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Purpose: This study examines the differences in suicide, homicide, and all-cause mortality between transgender and cisgender Veterans Health Administration (VHA) patients. Methods: VHA electronic m...

BACKGROUND Compared with non-Veterans, Veterans are at higher risk of experiencing homelessness, which is associated with opioid overdose. OBJECTIVE To understand how homelessness and Veteran status are related to risks of nonfatal and fatal opioid overdose in Massachusetts. DESIGN A cross-sectional study. PARTICIPANTS All residents aged 18 years and older during 2011-2015 in the Massachusetts Department of Public Health's Data Warehouse (Veterans: n=144,263; non-Veterans: n=6,112,340). A total of 40,036 individuals had a record of homelessness, including 1307 Veterans and 38,729 non-Veterans. MAIN MEASURES The main independent variables were homelessness and Veteran status. Outcomes included nonfatal and fatal opioid overdose. RESULTS A higher proportion of Veterans with a record of homelessness were older than 45 years (77% vs. 48%), male (80% vs. 62%), or receiving high-dose opioid therapy (23% vs. 15%) compared with non-Veterans. The rates of nonfatal and fatal opioid overdose in Massachusetts were 85 and 16 per 100,000 residents, respectively. Among individuals with a record of homelessness, these rates increased 31-fold to 2609 and 19-fold to 300 per 100,000 residents. Homelessness and Veteran status were independently associated with higher odds of nonfatal and fatal opioid overdose. There was a significant interaction between homelessness and Veteran status in their effects on risk of fatal overdose. CONCLUSIONS Both homelessness and Veteran status were associated with a higher risk of fatal opioid overdoses. An understanding of health care utilization patterns can help identify treatment access points to improve patient safety among vulnerable individuals both in the Veteran population and among those experiencing homelessness.

Background Among midlife and older women, menopause symptoms and menopausal hormone therapy have been linked to mental health disorders and other comorbidities related to suicide. However, the role of hormone therapy as a prognostic factor of suicide risk is largely unknown. Objectives To examine associations between menopausal hormone therapy, suicide attempts, and suicide among midlife and older women Veterans. Research design In this longitudinal analysis of national Veterans Health Administration data from women Veterans aged 50 years and above, we used Fine-Gray proportional hazards models to examine associations between menopausal hormone therapy (prescribed in 2012-2013) and incident suicide attempts and suicide (index date-2016). Measures Menopausal hormone therapy and psychoactive medications from pharmacy records; suicide attempts and suicide from national suicide data repositories; demographic variables, medical and psychiatric diagnoses, and substance use disorders from electronic medical record data and International Classification Diagnoses-9-CM codes. Results In this national sample of 291,709 women Veterans (mean age 60.47, SD 9.81), 6% were prescribed menopausal hormone therapy at baseline. Over an average of 4.5 years, 2673 had an incident suicide attempt (93%) or death by suicide (7%). Adjusting for age, race, and medical diagnoses, menopausal hormone therapy was associated with increased risk of suicide attempt (hazard ratio 1.41; 95% confidence interval, 1.22-1.64) and over 2-fold increased risk of death by suicide (hazard ratio 2.47; 95% confidence interval, 1.58-3.87). Associations with death by suicide remained significant after accounting for psychiatric comorbidity and psychoactive medications. Conclusions Menopausal hormone therapy may be an important indicator of suicide risk among midlife and older women.

