Publications by authors named "Patrick Dunn"

47 Publications

Nitrogen Fixation at Early Mars.

Astrobiology 2021 08 30;21(8):968-980. Epub 2021 Jul 30.

Department of Geological and Planetary Sciences, California Institute of Technology, Pasadena, California, USA.

The Mars Science Laboratory (MSL) recently discovered nitrates in Gale Crater (, Stern , 2015; Sutter , 2017). One possible mechanism for ancient nitrate deposition on Mars is through HNOx formation and rain out in the atmosphere, for which lightning-induced NO is likely the fundamental source. This study investigates nitrogen (N) fixation in early Mars' atmosphere, with implications for early Mars' habitability. We consider a 1 bar atmosphere of background CO, with abundance of N, hydrogen, and methane varied from 1% to 10% to explore a swath of potential early Mars climates. We derive lightning-induced thermochemical equilibrium fluxes of NO and HCN by coupling the lightning-rate parametrization from the study of Romps (2014) with chemical equilibrium with applications, and we use a Geant4 simulation platform to estimate the effect of solar energetic particle events. These fluxes are used as input into KINETICS, the Caltech/JPL coupled photochemistry and transport code, which models the chemistry of 50 species linked by 495 reactions to derive rain-out fluxes of HNOx and HCN. We compute equilibrium concentrations of cyanide and nitrate in a putative northern ocean at early Mars, assuming hydrothermal vent circulation and photoreduction act as the dominant loss mechanisms. We find average oceanic concentrations of ∼0.1-2 nM nitrate and ∼0.01-2 mM cyanide. HCN is critical for protein synthesis at concentrations >0.01 M (, Holm and Neubeck, 2009), and our result is astrobiologically significant if secondary local concentration mechanisms occurred. Nitrates may act as high-potential electron acceptors for early metabolisms, although the minimum concentration required is unknown. Our study derives concentrations that will be useful for future laboratory studies to investigate the habitability at early Mars. The aqueous nitrate concentrations correspond to surface nitrate precipitates of ∼1-8 × 10 wt % that may have formed after the evaporation of surface waters, and these values roughly agree with recent MSL measurements.
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http://dx.doi.org/10.1089/ast.2020.2273DOI Listing
August 2021

Delineating the genotypic and phenotypic spectrum of -related neurodevelopmental disorders.

J Med Genet 2021 Jul 28. Epub 2021 Jul 28.

GeneDx, Gaithersburg, Maryland, USA.

Background: Variants in have recently been reported to cause a neurodevelopmental disorder with hypotonia, seizures and impaired language; however, only six variants have been reported and the clinical characteristics have only broadly been defined.

Methods: Molecular and clinical data were collected from clinical and research cohorts. Massive parallel sequencing was performed and identified individuals with a related neurodevelopmental disorder.

Results: We identified 13 novel missense variants in in 22 unpublished cases, of which 18 were confirmed to have a de novo variant. In addition, we reviewed the genotypes and phenotypes of previously reported and new cases with variants (n=35 cases). All variants identified are missense, and the majority of likely pathogenic and pathogenic variants are located in or near the C-terminal HECT domain (88.2%). We identified several clustered variants and four recurrent variants (p.(Arg1191Gln);p.(Asn1199Lys);p.(Phe1327Ser);p.(Arg1330Trp)). Two variants, (p.(Arg1191Gln);p.(Arg1330Trp)), accounted for 22.9% and 20% of cases, respectively. Clinical characterisation suggests complete penetrance for hypotonia with or without spasticity (100%), developmental delay/intellectual disability (100%) and developmental language disorder (100%). Other common features are behavioural problems (88.9%), vision problems (83.9%), motor coordination/movement (75%) and gastrointestinal issues (70%). Seizures were present in 61.3% of individuals. Genotype-phenotype analysis shows that HECT domain variants are more frequently associated with cortical visual impairment and gastrointestinal issues. Seizures were only observed in individuals with variants in or near the HECT domain.

Conclusion: We provide a comprehensive review and expansion of the genotypic and phenotypic spectrum of disorders, aiding future molecular and clinical diagnosis and management.
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http://dx.doi.org/10.1136/jmedgenet-2021-107871DOI Listing
July 2021

Pragmatic Considerations in Incorporating Stakeholder Engagement Into a Palliative Care Transitions Study.

Med Care 2021 Aug;59(Suppl 4):S370-S378

Ronald O. Perelman Department of Emergency Medicine, New York University School of Medicine.

Background: Stakeholder involvement in health care research has been shown to improve research development, processes, and dissemination. The literature is developing on stakeholder engagement methods and preliminarily validated tools for evaluating stakeholder level of engagement have been proposed for specific stakeholder groups and settings.

Objectives: This paper describes the methodology for engaging a Study Advisory Committee (SAC) in research and reports on the use of a stakeholder engagement survey for measuring level of engagement.

Methods: Stakeholders with previous research connections were recruited to the SAC during the planning process for a multicenter randomized control clinical trial, which is ongoing at the time of this writing. All SAC meetings undergo qualitative analysis, while the Stakeholder Engagement Survey instrument developed by the Patient-Centered Outcomes Research Institute (PCORI) is distributed annually for quantitative evaluation.

