Approaches to analyzing binary data for large-scale A/B testing.

An industry-academic collaboration was established to evaluate the choice of statistical test and study design for A/B testing in larger-scale industry experiments. Specifically, the standard approach at the industry partner was to apply a t-test for all outcomes, both continuous and binary, and to apply naïve interim monitoring strategies that had not evaluated the potential implications on operating characteristics such as power and type I error rates. Although many papers have summarized the robustness of the t-test, its performance for the A/B testing context of large-scale proportion data, with or without interim analyses, is needed. Investigating the effect of interim analyses on the robustness of the t-test is important, because interim analyses rely on a fraction of the total sample size and one should ensure that desired properties are maintained when a t-test is implemented not just at the end of the study, but for making interim decisions. Through simulation studies, the performance of the t-test, Chi-squared test, and Chi-squared test with Yate's correction when applied to binary outcomes data is evaluated. Further, interim monitoring through a naïve approach with no correction for multiple testing versus the O'Brien-Fleming boundary are considered in designs that allow early termination for futility, difference, or both. Results indicate that the t-test achieves similar power and type I error rates for binary outcomes data with the large sample sizes used in industrial A/B tests with and without interim monitoring, and naïve interim monitoring without corrections leads to poorly performing studies.

Altered Immunoglobulin Repertoire and Decreased IgA Somatic Hypermutation in the Gut during Chronic HIV-1 Infection.

Humoral immune perturbations contribute to pathogenic outcomes in persons with HIV-1 infection (PWH). Gut barrier dysfunction in PWH is associated with microbial translocation and alterations in microbial communities (dysbiosis), and IgA, the most abundant immunoglobulin (Ig) isotype in the gut, is involved in gut homeostasis by interacting with the microbiome. We determined the impact of HIV-1 infection on the antibody repertoire in the gastrointestinal tract by comparing Ig gene utilization and somatic hypermutation (SHM) in colon biopsies from PWH (n = 19) versus age and sex-matched controls (n = 13). We correlated these Ig parameters with clinical, immunological, microbiome and virological data. Gene signatures of enhanced B cell activation were accompanied by skewed frequencies of multiple Ig Variable genes in PWH. PWH showed decreased frequencies of SHM in IgA and possibly IgG, with a substantial loss of highly mutated IgA sequences. The decline in IgA SHM in PWH correlated with gut CD4+ T cell loss and inversely correlated with mucosal inflammation and microbial translocation. Diminished gut IgA SHM in PWH was driven by transversion mutations at A or T deoxynucleotides, suggesting a defect not at the AID/APOBEC3 deamination step but at later stages of IgA SHM. These results expand our understanding of humoral immune perturbations in PWH that could have important implications in understanding mucosal immune defects in individuals with chronic HIV-1 infection. IMPORTANCE The gut is a major site of early HIV-1 replication and pathogenesis. Extensive CD4+ T cell depletion in this compartment results in a compromised epithelial barrier that facilitates the translocation of microbes into the underlying lamina propria and systemic circulation, resulting in chronic immune activation. To date, the consequences of microbial translocation on the mucosal humoral immune response (or vice versa) remains poorly integrated into the panoply of mucosal immune defects in PWH. We utilized next-generation sequencing approaches to profile the Ab repertoire and ascertain frequencies of somatic hypermutation in colon biopsies from antiretroviral therapy-naive PWH versus controls. Our findings identify perturbations in the Ab repertoire of PWH that could contribute to development or maintenance of dysbiosis. Moreover, IgA mutations significantly decreased in PWH and this was associated with adverse clinical outcomes. These data may provide insight into the mechanisms underlying impaired Ab-dependent gut homeostasis during chronic HIV-1 infection.

Examination of Sex Differences in a Chronic Rhinosinusitis Surgical Cohort.

