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Background: Associations between epigenetic aging with cognitive aging and neuropsychiatric measures are not well-understood. Objective: 1) To assess cross-sectional correlations between second-generation DNA methylation (DNAm)-based clocks of healthspan and lifespan (i.e., GrimAge, PhenoAge, and DNAm-based estimator of telomere length [DNAmTL]) and cognitive and neuropsychiatric measures; 2) To examine longitudinal associations between change in DNAm markers and change in cognition over 2 years. Methods: Participants were members of VITAL-DEP (VITamin D and OmegA-3 TriaL- Depression Endpoint Prevention) study. From previously ascertained cognitive groups (i.e., cognitively normal and mild cognitive impairment), we randomly selected 45 participants, aged≥60 years, who completed in-person neuropsychiatric assessments at baseline and 2 years. The primary outcome was global cognitive score (averaging z-scores of 9 tests). Neuropsychiatric Inventory severity scores were mapped from neuropsychiatric symptoms (NPS) from psychological scales and structured diagnostic interviews. DNAm was assayed using Illumina MethylationEPIC 850K BeadChip at baseline and 2 years. We calculated baseline partial Spearman\hfilneg correlations between DNAm markers and cognitive and NPS measures. We constructed multivariable linear regression models to examine longitudinal relations between DNAm markers and cognition. Results: At baseline, we observed a suggestive negative correlation between GrimAge clock markers and global cognition but no signal between DNAm markers and NPS measures. Over 2 years: each 1-year increase in DNAmGrimAge was significantly associated with faster declines in global cognition; each 100-base pair increase in DNAmTL was significantly associated with better global cognition. Conclusion: We found preliminary evidence of cross-sectional and longitudinal associations between DNAm markers and global cognition.

The Psychiatric Consultation Service at Massachusetts General Hospital sees medical and surgical inpatients with comorbid psychiatric symptoms and conditions. During their twice-weekly rounds, Dr Stern and other members of the Consultation Service discuss diagnosis and management of hospitalized patients with complex medical or surgical problems who also demonstrate psychiatric symptoms or conditions. These discussions have given rise to rounds reports that will prove useful for clinicians practicing at the interface of medicine and psychiatry.

The Psychiatric Consultation Service at Massachusetts General Hospital sees medical and surgical inpatients with comorbid psychiatric symptoms and conditions. During their twice-weekly rounds, Dr Stern and other members of the Consultation Service discuss diagnosis and management of hospitalized patients with complex medical or surgical problems who also demonstrate psychiatric symptoms or conditions. These discussions have given rise to rounds reports that will prove useful for clinicians practicing at the interface of medicine and psychiatry.

The Psychiatric Consultation Service at Massachusetts General Hospital sees medical and surgical inpatients with comorbid psychiatric symptoms and conditions. During their twice-weekly rounds, Dr Stern and other members of the Consultation Service discuss diagnosis and management of hospitalized patients with complex medical or surgical problems who also demonstrate psychiatric symptoms or conditions. These discussions have given rise to rounds reports that will prove useful for clinicians practicing at the interface of medicine and psychiatry.

LEARNING OBJECTIVES After participating in this activity, learners should be better able to:• Identify risk factors for late-life depression• Evaluate strategies to prevent late-life depression ABSTRACT: Late-life depression (LLD) is one of the major sources of morbidity and mortality in the world. Because LLD is related to increased public health burden, excess health care costs and utilization, reduced quality of life, and increased mortality, prevention is a priority. Older adults differ from younger adults with respect to key features, such as their chronicity and lifetime burden of depression and their constellation of comorbidities and risk factors. LLD likely arises from a complex interplay of risk factors, including medical, physiologic, psychosocial, behavioral, and environmental factors. Thus, a comprehensive understanding of LLD risk factors is necessary to inform prevention strategies. In this narrative literature review, we address both the risk architecture of LLD and several potential strategies for prevention. Our description of LLD risk factors and prevention approaches is informed by the framework developed by the National Academy of Medicine (formerly, Institute of Medicine), which includes indicated, selective, and universal approaches to prevention.

Objectives To determine associations between geographic region and late-life depression (LLD) severity, item-level symptom burden, and treatment; to evaluate whether racial/ethnic disparities in LLD, previously observed in the overall sample, vary by region. Methods We included 25,502 VITAL (Vitamin D and Omega-3 Trial) participants and administered the Patient Health Questionnaire-8 for depressive symptoms; participants also reported medication and/or counseling care for depression. Multivariable regression analyses were performed. Results Despite overall lower LLD severity and item-level symptom burden in the Midwest vs. Northeast, higher LLD severity and item-level burden were observed among minorities, especially Black and Hispanic adults, compared to non-Hispanic whites in this region. Racial/ethnic disparities in item-level symptoms (e.g., anhedonia, sadness, psychomotor changes) varied by region. There were no significant differences in depression care by region; furthermore, regional variation was not observed in racial disparities in care: e.g., among those with clinician/physician-diagnosed depression, Blacks vs. non-Hispanic whites had >50% lower odds of treatment in all regions. Conclusion LLD varied by geographic region. Furthermore, magnitudes of racial/ethnic disparities in LLD severity and item-level symptom burden, but not depression care, differed by region.

