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Background The effect of gender affirming hormone therapy (GAHT) on clinical laboratory parameters, including levels of liver enzymes alanine aminotransferase (ALT) and aspartate transaminase (AST), is an area of uncertainty in transgender health. Aim We sought to estimate the distribution parameters of liver enzyme levels among transmasculine (TM) and transfeminine (TF) persons receiving GAHT relative to the corresponding measures in cisgender reference groups, and to evaluate longitudinal changes in these laboratory measures following GAHT initiation. Methods The data for this longitudinal study included 624 TF and 438 transmasculine (TM) people as well as 4,090 cisgender males and 4,797 cisgender females enrolled in 3 integrated health systems. Time under observation was divided into 2 intervals: from the first blood test to the date of the first filled GAHT prescription and from GAHT initiation to the most recent ALT or AST measurement. Linear mixed models were used to compare changes in log-transformed ALT and AST values among transgender cohort members before and after GAHT initiation, and relative to the reference groups. The results were expressed as relative differences (in %) and the ratios of these differences (ratios-of-ratios) along with the 95% confidence intervals (CIs). Outcomes Changes in ALT and AST levels among transgender people over time and relative to the corresponding changes in cisgender referents. RESULTS Among TM study participants, the post GAHT ratios-of-ratios for AST were 1.61 (95% CI: 1.13, 2.31) and 1.57 (95% CI: 1.06, 2.31) relative to cisgender males and females respectively. For ALT, the corresponding comparisons yielded the ratios-of-ratios (95% CIs) of 2.06 (1.67, 2.54) and 1.90 (1.50, 2.40). No statistically significant changes were observed among TF participants. Other factors associated with higher liver enzyme levels included alcohol use/abuse and obesity. Clinical Implications TM persons may experience modest increases in ALT and AST concentrations following testosterone initiation; however, clinical significance of the observed association remains unclear and requires further investigation. By contrast, feminizing GAHT is unlikely to induce appreciable changes in liver enzyme levels. Strength and Limitations The strengths of this study are the longitudinal design and the ability to assemble an unselected cohort nested within large health systems. The main limitations include the lack of information on hormone levels and the inability to take into account GAHT doses and routes of administration. CONCLUSION The influence of long-term GAHT on ALT and AST levels appears modest and not likely to reflect clinically meaningful changes in liver function.

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.

Importance: Early detection of prostate cancer to reduce mortality remains controversial because there is often also overdiagnosis of low-risk disease and unnecessary treatment. Genetic scores may provide an objective measure of a man9s risk of dying from prostate cancer and thus inform screening decisions, especially in men of African ancestry, who have a higher average risk of prostate cancer death but are often treated as a homogeneous group. Objective: Determine whether a polygenic hazard score based on 290 genetic variants (PHS290) is associated with risk of metastatic or fatal prostate cancer in a racially and ethnically diverse population. Design: Million Veteran Program (MVP) cohort study, 2011-2021. Setting: Nation-wide study of United States military veterans. Participants: Population-based volunteer sample of male participants. Exposure(s): Genotype data were used to calculate the genetic score, PHS290. Family history of prostate cancer and ancestry group (harmonized genetic ancestry and self-reported race/ethnicity: European, African, Hispanic, or Asian) were also studied. Main Outcome(s) and Measure(s): Study designed after MVP data collected. Primary outcome: age at death from prostate cancer. Key secondary outcome: age at diagnosis of prostate cancer metastases. Hypothesis: A germline genetic score (PHS290) is associated with risk of fatal (or metastatic) prostate cancer. Results: 513,997 MVP participants were included. Median age at last follow-up: 69 years. PHS290 was associated with age at death from prostate cancer in the full cohort and for each ancestry group (p

