Gene-level association analysis of bivariate ordinal traits with functional regressions.

In genetic studies, many phenotypes have multiple naturally ordered discrete values. The phenotypes can be correlated with each other. If multiple correlated ordinal traits are analyzed simultaneously, the power of analysis may increase significantly while the false positives can be controlled well. In this study, we propose bivariate functional ordinal linear regression (BFOLR) models using latent regressions with cumulative logit link or probit link to perform a gene-based analysis for bivariate ordinal traits and sequencing data. In the proposed BFOLR models, genetic variant data are viewed as stochastic functions of physical positions, and the genetic effects are treated as a function of physical positions. The BFOLR models take the correlation of the two ordinal traits into account via latent variables. The BFOLR models are built upon functional data analysis which can be revised to analyze the bivariate ordinal traits and high-dimension genetic data. The methods are flexible and can analyze three types of genetic data: (1) rare variants only, (2) common variants only, and (3) a combination of rare and common variants. Extensive simulation studies show that the likelihood ratio tests of the BFOLR models control type I errors well and have good power performance. The BFOLR models are applied to analyze Age-Related Eye Disease Study data, in which two genes, CFH and ARMS2, are found to strongly associate with eye drusen size, drusen area, age-related macular degeneration (AMD) categories, and AMD severity scale.

Muscle activation patterns during active external rotation after reverse total shoulder arthroplasty: an electrophysiological study of the teres minor and associated musculature.

BACKGROUND: Preoperative teres minor insufficiency has been identified as a risk factor for poor restoration of external rotation (ER) after reverse total shoulder arthroplasty (RTSA). However, there has been little investigation regarding muscle activation patterns generating ER. This prospective study sought to determine the timing and activation levels of the shoulder girdle musculature during ER in well-functioning RTSAs with an intact teres minor using a lateralized design. METHODS: Patients who underwent RTSA ≥1 year previously with functional ER, an American Shoulder and Elbow Surgeons (ASES) score >70, superior rotator cuff deficiency, and an intact teres minor were identified. Electrophysiological and kinematic analyses were performed during ER in the modified neutral position (arm at side with 90° of elbow flexion) and in abduction (AB) (shoulder abducted 90° with 90° of elbow flexion). Dynamometer-recorded torque and position were pattern matched to electromyography during ER. The root-mean-square and integrated electromyography (in microvolts × milliseconds with standard deviation [SD]), as well as median frequency (MF) (in hertz with SD), were calculated to determine muscle recruitment. Pair-wise t test analysis compared muscle activation (P < .05 indicated significance). RESULTS: After an a priori power analysis, 16 patients were recruited. The average ASES score, visual analog scale pain score, and ASES subscore for ER in AB ("comb hair") were 87.7, 0.5, and 2.75 of 3, respectively. In AB, muscle activation began with the upper trapezius, middle trapezius, and latissimus dorsi, followed by the anterior deltoid activating to neutral. With ER beyond neutral, the teres major (9.6 µV × ms; SD, 9.2 µV × ms) initiated ER, followed by the teres minor (14.1 µV × ms; SD, 18.2 µV × ms) and posterior deltoid (11.1 µV × ms; SD, 9.3 µV × ms). MF analysis indicated equal contributions of the teres major (1.1 Hz; SD, 0.5 Hz), teres minor (1.2 Hz; SD, 0.4 Hz), and posterior deltoid (1.1 Hz; SD, 0.4 Hz) in ER beyond neutral. In the modified neutral position, the upper trapezius and middle trapezius were not recruited to the same level as in AB. For ER beyond neutral, the teres major (9.5 µV × ms [SD, 9 µV × ms]; MF, 1.1 Hz [SD, 0.5 Hz]), teres minor (11.4 µV × ms [SD, 15.1 µV × ms]; MF, 1.1 Hz [SD, 0.5 Hz]), and posterior deltoid (8.5 µV × ms [SD, 8 µV × ms]; MF, 1.2 Hz [SD, 0.3 Hz]) were activated in similar sequence and intensity as AB. No differences in muscle activation duration or intensity were noted among the teres major, teres minor, and posterior deltoid (P > .05). CONCLUSION: Active ER after RTSA is complex and is not governed by a single muscle-tendon unit. This study establishes a sequence, duration, and intensity of muscle activation for ER in well-functioning RTSAs. In both tested positions, the teres major, teres minor, and posterior deltoid function equally and sequentially to power ER.

