Digital Commons Network^™

Discovery Of Genomic And Transcriptomic Pleiotropy Between Kidney Function And Soluble Receptor For Advanced Glycation End Products Using Correlated Meta-Analyses: The Long Life Family Study, Mary F Feitosa, Shiow J Lin, Sandeep Acharya, Bharat Thyagarajan, Mary K Wojczynski, Allison L Kuipers, Alexander Kulminski, Kaare Christensen, Joseph M Zmuda, Michael R Brent, Michael A Province

2020-Current year OA Pubs

Patients with chronic kidney disease (CKD) have increased oxidative stress and chronic inflammation, which may escalate the production of advanced glycation end-products (AGEs). High soluble receptor for AGE (sRAGE) and low estimated glomerular filtration rate (eGFR) levels are associated with CKD and aging. We evaluated whether eGFR calculated from creatinine and cystatin C share pleiotropic genetic factors with sRAGE. We employed whole-genome sequencing and correlated meta-analyses on combined genome-wide association study (GWAS) p-values in 4182 individuals (age range: 24-110) from the Long Life Family Study (LLFS). We also conducted transcriptome-wide association studies (TWAS) on whole blood in a subset of …

Immune Checkpoint Markers And Tumour Mutation Burden In Wilms Tumour: A Study Of 59 Cases, Aidas J Mattis, Jie-Fu Chen, Ivan A Gonzalez, Rehan Rais, Louis P Dehner, John Pfeifer, Mai He

2020-Current year OA Pubs

Wilms tumour (WT) is the most common renal tumour in children, and studies of immune checkpoint inhibitors (ICIs) treatment and markers are limited in number. In this study we investigated the ICIs' related immune landscape by examining the expression of PD-L1, PD-1, CD8 and DNA mismatch repair (MMR) proteins by immunohistochemistry (IHC), tumour mutation burden (TMB), and correlations with histology and clinical outcome. Positive PD-L1 (SP263) expression was defined as modified combined positive score (CPS) ≥1. A total of 59 WTs (from 2000 to 2017), including eight (14.0%) with anaplasia, from 46 patients were analysed (45 primary and 14 metastatic). …

Type I Ifn Signaling In The Absence Of Irgm1 Promotes M. Tuberculosis Replication In Immune Cells By Suppressing T Cell Responses, Sumanta K Naik, Michael E Mcnehlan, Yassin Mreyoud, Rachel L Kinsella, Asya Smirnov, Chanchal Sur Chowdhury, Samuel R Mckee, Neha Dubey, Reilly Woodson, Darren Kreamalmeyer, Christina L Stallings

2020-Current year OA Pubs

Polymorphisms in the IRGM gene are associated with susceptibility to tuberculosis in humans. A murine ortholog of Irgm, Irgm1, is also essential for controlling Mycobacterium tuberculosis (Mtb) infection in mice. Multiple processes have been associated with IRGM1 activity that could impact the host response to Mtb infection, including roles in autophagy-mediated pathogen clearance and expansion of activated T cells. However, what IRGM1-mediated pathway is necessary to control Mtb infection in vivo and the mechanistic basis for this control remains unknown. We dissected the contribution of IRGM1 to immune control of Mtb pathogenesis in vivo and found that Irgm1 deletion leads …

Ms Treatment De-Escalation: Review And Commentary, Krzysztof Selmaj, Hans-Peter Hartung, Marcin P Mycko, Igor Selmaj, Anne H Cross

2020-Current year OA Pubs

Almost all currently licensed disease-modifying therapies (DMTs) for MS treatment require prolonged if not lifelong administration. Yet, as people age, the immune system has increasingly reduced responsiveness, known as immunosenescence. Many MS DMTs reduce the responsiveness of the immune system, increasing the risks for infections and possibly cancers. As people with MS (pwMS) age, it is recognized that inflammatory MS activity declines. Several studies have addressed de-escalation of DMTs for relapsing MS under special circumstances. Here, we review evidence for de-escalating DMTs as a strategy that is particularly relevant to pwMS of older age. Treatment de-escalation can involve various strategies, …

New Insights Into Innate Immunity In Alzheimer's Disease: From Apoe Protective Variants To Therapies, Yun Chen, David M Holtzman