OBJECTIVE: Sex discrepancies have been reported in chronic rhinosinusitis (CRS), but limited data exist exploring sex-specific biological processes and sinonasal quality of life. STUDY DESIGN: Prospective cohort. SETTING: Academic medical center. METHODS: Demographics, clinical data, and sinonasal mucus were collected from patients with CRS presenting for surgical consideration over a 5-year period. A random forest model and linear regression were used to assess predictor variables for the 22-item Sino-Nasal Outcome Test (SNOT-22) and subdomains. Enzyme-linked immunosorbent assays were used to measure substance P and tryptase in a subset of mucus samples to explore biological differences by sex. RESULTS: In total, 520 patients were studied (mean age 48.3 years, 50.9% female). Males were older (50.1 vs 46.6 years, P = .008), had more polyp disease (48.2% vs 35.5%, P = .004), and had higher mean Lund-Mackay CT score (11.3 vs 9.5, P = .004). Females had a higher overall mean SNOT-22 (40.9 vs 46.9, P = .001) and higher scores in ear/facial, psychological, and sleep domains (P < .01). Age, objective disease measures, and sex were top predictors for total SNOT-22. Neither mucus substance P or tryptase, alone or paired with sex, correlated with total SNOT-22. Analysis of mucus biomarkers by sex revealed correlation between mucus tryptase in females with the extranasal subdomain (P = .01). CONCLUSION: Sex differences exist in CRS disease manifestations and presentation for surgical consideration. Detection of mucus (substance P and tryptase) was reliable, but in this exploratory study, we were not able to establish neurogenic or allergic inflammatory processes as a large source of differential disease features between sexes.

Association of Sputum Neutrophil Extracellular Trap Subsets With IgA Anti-Citrullinated Protein Antibodies in Subjects at Risk for Rheumatoid Arthritis.

OBJECTIVE: Mechanisms leading to anti-citrullinated protein antibody (ACPA) generation in rheumatoid arthritis (RA) are hypothesized to originate in the lung. We undertook this study to understand associations between neutrophil extracellular trap (NET) formation in the lung and local ACPA generation in subjects at risk of developing RA. METHODS: Induced sputum was collected from 49 subjects at risk of developing RA, 12 patients with RA, and 18 controls. Sputum neutrophils were tested for ex vivo NET formation, and sputum-induced NET formation of control neutrophils was measured using immunofluorescence imaging. Sputum macrophages were tested for ex vivo endocytosis of apoptotic and opsonized cells. Levels of ACPA, NET remnants, and inflammatory proteins were quantified in sputum supernatant. RESULTS: Spontaneous citrullinated histone H3 (Cit-H3)-expressing NET formation was higher in sputum neutrophils from at-risk subjects and RA patients compared to controls (median 12%, 22%, and 0%, respectively; P < 0.01). In at-risk subjects, sputum IgA ACPA correlated with the percentage of neutrophils that underwent Cit-H3+ NET formation (r = 0.49, P = 0.002) and levels of Cit-H3+ NET remnants (r = 0.70, P < 0.001). Reduced endocytic capacity of sputum macrophages was found in at-risk subjects and RA patients compared to controls. Using a mediation model, we found that sputum inflammatory proteins were associated with sputum IgA ACPA through a pathway mediated by Cit-H3+ NET remnants. Sputum-induced Cit-H3+ NET formation also correlated with sputum levels of interleukin-1ß (IL-1ß), IL-6, and tumor necrosis factor in at-risk subjects, suggesting a causal relationship. CONCLUSION: These data support a potential mechanism for mucosal ACPA generation in subjects at risk of developing RA, whereby inflammation leads to increased citrullinated protein-expressing NETs that promote local ACPA generation.

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.

An exercise intervention alters stool microbiota and metabolites among older, sedentary adults.

BACKGROUND: Physiologic aging has been associated with gut dysbiosis. Although short exercise interventions have been linked to beneficial changes in gut microbiota in younger adults, limited data are available from older populations. We hypothesized that exercise would produce beneficial shifts in microbiota and short-chain fatty acid (SCFA) levels in older persons. METHODS: Stool samples were collected before and at completion of a supervised 24-week cardiovascular and resistance exercise intervention among 50-75-year-old participants. SCFA levels were analyzed by gas chromatography and microbiome by 16S rRNA gene sequencing. Negative binomial regression models compared pre- and post-differences using false discovery rates for multiple comparison. RESULTS: A total of 22 participants provided pre-intervention samples; 15 provided samples at study completion. At baseline, the majority of participants were men (95%), mean age 58.0 (8.8) years, mean body mass index 27.4 (6.4) kg/m2. After 24 weeks of exercise, at the genus level, exercise was associated with significant increases in Bifidobacterium (and other unidentified genera within Bifidobacteriaceae), Oscillospira, Anaerostipes, and decreased Prevotella and Oribacterium (p < 0.001). Stool butyrate increased with exercise [5.44 (95% confidence interval 1.54, 9.24) mmol/g, p = 0.02], though no significant differences in acetate or propionate (p ⩾ 0.09) were seen. CONCLUSION: Our pilot study suggested that an exercise intervention is associated with changes in the microbiome of older adults and a key bacterial metabolite, butyrate. Although some of these changes could potentially reverse age-related dysbiosis, future studies are required to determine the contribution of changes to the microbiome in the beneficial effect of exercise on overall health of older adults. Clinical Trials NCT02404792.

