Digital Commons Network^™

Novel Variants In Kat6b Spectrum Of Disorders Expand Our Knowledge Of Clinical Manifestations And Molecular Mechanisms, Megan Yabumoto, Catherine Gooch, Et Al

Open Access Publications

The phenotypic variability associated with pathogenic variants in Lysine Acetyltransferase 6B (KAT6B, a.k.a. MORF, MYST4) results in several interrelated syndromes including Say-Barber-Biesecker-Young-Simpson Syndrome and Genitopatellar Syndrome. Here we present 20 new cases representing 10 novel KAT6B variants. These patients exhibit a range of clinical phenotypes including intellectual disability, mobility and language difficulties, craniofacial dysmorphology, and skeletal anomalies. Given the range of features previously described for KAT6B-related syndromes, we have identified additional phenotypes including concern for keratoconus, sensitivity to light or noise, recurring infections, and fractures in greater numbers than previously reported. We surveyed clinicians to qualitatively assess the ways families …

Generation Of Two Induced Pluripotent Stem Cell Lines With Heterozygous And Homozygous Gag Deletion In Tor1a Gene From A Healthy Hipsc Line, Masuma Akter, Haochen Cui, Yi-Hsien Chen, Baojin Ding

Open Access Publications

A typical DYT1 dystonia is caused by a heterozygous GAG deletion (c.907-909) in the TOR1A gene (ΔE, p.Glu303del) and the pathogenesis is not clear. In this study, human induced pluripotent stem cell (hiPSC) lines carrying the heterozygous or homozygous GAG deletion in TOR1A gene were generated by genetic modification of a healthy hiPSC line (WTC11, UCSFi001-A). These hiPSC lines showed the normal stem cell morphology and karyotype, expressed the same pluripotency markers as their parental line, and had the capacity to differentiate into three germ layers, providing a valuable resource in determining the pathogenesis of human DYT1 dystonia.

Data-Driven Clustering Identifies Features Distinguishing Multisystem Inflammatory Syndrome From Acute Covid-19 In Children And Adolescents, Alon Geva, Philip C Spinella, Et Al

Open Access Publications

Background: Multisystem inflammatory syndrome in children (MIS-C) consensus criteria were designed for maximal sensitivity and therefore capture patients with acute COVID-19 pneumonia.

Methods: We performed unsupervised clustering on data from 1,526 patients (684 labeled MIS-C by clinicians) <21 years old hospitalized with COVID-19-related illness admitted between 15 March 2020 and 31 December 2020. We compared prevalence of assigned MIS-C labels and clinical features among clusters, followed by recursive feature elimination to identify characteristics of potentially misclassified MIS-C-labeled patients.

Findings: Of 94 clinical features tested, 46 were retained for clustering. Cluster 1 patients (

Interpretation: Using a data driven, unsupervised approach, we identified features that cluster patients into a group with high likelihood of having MIS-C. Other features identified a cluster of patients more likely to have acute severe COVID-19 pulmonary disease, and patients in this cluster labeled by clinicians as MIS-C …

Parasitic Nematode Fatty Acid- And Retinol-Binding Proteins Compromise Host Immunity By Interfering With Host Lipid Signaling Pathways, Sophia C. Parks, Susan Nguyen, Shyon Nasrolahi, Chaitra Bhat, Damian Juncaj, Dihong Lu, Raghavendran Ramaswamy, Harpal Dhillon, Hideji Fujiwara, Anna Buchman, Omar S. Akbari, Naoki Yamanaka, Martin J. Boulanger, Adler R. Dillman

Open Access Publications

Parasitic nematodes cause significant morbidity and mortality globally. Excretory/secretory products (ESPs) such as fatty acid- and retinol- binding proteins (FARs) are hypothesized to suppress host immunity during nematode infection, yet little is known about their interactions with host tissues. Leveraging the insect parasitic nematode, Steinernema carpocapsae, we describe here the first in vivo study demonstrating that FARs modulate animal immunity, causing an increase in susceptibility to bacterial co-infection. Moreover, we show that FARs dampen key components of the fly immune response including the phenoloxidase cascade and antimicrobial peptide (AMP) production. Our data also reveal that FARs deplete lipid signaling precursors …

X-Treme Loss Of Sequence Diversity Linked To Neo-X Chromosomes In Filarial Nematodes, John Mattick, Ramakrishna Rao, Et Al

