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M6a Modifications Regulate Intestinal Immunity And Rotavirus Infection, Anmin Wang, Gaopeng Hou, Siyuan Ding, Et Al

Open Access Publications

N6-methyladenosine (m6A) is an abundant mRNA modification and affects many biological processes. However, how m6A levels are regulated during physiological or pathological processes such as virus infections, and the in vivo function of m6A in the intestinal immune defense against virus infections are largely unknown. Here, we uncover a novel antiviral function of m6A modification during rotavirus (RV) infection in small bowel intestinal epithelial cells (IECs). We found that rotavirus infection induced global m6A modifications on mRNA transcripts by down-regulating the m6a eraser ALKBH5. Mice lacking the m6A writer enzymes METTL3 in IECs (

A Test Of The Pioneer Factor Hypothesis Using Ectopic Liver Gene Activation, Jeffrey L. Hansen, Kaiser J. Loell, Barak A. Cohen

Open Access Publications

The pioneer factor hypothesis (PFH) states that pioneer factors (PFs) are a subclass of transcription factors (TFs) that bind to and open inaccessible sites and then recruit non-pioneer factors (non-PFs) that activate batteries of silent genes. The PFH predicts that ectopic gene activation requires the sequential activity of qualitatively different TFs. We tested the PFH by expressing the endodermal PF FOXA1 and non-PF HNF4A in K562 lymphoblast cells. While co-expression of FOXA1 and HNF4A activated a burst of endoderm-specific gene expression, we found no evidence for a functional distinction between these two TFs. When expressed independently, both TFs bound and …

The Mutationathon Highlights The Importance Of Reaching Standardization In Estimates Of Pedigree-Based Germline Mutation Rates, Lucie A. Bergeron, Tychele Turner, Et Al

Open Access Publications

In the past decade, several studies have estimated the human per-generation germline mutation rate using large pedigrees. More recently, estimates for various nonhuman species have been published. However, methodological differences among studies in detecting germline mutations and estimating mutation rates make direct comparisons difficult. Here, we describe the many different steps involved in estimating pedigree-based mutation rates, including sampling, sequencing, mapping, variant calling, filtering, and appropriately accounting for false-positive and false-negative rates. For each step, we review the different methods and parameter choices that have been used in the recent literature. Additionally, we present the results from a 'Mutationathon,' a …

Intrinsic Mechanisms In The Gating Of Resurgent Na+ Currents, Joseph L. Ransdell, Jonathan D. Moreno, Druv Bhagavan, Jonathan R. Silva, Jeanne M. Nerbonne

Open Access Publications

The resurgent component of the voltage-gated sodium current (I

Tumor Lysis Syndrome In A Patient With Metastatic Endometrial Cancer Treated With Lattice Stereotactic Body Radiation Therapy, Joshua P Schiff, Matthew B Spraker, Sai Duriseti, Sana Shaikh, Haris F Murad, David G Mutch, Clifford G Robinson, James Kavanaugh, Alexander J Lin

Open Access Publications

No abstract provided.

Perceptions Of Telemedicine And Costs Incurred By A Visit To A General Infectious Diseases Clinic: A Survey, Emily C. Evers, Stephanie A. Fritz, Graham A. Colditz, Jason P. Burnham

Open Access Publications

Background: The costs of attending in-person general infectious diseases clinics and preferences for visit type (telemedicine vs in-person) are not well known. We aimed to measure the time-related, monetary, social, and societal costs associated with travel to an in-person clinic visit and to assess patients' preferences, questions, and concerns regarding telemedicine.

Methods: Patients (≥18 years, living ≥25 miles from clinic at time of clinic visit) were recruited for this survey study from the general infectious diseases (ID) clinic at Washington University from June 2019 to February 2020. We calculated time and money potentially saved by telemedicine, as well as carbon …

Perceptions Of Risk Of Sars-Cov-2 Transmission In Social And Educational Activities By Infectious Diseases And General Pediatric Healthcare Providers, A Pre-Vaccine Risk Perception Cross-Sectional Survey, Andrew B. Janowski, Philip M. Polgreen, Susan E. Beekmann, Jason G. Newland

Open Access Publications

BACKGROUND: The perception of the transmission risks of SARS-CoV-2 in social and educational settings by US healthcare providers have not been previously quantified.

