Reimagining How We Synthesize Information to Impact Clinical Care, Policy, and Research Priorities in Real Time: Examples and Lessons Learned from COVID-19.

Real-time clinical care, policy, and research decisions need real-time evidence synthesis. However, as we found during the COVID-19 pandemic, it is challenging to rapidly address key clinical and policy questions through rigorous, relevant, and usable evidence. Our objective is to present three exemplar cases of rapid evidence synthesis products from the Veterans Healthcare Administration Evidence Synthesis Program (ESP) and, in the context of these examples, outline ESP products, challenges, and lessons learned. We faced challenges in (1) balancing scientific rigor with the speed in which evidence synthesis was needed, (2) sorting through rapidly evolving large bodies of evidence, and (3) assessing the impact of evidence synthesis products on clinical care, policy, and research. We found solutions in (1) engaging stakeholders early, (2) utilizing artificial intelligence capabilities, (3) building infrastructure to establish living reviews, and (4) planning for dissemination to maximize impact.

GSM and Quality of Life Measures.

The impact of bothersome vulvovaginal symptoms related to hypoestrogenism on quality of life (QOL) has been evaluated in large international surveys and qualitative studies of vulvovaginal atrophy, most of which were completed before the introduction of the term genitourinary syndrome of menopause (GSM) and focus primarily on vulvovaginal atrophy. The QOL domain most affected in these studies is sexual function, although women also report impacts on self-confidence, self-esteem, sleep, and general enjoyment of life. Health-related QOL measures are available that evaluate the impact of some symptoms associated with GSM on QOL; new measures are in development that assess the full range of symptoms associated with GSM.

Drive Time and Receipt of Guideline-Recommended Screening, Diagnosis, and Treatment.

Importance: Many patients do not receive recommended services. Drive time to health care services may affect receipt of guideline-recommended care, but this has not been comprehensively studied. Objective: To assess associations between drive time to care and receipt of guideline-recommended screening, diagnosis, and treatment interventions. Design, Setting, and Participants: This cohort study used administrative data from the National Veterans Health Administration (VA) data merged with Medicare data. Eligible participants were patients using VA services between January 2016 and December 2019. Women ages 65 years or older without underlying bone disease were assessed for osteoporosis screening. Patients with new diagnosis of chronic obstructive pulmonary disease (COPD) indicated by at least 2 encounter codes for COPD or at least 1 COPD-related hospitalization were assessed for receipt of diagnostic spirometry. Patients hospitalized for ischemic heart disease were assessed for cardiac rehabilitation treatment. Exposures: Drive time from each patient's residential address to the closest VA facility where the service was available, measured using geocoded addresses. Main Outcomes and Measures: Binary outcome at the patient level for receipt of osteoporosis screening, spirometry, and cardiac rehabilitation. Multivariable logistic regression models were used to assess associations between drive time and receipt of services. Results: Of 110 780 eligible women analyzed, 36 431 (32.9%) had osteoporosis screening (mean [SD] age, 66.7 [5.4] years; 19 422 [17.5%] Black, 63 403 [57.2%] White). Of 281 130 patients with new COPD diagnosis, 145 249 (51.7%) had spirometry (mean [SD] age, 68.2 [11.5] years; 268 999 [95.7%] men; 37 834 [13.5%] Black, 217 608 [77.4%] White). Of 73 146 patients hospitalized for ischemic heart disease, 11 171 (15.3%) had cardiac rehabilitation (mean [SD] age, 70.0 [10.8] years; 71 217 [97.4%] men; 15 213 [20.8%] Black, 52 144 [71.3%] White). The odds of receiving recommended services declined as drive times increased. Compared with patients with a drive time of 30 minutes or less, patients with a drive time of 61 to 90 minutes had lower odds of receiving osteoporosis screening (adjusted odds ratio [aOR], 0.90; 95% CI, 0.86-0.95) and spirometry (aOR, 0.90; 95% CI, 0.88-0.92) while patients with a drive time of 91 to 120 minutes had lower odds of receiving cardiac rehabilitation (aOR, 0.80; 95% CI, 0.74-0.87). Results were similar in analyses restricted to urban patients or patients whose primary care clinic was in a tertiary care center. Conclusions and Relevance: In this retrospective cohort study, longer drive time was associated with less frequent receipt of guideline-recommended services across multiple components of care. To improve quality of care and health outcomes, health systems and clinicians should adopt strategies to mitigate travel burden, even for urban patients.

COVID-19 postacute care major organ damage: a systematic review.

