A concept‐wide association study to identify potential risk factors for nonadherence among prevalent users of antihypertensives

PurposeWe sought to determine whether an association study using information contained in clinical notes could identify known and potentially novel risk factors for nonadherence to antihypertensive medications.MethodsWe conducted a retrospective concept‐wide association study (CWAS) using clinical notes to identify potential risk factors for medication nonadherence, adjusting for age, sex, race, baseline blood pressure, estimated glomerular filtration rate, and a combined comorbidity score. Participants included Medicare beneficiaries 65 years and older receiving care at the Harvard Vanguard Medical Associates network from 2010‐2012 and enrolled in a Medicare Advantage program. Concepts were extracted from clinical notes in the year prior to the index prescription date for each patient. We tested associations with the outcome for 5013 concepts extracted from clinical notes in a derivation cohort (4382 patients) and accounted for multiple hypothesis testing by using a false discovery rate threshold of less than 5% (q < .05). We then confirmed the associations in a validation cohort (3836 patients). Medication nonadherence was defined using a proportion of days covered (PDC) threshold less than 0.8 using pharmacy claims data.ResultsWe found 415 concepts associated with nonadherence, which we organized into 11 clusters using a hierarchical clustering approach. Volume depletion and overload, assessment of needs at the point of discharge, mood disorders, neurological disorders, complex coordination of care, and documentation of noncompliance were some of the factors associated with nonadherence.ConclusionsThis approach was successful in identifying previously described and potentially new risk factors for antihypertensive nonadherence using the clinical narrative.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151999/1/pds4850.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151999/2/pds4850_am.pd

Selection and validation of a set of reliable reference genes for quantitative sod gene expression analysis in C. elegans

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Electron-nucleus scattering in the NEUT event generator

The NEUT event generator is a widely-used tool to simulate neutrino interactions for energies between 10s of MeV and a few TeV. NEUT plays a crucial role in neutrino oscillation analyses for the T2K and Hyper-K experiments, providing the primary simulation of the neutrino interactions whose final-state products are measured to infer the oscillation parameters. NEUT is also capable of simulating nucleon decay and hadron scattering. These proceedings present an expansion of NEUT to simulate electron scattering before showing comparisons to experimental measurements and using discrepancies to derive an empirical correction to NEUT's treatment of nuclear removal energy.Comment: 5 pages, 3 figures. NuFact2022 proceedings submissio

A Proposal for Integrated Efficacy-to-Effectiveness (E2E) Clinical Trials

We propose an “efficacy-to-effectiveness” (E2E) clinical trial design, in which an effectiveness trial would commence seamlessly upon completion of the efficacy trial. Efficacy trials use inclusion/exclusion criteria to produce relatively homogeneous samples of participants with the target condition, conducted in settings that foster adherence to rigorous clinical protocols. Effectiveness trials use inclusion/exclusion criteria that generate heterogeneous samples that are more similar to the general patient spectrum, conducted in more varied settings, with protocols that approximate typical clinical care. In E2E trials, results from the efficacy trial component would be used to design the effectiveness trial component, to confirm and/or discern associations between clinical characteristics and treatment effects in typical care, and potentially to test new hypotheses. An E2E approach may improve the evidentiary basis for selecting treatments, expand understanding of the effectiveness of treatments in subgroups with particular clinical features, and foster incorporation of effectiveness information into regulatory processes.National Center for Research Resources (U.S.) (Grant UL1 RR025752)National Center for Advancing Translational Sciences (U.S.) (Grant UL1 TR000073

Phenotypic covariance of longevity, immunity and stress resistance in the Caenorhabditis nematodes

Background \ud Ageing, immunity and stresstolerance are inherent characteristics of all organisms. In animals, these traits are regulated, at least in part, by forkhead transcription factors in response to upstream signals from the Insulin/Insulin– like growth factor signalling (IIS) pathway. In the nematode Caenorhabditis elegans, these phenotypes are molecularly linked such that activation of the forkhead transcription factor DAF-16 both extends lifespan and simultaneously increases immunity and stress resistance. It is known that lifespan varies significantly among the Caenorhabditis species but, although DAF-16 signalling is highly conserved, it is unclear whether this phenotypic linkage occurs in other species. Here we investigate this phenotypic covariance by comparing longevity, stress resistance and immunity in four \ud Caenorhabditis species. \ud \ud Methodology/Principal Findings \ud We show using phenotypic analysis of DAF-16 influenced phenotypes that among four closely related Caenorhabditis nematodes, the gonochoristic species (Caenorhabditis remanei and Caenorhabditis brenneri) have diverged \ud significantly with a longer lifespan, improved stress resistance and higher immunity than the hermaphroditic species (C. elegans and Caenorhabditis briggsae). Interestingly, we also observe significant differences in expression levels between the daf-16 homologues in these species using Real-Time PCR, which positively correlate with the observed phenotypes. Finally, we provide additional evidence in support of a role for DAF-16 in regulating phenotypic coupling by using a combination of wildtype isolates, constitutively active daf-16 mutants and bioinformatic analysis. \ud \ud Conclusions \ud The gonochoristic species display a significantly longer lifespan (p < 0.0001)and more robust immune and stress response (p<0.0001, thermal stress; p<0.01, heavy metal stress; p<0.0001, pathogenic stress) than the hermaphroditic species. Our data suggests that divergence in DAF-16 mediated phenotypes may underlie many of the differences observed between these four species of Caenorhabditis nematodes. These findings are further supported by the correlative higher daf-16 expression levels among the gonochoristic species and significantly higher lifespan, immunity and stress tolerance in the constitutively active daf-16 hermaphroditic mutants

Phenotypic covariance of Longevity, Immunity and Stress Resistance in the Caenorhabditis Nematodes