Background Rates of suicide and unintended overdose death are high among midlife and older women, yet there is paucity of data identifying women at greatest risk. Psychoactive medications, commonly prescribed and co-prescribed in this population, may serve as salient indicators of risk for these outcomes. Objective To determine whether long-term psychoactive medications and psychoactive polypharmacy predict risk of suicide and unintended overdose death among midlife and older women Veterans above and beyond other recognized factors. Design Longitudinal cohort study Participants Women Veterans aged ≥ 50 with at least one Veterans Health Administration (VHA) clinical encounter in FY2012–2013. Main Measures Long-term psychoactive medications (opioids, benzodiazepines, sedative-hypnotics, antidepressants, antipsychotics, and antiepileptics, prescribed for ≥ 90/180 days) and psychoactive polypharmacy (overlapping for ≥ 1 day) from VHA pharmacy records; suicide and unintended overdose death through December 31, 2018. Key Results In this national sample of 154,558 midlife and older women Veterans (mean age 63.4, SD 9.3 years), 130 died by suicide and 175 died from unintentional overdose over an average of 5.6 years. In fully adjusted models, long-term opioids (hazard ratio (HR) 2.01, 95% CI 1.21–3.35) and benzodiazepines (HR 2.99, 95% CI 1.82–4.91) were associated with death by suicide; opioids (HR 3.62, 95% CI 2.46–5.34), benzodiazepines (HR 2.77, 95% CI 1.73–4.42), sedative-hypnotics (HR 1.87, 95% CI 1.06–3.29), antidepressants (HR 1.47, 95% CI 1.03–2.12), antipsychotics (HR 1.81, 95% CI 1.02–3.22), and antiepileptics (HR 2.17, 95% CI 1.48–3.19) were associated with unintended overdose death. Women who were co-prescribed ≥ 3 psychoactive medications had over 2-fold increased risk of suicide (HR 2.83, 95% CI 1.65–4.84) and unintended overdose death (HR 2.60, 95% CI 1.72–3.94). Conclusions Long-term psychoactive medications and psychoactive medication polypharmacy were important indicators of risk for death by suicide and death by unintended overdose among midlife and older women Veterans, even after accounting for psychiatric and substance use disorders.

We sought to operationalize and validate data-driven approaches for identifying transgender individuals in the Veterans Health Administration (VHA) of the US Department of Veterans Affairs (VA) through a retrospective analysis using VA administrative data from 2006–2018. Besides diagnoses of gender identity disorder (GID), a combination of non-GID data elements was used to identify potentially transgender veterans, including 1) an International Classification of Diseases (Ninth or Tenth Revision) code of endocrine disorder, unspecified or not otherwise specified; 2) receipt of sex hormones not associated with the sex documented in the veteran’s records (gender-affirming hormone therapy); and 3) a change in the veteran’s administratively recorded sex. Both GID and non-GID data elements were applied to a sample of 13,233,529 veterans utilizing the VHA of the VA between January 2006 and December 2018. We identified 10,769 potentially transgender veterans. Based on a high positive predictive value for GID-coded veterans (83%, 95% confidence interval: 77, 89) versus non–GID-coded veterans (2%, 95% confidence interval: 1, 11) from chart review validation, the final analytical sample comprised only veterans with a GID diagnosis code (n = 9,608). In the absence of self-identified gender identity, findings suggest that relying entirely on GID diagnosis codes is the most reliable approach for identifying transgender individuals in the VHA of the VA.

Background Large administrative databases often do not capture gender identity data, limiting researchers' ability to identify transgender people and complicating the study of this population. Objective The objective of this study was to develop methods for identifying transgender people in a large, national dataset for insured adults. Research design This was a retrospective analysis of administrative claims data. After using gender identity disorder (GID) diagnoses codes, the current method for identifying transgender people in administrative data, we used the following 2 strategies to improve the accuracy of identifying transgender people that involved: (1) Endocrine Disorder Not Otherwise Specified (Endo NOS) codes and a transgender-related procedure code; or (2) Receipt of sex hormones not associated with the sex recorded in the patient's chart (sex-discordant hormone therapy) and an Endo NOS code or transgender-related procedure code. Subjects Seventy-four million adults 18 years and above enrolled at some point in commercial or Medicare Advantage plans from 2006 through 2017. Results We identified 27,227 unique transgender people overall; 18,785 (69%) were identified using GID codes alone. Using Endo NOS with a transgender-related procedure code, and sex-discordant hormone therapy with either Endo NOS or transgender-related procedure code, we added 4391 (16%) and 4051 (15%) transgender people, respectively. Of the 27,227 transgender people in our cohort, 8694 (32%) were transmasculine, 3959 (15%) were transfeminine, and 14,574 (54%) could not be classified. Conclusion In the absence of gender identity data, additional data elements beyond GID codes improves the identification of transgender people in large, administrative claims databases.

