Epigenetic age acceleration is associated with blood lipid levels in a multi-ancestry sample of older U.S. adults.

BACKGROUND: Dyslipidemia, which is characterized by an unfavorable lipid profile, is a key risk factor for cardiovascular disease (CVD). Understanding the relationships between epigenetic aging and lipid levels may help guide early prevention and treatment efforts for dyslipidemia. METHODS: We used weighted linear regression to cross-sectionally investigate the associations between five measures of epigenetic age acceleration estimated from whole blood DNA methylation (HorvathAge Acceleration, HannumAge Acceleration, PhenoAge Acceleration, GrimAge Acceleration, and DunedinPACE) and four blood lipid measures (total cholesterol (TC), LDL-C, HDL-C, and triglycerides (TG)) in 3,813 participants (mean age = 70 years) from the Health and Retirement Study (HRS). As a sensitivity analysis, we examined the same associations in participants who fasted prior to the blood draw (n = 2,531) and in participants who did not take lipid-lowering medication (n = 1,869). Using interaction models, we also examined whether demographic factors including age, sex, and educational attainment modified the relationships between epigenetic age acceleration and blood lipids. RESULTS: After adjusting for age, race/ethnicity, sex, fasting status, and lipid-lowering medication use, greater epigenetic age acceleration was associated with lower TC, HDL-C, and LDL-C, and higher TG (p < 0.05), although the effect sizes were relatively small (e.g., < 7 mg/dL of TC per standard deviation in epigenetic age acceleration). GrimAge acceleration and DunedinPACE associations with all lipids remained significant after further adjustment for body mass index, smoking status, and educational attainment. These associations were stronger in participants who fasted and who did not use lipid-lowering medication, particularly for LDL-C. We observed the largest number of interactions between DunedinPACE and demographic factors, where the associations with lipids were stronger in younger participants, females, and those with higher educational attainment. CONCLUSION: Multiple measures of epigenetic age acceleration are associated with blood lipid levels in older adults. A greater understanding of how these associations differ across demographic groups can help shed light on the relationships between aging and downstream cardiovascular diseases. The inverse associations between epigenetic age and TC and LDL-C could be due to sample limitations or non-linear relationships between age and these lipids, as both TC and LDL-C decrease faster at older ages.

Transoral Robotic Surgery for Eagle Syndrome: A Systematic Review.

Objectives: Transoral robotic surgery (TORS) is gaining popularity and has been introduced for the treatment of Eagle syndrome. This review aims to evaluate the safety and efficacy of TORS for the treatment of Eagle syndrome. Methods: A systematic review of the English language literature using multiple databases was completed for studies describing TORS for Eagle syndrome. The quality of studies and risk of bias were evaluated using the MINORS scoring system. Results: Out of 1495 articles screened, 4 studies met criteria for inclusion in the final analysis. Across all studies, there was a 100% surgical success rate. In total, every patient had some level of symptom improvement with 84% of patients having complete symptom improvement and 16% having partial improvement. Reported estimated blood loss averaged 12.5 mL. A total of 94.7% of patients had no surgical complications and no cases were complicated by postoperative bleeding. Operative time averaged 65 minutes. The average length of stay was 2.1 days. A total of 92% of patients resumed their diet on postoperative day 1, with the remainder resuming on postoperative day 2. MINORS criteria scoring suggested moderate risk of bias in all studies. Conclusion: Based on limited quality evidence, this review suggests that TORS is a safe and effective surgical approach in the treatment of Eagle syndrome with low complication rates. Further large-scale prospective studies are warranted.

Epigenetic age acceleration is associated with blood lipid levels in a multi-ancestry sample of older U.S. adults.

