Medicine and Health Sciences Commons^™

Allogeneic Natural Killer Cell Therapy, Melissa M Berrien-Elliott, Miriam T Jacobs, Todd A Fehniger

2020-Current year OA Pubs

Interest in adoptive cell therapy for treating cancer is exploding owing to early clinical successes of autologous chimeric antigen receptor (CAR) T lymphocyte therapy. However, limitations using T cells and autologous cell products are apparent as they (1) take weeks to generate, (2) utilize a 1:1 donor-to-patient model, (3) are expensive, and (4) are prone to heterogeneity and manufacturing failures. CAR T cells are also associated with significant toxicities, including cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and prolonged cytopenias. To overcome these issues, natural killer (NK) cells are being explored as an alternative cell source for allogeneic cell …

[18f]Tosyl Fluoride As A Versatile [18f]Fluoride Source For The Preparation Of 18f-Labeled Radiopharmaceuticals, Dong Zhou, Wenhua Chu, Jinbin Xu, Sally Schwarz, John A Katzenellenbogen

2020-Current year OA Pubs

Positron emission tomography (PET) is an in vivo imaging technology that utilizes positron-emitting radioisotope-labeled compounds as PET radiotracers that are commonly used in clinic and in various research areas, including oncology, cardiology, and neurology. Fluorine-18 is the most widely used PET-radionuclide and commonly produced by proton bombardment of

Uncovering The Complex Genetic Architecture Of Human Plasma Lipidome Using Machine Learning Methods, Miikael Lehtimäki, Binisha H Mishra, Coral Del-Val, Leo-Pekka Lyytikäinen, Mika Kähönen, C Robert Cloninger, Olli T Raitakari, Reijo Laaksonen, Igor Zwir, Terho Lehtimäki, Pashupati P Mishra

2020-Current year OA Pubs

Genetic architecture of plasma lipidome provides insights into regulation of lipid metabolism and related diseases. We applied an unsupervised machine learning method, PGMRA, to discover phenotype-genotype many-to-many relations between genotype and plasma lipidome (phenotype) in order to identify the genetic architecture of plasma lipidome profiled from 1,426 Finnish individuals aged 30-45 years. PGMRA involves biclustering genotype and lipidome data independently followed by their inter-domain integration based on hypergeometric tests of the number of shared individuals. Pathway enrichment analysis was performed on the SNP sets to identify their associated biological processes. We identified 93 statistically significant (hypergeometric p-value < 0.01) lipidome-genotype relations. Genotype biclusters in these 93 relations contained 5977 SNPs across 3164 genes. Twenty nine of the 93 relations contained genotype biclusters with more than 50% unique SNPs and participants, thus representing most distinct subgroups. We identified 30 significantly enriched biological processes among the SNPs involved in 21 of these 29 most distinct genotype-lipidome subgroups through which the identified genetic variants can influence and regulate plasma lipid related metabolism and profiles. This study identified 29 distinct genotype-lipidome subgroups in the studied Finnish population that may have distinct disease trajectories and therefore could be useful in precision medicine research.

Skeletal Dysplasia-Causing Trpv4 Mutations Suppress The Hypertrophic Differentiation Of Human Ipsc-Derived Chondrocytes, Amanda R Dicks, Grigory I Maksaev, Zainab Harissa, Alireza Savadipour, Ruhang Tang, Nancy Steward, Wolfgang Liedtke, Colin G Nichols, Chia-Lung Wu, Farshid Guilak

2020-Current year OA Pubs

Mutations in the TRPV4 ion channel can lead to a range of skeletal dysplasias. However, the mechanisms by which TRPV4 mutations lead to distinct disease severity remain unknown. Here, we use CRISPR-Cas9-edited human-induced pluripotent stem cells (hiPSCs) harboring either the mild V620I or lethal T89I mutations to elucidate the differential effects on channel function and chondrogenic differentiation. We found that hiPSC-derived chondrocytes with the V620I mutation exhibited increased basal currents through TRPV4. However, both mutations showed more rapid calcium signaling with a reduced overall magnitude in response to TRPV4 agonist GSK1016790A compared to wildtype (WT). There were no differences in …