Background: Ageing, immunity and stresstolerance are inherent characteristics of all organisms. In animals, these traits are regulated, at least in part, by forkhead transcription factors in response to upstream signals from the Insulin/Insulin–like growth factor signalling (IIS) pathway. In the nematode Caenorhabditis elegans, these phenotypes are molecularly linked such that activation of the forkhead transcription factor DAF-16 both extends lifespan and simultaneously increases immunity and stress resistance. It is known that lifespan varies significantly among the Caenorhabditis species but, although DAF-16 signalling is highly conserved, it is unclear whether this phenotypic linkage occurs in other species. Here we investigate this phenotypic covariance by comparing longevity, stress resistance and immunity in four Caenorhabditis species. \ud \ud Methodology/Principal Findings: We show using phenotypic analysis of DAF-16 influenced phenotypes that among four closely related Caenorhabditis nematodes, the gonochoristic species (Caenorhabditis remanei and Caenorhabditis brenneri) have diverged significantly with a longer lifespan, improved stress resistance and higher immunity than the hermaphroditic species (C. elegans and Caenorhabditis briggsae). Interestingly, we also observe significant differences in expression levels between the daf-16 homologues in these species using Real-Time PCR, which positively correlate with the observed phenotypes. Finally, we provide additional evidence in support of a role for DAF-16 in regulating phenotypic coupling by using a combination of wildtype isolates, constitutively active daf-16 mutants and bioinformatic analysis. \ud \ud Conclusions: The gonochoristic species display a significantly longer lifespan (p<0.0001) and more robust immune and stress response (p<0.0001, thermal stress; p<0.01, heavy metal stress; p<0.0001, pathogenic stress) than the hermaphroditic species. Our data suggests that divergence in DAF-16 mediated phenotypes may underlie many of the differences observed between these four species of Caenorhabditis nematodes. These findings are further supported by the correlative higher daf-16 expression levels among the gonochoristic species and significantly higher lifespan, immunity and stress tolerance in the constitutively active daf-16 hermaphroditic mutants

International sourcing decisions in the wake of a food scandal

This research investigates whether and how the 2013 Horsemeat Scandal has altered European food retailers’ efforts to mitigate fraud in the international agri-food supply chain. We construct an econometric model that matches fraud alert data from the European Union (EU) Rapid Alert System for Food and Feed (RASFF) from 2006 to 2016 with annual data on bilateral trade flows. We find that—prior to the horsemeat scandal—detection of fraud along the supply chain induced a small amount of trade diversion toward third-country sources, but did not substantially affect total trade into the EU. In contrast, in the years after the scandal, the detection of fraud by international suppliers was substantially trade destructive. Detection of fraud reduced trade, not only with the country from which the fraudulent product originated, but also from third-country exporters of the same product. These findings extend beyond trade in meat products and to importing countries outside Western and Northern Europe

Hair Follicle Mesenchyme-Associated PD-L1 Regulates T-Cell Activation Induced Apoptosis: A Potential Mechanism of Immune Privilege

The immune privilege (IP) of hair follicles (HFs) has been well established in previous studies. However, whether cultured HF cells still exhibit IP properties, the individual factors involved in this process, and the detailed mechanisms that drive and maintain IP, are largely unidentified. We found preferential expression of IP-associated genes in cultured HF dermal papilla and dermal sheath cup cells (DSCCs) compared with non-follicular fibroblasts (FBs) at passage 4, suggesting a potential for functional IP. Notably, programmed cell death 1 ligand 1 (PD-L1) was significantly upregulated in DSCCs and dermal papilla cells relative to FBs. IFNγ secretion from peripheral blood mononuclear cells (PBMCs) co-cultured with histoincompatible DSCCs was significantly lower than with FB and higher percentages of early apoptotic, Annexin V+ cells were observed in PBMC co-cultured with DSCCs. Knockdown of PD-L1 translation by silencing interfering RNA in DSCCs enabled increased IFNγ secretion by PBMCs, whereas transfection of pCMV6-XL4/hPD-L1 in FB significantly reduced IFNγ secretion and increased apoptosis in co-cultured PBMCs. We also found that apoptosis in allogeneic T cells induced by DSCCs was largely dependent on the mitochondrial pathway. Our study suggests IP properties are exhibited in cultured DSCCs in part through expression of negative co-signaling molecule PD-L1

Fibroblast cell-based therapy prevents induction of alopecia areata in an experimental model

YesAlopecia areata (AA) is an autoimmune hair loss disease with infiltration of proinflammatory cells into hair follicles. Current therapeutic regimens are unsatisfactory mainly because of the potential for side effects and/or limited efficacy. Here we report that cultured, transduced fibroblasts, which express the immunomodulatory molecule indoleamine 2,3-dioxygenase (IDO), can be applied to prevent hair loss in an experimental AA model. A single intraperitoneal (IP) injection of IDO-expressing primary dermal fibroblasts was given to C3H/HeJ mice at the time of AA induction. While 60–70% of mice that received either control fibroblasts or vehicle injections developed extensive AA, none of the IDO-expressing fibroblast-treated mice showed new hair loss up to 20 weeks post injection. IDO cell therapy significantly reduced infiltration of CD4+ and CD8+ T cells into hair follicles and resulted in decreased expression of TNF-α, IFN-γ and IL-17 in the skin. Skin draining lymph nodes of IDO fibroblast-treated mice were significantly smaller, with more CD4+ CD25+ FoxP3+ regulatory T cells and fewer Th17 cells than those of control fibroblast and vehicle-injected mice. These findings indicate that IP injected IDO-expressing dermal fibroblasts can control inflammation and thereby prevent AA hair loss.Canadian Institutes of Health Researches (Funding Reference Number: 134214 and 136945)