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Katy E Trinkley,1– 4 Michael G Kahn,5 Larry A Allen,2,4 Heather Haugen,6 Miranda E Kroehl,7 Chen-Tan Lin,2,3 Daniel C Malone,8 Daniel D Matlock2,4,9 1Department of Clinical Pharmacy, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA; 2Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA; 3Clinical Informatics, University of Colorado Health, Aurora, CO, USA; 4Adult and Child Consortium for Outcomes Research and Delivery Science, Aurora, CO, USA; 5Section of Informatics and Data Science, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA; 6University of Colorado, Colorado Clinical and Translational Sciences Institute (CCTSI), Aurora, CO, USA; 7Charter Communications Corporation, Greenwood Village, CO, USA; 8Department of Pharmacotherapy, University of Utah Skaggs College of Pharmacy, Salt Lake City, UT, USA; 9VA Eastern Colorado Geriatric Research Education and Clinical Center, Aurora, CO, USACorrespondence: Katy E TrinkleyUniversity of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, 12850 E Montview Blvd., Mail Stop C238, Aurora, CO 80045, USATel +1-303-724-6563Fax +1-303-724-0979Email katy.trinkley@cuanschutz.eduIntroduction: 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.Keywords: heart failure, treatment preferences, medication preferences, patient preferences

This paper proposes a platform trial for conducting A/B tests with multiple arms and interim monitoring to investigate the impact of several factors on the expected sample size and probability of early stopping. We examined the performance of three stopping boundaries: O'Brien Fleming (OBF) stopping for either futility or difference (both), Pocock stopping for futility only, and fixed sample size design. We simulated twelve scenarios of different orders of arms based on various effect sizes, as well as considered 1 or 3 interim looks. The overall findings are summarizing in a flowchart to provide intuitive guidance for the design of the platform based on the simulation. We found that it is better to use OBF stopping for both if there is any effective variant and the trial is sufficiently powered to detect the expected effect size. If the study is underpowered to detect a difference, we recommend fixed sample size design to gather as much information as possible, however if the expected sample size is important to minimize, we recommend using Pocock boundaries with futility monitoring. Our results aimed at helping high-tech companies conduct their own studies without requiring extensive knowledge of clinical trial design and statistical methodology., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

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., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier Inc.)

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.

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.

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-1β (IL-1β), 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., (© 2021 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

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/m 2 . 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., Competing Interests: Conflict of interest statement: KME has received research funding (to the University of Colorado) from Gilead Sciences, and consulting payments from Theratechnologies, Gilead Sciences, and ViiV Pharmaceuticals., (© The Author(s), 2021.)

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., Competing Interests: Disclosures: The authors have no conflicts of interest to declare., (© 2021 CPNP. The Mental Health Clinician is a publication of the College of Psychiatric and Neurologic Pharmacists.)

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.

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., Competing Interests: The authors have declared that no competing interests exist.

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., Competing Interests: JF is a consultant to the scientific advisory board of Janssen Pharmaceuticals. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Soderborg, Carpenter, Janssen, Weir, Robertson, Ir, Young, Krebs, Hernandez, Barbour, Frank, Kroehl and Friedman.)

The Type I Interferons (IFN-Is) are innate antiviral cytokines that include 12 different IFNα subtypes and IFNβ 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 IFNβ 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, IFNβ induced a broader interferome than the individual IFNα subtypes. Since IFNβ, and not IFNα, is upregulated during chronic HIV-1 infection in the gut, we compared core ISGs and IFNβ-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 IFNβ levels, and negatively correlated with gut CD4 T cell frequencies. In sharp contrast, IFNβ-specific ISGs linked to protein translation and anti-inflammatory responses were significantly downregulated in PWH, negatively correlated with gut IFNβ 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 IFNβ may drive HIV-1 pathogenesis in the gut., Competing Interests: The authors have declared that no competing interests exist.

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., Competing Interests: FRG has been funded by the Agency for Healthcare Research and Quality during this study period. During the study period, he received no funding or equity from the company RxREVU (SwiftRx), which he now serves as a consultant and receives equity compensation. KB also received no funding or equity from the company RxREVU (SwiftRx) during the study period but now receives equity compensation. FRG and KB's financial interests have been reviewed by University of Colorado Hospital and University of Colorado School of Medicine in accordance with their institutional policies. No other disclosures were reported., (© 2020 The Authors. JACEP Open published by Wiley Periodicals, Inc. on behalf of the American College of Emergency Physicians.)

