HIV-Exposed Uninfected Infants Have Increased Regulatory T Cells That Correlate With Decreased T Cell Function

Background: HIV-exposed uninfected infants (HEU) are at higher risk of severe infections, hospitalizations and death compared with HIV-unexposed uninfected infants (HUU), but the immune deficit underlying it is not known. To address this gap, we investigated T cell functionality and its relationship to phenotypic profiles of T cells and antigen presenting cells (APC) in HEU and HUU.Methods: Blood mononuclear cells from 55 HEU and 16 HUU were stimulated with Staphylococcal Enterotoxin B (SEB) or mock for 72 h, and tested by flow cytometry for proliferation and expression of Th1, Th2, and regulatory (Treg) markers. In parallel, cells were phenotypically assessed for differentiation profiles of Treg, conventional T cell (Tconv) and APC in unstimulated cells.Results: HEU had lower CD4+ functional responses to SEB/mock and similar CD8+ responses compared with HUU. In the phenotypic T cell panel, HEU showed higher proportions of CD4+ and CD8+ Treg expressing IL10, FOXP3, and CD25; higher effector Tconv and Treg; and lower naïve and CD4+TGFβ+ Treg compared with HUU. In the phenotypic APC panel, HEU showed higher proportions of CD1c+ cDC2, CD123+ pDC, CD16+ inflammatory monocytes and cDC and higher expression of CD103 on CD1c-CD123-CD16-cDC1 compared with HUU. Regression analyses adjusted for HIV exposure and multiple comparisons showed that higher CD8+IL10+ and CD8+FOXP3+ Treg in unstimulated cells were associated with lower CD8+ T cell functional responses to SEB/mock. Functionality was not affected by Tconv differentiation, but higher APC activation in aggregate was associated with higher CD8+IL10+ Treg responses to SEB.Conclusions: T cell functionality was decreased in HEU compared with HUU. High CD8+ Treg proportions were the most important predictors of decreased T cell functionality in HEU and HUU

An evaluation of clinical decision support tools for Patient Health Questionnaire-9 administration

Introduction: Many health care institutions are working to improve depression screening and management with the use of the Patient Health Questionnaire 9 (PHQ-9). Clinical decision support (CDS) within the EHR is one strategy, but little is known about effective approaches to design or implement such CDS. The purpose of this study is to compare implementation outcomes of two versions of a CDS tool to improve PHQ-9 administration for patients with depression. Methods: This was a retrospective, observational study comparing two versions of a CDS. Version 1 interrupted clinician workflow, and version 2 did not interrupt workflow. Outcomes of interest included reach, adoption, and effectiveness. PHQ-9 administration was determined by chart review. Chi-square tests were used to evaluate associations between PHQ-9 administration with versions 1 and 2. Results: Version 1 resulted in PHQ-9 administration 77 times (15.3% of 504 unique encounters) compared with 49 times (9.8% of 502 unique encounters) with version 2 (P = .011). Discussion: An interruptive CDS tool may be more effective at increasing PHQ-9 administration, but a noninterruptive CDS tool may be preferred to minimize alert fatigue despite a decrease in effectiveness

Permutation-based methods for mediation analysis in studies with small sample sizes

Background Mediation analysis can be used to evaluate the effect of an exposure on an outcome acting through an intermediate variable or mediator. For studies with small sample sizes, permutation testing may be useful in evaluating the indirect effect (i.e., the effect of exposure on the outcome through the mediator) while maintaining the appropriate type I error rate. For mediation analysis in studies with small sample sizes, existing permutation testing methods permute the residuals under the full or alternative model, but have not been evaluated under situations where covariates are included. In this article, we consider and evaluate two additional permutation approaches for testing the indirect effect in mediation analysis based on permutating the residuals under the reduced or null model which allows for the inclusion of covariates. Methods Simulation studies were used to empirically evaluate the behavior of these two additional approaches: (1) the permutation test of the Indirect Effect under Reduced Models (IERM) and (2) the Permutation Supremum test under Reduced Models (PSRM). The performance of these methods was compared to the standard permutation approach for mediation analysis, the permutation test of the Indirect Effect under Full Models (IEFM). We evaluated the type 1 error rates and power of these methods in the presence of covariates since mediation analysis assumes no unmeasured confounders of the exposure–mediator–outcome relationships. Results The proposed PSRM approach maintained type I error rates below nominal levels under all conditions, while the proposed IERM approach exhibited grossly inflated type I rates in many conditions and the standard IEFM exhibited inflated type I error rates under a small number of conditions. Power did not differ substantially between the proposed PSRM approach and the standard IEFM approach. Conclusions The proposed PSRM approach is recommended over the existing IEFM approach for mediation analysis in studies with small sample sizes