Results: The trial's SAC is composed of 18 members from 3 stakeholder groups: patients and their caregivers; patient advocacy organizations; and health care payers. After an initial in-person meeting, the SAC meets quarterly by telephone and annually in-person. The SAC monitors research progress and provides feedback on all study processes. The stakeholder engagement survey reveals improved engagement over time as well as continued challenges.

Conclusions: Stakeholder engagement in the research process has meaningfully contributed to the study design, patient recruitment, and preliminary analysis of findings.
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http://dx.doi.org/10.1097/MLR.0000000000001583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263137PMC
August 2021

Temporal changes in personal activity intelligence and mortality: Data from the aerobics center longitudinal study.

Prog Cardiovasc Dis 2021 Jan-Feb;64:127-134. Epub 2020 Dec 25.

Department of Circulation and Medical Imaging, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway; Healthy Living for Pandemic Event Protection (HL - PIVOT) Network, Chicago, IL, USA; School of Human Movement & Nutrition Sciences, University of Queensland, Australia.

Background: Personal activity intelligence (PAI) is a metric developed to simplify a physically active lifestyle for the participants. Regardless of following today's advice for physical activity, a PAI score ≥100 per week at baseline, an increase in PAI score, and a sustained high PAI score over time were found to delay premature cardiovascular disease (CVD) and all-cause mortality in a large population of Norwegians. However, the association between long-term temporal change in PAI and mortality in other populations have not been investigated.

Objective: To test whether temporal change in PAI is associated with CVD and all-cause mortality in a large population from the United States.

Methods: We studied 17,613 relatively healthy participants who received at least two medical examinations in the Aerobics Center Longitudinal Study between 1974 and 2002. The participant's weekly PAI scores were estimated twice, and adjusted hazard ratios (AHR) and 95% confidence intervals (CI) for CVD and all-cause mortality related to changes in PAI between baseline and last examination were assessed using Cox proportional hazard regression analyses.

Results: During a median follow-up time of 9.3 years [interquartile range, 2.6-16.6; 181,765 person-years], there were 1144 deaths, including 400 CVD deaths. We observed an inverse linear association between change in PAI and risk of CVD mortality (P=0.007 for linear trend, and P=0.35 for quadratic trend). Compared to participants with zero PAI at both examinations, multivariable-adjusted analyses demonstrated that participants who maintained high PAI scores (≥100 PAI at both examinations) had a 51% reduced risk of CVD mortality [AHR, 0.49: 95% CI, 0.26-0.95)], and 42% reduced risk of all-cause mortality [AHR, 0.58: 95% CI, 0.41-0.83)]. For participants who increased their PAI scores over time (PAI score of zero at first examination and ≥100 at last examination), the AHRs were 0.75 (95% CI, 0.55-1.02) for CVD mortality, and 0.82 (95% CI, 0.69-0.99) for all-cause mortality. Participants who maintained high PAI score had 4.8 (95% CI, 3.3-6.4) years of life gained. For those who increased their PAI score over time, the corresponding years gained were 1.8 years (95% CI, 0.1-3.5).

Conclusion: Among relatively healthy participants, an increase in PAI and maintaining a high PAI score over time was associated with reduced risk of CVD and all-cause mortality.

Condensed Abstract: Our objective was to investigate the association between temporal changes in PAI and mortality in a large population from the United States. In this prospective cohort study of 17,613 relatively healthy participants at baseline, maintaining a high PAI score and an increase in PAI score over an average period of 6.3 years was associated with a significant reduction in CVD and all-cause mortality. Based on our results, clinicians can easily recommend that patients obtain at least 100 PAI for most favourable protection against CVD- and all-cause mortality, but can also mention that significant benefits also occur at maintaining low-to-moderate PAI levels.
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http://dx.doi.org/10.1016/j.pcad.2020.12.001DOI Listing
May 2021

Food Insecurity and Mortality in American Adults: Results From the NHANES-Linked Mortality Study.

Health Promot Pract 2021 03 4;22(2):204-214. Epub 2020 Aug 4.

Walden University, Minneapolis, MN, USA.

Food insecurity is a significant public health problem in the United States leading to substantial social, economic, and health care-related burdens. While studies continue to estimate the prevalence of food insecurity, the long-term outcomes are not extensively explored. The purpose of this study was to assess the impact of food insecurity on mortality. We analyzed data on adults (≥ 20 years) from the 1999-2010 National Health and Nutrition Examination Survey, with mortality data obtained through 2015. Among the total study participants (n = 25,247), 17.6% reported food insecurity. Food-insecure individuals were more likely to be younger in age, minorities, poorer, with lesser education, obese, smokers, and with diabetes compared to food-secure counterparts. During a 10.2-year follow-up, among the food insecure, 821 individuals died (11%). The hazard ratio (HR) for mortality among the food insecure compared with the food secure, with adjustment for age and gender only, was 1.58; 95% confidence interval [CI: 1.25, 2.01]. The adjusted HRs for all-cause mortality, HR = 1.46, CI [1.23, 1.72], p < .001, and cardiovascular mortality, HR = 1.75, CI [1.19, 2.57], p < .01, were statistically significantly higher among food-insecure individuals, after adjustment for multiple demographic and health risk factors. Individuals who are food-insecure have a significantly higher probability of death from any cause or cardiovascular disease in long-term follow-up. Comprehensive and interdisciplinary approaches to reducing food insecurity-related disparities and health risks should be implemented. Including food insecurity in health risk assessments and addressing food insecurity as a determinant of long-term outcomes may contribute to lower premature death rates.
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http://dx.doi.org/10.1177/1524839920945927DOI Listing
March 2021

Personal activity intelligence and mortality - Data from the Aerobics Center Longitudinal Study.