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.

Objective: Clinical pharmacists use population health methods to generate chronic disease management referrals for patients with uncontrolled chronic conditions. The purpose of this study was to compare primary care providers' (PCPs) referral responses for 4 pharmacist-managed indications and to identify provider and patient characteristics that are predictive of PCP response., Design: Retrospective cohort study., Setting: This study occurred in an academic internal medicine clinic., Participants: Clinical pharmacy referrals generated through a population health approach between 2012 and 2016 for hypertension, chronic pain, depression, and benzodiazepine management were included., Main Outcome Measures: Proportion of referrals accepted, left pending, or rejected and influencing provider and patient characteristics., Results: Of 1769 referrals generated, PCPs accepted 869 (49%), left pending 300 (17%), and rejected 600 (34%). Compared with referrals for hypertension, benzodiazepine management, and depression, chronic pain referrals had the lowest likelihood of rejection (odds ratio [OR] 0.31; 95% CI 0.19-0.49). Depression referrals had an equal likelihood of being accepted or rejected (OR 1.04; 95% CI 0.66-1.64). Provider characteristics were not significantly associated with referral response, but residents were more likely to accept referrals. Patient characteristics associated with lower referral rejection included black race (OR 0.39; 95% CI 0.18-0.87), higher systolic blood pressure (OR 0.98; 95% CI 0.97-0.99), and missed visits (OR 0.24; 95% CI 0.07-0.81)., Conclusion: The majority of referrals for clinical pharmacists in primary care settings were responded to, varying mostly between acceptance and rejection. There was variability in referral acceptance across indications, and some patient characteristics were associated with increased referral acceptance., (Copyright © 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Background: HIV-1 infection and physiological aging are independently linked to elevated systemic inflammation and changes in enteric microbial communities (dysbiosis). However, knowledge of the direct effect of HIV infection on the aging microbiome and potential links to systemic inflammation is lacking., Methods: In a cross-sectional study of older people living with HIV (PLWH) (median age 61.5 years, N = 14) and uninfected controls (median 58 years, n = 22) we compared stool microbiota, levels of microbial metabolites (short-chain fatty acid levels, SCFA) and systemic inflammatory biomarkers by HIV serostatus and age., Findings: HIV and age were independently associated with distinct changes in the stool microbiome. For example, abundances of Enterobacter and Paraprevotella were higher and Eggerthella and Roseburia lower among PLWH compared to uninfected controls. Age-related microbiome changes also differed by HIV serostatus. Some bacteria with inflammatory potential (e.g. Escherichia) increased with age among PLWH, but not controls. Stool SCFA levels were similar between the two groups yet patterns of associations between individual microbial taxa and SCFA levels differed. Abundance of various genera including Escherichia and Bifidobacterium positively associated with inflammatory biomarkers (e.g. soluble Tumor Necrosis Factor Receptors) among PLWH, but not among controls., Interpretation: The age effect on the gut microbiome and associations between microbiota and microbial metabolites or systemic inflammation differed based on HIV serostatus, raising important implications for the impact of therapeutic interventions, dependent on HIV serostatus or age., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

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.

