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.

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-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.

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.

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.

Efficacy of Postoperative Oral Antibiotics in Foot and Ankle Surgery.

BACKGROUND: Preoperative oral antibiotic use in patients undergoing foot and ankle surgery is standard practice, but no consensus has been reached regarding the efficacy of postoperative oral antibiotics. The purpose of this study was to determine whether postoperative oral antibiotics reduce the rate of surgical site infections (SSIs) in patients, with and without comorbidities, undergoing foot and ankle surgery. METHODS: A retrospective chart review was conducted identifying patients who underwent foot and ankle surgery by 4 fellowship-trained, foot and ankle orthopaedic surgeons between January 1, 2015, and January 1, 2019. Patients were divided into 2 groups: those who received postoperative oral antibiotics (group 1) and those who did not (group 2). Two surgeons routinely prescribed postoperative oral antibiotics, and 2 did not. Demographics, comorbidities, and procedure complexity based on surgical site and Current Procedural Terminology code were recorded from the charts. The primary outcome was postoperative infection (superficial or deep) within 6 months after surgery. Patients with antibiotic use prior to surgery, preoperative infection, or lack of follow-up >6 weeks were excluded. Multivariate logistic regression modeling was used to analyze differences in infection rate and severity. RESULTS: Chart review identified 3631 patients, 1227 of whom did not receive postoperative oral antibiotics whereas 2394 patients did. Routine postoperative oral antibiotic use did not significantly affect postoperative infection rates or severity. However, all covariates studied (diabetes, hypertension, obesity, tobacco use, alcohol use, rheumatoid conditions, and age) influenced postoperative infection rates and severity. CONCLUSION: The results of this study indicate that postoperative oral antibiotics are not associated with differences in infection rates or severity. We do not recommend routine use in foot and ankle surgery.

The Lean Six Sigma Define, Measure, Analyze, Implement, Control (LSS DMAIC) Framework: An Innovative Strategy for Quality Improvement of Pharmacist Vaccine Recommendations in Community Pharmacy.

Community pharmacies represent a highly accessible and convenient setting for vaccination. However, setting-specific barriers exist which contribute to suboptimal vaccination rates, particularly for pneumococcal vaccinations. One proven quality improvement framework growing in use within healthcare settings is Lean Six Sigma (LSS). This paper describes the application of the LSS framework in select locations of a national pharmacy chain. The implementation of a training program for improved recommendation techniques to promote higher rates of pneumococcal vaccinations in high-risk adult populations is also addressed. A mixed-methods approach including pre/post quasi-experimental design and in-depth key informant interviews was used.

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.

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.

Hydroxychloroquine Causes Early Inner Retinal Toxicity and Affects Autophagosome-Lysosomal Pathway and Sphingolipid Metabolism in the Retina.

Hydroxychloroquine (HCQ) is an anti-malarial drug but also widely used to treat autoimmune diseases like arthritis and lupus. Although there have been multiple reports of the adverse effect of prolonged HCQ usage on the outer retina, leading to bull's-eye maculopathy, the effect of HCQ toxicity on the inner retina as well as on overall visual functions has not been explored in detail. Furthermore, lack of an established animal model of HCQ toxicity hinders our understanding of the underlying molecular mechanisms. Here, using a small clinical study, we confirmed the effect of HCQ toxicity on the inner retina, in particular the reduction in central inner retinal thickness, and established a mouse model of chronic HCQ toxicity that recapitulates the effects observed in human retina. Using the mouse model, we demonstrated that chronic HCQ toxicity results in loss of inner retinal neurons and retinal ganglion cells (RGC) and compromises visual functions. We further established that HCQ treatment prevents autophagosome-lysosome fusion and alters the sphingolipid homeostasis in mouse retina. Our results affirm the notion that HCQ treatment causes early damage to the inner retina and affects visual functions before leading to characteristic toxicity in the macular region of the outer retina, 'bull's-eye maculopathy.' We also provide insights into the underlying molecular mechanisms of HCQ retinal toxicity that may involve autophagy-lysosomal defects and alterations in sphingolipid metabolism.

Pathway-based metabolomics study of sarcopenia-related traits in two US cohorts.