Prog Cardiovasc Dis 2021 Jan-Feb;64:121-126. Epub 2020 Jun 16.

Department of Circulation and Medical Imaging, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway; Healthy Living for Pandemic Event Protection (HL - PIVOT) Network, Chicago, IL, USA; School of Human Movement & Nutrition Sciences, University of Queensland, Australia.

Importance: Personal activity intelligence (PAI) is a novel activity metric that can be integrated into self-assessment heart rate devices, and translates heart rate variations during exercise into a weekly score. Previous studies relating to PAI have been conducted in the same populations from Norway where the PAI metric has been derived, limiting generalizability of the results.

Objective: To test whether PAI is associated with total and cause-specific mortality in a large cohort from the United States.

Design: Aerobics Center Longitudinal Study (ACLS) - a prospective cohort between January 1974 and December 2002 with a mean follow-up of 14.5 years.

Setting: Population-based.

Participants: 56,175 relatively healthy participants (26.5% women) who underwent extensive preventive medical examinations at Cooper Clinic (Dallas, TX).

Exposure: Personal activity intelligence (PAI) score per week was estimated and divided into 4 groups (PAI scores of 0, ≤50, 51-99, and ≥100).

Main Outcomes And Measures: Total and cause-specific mortality.

Results: During a median follow-up time of 14.9 (interquartile range, 6.7-21.4) years, there were 3434 total deaths including 1258 cardiovascular (CVD) deaths. Compared with the inactive (0 PAI) group, participants with a baseline weekly ≥100 PAI had lower risk of mortality: adjusted hazard ratio (AHR), 0.79: 95% CI, 0.71-0.87 for all-cause mortality, and AHR, 0.72: 95% CI, 0.60-0.87 for CVD mortality among men; AHR, 0.85: 95% CI, 0.64-1.12 for all-cause mortality, and AHR, 0.48: 95% CI, 0.26-0.91 for CVD mortality among women. For deaths from ischemic heart disease (IHD), PAI score ≥100 was associated with lower risk in both men and women (AHR, 0.70: 95% CI, 0.55-0.88). Obtaining ≥100 weekly PAI was also associated with significantly lower risk of CVD mortality in pre-specified age groups, and in participants with known CVD risk factors. Participants with ≥100 weekly PAI gained 4.2 (95% CI, 3.5-4.6) years of life when compared with those who were inactive at baseline.

Conclusions And Relevance: PAI is associated with long-term all-cause, CVD, and IHD, mortality. Clinicians and the general population can incorporate PAI recommendations and thresholds in their physical activity prescriptions and weekly physical activity assessments, respectively, to maximize health outcomes.

Key Points: Question: What is the association between personal activity intelligence (PAI), a novel activity metric, and mortality in a large cohort from the United States?

Findings: In this prospective study of 56,175 healthy participants at baseline, followed-up for a mean of 14.5 years, ≥100 PAI score/week was associated with significant 21% lower risk of all-cause and 30% lower risk of CVD mortality in comparison with inactive people. Participants with ≥100 PAI/week lived on average 4.2 years longer compared with inactive. Meaning: PAI is associated with long-term all-cause and CVD mortality. Clinicians and general population may incorporate PAI recommendations into weekly physical activity assessments to maximize CVD prevention.
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http://dx.doi.org/10.1016/j.pcad.2020.05.005DOI Listing
May 2021

TMEM163 Regulates ATP-Gated P2X Receptor and Behavior.

Cell Rep 2020 06;31(9):107704

Department of Cellular and Molecular Physiology, Department of Neuroscience, Program in Cellular Neuroscience, Neurodegeneration and Repair, The Yale Kavli Institute, Yale University School of Medicine, New Haven, CT 06520, USA; Interdepartmental Neuroscience Program, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address:

Fast purinergic signaling is mediated by ATP and ATP-gated ionotropic P2X receptors (P2XRs), and it is implicated in pain-related behaviors. The properties exhibited by P2XRs vary between those expressed in heterologous cells and in vivo. Several modulators of ligand-gated ion channels have recently been identified, suggesting that there are P2XR functional modulators in vivo. Here, we establish a genome-wide open reading frame (ORF) collection and perform functional screening to identify modulators of P2XR activity. We identify TMEM163, which specifically modulates the channel properties and pharmacology of P2XRs. We also find that TMEM163 is required for full function of the neuronal P2XR and a pain-related ATP-evoked behavior. These results establish TMEM163 as a critical modulator of P2XRs in vivo and a potential target for the discovery of drugs for treating pain.
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http://dx.doi.org/10.1016/j.celrep.2020.107704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337098PMC
June 2020

Laser Capture Microdissection of Glioma Subregions for Spatial and Molecular Characterization of Intratumoral Heterogeneity, Oncostreams, and Invasion.