Purpose: Despite recent advancements in the use of thrombelastography (TEG) in the surgical setting, adequate technology to accurately predict bleeding phenotypes for patients undergoing cardiopulmonary bypass on the basis of non-mechanical parameters is lacking. While basic science and translational studies have provided key mechanistic insights about the protein components of coagulation cascades and regulatory mediators of hemostasis and fibrinolysis, targeted protein assays are still missing and the association of protein profiles to bleeding phenotypes and TEG readouts have yet to be discovered., Objective: To identify protein biomarkers of bleeding phenotypes of cardiopulmonary bypass patients in pre-operative plasma., Experimental Design: We applied a targeted proteomics approach to quantify 123 plasma proteins from 23 patients undergoing cardiopulmonary bypass (CPB) and sternotomy. We then correlated these measurements to bleeding outcomes and TEG parameters, associated with speed of clot formation and strength., Results: In this pilot study, we demonstrate the feasibility of protein quantitation as a viable strategy to predict low versus high bleeding phenotypes (loss of < or > than 20% of estimated blood volume, calculated as 70 mL/kg for BMI<29.9, 60 mL/kg for BMI = 30-39.9, and 50 mL/kg for BMI>40. Statistical elaborations highlighted a core set of proteins showing significant correlations to either total blood loss or TEG R/MA parameters., Conclusion and Clinical Relevance: Though prospective verification and validation in larger cohorts will be necessary, this report suggests a potential for targeted quantitative proteomics of pre-operative plasma protein concentrations in the prediction of estimated blood loss following CPB., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Purpose: Determine the prevalence of pyramidal molars (PMs), associated tooth anomalies, and medical conditions (MC)., Methods: Pantomograms from 10,168 subjects were searched for PMs., Results: A total of 148 individuals (75.7 percent females), aged 9.7 to 18.9 years old, had PMs. Subjects with MCs (53.4 percent) had on average 17 percent more PMs (P=.0476) and 2.8 times greater odds of palatally displaced canines (P=.0309). The mean number of pyramidal and taurodont molars per subject was 2.9±1.4 (SD) and 3.1±1.7 (SD), respectively. In both sexes, 63.5 percent of all observed PMs were located in the maxilla and 78.5 percent of all PMs were second molars. Taurodont molars increased by 9.4 percent as other tooth anomalies increased by one, but decreased by 8.2 percent for each additional PM. Tooth anomalies associated with PMs were palatally displaced canines (17.6 percent) and short root anomaly of maxillary central incisors (6.1 percent). Delayed eruption was noted in 9.5 percent, tooth agenesis in 6.1 percent, and supernumerary teeth in 3.4 percent., Conclusions: The prevalence of pyramidal molars was 1.4 percent, and the female-to-male ratio was 3.1 to one. Pyramidal molars are often associated with medical conditions and other tooth anomalies.

Background: People with end-stage heart failure may have to decide about destination-therapy left ventricular assist device (DT-LVAD). Individuals facing difficult decisions often rely on heuristics, such as anchoring, which predictably bias decision outcomes. We aimed to investigate whether showing a larger historical Heartmate XVE creates an anchoring effect, making the smaller Heartmate II (HMII) appear more favorable., Methods: With the use of Amazon Mechanical Turk, participants watched videos asking them to imagine themselves dying of end-stage heart failure, then were presented the option of LVAD as potentially life-prolonging therapy. Participants were randomized to a control group who were only shown the HMII device, and the intervention group who saw the XVE device before the HMII. Participants then completed surveys., Results: A total of 487 participants completed the survey (control = 252; intervention = 235); 79% were <40 years of age, 84% were white, and 55% were male. The intervention group was not more likely to accept the LVAD therapy (68% vs 61%; P = .37). However, participants in the intervention group were more likely (51% vs 17%; P < .01) to agree or strongly agree with the statement that the HMII was "smaller than expected." Participants in the intervention group were also more likely to rate the size of the device as "important" or "very important" in their decision (61% vs 46%; P < .01)., Conclusions: Although the XVE anchor did not affect likelihood of accepting the LVAD, it did affect device perception. This article highlights an important point with clinical implications: factors such as anchoring have the potential to inappropriately influence perceptions and decisions and should be carefully considered in research and practice., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Bystander cardiopulmonary resuscitation (CPR) improves survival after prehospital cardiac arrest. While community CPR training programs have been implemented across the US, little is known about their acceptability in non-US Latino populations., Objectives: The purpose of this study was to identify barriers to enrolling in CPR training classes and performing CPR in San José, Costa Rica., Methods: After consulting 10 San José residents, a survey was created, pilot-tested, and distributed to a convenience sample of community members in public gathering places in San José. Questions included demographics, CPR knowledge and beliefs, prior CPR training, having a family member with heart disease, and prior witnessing of a cardiac arrest. Questions also addressed barriers to enrolling in CPR classes (cost/competing priorities). The analysis focused on two main outcomes: likelihood of registering for a CPR class and willingness to perform CPR on an adult stranger. Odds ratios and 95% CIs were calculated to test for associations between patient characteristics and these outcomes., Results: Among 371 participants, most were male (60%) and <40 years old (77%); 31% had a college degree. Many had family members with heart disease (36%), had witnessed a cardiac arrest (18%), were trained in CPR (36%), and knew the correct CPR steps (70%). Overall, 55% (95% CI, 50-60%) indicated they would "likely" enroll in a CPR class; 74% (95% CI, 70-78%) would perform CPR on an adult stranger. Cardiopulmonary resuscitation class enrollment was associated with prior CPR training (OR: 2.6; 95% CI, 1.6-4.3) and a prior witnessed cardiac arrest (OR: 2.0; 95% CI, 1.1-3.5). Willingness to perform CPR on a stranger was associated with a prior witnessed cardiac arrest (OR: 2.5; 95% CI, 1.2-5.4) and higher education (OR: 1.9; 95% CI, 1.1-3.2). Believing that CPR does not work was associated with a higher likelihood of not attending a CPR class (OR: 2.4; 95% CI, 1.7-7.9). Fear of performing mouth-mouth, believing CPR is against God's will, and fear of legal risk were associated with a likelihood of not attending a CPR class and not performing CPR on a stranger (range of ORs: 2.4-3.9)., Conclusion: Most San José residents are willing to take CPR classes and perform CPR on a stranger. To implement a community CPR program, barriers must be considered, including misgivings about CPR efficacy and legal risk. Hands-only CPR programs may alleviate hesitancy to perform mouth-to-mouth. Schmid KM , Mould-Millman NK , Hammes A , Kroehl M , Quiros García R , Umaña McDermott M , Lowenstein SR . Barriers and facilitators to community CPR education in San José, Costa Rica. Prehosp Disaster Med. 2016;31(5):509-515.

