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.

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.

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 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.

A randomized pilot program to reduce opioid use following dental surgery and increase safe medication return.

Research indicates that increased cumulative exposure (duration of administration and strength of dose) is associated with long-term opioid use. Because dentists represent some of the highest opioid prescribing medical professionals in the US, dental practices offer a critical site for intervention. The current study used a randomized clinical trial design to examine the efficacy of an opioid misuse prevention program (OMPP), presented as a brief intervention immediately prior to dental extraction surgery. The OMPP provided educational counseling about risks and appropriate use of opioid medication, as well as 28 tablets of ibuprofen (200 mg) and 28 tablets of acetaminophen (500 mg) for weaning off opioid medication. This was compared with a Treatment as Usual (TAU) control condition. Participants were individuals presenting for surgery who were eligible for opioid medication (N = 76). Follow up assessment was conducted at 1 week following surgery, with 4 individuals refusing follow up or not prescribed opioid. Intent to treat analysis indicated a non-significant treatment group effect (N = 72, Beta = 0.16, p = .0835), such that the OMPP group self-reported less opioid use (in morphine milligram equivalents, MMEs) than the TAU group (37.94 vs. 47.79, effect size d = 0.42). Sensitivity analysis, excluding individuals with complications following surgery (n = 6) indicated a significant treatment group effect (N = 66, Beta = 0.24, p = .0259), such that the OMPP group self-reported significantly less MMEs than the TAU group (29.74 vs. 43.59, effect size d = 0.56). Results indicate that a 10-minute intervention and provision of non-narcotic pain medications may reduce the amount of self-administered opioid medication following dental surgery.

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.

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).

Lifestyle, metabolite, and genetic determinants of formate concentrations in a cross-sectional study in young, healthy adults.

Background: Formate is an important metabolite that serves as a donor of one-carbon groups to the intracellular tetrahydrofolate pool. However, little is known of its circulating concentrations or of their determinants. Objective: This study aimed to define formate concentrations and their determinants in a healthy young population. Design: Serum formate was measured in 1701 participants from the Trinity Student Study. The participants were men and women, aged 18 to 28 y, enrolled at Trinity College, Dublin. Formate concentrations were compared with other one-carbon metabolites, vitamin status, potential formate precursors, genetic polymorphisms, and lifestyle factors. Results: Serum formate concentrations ranged from 8.7 to 96.5 µM, with a mean of 25.9 µM. Formate concentrations were significantly higher in women than in men; oral contraceptive use did not further affect them. There was no effect of smoking or of alcohol ingestion, but the TT genotype of the methylenetetrahydrofolate reductase (MTHFR) 677C→T (rs1801133) polymorphism was associated with a significantly decreased formate concentration. Formate was positively associated with potential metabolic precursors (serine, methionine, tryptophan, choline) but not with glycine. Formate concentrations were positively related to serum folate and negatively related to serum vitamin B-12. Conclusions: Formate concentrations were sensitive to the concentrations of metabolic precursors. In view of the increased susceptibility of women with the TT genotype of MTHFR to give birth to infants with neural tube defects as well as the effectiveness of formate supplementation in decreasing the incidence of folate-resistant neural tube defects in susceptible mice, it will be important to understand how this genotype decreases the serum formate concentration. This trial was registered at www.clinicaltrials.gov as NCT03305900.

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.