Low vitamin D levels have been associated with cognitive decline; however, few randomized trials have been conducted. In a trial, we evaluated vitamin D3 supplementation on cognitive decline. We included participants aged 60+ years (mean[SD] = 70.9[5.8] years) free of cardiovascular disease and cancer in two substudies in the VITAL 2 × 2 randomized trial of vitamin D3 (2000 IU/day of cholecalciferol) and fish oil supplements: 3424 had cognitive assessments by phone (eight neuropsychologic tests; 2.8 years follow-up) and 794 had in-person assessments (nine tests; 2.0 years follow-up). The primary, pre-specified outcome was decline over two assessments in global composite score (average z-scores of all tests); substudy-specific results were meta-analyzed. The pooled mean difference in annual rate of decline (MD) for vitamin D3 versus placebo was 0.01 (95% CI − 0.01, 0.02; p = 0.39). We observed no interaction with baseline 25-hydroxyvitamin-D levels (p-interaction = 0.84) and a significant interaction with self-reported race (p-interaction = 0.01). Among Black participants (19%), those assigned vitamin D3 versus placebo had better cognitive maintenance (MD = 0.04, 95% CI 0.01, 0.08, similar to that observed for Black participants 1.2 years apart in age). Thus, vitamin D3 (2000 IU/day cholecalciferol) supplementation was not associated with cognitive decline over 2–3 years among community-dwelling older participants but may provide modest cognitive benefits in older Black adults, although these results need confirmation.Trial registration ClinicalTrials.gov; VITAL (NCT01169259), VITAL-DEP (NCT01696435) and VITAL-Cog (NCT01669915); the date the registration for the parent trial (NCT01169259) was submitted to the registry: 7/26/2010 and the date of first patient enrollment in either of the ancillary studies for cognitive function in a subset of eligible VITAL participants: 9/14/2011.

Introduction There is evidence of racial/ethnic disparities in late-life depression (LLD) burden and treatment in the US. Geographic region may be a novel social determinant of this disparity, yet limited evidence exists regarding the interplay of geographic region with racial/ethnic differences in LLD symptoms, severity and treatment. Methods We conducted a cross-sectional study among participants of the VITAL-DEP (VITamin D and OmegA-3 TriaL-Depression Endpoint Prevention) study, which is ancillary to the VITAL trial of heart disease and cancer prevention. Participants are 25,871 men and women, aged 50+ and 55+ years, with extensive social, demographic, lifestyle, behavioral and health variables ascertained at baseline. Racial/ethnic groups included Non-Hispanic White, Black, Hispanic, Asian and Pacific Islander, and other groups (including Native American/Alaskan Native and other, multiple or unspecified race/ethnicity). Depressive symptoms were assessed using the Patient Health Questionnaire-8 (PHQ-8); participants reported clinician/physician diagnosis of depression and medication and/or counseling treatment for depression. Associations of geographic region with likelihood of LLD were examined using multivariable zero-inflated negative binomial regression; regression models were used to evaluate further the patterns of racial/ethnic disparities in LLD outcomes within geographic regions. Results We included 25,502 participants with depression data: 7066 from Northeast, 7133 from Southeast, 5471 from Midwest, and 5832 from Southwest geographical regions. The mean age was 67.1 years; 12888 [50.5%] were females. There were 17828 [69.9%] non-Hispanic White, 5004 [19.6%] Black, 1001 [3.9%] Hispanic, 377 [1.5%] Asian, and 1292 [5.1%] other race/ethnicity-reporting participants. In the full sample, only Midwest region was significantly associated with likelihood of LLD, compared to Northeast (reference) region (multivariable-adjusted incidence rate ratio (IRR), 95% confidence interval (CI): 0.85, 0.79-0.90); p Conclusions In this large cross-sectional study of diverse older adults in the US, geographic region was significantly associated with late-life depression, and significant variations in the extent of racial/ethnic disparities in depression severity, symptoms and treatment were observed by geographic region. Future longitudinal investigations may clarify the role of geographic region as a novel social determinant of racial/ethnic disparities in LLD. This research was funded by: VITAL-DEP is supported by R01 MH091448

Introduction IMPORTANCE: Knowledge gaps persist regarding racial and ethnic variation in late-life depression (LLD), including differences in specific depressive symptoms and disparities in care. Identifying disparities in symptom presentation and treatment of LLD is important, as doing so may guide approaches to reduce morbidity and mortality from LLD. Thus, we aimed to evaluate racial/ethnic differences in depression severity, item-level depressive symptom burden, and depression care. Methods DESIGN, SETTING, PARTICIPANTS: In this community based large cross-sectional study, we included 25,503 participants (mean age=67.1 years) in the late-life depression prevention ancillary study (VITAL-DEP) to the VITamin D and OmegA-3 TriaL, a randomized trial of cancer and cardiovascular disease prevention among 25,871 adults. EXPOSURE: Racial and ethnic group (Non-Hispanic White, Black, Hispanic, Asian and Others/unspecified). MAIN OUTCOMES AND MEASURES: Depressive symptoms were assessed using the Patient Health Questionnaire-8 (PHQ-8); participants reported diagnosis and medication and/or counseling for depression. Differences across racial/ethnic groups were evaluated using: multivariable zero-inflated negative binomial regression to compare PHQ-8 scores; multivariable logistic regression to estimate odds of item-level symptom burden and odds of depression treatment among those with diagnosed depression. Results There were 25,503 participants with adequate depression data (mean [standard deviation] age=67.1 [7.1] years), including: 12888 [50.5%] female, 17828 [69.9%] non-Hispanic White, 5004 [19.6%] Black, 1001 [3.9%] Hispanic, 377 [1.5%] Asian and 1293 [5.1%] Other-reporting/race-unspecified participants. After adjustment for sociodemographic, lifestyle and health confounders, compared to non-Hispanic Whites: Black participants had a 8% higher severity level of PHQ-8 scores (IRR (incidence rate ratio)=1.08, 95% CI: 1.02-1.15; p=0.01); Hispanic participants had 26% higher severity of PHQ-8 (IRR=1.26, 95% CI: 1.12-1.42; p Conclusions In this large cross-sectional study, we observed significant racial and ethnic differences in late-life depression severity, item-level symptom burden, and depression care, after adjustment for numerous confounders. Findings suggest a need for further examination of novel patient- and provider-level factors underlying these associations. This research was funded by: VITAL-DEP is supported by R01 MH091448 from NIMH.