BACKGROUND: Major organ complications have been reported in patients hospitalised for COVID-19; most studies lacked controls. OBJECTIVE: Examine major organ damage postdischarge among adults hospitalised for COVID-19 versus non-COVID-19 controls. DATA SOURCES: MEDLINE, Embase and Cochrane Library from 1 January 2020 to 19 May 2021. STUDY ELIGIBILITY CRITERIA: English language studies of adults discharged from hospital for COVID-19; reporting major organ damage. Single review of abstracts; independent dual review of full text. STUDY APPRAISAL AND SYNTHESIS METHODS: Study quality was assessed using the Joanna Briggs Institute Appraisal Checklist for Cohort Studies. Outcome data were not pooled due to heterogeneity in populations, study designs and outcome assessment methods; findings are narratively synthesised. RESULTS: Of 124 studies in a full evidence report, 9 included non-COVID controls and are described here. Four of the nine (three USA, one UK) used large administrative databases. Four of the remaining five studies enrolled <600 COVID-19 patients. Mean or median age ranged from 49 to 70 years with 46%-94% male and 48%-78% White race; 10%-40% had been in intensive care units. Follow-up ranged from 4 weeks to 22 weeks postdischarge. Four used hospitalised controls, three non-hospitalised controls and two were unclear. Studies used various definitions of, and methods to assess, major organ damage outcomes. While the magnitude of effect differed across studies, incident cardiac, pulmonary, liver, acute and chronic kidney, stroke, diabetes, and coagulation disorders were consistently greater in adults hospitalised for COVID-19 compared with non-COVID-19 controls. LIMITATIONS: Applicability to subgroups (age, gender, COVID-19 severity, treatment, vaccination status) and non-hospitalised patients is unknown. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: Postacute COVID-19 major organ damage is common and likely higher than controls. However, there is substantial uncertainty. More consistent reporting of clinical outcomes and pre-COVID health status along with careful selection of control groups are needed to address evidence gaps. PROSPERO REGISTRATION NUMBER: CRD42020204788.

Life-space mobility and healthcare costs and utilization in older men.

OBJECTIVES: To determine the association of life-space score with subsequent healthcare costs and utilization. DESIGN: Prospective cohort study (Osteoporotic Fracture in Men [MrOS]). SETTING: Six U.S. sites. PARTICIPANTS: A total of 1555 community-dwelling men (mean age 79.3 years; 91.5% white, non-Hispanic) participating in the MrOS Year 7 (Y7) examination linked with their Medicare claims data. MEASUREMENTS: Life-space during the past month was assessed as 0 (daily restriction to one's bedroom) to 120 (daily trips outside one's town without assistance) and categorized (0-40, 41-60, 61-80, 81-100, 101-120). Total annualized direct healthcare costs and utilization were ascertained during 36 months after the Y7 examination. RESULTS: Mean total annualized costs (2020 U.S. dollars) steadily increased across category of life-space score, from $7954 (standard deviation [SD] 16,576) among men with life-space scores of 101-120 to $26,430 (SD 28,433) among men with life-space scores of 0-40 (p < 0.001). After adjustment for demographics, men with a life-space score of 0-40 versus men with a life-space score of 101-120 had greater mean total costs (cost ratio [CR] = 2.52; 95% confidence interval [CI] = 1.84-3.45) and greater risk of subsequent hospitalization (odds ratio [OR] 4.72, 95% CI 2.61-8.53) and skilled nursing facility (SNF) stay (OR 7.32, 95% CI 3.65-14.66). Life-space score was no longer significantly associated with total healthcare costs (CR for 0-40 vs 101-120 1.29; 95% CI 0.91-1.84) and hospitalization (OR 1.76, 95% CI 0.89-3.51) after simultaneous consideration of demographics, medical factors, self-reported health and function, and the frailty phenotype; the association of life-space with SNF stay remained significant (OR 2.86, 95% CI 1.26-6.49). CONCLUSION: Our results highlight the importance of function and mobility in predicting future healthcare costs and suggest the simple and convenient life-space score may in part capture risks from major geriatric domains and improve identification of older, community-dwelling men likely to require costly care.

Association between post-stroke disability and 5-year hip-fracture risk: The Women's Health Initiative.

BACKGROUND: Hip fractures are a significant post-stroke complication. We examined predictors of hip fracture risk after stroke using data from the Women's Health Initiative (WHI). In particular, we examined the association between post-stroke disability levels and hip fracture risk. METHODS: The WHI is a prospective study of 161,808 postmenopausal women aged 50-79 years. Trained physicians adjudicated stroke events and hip fractures. Our study included stroke survivors from the observational and clinical trial arms who had a Glasgow Outcome Scale of good recovery, moderately disabled, or severely disabled and survived more than 7 days post-stroke. Hip fracture-free status was compared across disability levels. Secondary analysis examined hip fracture risk while accounting for competing risk of death. RESULTS: Average age at time of stroke was 74.6±7.2 years; 84.3% were white. There were 124 hip fractures among 4,640 stroke survivors over a mean follow-up time of 3.1±1.8 years. Mortality rate was 23.3%. Severe disability at discharge (Hazard Ratio (HR): 2.1 (95% Confidence Interval (CI): 1.4-3.2), but not moderate disability (HR: 1.1 (95%CI: 0.7-1.7), was significantly associated with an increased risk of hip fracture compared to good recovery status. This association was attenuated after accounting for mortality. White race, increasing age and higher Fracture Risk Assessment Tool (FRAX)-predicted hip fracture risk (without bone density information) were associated with an increased hip fracture risk. After accounting for mortality, higher FRAX risk and white race remained significant. CONCLUSION: Severe disability after stroke and a higher FRAX risk score were associated with risk of subsequent hip fracture. After accounting for mortality, only the FRAX risk score remained significant. The FRAX risk score appears to identify stroke survivors at high risk of fractures. Our results suggest that stroke units can consider the incorporation of osteoporosis screening into care pathways.