Open Access Publications

The sequence diversity of natural and laboratory populations of Brugia pahangi and Brugia malayi was assessed with Illumina resequencing followed by mapping in order to identify single nucleotide variants and insertions/deletions. In natural and laboratory Brugia populations, there is a lack of sequence diversity on chromosome X relative to the autosomes (πX/πA = 0.2), which is lower than the expected (πX/πA = 0.75). A reduction in diversity is also observed in other filarial nematodes with neo-X chromosome fusions in the genera Onchocerca and Wuchereria, but not those without neo-X chromosome fusions in the genera Loa and Dirofilaria. In the species …

Cortical Feedback And Gating In Odor Discrimination And Generalization, Gaia Tavoni, David E. Chen Kersen, Vijay Balasubramanian

Open Access Publications

A central question in neuroscience is how context changes perception. In the olfactory system, for example, experiments show that task demands can drive divergence and convergence of cortical odor responses, likely underpinning olfactory discrimination and generalization. Here, we propose a simple statistical mechanism for this effect based on unstructured feedback from the central brain to the olfactory bulb, which represents the context associated with an odor, and sufficiently selective cortical gating of sensory inputs. Strikingly, the model predicts that both convergence and divergence of cortical odor patterns should increase when odors are initially more similar, an effect reported in recent …

Histologic Findings In Mucosa And Muscularis Propria Biopsied During Peroral Endoscopic Myotomy In Patients With Achalasia, Xiuli Liu, Enoch Kuo, Kai Wang, Yassen B Perbtani, Dennis Yang, Peter Draganov

Open Access Publications

Background: Peroral endoscopic myotomy (POEM) has been increasingly used to treat achalasia. Previous studies have reported high frequency of muscular eosinophilic infiltration in achalasia. Esophageal mucosal changes in achalasia have only been studied in esophagectomy specimens. Cardia mucosal changes in achalasia have not been reported previously. We aimed to further characterize the esophageal, gastric cardia, and muscularis propria changes in achalasia.

Methods: This was a pilot study. Patients with clinically and radiographically confirmed achalasia who underwent POEM were enrolled in the study. Mucosal biopsies were taken 1 cm proximal and 1 cm distal to the gastroesophageal junction, and muscularis propria …

Deep Learning-Based Method To Accurately Estimate Breast Tissue Optical Properties In The Presence Of The Chest Wall, Menghao Zhang, Shuying Li, Yun Zou, Quing Zhu

Open Access Publications

SIGNIFICANCE: In general, image reconstruction methods used in diffuse optical tomography (DOT) are based on diffusion approximation, and they consider the breast tissue as a homogenous, semi-infinite medium. However, the semi-infinite medium assumption used in DOT reconstruction is not valid when the chest wall is underneath the breast tissue.

AIM: We aim to reduce the chest wall's effect on the estimated average optical properties of breast tissue and obtain accurate forward model for DOT reconstruction.

APPROACH: We propose a deep learning-based neural network approach where a convolution neural network (CNN) is trained to simultaneously obtain accurate optical property values for …

Investigation Of Effect Of Modulation Frequency On High-Density Diffuse Optical Tomography Image Quality, Weihao Fan, Hamid Dehghani, Adam Eggebrecht

Open Access Publications

No abstract provided.

Protocol For Draup: A Deimplementation Programme To Decrease Routine Chest Radiographs After Central Venous Catheter Insertion, Enyo Ablordeppey, Byron Powell, Virginia Mckay, Shannon Keating, Aimee James, Christopher Carpenter, Marin Kollef, Richard Griffey

Open Access Publications

INTRODUCTION: Avoiding low value medical practices is an important focus in current healthcare utilisation. Despite advantages of point-of-care ultrasound (POCUS) over chest X-ray including improved workflow and timeliness of results, POCUS-guided central venous catheter (CVC) position confirmation has slow rate of adoption. This demonstrates a gap that is ripe for the development of an intervention.

METHODS: The intervention is a deimplementation programme called DRAUP (

ETHICS AND DISSEMINATION: Approval of the study by the Human Research Protection Office has been obtained. This work will be disseminated by publication of peer-reviewed manuscripts, presentation in abstract form at scientific meetings and data …

Diffusion-Weighted Imaging Reveals Distinct Patterns Of Cytotoxic Edema In Patients With Subdural Hematomas, David Robinson, Natalie Kreitzer, Laura B Ngwenya, Opeolu Adeoye, Daniel Woo, Jed Hartings, Brandon Foreman

Open Access Publications

Subdural hematomas (SDHs) are increasingly common and can cause ischemic brain injury. Previous work has suggested that this is driven largely by vascular compression from herniation, although this work was done before the era of magnetic resonance imaging (MRI). We thus sought to study SDH-related ischemic brain injury by looking at patterns of cytotoxic edema on diffusion-weighted MRI. To do so, we identified all SDH patients at a single institution from 2015 to 2019 who received an MRI within 2 weeks of presentation. We reviewed all MRIs for evidence of restricted diffusion consistent with cytotoxic edema. Cases were excluded if …

Cd177 Modulates The Function And Homeostasis Of Tumor-Infiltrating Regulatory T Cells, Myung-Chul Kim, Nicholas Borcherding, Kawther K. Ahmed, Andrew P. Voigt, Gaurav Pandey, Et Al

Open Access Publications

No abstract provided.