2020-Current year OA Pubs

Recent discoveries of rare variants of human APOE may shed light on novel therapeutic strategies for Alzheimer's disease (AD). Here, we highlight the newly identified protective variant [APOE3 Christchurch (APOE3ch, R136S)] as an example. We summarize human AD and mouse amyloidosis and tauopathy studies from the past 5 years that have been associated with this R136S variant. We also propose a potential mechanism for how this point mutation might lead to protection against AD pathology, from the molecular level, to cells, to mouse models, and potentially, to humans. Lastly, we extend our discussion of the recent insights gained regarding different …

Development And Optimization Of A Diluted Whole Blood Elispot Assay To Test Immune Function, Ricardo F Ungaro, Richard S Hotchkiss, Isaiah R Turnbull, Et Al.

2020-Current year OA Pubs

Sepsis remains a leading cause of death worldwide with no proven immunomodulatory therapies. Stratifying Patient Immune Endotypes in Sepsis ('SPIES') is a prospective, multicenter observational study testing the utility of ELISpot as a functional bioassay specifically measuring cytokine-producing cells after stimulation to identify the immunosuppressed endotype, predict clinical outcomes in septic patients, and test potential immune stimulants for clinical development. Most ELISpot protocols call for the isolation of PBMC prior to their inclusion in the assay. In contrast, we developed a diluted whole blood (DWB) ELISpot protocol that has been validated across multiple laboratories. Heparinized whole blood was collected from …

Integrating Audiovisual Immersion Into Pediatric Radiation Therapy Across Multiple Centers: Methodology, Timeliness, And Cost Of The Audiovisual-Assisted Therapeutic Ambience In Radiation Therapy Prospective Multi-Institutional Trial, Justin Oh, Stephanie M Perkins, Et Al.

2020-Current year OA Pubs

PURPOSE: The Audiovisual-Assisted Therapeutic Ambience in Radiotherapy (AVATAR) trial was a prospective multicenter study (NCT03991156) examining the combination of video immersion with radiation therapy and was successfully conducted through the collaboration of pediatric radiation oncology teams at 10 institutions independent of any pre-existing consortium. We sought to analyze and report the methodology of trial conception and development, process map, and cost.

METHODS AND MATERIALS: The study enrolled patients aged 3 to 10 years preparing to undergo radiation therapy, integrated the combination of AVATAR-based video immersion with radiation therapy at each institution, and offered AVATAR use as an alternative to anesthesia, …

Prophylactic Antibiotics For Excision Of Premalignant Vulvar Lesions: A Pilot Randomized Controlled Trial, Mary M Mullen, Whitney R Grither, Hannah Millimet, David G Mutch, Andrea R Hagemann, Carolyn K Mccourt, Matthew A Powell, Premal H Thaker, Dineo Khabele, Lindsay M Kuroki

2020-Current year OA Pubs

No prospective data have been described to inform guidelines on antibiotic prophylaxis for partial vulvectomies. Thus, we conducted a single-center, pilot, double-blind randomized controlled trial to assess the effectiveness of prophylactic antibiotics to prevent wound complications after partial vulvectomies. Patients were randomly assigned 1:1 to preoperative antibiotics or no preoperative antibiotics. The primary outcome of 30-day postoperative wound complications occurred in 31 (62 %) of all patients, with no differences between groups. The most common wound complications were superficial separation (54.2 % antibiotic prophylaxis vs. 65.3 % no prophylaxis, p = 0.37) and surgical site infection (0 % antibiotic prophylaxis …

Corticosteroid Burst Therapy In Patients With Acute Heart Failure: Design Of The Cortahf Pilot Study, Gad Cotter, Douglas L Mann, Et Al.

2020-Current year OA Pubs

AIMS: Inflammation has emerged as a potential key pathophysiological mechanism in heart failure (HF) in general and acute HF (AHF) specifically, with inflammatory biomarkers shown to be highly predictive of adverse outcomes in these patients. The CORTAHF study builds on both these data and the fact that steroid burst therapy has been shown to be effective in the treatment of respiratory diseases and COVID-19. Our hypothesis is that in patients with AHF and elevated C-reactive protein (CRP) levels without symptoms or signs of infection, a 7-day course of steroid therapy will lead to reduced inflammation and short-term improvement in quality …

The Good News Of The Investigative Judgment: Finding Joy In An Unlikely Doctrine, Richard M. Davidson

Faculty Publications

No abstract provided.