J Vis Exp 2020 04 12(158). Epub 2020 Apr 12.

Dept. of Neurosurgery, University of Michigan Medical School; Dept. of Cell and Developmental Biology, University of Michigan Medical School; Rogel Cancer Center, University of Michigan Medical School;

Gliomas are primary brain tumors characterized by their invasiveness and heterogeneity. Specific histological patterns such as pseudopalisades, microvascular proliferation, mesenchymal transformation and necrosis characterize the histological heterogeneity of high-grade gliomas. Our laboratory has demonstrated that the presence of high densities of mesenchymal cells, named oncostreams, correlate with tumor malignancy. We have developed a unique approach to understand the mechanisms that underlie glioma's growth and invasion. Here, we describe a comprehensive protocol that utilizes laser capture microdissection (LMD) and RNA sequencing to analyze differential mRNA expression of intra-tumoral heterogeneous multicellular structures (i.e., mesenchymal areas or areas of tumor invasion). This method maintains good tissue histology and RNA integrity. Perfusion, freezing, embedding, sectioning, and staining were optimized to preserve morphology and obtain high-quality laser microdissection samples. The results indicate that perfusion of glioma bearing mice using 30% sucrose provides good morphology and RNA quality. In addition, staining tumor sections with 4% Cresyl violet and 0.5% eosin results in good nuclear and cellular staining, while preserving RNA integrity. The method described is sensitive and highly reproducible and it can be utilized to study tumor morphology in various tumor models. In summary, we describe a complete method to perform LMD that preserves morphology and RNA quality for sequencing to study the molecular features of heterogeneous multicellular structures within solid tumors.
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http://dx.doi.org/10.3791/60939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253033PMC
April 2020

A structured model for immune exposures.

Database (Oxford) 2020 01;2020

Division for Vaccine Discovery, 9420 Athena Circle La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.

An Immune Exposure is the process by which components of the immune system first encounter a potential trigger. The ability to describe consistently the details of the Immune Exposure process was needed for data resources responsible for housing scientific data related to the immune response. This need was met through the development of a structured model for Immune Exposures. This model was created during curation of the immunology literature, resulting in a robust model capable of meeting the requirements of such data. We present this model with the hope that overlapping projects will adopt and or contribute to this work.
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http://dx.doi.org/10.1093/database/baaa016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7153954PMC
January 2020

ABC transporters control ATP release through cholesterol-dependent volume-regulated anion channel activity.

J Biol Chem 2020 04 27;295(16):5192-5203. Epub 2020 Jan 27.

Department of Cellular and Molecular Physiology, Department of Neuroscience, Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale Kavli Institute, Yale University School of Medicine, New Haven, Connecticut 06520. Electronic address:

Purinergic signaling by extracellular ATP regulates a variety of cellular events and is implicated in both normal physiology and pathophysiology. Several molecules have been associated with the release of ATP and other small molecules, but their precise contributions have been difficult to assess because of their complexity and heterogeneity. Here, we report on the results of a gain-of-function screen for modulators of hypotonicity-induced ATP release using HEK-293 cells and murine cerebellar granule neurons, along with bioluminescence, calcium FLIPR, and short hairpin RNA-based gene-silencing assays. This screen utilized the most extensive genome-wide ORF collection to date, covering 90% of human, nonredundant, protein-encoding genes. We identified two ABCG1 (ABC subfamily G member 1) variants, which regulate cellular cholesterol, as modulators of hypotonicity-induced ATP release. We found that cholesterol levels control volume-regulated anion channel-dependent ATP release. These findings reveal novel mechanisms for the regulation of ATP release and volume-regulated anion channel activity and provide critical links among cellular status, cholesterol, and purinergic signaling.
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http://dx.doi.org/10.1074/jbc.RA119.010699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170513PMC
April 2020

Fyn tyrosine kinase, a downstream target of receptor tyrosine kinases, modulates antiglioma immune responses.

Neuro Oncol 2020 06;22(6):806-818

Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan.

Background: High-grade gliomas are aggressive and immunosuppressive brain tumors. Molecular mechanisms that regulate the inhibitory immune tumor microenvironment (TME) and glioma progression remain poorly understood. Fyn tyrosine kinase is a downstream target of the oncogenic receptor tyrosine kinase pathway and is overexpressed in human gliomas. Fyn's role in vivo in glioma growth remains unknown. We investigated whether Fyn regulates glioma initiation, growth and invasion.

Methods: We evaluated the role of Fyn using genetically engineered mouse glioma models (GEMMs). We also generated Fyn knockdown stem cells to induce gliomas in immune-competent and immune-deficient mice (nonobese diabetic severe combined immunodeficient gamma mice [NSG], CD8-/-, CD4-/-). We analyzed molecular mechanism by RNA sequencing and bioinformatics analysis. Flow cytometry was used to characterize immune cellular infiltrates in the Fyn knockdown glioma TME.