Gene-level association analysis of ordinal traits with functional ordinal logistic regressions.

In this paper, we develop functional ordinal logistic regression (FOLR) models to perform gene-based analysis of ordinal traits. In the proposed FOLR models, genetic variant data are viewed as stochastic functions of physical positions and the genetic effects are treated as a function of physical positions. The FOLR models are built upon functional data analysis which can be revised to analyze the ordinal traits and high dimension genetic data. The proposed methods are capable of dealing with dense genotype data which is usually encountered in analyzing the next-generation sequencing data. The methods are flexible and can analyze three types of genetic data: (1) rare variants only, (2) common variants only, and (3) a combination of rare and common variants. Simulation studies show that the likelihood ratio test statistics of the FOLR models control type I errors well and have good power performance. The proposed methods achieve the goals of analyzing ordinal traits directly, reducing high dimensionality of dense genetic variants, being computationally manageable, facilitating model convergence, properly controlling type I errors, and maintaining high power levels. The FOLR models are applied to analyze Age-Related Eye Disease Study data, in which two genes are found to strongly associate with four ordinal traits.

Distinctive lower incidence rates of cutaneous melanoma on the hips and lower extremities of men.

BACKGROUND: Cutaneous melanomas (CMs) are more frequently found on the trunk in men, and on the hip and lower extremities (legs) in women. This discrepancy has been attributed to greater exposure to ultraviolet (UV) radiation of women's legs due to their dressing habits. OBJECTIVES: To understand the sex difference in the bodily distribution of CMs, especially those on the legs. METHODS: This was a cancer registry-based cohort study. CM incidences, relative tumour density and tumour mutational burdens (TMBs) were compared among different body sites in different sex and racial groups using the SEER (Surveillance, Epidemiology, and End Results) and TCGA SKCM (The Cancer Genome Atlas skin cutaneous melanoma) databases. RESULTS: White men had lower rates and lower relative tumour density (RTD) of CMs on their legs compared with the rest of their body sites, or compared with White women. Men classified by SEER into racial groups other than White did not show such a trend. White women had comparable RTDs among different body sites. The ratios between the 'White' and the 'other' groups were used to evaluate the approximate effect of sun exposure at different body sites, which further validated a distinct protective effect of men's legs in melanoma. TMB on leg melanomas was lower than on other sites in both sexes. CONCLUSIONS: The legs of both sexes in White patients show lower RTDs and lower levels of TMB, suggesting a weaker association with UV exposure. Furthermore, White men are especially protected against CM on their legs, suggesting an unknown intrinsic protective factor as compared with women.

Gene-based analysis of bi-variate survival traits via functional regressions with applications to eye diseases.

Genetic studies of two related survival outcomes of a pleiotropic gene are commonly encountered but statistical models to analyze them are rarely developed. To analyze sequencing data, we propose mixed effect Cox proportional hazard models by functional regressions to perform gene-based joint association analysis of two survival traits motivated by our ongoing real studies. These models extend fixed effect Cox models of univariate survival traits by incorporating variations and correlation of multivariate survival traits into the models. The associations between genetic variants and two survival traits are tested by likelihood ratio test statistics. Extensive simulation studies suggest that type I error rates are well controlled and power performances are stable. The proposed models are applied to analyze bivariate survival traits of left and right eyes in the age-related macular degeneration progression.

Correlates of Early Prenatal Care Access among U.S. Women: Data from the Pregnancy Risk Assessment Monitoring System (PRAMS).