Interpregnancy Maternal Weight Change Is Not Associated With Offspring Weight And Obesity At Age 2 Years, Kate Maslin, Lieveke Ameye, Diederik Vancoppenolle, Anne Rochtus, Hanne Van Uytsel, Jill Shawe, Roland Devlieger, Annick Bogaerts

School of Nursing and Midwifery

Background: Weight retention between pregnancies is associated with increased risk of perinatal complications, but it is unclear whether there is an association with offspring weight status. This study aimed to determine whether maternal interpregnancy weight change is associated with offspring overweight/obesity, controlling for confounding variables. Subjects/methods: Routinely collected linked data from perinatal and child datasets, in Flanders, Belgium were used. Women having their first and second live births between 2009–2018 were included. The association between maternal interpregnancy weight change and overweight/obesity in the second child at 2 years was examined by logistical regression models. Results: A total of 33,172 women …

Time Scales And Mechanisms Of Uranium Uptake In Altered Ocean Crust; Observations From The ∼15 Million Year-Old Site 1256 In The Eastern Equatorial Pacific, Morten B. Andersen, Joel B. Rodney, Heye Freymuth, Flurin Vils, Michelle Harris, Kari Cooper, Damon A.H. Teagle, Tim Elliott

School of Geography, Earth and Environmental Sciences

The alteration of ocean crust through hydrothermal seawater circulation facilitates chemical exchange between Earth's surface and interior. Hydrothermal alteration leads to uranium (U) removal from seawater and net U uptake by the ocean crust, particularly during low temperature alteration that occurs on the vast ocean ridge flanks away from the spreading axes. Determining the timescales of U uptake and its associated ²³⁸U/²³⁵U signature has important implications for understanding U exchange processes during subduction and recycling into the mantle. Here we study the U systematics of ∼15 million year-old ocean crust drilled at Site 1256 on the eastern …

An Investigation Of Ransomware Incidents In The Maritime Industry: Exploring The Key Risk Factors, Ömer Söner, Gizem Kayisoglu, Pelin Bolat, Kimberly Tam

School of Engineering, Computing and Mathematics

Ransomware is a subset of malicious cyberattacks that aim to hold an organization’s data or critical infrastructure at ransom, compromising or blocking access. If the attack is public or made public after the initial attack, it can also severely jeopardize an organization’s reputation. Given the direct and immediate impact ransomware attacks can have and the lack of in-depth sharing, additional research is needed to analyze ransomware incidents in order to understand the underlying causes of incidents in addition to the detection and prevention methods. In this paper, 22 public ransomware incidents within the marine industry have been investigated to determine …

Harvesting Tacit Knowledge For Composites Workforce Development, John Summerscales

School of Engineering, Computing and Mathematics

Explicit knowledge can often be shared through textbooks, technical papers, instruction manuals, guides, and videos. It is normally objective, logical and technical. However, tacit (implicit) knowledge is any information or skills that arise from personal and professional experiences. It is often subjective, cognitive and experiential. When an individual leaves an organisation, they can take intellectual property with them that could compromise future operations, unless that knowledge is harvested. This brief review considers how transient knowledge might be retained in an organisation.

Exploring Children’S Attitudes Towards Digital Good/Bad Through Hybrid Arts Practices. Final Project Report., Dylan Yamada-Rice, John Potter, Steve Love, Eleanor Dare, Angus Main, Richard Nash

School of Art, Design and Architecture

This report shares the findings of a project funded by the Economic and Social Research Council’s (ESRC) Digital Good Network that sought to explore children’s attitudes towards notions of digital good and conversely digital bad through hybrid arts practice. The project built on our previous work that has centred on one or more emerging technologies, exploring what this might mean in terms of children’s entertainment, play, education and/or health. To tie in with the wider Network’s provocation about whether a digital good society is possible and if so what it would look like, we connected our ideas to a project …

The Use Of Insect Cell Line Sf21 For Ecotoxicity Testing, Trevor Grigg, Richard D. Handy, Richard A. Billington