Results: We demonstrate that Fyn knockdown in diverse immune-competent GEMMs of glioma reduced tumor progression and significantly increased survival. Gene ontology (GO) analysis of differentially expressed genes in wild-type versus Fyn knockdown gliomas showed enrichment of GOs related to immune reactivity. However, in NSG and CD8-/- and CD4-/- immune-deficient mice, Fyn knockdown gliomas failed to show differences in survival. These data suggest that the expression of Fyn in glioma cells reduces antiglioma immune activation. Examination of glioma immune infiltrates by flow cytometry displayed reduction in the amount and activity of immune suppressive myeloid derived cells in the Fyn glioma TME.

Conclusions: Gliomas employ Fyn mediated mechanisms to enhance immune suppression and promote tumor progression. We propose that Fyn inhibition within glioma cells could improve the efficacy of antiglioma immunotherapies.
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http://dx.doi.org/10.1093/neuonc/noaa006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283034PMC
June 2020

Risk Factors for Symptomatic Atrial Fibrillation-Analysis of an Outpatient Database.

J Atr Fibrillation 2019 Jun 30;12(1):2141. Epub 2019 Jun 30.

Penn State University College of Medicine.

Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in practice and is the leading cause of debilitating strokes with significant economic burden. It is currently not known whether asymptomatic undiagnosed AF should be treated if detected by various screening methods. Currently, United States guidelines have no recommendations for identifying patients with asymptomatic undiagnosed AF due to lack of evidence. The American Heart Association Center for Health Technology & Innovation undertook a plan to identify tools in 3 phases that may be useful in improving outcomes in patients with undiagnosed AF. In phase I we sought to identify AF risk factors that can be used to develop a risk score to identify high-risk patients using a large commercial insurance dataset. The principal findings of this study show that individuals at high risk for AF are those with advanced age, the presence of heart failure, coronary artery disease, hypertension, metabolic disorders, and hyperlipidemia. Our analysis also found that chronic respiratory failure was a significant risk factor for those over 65 years of age and chronic kidney disease for those less than 65 years of age.
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http://dx.doi.org/10.4022/jafib.2141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6811334PMC
June 2019

Special issue on digital health literacy: Introduction.

Authors:
Patrick Dunn

Int J Cardiol 2020 01 30;299:301-302. Epub 2019 Aug 30.

American Heart Association, United States of America; Walden University, United States of America. Electronic address:

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http://dx.doi.org/10.1016/j.ijcard.2019.08.055DOI Listing
January 2020

Technology approaches to digital health literacy.

Int J Cardiol 2019 10 15;293:294-296. Epub 2019 Jun 15.

TupeloLife Services, Dallas, TX, USA. Electronic address:

Digital health literacy is an extension of health literacy and uses the same operational definition, but in the context of technology. Technology solutions have the potential to both promote health literacy or be a barrier. To be effective, health technology solutions should go beyond building literacy and numeracy skills to functional and critical skills, such as navigating the healthcare system, communication with healthcare providers, and shared decision making. New and emerging technologies are highlighted: AI/machine learning, voice first, remote patient monitoring, wearables, and apps and web sites. Health technology represents enormous promise in the building of digital health literacy skills and improved health outcomes in patients with cardiovascular and other chronic conditions. This is a promise, however, that is yet to be fulfilled. TOPICS: Hypertension, Rehabilitation, Metabolic Syndrome, Health Policy, Risk Factor.
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http://dx.doi.org/10.1016/j.ijcard.2019.06.039DOI Listing
October 2019

Reporting and connecting cell type names and gating definitions through ontologies.

BMC Bioinformatics 2019 Apr 25;20(Suppl 5):182. Epub 2019 Apr 25.

Division for Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA.

Background: Human immunology studies often rely on the isolation and quantification of cell populations from an input sample based on flow cytometry and related techniques. Such techniques classify cells into populations based on the detection of a pattern of markers. The description of the cell populations targeted in such experiments typically have two complementary components: the description of the cell type targeted (e.g. 'T cells'), and the description of the marker pattern utilized (e.g. CD14-, CD3+).

Results: We here describe our attempts to use ontologies to cross-compare cell types and marker patterns (also referred to as gating definitions). We used a large set of such gating definitions and corresponding cell types submitted by different investigators into ImmPort, a central database for immunology studies, to examine the ability to parse gating definitions using terms from the Protein Ontology (PRO) and cell type descriptions, using the Cell Ontology (CL). We then used logical axioms from CL to detect discrepancies between the two.

Conclusions: We suggest adoption of our proposed format for describing gating and cell type definitions to make comparisons easier. We also suggest a number of new terms to describe gating definitions in flow cytometry that are not based on molecular markers captured in PRO, but on forward- and side-scatter of light during data acquisition, which is more appropriate to capture in the Ontology for Biomedical Investigations (OBI). Finally, our approach results in suggestions on what logical axioms and new cell types could be considered for addition to the Cell Ontology.
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http://dx.doi.org/10.1186/s12859-019-2725-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6509839PMC
April 2019

Digital health literacy in a person-centric world.

Int J Cardiol 2019 09 17;290:154-155. Epub 2019 May 17.