Maternal treatment with short-chain fatty acids modulates the intestinal microbiota and immunity and ameliorates type 1 diabetes in the offspring.

We recently hypothesized that the intestinal microbiota and the innate immune system play key roles in the mechanism of Kilham Rat Virus-induced type 1 diabetes in the LEW1.WR1 rat. We used this animal model to test the hypothesis that maternal therapy with short-chain fatty acids can modulate the intestinal microbiota and reverse virus-induced proinflammatory responses and type 1 diabetes in rat offspring. We observed that administration of short-chain fatty acids to rat breeders via drinking water prior to pregnancy and further treatment of the offspring with short-chain fatty acids after weaning led to disease amelioration. In contrast, rats that were administered short-chain fatty acids beginning at weaning were not protected from type 1 diabetes. Short-chain fatty acid therapy exerted a profound effect on the intestinal microbiome in the offspring reflected by a reduction and an increase in the abundances of Firmicutes and Bacteroidetes taxa, respectively, on day 5 post-infection, and reversed virus-induced alterations in certain bacterial taxa. Principal component analysis and permutation multivariate analysis of variance tests further revealed that short-chain fatty acids induce a distinct intestinal microbiota compared with uninfected animals or rats that receive the virus only. Short-chain fatty acids downregulated Kilham Rat Virus-induced proinflammatory responses in the intestine. Finally, short-chain fatty acids altered the B and T cell compartments in Peyer's patches. These data demonstrate that short-chain fatty acids can reshape the intestinal microbiota and prevent virus-induced islet autoimmunity and may therefore represent a useful therapeutic strategy for disease prevention

Clinical pharmacists in primary care: Provider satisfaction and perceived impact on quality of care provided

Purpose: The purpose of this study is to evaluate primary care provider satisfaction and perceived impact of clinical pharmacy services on the disease state management in primary care. Methods: A cross-sectional survey with 24 items and 4 domains was distributed anonymously to pharmacy residency program directors across the United States who were requested to forward the survey to their primary care provider colleagues. Primary care providers were asked to complete the survey. Results: A total of 144 primary care providers responded to the survey, with 130 reporting a clinical pharmacist within their primary care practice and 114 completing the entire survey. Primary care providers report pharmacists positively impact quality of care (mean = 5.5 on Likert scale of 1–6; standard deviation = 0.72), high satisfaction with pharmacy services provided (5.5; standard deviation = 0.79), and no increase in workload as a result of clinical pharmacists (5.5; standard deviation = 0.77). Primary care providers would recommend clinical pharmacists to other primary care practices (5.7; standard deviation = 0.59). Primary care providers perceived specific types of pharmacy services to have the greatest impact on patient care: medication therapy management (38.6%), disease-focused management (29.82%), and medication reconciliation (11.4%). Primary care providers indicated the most valuable disease-focused pharmacy services as diabetes (58.78%), hypertension (9.65%), and pain (11.4%). Conclusion: Primary care providers report high satisfaction with and perceived benefit of clinical pharmacy services in primary care and viewed medication therapy management and disease-focused management of diabetes, hypertension, and pain as the most valuable clinical pharmacy services. These results can be used to inform development or expansion of clinical pharmacy services in primary care

Twice-daily versus once-daily lisinopril and losartan for hypertension: Real-world effectiveness and safety.