Specialized pro-resolving mediator lipidome and 16S rRNA bacterial microbiome data associated with human chronic rhinosinusitis.

Chronic rhinosinusitis (CRS) is a clinical syndrome defined by symptoms including nasal congestion, facial pain and pressure, anosmia, and rhinorrhea lasting more than 12 weeks. Several mechanistically distinct processes lead to the development of clinical symptoms in CRS including innate immune dysfunction, dysregulated eicosanoid metabolism and perturbations in host-microbiome interactions [1]. We developed a database comprised of patient demographic information, lipid mediator metabolomic profiles, and 16S bacterial rRNA gene sequence data from 66 patients undergoing endoscopic sinus surgery. Briefly, ethmoid sinus tissue and middle meatal swabs were collected from patients, including non-CRS controls, CRS with polyps (CRSwNP), and CRS without polyps (CRSsNP). Lipid mediator pathways from arachidonic acid (AA) and docosahexanoic acid (DHA) were analyzed by liquid chromatography/tandem mass spectrometry. Bacterial taxa were profiled in parallel by 16S rRNA gene sequencing. This database provides a useful compendium of AA/DHA metabolomic profiles and associated bacterial microbiota in patients with varying disease subtypes, demographics, and risk factors/comorbidities.

Depression-related stigma among primary care providers.

INTRODUCTION: Depression is one of the most common mental illnesses in the United States and is often treated in primary care settings. Despite its prevalence, depression remains underdiagnosed and undertreated for a variety of reasons, including stigma. This may result in suboptimal management of depression. Studies evaluating stigma in US primary care providers (PCP) are scarce. The main objective of this study was to describe stigma in a cohort of PCPs. METHODS: We utilized a validated questionnaire to measure stigma (score range 15 to 75 with lower scores indicating lower stigma levels). PCPs in 2 academic internal medicine clinics were sent an electronic questionnaire and received a small monetary incentive for responding. In addition to the stigma survey, we collected demographic data, including age, provider type, gender, and other data related to social proximity to mental illness. To describe stigma, differences in stigma between provider characteristics were evaluated using t tests and ANOVA tests as appropriate. RESULTS: Of 107 PCPs, 71 responded (66.4% response rate). Male responders displayed higher stigma scores than females (31.8 vs 27.4, P = .0021). Medical residents displayed higher stigma scores than nonresidents (31.3 vs 27.2, P = .0045). Providers with personal exposure to mental illness and those who reported they frequently treated depression had less stigma. DISCUSSION: Overall, a range of stigma was present among PCPs surveyed. Higher levels of stigma were found in men, medical residents, those without personal exposure to mental illness, younger PCPs, and those who reported treating depression less frequently. Future studies should utilize larger sample sizes and focus on the impact of stigma on quality of care.

Applying Clinical Decision Support Design Best Practices With the Practical Robust Implementation and Sustainability Model Versus Reliance on Commercially Available Clinical Decision Support Tools: Randomized Controlled Trial.