METHODS: Respondents completed an online survey between September and October 2020 to estimate the risk of SARS-CoV-2 transmission on a scale of 0-10 for different social and educational activities prior to the availability of the SARS-CoV-2 vaccines. Demographic information and experiences during the pandemic were also collected. The risk assessment was emailed to three listservs of healthcare providers, including national listservs of pediatric (PID) and adult infectious diseases (AID) providers, and a listserv of general pediatric practitioners …

A Rare Case Of Synovial Sarcoma Of The Prostate Causing Urinary Retention, Syed Ehsanullah, Syeda Zarmeena Rashid, Adeel Haq, Saiyed Abdullah A. Ehsanullah

Open Access Publications

Synovial sarcomas of the prostate are exceedingly rare malignant tumors. Only a few cases have been reported so far. We discuss a case of a 52-year-old male who presented with signs and symptoms of benign prostate hyperplasia (BPH) and was diagnosed with synovial sarcoma of the prostate. Since this sarcoma is rare, it can easily be misdiagnosed with BPH or adenocarcinoma of the prostate.

Ultrasound-Guided Thrombin Injection For The Treatment Of Bleeding Following Kidney And Liver Biopsies, Mark J Hoegger, William D Middleton

Open Access Publications

The purpose of this study was to describe the technique and outcomes of percutaneous thrombin injection into the superficial aspect of actively bleeding liver and kidney biopsy tracks identified with color Doppler ultrasound with the aim of hemorrhage termination. After percutaneous thrombin injection, 15/16 (94%) patients did not require further intervention. Ultrasound-guided thrombin injection into the superficial site of active bleeding is an effective technique for terminating bleeding in the immediate post-procedure period following kidney and liver biopsies and should be considered if active bleeding persists on color Doppler after ≥30 minutes of compression and observation.

One-Carbon Metabolism In Children With Marasmus And Kwashiorkor, Thaddaeus May, Bethany De La Haye, Gabrielle Nord, Kevin Klatt, Kevin Stephenson, Sara Adams, Lucy Bollinger, Neil Hanchard, Erland Arning, Teodoro Bottiglieri, Kenneth Maleta, Mark Manary, Farook Jahoor

Open Access Publications

BACKGROUND: Kwashiorkor is a childhood syndrome of edematous malnutrition. Its precise nutritional precipitants remain uncertain despite nine decades of study. Remarkably, kwashiorkor's disturbances resemble the effects of experimental diets that are deficient in one-carbon nutrients. This similarity suggests that kwashiorkor may represent a nutritionally mediated syndrome of acute one-carbon metabolism dysfunction. Here we report findings from a cross-sectional exploration of serum one-carbon metabolites in Malawian children.

METHODS: Blood was collected from children aged 12-60 months before nutritional rehabilitation: kwashiorkor (N = 94), marasmic-kwashiorkor (N = 43) marasmus (N = 118), moderate acute malnutrition (N = 56) and controls (N = …

Effect Of Early Treatment With Fluvoxamine On Risk Of Emergency Care And Hospitalisation Among Patients With Covid-19: The Together Randomised, Platform Clinical Trial, Gilmar Reis, Eric J Lenze, Angela M Reiersen, Et Al

Open Access Publications

BACKGROUND: Recent evidence indicates a potential therapeutic role of fluvoxamine for COVID-19. In the TOGETHER trial for acutely symptomatic patients with COVID-19, we aimed to assess the efficacy of fluvoxamine versus placebo in preventing hospitalisation defined as either retention in a COVID-19 emergency setting or transfer to a tertiary hospital due to COVID-19.