BackgroundLisinopril and losartan manufacturer labels recommend twice-daily dosing (BID) if once-daily (QDay) is insufficient to lower blood pressure (BP).Methods and resultsRetrospective cohort study of patients taking QDay lisinopril and losartan who experienced a dose-doubling (index date). A text-processing tool categorized BID and QDay groups at the index date based on administration instructions. We excluded: pregnant/hospice, regimens other than BID/QDay, and without BP measurements -6 months/+12 months of the index date. The most proximal BP measurements -6 months and +2 weeks to 12 months of the index date were used to evaluate BP differences. Propensity scores were generated, and differences in BP and adverse events (angioedema, acute kidney injury, hyperkalemia) between BID/QDay groups were analyzed within dosing cohorts using inverse propensity of treatment-weighted regression models. Of 11,210 and 6,051 patients who met all criteria for lisinopril and losartan, 784 (7.0%) and 453 (7.5%) were taking BID, respectively. BID patients were older and had higher comorbidity and medication burdens. There were no differences in systolic/diastolic BP between BID and QDay, with absolute differences in mean systolic BP ranging from -1.8 to 0.7 mmHg and diastolic BP ranging from -1.1 to 0.1 mmHg (all 95% confidence intervals [CI] cross 0). Lisinopril 10mg BID was associated with an increased odds of angioedema compared to lisinopril 20mg QDay (odds ratio 2.27, 95%CI 1.13-4.58).ConclusionsAdjusted models do not support improved effectiveness or safety of BID lisinopril and losartan

Examining the role of unmeasured confounding in mediation analysis with genetic and genomic applications

Abstract Background In mediation analysis if unmeasured confounding is present, the estimates for the direct and mediated effects may be over or under estimated. Most methods for the sensitivity analysis of unmeasured confounding in mediation have focused on the mediator-outcome relationship. Results The Umediation R package enables the user to simulate unmeasured confounding of the exposure-mediator, exposure-outcome, and mediator-outcome relationships in order to see how the results of the mediation analysis would change in the presence of unmeasured confounding. We apply the Umediation package to the Genetic Epidemiology of Chronic Obstructive Pulmonary Disease (COPDGene) study to examine the role of unmeasured confounding due to population stratification on the effect of a single nucleotide polymorphism (SNP) in the CHRNA5/3/B4 locus on pulmonary function decline as mediated by cigarette smoking. Conclusions Umediation is a flexible R package that examines the role of unmeasured confounding in mediation analysis allowing for normally distributed or Bernoulli distributed exposures, outcomes, mediators, measured confounders, and unmeasured confounders. Umediation also accommodates multiple measured confounders, multiple unmeasured confounders, and allows for a mediator-exposure interaction on the outcome. Umediation is available as an R package at https://github.com/SharonLutz/Umediation A tutorial on how to install and use the Umediation package is available in the Additional file 1

T and B cell frequencies and numbers in the Peyer’s patches from LEW1.WR1 rats treated with SCFAs.

<p>Rats were treated with SCFAs and were infected with KRV using Protocol 1. On day 5, cells from the Peyer’s patches were harvested, counted, and stained with fluorochrome-conjugated mAbs directed against CD4, CD25, Foxp3, and CD45R, followed by flow cytometry analysis. Panel A includes representative histograms of lymphocyte subsets in the Peyer’s patches from rats treated with sodium butyrate. The shaded areas show staining with the isotype control. The frequency of cells stained is indicated in the upper right corner. Data shown in Panel B represent the frequency and cell number of the indicated subsets found in Peyer’s patches from individual rats. The lines in Panel B represent the mean and SD. The numbers in brackets indicate the animal number. Statistical analyses were performed using an ANOVA with Bonferroni's multiple comparison adjustments. *<i>p</i> < 0.001; **<i>p</i> < 0.01; ***<i>p</i> < 0.05.</p

Median abundance of bacterial communities in LEW1.WR1 rats treated with SCFAs.

<p>Median abundance of bacterial communities in LEW1.WR1 rats treated with SCFAs.</p