Background: Dyslipidemia, which is characterized by an unfavorable lipid profile, is a key risk factor for cardiovascular disease (CVD). Understanding the relationships between epigenetic aging and lipid levels may help guide early prevention and treatment efforts for dyslipidemia. Methods: We used weighted linear regression to cross-sectionally investigate the associations between five measures of epigenetic age acceleration estimated from whole blood DNA methylation (HorvathAge Acceleration, HannumAge Acceleration, PhenoAge Acceleration, GrimAge Acceleration, and DunedinPACE) and four blood lipid measures (total cholesterol (TC), LDL-C, HDL-C, and triglycerides (TG)) in 3,813 participants (mean age = 70 years) from the Health and Retirement Study (HRS). As a sensitivity analysis, we examined the same associations in participants who fasted prior to the blood draw (n = and f) and in participants who did not take lipid-lowering medication (n = 1,869). Using interaction models, we also examined whether the relationships between epigenetic age acceleration and blood lipids differ by demographic factors including age, sex, and educational attainment. Results: After adjusting for age, race/ethnicity, sex, fasting status, and lipid-lowering medication use, greater epigenetic age acceleration was associated with lower TC, HDL-C, and LDL-C, and higher TG (p < 0.05). GrimAge acceleration and DunedinPACE associations with all lipids remained significant after further adjusting for body mass index, smoking status, and educational attainment. These associations were stronger in participants who fasted and who did not use lipid-lowering medication, particularly for LDL-C. We observed the largest number of interactions between DunedinPACE and demographic factors, where the associations with lipids were stronger in younger participants, females, and those with higher educational attainment. Conclusion: Epigenetic age acceleration, a powerful biomarker of cellular aging, is highly associated with blood lipid levels in older adults. A greater understanding of how these associations differ across demographic groups can help shed light on the relationships between aging and downstream cardiovascular diseases. The inverse associations between epigenetic age and TC and LDL-C could be due to sample limitations or the non-linear relationship between age and these lipids, as both TC and LDL-C decrease faster at older ages. More studies are needed to further understand the temporal relationships between epigenetic age acceleration on blood lipids and other health outcomes.

Blood-based DNA methylation and exposure risk scores predict PTSD with high accuracy in military and civilian cohorts.

Background: Incorporating genomic data into risk prediction has become an increasingly useful approach for rapid identification of individuals most at risk for complex disorders such as PTSD. Our goal was to develop and validate Methylation Risk Scores (MRS) using machine learning to distinguish individuals who have PTSD from those who do not. Methods: Elastic Net was used to develop three risk score models using a discovery dataset (n = 1226; 314 cases, 912 controls) comprised of 5 diverse cohorts with available blood-derived DNA methylation (DNAm) measured on the Illumina Epic BeadChip. The first risk score, exposure and methylation risk score (eMRS) used cumulative and childhood trauma exposure and DNAm variables; the second, methylation-only risk score (MoRS) was based solely on DNAm data; the third, methylation-only risk scores with adjusted exposure variables (MoRSAE) utilized DNAm data adjusted for the two exposure variables. The potential of these risk scores to predict future PTSD based on pre-deployment data was also assessed. External validation of risk scores was conducted in four independent cohorts. Results: The eMRS model showed the highest accuracy (92%), precision (91%), recall (87%), and f1-score (89%) in classifying PTSD using 3730 features. While still highly accurate, the MoRS (accuracy = 89%) using 3728 features and MoRSAE (accuracy = 84%) using 4150 features showed a decline in classification power. eMRS significantly predicted PTSD in one of the four independent cohorts, the BEAR cohort (beta = 0.6839, p-0.003), but not in the remaining three cohorts. Pre-deployment risk scores from all models (eMRS, beta = 1.92; MoRS, beta = 1.99 and MoRSAE, beta = 1.77) displayed a significant (p < 0.001) predictive power for post-deployment PTSD. Conclusion: Results, especially those from the eMRS, reinforce earlier findings that methylation and trauma are interconnected and can be leveraged to increase the correct classification of those with vs. without PTSD. Moreover, our models can potentially be a valuable tool in predicting the future risk of developing PTSD. As more data become available, including additional molecular, environmental, and psychosocial factors in these scores may enhance their accuracy in predicting the condition and, relatedly, improve their performance in independent cohorts.