This cohort study analyzes the association between testosterone and opioid use and improved health outcomes among male US military veterans with opioid-induced androgen deficiency., Key Points Question What are the health outcomes among long-term opioid users who receive testosterone treatment compared with opioid users who do not? Findings In this cohort study of 21 272 male long-term opioid users with testosterone deficiency, those who received opioids plus testosterone therapy had significantly lower all-cause mortality and lower incidence of major adverse cardiovascular events, anemia, and femoral or hip fractures than their counterparts who received opioids only in covariate-adjusted and propensity score–matched models. Meaning This study’s findings suggest that receiving opioids plus testosterone treatment is associated with lower all-cause mortality and a lower incidence of other adverse health outcomes among men with opioid-induced androgen deficiency., Importance Androgen deficiency is common among male opioid users, and opioid use has emerged as a common antecedent of testosterone treatment. The long-term health outcomes associated with testosterone therapy remain unknown, however. Objective To compare health outcomes between long-term opioid users with testosterone deficiency who filled testosterone prescriptions and those with the same condition but who did not receive testosterone treatment. Design, Setting, and Participants This cohort study focused on men in the care of the Veterans Health Administration (VHA) facilities throughout the United States from October 1, 2008, to September 30, 2014. It included male veterans who were long-term opioid users, had low testosterone levels (

Use of nonbenzodiazepine sedative hypnotics, especially zolpidem, has grown substantially, raising concerns about safety. Here, we evaluated prescribing patterns of zolpidem in the Veterans Health Administration.A cross-sectional study of veterans receiving zolpidem in the outpatient setting from October 1, 2011, to September 30, 2016.The study population consisted of 500,332 zolpidem users (58,598 women and 441,734 men) and a random 10% sample (n = 631,449) of nonusers. We examined 2 outcomes related to inappropriate prescribing: high-dose zolpidem prescribing and overlap with benzodiazepines. We generated interrupted time series and logistic regression models to analyze these outcomes in men and women separately.In 2016, 29.7% of female veterans received an inappropriately high guideline-discordant dosage compared with 0.1% of male veterans (P.001 for all reported comparisons). Furthermore, more women than men had overlapping benzodiazepine and zolpidem prescriptions (18.8% vs 14.3%). In fully adjusted models, inappropriately high doses were more commonly received by younger women (adjusted odds ratios [AORs]: 2.75 for 21-39 years and 2.97 for 40-49 years compared with ≥80 years) and women with substance use disorder (AOR, 1.48). In the second inappropriateness outcome models, women with anxiety (AOR, 2.28) or schizophrenia (AOR, 2.05) and men with cancer (AOR, 1.42), anxiety (AOR, 2.66), or schizophrenia (AOR, 2.46) were more likely to receive an overlapping prescription of zolpidem and benzodiazepines.We found evidence of inappropriate zolpidem prescribing among veterans, particularly women. Greater understanding of the drivers of this inappropriate prescribing is necessary to develop interventions to promote safer, more guideline-concordant prescribing.

