289 research outputs found
Advancing Culturally and Linguistically Appropriate Services at all Phases of a Disaster
The Mycobacterium tuberculosis MmpL11 cell wall lipid transporter is important for biofilm formation, intracellular growth, and nonreplicating persistence
Ornithine decarboxylase supports ILC3 responses in infectious and autoimmune colitis through positive regulation of IL-22 transcription
Group 3 innate lymphoid cells (ILC3s) are RORÎł
Design patterns for the development of electronic health record-driven phenotype extraction algorithms
AbstractBackgroundDesign patterns, in the context of software development and ontologies, provide generalized approaches and guidance to solving commonly occurring problems, or addressing common situations typically informed by intuition, heuristics and experience. While the biomedical literature contains broad coverage of specific phenotype algorithm implementations, no work to date has attempted to generalize common approaches into design patterns, which may then be distributed to the informatics community to efficiently develop more accurate phenotype algorithms.MethodsUsing phenotyping algorithms stored in the Phenotype KnowledgeBase (PheKB), we conducted an independent iterative review to identify recurrent elements within the algorithm definitions. We extracted and generalized recurrent elements in these algorithms into candidate patterns. The authors then assessed the candidate patterns for validity by group consensus, and annotated them with attributes.ResultsA total of 24 electronic Medical Records and Genomics (eMERGE) phenotypes available in PheKB as of 1/25/2013 were downloaded and reviewed. From these, a total of 21 phenotyping patterns were identified, which are available as an online data supplement.ConclusionsRepeatable patterns within phenotyping algorithms exist, and when codified and cataloged may help to educate both experienced and novice algorithm developers. The dissemination and application of these patterns has the potential to decrease the time to develop algorithms, while improving portability and accuracy
Desiderata for the development of next-generation electronic health record phenotype libraries
BackgroundHigh-quality phenotype definitions are desirable to enable the extraction of patient cohorts from large electronic health record repositories and are characterized by properties such as portability, reproducibility, and validity. Phenotype libraries, where definitions are stored, have the potential to contribute significantly to the quality of the definitions they host. In this work, we present a set of desiderata for the design of a next-generation phenotype library that is able to ensure the quality of hosted definitions by combining the functionality currently offered by disparate tooling.MethodsA group of researchers examined work to date on phenotype models, implementation, and validation, as well as contemporary phenotype libraries developed as a part of their own phenomics communities. Existing phenotype frameworks were also examined. This work was translated and refined by all the authors into a set of best practices.ResultsWe present 14 library desiderata that promote high-quality phenotype definitions, in the areas of modelling, logging, validation, and sharing and warehousing.ConclusionsThere are a number of choices to be made when constructing phenotype libraries. Our considerations distil the best practices in the field and include pointers towards their further development to support portable, reproducible, and clinically valid phenotype design. The provision of high-quality phenotype definitions enables electronic health record data to be more effectively used in medical domains
The Canadian Women's Heart Health Alliance atlas on the epidemiology, diagnosis, and management of cardiovascular disease in women - Chapter 6 : sex- and gender-specific diagnosis and treatment