BACKGROUND: Limited consideration of clinical decision support (CDS) design best practices, such as a user-centered design, is often cited as a key barrier to CDS adoption and effectiveness. The application of CDS best practices is resource intensive; thus, institutions often rely on commercially available CDS tools that are created to meet the generalized needs of many institutions and are not user centered. Beyond resource availability, insufficient guidance on how to address key aspects of implementation, such as contextual factors, may also limit the application of CDS best practices. An implementation science (IS) framework could provide needed guidance and increase the reproducibility of CDS implementations. OBJECTIVE: This study aims to compare the effectiveness of an enhanced CDS tool informed by CDS best practices and an IS framework with a generic, commercially available CDS tool. METHODS: We conducted an explanatory sequential mixed methods study. An IS-enhanced and commercial CDS alert were compared in a cluster randomized trial across 28 primary care clinics. Both alerts aimed to improve beta-blocker prescribing for heart failure. The enhanced alert was informed by CDS best practices and the Practical, Robust, Implementation, and Sustainability Model (PRISM) IS framework, whereas the commercial alert followed vendor-supplied specifications. Following PRISM, the enhanced alert was informed by iterative, multilevel stakeholder input and the dynamic interactions of the internal and external environment. Outcomes aligned with PRISM's evaluation measures, including patient reach, clinician adoption, and changes in prescribing behavior. Clinicians exposed to each alert were interviewed to identify design features that might influence adoption. The interviews were analyzed using a thematic approach. RESULTS: Between March 15 and August 23, 2019, the enhanced alert fired for 61 patients (106 alerts, 87 clinicians) and the commercial alert fired for 26 patients (59 alerts, 31 clinicians). The adoption and effectiveness of the enhanced alert were significantly higher than those of the commercial alert (62% vs 29% alerts adopted, P<.001; 14% vs 0% changed prescribing, P=.006). Of the 21 clinicians interviewed, most stated that they preferred the enhanced alert. CONCLUSIONS: The results of this study suggest that applying CDS best practices with an IS framework to create CDS tools improves implementation success compared with a commercially available tool. TRIAL REGISTRATION: ClinicalTrials.gov NCT04028557; http://clinicaltrials.gov/ct2/show/NCT04028557.

tidyMicro: a pipeline for microbiome data analysis and visualization using the tidyverse in R.

BACKGROUND: The drive to understand how microbial communities interact with their environments has inspired innovations across many fields. The data generated from sequence-based analyses of microbial communities typically are of high dimensionality and can involve multiple data tables consisting of taxonomic or functional gene/pathway counts. Merging multiple high dimensional tables with study-related metadata can be challenging. Existing microbiome pipelines available in R have created their own data structures to manage this problem. However, these data structures may be unfamiliar to analysts new to microbiome data or R and do not allow for deviations from internal workflows. Existing analysis tools also focus primarily on community-level analyses and exploratory visualizations, as opposed to analyses of individual taxa. RESULTS: We developed the R package "tidyMicro" to serve as a more complete microbiome analysis pipeline. This open source software provides all of the essential tools available in other popular packages (e.g., management of sequence count tables, standard exploratory visualizations, and diversity inference tools) supplemented with multiple options for regression modelling (e.g., negative binomial, beta binomial, and/or rank based testing) and novel visualizations to improve interpretability (e.g., Rocky Mountain plots, longitudinal ordination plots). This comprehensive pipeline for microbiome analysis also maintains data structures familiar to R users to improve analysts' control over workflow. A complete vignette is provided to aid new users in analysis workflow. CONCLUSIONS: tidyMicro provides a reliable alternative to popular microbiome analysis packages in R. We provide standard tools as well as novel extensions on standard analyses to improve interpretability results while maintaining object malleability to encourage open source collaboration. The simple examples and full workflow from the package are reproducible and applicable to external data sets.

Altered tissue specialized pro-resolving mediators in chronic rhinosinusitis.

Current literature implicates arachidonic acid-derived leukotrienes and prostaglandins in the pathogenesis of chronic rhinosinusitis. However, other omega-3 and omega-6 derived lipid mediators, such as specialized pro-resolving mediators (SPMs), may also be important in chronic inflammatory disorders of the upper airway. We hypothesize that SPMs differ among CRS subtypes compared to controls and in relation to sinonasal microbiota. Ethmoid sinus tissue and middle meatal swabs were collected from a convenience sample of 66 subjects, including non-CRS controls, CRS with polyps (CRSwNP), and CRS without polyps (CRSsNP). Lipid mediator pathways were analyzed by liquid chromatography/tandem mass spectrometry. Bacterial taxa were profiled in parallel by 16S rRNA gene sequencing. Resolvin D2 was elevated in both CRSwNP (p = 0.00076) and CRSsNP (p = 0.030) compared with non-CRS controls. Lipoxin A4 was significantly increased in CRSwNP compared with CRSsNP (p = 0.000033) and controls (p = 0.044). Cigarette smoking was associated with significantly lower concentrations of several 15-lipoxygenase metabolites including resolvin D1 (p = 0.0091) and resolvin D2 (p = 0.0097), compared with never-smokers. Several of the lipid compounds also correlated with components of the sinonasal mucosal microbiota, including bacterial pathogens such as Pseudomonas aeruginosa. These data suggest that dysfunctional lipid mediator pathways in CRS extend beyond the traditional descriptions of leukotrienes and prostaglandins and include SPMs. Furthermore, dysregulated SPM signaling may contribute to persistent inflammation and bacterial colonization in CRS.