American Heart Association, United States of America; Walden University, United States of America. Electronic address:

The digital age is beginning to impact the healthcare system. Smartphones and other devices based on cellular technology have made access to information ubiquitous among consumers throughout the world. There has been a shift from devices that collect data to systems for those medical conditions, such as atrial fibrillation. This changes the focus from health literacy to digital health literacy and the information-communication between the healthcare professional and the individual. Moving from health literacy to digital health literacy, therefore also means shifting from patients to persons and from managing health to empowering people to live a healthier life. Digital solutions will uncover an even greater tool, the engaged patient.
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http://dx.doi.org/10.1016/j.ijcard.2019.05.033DOI Listing
September 2019

The 10,000 Immunomes Project: Building a Resource for Human Immunology.

Cell Rep 2018 10;25(2):513-522.e3

Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address:

There is increasing appreciation that the immune system plays critical roles not only in the traditional domains of infection and inflammation but also in many areas of biology, including tumorigenesis, metabolism, and even neurobiology. However, one of the major barriers for understanding human immunological mechanisms is that immune assays have not been reproducibly characterized for a sufficiently large and diverse healthy human cohort. Here, we present the 10,000 Immunomes Project (10KIP), a framework for growing a diverse human immunology reference, from ImmPort, a publicly available resource of subject-level immunology data. Although some measurement types are sparse in the presently deposited ImmPort database, the extant data allow for a diversity of robust comparisons. Using 10KIP, we describe variations in serum cytokines and leukocytes by age, race, and sex; define a baseline cell-cytokine network; and describe immunologic changes in pregnancy. All data in the resource are available for visualization and download at http://10kimmunomes.org/.
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http://dx.doi.org/10.1016/j.celrep.2018.09.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6263160PMC
October 2018

Improving health literacy in patients with chronic conditions: A call to action.

Int J Cardiol 2018 Dec 30;273:249-251. Epub 2018 Aug 30.

Converging Health, Dallas, TX, USA.

Knowledge and education is foundational to an individual receiving care, and health literacy is the ability of patients to understand and act on health information. Cardiovascular disease and diabetes are complex conditions that require active participation on the part of the patient. Lack of understanding on the condition and participation in self-care behaviors limits the effectiveness of treatment. An effective model is needed to better understand how patients with cardiovascular disease and diabetes acquire the knowledge and skills necessary to manage their health. In working together, the authors have created multiple programs that have been delivered at medical offices and corporations, resulting in a model for building functional and critical health literacy skills. This model is a progression that begins with health literacy, including the knowledge and understanding of the condition. Functional literacy includes numeracy, which is the ability to understand and manipulate numbers, and navigation, which is an understanding of what to do with the information. Finally, critical health literacy includes communication skills, including knowing what questions to ask and what information to share, and decision making, which can include shared decision making. These five levels of health literacy form a progression in the ability of the patient to become an active participant in their care, and inform the healthcare provider on effective educational methods.
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http://dx.doi.org/10.1016/j.ijcard.2018.08.090DOI Listing
December 2018

Synthesis, pharmacology and preclinical evaluation of C-labeled 1,3-dihydro-2H-benzo[d]imidazole-2-ones for imaging γ8-dependent transmembrane AMPA receptor regulatory protein.

Eur J Med Chem 2018 Sep 9;157:898-908. Epub 2018 Aug 9.

Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, MA, 02114, USA. Electronic address:

a-Amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are implicated in the pathology of neurological diseases such as epilepsy and schizophrenia. As pan antagonists for this target are often accompanied with undesired effects at high doses, one of the recent drug discovery approaches has shifted to subtype-selective AMPA receptor (AMPAR) antagonists, specifically, via modulating transmembrane AMPAR regulatory proteins (TARPs). The quantification of AMPARs by positron emission tomography (PET) would help obtain insights into disease conditions in the living brain and advance the translational development of AMPAR antagonists. Herein we report the design, synthesis and preclinical evaluation of a series of TARP γ-8 antagonists, amenable for radiolabeling, for the development of subtype-selective AMPAR PET imaging agents. Based on the pharmacology evaluation, molecular docking studies and physiochemical properties, we have identified several promising lead compounds 3, 17-19 and 21 for in vivo PET studies. All candidate compounds were labeled with [C]COCl in high radiochemical yields (13-31% RCY) and high molar activities (35-196 GBq/μmol). While tracers 30 ([C]17) &32 ([C]21) crossed the blood-brain barrier and showed heterogeneous distribution in PET studies, consistent with TARP γ-8 expression, high nonspecific binding prevented further evaluation. To our delight, tracer 31 ([C]3) showed good in vitro specific binding and characteristic high uptake in the hippocampus in rat brain tissues, which provides the guideline for further development of a new generation subtype selective TARP γ-8 dependent AMPAR tracers.
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http://dx.doi.org/10.1016/j.ejmech.2018.08.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6245653PMC
September 2018

MetaCyto: A Tool for Automated Meta-analysis of Mass and Flow Cytometry Data.