Few large, randomized trials have evaluated marine n-3 supplements and cognition in healthy older adults.: Healthy community-dwelling participants aged 60+ years (mean [standard deviation] = 70.9 [5.8] years) in VITAL (randomized trial of n-3 fats [1 g/day, including 840 mg of eicosapentaenoic acid + docosahexaenoic acid] and vitamin D) were included: 3424 whose cognition was assessed by phone (VITAL-Cog; eight neuropsychological tests; 2.8 years) and 794 evaluated in person (CTSC-Cog; nine tests; 2.0 years). The primary outcome was a global score (average of test z-scores) of change over two assessments. We used multivariable-adjusted linear mixed models; substudy-specific results were meta-analyzed.: We observed no significant effect of n-3 supplementation: the mean difference in annual rate of cognitive change for the n-3 versus placebo group was -0.01 standard units (95% confidence interval [CI]: -0.02, 0.003) in VITAL-Cog and -0.002 (95% CI: -0.04, 0.03) in CTSC-Cog; the pooled difference was -0.01 (95% CI: -0.02, 0.003;: Marine n-3 supplementation (1 g/day) did not confer cognitive benefits over 2 to 3 years in community-dwelling older adults.

The Psychiatric Consultation Service at Massachusetts General Hospital sees medical and surgical inpatients with comorbid psychiatric symptoms and conditions. During their twice-weekly rounds, Dr Stern and other members of the Consultation Service discuss diagnosis and management of hospitalized patients with complex medical or surgical problems who also demonstrate psychiatric symptoms or conditions. These discussions have given rise to rounds reports that will prove useful for clinicians practicing at the interface of medicine and psychiatry.

IMPORTANCE: Low levels of 25-hydroxyvitamin D have been associated with higher risk for depression later in life, but there have been few long-term, high-dose large-scale trials. OBJECTIVE: To test the effects of vitamin D(3) supplementation on late-life depression risk and mood scores. DESIGN, SETTING, AND PARTICIPANTS: There were 18 353 men and women aged 50 years or older in the VITAL-DEP (Vitamin D and Omega-3 Trial-Depression Endpoint Prevention) ancillary study to VITAL, a randomized clinical trial of cardiovascular disease and cancer prevention among 25 871 adults in the US. There were 16 657 at risk for incident depression (ie, no depression history) and 1696 at risk for recurrent depression (ie, depression history but no treatment for depression within the past 2 years). Randomization occurred from November 2011 through March 2014; randomized treatment ended on December 31, 2017, and this was the final date of follow-up. INTERVENTION: Randomized assignment in a 2 × 2 factorial design to vitamin D(3) (2000 IU/d of cholecalciferol) and fish oil or placebo; 9181 were randomized to vitamin D(3) and 9172 were randomized to matching placebo. MAIN OUTCOMES AND MEASURES: The primary outcomes were the risk of depression or clinically relevant depressive symptoms (total of incident and recurrent cases) and the mean difference in mood scores (8-item Patient Health Questionnaire depression scale [PHQ-8]; score range, 0 points [least symptoms] to 24 points [most symptoms]; the minimal clinically important difference for change in scores was 0.5 points). RESULTS: Among the 18 353 randomized participants (mean age, 67.5 [SD, 7.1] years; 49.2% women), the median treatment duration was 5.3 years and 90.5% completed the trial (93.5% among those alive at the end of the trial). Risk of depression or clinically relevant depressive symptoms was not significantly different between the vitamin D(3) group (609 depression or clinically relevant depressive symptom events; 12.9/1000 person-years) and the placebo group (625 depression or clinically relevant depressive symptom events; 13.3/1000 person-years) (hazard ratio, 0.97 [95% CI, 0.87 to 1.09]; P = .62); there were no significant differences between groups in depression incidence or recurrence. No significant differences were observed between treatment groups for change in mood scores over time; mean change in PHQ-8 score was not significantly different from zero (mean difference for change in mood scores, 0.01 points [95% CI, −0.04 to 0.05 points]). CONCLUSIONS AND RELEVANCE: Among adults aged 50 years or older without clinically relevant depressive symptoms at baseline, treatment with vitamin D(3) compared with placebo did not result in a statistically significant difference in the incidence and recurrence of depression or clinically relevant depressive symptoms or for change in mood scores over a median follow-up of 5.3 years. These findings do not support the use of vitamin D(3) in adults to prevent depression. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT01169259 and NCT01696435