School of Biological and Marine Sciences

Insect cell lines are finding utility in many areas of biology, but their application as an in vitro tool for ecotoxicity testing has been given less attention. Our study aimed to demonstrate the utility and sensitivity of Sf21 cells to commonly used fungicides: Propiconazole and CuSO₄, as well as dimethyl sulphoxide (DMSO) an industrial solvent. Sf21 cells were readily cultured from frozen stocks in 3-4 days and showed utility as an invertebrate in vitro acute toxicity test. The data showed the threshold levels of cell survivability against propiconazole and CuSO₄. The EC₅₀ values were 135.1 …

Intertidal Seagrass Extent From Sentinel-2 Time-Series Show Distinct Trajectories In Western Europe, Bede Ffinian Rowe Davies, Simon Oiry, Philippe Rosa, Maria Laura Zoffoli, Ana I. Sousa, Oliver R. Thomas, Dan A. Smale, Melanie C. Austen, Lauren Biermann, Martin J. Attrill, Alejandro Roman, Gabriel Navarro, Anne Laure Barillé, Nicolas Harin, Daniel Clewley, Victor Martinez-Vicente, Pierre Gernez, Laurent Barillé

School of Biological and Marine Sciences

Intertidal areas, which emerge during low tide, form a vital link between terrestrial and marine environments. Seagrasses, a well-studied intertidal habitat, provide a multitude of different ecosystem goods and services. However, owing to their relatively high exposure to anthropogenic impacts, seagrasss meadows and other intertidal habitats have seen extensive declines. Remote sensing methods that can capture the spatial and temporal variation of marine habitats are essential to best assess the trajectories of seagrass ecosystems. An advanced machine learning method has been developed to map intertidal vegetation from satellite-derived surface reflectance at a 12-band multispectral resolution and distinguish between similarly pigmented …

'How Far I'Ve Come': The Value Of Reviewing Past Written Reflections, Rachel Leyland, Miranda Heath, Tracey Collett, Elizabeth Drake, Hilary Neve

Peninsula Medical School

Promoting reflection on experience and developing students’ reflectiveskills is an important element of curricula across the health professions.Students often do not find reflection easy and educators usea range of approaches to facilitate this. This qualitative study analysedfinal year medical students’ written reflections about important anddifficult concepts they had encountered at medical school and personalchange. As part of this, students were expected to look back ontheir written reflections from earlier years of the undergraduate programme.An initial analysis identified ‘learning from past reflections’ asan important theme. Here we report an in-depth analysis of this theme.Thirty-six final year volunteer students’ reflections were analysed …

Himal: Multimodal Hierarchical Multi-Task Auxiliary Learning Framework For Predicting Alzheimer's Disease Progression, Sayantan Kumar, Sean C Yu, Andrew Michelson, Thomas Kannampallil, Philip R O Payne

2020-Current year OA Pubs

OBJECTIVE: We aimed to develop and validate a novel multimodal framework

MATERIALS AND METHODS: HiMAL utilized multimodal longitudinal visit data including imaging features, cognitive assessment scores, and clinical variables from MCI patients in the Alzheimer's Disease Neuroimaging Initiative dataset, to predict at each visit if an MCI patient will progress to AD within the next 6 months. Performance of HiMAL was compared with state-of-the-art single-task and multitask baselines using area under the receiver operator curve (AUROC) and precision recall curve (AUPRC) metrics. An ablation study was performed to assess the impact of each input modality on model performance. Additionally, longitudinal …

Structural Basis For Adhesin Secretion By The Outer-Membrane Usher In Type 1 Pili, Ryan M Bitter, Maxwell I Zimmerman, Brock T Summers, Jerome S Pinkner, Karen W Dodson, Scott J Hultgren, Peng Yuan

2020-Current year OA Pubs

Gram-negative bacteria produce chaperone-usher pathway pili, which are extracellular protein fibers tipped with an adhesive protein that binds to a receptor with stereochemical specificity to determine host and tissue tropism. The outer-membrane usher protein, together with a periplasmic chaperone, assembles thousands of pilin subunits into a highly ordered pilus fiber. The tip adhesin in complex with its cognate chaperone activates the usher to allow extrusion across the outer membrane. The structural requirements to translocate the adhesin through the usher pore from the periplasm to the extracellular space remains incompletely understood. Here, we present a cryoelectron microscopy structure of a quaternary …

Mucosal Adenovirus Vaccine Boosting Elicits Iga And Durably Prevents Xbb.1.16 Infection In Nonhuman Primates, Matthew Gagne, James Brett Case, Igor P Dmitriev, Elena A Kashentseva, Baoling Ying, David T Curiel, Michael S Diamond, Et Al.