OBJECTIVES: Early first trimester prenatal counseling could reduce adverse maternal and child health outcomes. Existing literature does not identify the length of time between suspecting pregnancy and attending their first prenatal visit. Identifying this potential window for change is critical for clinical practice, intervention programming and policy change. METHODS: The study sample was composed of women in the United States who responded to the Pregnancy Risk Assessment Monitoring Systems survey in 2016, for the following questions-when they first suspected pregnancy, when they attended their first prenatal visit, were they able to receive prenatal care as early as they wished, and perceived barriers to receiving prenatal care. RESULTS: On average, participants became certain they were pregnant at 6.0 (SE = 0.1) weeks gestation, while participants reported having their first prenatal care visit at 9.3 (SE = 0.1) weeks, with clear health disparities by race, age, WIC participation, education level, and marital status. About 15% of women reported not receiving prenatal care as early as they wished. Structural or financial barriers in the health care system were common: 38.1% reported that no appointments available, 28.2% reported not having money or insurance to pay for the visit, 27.3% reported that the doctor or health plan would not start care, and 22.5% reported not having a Medicaid card. CONCLUSIONS FOR PRACTICE: This study illustrates a window for opportunity to provide earlier prenatal care, which would facilitate earlier implementation of prenatal counseling. Strategies to address barriers to care on the patient, provider and systemic levels, particularly among vulnerable population groups, are warranted. WHAT IS ALREADY KNOWN ON THIS SUBJECT?: Seeking prenatal care early is associated with better health outcomes for women and infants. A window of opportunity exists between suspecting pregnancy and attending a first prenatal visit. WHAT THIS STUDY ADDS?: Clear health disparities were apparent in both recognizing their pregnancies, and receiving early prenatal care by race, age, WIC participation, education level, and marital status. About 15% of women reported not receiving prenatal care as early as they wished, and many attributed this later care to structural or financial barriers in the health care system.

Facilitating pneumococcal vaccination among high-risk adults: Impact of an assertive communication training program for community pharmacists.

BACKGROUND: Community pharmacies are vital access points to provide a range of vaccines to adults, including pneumococcal vaccines; however, despite a growth in the number of vaccines given at these sites, the most recent rates of adults being immunized against pneumococcal disease remain below the goals set by Health People 2020. Low patient awareness is a leading reason for suboptimal vaccination rates, suggesting that a need exists to improve provider communication in recommending pneumococcal vaccination in high-risk adults. OBJECTIVES: To evaluate the impact of a communication training program to improve pharmacist promotion of the pneumococcal vaccine among high-risk adults in Tennessee. METHODS: A multiphase training program was initiated in partnership with 2 regions of a nationwide community pharmacy chain (n = 100) focusing on improving evidence-based, presumptive recommendations related to pneumococcal vaccination. All locations were randomized to one of 3 arms on the basis of training intensity: (1) no training; (2) online training only; and (3) online and in-person simulation training. The program focused on improving evidence-based, pharmacist vaccine recommendations using health behavior theories, sales techniques, and improvisation provided through online and in-person simulation training. Changes in vaccinations (compared with the same 6-month period in the previous year) and provider self-efficacy were evaluated by Mann-Whitney U tests, chi-square tests, and general linear models. RESULTS: Completing the full training program led to nominal changes in pharmacist self-efficacy across the 6 items measured (P > 0.05). Overall counts of all pneumococcal vaccines were lower (-11.3%) across all stores in the period after training; however, a small increase (2.1%) was observed in the stores that underwent the full training, versus changes of -22.0% (P = 0.084) and -9.4% (P = 0.199) in control and online-only training comparisons, respectively. CONCLUSIONS: Pharmacists' vaccine-related self-efficacy may be improved through an evidence-based communication training program, but a more holistic focus on all recommended adult vaccines may be necessary to realize meaningful improvements.

Gene-based association analysis of survival traits via functional regression-based mixed effect cox models for related samples.

The importance to integrate survival analysis into genetics and genomics is widely recognized, but only a small number of statisticians have produced relevant work toward this study direction. For unrelated population data, functional regression (FR) models have been developed to test for association between a quantitative/dichotomous/survival trait and genetic variants in a gene region. In major gene association analysis, these models have higher power than sequence kernel association tests. In this paper, we extend this approach to analyze censored traits for family data or related samples using FR based mixed effect Cox models (FamCoxME). The FamCoxME model effect of major gene as fixed mean via functional data analysis techniques, the local gene or polygene variations or both as random, and the correlation of pedigree members by kinship coefficients or genetic relationship matrix or both. The association between the censored trait and the major gene is tested by likelihood ratio tests (FamCoxME FR LRT). Simulation results indicate that the LRT control the type I error rates accurately/conservatively and have good power levels when both local gene or polygene variations are modeled. The proposed methods were applied to analyze a breast cancer data set from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA). The FamCoxME provides a new tool for gene-based analysis of family-based studies or related samples.