Background Adherence to healthy lifestyles/behaviours promotes healthy ageing. However, little is known about whether age, sex and/or race/ethnicity moderate associations of lifestyle/behavioural factors with relative telomere length (RTL), a potential biomarker of ageing. Methods We included 749 midlife to older non-Hispanic White (n = 254), Black (n = 248) and Hispanic (n = 247) US participants [mean (standard deviation) age = 69.3 (7.2) years; women: 50.5%]. We extracted genomic DNA from peripheral leucocytes. RTL was assayed using real-time quantitative polymerase chain reaction. Multivariable regression was used to examine associations between lifestyle/behavioural exposures (i.e. physical activity, alcohol consumption, smoking and depression) with RTL. Results Increasing chronological age was associated with shorter RTL (P Conclusion We observed novel variations by sex and race/ethnicity in associations between lifestyle/behavioural factors and RTL. Further work is needed to replicate these findings and to address potential public health implications for modifying strategies by sex or across racial/ethnic groups to optimise lifestyles/behaviours for healthy ageing.

Mitochondrial DNA copy number (mtDNAcn) is a putative biomarker of oxidative stress and biological aging. Modifiable factors, including physical activity (PA), avoidance of heavy alcohol use and smoking, and maintaining good mental health, may reduce oxidative stress and promote healthy aging. Yet, limited data exist regarding how these factors are associated with mtDNAcn or whether age, sex or race/ethnicity moderate associations. In this cross-sectional study, we selected 391 adults (183 non-Hispanic White, 110 Black and 98 Hispanic; mean = 67 years) from the VITAL-DEP (VITamin D and OmegA-3 TriaL-Depression Endpoint Prevention) ancillary to the VITAL trial. We estimated associations between lifestyle and behavioral factors (PA, alcohol consumption, cigarette smoking and depression) and log-transformed mtDNAcn using multivariable linear regression models. MtDNAcn was not correlated with chronological age; women had ~17% higher mtDNAcn compared to men. There were no significant associations between PA measures (frequency, amount or intensity) or alcohol consumption with mtDNAcn. Cigarette smoking (per 5 pack-years) was significantly associated with mtDNAcn (percent difference = -2.9% (95% confidence interval (CI) = -5.4%, -0.4%)); a large contrast was observed among heavy vs. non-smokers (≥30 vs. 0 pack-years): percent difference = -28.5% (95% CI = -44.2%, -8.3%). The estimate of mtDNAcn was suggestively different for past vs. no depression history (percent difference = -15.1% 95% CI = -30.8%, 4.1%), but this difference was not statistically significant. The association between smoking and log-mtDNAcn varied by sex and race/ethnicity; it was stronger in men and Black participants. While chance findings cannot be excluded, results from this study support associations of smoking, but not chronological age, with mtDNAcn and suggest nuanced considerations of mtDNAcn as indicative of varying oxidative stress states vs. biological aging itself.

Thyroid dysfunction during tyrosine kinase inhibitor (TKI) cancer treatment is common, but predisposing risk factors have not been determined. Recommendations for monitoring patients treated with one or multiple TKI and in conjunction with other relevant cancer therapies could be improved. The study objective was to assess the risk factors for new thyroid dysfunction in TKI-treated previously euthyroid cancer patients.A retrospective cohort study of patients with advanced nonthyroidal cancer treated with TKI from 2000 to 2017, having available thyroid function tests showing initial euthyroid status, excluding patients with preexisting thyroid disease or lack of follow-up thyroid function tests. During TKI treatment, patients were classified as euthyroid (thyrotropin [TSH] normal), subclinical hypothyroidism (TSH 5-10 mIU/L, or higher TSH if free thyroxine normal), or overt hypothyroidism (TSH10 mIU/L, low free thyroxine, or requiring thyroid hormone replacement). The timing of thyroid dysfunction and TKI used were assessed. Risk factors for incident hypothyroidism were evaluated using multivariate models.In 538 adult patients included, subclinical hypothyroidism occurred in 71 (13.2%) and overt hypothyroidism occurred in 144 (26.8%) patients with TKI therapy, following a median cumulative TKI exposure of 196 days (interquartile range [IQR] 63.5-518.5 days). The odds of hypothyroidism were greatest during the first six months on a TKI. Median exposure time on the TKI concurrent with thyroid dysfunction in patients treated with only one TKI was 85 days (IQR 38-293.5 days) and was similar to the 74 days (IQR 38-133.3 days) in patients treated previously with other TKI (p = 0.41). Patients who developed hypothyroidism compared to those who remained euthyroid had greater odds of being female (odds ratio = 1.99 [confidence interval 1.35-2.93], p 0.01), but greater cumulative TKI exposure and greater number of TKI received were not associated with thyroid dysfunction.Thyroid dysfunction occurred in 40% of euthyroid patients. Monitoring thyroid function in TKI-treated patients is recommended, with particular attention to female patients and within the first six months of exposure to a new TKI.