We aimed to validate two metabolites, aspartic acid and glutamic acid, which were associated with sarcopenia-related traits, muscle mass and strength, in our previous untargeted metabolomics study and to identify novel metabolites from five metabolic pathways involving these two metabolites. We included a discovery cohort of 136 white women aged 20-40 years (used for the previous untargeted metabolomics analysis) and a validation cohort of 174 subjects aged ≥ 60 years, including men and women of white and black. A targeted LC-MS assay successfully detected 12 important metabolites from these pathways. Aspartic acid was associated with muscle mass and strength in the discovery cohort, but not in the validation cohort. However, glutamic acid was associated with these sarcopenia traits in both cohorts. Additionally, N-acetyl-L-aspartic acid and carnosine were the newly identified metabolites that were associated with muscle strength in the discovery and validation cohorts, respectively. We did not observe any significant sex and race differences in the associations of these metabolites with sarcopenia traits in the validation cohort. Our findings indicated that glutamic acid might be consistently associated with sarcopenia-related traits across age, sex, and race. They also suggested that age-specific metabolites and metabolic pathways might be involved in muscle regulation.

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.

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.

The Sex Differences in Uveal Melanoma: Potential Roles of EIF1AX, Immune Response and Redox Regulation.

BACKGROUND: Uveal melanoma (UVM) is a rare cancer that shows sex difference in incidence and survival, with little previous report for the underlying mechanism. METHODS: This study used the SEER data (1974-2016) for an age-dependent analysis on sex difference in UVM, and further used the TCGA-UVM genomics dataset for analyzing the differential gene expression profiles in tumors from men and women. RESULTS: Our results demonstrate a sex difference in older age (≥40 years) but not in younger patients, with men exhibiting a higher incidence rate than women. However, younger women have shown a continuous increasing trend since 1974. Examining the 11 major oncogenes and tumor suppressors in UVM revealed that EIF1AX showed a significant sex difference in mRNA accumulation and copy number variation, with female tumors expressing higher levels of EIF1AX and exhibiting more variations in copy numbers. EIF1AX mRNA levels were significantly inversely correlated with EIF1AX copy numbers in female tumors only, but not in male tumors. Differential gene expression analysis at the whole genomic level identified a set of 92 protein-coding and 16 RNA-coding genes which exhibited differential expression in men and women (fold of change cutoff at 1.7, adjusted p value < 0.05, FDR < 0.05). Network analysis showed significant difference in immune response and in disulfide bond formation, with EGR1/EGR2 and PDIA2 genes as regulators for immune response and disulfide bond formation, respectively. The melanocortin pathway which is linked to both melanin synthesis and obesity seems to be altered with unclear significance, as the sex difference in POMC, DCT/TYRP2, and MRAP2 was observed but with no clear direction. CONCLUSION: This study reveals possible mechanisms for the sex difference in tumorigenesis of UVM which has potentials for better understanding and prevention of UVM.

Gene-Based Association Testing of Dichotomous Traits With Generalized Functional Linear Mixed Models Using Extended Pedigrees: Applications to Age-Related Macular Degeneration.

Genetics plays a role in age-related macular degeneration (AMD), a common cause of blindness in the elderly. There is a need for powerful methods for carrying out region-based association tests between a dichotomous trait like AMD and genetic variants on family data. Here, we apply our new generalized functional linear mixed models (GFLMM) developed to test for gene-based association in a set of AMD families. Using common and rare variants, we observe significant association with two known AMD genes: CFH and ARMS2. Using rare variants, we find suggestive signals in four genes: ASAH1, CLEC6A, TMEM63C, and SGSM1. Intriguingly, ASAH1 is down-regulated in AMD aqueous humor, and ASAH1 deficiency leads to retinal inflammation and increased vulnerability to oxidative stress. These findings were made possible by our GFLMM which model the effect of a major gene as a fixed mean, the polygenic contributions as a random variation, and the correlation of pedigree members by kinship coefficients. Simulations indicate that the GFLMM likelihood ratio tests (LRTs) accurately control the Type I error rates. The LRTs have similar or higher power than existing retrospective kernel and burden statistics. Our GFLMM-based statistics provide a new tool for conducting family-based genetic studies of complex diseases. Supplementary materials for this article, including a standardized description of the materials available for reproducing the work, are available as an online supplement.

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 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.