2020-Current year OA Pubs

A mucosal route of vaccination could prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication at the site of infection and limit transmission. We compared protection against heterologous XBB.1.16 challenge in nonhuman primates (NHPs) ~5 months following intramuscular boosting with bivalent mRNA encoding WA1 and BA.5 spike proteins or mucosal boosting with a WA1-BA.5 bivalent chimpanzee adenoviral-vectored vaccine delivered by intranasal or aerosol device. NHPs boosted by either mucosal route had minimal virus replication in the nose and lungs, respectively. By contrast, protection by intramuscular mRNA was limited to the lower airways. The mucosally delivered vaccine elicited durable airway IgG …

Cross-Ancestry Genetic Investigation Of Schizophrenia, Cannabis Use Disorder, And Tobacco Smoking, Emma C Johnson, Isabelle Austin-Zimmerman, Hayley H A Thorpe, Daniel F Levey, David A A Baranger, Sarah M C Colbert, Ditte Demontis, Jibran Y Khokhar, Lea K Davis, Howard J Edenberg, Marta Di Forti, Sandra Sanchez-Roige, Joel Gelernter, Arpana Agrawal

2020-Current year OA Pubs

Individuals with schizophrenia frequently experience co-occurring substance use, including tobacco smoking and heavy cannabis use, and substance use disorders. There is interest in understanding the extent to which these relationships are causal, and to what extent shared genetic factors play a role. We explored the relationships between schizophrenia (Scz; European ancestry N = 161,405; African ancestry N = 15,846), cannabis use disorder (CanUD; European ancestry N = 886,025; African ancestry N = 120,208), and ever-regular tobacco smoking (Smk; European ancestry N = 805,431; African ancestry N = 24,278) using the largest available genome-wide studies of these phenotypes in individuals of …

Impacts Of Employment Status, Partnership, Cancer Type, And Surgical Treatment On Health-Related Quality Of Life In Irradiated Head And Neck Cancer Survivors, Ching-Rong Lin, Tsung-Min Hung, Eric Yi-Liang Shen, Ann-Joy Cheng, Po-Hung Chang, Shiang-Fu Huang, Chung-Jan Kang, Tuan-Jen Fang, Li-Ang Lee, Chih-Hung Chang, Joseph Tung-Chieh Chang

2020-Current year OA Pubs

No abstract provided.

Endosomal Fusion Of Ph-Dependent Enveloped Viruses Requires Ion Channel Trpm7, Catherine A Doyle, Marta E Stremska, Louis-Marie Bloyet, Cassandra E Thompson, Paul W Rothlauf, Sean P J Whelan, Et Al.

2020-Current year OA Pubs

The majority of viruses classified as pandemic threats are enveloped viruses which enter the cell through receptor-mediated endocytosis and take advantage of endosomal acidification to activate their fusion machinery. Here we report that the endosomal fusion of low pH-requiring viruses is highly dependent on TRPM7, a widely expressed TRP channel that is located on the plasma membrane and in intracellular vesicles. Using several viral infection systems expressing the envelope glycoproteins of various viruses, we find that loss of TRPM7 protects cells from infection by Lassa, LCMV, Ebola, Influenza, MERS, SARS-CoV-1, and SARS-CoV-2. TRPM7 ion channel activity is intrinsically necessary to …

Dopamine-Mediated Interactions Between Short- And Long-Term Memory Dynamics, Cheng Huang, Junjie Luo, Seung Je Woo, Lucas A Roitman, Jizhou Li, Vincent A Pieribone, Madhuvanthi Kannan, Ganesh Vasan, Mark J Schnitzer

2020-Current year OA Pubs

In dynamic environments, animals make behavioural decisions on the basis of the innate valences of sensory cues and information learnt about these cues across multiple timescales

15-Gene Expression Profile And Prame As Integrated Prognostic Test For Uveal Melanoma: First Report Of Collaborative Ocular Oncology Group Study No. 2 (Coog2.1), J William Harbour, Kisha D Piggott, Et Al.