BACKGROUND: Inappropriate testosterone use and variations in testosterone prescribing patterns exist in the Veterans Health Administration (VHA) despite the presence of clinical guidelines. OBJECTIVE: We examined system and clinician factors that contribute to patterns of potentially inappropriate testosterone prescribing in VHA. DESIGN: Qualitative study using a positive deviance approach to understand practice variation in high- and low-testosterone prescribing sites. PARTICIPANTS: Twenty-two interview participants included primary care and specialty clinicians, key opinion leaders, and pharmacists at 3 high- and 3 low-testosterone prescribing sites. APPROACH: Semi-structured phone interviews were conducted, transcribed, and coded using a priori theoretical constructs and emergent themes. Case studies were developed for each site and a cross-case matrix was created to evaluate variation across high- and low-prescribing sites. KEY RESULTS: We identified four system-level domains related to variation in testosterone prescribing: organizational structures and processes specific to testosterone prescribing, availability of local guidance on testosterone prescribing, well-defined dissemination process for local testosterone polices, and engagement in best practices related to testosterone prescribing. Two clinician-level domains were also identified, specifically, structured initial testosterone prescribing process and specified follow-up testosterone prescribing process. High- and low-testosterone prescribing sites systematically varied in the four system-level domains, while the clinician-level domains looked similar across all sites. The third high-prescribing site was unusual in that it exhibited the four domains similar to the 3 low-prescribing sites at the time of our visit. This site had greatly reduced its prescribing of testosterone in the interim. CONCLUSIONS: Findings suggest that local organizational factors play an important role in influencing prescribing. Sites have the potential to transform their utilization patterns by providing access to specialty care expertise, an electronic health record-based system to facilitate guideline-concordant prescribing, well-defined dissemination processes for information, guidance from multiple sources, and clarity regarding best practices for prescribing. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11606-019-05270-6) contains supplementary material, which is available to authorized users.

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 Valid and reliable quality measures can help catalyze improvements in health care. The care of transgender patients is ripe for quality measurement, as there is increasing awareness of the increasing prevalence of this population and the urgency of improving the health care they receive. While best practices may not exist for some aspects of transgender health care, other aspects are characterized by well-developed and highly evidence-based recommendations. Our objective was to create a list of potential quality measures for transgender care. Methods and results In consultation with our advisory panel, which consisted of clinical and academic experts in transgender medicine, we selected eight prominent clinical practice guidelines of transgender health care for review. Our four team investigators carefully reviewed all eight clinical practice guidelines. Through the course of multiple consensus-building meetings, we iteratively refined items until we had agreed upon a list of forty potential quality measures, all of which met the criteria for quality measures set forth in the Center for Medicare and Medicaid Services Blueprint for developing quality measures. Conclusions This manuscript explains the origin of the quality measures we developed, and also provides a useful roadmap to any group hoping to develop quality measures for a field that has not previously had any.

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 (

Medications are often prescribed suboptimally; some effective medications are underused, some ineffective medications are overused, and some medications that should be received by a few are instead given to many. The underlying causes of suboptimal prescribing likely differ for each medication, and therefore must be understood anew, although previous studies can help generate hypotheses. This perspective sets forth a 3-step research agenda, which has worked well for us in several recently completed and ongoing projects. The three steps are to 1) demonstrate variation in suboptimal prescribing for the targeted medication; 2a) use mixed methods to understand the patient-, provider-, and system-level causes of suboptimal prescribing for this medication; 2b) develop a justification for improving the use of this medication, often involving a business case analysis; and 3) develop and implement interventions to improve prescribing of the targeted medication, informed by what has been learned in Steps 1 and 2 and relying on the principles of implementation science. Previous efforts have focused disproportionately on Step 1, or documenting gaps in practice, and Step 3, or deploying and evaluating efforts to improve practice. Our contention is that addressing all three steps sequentially, while effort-intensive, will maximize the chances of deploying a more effective intervention that will impact population health. We commend this three-step approach to health services researchers who wish to maximize impact by basing their research on a natural progression from documenting problems, to understanding their causes, to formulating and deploying a solution.