The aim of this study was to evaluate whether veterans in Massachusetts receiving opioids and/or benzodiazepines from both Veterans Health Administration (VHA) and non-VHA pharmacies are at higher risk of adverse events compared with those receiving opioids at VHA pharmacies only.A cohort study of veterans who filled a prescription for any Schedule II through V substance at a Massachusetts VHA pharmacy. Prescriptions were recorded in the Massachusetts Department of Public Health Chapter 55 data set.The study sample included 16,866 veterans residing in Massachusetts, of whom 9238 (54.8%) received controlled substances from VHA pharmacies only and 7628 (45.2%) had filled prescriptions at both VHA and non-VHA pharmacies ("dual care users") between October 1, 2013, and December 31, 2015. Our primary outcomes were nonfatal opioid overdose, fatal opioid overdose, and all-cause mortality.Compared with VHA-only users, more dual care users resided in rural areas (12.6% vs 10.6%), received high-dose opioid therapy (26.3% vs 7.3%), had concurrent prescriptions of opioids and benzodiazepines (34.8% vs 8.2%), and had opioid use disorder (6.8% vs 1.6%) (P.0001 for all). In adjusted models, dual care users had higher odds of nonfatal opioid overdose (odds ratio [OR], 1.29; 95% CI, 0.98-1.71) and all-cause mortality (OR, 1.66; 95% CI, 1.43-1.93) compared with VHA-only users. Dual care use was not associated with fatal opioid overdoses.Among veterans in Massachusetts, receipt of opioids from multiple sources was associated with worse outcomes, specifically nonfatal opioid overdose and mortality. Better information sharing between VHA and non-VHA pharmacies and prescribers has the potential to improve patient safety.

Testosterone supplementation has been widely used in those infected with human immunodeficiency virus (HIV) for hypogonadism, and wasting. But with effective antiretroviral therapy and increasing recognition of atherosclerotic disease and adults infected with HIV, the risks of inappropriate testosterone use in HIV-infected patients are far better recognized than previously. Testosterone use has expanded among U.S. males, but few studies have examined prescribing in those infected with HIV. In a national cohort of males with at least one outpatient prescription in the Veterans Health Administration (VHA), we examined 9475 HIV-infected males, including 2484 who had received testosterone and a randomly selected 6991 who had not. For comparison, we identified 1,387,241 uninfected males (189,369 had received testosterone and a randomly selected 1,197,872 had not). We determined rates of new and prevalent testosterone use, and also examined the adequacy of the diagnostic evaluation that had preceded testosterone initiation among our HIV-infected and uninfected testosterone groups. Our main results were as follows. HIV-infected men had higher rates of initiation (0.8% vs. 0.4% in FY09; p 0.001) and prevalence of testosterone use (2.2% vs. 0.8% in FY08; p 0.001) compared to the uninfected men across the entire period. Trends of prescribing for both groups followed a similar pattern, rising from FY08, reaching a peak in FY13, and then dipping in FY 14. Only 1.1% of HIV-infected patients had a fully guideline-concordant workup before starting testosterone therapy, compared to 3.5% of uninfected patients (p 0.001). In conclusion, testosterone use among HIV-infected patients in the VHA system rose to a peak in FY13 and has decreased somewhat since. Only a small minority of HIV-infected patients who receive testosterone therapy from VHA have undergone an appropriate workup before starting therapy, suggesting an opportunity for improvement.

SummaryAmong patients receiving oral anticoagulation for atrial fibrillation (AF), heart failure (HF) is associated with poor anticoagulation control. However, it is not known which patients with heart failure are at greatest risk of adverse outcomes. We evaluated 62,156 Veterans Health Administration (VA) patients receiving warfarin for AF between 10/1/06–9/30/08 using merged VA-Medicare dataset. We predicted time in therapeutic range (TTR) and rates of adverse events by categorising patients into those with 0, 1, 2, or 3+ of five putative markers of HF severity such as aspartate aminotransferase (AST)> 80 U/l, alkaline phosphatase> 150 U/l, serum sodium< 130 mEq/l, any receipt of metolazone, and any inpatient admission for HF exacerbation. These risk categories predicted TTR: patients without HF (referent) had a mean TTR of 65.0 %, while HF patients with 0, 1, 2, 3 or more markers had mean TTRs of 62.2 %, 57.2 %, 53.5 %, and 50.7 %, respectively (p< 0.001). These categories also discriminated for major haemorrhage well; compared to patients without HF, HF patients with increasing severity had hazard ratios of 1.84, 3.06, 3.52 and 5.14 respectively (p< 0.001). However, although patients with HF had an elevated hazard for bleeding compared to those without HF, these categories did not effectively discriminate risk of ischaemic stroke across HF. In conclusion, we developed a HF severity model using easily available clinical characteristics that performed well to risk-stratify patients with HF who are receiving anticoagulation for AF with regard to major haemorrhage.