Polygenic risk for suicide attempt is associated with lifetime suicide attempt in US soldiers independent of parental risk.

BACKGROUND: Suicide is a leading cause of death worldwide. Whereas some studies have suggested that a direct measure of common genetic liability for suicide attempts (SA), captured by a polygenic risk score for SA (SA-PRS), explains risk independent of parental history, further confirmation would be useful. Even more unsettled is the extent to which SA-PRS is associated with lifetime non-suicidal self-injury (NSSI). METHODS: We used summary statistics from the largest available GWAS study of SA to generate SA-PRS for two non-overlapping cohorts of soldiers of European ancestry. These were tested in multivariable models that included parental major depressive disorder (MDD) and parental SA. RESULTS: In the first cohort, 417 (6.3 %) of 6573 soldiers reported lifetime SA and 1195 (18.2 %) reported lifetime NSSI. In a multivariable model that included parental history of MDD and parental history of SA, SA-PRS remained significantly associated with lifetime SA [aOR = 1.26, 95%CI:1.13-1.39, p < 0.001] per standardized unit SA-PRS]. In the second cohort, 204 (4.2 %) of 4900 soldiers reported lifetime SA, and 299 (6.1 %) reported lifetime NSSI. In a multivariable model that included parental history of MDD and parental history of SA, SA-PRS remained significantly associated with lifetime SA [aOR = 1.20, 95%CI:1.04-1.38, p = 0.014]. A combined analysis of both cohorts yielded similar results. In neither cohort or in the combined analysis was SA-PRS significantly associated with NSSI. CONCLUSIONS: PRS for SA conveys information about likelihood of lifetime SA (but not NSSI, demonstrating specificity), independent of self-reported parental history of MDD and parental history of SA. LIMITATIONS: At present, the magnitude of effects is small and would not be immediately useful for clinical decision-making or risk-stratified prevention initiatives, but this may be expected to improve with further iterations. Also critical will be the extension of these findings to more diverse populations.

Alcohol Use and Mortality Among Older Couples in the United States: Evidence of Individual and Partner Effects.

BACKGROUND AND OBJECTIVES: Spouses with concordant (i.e., similar) drinking behaviors often report better quality marriages and are married longer compared with those who report discordant drinking behaviors. Less is known regarding whether concordant or discordant patterns have implications for health, as couples grow older. The present study examined whether drinking patterns among older couples are associated with mortality over time. RESEARCH DESIGN AND METHODS: The Health and Retirement Study (HRS) is a nationally representative sample of individuals and their partners (married/cohabiting) over age 50 in the United States, in which participants completed surveys every 2 years. Participants included 4,656 married/cohabiting different-sex couples (9,312 individuals) who completed at least 3 waves of the HRS from 1996 to 2016. Participants reported whether they drank alcohol at all in the last 3 months, and if so, the average amount they drank per week. Mortality data were from 2016. RESULTS: Analyses revealed concordant drinking spouses (both indicated they drank in the last 3 months) survived longer than discordant drinking spouses (1 partner drinks and the other does not) and concordant nondrinking spouses. Analysis of average drinks per week showed a quadratic association with mortality such that light drinking predicted better survival rates among individuals and their partners compared with abstaining and heavy drinking. Further, similar levels of drinking in terms of the amount of drinking were associated with greater survival, particularly among wives. DISCUSSION AND IMPLICATIONS: This study moves the field forward by showing that survival varies as a function of one's own and one's partner's drinking.

Systematic review of the free thoracodorsal artery perforator flap for head and neck reconstruction.