Linear mixed models for association analysis of quantitative traits with next-generation sequencing data.

We develop linear mixed models (LMMs) and functional linear mixed models (FLMMs) for gene-based tests of association between a quantitative trait and genetic variants on pedigrees. The effects of a major gene are modeled as a fixed effect, the contributions of polygenes are modeled as a random effect, and the correlations of pedigree members are modeled via inbreeding/kinship coefficients. F -statistics and χ 2 likelihood ratio test (LRT) statistics based on the LMMs and FLMMs are constructed to test for association. We show empirically that the F -distributed statistics provide a good control of the type I error rate. The F -test statistics of the LMMs have similar or higher power than the FLMMs, kernel-based famSKAT (family-based sequence kernel association test), and burden test famBT (family-based burden test). The F -statistics of the FLMMs perform well when analyzing a combination of rare and common variants. For small samples, the LRT statistics of the FLMMs control the type I error rate well at the nominal levels α = 0.01 and 0.05 . For moderate/large samples, the LRT statistics of the FLMMs control the type I error rates well. The LRT statistics of the LMMs can lead to inflated type I error rates. The proposed models are useful in whole genome and whole exome association studies of complex traits.

Exploring the early phase of implementation of a vaccine-based clinical decision support system in the community pharmacy.

OBJECTIVE: To explore the implementation strategy of a recombinant zoster vaccine (RZV) clinical decision support (CDS) intervention in community pharmacy workflow to increase second-dose vaccination rates. SETTING: The level of analysis was the unit (e.g., pharmacy). The participants were selected from across approximately 2200 pharmacies in 37 states on the basis of criteria believed to affect implementation success (e.g., size, location) using a sampling matrix. PRACTICE DESCRIPTION: Large supermarket pharmacy chain. PRACTICE INNOVATION: Vaccine-based CDS intervention in community pharmacy workflow. EVALUATION: A mixed-methods contextual inquiry approach explored the implementation of a new RZV CDS workflow intervention. Data collection involved key informant, semistructured interviews and an electronic, Web-based survey. The survey was based on a validated instrument and was made available to all pharmacists nationwide within the study organization to assess views of the implementation's appropriateness, acceptability, and feasibility during early implementation. Afterward, a series of semistructured, in-depth interviews were conducted until a point of saturation was reached. The interview guide was based on selected constructs of the Consolidated Framework for Implementation Research. RESULTS: A total of 1128 survey responses were collected. Survey respondents agreed or strongly agreed that the implementation was acceptable (78.34%), appropriate (79.92%), and feasible (80.53%). Twelve pharmacist participants were interviewed via telephone. Five themes emerged from the interviews, revealing facilitators and barriers that affected implementation of the intervention: intervention characteristics, outer setting, inner setting, characteristics of individuals, and process. CONCLUSION: The implementation of the RZV CDS "nudge" intervention was welcomed, suitable, and operable in the community pharmacy setting to meet the needs of the organization, employees, and patients. The contextual factors identified during the implementation process of this CDS intervention in a community pharmacy setting may be used in scaling this and future CDS interventions for public health initiatives aimed at pharmacists in this setting.

No CFH or ARMS2 Interaction with Omega-3 Fatty Acids, Low versus High Zinc, or ß-Carotene versus Lutein and Zeaxanthin on Progression of Age-Related Macular Degeneration in the Age-Related Eye Disease Study 2: Age-Related Eye Disease Study 2 Report No. 18.