METHODS: This placebo-controlled, randomised, adaptive platform trial done among high-risk symptomatic Brazilian adults confirmed positive for SARS-CoV-2 included eligible patients from 11 clinical sites in Brazil with a known risk factor for progression to severe disease. Patients were randomly assigned (1:1) to either fluvoxamine (100 mg twice …

Loss Of Kmt2c Reprograms The Epigenomic Landscape In Hpscs Resulting In Nodal Overexpression And A Failure Of Hemogenic Endothelium Specification, Shailendra Maurya, Wei Yang, Minori Tamai, Qiang Zhang, Petra Erdmann-Gilmore, Amelia Bystry, Fernanda Martins Rodrigues, Mark C Valentine, Wing H Wong, Reid Townsend, Todd E Druley

Open Access Publications

Germline or somatic variation in the family of KMT2 lysine methyltransferases have been associated with a variety of congenital disorders and cancers. Notably,

Mean Lifetime Survival Estimates Following Solid Organ Transplantation In The Us And Uk, Christopher N Graham, Crystal Watson, Arie Barlev, Matt Stevenson, Vikas R Dharnidharka

Open Access Publications

AIMS: Accurately estimating mean survival after solid organ transplant (SOT) is crucial for efficient healthcare resource allocation decisions. However, registry-based post-transplant recipient survival estimates vary greatly and are incomplete. Often, the methods used in lifetime survival extrapolation may not fit complex transplant data and therefore alternative methods are required. We aimed to explore the flexible cubic spline methodology as a meaningful alternative for estimating lifetime survival following SOT.

METHODS: Survival analyses were conducted in kidney, liver, heart, and lung transplant recipients. Mean survival was estimated using flexible cubic splines on the hazard scale fitted with three knots, based on where …

Single-Cell Genomics For Resolution Of Conserved Bacterial Genes And Mobile Genetic Elements Of The Human Intestinal Microbiota Using Flow Cytometry, Dylan Lawrence, Danielle E Campbell, Lawrence A Schriefer, Rachel Rodgers, Forrest C Walker, Marissa Turkin, Lindsay Droit, Miles Parkes, Scott A Handley, Megan T Baldridge

Open Access Publications

As our understanding of the importance of the human microbiota in health and disease grows, so does our need to carefully resolve and delineate its genomic content. 16S rRNA gene-based analyses yield important insights into taxonomic composition, and metagenomics-based approaches reveal the functional potential of microbial communities. However, these methods generally fail to directly link genetic features, including bacterial genes and mobile genetic elements, to each other and to their source bacterial genomes. Further, they are inadequate to capture the microdiversity present within a genus, species, or strain of bacteria within these complex communities. Here, we present a method utilizing …

Augmented Cardiac Growth Hormone Signaling Contributes To Cardiomyopathy Following Genetic Disruption Of The Cardiomyocyte Circadian Clock, Ravi Sonkar, Ryan Berry, Mary N Latimer, Sumanth D Prabhu, Martin E Young, Stuart J Frank

Open Access Publications

Circadian clocks regulate numerous biological processes, at whole body, organ, and cellular levels. This includes both hormone secretion and target tissue sensitivity. Although growth hormone (GH) secretion is time-of-day-dependent (increased pulse amplitude during the sleep period), little is known regarding whether circadian clocks modulate GH sensitivity in target tissues. GH acts in part through induction of insulin-like growth factor 1 (IGF1), and excess GH/IGF1 signaling has been linked to pathologies such as insulin resistance, acromegaly, and cardiomyopathy. Interestingly, genetic disruption of the cardiomyocyte circadian clock leads to cardiac adverse remodeling, contractile dysfunction, and reduced lifespan. These observations led to the …

What Can Brinley Plots Tell Us About Cognitive Aging? Exploring Simulated Data And Modified Brinley Plots, Jessica Nicosia, Emily R Cohen-Shikora, Michael J Strube

Open Access Publications

Cognitive aging researchers have been challenged with demonstrating age-related effects above and beyond global slowing ever since Cerella raised this issue in 1990. As the literature has made clear, this has indeed proved to be a difficult task and continues to plague the field. One way that researchers have attempted to test for disproportionate age differences across task conditions is by using Brinley plots, or plotting the mean response latencies of older adults against the mean latencies for younger adults. The simplicity and large proportion of variance accounted for by these models has led to the widespread use of Brinley …