Background: Timing of solid food introduction in infancy has been associated with several chronic diseases. To explore potential mechanisms, we investigated the relationship between timing of solid food introduction and F2-isoprostanes-a marker of oxidative stress., Methods: Urinary F2-isoprostanes were assessed in 336 healthy children aged less than 11.5 y with 1,266 clinic visits (mean = 3.8 visits per child) in the Diabetes Autoimmunity Study in the Young. We analyzed the association between F2-isoprostane concentrations and infant diet exposures using linear mixed models adjusted for age, age(2), HLA-DR3/4,DQB1*0302 genotype, first-degree relative with type 1 diabetes, maternal age, maternal education, sex, and exposure to in utero cigarette smoke., Results: Later solid food introduction was associated with lower F2-isoprostane concentrations in childhood (on average, 0.10 ng/mg per month of age at introduction; estimate: -0.10 (95% confidence interval (CI): -0.18, -0.02) P value = 0.02). Moreover, childhood F2-isoprostane concentrations were, on average, 0.24 ng/mg lower in individuals breastfed at solid food introduction (estimate: -0.24 (95% CI: -0.47, -0.01) P value = 0.04) compared with those who were not. Associations remained significant after limiting analyses to F2-isoprostanes after 2 y of age., Conclusion: Our results suggest a long-term protective effect of later solid food introduction and breastfeeding at solid food introduction against increased F2-isoprostane concentrations throughout childhood.

Aims/hypothesis: Dietary sugar intake may increase insulin production, stress the beta cells and increase the risk for islet autoimmunity (IA) and subsequent type 1 diabetes., Methods: Since 1993, the Diabetes Autoimmunity Study in the Young (DAISY) has followed children at increased genetic risk for type 1 diabetes for the development of IA (autoantibodies to insulin, GAD or protein tyrosine phosphatase-like protein [IA2] twice or more in succession) and progression to type 1 diabetes. Information on intake of fructose, sucrose, total sugars, sugar-sweetened beverages, beverages with non-nutritive sweetener and juice was collected prospectively throughout childhood via food frequency questionnaires (FFQs). We examined diet records for 1,893 children (mean age at last follow-up 10.2 years); 142 developed IA and 42 progressed to type 1 diabetes. HLA genotype was dichotomised as high risk (HLA-DR3/4,DQB1*0302) or not. All Cox regression models were adjusted for total energy, FFQ type, type 1 diabetes family history, HLA genotype and ethnicity., Results: In children with IA, progression to type 1 diabetes was significantly associated with intake of total sugars (HR 1.75, 95% CI 1.07-2.85). Progression to type 1 diabetes was also associated with increased intake of sugar-sweetened beverages in those with the high-risk HLA genotype (HR 1.84, 95% CI 1.25-2.71), but not in children without it (interaction p value = 0.02). No sugar variables were associated with IA risk., Conclusions/interpretation: Sugar intake may exacerbate the later stage of type 1 diabetes development; sugar-sweetened beverages may be especially detrimental to children with the highest genetic risk of developing type 1 diabetes.

