robin Aupperle

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Neurocognitive deficits (NCDs) and associated meta-cognition difficulties associated with chronic substance use often delay the learning and change process necessary for addiction recovery and relapse prevention. However, very few cognitive remediation programs have been developed to target NCDs and meta-cognition for substance users. The study described herein aims to investigate the efficacy of a multi-component neurocognitive rehabilitation and awareness program termed "Neurocognitive Empowerment for Addiction Treatment" (NEAT). NEAT is a fully manualized, cartoon-based intervention involving psychoeducation, cognitive practice, and compensatory strategies relevant across 10 major cognitive domains, including aspects of attention, memory, executive functions, and decision-making.

METHOD/DESIGN: In a …

Invasive Therapies For Acute Coronary Syndromes In The Covid-19 Era, Sanket Borgaonkar, Joshua Hahn, Marilyne Daher, Waleed Kayani, Hani Jneid

Faculty, Staff and Students Publications

PURPOSE OF REVIEW: To identify and address the challenges associated with the care of ACS patients during the coronavirus 2019 pandemic.

RECENT FINDINGS: The COVID-19 pandemic has had a considerable global impact with over 2.0 million deaths worldwide so far. There has been considerable evidence suggesting that COVID-19 increases the risk of acute coronary syndromes (ACS). We propose characterizing ACS patients into 3 distinct categories to better assist in appropriate triage and management: critically ill patients, non-critically ill ST elevation myocardial infarction (STEMI) patients, and non-critically ill non-ST elevation myocardial infarction (NSTEMI)/unstable angina (UA) patients. We thoroughly review treatments strategies, …

Model Organisms Contribute To Diagnosis And Discovery In The Undiagnosed Diseases Network: Current State And A Future Vision, Dustin Baldridge, Michael F Wangler, Angela N Bowman, Shinya Yamamoto, Undiagnosed Diseases Network, Tim Schedl, Stephen C Pak, John H Postlethwait, Jimann Shin, Lilianna Solnica-Krezel, Hugo J Bellen, Monte Westerfield

2020-Current year OA Pubs

Decreased sequencing costs have led to an explosion of genetic and genomic data. These data have revealed thousands of candidate human disease variants. Establishing which variants cause phenotypes and diseases, however, has remained challenging. Significant progress has been made, including advances by the National Institutes of Health (NIH)-funded Undiagnosed Diseases Network (UDN). However, 6000-13,000 additional disease genes remain to be identified. The continued discovery of rare diseases and their genetic underpinnings provides benefits to affected patients, of whom there are more than 400 million worldwide, and also advances understanding the mechanisms of more common diseases. Platforms employing model organisms enable …

Immunodeficiency And Bone Marrow Failure With Mosaic And Germline Tlr8 Gain Of Function, Jahnavi Aluri, Alicia Bach, Saara Kaviany, Luana Chiquetto Paracatu, Maleewan Kitcharoensakkul, Magdalena A. Walkiewicz, Christopher D. Putnam, Marwan Shinawi, Nermina Saucier, Elise M. Rizzi, Michael T. Harmon, Molly P. Keppel, Michelle Ritter, Morgan Similuk, Elaine Kulm, Michael Joyce, Adriana A. De Jesus, Raphaela Goldbach-Mansky, Yi-Shan Lee, Marina Cella, Peggy L. Kendall, Mary C. Dinauer, Jeffrey J. Bednarski, Christina Bemrich-Stolz, Scott W. Canna, Shirley M. Abraham, Matthew M. Demczko, Jonathan Powell, Stacie M. Jones, Amy M. Scurlock, Suk See De Ravin, Jack J. Bleesing, James A. Connelly, V Koneti Rao, Laura G. Schuettpelz, Megan A. Cooper

Pediatrics Research and Scholarship

Inborn errors of immunity (IEI) are a genetically heterogeneous group of disorders with a broad clinical spectrum. Identification of molecular and functional bases of these disorders is important for diagnosis, treatment, and an understanding of the human immune response. We identified 6 unrelated males with neutropenia, infections, lymphoproliferation, humoral immune defects, and in some cases bone marrow failure associated with 3 different variants in the X-linked gene TLR8, encoding the endosomal Toll-like receptor 8 (TLR8). Interestingly, 5 patients had somatic variants in TLR8 with

Neurological Diseases And Covid-19: Prospective Analyses Using The Uk Biobank, Nicola Veronese, Lee Smith, Mario Barbagallo, Gianluigi Giannelli, Maria Gabriella Caruso, Anna Maria Cisternino, Maria Notarnicola, Chao Cao, Thomas Waldhoer, Lin Yang

2020-Current year OA Pubs

COVID-19 (Coronavirus disease-19) may present with neurological signs, but whether people already affected by neurological conditions are at a higher risk of contracting COVID-19 is still not known. We, therefore, aimed to investigate the association of previously diagnosed neurological conditions with COVID-19. 502,536 community-dwelling UK Biobank participants (54.4% male, mean age 56.6 ± 10.3 years) were included. Among these, 57,463 participants had a diagnosis of neurological conditions (11.43%) and a total of 1326 COVID-19-positive cases were identified (0.26%). Neurological conditions were identified through medical history and linkage to data on hospital admissions (ICD-10 code G00-G99). COVID-19 presence was diagnosed using …

Multi-Omic Analysis Elucidates The Genetic Basis Of Hydrocephalus, Andrew T Hale, Lisa Bastarache, Diego M Morales, John C Wellons Iii, David D Limbrick Jr., Eric R Gamazon

Open Access Publications

We conducted PrediXcan analysis of hydrocephalus risk in ten neurological tissues and whole blood. Decreased expression of MAEL in the brain was significantly associated (Bonferroni-adjusted p < 0.05) with hydrocephalus. PrediXcan analysis of brain imaging and genomics data in the independent UK Biobank (N = 8,428) revealed that MAEL expression in the frontal cortex is associated with white matter and total brain volumes. Among the top differentially expressed genes in brain, we observed a significant enrichment for gene-level associations with these structural phenotypes, suggesting an effect on disease risk through regulation of brain structure and integrity. We found additional support for these genes through analysis of the choroid plexus transcriptome of a murine model of hydrocephalus. Finally, differential protein expression analysis in patient cerebrospinal fluid recapitulated disease-associated expression changes in neurological tissues, but not in whole blood. Our findings provide convergent evidence highlighting the importance of tissue-specific pathways and mechanisms in the pathophysiology of hydrocephalus.

Identifying And Predicting Food Parenting Practice Profiles Among Canadian Parents, Claire N Tugault-Lafleur, Olivia De-Jongh González, Teresia M O'Connor, Sheryl O Hughes, Louise C Mâsse

Children’s Nutrition Research Center Staff Publications

Background: Food parenting practices (FPP) can affect children's eating behaviours, yet little is known about how various FPP co-occur. The primary aim was to identify profiles of FPPs use among Canadian parents. Secondary aims included examining sociodemographic correlates of FPP profiles and evaluating whether children's eating behaviours differed across FPP profiles.

Methods: Parents (n = 799) of 5-12-year-old children completed a validated FPP Item Bank and the Children's Eating Behaviour Questionnaire. Latent Class Analysis (LCA) was used to identify distinct FPP profiles. Regression analyses were used to explore associations between FPP profiles, sociodemographic variables (race, sex and education) and children's …

Protecting Sanitation Workers In Low-Middle Income Countries Amid Covid-19, Muhammad Mainuddin Patwary, Md Riad Hossain, Faysal Kabir Shuvo, Sadia Ashraf, Rabeya Sultana, Md Ashraful Alam

Faculty, Staff and Student Publications

No abstract provided.