PURPOSE: To assess whether genotypes at 2 major loci associated with age-related macular degeneration (AMD), complement factor H (CFH), or age-related maculopathy susceptibility 2 (ARMS2), modify the response to oral nutrients for the treatment of AMD in the Age-Related Eye Disease Study 2 (AREDS2). DESIGN: Post hoc analysis of a randomized trial. PARTICIPANTS: White AREDS2 participants. METHODS: AREDS2 participants (n = 4203) with bilateral large drusen or late AMD in 1 eye were assigned randomly to lutein and zeaxanthin, omega-3 fatty acids, both, or placebo, and most also received the AREDS supplements. A secondary randomization assessed modified AREDS supplements in 4 treatment arms: lower zinc dosage, omission of ß-carotene, both, or no modification. To evaluate the progression to late AMD, fundus photographs were obtained at baseline and annual study visits, and history of treatment for late AMD was obtained at study visits and 6-month interim telephone calls. Participants were genotyped for the single-nucleotide polymorphisms rs1061170 in CFH and rs10490924 in ARMS2. Bivariate frailty models using both eyes were conducted, including a gene-supplement interaction term and adjusting for age, gender, level of education, and smoking status. The main treatment effects, as well as the direct comparison between lutein plus zeaxanthin and ß-carotene, were assessed for genotype interaction. MAIN OUTCOME MEASURES: The interaction between genotype and the response to AREDS2 supplements regarding progression to late AMD, any geographic atrophy (GA), and neovascular AMD. RESULTS: Complete data were available for 2775 eyes without baseline late AMD (1684 participants). The participants (mean age ± standard deviation, 72.1±7.7 years; 58.5% female) were followed up for a median of 5 years. The ARMS2 risk allele was associated significantly with progression to late AMD and neovascular AMD (P = 2.40 × 10-5 and P = 0.002, respectively), but not any GA (P = 0.097). The CFH risk allele was not associated with AMD progression. Genotype did not modify significantly the response to any of the AREDS2 supplements. CONCLUSIONS: CFH and ARMS2 risk alleles do not modify the response to the AREDS2 nutrient supplements with respect to the progression to late AMD (GA and neovascular AMD).

A comparison study of multivariate fixed models and Gene Association with Multiple Traits (GAMuT) for next-generation sequencing.

In this paper, extensive simulations are performed to compare two statistical methods to analyze multiple correlated quantitative phenotypes: (1) approximate F-distributed tests of multivariate functional linear models (MFLM) and additive models of multivariate analysis of variance (MANOVA), and (2) Gene Association with Multiple Traits (GAMuT) for association testing of high-dimensional genotype data. It is shown that approximate F-distributed tests of MFLM and MANOVA have higher power and are more appropriate for major gene association analysis (i.e., scenarios in which some genetic variants have relatively large effects on the phenotypes); GAMuT has higher power and is more appropriate for analyzing polygenic effects (i.e., effects from a large number of genetic variants each of which contributes a small amount to the phenotypes). MFLM and MANOVA are very flexible and can be used to perform association analysis for (i) rare variants, (ii) common variants, and (iii) a combination of rare and common variants. Although GAMuT was designed to analyze rare variants, it can be applied to analyze a combination of rare and common variants and it performs well when (1) the number of genetic variants is large and (2) each variant contributes a small amount to the phenotypes (i.e., polygenes). MFLM and MANOVA are fixed effect models that perform well for major gene association analysis. GAMuT can be viewed as an extension of sequence kernel association tests (SKAT). Both GAMuT and SKAT are more appropriate for analyzing polygenic effects and they perform well not only in the rare variant case, but also in the case of a combination of rare and common variants. Data analyses of European cohorts and the Trinity Students Study are presented to compare the performance of the two methods.

A Comparison Study of Fixed and Mixed Effect Models for Gene Level Association Studies of Complex Traits.