Background: Cow's milk intake has been inconsistently associated with islet autoimmunity (IA) and type 1 diabetes (T1D) development. Genetic and environmental factors may modify the effect of cow's milk on IA and T1D risk., Methods: The Diabetes Autoimmunity Study in the Young (DAISY) follows children at increased T1D risk of IA (presence of autoantibodies to insulin, GAD65, or IA-2 twice in succession) and T1D development. We examined 1835 DAISY children with data on cow's milk intake: 143 developed IA, 40 subsequently developed T1D. Cow's milk protein and lactose intake were calculated from prospectively collected parent- and self-reported food frequency questionnaires (FFQ). High risk HLA-DR genotype: HLA-DR3/4,DQB1*0302; low/moderate risk: all other genotypes. We examined interactions between cow's milk intake, age at cow's milk introduction, and HLA-DR genotype in IA and T1D development. Interaction models contained the base terms (e.g., cow's milk protein and HLA-DR genotype) and an interaction term (e.g., cow's milk protein*HLA-DR genotype)., Results: In survival models adjusted for total calories, FFQ type, T1D family history, and ethnicity, greater cow's milk protein intake was associated with increased IA risk in children with low/moderate risk HLA-DR genotypes [hazard ratio (HR): 1.41, 95% confidence interval (CI): 1.08-1.84], but not in children with high risk HLA-DR genotypes. Cow's milk protein intake was associated with progression to T1D (HR: 1.59, CI: 1.13-2.25) in children with IA., Conclusions: Greater cow's milk intake may increase risk of IA and progression to T1D. Early in the T1D disease process, cow's milk intake may be more influential in children with low/moderate genetic T1D risk., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Type 1 diabetes (T1D), a chronic autoimmune disease, is often preceded by a preclinical phase of islet autoimmunity (IA) where the insulin-producing beta cells of the pancreas are destroyed and circulating autoantibodies can be detected. The goal of this study was to demonstrate methods for identifying exposures that differentially influence the disease process at certain ages by assessing age-related heterogeneity. The Diabetes Autoimmunity Study in the Young (DAISY) has followed 2,547 children at increased genetic risk for T1D from birth since 1993 in Denver, Colorado, 188 of whom developed IA. Using the DAISY population, we evaluated putative determinants of IA, including non-Hispanic white (NHW) ethnicity, maternal age at birth, and erythrocyte membrane n-3 fatty acid (FA) levels, for age-related heterogeneity. A supremum test, weighted Schoenfeld residuals, and restricted cubic splines were used to assess nonproportional hazards, that is, an age-related association of the exposure with IA risk. NHW ethnicity, maternal age, and erythrocyte membrane n-3 FA levels demonstrated a significant age-related association with IA risk. Assessing heterogeneity in disease etiology enables researchers to identify associations that may lead to better understanding of complex chronic diseases.

Aims/hypotheses: We previously reported that lower n-3 fatty acid intake and levels in erythrocyte membranes were associated with increased risk of islet autoimmunity (IA) but not progression to type 1 diabetes in children at increased risk for diabetes. We hypothesise that specific n-3 fatty acids and genetic markers contribute synergistically to this increased risk of IA in the Diabetes Autoimmunity Study in the Young (DAISY)., Methods: DAISY is following 2,547 children at increased risk for type 1 diabetes for the development of IA, defined as being positive for glutamic acid decarboxylase (GAD)65, IA-2 or insulin autoantibodies on two consecutive visits. Using a case-cohort design, erythrocyte membrane fatty acids and dietary intake were measured prospectively in 58 IA-positive children and 299 IA-negative children., Results: Lower membrane levels of the n-3 fatty acid, docosapentaenoic acid (DPA), were predictive of IA (HR 0.23; 95% CI 0.09, 0.55), while α-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were not, adjusting for HLA and diabetes family history. We examined whether the effect of dietary intake of the n-3 fatty acid ALA on IA risk was modified by fatty acid elongation and desaturation genes. Adjusting for HLA, diabetes family history, ethnicity, energy intake and questionnaire type, ALA intake was significantly more protective for IA in the presence of an increasing number of minor alleles at FADS1 rs174556 (pinteraction = 0.017), at FADS2 rs174570 (pinteraction = 0.016) and at FADS2 rs174583 (pinteraction = 0.045)., Conclusions/interpretation: The putative protective effect of n-3 fatty acids on IA may result from a complex interaction between intake and genetically controlled fatty acid desaturation.