In older patients, thyroid nodules are frequently detected and referred for evaluation, though usually prove to be benign disease or low-risk cancer. Therefore, management should be guided not solely by malignancy risk, but also by the relative risks of any intervention. Unfortunately, few such data are available for patients ≥70 years old.All consecutive patients ≥70 years old assessed by ultrasound (US) and fine-needle aspiration (FNA) between 1995 and 2015 were analyzed. Clinical, US, and histologic data, including patient comorbidities and outcomes, were obtained. Imaging and cytology results from initial evaluation were reviewed to detect significant-risk thyroid cancer (SRTC), which was defined as anaplastic, medullary, or poorly differentiated carcinoma, or the presence of distant metastases. Overall survival analyses were then performed to assist with risk-to-benefit assessment.A total of 1129 patients ≥70 years old with 2527 nodules ≥1 cm were evaluated. FNA was safe in all, and cytology proved benign in 67.3% of patients. However, FNA led to surgery in 208 patients, of whom 93 (44.7%) had benign histopathology. Among all patients who underwent FNA, only 17 (1.5%) SRTC were identified, all of which were preoperatively identifiable by imaging and/or cytology. These SRTC were responsible for all (n = 10; 0.9%) thyroid cancer deaths. Among all other patients (n = 1112), 160 deaths (14.4%) were confirmed during a median follow-up of four years. None of these were thyroid cancer related. Survival analysis for these 1112 patients demonstrated that a separate non-thyroidal malignancy or coronary artery disease at the time of nodule evaluation was associated with increased mortality compared to those without these diagnoses (hazard ratio = 2.32 [confidence interval 1.66-3.26]; p 0.01), confirming these are important variables to identify prior to thyroid nodule evaluation.For patients ≥70 years old, US and FNA are safe and prove helpful in identifying SRTC and benign cytology. However, the surgical management of patients ≥70 years old presenting without high-risk findings should be tempered, especially when comorbid illness is identified.

Diagnostic hemithyroidectomy (HT) is the most widely recommended surgical procedure for a nodule with indeterminate cytology; however, additional details may make initial total thyroidectomy (TT) preferable. We sought to identify patient-specific factors (PSFs) associated with initial TT in patients with indeterminate thyroid nodules. Retrospective analysis of all patients with a thyroid nodule ≥ 1 cm and initial cytology of atypia of undetermined significance or suspicious for follicular neoplasm between 2012 and 2015 who underwent thyroidectomy. Medical records were reviewed for patient demographics, neck symptoms, nodule size, cytology, molecular test results, final histopathology, and additional PSFs influencing surgical management. Variables were analyzed to determine associations with the use of initial TT. Logistic regression analyses were performed to identify independent associations. Of 325 included patients, 182/325 (56.0%) had HT and 143/325 (44.0%) had TT. While patient age and sex, nodule size, and cytology result were not associated with initial treatment, five PSFs were associated with initial TT (p

Introduction Accelerated biological aging is related to worse brain aging. However, the interface of Alzheimer's Disease (AD) and the biology of aging is little understood. The study of epigenetics and epigenetic aging may yield advances in prevention and treatment of AD by identifying new therapeutic targets or approaches. Further, signals from epigenetic measures may provide novel mechanistic links between neuropsychiatric symptoms (NPS) and cognitive outcomes in aging; NPS are highly prevalent in Alzheimer's Disease and related dementia (ADRD) and even appear in pre-clinical and early stages. Methods We included 45 adults aged 60+ years who are participants in a depression prevention ancillary study (VITAL-DEP) to the VITamin D and OmegA-3 TriaL, a randomized trial of fish oil and vitamin D supplements. We identified the presence of NPS using established behavioral measures. Neuropsychiatric Inventory (NPI) severity scores were mapped from dozens of item-level NPS variables extracted from mood and anxiety questionnaires and structured psychiatric diagnostic interviews in the VITAL-DEP protocol. We defined 3 groups based on cognitive status: normal cognition with or without NPS (n=20), and mild cognitive impairment (MCI) with or without NPS (n=25). Genomic DNA was extracted from leukocytes, and DNA methylation was assayed using Illumina Infinium MethylationEPIC BeadArray technology (Methyl850K chip) at baseline and year-2 follow-up. Epigenetic aging metrics [DNA methylation age (DNAmAge), AgeAccel, DNAmGrimAge, DNAmPhenoAge] were computed using the DNA epigenetic clock - Horvath method. Results The mean age of participants was 69.8 (range=60.3-83.4) years; percentages of who were females=48.9% and with post-graduate education=62.2%. In preliminary analysis , epigenetic measures were significantly correlated with chronological age (Spearman correlation (rho): for DNAmAge=0.51, p Conclusions Our preliminary results suggest that accelerated biological aging may be related to cognitive and neuropsychiatric phenotypes.