Selected Histone Deacetylase Inhibitors Reverse The Frataxin Transcriptional Defect In A Novel Friedreich's Ataxia Induced Pluripotent Stem Cell-Derived Neuronal Reporter System, Anna M Schreiber, Yanjie Li, Yi-Hsien Chen, Jill S Napierala, Marek Napierala

Open Access Publications

Friedreich's ataxia (FRDA) is a neurodegenerative disorder caused by the expansion of guanine-adenine-adenine repeats within the first intron of the frataxin (

Isolation Of Sars-Cov-2 In Viral Cell Culture In Immunocompromised Patients With Persistently Positive Rt-Pcr Results, Abby Sung, Adam L Bailey, Henry B Stewart, David Mcdonald, Meghan A Wallace, Kate Peacock, Candace Miller, Kimberly A Reske, Caroline A O'Neil, Victoria J Fraser, Michael S Diamond, Carey-Ann D Burnham, Hilary M Babcock, Jennie H Kwon

Open Access Publications

Immunocompromised adults can have prolonged acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive RT-PCR results, long after the initial diagnosis of coronavirus disease 2019 (COVID-19). This study aimed to determine if SARS-CoV-2 virus can be recovered in viral cell culture from immunocompromised adults with persistently positive SARS-CoV-2 RT-PCR tests. We obtained 20 remnant SARS-CoV-2 PCR positive nasopharyngeal swabs from 20 immunocompromised adults with a positive RT-PCR test ≥14 days after the initial positive test. The patients' 2

Ethical, Regulatory, And Practical Barriers To Covid-19 Research: A Stakeholder-Informed Inventory Of Concerns, Bryan A. Sisk, Kari Baldwin, Meredith Parsons, James M. Dubois

Open Access Publications

INTRODUCTION: SARS-CoV-2 (COVID-19) has caused death and economic injury around the globe. The urgent need for COVID-19 research created new ethical, regulatory, and practical challenges. The next public health emergency could be worse than COVID-19. We must learn about these challenges from the experiences of researchers and Research Ethics Committee professionals responsible for these COVID-19 studies to prepare for the next emergency.

MATERIALS AND METHODS: We conducted an online survey to identify the ethical, oversight, and regulatory challenges of conducting COVID-19 research during the early pandemic, and proposed solutions for overcoming these barriers. Using criterion-based, convenience sampling, we invited researchers …

Hemodynamic Profiles By Non-Invasive Monitoring Of Cardiac Index And Vascular Tone In Acute Heart Failure Patients In The Emergency Department: External Validation And Clinical Outcomes, Nicholas Eric Harrison, Sarah Meram, Xiangrui Li, Morgan B. White, Sarah Henry, Sushane Gupta, Dongxiao Zhu, Peter Pang, Phillip Levy

Open Access Publications

BACKGROUND: Non-invasive finger-cuff monitors measuring cardiac index and vascular tone (SVRI) classify emergency department (ED) patients with acute heart failure (AHF) into three otherwise-indistinguishable subgroups. Our goals were to validate these "hemodynamic profiles" in an external cohort and assess their association with clinical outcomes.

METHODS: AHF patients (n = 257) from five EDs were prospectively enrolled in the validation cohort (VC). Cardiac index and SVRI were measured with a ClearSight finger-cuff monitor (formerly NexFin, Edwards Lifesciences) as in a previous study (derivation cohort, DC, n = 127). A control cohort (CC, n = 127) of ED patients with sepsis was …

Association Of A Perioperative Multicomponent Fall Prevention Intervention With Falls And Quality Of Life After Elective Inpatient Surgical Procedures, Bradley A. Fritz, Christopher R. King, Divya Mehta, Emily Somerville, Alex Kronzer, Arbi Ben Abdallah, Troy Wildes, Michael S. Avidan, Eric J. Lenze, Susan Stark

Open Access Publications

Importance: Falls after elective inpatient surgical procedures are common and have physical, emotional, and financial consequences. Close interactions between patients and health care teams before and after surgical procedures may offer opportunities to address modifiable risk factors associated with falls.