BACKGROUND: The thoracodorsal artery perforator (TDAP) flap has gained interest as a option for reconstruction of head and neck defects while minimizing donor site morbidity as compared to traditional workhorse flaps. The primary aim of this systematic review is to assess the postoperative outcomes and efficacy of this flap. METHODS: Several databases were screened for relevant citations. The quality of studies and risk of bias were evaluated using the MINORS scoring system. RESULTS: Twenty articles containing 168 patients undergoing at least one TDAP flap reconstruction met the inclusion criteria. There were no incidences of total flap failure and only 10 incidences of partial flap failure (5.95 %). Flap complications and donor site morbidity was low. The average MINORS score of the studies suggested a moderately high amount of bias. CONCLUSIONS: Based on limited quality evidence, this review suggests that TDAP flap is a safe and feasible option for head and neck reconstruction with comparable success rates as other commonly used flaps, with low complication rate and donor site morbidity. Further large-scale studies are warranted.

Decomposing interaction and mediating effects of race/ethnicity and circulating blood levels of cystatin C on cognitive status in the United States health and retirement study.

Background and objectives: Elevated circulating cystatin C is associated with cognitive impairment in non-Hispanic Whites, but its role in racial disparities in dementia is understudied. In a nationally representative sample of older non-Hispanic White, non-Hispanic Black, and Hispanic adults in the United States, we use mediation-interaction analysis to understand how racial disparities in the cystatin C physiological pathway may contribute to racial disparities in prevalent dementia. Methods: In a pooled cross-sectional sample of the Health and Retirement Study (n = 9,923), we employed Poisson regression to estimate prevalence ratios and to test the relationship between elevated cystatin C (>1.24 vs. ≤1.24 mg/L) and impaired cognition, adjusted for demographics, behavioral risk factors, other biomarkers, and chronic conditions. Self-reported racialized social categories were a proxy measure for exposure to racism. We calculated additive interaction measures and conducted four-way mediation-interaction decomposition analysis to test the moderating effect of race/ethnicity and mediating effect of cystatin C on the racial disparity. Results: Overall, elevated cystatin C was associated with dementia (prevalence ratio [PR] = 1.2; 95% CI: 1.0, 1.5). Among non-Hispanic Black relative to non-Hispanic White participants, the relative excess risk due to interaction was 0.7 (95% CI: -0.1, 2.4), the attributable proportion was 0.1 (95% CI: -0.2, 0.4), and the synergy index was 1.1 (95% CI: 0.8, 1.8) in a fully adjusted model. Elevated cystatin C was estimated to account for 2% (95% CI: -0, 4%) for the racial disparity in prevalent dementia, and the interaction accounted for 8% (95% CI: -5, 22%). Analyses for Hispanic relative to non-white participants suggested moderation by race/ethnicity, but not mediation. Discussion: Elevated cystatin C was associated with dementia prevalence. Our mediation-interaction decomposition analysis suggested that the effect of elevated cystatin C on the racial disparity might be moderated by race/ethnicity, which indicates that the racialization process affects not only the distribution of circulating cystatin C across minoritized racial groups, but also the strength of association between the biomarker and dementia prevalence. These results provide evidence that cystatin C is associated with adverse brain health and this effect is larger than expected for individuals racialized as minorities had they been racialized and treated as non-Hispanic White.

Sex-specific DNA methylation in saliva from the multi-ethnic Future of Families and Child Wellbeing Study.

The prevalence and severity of many diseases differs by sex, potentially due to sex-specific patterns in DNA methylation. Autosomal sex-specific differences in DNA methylation have been observed in cord blood and placental tissue but are not well studied in saliva or in diverse populations. We sought to characterize sex-specific DNA methylation on autosomal chromosomes in saliva samples from children in the Future of Families and Child Wellbeing Study, a multi-ethnic prospective birth cohort containing an oversampling of Black, Hispanic and low-income families. DNA methylation from saliva samples was analysed on 796 children (50.6% male) at both ages 9 and 15 with DNA methylation measured using the Illumina HumanMethylation 450k array. An epigenome-wide association analysis of the age 9 samples identified 8,430 sex-differentiated autosomal DNA methylation sites (P < 2.4 × 10-7), of which 76.2% had higher DNA methylation in female children. The strongest sex-difference was in the cg26921482 probe, in the AMDHD2 gene, with 30.6% higher DNA methylation in female compared to male children (P < 1 × 10-300). Treating the age 15 samples as an internal replication set, we observed highly consistent results between the ages 9 and 15 measurements, indicating stable and replicable sex-differentiation. Further, we directly compared our results to previously published DNA methylation sex differences in both cord blood and saliva and again found strong consistency. Our findings support widespread and robust sex-differential DNA methylation across age, human tissues, and populations. These findings help inform our understanding of potential biological processes contributing to sex differences in human physiology and disease.