Cell Rep 2018 07;24(5):1377-1388

Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address:

While meta-analysis has demonstrated increased statistical power and more robust estimations in studies, the application of this commonly accepted methodology to cytometry data has been challenging. Different cytometry studies often involve diverse sets of markers. Moreover, the detected values of the same marker are inconsistent between studies due to different experimental designs and cytometer configurations. As a result, the cell subsets identified by existing auto-gating methods cannot be directly compared across studies. We developed MetaCyto for automated meta-analysis of both flow and mass cytometry (CyTOF) data. By combining clustering methods with a silhouette scanning method, MetaCyto is able to identify commonly labeled cell subsets across studies, thus enabling meta-analysis. Applying MetaCyto across a set of ten heterogeneous cytometry studies totaling 2,926 samples enabled us to identify multiple cell populations exhibiting differences in abundance between demographic groups. Software is released to the public through Bioconductor (http://bioconductor.org/packages/release/bioc/html/MetaCyto.html).
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http://dx.doi.org/10.1016/j.celrep.2018.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583920PMC
July 2018

Digital health literacy in cardiovascular research.

Int J Cardiol 2018 10 4;269:274-275. Epub 2018 Jul 4.

Converging Health, Dallas, TX, USA.

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http://dx.doi.org/10.1016/j.ijcard.2018.07.011DOI Listing
October 2018

Molecular ablation of tumor blood vessels inhibits therapeutic effects of radiation and bevacizumab.

Neuro Oncol 2018 09;20(10):1356-1367

Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan.

Background: Glioblastoma (GBM) is an aggressive and highly vascular tumor with median survival below 2 years. Despite advances in surgery, radiotherapy, and chemotherapy, survival has improved modestly. To combat glioma vascular proliferation, anti-angiogenic agents targeting vascular endothelial growth factor (VEGF) were introduced. Preclinically these agents were effective, yet they did not improve overall survival in phase III trials. We tested the hypothesis that ganciclovir (GCV)-mediated killing of proliferating endothelial cells expressing herpes simplex virus type 1 thymidine kinase (HSV1-TK) would have direct antitumor effects, and whether vessel ablation would affect the antitumor activity of anti-VEGF antibodies and radiotherapy.

Methods: Proliferating endothelial cells were eliminated using GCV-mediated killing of proliferating endothelial cells expressing HSV1-TK (in Tie2-TK-IRES-GFP mice). Syngeneic NRAS/p53 (NP) gliomas were implanted into the brains of Tie2-TK-IRES-GFP mice. Endothelial proliferation activates the Tie2 promoter and HSV1-TK expression. Administration of GCV kills proliferating tumor endothelial cells and slows tumor growth. The effects of endothelial cell ablation on anti-angiogenic therapy were examined using anti-VEGF antibodies or irradiation.

Results: GCV administration reduced tumor growth and vascular density, increased tumor apoptosis, and prolonged survival. Anti-VEGF antibodies or irradiation also prolonged survival. Surprisingly, combining GCV with irradiation, or with anti-VEGF antibodies, reduced their individual therapeutic effects.

Conclusion: GCV-mediated killing of proliferating endothelial cells expressing HSV1-TK, anti-VEGF antibodies, or irradiation all reduced growth of a murine glioma. However, elimination of microvascular proliferation decreased the efficacy of anti-VEGF or irradiation therapy. We conclude that, in our model, the integrity of proliferating vessels is necessary for the antiglioma effects of anti-VEGF and radiation therapy.
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http://dx.doi.org/10.1093/neuonc/noy055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6140787PMC
September 2018

Chronic Care Model in research and in practice.

Int J Cardiol 2018 05;258:295-296

Converging Health, Dallas, TX, USA.

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http://dx.doi.org/10.1016/j.ijcard.2018.01.078DOI Listing
May 2018

ImmPort, toward repurposing of open access immunological assay data for translational and clinical research.

Sci Data 2018 02 27;5:180015. Epub 2018 Feb 27.

Institute for Computational Health Sciences, University of California, San Francisco, CA 94158, USA.

Immunology researchers are beginning to explore the possibilities of reproducibility, reuse and secondary analyses of immunology data. Open-access datasets are being applied in the validation of the methods used in the original studies, leveraging studies for meta-analysis, or generating new hypotheses. To promote these goals, the ImmPort data repository was created for the broader research community to explore the wide spectrum of clinical and basic research data and associated findings. The ImmPort ecosystem consists of four components-Private Data, Shared Data, Data Analysis, and Resources-for data archiving, dissemination, analyses, and reuse. To date, more than 300 studies have been made freely available through the Shared Data portal (www.immport.org/immport-open), which allows research data to be repurposed to accelerate the translation of new insights into discoveries.
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http://dx.doi.org/10.1038/sdata.2018.15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5827693PMC
February 2018

Data discovery with DATS: exemplar adoptions and lessons learned.

J Am Med Inform Assoc 2018 01;25(1):13-16

Oxford e-Research Centre, Engineering Science, University of Oxford, Oxford, UK.

The DAta Tag Suite (DATS) is a model supporting dataset description, indexing, and discovery. It is available as an annotated serialization with schema.org, a vocabulary used by major search engines, thus making the datasets discoverable on the web. DATS underlies DataMed, the National Institutes of Health Big Data to Knowledge Data Discovery Index prototype, which aims to provide a "PubMed for datasets." The experience gained while indexing a heterogeneous range of >60 repositories in DataMed helped in evaluating DATS's entities, attributes, and scope. In this work, 3 additional exemplary and diverse data sources were mapped to DATS by their representatives or experts, offering a deep scan of DATS fitness against a new set of existing data. The procedure, including feedback from users and implementers, resulted in DATS implementation guidelines and best practices, and identification of a path for evolving and optimizing the model. Finally, the work exposed additional needs when defining datasets for indexing, especially in the context of clinical and observational information.
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http://dx.doi.org/10.1093/jamia/ocx119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481379PMC
January 2018

PDX-MI: Minimal Information for Patient-Derived Tumor Xenograft Models.