Patient Outreaches for Clinical Pharmacy Services: A Population Health Management Program Assessment.

BACKGROUND: Pharmacists in ambulatory care can utilize population health approaches to identify patients needing disease management and improve outcomes. However, population health is only effective when identified patients are successfully outreached and show to appointments. OBJECTIVE: Describe a population health approach utilized by pharmacists in primary care, report outcomes of outreach attempts and scheduled appointments, and determine whether patient and referral characteristics predict no-show appointments. METHODS: Retrospective cohort study of patients referred for pharmacist management of hypertension or chronic pain through population health between 2013-2016. Outreach attempt and appointments outcomes were collected. Patient and referral characteristics were analyzed to determine whether predictive of no-show appointments using logistic regression. RESULTS: Of 450 outreach attempts, 250 (56%) patients were not reached, 164 (36%) scheduled appointments, and 36 (8%) were reached but declined an appointment. Of 164 patients with appointments, 71 (43%) no-showed. Patients with higher systolic blood pressure were more likely to no-show (OR: 1.02, 95% CI: 1.00-1.04). Other characteristics were not predictive of no-show appointments. CONCLUSION: Successful outreach and showed appointments are essential components of successful population health programs. Using multiple outreach modalities and further identifying factors predictive of no-show appointments to refine the current approach may lead to increased efficiency.

Gestational Diabetes Is Uniquely Associated With Altered Early Seeding of the Infant Gut Microbiota.

Gestational diabetes mellitus (GDM) is a worldwide public health problem affecting up to 27% of pregnancies with high predictive values for childhood obesity and inflammatory diseases. Compromised seeding of the infant gut microbiota is a risk factor for immunologic and metabolic diseases in the offspring; however, how GDM along with maternal obesity interact to alter colonization remains unknown. We hypothesized that GDM individually and in combination with maternal overweight/obesity would alter gut microbial composition, diversity, and short-chain fatty acid (SCFA) levels in neonates. We investigated 46 full-term neonates born to normal-weight or overweight/obese mothers with and without GDM, accounting for confounders including cesarean delivery, lack of breastfeeding, and exposure to antibiotics. Gut microbiota in 2-week-old neonates born to mothers with GDM exhibited differences in abundance of 26 microbial taxa; 14 of which showed persistent differential abundance after adjusting for pre-pregnancy BMI. Key pioneering gut taxa, including potentially important taxa for establishing neonatal immunity, were reduced. Lactobacillus, Flavonifractor, Erysipelotrichaceae, and unspecified families in Gammaproteobacteria were significantly reduced in neonates from mothers with GDM. GDM was associated with an increase in microbes involved in suppressing early immune cell function (Phascolarctobacterium). No differences in infant stool SCFA levels by maternal phenotype were noted; however, significant correlations were found between microbial abundances and SCFA levels in neonates. Our results suggest that GDM alone and together with maternal overweight/obesity uniquely influences seeding of specific infant microbiota in patterns that set the stage for future risk of inflammatory and metabolic disease.

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

BACKGROUND: Lisinopril and losartan manufacturer labels recommend twice-daily dosing (BID) if once-daily (QDay) is insufficient to lower blood pressure (BP). METHODS AND RESULTS: Retrospective 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). CONCLUSIONS: Adjusted models do not support improved effectiveness or safety of BID lisinopril and losartan.

Patient Treatment Preferences for Heart Failure Medications: A Mixed Methods Study.