Depressive symptoms are associated with DNA methylation age acceleration in a cross-sectional analysis of adults over age 50 in the United States.

Background: Major depressive disorder affects mental well-being and accelerates DNA methylation age, a marker of biological aging. Subclinical depressive symptoms and DNA methylation aging have not been explored. Objective: To assess the cross-sectional association between depressive symptoms and accelerated DNA methylation aging among United States adults over age 50. Methods: We included 3,793 participants from the 2016 wave of the Health and Retirement Study. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression scale and operationalized as high versus low/no. Blood DNA methylation GrimAge was regressed on chronologic age to obtain acceleration. Multiple linear regression assessed the relationship between high depressive symptoms and GrimAge acceleration, controlling for demographic factors, health behaviors, and cell type proportions. We investigated sex and race/ethnicity stratified associations. Results: Participants were 42% male, 14% had high depressive symptoms, 44% had accelerated GrimAge, and were mean age 70 years. In our fully adjusted model, those with high depressive symptoms had 0.40 (95%CI: 0.06, 0.73) years accelerated GrimAge, compared to those with low/no depressive symptoms. The association between depressive symptoms and GrimAge acceleration was larger in male participants ( P = 0.04). Conclusion: Higher depressive symptoms were associated with accelerated DNA methylation age among older adults.

The Mediating Role of Systemic Inflammation and Moderating Role of Race/Ethnicity in Racialized Disparities in Incident Dementia: A Decomposition Analysis.

Background: Exposure to systemic racism is linked to increased dementia burden. To assess systemic inflammation as a potential pathway linking exposure to racism and dementia disparities, we investigated the mediating role of C-reactive protein (CRP), a systemic inflammation marker, and the moderating role of race/ethnicity on racialized disparities in incident dementia. Methods: In the US Health and Retirement Study (n=5,143), serum CRP was measured at baseline (2006, 2008 waves). Incident dementia was classified by cognitive tests over a six-year follow-up. Self-reported racialized categories were a proxy for exposure to the racialization process. We decomposed racialized disparities in dementia incidence (non-Hispanic Black and/or Hispanic vs. non-Hispanic White) into 1) the mediated effect of CRP, 2) the moderated portion attributable to the interaction between racialized group membership and CRP, and 3) the controlled direct effect (other pathways through which racism operates). Results: The 6-year cumulative incidence of dementia was 15.5%. Among minoritized participants (i.e., non-Hispanic Black and/or Hispanic), high CRP levels (> 75th percentile or 4.57mcg/mL) was associated with 1.27 (95%CI: 1.01,1.59) times greater risk of incident dementia than low CRP (<4.57mcg/mL). Decomposition analysis comparing minoritized versus non-Hispanic White participants showed that the mediating effect of CRP accounted for 2% (95% CI: 0%, 6%) of the racial disparity, while the interaction effect between minoritized group status and high CRP accounted for 12% (95% CI: 2%, 22%) of the disparity. Findings were robust to potential violations of causal mediation assumptions. Conclusions: Systemic inflammation mediates racialized disparities in incident dementia.

The Mediating Role of Systemic Inflammation and Moderating Role of Race/Ethnicity in Racialized Disparities in Incident Dementia: A Decomposition Analysis.