Key Points Question What are veterans’ attitudes and intentions associated with COVID-19 vaccination? Findings In this survey study of 1178 US veterans in March 2021, 71% of veterans reported being vaccinated against COVID-19. Fears about side effects and worry about the newness of vaccines were the primary reasons given for not getting vaccinated, reflecting vaccine skepticism and deliberation. Meaning These findings suggest that targeting veterans’ concerns around the adverse effects and safety of COVID-19 vaccines through conversations with trusted Veterans Health Administration health care practitioners is key to increasing vaccine acceptance., This survey study assesses veterans’ attitudes toward and intentions to receive COVID-19 vaccines., Importance Compared with the general population, veterans are at high risk for COVID-19 and have a complex relationship with the government. This potentially affects their attitudes toward receiving COVID-19 vaccines. Objective To assess veterans’ attitudes toward and intentions to receive COVID-19 vaccines. Design, Setting, and Participants This cross-sectional web-based survey study used data from the Department of Veterans Affairs (VA) Survey of Healthcare Experiences of Patients’ Veterans Insight Panel, fielded between March 12 and 28, 2021. Of 3420 veterans who were sent a link to complete a 58-item web-based survey, 1178 veterans (34%) completed the survey. Data were analyzed from April 1 to August 25, 2021. Exposures Veterans eligible for COVID-19 vaccines. Main Outcomes and Measures The outcomes of interest were veterans’ experiences with COVID-19, vaccination status and intention groups, reasons for receiving or not receiving a vaccine, self-reported health status, and trusted and preferred sources of information about COVID-19 vaccines. Reasons for not getting vaccinated were classified into categories of vaccine deliberation, dissent, distrust, indifference, skepticism, and policy and processes. Results Among 1178 respondents, 974 (83%) were men, 130 (11%) were women, and 141 (12%) were transgender or nonbinary; 58 respondents (5%) were Black, 54 veterans (5%) were Hispanic or Latino, and 987 veterans (84%) were non-Hispanic White. The mean (SD) age of respondents was 66.7 (10.1) years. A total of 817 respondents (71%) self-reported being vaccinated against COVID-19. Of 339 respondents (29%) who were not vaccinated, those unsure of getting vaccinated were more likely to report fair or poor overall health (32 respondents [43%]) and mental health (33 respondents [44%]) than other nonvaccinated groups (overall health: range, 20%-32%; mental health: range, 18%-40%). Top reasons for not being vaccinated were skepticism (120 respondents [36%] were concerned about side effects; 65 respondents [20%] preferred using few medications; 63 respondents [19%] preferred gaining natural immunity), deliberation (74 respondents [22%] preferred to wait because vaccine is new), and distrust (61 respondents [18%] did not trust the health care system). Among respondents who were vaccinated, preventing oneself from getting sick (462 respondents [57%]) and contributing to the end of the COVID-19 pandemic (453 respondents [56%]) were top reasons for getting vaccinated. All veterans reported the VA as 1 of their top trusted sources of information. The proportion of respondents trusting their VA health care practitioner as a source of vaccine information was higher among those unsure about vaccination compared with those who indicated they would definitely not or probably not get vaccinated (18 respondents [26%] vs 15 respondents [15%]). There were no significant associations between vaccine intention groups and age (χ24 = 5.90; P = .21) or gender (χ22 = 3.99; P = .14). Conclusions and Relevance These findings provide information needed to develop trusted messages used in conversations between VA health care practitioners and veterans addressing specific vaccine hesitancy reasons, as well as those in worse health. Conversations need to emphasize societal reasons for getting vaccinated and benefits to one’s own health.