Lost In Translation: A Disconnect Between The Science And Medicare Coverage Criteria For Continuous Subcutaneous Insulin Infusion, Grazia Aleppo, Christopher G Parkin, Anders L Carlson, Rodolfo J Galindo, Davida F Kruger, Carol J Levy, Guillermo E Umpierrez, Gregory P Forlenza, Janet B Mcgill

Open Access Publications

Numerous studies have demonstrated the clinical value and safety of insulin pump therapy in type 1 diabetes and type 2 diabetes populations. However, the eligibility criteria for insulin pump coverage required by the Centers for Medicare & Medicaid Services (CMS) discount conclusive evidence that supports insulin pump use in diabetes populations that are currently deemed ineligible. This article discusses the limitations and inconsistencies of the insulin pump eligibility criteria relative to current scientific evidence and proposes workable solutions to address this issue and improve the safety and care of all individuals with diabetes.

Upstaging And Survival Outcomes For Non-Muscle Invasive Bladder Cancer After Radical Cystectomy: Results From The International Robotic Cystectomy Consortium, Umar Iqbal, Eric Kim, Et Al

Open Access Publications

No abstract provided.

Augmented Reality In Spinal Surgery: Highlights From Augmented Reality Lectures At The Emerging Technologies Annual Meetings, Syed-Abdullah Uddin, George Hanna, Lindsey Ross, Camilo Molina, Timur Urakov, Patrick Johnson, Terrence Kim, Doniel Drazin

Open Access Publications

Introduction Augmented reality (AR) is an advanced technology and emerging field that has been adopted into spine surgery to enhance care and outcomes. AR superimposes a three-dimensional computer-generated image over the normal anatomy of interest in order to facilitate visualization of deep structures without the ability to directly see them. Objective To summarize the latest literature and highlight AR from the annual "Spinal Navigation, Emerging Technologies and Systems Integration" meeting lectures presented by the Seattle Science Foundation (SSF) on the development and use of augmented reality in spinal surgery. Methods We performed a comprehensive literature review from 2016 to 2020 …

Recognizing The Vulnerable: Perspectives, Attitudes, And Interests Of Women With Uterine Factor Infertility Towards Uterus Allotransplantation, Helen Xun, Darya Fadavi, Halley Darrach, Nicole Fischer, Pooja Yesantharao, Franca Kraenzlin, Amanda Nickles Fader, James H. Segars, Justin M. Sacks

Open Access Publications

BACKGROUND: Uterine allotransplantation (UTx) is a novel therapy to allow women with uterine factor infertility (UFI) to bear their own children. To date, over 60 UTx have been performed, resulting in 15 live births. Our study investigates the attitudes, perspectives, and interests of women with UFI towards UTx.

METHODS: Anonymous questionnaires were distributed electronically to women diagnosed with UFI at Johns Hopkins Hospital between the years 2003 and 2018.

RESULTS: Thirty-one women with UFI were identified, resulting in 10 completed surveys. The average age was 31.7 ± 6.31 years, and the average age of diagnosis was 20 years (range 14-31); …

Acute Appendicitis Associated With Kawasaki Disease: Case Report And Review Of The Literature, Kaku Kuroda, Morgan Stottlemyre

Open Access Publications

Acute appendicitis is a rare complication of Kawasaki disease in the setting of the absence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We experienced a rare case of acute appendicitis associated with Kawasaki disease. The patient is a six-year-old male who was brought to the emergency department by his mother with a pruritic rash, nausea, vomiting, and abdominal pain. Given fever, tenderness in the right lower quadrant on physical examination, leukocytosis with bandemia, and a non-compressible and dilated appendix on ultrasound, he was diagnosed with acute appendicitis and was treated with a laparoscopic appendectomy. He developed persistent fevers …

Pretreatment Neutrophil-To-Lymphocyte Ratio As An Important Prognostic Marker In Stage Iii Locally Advanced Non-Small Cell Lung Cancer: Confirmatory Results From The Proclaim Phase Iii Clinical Trial, Tithi Biswas, Rohin Gawdi, Charulata Jindal, Sharanya Iyer, Kylie H. Kang, David Bajor, Mitchell Machtay, Yuk Ming Choi, Jimmy T. Efird

Open Access Publications

Background: Neutrophil-to-lymphocyte ratio (NLR) is an important pretreatment marker of systemic inflammation and tumor aggressiveness. Increased levels of this ratio have been associated with reduced survival in several observational studies of lung cancer. However, supporting analyses from large clinical trial data are lacking.