Identifying Factors Which Influence Eating Disorder Risk During Behavioral Weight Management: A Consensus Study, Hiba Jebeile, Caitlin M Mcmaster, Brittany J Johnson, Sarah P Garnett, Susan J Paxton, Anna L Seidler, Rebecca A Jones, Andrew J Hill, Sarah Maguire, Caroline Braet, Genevieve Dammery, Denise E Wilfley, Louise A Baur, Natalie B Lister, On Behalf Of The Eating Disorders In Weight-Related Therapy (Edit) Collaboration

2020-Current year OA Pubs

This study aimed to understand clinician, researcher and consumer views regarding factors which influence eating disorder (ED) risk during behavioral weight management, including individual risk factors, intervention strategies and delivery features. Eighty-seven participants were recruited internationally through professional and consumer organizations and social media and completed an online survey. Individual characteristics, intervention strategies (5-point scale) and delivery features (important/unimportant/unsure) were rated. Participants were mostly women (n = 81), aged 35-49 y, from Australia or United States, were clinicians and/or reported lived experience of overweight/obesity and/or ED. There was agreement (64% to 99%) that individual characteristics were relevant to ED risk, …

The Toxoplasma Micropore Mediates Endocytosis For Selective Nutrient Salvage From Host Cell Compartments, Wenyan Wan, Hui Dong, De-Hua Lai, Jiong Yang, Kai He, Xiaoyan Tang, Qun Liu, Geoff Hide, Xing-Quan Zhu, L David Sibley, Zhao-Rong Lun, Shaojun Long

2020-Current year OA Pubs

Apicomplexan parasite growth and replication relies on nutrient acquisition from host cells, in which intracellular multiplication occurs, yet the mechanisms that underlie the nutrient salvage remain elusive. Numerous ultrastructural studies have documented a plasma membrane invagination with a dense neck, termed the micropore, on the surface of intracellular parasites. However, the function of this structure remains unknown. Here we validate the micropore as an essential organelle for endocytosis of nutrients from the host cell cytosol and Golgi in the model apicomplexan Toxoplasma gondii. Detailed analyses demonstrated that Kelch13 is localized at the dense neck of the organelle and functions as …

Setd2 Regulates Chromatin Accessibility And Transcription To Suppress Lung Tumorigenesis, Yuchen Xie, Merve Sahin, Toru Wakamatsu, Akane Inoue-Yamauchi, Wanming Zhao, Song Han, Amrita M. Nargund, Shaoyuan Yang, Yang Lyu, James J. Hsieh, Christina S. Leslie, Emily H. Cheng

2020-Current year OA Pubs

SETD2, a H3K36 trimethyltransferase, is the most frequently mutated epigenetic modifier in lung adenocarcinoma, with a mutation frequency of approximately 9%. However, how SETD2 loss of function promotes tumorigenesis remains unclear. Using conditional Setd2-KO mice, we demonstrated that Setd2 deficiency accelerated the initiation of KrasG12D-driven lung tumorigenesis, increased tumor burden, and significantly reduced mouse survival. An integrated chromatin accessibility and transcriptome analysis revealed a potentially novel tumor suppressor model of SETD2 in which SETD2 loss activates intronic enhancers to drive oncogenic transcriptional output, including the KRAS transcriptional signature and PRC2-repressed targets, through regulation of chromatin accessibility and histone chaperone recruitment. …

Predicting Later Categories Of Upper Limb Activity From Earlier Clinical Assessments Following Stroke: An Exploratory Analysis, Jessica Barth, Keith R Lohse, Marghuretta D Bland, Catherine E Lang

2020-Current year OA Pubs

BACKGROUND: Accelerometers allow for direct measurement of upper limb (UL) activity. Recently, multi-dimensional categories of UL performance have been formed to provide a more complete measure of UL use in daily life. Prediction of motor outcomes after stroke have tremendous clinical utility and a next step is to explore what factors might predict someone's subsequent UL performance category.