Cancer Res 2017 11;77(21):e62-e66

Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas.

Patient-derived tumor xenograft (PDX) mouse models have emerged as an important oncology research platform to study tumor evolution, mechanisms of drug response and resistance, and tailoring chemotherapeutic approaches for individual patients. The lack of robust standards for reporting on PDX models has hampered the ability of researchers to find relevant PDX models and associated data. Here we present the PDX models minimal information standard (PDX-MI) for reporting on the generation, quality assurance, and use of PDX models. PDX-MI defines the minimal information for describing the clinical attributes of a patient's tumor, the processes of implantation and passaging of tumors in a host mouse strain, quality assurance methods, and the use of PDX models in cancer research. Adherence to PDX-MI standards will facilitate accurate search results for oncology models and their associated data across distributed repository databases and promote reproducibility in research studies using these models. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-0582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5738926PMC
November 2017

Design and Rationale of a Randomized Trial of a Care Transition Strategy in Patients With Acute Heart Failure Discharged From the Emergency Department: GUIDED-HF (Get With the Guidelines in Emergency Department Patients With Heart Failure).

Circ Heart Fail 2017 Feb;10(2)

From the Department of Emergency Medicine, University of Cincinnati, OH (G.J.F.); Department of Emergency Medicine, Wayne State University, Detroit, MI (P.D.L., S.I.A., V.A.K., S.R., J.W.); Department of Emergency Medicine, Indiana University School of Medicine, Indianapolis (P.P.); Division of Cardiovascular Medicine (J.B.) and Department of Emergency Medicine (A.S.), Stony Brook University, NY; Division of Emergency Medicine, Washington University, St. Louis, MO (D.C.); American Heart Association/American Stroke Association, Dallas, TX (P.D., Y.K.); Department of Biostatistics (C.A.J., D.L.), Department of Emergency Medicine (C.K., K.M., A.B.S., C.W., S.P.C.), Division of Cardiovascular Disease (J.L.), and Department of Internal Medicine, Pediatrics and Health Policy (R.L.R.), Vanderbilt University, Nashville, TN; Department of Emergency Medicine, Baylor College of Medicine, Houston, TX (W.F.P.); Department of Medicine, Emory University School of Medicine, Atlanta, GA (C.R.); Department of Emergency Medicine, Metro Health, Cleveland, OH (J.S.); and Department of Emergency Medicine, University of Mississippi Medical Center, Jackson (S.A.S.).

GUIDED-HF (Get With the Guidelines in Emergency Department Patients With Heart Failure) is a multicenter randomized trial of a patient-centered transitional care intervention in patients with acute heart failure (AHF) who are discharged either directly from the emergency department (ED) or after a brief period of ED-based observation. To optimize care and reduce ED and hospital revisits, there has been significant emphasis on improving transitions at the time of hospital discharge for patients with HF. Such efforts have been almost exclusively directed at hospitalized patients; individuals with AHF who are discharged from the ED or ED-based observation are not included in these transitional care initiatives. Patients with AHF discharged directly from the ED or after a brief period of ED-based observation are randomly assigned to our transition GUIDED-HF strategy or standard ED discharge. Patients in the GUIDED arm receive a tailored discharge plan via the study team, based on their identified barriers to outpatient management and associated guideline-based interventions. This plan includes conducting a home visit soon after ED discharge combined with close outpatient follow-up and subsequent coaching calls to improve postdischarge care and avoid subsequent ED revisits and inpatient admissions. Up to 700 patients at 11 sites will be enrolled over 3 years of the study. GUIDED-HF will test a novel approach to AHF management strategy that includes tailored transitional care for patients discharged from the ED or ED-based observation. If successful, this program may significantly alter the current paradigm of AHF patient care.

Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02519283.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.116.003581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5319725PMC
February 2017

Adapting Conceptual Frameworks for Patient Engagement in Emergency Department Research.

Acad Emerg Med 2016 12 25;23(12):1332-1336. Epub 2016 Nov 25.

Ronald O. Perelman Department of Emergency Medicine, NYU School of Medicine, New York City, NY.

For many people the emergency department (ED) is the first point of access to healthcare for acute needs and a recurring location for many with chronic healthcare needs. While the ED is well placed to identify unmet needs it can also be a net that people slip through when faced with uncoordinated and expensive healthcare challenges. Thus the ED has a responsibility to set patients on a safe and meaningful care trajectory, which can only be done in consultation and partnership with the patients themselves. The purpose of this article is to present crucial aspects of patient engagement that are essential for future research to foster an environment of colearning and respect that encourages ongoing involvement by patients, families, and staff.
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http://dx.doi.org/10.1111/acem.13066DOI Listing
December 2016
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