Context Testosterone prescribing rates have increased substantially in the past decade. However, little is known about the context within which such prescriptions occur. Objective We evaluated provider- and site-level determinants of receipt of testosterone and of guideline-concordant testosterone prescribing. Design This study was cross-sectional in design. Setting This study was conducted at the Veterans Health Administration (VA). Participants Study participants were a national cohort of male patients who had received at least one outpatient prescription within the VA during fiscal year (FY) 2008 to FY 2012. A total of 38,648 providers and 130 stations were associated with these patients. Main Outcome Measure This study measured receipt of testosterone and guideline-concordant testosterone prescribing. Results Providers ranging in age from 31 to 60 years, with less experience in the VA [all adjusted odds ratio (AOR)

Background— Chronic liver disease presents a relative contraindication to warfarin therapy, but some patients with liver disease nevertheless require long-term anticoagulation. The goal is to identify which patients with liver disease might safely receive warfarin. Methods and Results— Among 102 134 patients who received warfarin from the Veterans Affairs from 2007 to 2008, International Classification of Diseases -Ninth Revision codes identified 1763 patients with chronic liver disease. Specific diagnoses and laboratory values (albumin, aspartate aminotransferase, alanine aminotransferase, creatinine, and cholesterol) were examined to identify risk of adverse outcomes, while controlling for available bleeding risk factors. Outcomes included percent time in therapeutic range, a measure of anticoagulation control, and major hemorrhagic events, by International Classification of Diseases -Ninth Revision codes. Patients with liver disease had lower mean time in therapeutic range (53.5%) when compared with patients without (61.7%; P P P =0.59), whereas those with the worst score (4) had poor control (29.4%) and high hazard of hemorrhage (hazard ratio, 8.53; P Conclusions— Patients with liver disease receiving warfarin have poorer anticoagulation control and more hemorrhages. A simple 4-point scoring system using albumin and creatinine identifies those at risk for poor outcomes.

Warfarin is effective in preventing thromboembolic events, but concerns exist regarding its use in patients with substance abuse.Identify which patients with substance abuse who receive warfarin are at risk for poor outcomes.Retrospective cohort study. Diagnostic codes, lab values, and other factors were examined to identify risk of adverse outcomes.Veterans AffaiRs Study to Improve Anticoagulation (VARIA) database of 103,897 patients receiving warfarin across 100 sites.Outcomes included percent time in therapeutic range (TTR), a measure of anticoagulation control, and major hemorrhagic events by ICD-9 codes.Nonusers had a higher mean TTR (62 %) than those abusing alcohol (53 %), drugs (50 %), or both (44 %, p 0.001). Among alcohol abusers, an increasing ratio of the serum hepatic transaminases aspartate aminotransferase/alanine aminotransferase (AST:ALT) correlated with inferior anticoagulation control; normal AST:ALT ≤ 1.5 predicted relatively modest decline in TTR (54 %, p 0.001), while elevated ratios (AST:ALT 1.50-2.0 and2.0) predicted progressively poorer anticoagulation control (49 % and 44 %, p 0.001 compared to nonusers). Age-adjusted hazard ratio for major hemorrhage was 1.93 in drug and 1.37 in alcohol abuse (p 0.001 compared to nonusers), and remained significant after also controlling for anticoagulation control and other bleeding risk factors (1.69 p 0.001 and 1.22 p = 0.003). Among alcohol abusers, elevated AST:ALT2.0 corresponded to more than three times the hemorrhages (HR 3.02, p 0.001 compared to nonusers), while a normal ratio AST:ALT ≤ 1.5 predicted a rate similar to nonusers (HR 1.19, p 0.05).Anticoagulation control is particularly poor in patients with substance abuse. Major hemorrhages are more common in both alcohol and drug users. Among alcohol abusers, the ratio of AST/ALT holds promise for identifying those at highest risk for adverse events.