PURPOSE: To explore how different machine learning techniques can be used to understand how clinical measures and participant demographics captured early after stroke are associated with the subsequent UL performance categories.

METHODS: This study analyzed data from two time points from a …

Effects Of Particle Diameter And Inlet Flow Rate On Gas-Solid Flow Patterns Of Fluidized Bed, Zhenjiang Zhao, Ling Zhou, Ling Bai, Wanning Lv, Ramesh K Agarwal

2020-Current year OA Pubs

The complex multiscale characteristics of particle flow are notoriously difficult to predict. In this study, the evolution process of bubbles and the variation of bed height were investigated by conducting high-speed photographic experiments to verify the reliability of numerical simulations. The gas-solid flow characteristics of bubbling fluidized beds with different particle diameters and inlet flow rates were systematically investigated by coupling computational fluid dynamics (CFD) and discrete element method (DEM). The results show that the fluidization in the fluidized bed will change from bubbling fluidization to turbulent fluidization and finally to slugging fluidization, and the conversion process is related to …

Creating Research-Ready Partnerships: The Initial Development Of Seven Implementation Laboratories To Advance Cancer Control, Gina R Kruse, Erica Hale, Justin E Bekelman, Jennifer E Devoe, Rachel Gold, Peggy A Hannon, Thomas K Houston, Aimee S James, Ashley Johnson, Lisa M Klesges, Andrea L Nederveld

2020-Current year OA Pubs

BACKGROUND: In 2019-2020, with National Cancer Institute funding, seven implementation laboratory (I-Lab) partnerships between scientists and stakeholders in 'real-world' settings working to implement evidence-based interventions were developed within the Implementation Science Centers in Cancer Control (ISC3) consortium. This paper describes and compares approaches to the initial development of seven I-Labs in order to gain an understanding of the development of research partnerships representing various implementation science designs.

METHODS: In April-June 2021, members of the ISC3 Implementation Laboratories workgroup interviewed research teams involved in I-Lab development in each center. This cross-sectional study used semi-structured interviews and case-study-based methods to collect and …

Ccl17 Protects Against Viral Myocarditis By Suppressing The Recruitment Of Regulatory T Cells, Guoshuai Feng, Cuige Zhu, Chieh-Yu Lin, Andrea Bredemeyer, Irmgard Förster, Daniel Kreisel, Kory J Lavine

2020-Current year OA Pubs

Background Viral myocarditis is characterized by leukocyte infiltration of the heart and cardiomyocyte death. We recently identified C-C chemokine ligand (CCL) 17 as a proinflammatory effector of C-C chemokine receptor 2-positive macrophages and dendritic cells that are recruited to the heart and contribute to adverse left ventricular remodeling following myocardial infarction and pressure overload. Methods and Results Mouse encephalomyocarditis virus was used to investigate the function of CCL17 in a viral myocarditis model.

Efficacy And Safety Of Non-Steroidal Anti-Inflammatory Drugs (Nsaids) For The Treatment Of Acute Pain After Orthopedic Trauma: A Practice Management Guideline From The Eastern Association For The Surgery Of Trauma And The Orthopedic Trauma Association, Patrick B. Murphy, Anna Miller, Et Al.

2020-Current year OA Pubs

OBJECTIVES: Fracture is a common injury after a traumatic event. The efficacy and safety of non-steroidal anti-inflammatory drugs (NSAIDs) to treat acute pain related to fractures is not well established.

METHODS: Clinically relevant questions were determined regarding NSAID use in the setting of trauma-induced fractures with clearly defined patient populations, interventions, comparisons and appropriately selected outcomes (PICO). These questions centered around efficacy (pain control, reduction in opioid use) and safety (non-union, kidney injury). A systematic review including literature search and meta-analysis was performed, and the quality of evidence was graded per the Grading of Recommendations Assessment, Development and Evaluation (GRADE) …

The Status Of Digital Pathology And Associated Infrastructure Within Alzheimer's Disease Centers, Rebeca Scalco, Richard J Perrin, Et Al.