This chapter summarizes the sex- and gender-specific diagnosis and treatment of acute/unstable presentations and nacute/stable presentations of cardiovascular disease in women. Guidelines, scientific statements, systematic reviews/meta-analyses, and primary research studies related to diagnosis and treatment of coronary artery disease, cerebrovascular disease (stroke), valvular heart disease, and heart failure in women were reviewed. The evidence is summarized as a narrative, and when available, sex- and gender-specific practice and research recommendations are provided. Acute coronary syndrome presentations and emergency department delays are different in women than they are in men. Coronary angiography remains the gold-standard test for diagnosis of obstructive coronary artery disease. Other diagnostic imaging modalities for ischemic heart disease detection (eg, positron emission tomography, echocardiography, single-photon emission computed tomography, cardiovascular magnetic resonance, coronary computed tomography angiography) have been shown to be useful in women, with their selection dependent upon both the goal of the individualized assessment and the testing resources available. Noncontrast computed tomography and computed tomography angiography are used to diagnose stroke in women. Although sex-specific differences appear to exist in the efficacy of standard treatments for diverse presentations of acute coronary syndrome, many cardiovascular drugs and interventions tested in clinical trials were not powered to detect sex-specific differences, and knowledge gaps remain. Similarly, although knowledge is evolving about sex-specific difference in the management of valvular heart disease, and heart failure with both reduced and preserved ejection fraction, current guidelines are lacking in sex-specific recommendations, and more research is needed.Ce chapitre prĂ©sente un rĂ©sumĂ© sur le diagnostic et le traitement des tableaux cliniques aigus/instables et non aigus/stables des maladies cardiovasculaires chez les femmes, et les diffĂ©rences propres Ă chacun des deux sexes. Les lignes directrices, les Ă©noncĂ©s scientifiques, les revues systĂ©matiques/mĂ©ta-analyses et les Ă©tudes de recherche originale sur le diagnostic et le traitement des coronaropathies, des maladies vasculaires cĂ©rĂ©brales (AVC), des valvulopathies cardiaques et de lâinsuffisance cardiaque chez les femmes ont Ă©tĂ© examinĂ©s. Les donnĂ©es probantes sont rĂ©sumĂ©es sous forme narrative et, lorsquâelles sont disponibles, des recommandations en matiĂšre de pratique et de recherche pour chacun des deux sexes sont prĂ©sentĂ©es. Les tableaux cliniques du syndrome coronarien aigu et les dĂ©lais dâattente Ă lâurgence sont diffĂ©rents selon quâune femme ou un homme en est atteint. Lâangiographie coronarienne reste lâexamen de rĂ©fĂ©rence pour le diagnostic des coronaropathies obstructives. Dâautres examens dâimagerie diagnostique (p. ex. la tomographie par Ă©mission de positons, lâĂ©chocardiographie, la tomographie d'Ă©mission Ă photon unique, la rĂ©sonance magnĂ©tique cardiovasculaire, lâangiographie coronarienne par tomodensitomĂ©trie) se sont avĂ©rĂ©s utiles pour la dĂ©tection des cardiopathies ischĂ©miques chez les femmes. Le recours Ă ces modalitĂ©s dĂ©pend de lâobjectif de lâĂ©valuation personnalisĂ©e et des ressources disponibles. La tomodensitomĂ©trie sans agent de contraste et lâangiographie par tomodensitomĂ©trie sont utilisĂ©es pour le diagnostic des AVC chez les femmes. MalgrĂ© les diffĂ©rences entre les sexes quant Ă lâefficacitĂ© des traitements de rĂ©fĂ©rence des divers tableaux cliniques du syndrome coronarien aigu, bon nombre des mĂ©dicaments et des interventions cardiovasculaires qui ont fait lâobjet dâessais cliniques nâavaient pas la puissance statistique nĂ©cessaire pour dĂ©tecter des diffĂ©rences selon les sexes, de sorte que les connaissances restent fragmentaires sur ce sujet. De mĂȘme, malgrĂ© lâĂ©volution des connaissances sur les diffĂ©rences sexuelles quant Ă la prise en charge des valvulopathies cardiaques et de lâinsuffisance cardiaque avec fraction dâĂ©jection rĂ©duite ou prĂ©servĂ©e, on ne trouve pas de recommandations pour chaque sexe dans les lignes directrices actuelles, dâoĂč la pertinence dâĂ©tudes supplĂ©mentaires portant sur cette question
Specific immune modulation of experimental colitis drives enteric alpha-synuclein accumulation and triggers age-related Parkinson-like brain pathology
Background: In some people with Parkinsonâs disease (PD), a-synuclein (αSyn) accumulation may begin in the enteric nervous system (ENS) decades before development of brain pathology and disease diagnosis.
Objective: To determine how different types and severity of intestinal inflammation could trigger αSyn accumulation in the ENS and the subsequent development of αSyn brain pathology.
Methods: We assessed the effects of modulating short- and long-term experimental colitis on αSyn accumulation in the gut of αSyn transgenic and wild type mice by immunostaining and gene expression analysis. To determine the long-term effect on the brain, we induced dextran sulfate sodium (DSS) colitis in young αSyn transgenic mice and aged them under normal conditions up to 9 or 21 months before tissue analyses.