Introduction Identifying major bleeding is fundamental to assessing the outcomes of anticoagulation therapy. This drives the need for a credible implementation in automated data for the International Society of Thrombosis and Haemostasis (ISTH) definition of major bleeding. Materials and Methods We studied 102,395 patients who received 158,511 person-years of warfarin treatment from the Veterans Health Administration (VA) between 10/1/06-9/30/08. We constructed a list of ICD-9-CM codes of "candidate" bleeding events. Each candidate event was identified as a major hemorrhage if it fulfilled one of four criteria: 1) associated with death within 30days; 2) bleeding in a critical anatomic site; 3) associated with a transfusion; or 4) was coded as the event that precipitated or was responsible for the majority of an inpatient hospitalization. Results This definition classified 11,240 (15.8%) of 71, 338 candidate events as major hemorrhage. Typically, events more likely to be severe were retained at higher rates than those less likely to be severe. For example, Diverticula of Colon with Hemorrhage (562.12) and Hematuria (599.7) were retained 46% and 4% of the time, respectively. Major, intracranial, and fatal hemorrhage were identified at rates comparable to those found in randomized clinical trials however, higher than those reported in observational studies: 4.73, 1.29, and 0.41 per 100 patient years, respectively. Conclusions We describe here a workable definition for identifying major hemorrhagic events from large automated datasets. This method of identifying major bleeding may have applications for quality measurement, quality improvement, and comparative effectiveness research.

The effect of diet quality on weight change, relative to other body weight determinants, is insufficiently understood. Furthermore, research on long-term weight change in U.S. adults is limited. We evaluated prospectively patterns and predictors of weight change in Framingham Offspring/Spouse (FOS) women and men (n = 1515) aged > or =30 y with BMI > or = 18.5 kg/m2 and without cardiovascular disease, diabetes, and cancer at baseline over a 16-y period. Diet quality was assessed using the validated Framingham Nutritional Risk Score. In women, older age (P < 0.0001) and physical activity (P < 0.05) were associated with lower weight gain. Diet quality interacted with former smoking status (P-interaction = 0.02); former smokers with lower diet quality gained an additional 5.2 kg compared with those with higher diet quality (multivariable-adjusted P-trend = 0.06). Among men, older age (P < 0.0001) and current smoking (P < 0.01) were associated with lower weight gain, and weight fluctuation (P < 0.01) and former smoking status (P < 0.0001) were associated with greater weight gain. Age was the strongest predictor of weight change in both women (partial R(2) = 11%) and men (partial R(2) = 8.6%). Normal- and overweight women gained more than obese women (P < 0.05) and younger adults gained more weight than older adults (P < 0.0001). Patterns and predictors of weight change differ by sex. Age in both sexes and physical activity among women as well as weight fluctuation and smoking status in men were stronger predictors of weight change than diet quality among FOS adults. Women who stopped smoking over follow-up and had poor diet quality gained the most weight. Preventive interventions need to be sex-specific and consider lifestyle factors.