Background: Exposure to systemic racism is linked to increased dementia burden. To assess systemic inflammation as a potential pathway linking exposure to racism and dementia disparities, we investigated the mediating role of C-reactive protein (CRP), a systemic inflammation marker, and the moderating role of race/ethnicity on racialized disparities in incident dementia. Methods: In the US Health and Retirement Study (n=5,143), serum CRP was measured at baseline (2006, 2008 waves). Incident dementia was classified by cognitive tests over a six-year follow-up. Self-reported racialized categories were a proxy for exposure to the racialization process. We decomposed racialized disparities in dementia incidence (non-Hispanic Black and/or Hispanic vs. non-Hispanic White) into 1) the mediated effect of CRP, 2) the moderated portion attributable to the interaction between racialized group membership and CRP, and 3) the controlled direct effect (other pathways through which racism operates). Results: The 6-year cumulative incidence of dementia was 15.5%. Among minoritized participants (i.e., non-Hispanic Black and/or Hispanic), high CRP levels (> 75th percentile or 4.57µg/mL) was associated with 1.27 (95%CI: 1.01,1.59) times greater risk of incident dementia than low CRP (≤4.57µg/mL). Decomposition analysis comparing minoritized versus non-Hispanic White participants showed that the mediating effect of CRP accounted for 2% (95% CI: 0%, 6%) of the racial disparity, while the interaction effect between minoritized group status and high CRP accounted for 12% (95% CI: 2%, 22%) of the disparity. Findings were robust to potential violations of causal mediation assumptions. Conclusions: Systemic inflammation mediates racialized disparities in incident dementia.

A systematic review and meta-analysis on the outcomes of type I thyroplasty in the irradiated neck.

BACKGROUND: Type I thyroplasty has been well-documented as a safe and effective treatment modality for vocal fold motion impairment, as well as other select cases of persistent glottic insufficiency. However, history of prior radiation to the neck has traditionally been viewed as a relative, if not formal contra-indication to this procedure. The objective of this systematic review was to analyze all available data in the literature on type I thyroplasty in previously irradiated patients and perform a meta-analysis assessing whether complications and revision rates are significantly different between radiated and non-irradiated patients. Secondary outcomes were to compare voice outcomes between these cohorts. METHODS: Several databases were screened for relevant citations using the PICO process. The quality of studies and risk of bias were evaluated using the MINORS scoring system. Main endpoints for analysis in this study were complication rate and revision rate. Secondary endpoint was reported voice outcome. RESULTS: Three articles were included in the analysis. Zero major complications were reported, including no instances of implant extrusion or explantation. There was an 11.8 % rate of minor complications. There were similar rates of revision between radiation and control groups. There was no significant difference in voice outcomes between groups. The average MINORS score of the studies suggested a high risk of bias. CONCLUSIONS: Based on limited quality evidence, this review suggests that type I thyroplasty is safe and feasible in carefully selected irradiated patients, with comparable complication and success rates as their non-irradiated cohorts. Further large-scale studies are warranted.

Relationship between alcohol consumption and dementia with Mendelian randomization approaches among older adults in the United States.

Background: In observational studies, the association between alcohol consumption and dementia is mixed. Methods: We performed two-sample Mendelian randomization (MR) using summary statistics from genome-wide association studies of weekly alcohol consumption and late-onset Alzheimer's disease and one-sample MR in the Health and Retirement Study (HRS), wave 2012. Inverse variance weighted two-stage regression provided odds ratios of association between alcohol exposure and dementia or cognitively impaired, non-dementia relative to cognitively normal. Results: Alcohol consumption was not associated with late-onset Alzheimer's disease using two-sample MR (OR=1.15, 95% confidence interval (CI):[0.78, 1.72]). In HRS, doubling weekly alcohol consumption was not associated with dementia (African ancestries, n=1,322, OR=1.00, 95% CI [0.45, 2.25]; European ancestries, n=7,160, OR=1.37, 95% CI [0.53, 3.51]) or cognitively impaired, non-dementia (African ancestries, n=1,322, OR=1.17, 95% CI [0.69, 1.98]; European ancestries, n=7,160, OR=0.75, 95% CI [0.47, 1.22]). Conclusion: Alcohol consumption was not associated with cognitively impaired, non-dementia or dementia status.