IMPORTANCE: Marine omega-3 fatty acid (omega-3) supplements have been used to treat depression but their ability to prevent depression in the general adult population is unknown. OBJECTIVE: To test effects of omega-3 supplementation on late-life depression risk and mood scores. DESIGN, SETTING, AND PARTICIPANTS: A total of 18 353 adults participated in the VITAL-DEP (Vitamin D and Omega-3 Trial-Depression Endpoint Prevention) ancillary study to VITAL, a randomized trial of cardiovascular disease and cancer prevention among 25 871 US adults. There were 16 657 at risk of incident depression (no previous depression) and 1696 at risk of recurrent depression (previous depression, but not for the past 2 years). Randomization occurred from November 2011 through March 2014; randomized treatment ended on December 31, 2017. INTERVENTIONS: Randomized 2 × 2 factorial assignment to vitamin D(3) (2000 IU/d), marine omega-3 fatty acids (1 g/d of fish oil, including 465 mg of eicosapentaenoic acid and 375 mg of docosahexaenoic acid) or placebo; 9171 were randomized to omega-3 and 9182 were randomized to matching placebo. MAIN OUTCOMES AND MEASURES: Prespecified coprimary outcomes were risk of depression or clinically relevant depressive symptoms (total of incident + recurrent cases); mean difference in mood score (8-item Patient Health Questionnaire [PHQ-8] depression scale). RESULTS: Among 18 353 participants who were randomized (mean age, 67.5 [SD, 7.1] years; 49.2% women), 90.3% completed the trial (93.5% among those alive at the end of the trial); the median treatment duration was 5.3 years. The test for interaction between the omega-3 and the vitamin D agents was not significant (P for interaction = .14). Depression risk was significantly higher comparing omega-3 (651 events, 13.9 per 1000 person-years) with placebo (583 events, 12.3 per 1000 person-years; hazard ratio [HR], 1.13; 95% CI, 1.01-1.26; P = .03). No significant differences were observed comparing omega-3 with placebo groups in longitudinal mood scores: the mean difference in change in PHQ-8 score was 0.03 points (95% CI, −0.01 to 0.07; P = .19). Regarding serious and common adverse events, the respective prevalence values in omega-3 vs placebo groups were major cardiovascular events (2.7% vs 2.9%), all-cause mortality (3.3% vs 3.1%), suicide (0.02% vs 0.01%), gastrointestinal bleeding (2.6% vs 2.7%), easy bruising (24.8% vs 25.1%), and stomach upset or pain (35.2% vs 35.1%). CONCLUSIONS AND RELEVANCE: Among adults aged 50 years or older without clinically relevant depressive symptoms at baseline, treatment with omega-3 supplements compared with placebo yielded mixed results, with a small but statistically significant increase in risk of depression or clinically relevant depressive symptoms but no difference in mood scores, over a median follow-up of 5.3 years. These findings do not support the use of omega-3 supplements in adults to prevent depression. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT01696435 and NCT01169259

Thyroid nodule growth was once considered concerning for malignancy, but data showing that benign nodules grow questioned the use of this paradigm. To date, however, no studies have adequately evaluated whether growth rates differ in malignant vs. benign nodules.To sonographically evaluate growth rates in benign and malignant thyroid nodules ≥1 cm.Prospective, cohort study of patients with tissue diagnosis of benign or malignant disease, with repeated ultrasound evaluation six or more months apart.Growth rate in largest dimension of malignant compared with benign thyroid nodules. Regression models were used to evaluate predictors of growth.Malignant nodules (126) met inclusion criteria (≥6-month nonoperative followup) and were compared with 1363 benign nodules. Malignant nodules were not found to be uniquely selected or prospectively observed solely for low-risk phenotype. Median ultrasound intervals were similar (21.8 months for benign nodules; 20.9 months for malignant nodules). Malignant nodules were more likely to grow2 mm/y compared with benign nodules [relative risk (RR) = 2.5, 95% confidence interval (CI), 1.6 to 3.1; P0.001], which remained true after adjustment for clinical factors. The RR of a nodule being malignant increased with faster growth rates. Malignant nodules growing2 mm/y had greater odds of being more aggressive cancers [intermediate risk: odds ratio (OR) = 2.99; 95% CI, 1.20 to 7.47; P = 0.03; higher risk: OR = 8.69; 95% CI, 1.78 to 42.34; P = 0.02].Malignant nodules, especially higher-risk phenotypes, grow faster than benign nodules. As growth2 mm/y predicts malignant compared with benign disease, this clinical parameter can contribute to the assessment of thyroid cancer risk.

This chapter introduces the therapeutic approaches and major clinical themes in the treatment of late-life anxiety. Late-life anxiety disorders are prevalent, disabling, and often undertreated. Furthermore, when treatment is sought, most older adults are not offered empirically supported care, making effective treatment less likely. However, numerous modalities for effective treatment exist, including pharmacologic and non-pharmacologic approaches. Many older adults respond well to monotherapy strategies, while others benefit from augmented or combined approaches to address the needs most relevant to older adults. In this chapter, we review the evidence regarding appropriate psychopharmacologic and psychotherapeutic interventions for treating late-life anxiety disorders. We also address themes common to older adults, including cognitive impairment, age-related socioemotional changes, medical comorbidities, and treatment underutilization, and provide the reader with strategies for managing these complex issues in late-life anxiety.

INTRODUCTION AND OBJECTIVES:The need to differentiate patients at risk for developing aggressive prostate cancer (CaP) from those at risk for less aggressive disease has led to efforts to identify ...

Relations of DNA methylation markers to other biological aging markers and to psychosocial, behavioral, and health measures remain unclear. The sample included 23 participants (n = 11 cases with psychiatric diagnoses and n = 12 controls without current or lifetime psychiatric disorder), balanced by age and sex. Genomic DNA was extracted from blood samples; the following were performed: genome-wide DNA methylation assay using Illumina 850k methylationEPIC; PCR assays for relative telomere length (RTL) and mitochondrial DNA copy number (mtCN). Exposures were: case status; depression and anxiety symptoms; psychosocial support; subjective and objective cognition. Outcomes were: DNA methylation age (DNAm age); RTL; mtCN; extrinsic and intrinsic epigenetic age acceleration (EEAA and IEAA). Stronger correlation with chronological age was observed for DNAm age (ρ = 0.86; p ρ = −0.53; p ρ = 0.36; p = 0.10); smoking pack-years (ρ = 0.37; p = 0.08); physical activity (ρ = −0.56; p = 0.01); alcohol intake (ρ = 0.56; p = 0.01). DNAm age was inversely correlated with psychosocial support (ρ = −0.42; p = 0.048) and Modified Mini-Mental State score (ρ = −0.44; p = 0.01). Anxiety, psychosocial support, and objective cognition were significantly related to accelerated aging; depression and subjective cognition were not. In conclusion, DNAm age correlated more strongly with chronological age and key psychosocial, behavioral, and health variables than RTL or mtCN. Signals for associations with epigenetic aging were observed for psychosocial and neurobehavioral variables.