2020-Current year OA Pubs

Digital pathology (DP) has transformative potential, especially for Alzheimer disease and related disorders. However, infrastructure barriers may limit adoption. To provide benchmarks and insights into implementation barriers, a survey was conducted in 2019 within National Institutes of Health's Alzheimer's Disease Centers (ADCs). Questions covered infrastructure, funding sources, and data management related to digital pathology. Of the 35 ADCs to which the survey was sent, 33 responded. Most respondents (81%) stated that their ADC had digital slide scanner access, with the most frequent brand being Aperio/Leica (62.9%). Approximately a third of respondents stated there were fees to utilize the scanner. For …

Hydrogel Encapsulation Of Genome-Engineered Stem Cells For Long-Term Self-Regulating Anti-Cytokine Therapy, Kelsey H Collins, Lara Pferdehirt, Leila S Saleh, Alireza Savadipour, Luke E Springer, Kristin L Lenz, Dominic M Thompson, Sara J Oswald, Christine T N Pham, Farshid Guilak

2020-Current year OA Pubs

Biologic therapies have revolutionized treatment options for rheumatoid arthritis (RA) but their continuous administration at high doses may lead to adverse events. Thus, the development of improved drug delivery systems that can sense and respond commensurately to disease flares represents an unmet medical need. Toward this end, we generated induced pluripotent stem cells (iPSCs) that express interleukin-1 receptor antagonist (IL-1Ra, an inhibitor of IL-1) in a feedback-controlled manner driven by the macrophage chemoattractant protein-1 (Ccl2) promoter. Cells were seeded in agarose hydrogel constructs made from 3D printed molds that can be injected subcutaneously via a blunt needle, thus simplifying implantation …

Tcr-Engineered Adoptive Cell Therapy Effectively Treats Intracranial Murine Glioblastoma, Maximilian O. Schaettler, Rupen Desai, Anthony Z. Wang, Alexandra J. Livingstone, Dale K. Kobayashi, Andrew T. Coxon, Jay A. Bowman-Kirigin, Connor J. Liu, Mao Li, Diane E. Bender, Michael J. White, David M. Kranz, Tanner M. Johanns, Gavin P. Dunn

2020-Current year OA Pubs

BACKGROUND: Adoptive cellular therapies with chimeric antigen receptor T cells have revolutionized the treatment of some malignancies but have shown limited efficacy in solid tumors such as glioblastoma and face a scarcity of safe therapeutic targets. As an alternative, T cell receptor (TCR)-engineered cellular therapy against tumor-specific neoantigens has generated significant excitement, but there exist no preclinical systems to rigorously model this approach in glioblastoma.

METHODS: We employed single-cell PCR to isolate a TCR specific for the Imp3

RESULTS: We isolated and characterized the 3×1.1C TCR that displayed a high affinity for mImp3 but no wild-type cross-reactivity. To provide a …

The Gut Microbiota Of People With Asthma Influences Lung Inflammation In Gnotobiotic Mice, Naomi G Wilson, Ariel Hernandez-Leyva, Anne L Rosen, Natalia Jaeger, Ryan T Mcdonough, Jesus Santiago-Borges, Michael A Lint, Thomas R Rosen, Christopher P Tomera, Leonard B Bacharier, S Joshua Swamidass, Andrew L Kau

2020-Current year OA Pubs

The gut microbiota in early childhood is linked to asthma risk, but may continue to affect older patients with asthma. Here, we profile the gut microbiota of 38 children (19 asthma, median age 8) and 57 adults (17 asthma, median age 28) by 16S rRNA sequencing and find individuals with asthma harbored compositional differences from healthy controls in both adults and children. We develop a model to aid the design of mechanistic experiments in gnotobiotic mice and show enterotoxigenic

Hallmarks Of Neurodegenerative Diseases, David M Wilson 3rd, Mark R Cookson, Ludo Van Den Bosch, Henrik Zetterberg, David M Holtzman, Ilse Dewachter