Results: A single strong or sustained mild DSS colitis triggered αSyn accumulation in the submucosal plexus of wild type and αSyn transgenic mice, while short-term mild DSS colitis or inflammation induced by lipopolysaccharide did not have such an effect. Genetic and pharmacological modulation of macrophage-associated pathways modulated the severity of enteric αSyn. Remarkably, experimental colitis at three months of age exacerbated the accumulation of aggregated phospho-Serine 129 αSyn in the midbrain (including the substantia nigra), in 21- but not 9-month-old αSyn transgenic mice. This increase in midbrain αSyn accumulation is accompanied by the loss of tyrosine hydroxylase-immunoreactive nigral neurons.
Conclusions: Our data suggest that specific types and severity of intestinal inflammation, mediated by monocyte/macrophage signaling, could play a critical role in the initiation and progression of PD
A polygenic and phenotypic risk prediction for polycystic ovary syndrome evaluated by phenomewide association studies
Context: As many as 75% of patients with polycystic ovary syndrome (PCOS) are estimated tobe unidentified in clinical practice. Objective: Utilizing polygenic risk prediction, we aim to identify the phenome-widecomorbidity patterns characteristic of PCOS to improve accurate diagnosis and preventivetreatment.Design, Patients, and Methods: Leveraging the electronic health records (EHRs) of 124 852individuals, we developed a PCOS risk prediction algorithm by combining polygenic risk scores(PRS) with PCOS component phenotypes into a polygenic and phenotypic risk score (PPRS). Weevaluated its predictive capability across different ancestries and perform a PRS-based phenomewide association study (PheWAS) to assess the phenomic expression of the heightened risk ofPCOS.Results: The integrated polygenic prediction improved the average performance (pseudo-R2)for PCOS detection by 0.228 (61.5-fold), 0.224 (58.8-fold), 0.211 (57.0-fold) over the null modelacross European, African, and multi-ancestry participants respectively. The subsequent PRSpowered PheWAS identified a high level of shared biology between PCOS and a range ofmetabolic and endocrine outcomes, especially with obesity and diabetes: "morbid obesity","type 2 diabetes", "hypercholesterolemia", "disorders of lipid metabolism", "hypertension",and "sleep apnea" reaching phenome-wide significance.Conclusions: Our study has expanded the methodological utility of PRS in patient stratificationand risk prediction, especially in a multifactorial condition like PCOS, across different geneticorigins. By utilizing the individual genome-phenome data available from the EHR, our approachalso demonstrates that polygenic prediction by PRS can provide valuable opportunities todiscover the pleiotropic phenomic network associated with PCOS pathogenesis.Abbreviations: AA, African ancestry; ANOVA, analysis of variance; BMI, body mass index; EA,European ancestry; EHR, electronic health records; eMERGE, electronic Medical Records andGenomics Network; GWAS, genome-wide association study; IBD, identity-by-descent; ICDCM, International Classification of Diseases, Clinical Modification; LD, linkage disequilibrium;MA, multi-ancestry; MAF, minor allele frequency; NIH, National Institutes of Health; PCA,principal component analysis; PheWAS, phenome-wide association study; PCOS, polycysticovary syndrome; PPRS, polygenic and phenotypic risk score; PRS, polygenic risk sc
Sustained CD28 Expression Delays Multiple Features of Replicative Senescence in Human CD8 T Lymphocytes
CD28 costimulatory signal transduction in T lymphocytes is essential for optimal telomerase activity, stabilization of cytokine mRNAs, and glucose metabolism. During aging and chronic infection with HIV-1, there are increased proportions of CD8 T lymphocytes that lack CD28 expression and show additional features of replicative senescence. Moreover, the abundance of these cells correlates with decreased vaccine responsiveness, early mortality in the very old, and accelerated HIV disease progression. Here, we show that sustained expression of CD28, via gene transduction, retards the process of replicative senescence, as evidenced by enhanced telomerase activity, increased overall proliferative potential, and reduced secretion of pro-inflammatory cytokines. Nevertheless, the transduced cultures eventually do reach senescence, which is associated with increased CTLA-4 gene expression and a loss of CD28 cell surface expression. These findings further elucidate the central role of CD28 in the replicative senescence program, and may ultimately lead to novel therapies for diseases associated with replicative senescence
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