Background: Many transgender patients experience gender dysphoria as a result of an incongruence between their gender identity and sex assigned at birth. Gender-affirming hormone therapy improves the quality of life for transgender patients seeking to increase alignment of their secondary sex characteristics and gender identity. However, little is known about the patient factors that are associated with receipt of this therapy which is critical to identifying areas for improvement in care for transgender patients. Objective: To evaluate patient characteristics associated with transgender patients’ receipt of hormone therapy from the Veterans Health Administration (VHA). Methods: Inpatient and outpatient data were reviewed for transgender patients, identified through ICD-9/ICD-10 diagnosis codes for gender identity disorder (GID), receiving VHA health care from January 2006 to December 2018. We evaluated receipt of hormone therapy (testosterone or estrogen +/- spironolactone) from the VHA, socio-demographics, comorbidities, social stressors, military sexual trauma, and documented suicide attempts. Adjusted Odds Ratios (aOR) and 95% Confidence Intervals (CI) were obtained from a multivariable logistic regression model used to ascertain the relationship between patient characteristics and hormone therapy. Results: Of 9,406 patients with documented GID, 5,487 (58.3%) received hormone therapy from the VHA. Compared to patients not receiving hormone therapy, a higher proportion of patients receiving hormone therapy were younger (21-29 years: 18.1% vs. 11.6%; 30-39 years: 20.0% vs. 14.6%; 40-49 years: 16.2% vs. 13.6%), had documentation of a positive military sexual trauma screening (22.2% vs. 16.2%; p

Importance Substance use disorders are a major source of morbidity and mortality in the United States. National data comparing the prevalence of substance use disorder diagnoses (SUDDs) among transgender and cisgender individuals are lacking in the United States. Objectives To investigate the prevalence of SUDDs among transgender and cisgender adults and to identify within-group and between-group differences by age, gender, and geographic location. Design, Setting, and Participants This cross-sectional study used the OptumLabs Data Warehouse to analyze deidentified claims from approximately 74 million adults aged 18 years or older enrolled in commercial or Medicare Advantage insurance plans in 2017. A total of 15 637 transgender adults were identified based on a previously developed algorithm using a combination ofInternational Classification of Diseases, Tenth Revision (ICD-10) transgender-related diagnosis and procedure codes and sex-discordant hormone prescriptions. A cohort of 46 911 cisgender adults was matched to the transgender cohort in a 3:1 ratio based on age and geographic location. Main Outcomes and Measures SUDDs, based onICD-10codes, were assessed overall and compared between transgender and cisgender cohorts and by geographic region (ie, Northeast, Midwest, South, and West); age groups (eg, 18-25, 26-30, 31-35 years), and gender (ie, transfeminine [TF; assigned male sex at birth, identify along feminine gender spectrum], transmasculine [TM; assigned female sex at birth, identify along masculine gender spectrum], male, and female). Results In this study of 15 637 transgender adults (4955 [31.7%] TM) and 46 911 cisgender adults (23 664 [50.4%] female), most (8627 transgender adults [55.2%]; 25 882 cisgender adults [55.2%]) were aged between 18 and 40 years, and 6482 transgender adults (41.5%) and 19 446 cisgender adults (41.5%) lived in the South. Comparing transgender to cisgender groups, significant differences were found in the prevalence of a nicotine (2594 [16.6%] vs 2551 [5.4%];P Conclusions and Relevance In this study, the prevalence of SUDDs was significantly elevated among transgender adults relative to their cisgender peers. These findings underscore the need for culturally tailored clinical interventions to treat substance use disorder in transgender populations.