Introduction Depression is a major public health problem among older adults and among the leading causes of global burden of disease and disability. Yet, current understanding of pathophysiology and optimal prevention and/or treatment of late-life depression (LLD) is limited. Advanced approaches involving methods such as metabolomics present an innovative path to identify novel biomarkers of LLD outcomes. Several known biological pathways involving tryptophan and lipid-inflammatory molecules (eicosanoids) are relevant to depression; however, there have been few systematic investigations of metabolomic predictors of long-term trajectories of LLD. Methods This is a convenience sample of ∼7000 Nurses’ Health Study (NHS) participants with known metabolites and who completed depression items every four years from 1992-2016. Between 1989 and 1990, blood samples were collected and stored under standard conditions. In NHS, data on known metabolites were generated by merging the data from multiple case-control studies; however, all metabolites were profiled using liquid chromatography mass spectrometry in the same laboratory. Continuous metabolite values were transformed to probit scores to account for batch effects. We used a previously developed harmonized depressive symptom scale that was indexed to the five-item Mental Health Inventory (MHI-5, range=0-100 points). For cross-sectional analysis, we performed multivariable logistic regression models to evaluate the associations of baseline metabolite levels and likelihood of the moderate or severe depressive symptoms (MHI-5 cut-off=60); for longitudinal analysis, we used latent growth-curve analysis to identify group-based trajectories of depressive symptoms and then related baseline metabolite levels to long-term trajectories. Results The mean age of female nurses at blood draw was 57.0 (range=42.6-70.2) years. There were ∼6300 NHS participants with available data on tryptophan metabolites and ∼1300 NHS participants with available data on eicosanoids. We observed stronger signals for cross-sectional associations of higher circulating levels of tryptophan, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) with lower risk of moderate or severe depressive symptoms, adjusted for age at blood draw, fasting status, case-control status, physical activity, body mass index, diet index, alcohol use, and cigarette smoking [multivariable odds ratio (95% confidence interval): for tryptophan=0.86 (0.80-0.93), p Conclusions In this sample, tryptophan and omega-3 fatty acid metabolites were significantly related to LLD outcomes; these metabolites may play a role in the pathophysiology of LLD. Funding HMS Livingston Fellowship Award

There is evidence of racial/ethnic disparities in late-life depression (LLD) burden and treatment in the US. Geographic region may be a novel social determinant; yet, limited data exist regarding the interplay of geographic region with racial/ethnic differences in LLD severity, item-level symptom burden and treatment. We conducted a cross-sectional study among 25,503 men aged 50+ years and women aged 55+ years in VITAL-DEP (VITamin D and OmegA-3 TriaL-Depression Endpoint Prevention), an ancillary study to the VITAL trial. Racial/ethnic groups included Non-Hispanic White, Black, Hispanic, Asian, and other groups (Native American/Alaskan Native and other/multiple/unspecified-race/ethnicity). We assessed depression status using: the Patient Health Questionnaire-8 (PHQ-8); self-reported clinician/physician diagnosis of depression; medication and/or counseling treatment for depression. In the full sample, Midwest region was significantly associated with 12% lower severity of LLD, compared to Northeast region (rate ratio (RR) (95% confidence interval (CI)): 0.88 (0.83-0.93)). However, racial/ethnic differences in LLD varied by region. For example, in the Midwest, Blacks and Hispanics had significantly higher depression severity compared to non-Hispanic Whites (RR (95% CI): for Black, 1.16 (1.02-1.31); for Hispanic, 2.03 (1.38-3.00)). Furthermore, in multivariable-adjusted logistic regression models, minority vs. non-Hispanic White adults had 2- to 3-fold significantly higher odds of several item-level symptoms across all regions, especially in the Midwest and Southwest. Finally, among those endorsing PHQ-8≥10, Blacks had 60-80% significantly lower odds of depression treatment, compared to non-Hispanic Whites, in all regions. In summary, we observed significant geographic variation in patterns of racial/ethnic disparities in LLD outcomes. This requires further longitudinal investigation.