2020-Current year OA Pubs

PURPOSEValidated and accurate prognostic testing is critical for precision medicine in uveal melanoma (UM). Our aims were to (1) prospectively validate an integrated prognostic classifier combining a 15-gene expression profile (15-GEP) and

Perioperative Antibiotic Prophylaxis Duration In Patients Undergoing Cystectomy With Urinary Diversion: A Randomized Clinical Trial, Maria C Thurnheer, Astrid Schürmann, Markus Huber, Jonas Marschall, Patrick Y Wuethrich, Fiona C Burkhard

2020-Current year OA Pubs

IMPORTANCE: Perioperative antibiotic prophylaxis (PAP) reduces the incidence of surgical site infections (SSIs). Guidelines recommend 24 hours or less of PAP for cystectomy with urinary diversion; however, evidence specifying optimal PAP duration for this surgery is lacking, and prolonged administration of PAP is common practice.

OBJECTIVE: To establish noninferiority of 24-hour PAP vs extended-duration PAP in preventing SSIs within 90 days after cystectomy with urinary diversion.

DESIGN, SETTING, AND PARTICIPANTS: This single-center, noninferiority randomized clinical trial was performed from April 18, 2018, to August 18, 2022, in patients aged older than 18 years undergoing elective open cystectomy with urinary diversion. …

Rehabilitation Transition Program To Improve Community Participation Among Stroke Survivors: A Randomized Clinical Trial, Rebecca M Bollinger, Melissa J Krauss, Emily K Somerville, Brianna M Holden, Gabrielle Blenden, Holly Hollingsworth, Audrey A Keleman, Alexandre Carter, Timothy D Mcbride, Abigail R Barker, Yan Yan, Susan L Stark

2020-Current year OA Pubs

IMPORTANCE: Interventions are needed to support the long-term needs of stroke survivors when they transition from inpatient rehabilitation to home, where they face new home and community environmental barriers.

OBJECTIVE: To compare the efficacy of a novel, enhanced rehabilitation transition program with attentional control to improve community participation and activity of daily living (ADL) performance and to reduce environmental barriers in the home and community after stroke.

DESIGN, SETTING, AND PARTICIPANTS: This phase 2b, parallel randomized clinical trial assessed patients 50 years or older who had experienced an acute ischemic stroke or intracerebral hemorrhage, were independent in ADLs before stroke, …

Infectious Diseases Fellowship Training In Caring For People Who Use Drugs: A National Assessment Of An Emerging Training Need, Shilpa Vasishta, Raagini Jawa, Sarah Kurz, Nathanial S Nolan

2020-Current year OA Pubs

BACKGROUND: Infectious complications of substance use are increasingly encountered in infectious diseases (ID) clinical care. In this study, we surveyed ID fellows in the United States to assess training experiences, clinical practices, and perspectives in caring for people who use drugs (PWUD).

METHODS: An 18-item survey was distributed to ID fellows via email and social media platforms. Four focus groups were conducted with a subset of participants to elucidate themes in fellowship experiences and training needs.

RESULTS: Among 196 survey respondents (estimated 24% response rate), all reported caring for PWUD in ID fellowship. Forty-nine percent received some formal fellowship-based didactics …

Dominantly Inherited Muscle Disorders: Understanding Their Complexity And Exploring Therapeutic Approaches, Andrew R Findlay

2020-Current year OA Pubs

Treatments for disabling and life-threatening hereditary muscle disorders are finally close to becoming a reality. Research has thus far focused primarily on recessive forms of muscle disease. The gene replacement strategies that are commonly employed for recessive, loss-of-function disorders are not readily translatable to most dominant myopathies owing to the presence of a normal chromosome in each nucleus, hindering the development of novel treatments for these dominant disorders. This is largely due to their complex, heterogeneous disease mechanisms that require unique therapeutic approaches. However, as viral and RNA interference-based therapies enter clinical use, key tools are now in place to …