In association studies of complex traits, fixed-effect regression models are usually used to test for association between traits and major gene loci. In recent years, variance-component tests based on mixed models were developed for region-based genetic variant association tests. In the mixed models, the association is tested by a null hypothesis of zero variance via a sequence kernel association test (SKAT), its optimal unified test (SKAT-O), and a combined sum test of rare and common variant effect (SKAT-C). Although there are some comparison studies to evaluate the performance of mixed and fixed models, there is no systematic analysis to determine when the mixed models perform better and when the fixed models perform better. Here we evaluated, based on extensive simulations, the performance of the fixed and mixed model statistics, using genetic variants located in 3, 6, 9, 12, and 15 kb simulated regions. We compared the performance of three models: (i) mixed models that lead to SKAT, SKAT-O, and SKAT-C, (ii) traditional fixed-effect additive models, and (iii) fixed-effect functional regression models. To evaluate the type I error rates of the tests of fixed models, we generated genotype data by two methods: (i) using all variants, (ii) using only rare variants. We found that the fixed-effect tests accurately control or have low false positive rates. We performed simulation analyses to compare power for two scenarios: (i) all causal variants are rare, (ii) some causal variants are rare and some are common. Either one or both of the fixed-effect models performed better than or similar to the mixed models except when (1) the region sizes are 12 and 15 kb and (2) effect sizes are small. Therefore, the assumption of mixed models could be satisfied and SKAT/SKAT-O/SKAT-C could perform better if the number of causal variants is large and each causal variant contributes a small amount to the traits (i.e., polygenes). In major gene association studies, we argue that the fixed-effect models perform better or similarly to mixed models in most cases because some variants should affect the traits relatively large. In practice, it makes sense to perform analysis by both the fixed and mixed effect models and to make a comparison, and this can be readily done using our R codes and the SKAT packages.

Tumor Androgen Receptor Protein Level Is Positively Associated with a Better Overall Survival in Melanoma Patients.

Androgen receptor (AR) is expressed in numerous tissues and serves important biologic functions in skin, prostate, immune, cardiovascular, and neural systems, alongside sexual development. Several studies have associated AR expression and patient survival in various cancers, yet there are limited studies examining the relationship between AR expression and cutaneous melanoma. This study used genomics and proteomics data from The Cancer Proteome Atlas (TCPA) and The Cancer Genome Atlas (TCGA), with 470 cutaneous melanoma patient data points. Cox regression analyses evaluated the association between AR protein level with overall survival and revealed that a higher level of AR protein was positively associated with a better overall survival (OS) (p = 0.003). When stratified by sex, the AR association with OS was only significant for both sexes. The multivariate Cox models with justifications of sex, age of diagnosis, stage of disease, and Breslow depth of the tumor confirmed the AR-OS association in all patients. However, the significance of AR was lost when ulceration was included in the model. When stratified by sex, the multivariate Cox models indicated significant role of AR in OS of female patients but not in males. AR-associated genes were identified and enrichment analysis revealed shared and distinct gene network in male and female patients. Furthermore, AR was found significantly associated with OS in RAS mutant subtypes of melanoma but not in BRAF, NF1, or triple-wild type subtypes of melanoma. Our study may provide insight into the well-known female survival advantage in melanoma patients.

Impact of patient and provider nudges on addressing herpes zoster vaccine series completion.

OBJECTIVES: To determine the combined impact of provider-facing and text message-based, patient nudges on herpes zoster vaccine series completion. METHODS: Following a period during which Kroger Health implemented provider facing nudges, select US patients that initiated herpes zoster vaccination were randomized to receive timed text messages when the second dose was due and available as part of a quality improvement exercise. Main comparisons were between patients intervened by provider nudge only and those intervened by both provider and patient nudges. Data were assessed by GEE-basedlogistic and linear regression, controlling for available patient- and store-level characteristics, and geospatial analyses. RESULTS: During the baseline period, 100,627 adults received at least one HZ vaccine dose and 83.9% completed the series within 6 months over 88.6 days (SD: 26.53) on average. In the intervention period, 120,339 adults were vaccinated at least once and series completion was 88.3% (both provider nudges and text messaging) and 85.3% (not texted) during this observation window (both p < 0.0001). Time between doses was shorter for those who received text messages compared to both the baseline period and those in the intervention period that were not texted (both p < 0.001). Controlling for multiple characteristics, the odds of completion improved in the intervention period compared to baseline (OR: 1.07; 95% CI: 1.033-1.111), but a noticeably higher completion odds was observed amongst patients who received a text message in the intervention period (OR: 1.35; 95% CI: 1.286-1.414). Adjusting for patient and pharmacy factors, those who were texted received their second herpes zoster vaccine dose 8.6 days sooner (95% CI: -9.08 - -8.17, p < 0.0001) compared to those intervened by the provider nudge only. CONCLUSION: The combined use of clinical and patient-focused nudges is a simple mechanism by which pharmacies and other health care access points can address the multi-dose vaccine needs of diverse patient populations.