Interactions between the apolipoprotein E4 gene and modifiable risk factors for cognitive impairment: a nationally representative panel study.

BACKGROUND: Few studies using rigorous clinical diagnosis have considered whether associations with cognitive decline are potentiated by interactions between genetic and modifiable risk factors. Given the increasing burden of cognitive impairment (CI) and dementia, we assessed whether Apolipoprotein E ε4 (APOE4) genotype status modifies the association between incident CI and key modifiable risk factors . METHODS: Older adults (70+) in the US were included. APOE4 status was genotyped. Risk factors for CI were self-reported. Cognitive status (normal, CI, or dementia) was assigned by clinical consensus panel. In eight separate Cox proportional hazard models, we assessed for interactions between APOE4 status and other CI risk factors. RESULT: The analytical sample included 181 participants (mean age 77.7 years; 45.9% male). APOE4 was independently associated with a greater hazard of CI in each model (Hazard Ratios [HR] between 1.81-2.66, p < 0.05) except the model evaluating educational attainment (HR 1.65, p = 0.40). The joint effects of APOE4 and high school education or less (HR 2.25, 95% CI: 1.40-3.60, p < 0.001), hypertension (HR 2.46, 95% CI: 1.28-4.73, p = 0.007), elevated depressive symptoms (HR 5.09, 95% CI: 2.59-10.02, p < 0.001), hearing loss (HR 3.44, 95% CI: 1.87-6.33, p < 0.0001), vision impairment (HR 5.14, 95% CI: 2.31-11.43, p < 0.001), smoking (HR 2.35, 95% CI: 1.24-4.47, p = 0.009), or obesity (HR 3.80, 95% CI: 2.11-6.85, p < 0.001) were associated with the hazard of incident CIND (compared to no genetic or modifiable risk factor) in separate models. The joint effect of Apolipoprotein ε4 and type 2 diabetes was not associated with CIND (HR 1.58, 95% CI: 0.67-2.48, p = 0.44). DISCUSSION: The combination of APOE4 and selected modifiable risk factors conveys a stronger association with incident CI than either type of risk factor alone.

The Safety and Effectiveness of Early, Progressive Weight Bearing and Implant Choice after Traumatic Lower Extremity Fracture: A Systematic Review.

The goal of this systematic review was to examine existing evidence on the effectiveness of early, progressive weight bearing on patients after traumatic lower extremity fractures and relate these findings to device/implant choice. A search of the literature in PubMed/Medline, Embase, Web of Science, and the Cochrane Library was performed through January 2022. Randomized controlled trials and non-randomized, prospective longitudinal investigations of early, progressive weight bearing in skeletally mature adults after traumatic lower extremity fracture were included in the search, with 21 publications included in the final analysis. A summary of the loading progressions used in each study, along with the primary and additional outcomes, is provided. The progression of weight bearing was variable, dependent on fracture location and hardware fixation; however, overall outcomes were good with few complications. Most studies scored "high" on the bias tools and were predominately performed without physical therapist investigators. Few studies have investigated early, progressive weight bearing in patients after traumatic lower extremity fractures. The available clinical evidence provides variable progression guidelines. Relatively few complications and improved patient function were observed in this review. More research is needed from a rehabilitation perspective to obtain graded progression recommendations, informed by basic science concepts and tissue loading principles.

The Interplay of Epigenetic, Genetic, and Traditional Risk Factors on Blood Pressure: Findings from the Health and Retirement Study.