Objective: To assess whether a multicomponent intervention that incorporates education, home medication review, and home safety assessment is associated with reductions in the incidence of falls after elective inpatient surgical procedures.

Design, Setting, and Participants: This prospective propensity score-matched cohort study was a prespecified secondary analysis of data from the Electroencephalography Guidance of Anesthesia to Alleviate Geriatric Syndromes (ENGAGES) randomized …

Association Between Workplace Absenteeism And Alcohol Use Disorder From The National Survey On Drug Use And Health, 2015-2019, Ian C. Parsley, Ann Marie Dale, Sherri L. Fisher, Carrie M. Mintz, Sarah M. Hartz, Bradley A. Evanoff, Laura J. Bierut

Open Access Publications

Importance: Alcohol use disorder (AUD) is common and associated with increased morbidity. The degree to which AUD currently factors into workplace absenteeism needs further characterization in the US.

Objective: To examine the association between AUD and workplace absenteeism in a nationally representative sample.

Design, Setting, and Participants: This cross-sectional study used data from a nationally representative sample of noninstitutionalized US residents from the 2015-2019 National Survey on Drug Use and Health to examine the association of AUD with workplace absenteeism. Eligible respondents were aged 18 years and older who reported full-time employment. Data were analyzed from March to September 2021. …

Association Of Body Mass Index In Midlife With Morbidity Burden In Older Adulthood And Longevity, Sadiya S. Khan, Amy E. Krefman, Lihui Zhao, Lei Liu, Anna Chorniy, Martha L. Daviglus, Cuiping Schiman, Kiang Liu, Tina Shih, Daniel Garside, Thanh-Huyen T. Vu, Donald M. Lloyd-Jones, Norrina B. Allen

Open Access Publications

Importance: Abundant evidence links obesity with adverse health consequences. However, controversies persist regarding whether overweight status compared with normal body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) is associated with longer survival and whether this occurs at the expense of greater long-term morbidity and health care expenditures.

Objective: To examine the association of BMI in midlife with morbidity burden, longevity, and health care expenditures in adults 65 years and older.

Design, Setting, and Participants: Prospective cohort study at the Chicago Heart Association Detection Project in Industry, with baseline in-person examination between November 1967 …

Association Of Multidimensional Poverty With Dementia In Adults Aged 50 Years Or Older In South Africa, Jean-Francois Trani, Jacqueline Moodley, May Thu Thu Maw, Ganesh M. Babulal

Open Access Publications

Importance: Limited research exists investigating the association between multidimensional poverty and dementia in low-and middle-income countries (LMICs).

Objective: To investigate the association between multidimensional poverty and dementia among adults aged 50 years or older living in South Africa.

Design, Setting, and Participants: This cross-sectional study was conducted in Soweto, Johannesburg, South Africa, between November 11, 2019, and February 28, 2020. Participants included 227 adults aged 50 years or older. Data analysis was concluded from August 1 to 30, 2021.

Exposures: Multidimensional poverty included 7 dimensions that are central to well-being (education, health, economic activity, living standards, social participation, fair treatment, …

De Novo Missense Variants In Fbxo11 Alter Its Protein Expression And Subcellular Localization, Anne Gregor, Marwan Shinawi, Et Al

Open Access Publications

Recently, others and we identified de novo FBXO11 (F-Box only protein 11) variants as causative for a variable neurodevelopmental disorder (NDD). We now assembled clinical and mutational information on 23 additional individuals. The phenotypic spectrum remains highly variable, with developmental delay and/or intellectual disability as the core feature and behavioral anomalies, hypotonia and various facial dysmorphism as frequent aspects. The mutational spectrum includes intragenic deletions, likely gene disrupting and missense variants distributed across the protein. To further characterize the functional consequences of FBXO11 missense variants, we analyzed their effects on protein expression and localization by overexpression of 17 different mutant …

An Overview Of Treatment Options For Patients With Relapsed/Refractory Multiple Myeloma And Renal Impairment, Meletios A Dimopoulos, Joseph Mikhael, Evangelos Terpos, Xavier Leleu, Philippe Moreau, Joan Bladé, Jin Seok Kim, Keith Stockerl-Goldstein, Paul G Richardson