Clinical Nudge Impact on Herpes Zoster Vaccine Series Completion in Pharmacies.

INTRODUCTION: A new recombinant herpes zoster vaccine has advanced efforts to prevent shingles, but its multidose regimen introduces potential barriers to full protection that must be managed by community pharmacies. To address this potential patient management challenge, a pharmacy records clinical support tool was implemented to assist pharmacy staff in managing herpes zoster vaccine dose completion. METHODS: Beginning in November 2018, a large community pharmacy chain (operating in 36 states) implemented a provider nudge within its clinical decision support tool across all locations that fit seamlessly into the existing workflow, alerting the pharmacy staff of the need for a patient's second dose. Initial and second doses were followed over 2 overlapping, 10-month periods before and after system launch. Differences in vaccine completion rates before and after the system was operational were assessed by chi-square tests and predictors of completion, controlling for store- and patient-level characteristics, and were analyzed by multivariable logistic regression and generalized linear models throughout 2021. RESULTS: Across 2,271 pharmacies, 71,459 and 41,982 initial doses of the herpes zoster vaccine were given in the baseline and intervention period, respectively. The proportion of patients completing both doses increased slightly after system implementation (before: 71.9%, after: 75.2%; p<0.0001). However, dramatic improvements in time to dose completion were observed (before: 109.8 days, after: 93.3 days; p<0.001), and changes were significant in stores in all but 4 states. CONCLUSIONS: Results suggest that the use of a clinical nudge improved the occurrence of and time to herpes zoster vaccine dose completion in adults across the U.S.

Circulating Microbiota in Cardiometabolic Disease.

The rapid expansion of microbiota research has significantly advanced our understanding of the complex interactions between gut microbiota and cardiovascular, metabolic, and renal system regulation. Low-grade chronic inflammation has long been implicated as one of the key mechanisms underlying cardiometabolic disease risk and progression, even before the insights provided by gut microbiota research in the past decade. Microbial translocation into the bloodstream can occur via different routes, including through the oral and/or intestinal mucosa, and may contribute to chronic inflammation in cardiometabolic disease. Among several gut-derived products identifiable in the systemic circulation, bacterial endotoxins and metabolites have been extensively studied, however recent advances in microbial DNA sequencing have further allowed us to identify highly diverse communities of microorganisms in the bloodstream from an -omics standpoint, which is termed "circulating microbiota." While detecting microorganisms in the bloodstream was historically considered as an indication of infection, evidence on the circulating microbiota is continually accumulating in various patient populations without clinical signs of infection and even in otherwise healthy individuals. Moreover, both quantitative and compositional alterations of the circulating microbiota have recently been implicated in the pathogenesis of chronic inflammatory conditions, potentially through their immunostimulatory, atherogenic, and cardiotoxic properties. In this mini review, we aim to provide recent evidence on the characteristics and roles of circulating microbiota in several cardiometabolic diseases, such as type 2 diabetes, cardiovascular disease, and chronic kidney disease, with highlights of our emerging findings on circulating microbiota in patients with end-stage kidney disease undergoing hemodialysis.

Social determinants of health and adult influenza vaccination: a nationwide claims analysis.