INTRODUCTION: Consideration of patient preferences for guideline-directed medical therapies (GDMT) for heart failure with reduced ejection fraction (HFrEF) may help improve major gaps in prescribing and adherence. This study aimed to identify the range and relative priority of factors influencing patients' decisions to take HFrEF medications. MATERIALS AND METHODS: This was a convergent mixed methods study of patients with HFrEF. Focus groups were conducted to identify a list of factors followed by individuals rating and ranking the influence of each factor on their decision to take a medication. Using thematic analysis, we summarized preferences into categories. RESULTS: Two focus groups with 13 participants reported 22 factors. Of the factors, "keeping you alive" was most commonly ranked in the top three (seven participants), followed by "communication and understanding" (six participants). Factors were summarized into six categories (listed in order of patient-reported influence): 1) demonstrated improvements in quality of life and longevity, 2) decreased risk of hospitalization, 3) opportunity for shared decision-making and trust in provider, 4) absence of adverse events, 5) affordability, and 6) convenience of taking and absence of interference with daily life. CONCLUSION: Patients prioritize treatment benefits and being informed more than risks, cost and inconvenience of taking HFrEF medications.

Improved antibiotic prescribing using indication-based clinical decision support in the emergency department.

BACKGROUND: Evaluate an indication-based clinical decision support tool to improve antibiotic prescribing in the emergency department. METHODS: Encounters where an antibiotic was prescribed between January 2015 and October 2017 were analyzed before and after the introduction of a clinical decision support tool to improve clinicians' selection of a guideline-approved antibiotic based on clinical indication. Evaluation was conducted on a pre-defined subset of conditions that included skin and soft tissue infections, respiratory infections, and urinary infections. The primary outcome was ordering of a guideline-approved antibiotic prescription at the drug and duration of therapy level. A mixed model following a binomial distribution with a logit link was used to model the difference in proportions of guideline-approved prescriptions before and after the intervention. RESULTS: For conditions evaluated, selection rate of a guideline-approved antibiotic for a given indication improved from 67.1% to 72.2% (P < 0.001). When duration of therapy is included as a criterion, selection of a guideline-approved antibiotic was lower and improved from 24.7% to 31.4% (P < 0.001), highlighting that duration of therapy is often missing at the time of prescribing. The most substantial improvements were seen for pneumonia and pyelonephritis with an increase from 87.9% to 97.5% and 62.8% to 82.6%, respectively. Other significant improvements were seen for abscess, cellulitis, and urinary tract infections. CONCLUSION: Antibiotic prescribing can be improved both at the drug and duration of therapy level using a non-interruptive and indication based-clinical decision support approach. Future research and quality improvement efforts are needed to incorporate duration of therapy guidelines into the antibiotic prescribing process.

Qualitative Differences Between the IFNα subtypes and IFNß Influence Chronic Mucosal HIV-1 Pathogenesis.

The Type I Interferons (IFN-Is) are innate antiviral cytokines that include 12 different IFNα subtypes and IFNß that signal through the IFN-I receptor (IFNAR), inducing hundreds of IFN-stimulated genes (ISGs) that comprise the 'interferome'. Quantitative differences in IFNAR binding correlate with antiviral activity, but whether IFN-Is exhibit qualitative differences remains controversial. Moreover, the IFN-I response is protective during acute HIV-1 infection, but likely pathogenic during the chronic stages. To gain a deeper understanding of the IFN-I response, we compared the interferomes of IFNα subtypes dominantly-expressed in HIV-1-exposed plasmacytoid dendritic cells (1, 2, 5, 8 and 14) and IFNß in the earliest cellular targets of HIV-1 infection. Primary gut CD4 T cells from 3 donors were treated for 18 hours ex vivo with individual IFN-Is normalized for IFNAR signaling strength. Of 1,969 IFN-regulated genes, 246 'core ISGs' were induced by all IFN-Is tested. However, many IFN-regulated genes were not shared between the IFNα subtypes despite similar induction of canonical antiviral ISGs such as ISG15, RSAD2 and MX1, formally demonstrating qualitative differences between the IFNα subtypes. Notably, IFNß induced a broader interferome than the individual IFNα subtypes. Since IFNß, and not IFNα, is upregulated during chronic HIV-1 infection in the gut, we compared core ISGs and IFNß-specific ISGs from colon pinch biopsies of HIV-1-uninfected (n = 13) versus age- and gender-matched, antiretroviral-therapy naïve persons with HIV-1 (PWH; n = 19). Core ISGs linked to inflammation, T cell activation and immune exhaustion were elevated in PWH, positively correlated with plasma lipopolysaccharide (LPS) levels and gut IFNß levels, and negatively correlated with gut CD4 T cell frequencies. In sharp contrast, IFNß-specific ISGs linked to protein translation and anti-inflammatory responses were significantly downregulated in PWH, negatively correlated with gut IFNß and LPS, and positively correlated with plasma IL6 and gut CD4 T cell frequencies. Our findings reveal qualitative differences in interferome induction by diverse IFN-Is and suggest potential mechanisms for how IFNß may drive HIV-1 pathogenesis in the gut.