2020-Current year OA Pubs

Decades of research have identified genetic factors and biochemical pathways involved in neurodegenerative diseases (NDDs). We present evidence for the following eight hallmarks of NDD: pathological protein aggregation, synaptic and neuronal network dysfunction, aberrant proteostasis, cytoskeletal abnormalities, altered energy homeostasis, DNA and RNA defects, inflammation, and neuronal cell death. We describe the hallmarks, their biomarkers, and their interactions as a framework to study NDDs using a holistic approach. The framework can serve as a basis for defining pathogenic mechanisms, categorizing different NDDs based on their primary hallmarks, stratifying patients within a specific NDD, and designing multi-targeted, personalized therapies to effectively …

Fmr1 Mutation Alters The Early Development Of Sensory Coding And Hunting And Social Behaviors In Larval Zebrafish, Shuyu I Zhu, Michael H Mccullough, Zac Pujic, Jordan Sibberas, Biao Sun, Thomas Darveniza, Bianca Bucknall, Lilach Avitan, Geoffrey J Goodhill

2020-Current year OA Pubs

Autism spectrum disorders (ASDs) are developmental in origin; however, little is known about how they affect the early development of behavior and sensory coding. The most common inherited form of autism is Fragile X syndrome (FXS), caused by a mutation in

Benchmarking The Generalizability Of Brain Age Models: Challenges Posed By Scanner Variance And Prediction Bias, Robert J Jirsaraie, Tobias Kaufmann, Vishnu Bashyam, Guray Erus, Joan L Luby, Lars T Westlye, Christos Davatzikos, Deanna M Barch, Aristeidis Sotiras

2020-Current year OA Pubs

Machine learning has been increasingly applied to neuroimaging data to predict age, deriving a personalized biomarker with potential clinical applications. The scientific and clinical value of these models depends on their applicability to independently acquired scans from diverse sources. Accordingly, we evaluated the generalizability of two brain age models that were trained across the lifespan by applying them to three distinct early-life samples with participants aged 8-22 years. These models were chosen based on the size and diversity of their training data, but they also differed greatly in their processing methods and predictive algorithms. Specifically, one brain age model was …

Spontaneous Coronary Artery Dissection Complicated By Left Ventricular Free Wall Rupture In Turner Syndrome, Brendan F Caprio, Kunal Kotkar, Alan Zajarias, Alan C Braverman

2020-Current year OA Pubs

A 38-year-old with Turner syndrome presented with acute myocardial infarction due to multivessel spontaneous coronary artery dissection (SCAD) complicated by left ventricular free wall rupture. Conservative management for SCAD was pursued. She underwent sutureless repair for an oozing-type left ventricular free wall rupture. SCAD has not been previously reported in Turner syndrome. (

Developmental Programming: Adverse Sexually Dimorphic Transcriptional Programming Of Gestational Testosterone Excess In Cardiac Left Ventricle Of Fetal Sheep, Venkateswaran Ramamoorthi Elangovan, Nadia Saadat, Adel Ghnenis, Vasantha Padmanabhan, Arpita K Vyas

2020-Current year OA Pubs

Adverse in-utero insults during fetal life alters offspring's developmental trajectory, including that of the cardiovascular system. Gestational hyperandrogenism is once such adverse in-utero insult. Gestational testosterone (T)-treatment, an environment of gestational hyperandrogenism, manifests as hypertension and pathological left ventricular (LV) remodeling in adult ovine offspring. Furthermore, sexual dimorphism is noted in cardiomyocyte number and morphology in fetal life and at birth. This study investigated transcriptional changes and potential biomarkers of prenatal T excess-induced adverse cardiac programming. Genome-wide coding and non-coding (nc) RNA expression were compared between prenatal T-treated (T propionate 100 mg intramuscular twice weekly from days 30 to 90 …

Svep1 Is An Endogenous Ligand For The Orphan Receptor Pear1, Jared S Elenbaas, Upasana Pudupakkam, Katrina J Ashworth, Chul Joo Kang, Ved Patel, Katherine Santana, In-Hyuk Jung, Paul C Lee, Kendall H Burks, Junedh M Amrute, Robert P Mecham, Carmen M Halabi, Arturo Aliso, Jorge Di Paola, Nathan O Stitziel