Background Self-rated health is a commonly used global indicator of health status. Few studies have examined the association of self-rated health and mobility with estrone and estradiol in men. Accordingly, we determined the cross-sectional, incident, and mediating relations between circulating estrone and estradiol levels with self-rated health, mobility limitation, and physical performance in community-dwelling men. Methods The cross-sectional sample included 1,148 men, who attended Framingham Offspring Study Examinations 7 and 8. Estrone and estradiol levels were measured using liquid chromatography tandem mass spectrometry at Examination 7. Self-reported mobility limitation and self-rated health were assessed at Examinations 7 and 8. Additionally, short physical performance battery, usual walking speed, and grip strength were assessed at Examination 7. Results In incident analysis, estradiol levels at Examination 7 were associated with increased odds of fair or poor self-rated health at Examination 8, after adjusting for age, body mass index, comorbidities, and testosterone levels; in an individual with 50% greater estradiol than other, the odds of reporting "fair or poor" self-rated health increased by 1.78 (95% confidence interval: 1.25-2.55; p = .001). Neither estrone nor estradiol levels were associated with any physical performance measure at baseline. Conclusions Higher circulating levels of estradiol are associated with increased risk of incident fair/poor self-rated health in community-dwelling men. The mechanisms by which circulating levels of estradiol are related to self-rated health in men need further investigation.

Prescribing of exogenous testosterone is increasing. Because of the risks associated with testosterone, it is important to follow evidence-based procedures when initiating therapy.We evaluated whether dispensing of testosterone was preceded by appropriate ascertainment of androgen deficiency, and consideration of potential contraindications, in accordance with practice guidelines.A cross-sectional study.All outpatient clinics within Veterans Affairs (VA) during fiscal years 2009-2012 (FY09-FY12).A total of 111,631 men who had not previously received testosterone from VA, and received at least 1 testosterone dispensing during the study period. A 1-year "look-back" period was used to check for diagnostic tests that occurred before the first fill.Proportion who underwent appropriate diagnostic evaluation of androgen deficiency and ascertainment of contraindications for testosterone therapy during the year before receiving their first testosterone dispensing.New testosterone dispensing in VA increased from 20,437 in FY09 to 36,394 in FY12. Only 3.1% of men who received testosterone had 2 or more low (total or free) testosterone levels in the morning, LH and/or FSH level measured, and no contraindications to testosterone therapy. A total of 16.5% did not have their testosterone level checked at all. Among those prescribed therapy, 1.4% had prostate cancer, 7.6% had obstructive sleep apnea, and 3.5% had elevated hematocrit at baseline.Only a small proportion of men receiving testosterone in VA underwent appropriate testing, and some received this therapy despite important contraindications. Promoting a more uniform application of clinical guidelines may facilitate appropriate use of testosterone.

Patients with mental health conditions (MHCs) experience poor anticoagulation control when using warfarin, but we have limited knowledge of the association between specific mental illness and warfarin treatment outcomes.To examine the relationship between the severity of MHCs and outcomes of anticoagulation therapy.Retrospective cohort analysis.We studied 103,897 patients on warfarin for 6 or more months cared for by the Veterans Health Administration during fiscal years 2007-2008. We identified 28,216 patients with MHCs using ICD-9 codes: anxiety disorders, bipolar disorder, depression, post-traumatic stress disorder, schizophrenia, and other psychotic disorders.Outcomes included anticoagulation control, as measured by percent time in the therapeutic range (TTR), as well as major hemorrhage. Predictors included different categories of MHC, Global Assessment of Functioning (GAF) scores, and psychiatric hospitalizations.Patients with bipolar disorder, depression, and other psychotic disorders experienced TTR decreases of 2.63 %, 2.26 %, and 2.92 %, respectively (p 0.001), after controlling for covariates. Patients with psychotic disorders other than schizophrenia experienced increased hemorrhage after controlling for covariates [hazard ratio (HR) 1.24, p = 0.03]. Having any MHC was associated with a slightly increased hazard for hemorrhage (HR 1.19, p 0.001) after controlling for covariates.Patients with specific MHCs (bipolar disorder, depression, and other psychotic disorders) experienced slightly worse anticoagulation control. Patients with any MHC had a slightly increased hazard for major hemorrhage, but the magnitude of this difference is unlikely to be clinically significant. Overall, our results suggest that appropriately selected patients with MHCs can safely receive therapy with warfarin.