The epigenome likely interacts with traditional and genetic risk factors to influence blood pressure. We evaluated whether 13 previously reported DNA methylation sites (CpGs) are associated with systolic (SBP) or diastolic (DBP) blood pressure, both individually and aggregated into methylation risk scores (MRS), in 3070 participants (including 437 African ancestry (AA) and 2021 European ancestry (EA), mean age = 70.5 years) from the Health and Retirement Study. Nine CpGs were at least nominally associated with SBP and/or DBP after adjusting for traditional hypertension risk factors (p < 0.05). MRSSBP was positively associated with SBP in the full sample (ß = 1.7 mmHg per 1 standard deviation in MRSSBP; p = 2.7 × 10-5) and in EA (ß = 1.6; p = 0.001), and MRSDBP with DBP in the full sample (ß = 1.1; p = 1.8 × 10-6), EA (ß = 1.1; p = 7.2 × 10-5), and AA (ß = 1.4; p = 0.03). The MRS and BP-genetic risk scores were independently associated with blood pressure in EA. The effects of both MRSs were weaker with increased age (pinteraction < 0.01), and the effect of MRSDBP was higher among individuals with at least some college education (pinteraction = 0.02). In AA, increasing MRSSBP was associated with higher SBP in females only (pinteraction = 0.01). Our work shows that MRS is a potential biomarker of blood pressure that may be modified by traditional hypertension risk factors.

Polymethylation scores for prenatal maternal smoke exposure persist until age 15 and are detected in saliva in the Fragile Families and Child Wellbeing cohort.

Prenatal maternal smoking is associated with low birthweight, neurological disorders, and asthma in exposed children. DNA methylation signatures can function as biomarkers of prenatal smoke exposure. However, the robustness of DNA methylation signatures across child ages, genetic ancestry groups, or tissues is not clear. Using coefficients from a meta-analysis of prenatal smoke exposure and DNA methylation in newborn cord blood, we created polymethylation scores of saliva DNA methylation from children at ages 9 and 15 in the Fragile Families and Child Wellbeing study. In the full sample at age 9 (n = 753), prenatal smoke exposure was associated with a 0.51 (95%CI: 0.35, 0.66) standard deviation higher polymethylation score. The direction and magnitude of the association was consistent in European and African genetic ancestry samples. In the full sample at age 15 (n = 747), prenatal smoke exposure was associated with a 0.48 (95%CI: 0.32, 0.63) standard deviation higher polymethylation score, and the association was attenuated among the European and Admixed-Latin genetic ancestry samples. The polymethylation score classified prenatal smoke exposure accurately (AUC age 9 = 0.77, age 15 = 0.76). Including the polymethylation score increased the AUC of base model covariates by 5 (95% CI: (2.1, 7.2)) percentage points, while including a single candidate site in the AHRR gene did not (P-value = 0.19). Polymethylation scores for prenatal smoking were portable across genetic ancestries and more accurate than an individual DNA methylation site. Polymethylation scores from saliva samples could serve as robust and practical biomarkers of prenatal smoke exposure.

Saliva cell type DNA methylation reference panel for epidemiological studies in children.

Saliva is a widely used biological sample, especially in pediatric research, containing a heterogenous mixture of immune and epithelial cells. Associations of exposure or disease with saliva DNA methylation can be influenced by cell-type proportions. Here, we developed a saliva cell-type DNA methylation reference panel to estimate interindividual cell-type heterogeneity in whole saliva studies. Saliva was collected from 22 children (7-16 years) and sorted into immune and epithelial cells, using size exclusion filtration and magnetic bead sorting. DNA methylation was measured using the Illumina MethylationEPIC BeadChip. We assessed cell-type differences in DNA methylation profiles and tested for enriched biological pathways. Immune and epithelial cells differed at 181,577 (22.8%) DNA methylation sites (t-test p < 6.28 × 10-8). Immune cell hypomethylated sites are mapped to genes enriched for immune pathways (p < 3.2 × 10-5). Epithelial cell hypomethylated sites were enriched for cornification (p = 5.2 × 10-4), a key process for hard palette formation. Saliva immune and epithelial cells have distinct DNA methylation profiles which can drive whole-saliva DNA methylation measures. A primary saliva DNA methylation reference panel, easily implemented with an R package, will allow estimates of cell proportions from whole saliva samples and improve epigenetic epidemiology studies by accounting for measurement heterogeneity by cell-type proportions.