2020-Current year OA Pubs

Sushi, von Willebrand factor type A, EGF and pentraxin domain containing 1 (SVEP1) is an extracellular matrix protein that causally promotes vascular disease and associates with platelet reactivity in humans. Here, using a human genomic and proteomic approach, we identify a high affinity, disease-relevant, and potentially targetable interaction between SVEP1 and the orphan receptor Platelet and Endothelial Aggregation Receptor 1 (PEAR1). This interaction promotes PEAR1 phosphorylation and disease associated AKT/mTOR signaling in vascular cells and platelets. Mice lacking SVEP1 have reduced platelet activation, and exogenous SVEP1 induces PEAR1-dependent activation of platelets. SVEP1 and PEAR1 causally and concordantly relate to platelet …

Staphylococcus Aureus Breast Implant Infection Isolates Display Recalcitrance To Antibiotic Pocket Irrigants, Jesus M. Duran Ramirez, Jana Gomez, Blake M. Hanson, Taha Isa, Terence M. Myckatyn, Jennifer N. Walker

2020-Current year OA Pubs

Breast implant-associated infections (BIAIs) are the primary complication following placement of breast prostheses in breast cancer reconstruction. Given the prevalence of breast cancer, reconstructive failure due to infection results in significant patient distress and health care expenditures. Thus, effective BIAI prevention strategies are urgently needed. This study tests the efficacy of one infection prevention strategy: the use of a triple antibiotic pocket irrigant (TAPI) against Staphylococcus aureus, the most common cause of BIAIs. TAPI, which consists of 50,000 U bacitracin, 1 g cefazolin, and 80 mg gentamicin diluted in 500 mL of saline, is used to irrigate the breast implant …

Brain Aerobic Glycolysis And Resilience In Alzheimer Disease, Manu S Goyal, Tyler Blazey, Nicholas V Metcalf, Mark P Mcavoy, Jeremy F Strain, Maryam Rahmani, Tony J Durbin, Chengjie Xiong, Tammie L-S Benzinger, John C Morris, Marcus E Raichle, Andrei G Vlassenko

2020-Current year OA Pubs

The distribution of brain aerobic glycolysis (AG) in normal young adults correlates spatially with amyloid-beta (Aβ) deposition in individuals with symptomatic and preclinical Alzheimer disease (AD). Brain AG decreases with age, but the functional significance of this decrease with regard to the development of AD symptomatology is poorly understood. Using PET measurements of regional blood flow, oxygen consumption, and glucose utilization-from which we derive AG-we find that cognitive impairment is strongly associated with loss of the typical youthful pattern of AG. In contrast, amyloid positivity without cognitive impairment was associated with preservation of youthful brain AG, which was even higher …

Self-Renewing Macrophages In Dorsal Root Ganglia Contribute To Promote Nerve Regeneration, Rui Feng, Vishnu Muraleedharan Saraswathy, Mayssa H Mokalled, Valeria Cavalli

2020-Current year OA Pubs

Sensory neurons located in dorsal root ganglia (DRG) convey sensory information from peripheral tissue to the brain. After peripheral nerve injury, sensory neurons switch to a regenerative state to enable axon regeneration and functional recovery. This process is not cell autonomous and requires glial and immune cells. Macrophages in the DRG (DRGMacs) accumulate in response to nerve injury, but their origin and function remain unclear. Here, we mapped the fate and response of DRGMacs to nerve injury using macrophage depletion, fate-mapping, and single-cell transcriptomics. We identified three subtypes of DRGMacs after nerve injury in addition to a small population of …

Apolipoprotein E4 Has Extensive Conformational Heterogeneity In Lipid-Free And Lipid-Bound Forms, Melissa D Stuchell-Brereton, Maxwell I Zimmerman, Justin J Miller, Upasana L Mallimadugula, J Jeremías Incicco, Debjit Roy, Louis G Smith, Jasmine Cubuk, Berevan Baban, Gregory T Dekoster, Carl Frieden, Gregory R Bowman, Andrea Soranno