Methods: To validate the prognostic role of NLR, the current study evaluated data from a randomized phase III study (PROCLAIM; clinicaltrial.gov ID: NCT00686959) of patients with stage IIIA/B, unresectable, non-squamous, non-small cell lung cancer (NSCLC), originally comparing combination pemetrexed-cisplatin chemoradiotherapy with etoposide-cisplatin chemoradiotherapy. Adjusted hazard ratios (aHR) and 95% confidence intervals (CI) for survival were estimated using …

Dicer1 Tumor Predisposition Syndrome: An Evolving Story Initiated With The Pleuropulmonary Blastoma, Iván A González, Douglas R Stewart, Kris Ann P Schultz, Amanda P Field, D Ashley Hill, Louis P Dehner

Open Access Publications

DICER1 syndrome (OMIM 606241, 601200) is a rare autosomal dominant familial tumor predisposition disorder with a heterozygous DICER1 germline mutation. The most common tumor seen clinically is the pleuropulmonary blastoma (PPB), a lung neoplasm of early childhood which is classified on its morphologic features into four types (IR, I, II and III) with tumor progression over time within the first 4-5 years of life from the prognostically favorable cystic type I to the unfavorable solid type III. Following the initial report of PPB, its association with other cystic neoplasms was demonstrated in family studies. The detection of the germline mutation …

Mutation Of The Epha2 Tyrosine-Kinase Domain Dysregulates Cell Pattern Formation And Cytoskeletal Gene Expression In The Lens, Yuefang Zhou, Thomas M Bennett, Philip A Ruzycki, Alan Shiels

Open Access Publications

Genetic variations in ephrin type-A receptor 2 (EPHA2) have been associated with inherited and age-related forms of cataract in humans. Here, we have characterized the eye lens phenotype and transcript profile of germline

Frontal-Posterior Functional Imbalance And Aberrant Function Developmental Patterns In Schizophrenia, Dandan Sun, Fay Y. Womer, Et Al

Open Access Publications

No abstract provided.

Genetic Characterization, Current Model Systems And Prognostic Stratification In Pax Fusion-Negative Vs. Pax Fusion-Positive Rhabdomyosarcoma, Carina A Dehner, Amy E Armstrong, Marielle Yohe, Jack F Shern, Angela C Hirbe

Open Access Publications

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and adolescents and accounts for approximately 2% of soft tissue sarcomas in adults. It is subcategorized into distinct subtypes based on histological features and fusion status (

Antibiotic-Induced Disturbances Of The Gut Microbiota Result In Accelerated Breast Tumor Growth, Alastair M Mckee, Katherine N Weilbaecher, Et Al

Open Access Publications

The gut microbiota's function in regulating health has seen it linked to disease progression in several cancers. However, there is limited research detailing its influence in breast cancer (BrCa). This study found that antibiotic-induced perturbation of the gut microbiota significantly increases tumor progression in multiple BrCa mouse models. Metagenomics highlights the common loss of several bacterial species following antibiotic administration. One such bacteria,

Inhibition Of Chylomicron Assembly Leads To Dissociation Of Hepatic Steatosis From Inflammation And Fibrosis, Yan Xie, Elizabeth P Newberry, Elizabeth M Brunt, Samuel J Ballentine, Saeed Soleymanjahi, Elizabeth A Molitor, Nicholas O Davidson

Open Access Publications

Regulating dietary fat absorption may impact progression of nonalcoholic fatty liver disease (NAFLD). Here we asked if inducible inhibition of chylomicron assembly, as observed in intestine-specific microsomal triglyceride transfer protein knockout mice (Mttp-IKO), could retard NAFLD progression and/or reverse established fibrosis in two dietary models. Mttp-IKO mice fed a methionine/choline deficient (MCD) diet exhibited reduced hepatic triglycerides (TG), inflammation and fibrosis, associated with reduced oxidative stress and downstream activation of JNK and NFκB signaling pathways. However, when Mttp

Effectiveness Of Mrna Covid-19 Vaccine Among U.S. Health Care Personnel, Tamara Pilishvili, Jennie H. Kwon, Et Al

Open Access Publications

No abstract provided.