Importance Knowledge gaps persist regarding racial and ethnic variation in late-life depression, including differences in specific depressive symptoms and disparities in care. Objective To examine racial/ethnic differences in depression severity, symptom burden, and care. Design, Setting, and Participants This cross-sectional study included 25 503 of 25 871 community-dwelling older adults who participated in the Vitamin D and Omega-3 Trial (VITAL), a randomized trial of cancer and cardiovascular disease prevention conducted from November 2011 to December 2017. Data analysis was conducted from June to September 2018. Exposure Racial/ethnic group (ie, non-Hispanic white; black; Hispanic; Asian; and other, multiple, or unspecified race). Main Outcomes and Measures Depressive symptoms, assessed using the Patient Health Questionnaire–8 (PHQ-8); participant-reported diagnosis, medication, and/or counseling for depression. Differences across racial/ethnic groups were evaluated using multivariable zero-inflated negative binomial regression to compare PHQ-8 scores and multivariable logistic regression to estimate odds of item-level symptom burden and odds of depression treatment among those with diagnosed depression. Results There were 25 503 VITAL participants with adequate depression data (mean [SD] age, 67.1 [7.1] years) including 12 888 [50.5%] women, 17 828 [69.9%] non-Hispanic white participants, 5004 [19.6%] black participants, 1001 [3.9%] Hispanic participants, 377 [1.5%] Asian participants, and 1293 participants [5.1%] who were categorized in the other, multiple, or unspecified race group. After adjustment for sociodemographic, lifestyle, and health confounders, black participants had a 10% higher severity level of PHQ-8 scores compared with non-Hispanic white participants (rate ratio [RR], 1.10; 95% CI, 1.04-1.17;P Conclusions and Relevance In this cross-sectional study, significant racial and ethnic differences in late-life depression severity, item-level symptom burden, and depression care were observed after adjustment for numerous confounders. These findings suggest a need for further examination of novel patient-level and clinician-level factors underlying these associations.

Tyrosine kinase inhibitor (TKI)-induced thyroid dysfunction is recognized as a common adverse effect of treatment, but the importance of incident hypothyroidism during TKI therapy remains unclear. This study analyzed the prognostic significance of hypothyroidism during TKI therapy in cancer patients.This was a retrospective cohort study of adult patients with advanced nonthyroidal cancer treated with TKI and available thyroid function testing at three affiliated academic hospitals from 2000 to 2017. Patients with preexisting thyroid disease were excluded. Demographic, clinical, and cancer treatment data were collected. Thyroid status with TKI treatment was determined from thyroid function testing and initiation of thyroid medication, and classified as euthyroid (thyrotropin [TSH] normal), subclinical hypothyroidism (SCH; TSH 5-10 mIU/L, or higher TSH if free thyroxine normal), or overt hypothyroidism (OH; TSH10 mIU/L, low free thyroxine, or requiring replacement). Multivariate models were used to evaluate the effect of TKI-related hypothyroidism on overall survival (OS).Of 1120 initial patients, 538 remained after exclusion criteria. SCH occurred in 72 (13%) and OH in 144 (27%) patients with TKI therapy. Patients with hypothyroidism had significantly longer OS, with median OS in euthyroid patients of 685 days [confidence interval (CI) 523-851] compared to 1005 days [CI 634-1528] in SCH and 1643 days [CI 1215-1991] in OH patients (p 0.0001). After adjustment for age, sex, race/ethnicity, cancer type, cancer stage, ECOG performance status, and checkpoint inhibitor therapy, OH remained significantly associated with OS (hazard ratio = 0.561; p 0.0001), whereas SCH did not (hazard ratio = 0.796; p = 0.165). Analysis of hypothyroid patients (SCH and OH) with TSH5 and10 mIU/L stratified by hormone replacement status showed improved survival associated with hormone replacement.New hypothyroidism in cancer patients treated with TKI is associated with significantly improved OS, should not necessitate TKI dose reduction or discontinuation, and may provide independent prognostic information.

175 Background: The need to differentiate patients at risk for developing aggressive prostate cancer (CaP) from those at risk for less aggressive disease has led to efforts to identify genetic markers to predict disease course and personalize treatment. A study with participants from Johns Hopkins Medical Institutions (JHMI) and Washington University (WU) found single nucleotide polymorphisms (SNPs) in cell cycle genes were associated with risk of aggressive CaP. We sought to replicate those results in the European-American population of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Methods: We focused on variants associated with aggressive CaP in the JHMI and WU cohorts, which included 13 SNPs in 12 genes ( CCNC, CCND3, CCNG1, CCNT2, CDK2, CDK6, MDM2, SKP2, TERF2, WEE1, YWHAB, YWHAH). Variants were genotyped using the Pyrosequencing assay. Patients were classified into high risk (Gleason≥8, pT3b, N+, M+), low risk (Gleason≤7, ≤pT3a, N0, M0) or non-cancer control groups based on clinicopathologic characteristics. Logistic regression analysis was used to compare genotype frequencies of each variant between groups using the dominant model. Results: There were 108 aggressive and 1080 non-aggressive CaP patients, and 1155 controls . CDK6 ( rs8) was associated with increased risk of any CaP (OR 1.2, 95% CI 1.02-1.42; p = 0.032) and high risk disease (OR 1.63, 95% CI 1.09-2.42; p = 0.017) vs. controls. In contrast, the JHMI and WU cohort found CDK6 variants to be protective against aggressive CaP. CCNG1 ( rs11541970) approached significance (p = 0.052) between high risk and control groups, and CCNC conferred a protective effect consistent with the prior study, but did not reach significance (p = 0.101). No associations with any cell cycle gene variants were detected when comparing high and low risk patients. Conclusions: Our study did not replicate the results from the JHMI and WU cohorts. CDK6 predicted an increased risk of developing any CaP and high risk CaP. However, directionality was opposite to the prior study, indicating that this variant is unlikely to be a true predictor of increased risk of or protection from aggressive CaP.