OBJECTIVE In postmenopausal women and preclinical murine models, estrogen administration reduces diabetes risk; however, the relationship of estradiol and estrone to diabetes in men is poorly understood. We determined the relationship between circulating estradiol and estrone levels and diabetes risk in community-dwelling men of the Framingham Heart Study (FHS). RESEARCH DESIGN AND METHODS Cross-sectional relationships of estradiol and estrone levels with diabetes were assessed at examination 7 (1998–2001) in FHS generation 2 men (n = 1,458); prospective associations between hormone levels at examination 7 and incident diabetes were assessed 6.8 years later at examination 8. Type 2 diabetes mellitus was defined as fasting glucose >125 mg/dL, medication use, or both. Estradiol, estrone, and testosterone levels were measured with liquid chromatography–tandem mass spectrometry, and free estradiol and estrone were calculated. RESULTS In cross-sectional models, men with elevated estrone and estradiol had 40% and 62% increased likelihoods of existing diabetes per cross-sectional doubling of estrone and estradiol levels, respectively. Free estrone (cross-sectional odds ratio 1.28 [95% CI 1.02–1.62], P = 0.04) was associated with impaired fasting glucose at examination 7. There was an increase in risk of existing diabetes with increasing quartiles of total and free estrone and estradiol and an increase in risk of incident diabetes with increasing quartiles of estrone levels. In multivariate longitudinal analyses, a twofold increase in total or free estrone levels at examination 7 was associated with 77 and 93% increases, respectively, in odds of incident diabetes at examination 8. CONCLUSIONS Although both estradiol and estrone exhibit cross-sectional associations with diabetes in men, in longitudinal analyses estrone is a more sensitive marker of diabetes risk than is estradiol.

THE estrogens have been linked to the pathophysiology of gynecomastia, osteoporosis, inflammation, and cardiovascular disease (CVD), but the precise biologic role of the circulating estrone and estradiol in men remains poorly understood (1,2). The function of estrone, which is at least as abundant in the circulation as estradiol but is less potent than estradiol in some bioassays (3), has been even less well studied as compared with estradiol. In men, circulating estradiol is derived partly from direct testicular secretion and partly from peripheral aromatization of testosterone, whereas circulating estrone is derived predominantly from peripheral conversion of delta 4-androstenedione (3–10). A decline in testosterone and androstenedione levels with aging would, therefore, be expected to result in lower estradiol and estrone levels, respectively, in older men as compared with younger men. However, the data on age-related changes in estradiol levels are conflicting. Although some studies have reported lower estradiol levels in older men than in young men (11–15), others have noted stable (16,17) or even rising estradiol levels with age (18). Very few studies have investigated the age trends in estrone levels (14,15). Additionally, few studies have interpreted age trends in estrone and estradiol levels in the context of age-related changes in lifestyle and health-related factors. The estradiol levels were measured in most studies using direct immunoassays, whose accuracy in the low range prevalent in men has been questioned (19–21). Using cross-sectional data from the Framingham Heart Study (FHS), we examined the age distribution of estradiol and estrone concentrations and the relationship of these hormones to body mass index (BMI), total testosterone, sex hormone–binding globulin (SHBG), diabetes mellitus, C-reactive protein, and lifestyle factors such as smoking and alcohol consumption in a sample of community-dwelling men. We also determined how comorbid conditions, lifestyle factors, inflammation, testosterone, and SHBG levels influence the age trends in estrone and estradiol levels. We adjusted the analyses for SHBG, the major binding protein for circulating estradiol that has been associated with metabolic disorders, which may indirectly affect estrogen levels. We measured estrone and estradiol levels using liquid chromatography tandem mass spectrometry (LC-MS/MS), widely accepted as the method with the highest accuracy and sensitivity (19–21).