BACKGROUND: The health and economic benefits of the annual influenza vaccine are well documented, yet vaccination rates in the United States missed the Healthy People 2020 goal and remain a focus of Healthy People 2030 efforts. By identifying underlying reasons for low annual influenza vaccination, social elements that need targeting may be identified and could guide future interventions or policy development to achieve vaccination goals and improve overall public health. OBJECTIVE: To determine the influence of certain social determinants of health on adherence to annual influenza vaccination in American adults. METHODS: This was a retrospective cohort analysis using data from IBM MarketScan Commercial Claims and Encounters Database and national Medicare 5% sample data from 2013 to 2016. Study eligibility criteria included adults (aged 18 years and older) who were continuously enrolled for 3 influenza seasons between 2013 and 2016. Receipt of the influenza vaccine was counted over 3 consecutive influenza seasons, and select social determinants were extracted from publicly available sources. Patient characteristics, health resource utilization, and selected social determinants of health were included in bivariate and multivariate logistic regression analyses to determine their association with annual influenza vaccination. RESULTS: 6,694,571 adults across employer-sponsored and Medicare coverage groups were analyzed, of which 14.7% of Medicare-enrolled adults and 9.2% of commercially enrolled adults were vaccinated in all 3 seasons. Higher proportions of vaccine adherence (ie, all 3 seasons) were observed among females (9.6% vs 8.7% [commercial], 15.0% vs 14.4% [Medicare]), the immunocompromised (11.8% vs 8.3% [commercial], 15.9% vs 13.6% [Medicare]), rural residents (10.5% vs 9.0% [commercial], 15.4% vs 14.6% [Medicare]; all P < 0.0001), and those enrolled in a high-deductible health plan (10.3%). Multivariable logistic regression models indicated that the odds of vaccine adherence tended to be higher in areas of higher poverty (OR=1.012; 95% CI = 1.01-1.02 [commercial], OR=1.01; 95% CI = 1.01-1.01 [Medicare]) yet lower in areas with higher proportions of Democratic voters (OR=0.998; 95% CI = 0.998-0.998 [commercial], OR = 0.996; 95% CI = 0.996-0.997 [Medicare]). Among commercially insured adults, the odds of vaccine adherence were higher in areas of higher health literacy (OR=1.036; 95% CI = 1.036-1.037), but this effect was not observed among Medicare members. Conversely, the odds of vaccine adherence increased as the proportion of those residing in areas of limited Internet access increased (OR=1.007; 95% CI = 1.004-1.010) among Medicare members only. CONCLUSIONS: Key social determinants of health are important factors of vaccine adherence and can guide policy and intervention efforts toward addressing potential hesitancy. A deeper assessment of other contributing social factors is needed in seasonal influenza and other vaccines to better interpret the vaccine-seeking behaviors of adults. DISCLOSURES: This study received no outside funding. Gatwood, Hagemann, Hohmeier, and Chiu declare vaccine-related grant funding from Merck & Co. and GlaxoSmithKline for vaccine research unrelated to the current study. Ramachandran declares vaccine-related grant funding from Glaxo-SmithKline for research unrelated to the current study. Shuvo and Behal have nothing to disclose. Findings described in this study were presented as a poster and podium at the Academy of Managed Care Pharmacy Nexus 2020 Virtual meeting, October 19-23, 2020.

Comparing Rates of Fusion and Time to Fusion in Viable Cellular Allograft and Autograft.

BACKGROUND: Autograft or allograft frequently are used to enhance bone union in foot and ankle surgery. Viable cellular bone allograft uses viable cells and bone scaffolding in a gel base, but uncertainty remains around allograft's greater efficacy than autograft regarding rates of fusion (ROF) and time to fusion (TTF). METHODS: Autograft, viable cellular allograft, and viable cellular allograft with autograft were compared in 199 forefoot, midfoot, and hindfoot arthrodeses performed over a 6-year period. Data collected from electronic medical records and radiographs were analyzed to determine ROF and TTF as well as rates of revision surgery for delayed or nonunion and compared among groups. RESULTS: Eighty-seven patients comprised the autograft group, 81 the allograft group, and 31 the combined group. No significant differences were noted in patient demographics among the groups. No statistically significant differences in ROF were noted among the 3 groups, with 86% (75 of 87) fusion in the autograft group, 93% (75 of 81) in the allograft group, and 84% (26 of 31) in the combined group (P = .20). After conducting a multivariate analysis, we found no statistically significant difference for allograft or combined graft on TTF (P = .1379 and .2311, respectively). No significant difference was found in rate of revision surgery for nonunion, which was 1.2% (1 of 81) in the allograft group, 3.4% (3 of 87) in the autograft group, and 6.5% (2 of 31) in the combined group (P = .3). CONCLUSION: No significant difference was found in ROF, TTF, or rate of revision surgery when comparing viable cellular allograft to autograft or combined allograft-autograft. Viable cellular allograft may be a reasonable alternative to the gold standard of autograft and should be considered an option in patients undergoing arthrodesis in foot and ankle surgery. LEVEL OF EVIDENCE: Level III, therapeutic.