Integrating the Practical Robust Implementation and Sustainability Model With Best Practices in Clinical Decision Support Design: Implementation Science Approach.

BACKGROUND: Clinical decision support (CDS) design best practices are intended to provide a narrative representation of factors that influence the success of CDS tools. However, they provide incomplete direction on evidence-based implementation principles. OBJECTIVE: This study aims to describe an integrated approach toward applying an existing implementation science (IS) framework with CDS design best practices to improve the effectiveness, sustainability, and reproducibility of CDS implementations. METHODS: We selected the Practical Robust Implementation and Sustainability Model (PRISM) IS framework. We identified areas where PRISM and CDS design best practices complemented each other and defined methods to address each. Lessons learned from applying these methods were then used to further refine the integrated approach. RESULTS: Our integrated approach to applying PRISM with CDS design best practices consists of 5 key phases that iteratively interact and inform each other: multilevel stakeholder engagement, designing the CDS, design and usability testing, thoughtful deployment, and performance evaluation and maintenance. The approach is led by a dedicated implementation team that includes clinical informatics and analyst builder expertise. CONCLUSIONS: Integrating PRISM with CDS design best practices extends user-centered design and accounts for the multilevel, interacting, and dynamic factors that influence CDS implementation in health care. Integrating PRISM with CDS design best practices synthesizes the many known contextual factors that can influence the success of CDS tools, thereby enhancing the reproducibility and sustainability of CDS implementations. Others can adapt this approach to their situation to maximize and sustain CDS implementation success.

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.

A longitudinal intervention to improve young children's liking and consumption of new foods: findings from the Colorado LEAP study.

BACKGROUND: Many interventions have been conducted to improve young children's liking and consumption of new foods however their impacts on children's consumption have been limited. Consistent evidence supports the use of repeated exposure to improve liking for new foods however longitudinal effects lasting greater than 6 months often have not been demonstrated. Here we report the eating-related findings of the Colorado Longitudinal Eating And Physical Activity (LEAP) Study, a multi-component intervention, delivered primarily in the school setting, which aimed to improve children's liking and consumption of a target food via repeated exposure and positive experiential learning. METHODS: Four sites in rural Colorado, each housing Head Start preschool programs, matched on state vital statistics for childhood obesity rates, (2 intervention and 2 control sites) took part in a quasi-experimental study design which included 4 time points (baseline, post-intervention, one-year [Y1] and two- year [Y2] follow ups). A total of 250 children and families were enrolled (n = 143 intervention and n = 107 control; 41% Hispanic and 69% low-income). A 12-week intervention, Food Friends - Fun With New Foods®, delivered by trained preschool teachers and which focuses on positive and repeated experiences with new foods, and a 5-month (1 unit/month) social marketing "booster program" was delivered in kindergarten (one-year follow up) and 1st grade (two-year follow up). Main outcome measures included change in children's liking for new foods, analyzed by ordinal regression using generalized estimating equations, and change in weighed consumption of new foods over time, analyzed using a hierarchical mixed effects model. RESULTS: The intervention was delivered with good fidelity (87%). Both intervention and control groups demonstrated an increase in liking for the target food over time (p = 0.0001). The pattern of consumption of the target food was different, over time, for intervention and control groups (p < 0.005). In particular the change in intake between baseline and post-intervention was significantly greater in the intervention compared to the control group (p < 0.0001) though this pattern of change did not hold between baseline and Y2 follow up (p = 0.1144). Children in the intervention group who liked the target food consumed nearly double their baseline consumption at post-intervention (p < 0.0001;) and maintained this increase at Y2 follow up (p < 0.0001). CONCLUSIONS: The Food Friends intervention, which utilized positive, repeated experiences with new foods, and was delivered with good fidelity by trained preschool teachers, found that larger improvements were observed in children's eating behaviors than would be expected with developmentally-based changes in eating behaviors. TRIAL REGISTRATION NUMBER: This trial is registered at ClinicalTrials.gov : NCT01937481. Date registered: 09/09/2013; Retrospectively registered. Date first participant registered: 09/15/2010.