Methodological Rigor And Temporal Trends Of Cardiovascular Medicine Meta-Analyses In Highest-Impact Journals, Dhruv Mahtta, Ahmed Altibi, Mohamed M Gad, Amjad Samara, Amr F Barakat, Rodrigo Bagur, Hend Mansoor, Hani Jneid, Salim S Virani, Mamas A Mamas, Ahmad Masri, Islam Y Elgendy

Open Access Publications

Background Well-conducted meta-analyses are considered to be at the top of the evidence-based hierarchy pyramid, with an expansion of these publications within the cardiovascular research arena. There are limited data evaluating the trends and quality of such publications. The objective of this study was to evaluate the methodological rigor and temporal trends of cardiovascular medicine-related meta-analyses published in the highest impact journals. Methods and Results Using the Medline database, we retrieved cardiovascular medicine-related systematic reviews and meta-analyses published in

Increased Blood Pressure Variability And The Risk Of Probable Dementia Or Mild Cognitive Impairment: A Post Hoc Analysis Of The Sprint Mind Trial, Adam De Havenon, Mohammad Anadani, Shyam Prabhakaran, Ka-Ho Wong, Shadi Yaghi, Natalia Rost

Open Access Publications

Background Increased systolic blood pressure variability (BPV) is associated with stroke, cardiovascular disease, and dementia and mild cognitive impairment. However, prior studies assessing the relationship between BPV and dementia or mild cognitive impairment had infrequent measurement of blood pressure or suboptimal blood pressure control. Methods and Results We performed a post hoc analysis of the SPRINT (Systolic Blood Pressure Intervention Trial) MIND (Memory and Cognition in Decreased Hypertension) trial. The primary outcome was probable dementia during follow-up. We defined our exposure period, during which blood pressures were collected, as the first 600 days of the trial, and outcomes were ascertained …

Metformin Selectively Dampens The Acute Inflammatory Response Through An Ampk-Dependent Mechanism, Thomas S Postler, Vincent Peng, Dev M Bhatt, Sankar Ghosh

Open Access Publications

Metformin is a first-line drug in the treatment of type-2 diabetes mellitus (T2DM). In addition to its antigluconeogenic and insulin-sensitizing properties, metformin has emerged as a potent inhibitor of the chronic inflammatory response of macrophages. In particular, metformin treatment has been shown to reduce expression of interleukin (IL-) 1β during long-term exposure to the pro-inflammatory stimulus lipopolysaccharide (LPS) through a reduction in reactive oxygen species (ROS), which decreases the levels of the hypoxia-inducible factor (HIF) 1-α, and through enhanced expression of IL-10. However, the effect of metformin on the acute inflammatory response, before significant levels of ROS accumulate in the …

Exploring Contextual Factors Influencing The Implementation Of Evidence-Based Care For Hypertension In Rwanda: A Cross-Sectional Study Using The Coach Questionnaire, Ana Baumann, Cole Hooley, Charles Goss, Vincent Mutabazi, Angela Brown, Kenneth Schechtman, Marc Twagirumukiza, Lisa De Las Fuentes, Dominic Reeds, Makeda Williams, Eugene Mutimura, Anna Bergström, Aurore Nishimwe, Cecile Ingabire, Victor Davila-Roman

Open Access Publications

IMPORTANCE: Hypertension is the largest contributor to the Global Burden of Disease. In Rwanda, as in most low-income and middle-income countries, an increasing prevalence of hypertension and its associated morbidity and mortality is causing major healthcare and economic impact. Understanding healthcare systems context in hypertension care is necessary.

OBJECTIVE: To study the hypertension healthcare context as perceived by healthcare providers using the Context Assessment for Community Health (COACH) tool.

DESIGN: A cross-sectional cohort responded to the COACH questionnaire and a survey about hypertension training.

SETTING: Three tertiary care hospitals in Rwanda.

PARTICIPANTS: Healthcare professionals (n=223).

PRIMARY OUTCOMES AND MEASURES: The …

Trichomonas Vaginalis Detection In Urogenital Specimens From Symptomatic And Asymptomatic Men And Women By Use Of The Cobas Tv/Mg Test, Barbara Van Der Pol, David Eisenberg, Et Al

Open Access Publications

Trichomonas vaginalis is a prevalent sexually transmitted infection (STI). Diagnosis has historically relied on either microscopic analysis or culture, the latter being the previous gold standard. However, these tests are not readily available for male diagnosis, generally only perform well for symptomatic women, and are not as sensitive as nucleic acid amplification tests (NAATs). Men are largely asymptomatic but carry the organism and transmit to their sexual partners. This multicenter, prospective study evaluated the performance of the cobas T. vaginalis/Mycoplasma genitalium (TV/MG) assay for detection of T. vaginalis DNA compared with patient infection status (PIS) defined by a combination of …