Open Access Publications

Renal impairment (RI) is a relatively common complication of multiple myeloma, which increases in frequency as disease becomes more advanced and recovery of renal function becomes less likely as patients progress through lines of therapy. Clinical trials in the relapsed/refractory multiple myeloma (RRMM) setting have not uniformly included patients with RI or robustly reported their outcomes. Here, we review existing data among patients with RI and RRMM across drug classes (including immunomodulatory agents, proteasome inhibitors, monoclonal antibodies, antibody-drug conjugates, chimeric antigen receptor T-cell therapies, and exportin-1 inhibitor) to provide an improved understanding of available treatment options for this important population. …

Salaries, Degrees, And Babies: Trends In Fertility By Income And Education Among Japanese Men And Women Born 1943-1975-Analysis Of National Surveys, Cyrus Ghaznavi, Haruka Sakamoto, Lisa Yamasaki, Shuhei Nomura, Daisuke Yoneoka, Kenji Shibuya, Peter Ueda

Open Access Publications

BACKGROUND: While fertility rates have decreased during the second half of the 20th century in Japan, little is known regarding trends in the number of children that men and women have across birth cohorts and whether these differ by education and income.

METHODS: We used data from four rounds of the National Fertility Survey (1992, 2005, 2010 and 2015) and included men and women aged 40-49 years (16728 men and 17628 women). By 5-year birth cohorts, we assessed the distribution of number of children (0, 1, 2 and 3 or more) and total fertility (the mean number of children) at …

Treatment Patterns And Outcomes Following Disease Progression On Anti-Pd-1 Therapies For Advanced Melanoma, Beth L. Nordstrom, Melissa Hamilton, Jenna M. Collins, Dennis Earle, Ying Zhang, Shivani Srivastava, Leonel Hernandez-Aya

Open Access Publications

No abstract provided.

Nia Long Life Family Study: Objectives, Design, And Heritability Of Cross-Sectional And Longitudinal Phenotypes, Mary K. Wojczynski, Shiow Jiuan Lin, Paola Sebastiani, Thomas T. Perls, Joseph Lee, Alexander Kulminski, Anne Newman, Joe M. Zmuda, Kaare Christensen, Michael A. Province

Open Access Publications

The NIA Long Life Family Study (LLFS) is a longitudinal, multicenter, multinational, population-based multigenerational family study of the genetic and nongenetic determinants of exceptional longevity and healthy aging. The Visit 1 in-person evaluation (2006-2009) recruited 4 953 individuals from 539 two-generation families, selected from the upper 1% tail of the Family Longevity Selection Score (FLoSS, which quantifies the degree of familial clustering of longevity). Demographic, anthropometric, cognitive, activities of daily living, ankle-brachial index, blood pressure, physical performance, and pulmonary function, along with serum, plasma, lymphocytes, red cells, and DNA, were collected. A Genome Wide Association Scan (GWAS) (Ilumina Omni 2.5M …

Dysregulation Of The Leukocyte Signaling Landscape During Acute Covid-19, Isaiah R. Turnbull, Anja Fuchs, Kenneth E. Remy, Michael P. Kelly, Elfaridah P. Frazier, Sarbani Ghosh, Shin-Wen Chang, Monty B. Mazer, Annie Hess, Jennifer M. Leonard, Mark H. Hoofnagle, Marco Colonna, Richard S. Hotchkiss

Open Access Publications

The global COVID-19 pandemic has claimed the lives of more than 750,000 US citizens. Dysregulation of the immune system underlies the pathogenesis of COVID-19, with inflammation mediated tissue injury to the lung in the setting of suppressed systemic immune function. To define the molecular mechanisms of immune dysfunction in COVID-19 we utilized a systems immunology approach centered on the circulating leukocyte phosphoproteome measured by mass cytometry. We find that although COVID-19 is associated with wholesale activation of a broad set of signaling pathways across myeloid and lymphoid cell populations, STAT3 phosphorylation predominated in both monocytes and T cells. STAT3 phosphorylation …