Context: Vitamin D metabolism genes have been associated with type 1 diabetes (T1D) risk; however, these genes have not been investigated for association with the preclinical phase of T1D, islet autoimmunity (IA). Studies of vitamin D metabolism genes may elucidate the role of vitamin D in complex diseases., Objective: The objective of the study was to explore the association between seven vitamin D metabolism gene single-nucleotide polymorphisms (SNPs) and the risk of IA and progression to T1D., Design: The Diabetes Autoimmunity Study in the Young is a longitudinal, observational study., Setting: Newborn screening for human leukocyte antigen, sibling and offspring recruitment, and follow-up took place in Denver, Colorado., Participants: A total of 1708 children at increased genetic risk of T1D participated in the study: 148 developed IA and 62 IA-positive children progressed to T1D., Main Outcome Measures: IA, defined as positivity for glutamic acid decarboxylase, insulin, or IA-2 autoantibodies on two or more consecutive visits, and T1D, diagnosed by a physician, were the main outcome measures., Results: The risk of IA was associated with DHCR7/NADSYN1 rs12785878 and CYP27B1 rs4646536 [hazard ratio 1.36, 95% confidence interval 1.08-1.73 (for each additional minor allele) and hazard ratio 0.59, 95% confidence interval 0.39-0.89 (for A/G compared with the A/A genotype), respectively]. None of the vitamin D SNPs typed was associated with progression to T1D in IA-positive children. Six of the seven SNPs were significantly associated with 25-hydroxyvitamin D levels., Conclusions: DHCR7/NADSYN1 rs12785878 and CYP27B1 rs4646536 may play an important role in islet autoimmunity, the preclinical phase of T1D. These findings should be replicated in larger cohorts for confirmation.

Importance: The incidence of type 1 diabetes mellitus (T1DM) is increasing worldwide, with the most rapid increase among children younger than 5 years of age., Objective: To examine the associations between perinatal and infant exposures, especially early infant diet, and the development of T1DM., Design: The Diabetes Autoimmunity Study in the Young (DAISY) is a longitudinal, observational study., Setting: Newborn screening for human leukocyte antigen (HLA) was done at St. Joseph's Hospital in Denver, Colorado. First-degree relatives of individuals with T1DM were recruited from the Denver metropolitan area., Participants: A total of 1835 children at increased genetic risk for T1DM followed up from birth with complete prospective assessment of infant diet. Fifty-three children developed T1DM., Exposures: Early (<4 months of age) and late (≥6 months of age) first exposure to solid foods compared with first exposures at 4 to 5 months of age (referent)., Main Outcome and Measure: Risk for T1DM diagnosed by a physician., Results: Both early and late first exposure to any solid food predicted development of T1DM (hazard ratio [HR], 1.91; 95% CI, 1.04-3.51, and HR, 3.02; 95% CI, 1.26-7.24, respectively), adjusting for the HLA-DR genotype, first-degree relative with T1DM, maternal education, and delivery type. Specifically, early exposure to fruit and late exposure to rice/oat predicted T1DM (HR, 2.23; 95% CI, 1.14-4.39, and HR, 2.88; 95% CI, 1.36-6.11, respectively), while breastfeeding at the time of introduction to wheat/barley conferred protection (HR, 0.47; 95% CI, 0.26-0.86). Complicated vaginal delivery was also a predictor of T1DM (HR, 1.93; 95% CI, 1.03-3.61)., Conclusions and Relevance: These results suggest the safest age to introduce solid foods in children at increased genetic risk for T1DM is between 4 and 5 months of age. Breastfeeding while introducing new foods may reduce T1DM risk.

Previously, we examined 20 non-HLA SNPs for association with islet autoimmunity (IA) and/or progression to type 1 diabetes (T1D). Our objective was to investigate fourteen additional non-HLA T1D candidate SNPs for stage- and age-related heterogeneity in the etiology of T1D. Of 1634 non-Hispanic white DAISY children genotyped, 132 developed IA (positive for GAD, insulin, or IA-2 autoantibodies at two or more consecutive visits); 50 IA positive children progressed to T1D. Cox regression was used to analyze risk of IA and progression to T1D in IA positive children. Restricted cubic splines were used to model SNPs when there was evidence that risk was not constant with age. C1QTNF6 (rs229541) predicted increased IA risk (HR: 1.57, CI: 1.20-2.05) but not progression to T1D (HR: 1.13, CI: 0.75-1.71). SNP (rs10517086) appears to exhibit an age-related effect on risk of IA, with increased risk before age 2 years (age 2 HR: 1.67, CI: 1.08-2.56) but not older ages (age 4 HR: 0.84, CI: 0.43-1.62). C1QTNF6 (rs229541), SNP (rs10517086), and UBASH3A (rs3788013) were associated with development of T1D. This prospective investigation of non-HLA T1D candidate loci shows that some SNPs may exhibit stage- and age-related heterogeneity in the etiology of T1D.