2020-Current year OA Pubs

The ε4-allele variant of apolipoprotein E (ApoE4) is the strongest genetic risk factor for Alzheimer's disease, although it only differs from its neutral counterpart ApoE3 by a single amino acid substitution. While ApoE4 influences the formation of plaques and neurofibrillary tangles, the structural determinants of pathogenicity remain undetermined due to limited structural information. Previous studies have led to conflicting models of the C-terminal region positioning with respect to the N-terminal domain across isoforms largely because the data are potentially confounded by the presence of heterogeneous oligomers. Here, we apply a combination of single-molecule spectroscopy and molecular dynamics simulations to construct …

Mrna Vaccine Mitigates Sars-Cov-2 Infections And Covid-19, Christina M. Kackos, Sherri L. Surman, Bart G. Jones, Robert E. Sealy, Trushar Jeevan, Christopher J H Davitt, Sergei Pustylnikov, Tamarand L. Darling, Adrianus C M Boon, Julia L. Hurwitz, Marcelo M. Samsa, Richard J. Webby

2020-Current year OA Pubs

The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified in December of 2019 and is responsible for millions of infections and deaths across the globe. Vaccination against SARS-CoV-2 has proven effective to contain the spread of the virus and reduce disease. The production and distribution of these vaccines occurred at a remarkable pace, largely through the employment of the novel mRNA platform. However, interruptions in supply chain and high demand for clinical grade reagents have impeded the manufacture and distribution of mRNA vaccines at a time when accelerated vaccine deployment is crucial. Furthermore, the emergence of SARS-CoV-2 …

Barriers To Using Legally Authorized Representatives In Clinical Research With Older Adults, Jessica Mozersky, Erin D Solomon, Kari Baldwin, Matthew Wroblewski, Meredith Parsons, Melody Goodman, James M Dubois

2020-Current year OA Pubs

BACKGROUND: Older adults are at increased risk of cognitive impairments including Alzheimer's disease dementia. Legally authorized representatives (LARs) can provide informed consent when a participant is no longer able to, but little is known about barriers to incorporating them in research.

OBJECTIVE: Explore reasons for not asking and documenting participant decisions to appoint LARs among researchers conducting clinical intervention trials studying older adults or individuals with cognitive impairments.

METHODS: Mixed method design consisting of a survey (

RESULTS: 37% (

CONCLUSION: Resources and education to increase awareness and knowledge of LARs are needed. Researchers studying older adults should, at minimum, …

Amniotes Co-Opt Intrinsic Genetic Instability To Protect Germ-Line Genome Integrity, Yu H Sun, Xiaoyu Zhuo, Et Al.

2020-Current year OA Pubs

Unlike PIWI-interacting RNA (piRNA) in other species that mostly target transposable elements (TEs), >80% of piRNAs in adult mammalian testes lack obvious targets. However, mammalian piRNA sequences and piRNA-producing loci evolve more rapidly than the rest of the genome for unknown reasons. Here, through comparative studies of chickens, ducks, mice, and humans, as well as long-read nanopore sequencing on diverse chicken breeds, we find that piRNA loci across amniotes experience: (1) a high local mutation rate of structural variations (SVs, mutations ≥ 50 bp in size); (2) positive selection to suppress young and actively mobilizing TEs commencing at the pachytene …

Rate Of Tarsal And Metatarsal Bone Mineral Density Change In Adults With Diabetes Mellitus And Peripheral Neuropathy: A Longitudinal Study, Nicholas J Youmans, Rachana S Vaidya, Ling Chen, Hyo-Jung Jeong, Alexa York, Paul K Commean, Mary K Hastings, Jennifer A Zellers

2020-Current year OA Pubs

BACKGROUND: In people with diabetes (DM) and peripheral neuropathy (PN), loss of bone mineral density (BMD) in the tarsals and metatarsals contribute to foot complications; however, changes in BMD of the calcaneal bone is most commonly reported. This study reports rate of change in BMD of all the individual bones in the foot, in participants with DM and PN. Our aim was to investigate whether the rate of BMD change is similar across all the bones of the foot.

METHODS: Participants with DM and PN (n = 60) were included in this longitudinal cohort study. Rate of BMD change of …