RESEARCH OBJECTIVE: Inappropriate testosterone use and variations in testosterone prescribing patterns exist in the Veterans Health Administration (VHA) despite the presence of clinical guidelines. Understanding the context within which testosterone prescribing occurs is key to planning successful interventions to improve guideline‐concordant prescribing. We examined system‐ and clinician‐level factors that contribute to patterns of potentially inappropriate testosterone prescribing in VHA. STUDY DESIGN: We conducted a qualitative study using a positive deviance approach to understand practice variation in high‐ and low‐testosterone prescribing sites. Semi‐structured phone interviews were conducted, transcribed, and coded using a priori theoretical constructs and emergent themes. Case studies were developed for each site and a cross‐case matrix was created to evaluate variation across high‐ and low‐prescribing sites. POPULATION STUDIED: Twenty‐two interview participants included primary care and specialty clinicians, key opinion leaders, and pharmacists at 3 high‐ and 3 low‐testosterone prescribing sites. These high‐ and low‐testosterone‐prescribing sites were located in six states and all four regions of the United States. PRINCIPAL FINDINGS: We identified four system‐level domains related to variation in testosterone prescribing: organizational structures and processes specific to testosterone prescribing, availability of local guidance on testosterone prescribing, well‐defined dissemination process for local testosterone polices, and engagement in best practices related to testosterone prescribing. Two clinician‐level domains were also identified: structured initial testosterone prescribing process and well‐specified follow‐up protocols following testosterone prescription. The four system‐level domains were related systematically to level of testosterone prescribing whereas the clinician level domains were similar across all sites. At all sites, most testosterone prescriptions were initiated by patient request and clinicians varied in their adherence to guideline‐concordant prescribing. The third high‐prescribing site was unusual in that, at the time of our visit, it exhibited system‐level domain characteristics similar to the 3 low‐prescribing sites. This outlier had recognized its status as a high‐prescribing site and implemented several improvement strategies in the year between selection and interviews, resulting in greatly reduced rates of testosterone prescribing. CONCLUSIONS: In this study, we found that low‐prescribing sites shared some common features, including easier access to specialty care expertise, existence of an electronic health record‐based system to facilitate guideline‐concordant prescribing, well‐defined dissemination processes for information, availability of guidance from multiple sources, and clarity regarding what constitutes best practices for prescribing. Findings suggest that local organizational factors play an important role in influencing prescribing. Sites have the potential to transform their utilization patterns by providing access to specialty care expertise, an electronic health record‐based system to facilitate guideline‐concordant prescribing, well‐defined dissemination processes for information, guidance from multiple sources, and clarity regarding best practices for prescribing. IMPLICATIONS FOR POLICY OR PRACTICE: The use of these system‐level factors to change medication prescribing can also be extrapolated to improving other prescribing behavior, including safer prescribing of high‐risk drugs and facilitating deprescribing of unnecessary and/or harmful medications. Lessons learned from this study will serve as an exemplar for any site aiming to improve its testosterone‐prescribing practices and prescribing in general beyond testosterone. PRIMARY FUNDING SOURCE: Department of Veterans Affairs.

Use of nonbenzodiazepine sedative hypnotics, especially zolpidem, has grown substantially, raising concerns about safety. Gender‐specific guidelines have been recommended for appropriate zolpidem prescribing to address patient safety concerns. In line with an FDA recommendation in 2013, the Veterans Health Administration (VHA) issued a similar directive to lower the doses of zolpidem in women in 2013. However, little is known about zolpidem prescribing patterns in the VHA in general. Therefore, the goal of this study was to examine utilization trends and inappropriate prescribing of zolpidem in accordance with VHA guidelines in male and female veterans in the VHA. A cross‐sectional study of veterans receiving zolpidem in the outpatient setting from October 1, 2011, to September 30, 2016. We examined 2 outcomes related to inappropriate zolpidem prescribing: high‐dose and overlap with benzodiazepines. 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. Across the VHA, 7.1% of men and 10.0% of women received zolpidem at least once during the study period. In 2016, 29.7% of female veterans received an inappropriately high guideline‐discordant dosage compared with 0.1% of male veterans (P

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)

There has been an increase in the prescribing of testosterone therapy in the past decade. There is concern that at least part of this increase is driven by advertising rather than sound medical practice. The purpose of this review is to summarize the recent trends in testosterone prescribing, and to examine whether testosterone is being appropriately prescribed as per guidelines.Both global and U.S. data reflect an overall increase in the use of testosterone in the last decade, although there are early signs of a decline in testosterone sales since 2014. This increased prescribing has been accompanied with an overall increase in testing for testosterone levels, prescription of testosterone without the appropriate diagnostic evaluation recommended by clinical practice guidelines, and apparent use of this therapy for unproven medical conditions.Research to date suggests that there is room to improve our prescribing of testosterone. Greater understanding of the potential provider-level and system-level factors that contribute to the current prescribing practices may help accomplish such improvement.

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.

Reference ranges are essential for partitioning testosterone levels into low or normal and making the diagnosis of androgen deficiency. We established reference ranges for total testosterone (TT) and free testosterone (FT) in a community-based sample of men.TT was measured using liquid chromatography tandem mass spectrometry in nonobese healthy men, 19-40 yr old, in the Framingham Heart Study Generation 3; FT was calculated. Values below the 2.5th percentile of reference sample were deemed low. We determined the association of low TT and FT with physical dysfunction, sexual symptoms [European Male Aging Study (EMAS) only], and diabetes mellitus in three cohorts: Framingham Heart Study generations 2 and 3, EMAS, and the Osteoporotic Fractures in Men Study.In a reference sample of 456 men, mean (sd), median (quartile), and 2.5th percentile values were 723.8 (221.1), 698.7 (296.5), and 348.3 ng/dl for TT and 141. 8 (45.0), 134.0 (60.0), and 70.0 pg/ml for FT, respectively. In all three samples, men with low TT and FT were more likely to have slow walking speed, difficulty climbing stairs, or frailty and diabetes than those with normal levels. In EMAS, men with low TT and FT were more likely to report sexual symptoms than men with normal levels. Men with low TT and FT were more likely to have at least one of the following: sexual symptoms (EMAS only), physical dysfunction, or diabetes.Reference ranges generated in a community-based sample of men provide a rational basis for categorizing testosterone levels as low or normal. Men with low TT or FT by these criteria had higher prevalence of physical dysfunction, sexual dysfunction, and diabetes. These reference limits should be validated prospectively in relation to incident outcomes and in randomized trials.

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.

The purpose of this article is to describe the translation of research on tobacco and drug abuse prevention from basic science to program development to large-scale program dissemination, and from animal to human studies. Where relevant, continuity of translation is discussed by referring to two variables that have been studied for their potential relationship to drug use risk in both animals and humans: sensation and novelty seeking and low impulse control. Review of the research indicates relatively slow translation until the early 1990s. The authors recommend several mechanisms to promote more rapid translation across types of research that encourage reciprocal rather than unidirectional transmission of knowledge to expedite the development and diffusion of more timely, targeted drug abuse prevention programs.

The study examined the relationship between six characteristics of community coalitions (size of region covered, structure, professional representation, resource sharing, size, and breadth of prevention stakeholder representation) and community organizational progress in adopting drug prevention programs. The study utilized baseline data from community leaders (n=533) in 24 cities from Step Towards Effective Prevention (STEP), a multi-state, multi-city randomized trial that is evaluating the effects of a television-based prevention training intervention on adoption of evidence-based drug prevention programs. Confirmatory factor analysis yielded a measurement model with a good fit to the data on four of the characteristics. Structural equation modeling showed that these characteristics had significant positive relationships to organizational progress, with the exception of size of the region covered. Results suggest that coalitions which have a clear structure, professional focus, resource sharing, and a smaller service region are likely to show the most progress in adopting evidence-based drug prevention programs.

Background— Among patients receiving warfarin, percent time in therapeutic range (TTR) and international normalized ratio (INR) variability predict adverse events individually. Here, we examined what is added to the prediction of adverse events by using both measures together. Methods and Results— We included 40 404 patients anticoagulated for atrial fibrillation, aged 65+, within the Veterans Health Administration. TTR and log-transformed INR variability were calculated for each patient. Our study outcomes were ischemic stroke and major bleeding, defined using International Classification of Diseases-9 codes. We estimated the hazard ratios (HRs) for the study outcomes using 3 nested Cox regression models, including (1) TTR or log INR variability separately; (2) TTR and log INR variability together; and (3) both predictors together plus an interaction term. We divided TTR into 3 categories (high, >70%; moderate, 50% to 70%; low, Higher log INR variability (ie, unstable control) predicted ischemic stroke (HR=1.45, P P Conclusions— Unstable anticoagulation predicts warfarin adverse effects independent of TTR. Moreover, knowledge about anticoagulation stability further stratifies the risk for adverse events at given levels of TTR.

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).