Effects of pharmacologic and nonpharmacologic interventions on menopause-related quality of life: a pooled analysis of individual participant data from four MsFLASH trials.

OBJECTIVE: The Menopause Strategies: Finding Lasting Answers for Symptoms and Health network conducted three randomized clinical trials (RCTs) testing six interventions treating vasomotor symptoms (VMS), and also collected menopause-related quality of life (QOL) measures. A fourth RCT assessed an intervention for insomnia symptoms among women with VMS. We describe these seven interventions' effects on menopause-related QOL relative to control in women with VMS. METHODS: We pooled individual-level data from 1,005 peri- and postmenopausal women with 14 or more VMS/week across the four RCTs. Interventions included escitalopram 10 to 20 mg/d; yoga/aerobic exercise; 1.8 g/d omega-3-fatty acids; oral 17-beta-estradiol 0.5 mg/d; venlafaxine XR 75 mg/d; and cognitive behavioral therapy for insomnia (CBT-I). Outcomes measures were the Menopause-specific Quality of Life scale and its subscales. RESULTS: Significant improvements in total Menopause-specific Quality of Life from baseline were observed with estradiol, escitalopram, CBT-I, and yoga, with mean decreases of 0.3 to 0.5 points relative to control. The largest improvement in the vasomotor subscale was observed with estradiol (-1.2 points), with more modest but significant effects seen with escitalopram, yoga, and CBT-I. Significant improvements in the psychosocial subscale were observed for escitalopram, venlafaxine, and CBT-I. For the physical subscale, the greatest improvement was observed for CBT-I and exercise, whereas for the sexual subscale, the greatest improvement was observed for CBT-I, with yoga and estradiol demonstrating smaller effects. CONCLUSIONS: These results suggest that for menopause-related QOL, women have a variety of treatment strategies to choose from and can select an approach based on most bothersome symptoms and individual preferences.

Choosing Daily Labs Wisely in the Hospital: A Novel Tool for Assessing Laboratory Testing Appropriateness.

BACKGROUND: The Minnesota Lab Appropriateness (MLAB) criteria were developed for assessing appropriateness of complete blood counts (CBCs) and serum electrolyte panels (SEPs) ordered for adult inpatients. METHODS: Two independent raters used the MLAB criteria to rate appropriateness of labs ordered during 50 hospitalizations through retrospective medical record review. RESULTS: Evaluation of 208 CBCs and 253 SEPs on a 2-category scale (appropriate/inappropriate) resulted in an inappropriate lab rate of 24% and 25% for CBCs and SEPs, respectively. Using a 3-category Likert scale that included an "equivocal" rating to allow for clinical uncertainty, 17% of CBCs and 20% of SEPs were considered inappropriate. Interrater reliability was "substantial" using the dichotomous scale for both CBCs and SEPs. Using the 3-category Likert scale, reliability was "substantial" for CBCs and "moderate" for SEPs. CONCLUSION: The MLAB criteria identified inappropriate labs at a rate consistent with published figures, with good interrater reliability.

Efficacy and Safety of Testosterone Treatment in Men: An Evidence Report for a Clinical Practice Guideline by the American College of Physicians.

Background: Testosterone treatment rates in adult men have increased in the United States over the past 2 decades. Purpose: To assess the benefits and harms of testosterone treatment for men without underlying organic causes of hypogonadism. Data Sources: English-language searches of multiple electronic databases (January 1980 to May 2019) and reference lists from systematic reviews. Study Selection: 38 randomized controlled trials (RCTs) of at least 6 months' duration that evaluated transdermal or intramuscular testosterone therapies versus placebo or no treatment and reported prespecified patient-centered outcomes, as well as 20 long-term observational studies, U.S. Food and Drug Administration review data, and product labels that reported harms information. Data Extraction: Data extraction by a single investigator was confirmed by a second, 2 investigators assessed risk of bias, and evidence certainty was determined by consensus. Data Synthesis: Studies enrolled mostly older men who varied in age, symptoms, and testosterone eligibility criteria. Testosterone therapy improved sexual functioning and quality of life in men with low testosterone levels, although effect sizes were small (low- to moderate-certainty evidence). Testosterone therapy had little to no effect on physical functioning, depressive symptoms, energy and vitality, or cognition. Harms evidence reported in trials was judged to be insufficient or of low certainty for most harm outcomes. No trials were powered to assess cardiovascular events or prostate cancer, and trials often excluded men at increased risk for these conditions. Observational studies were limited by confounding by indication and contraindication. Limitation: Few trials exceeded a 1-year duration, minimum important outcome differences were often not established or reported, RCTs were not powered to assess important harms, few data were available in men aged 18 to 50 years, definitions of low testosterone varied, and study entry criteria varied. Conclusion: In older men with low testosterone levels without well-established medical conditions known to cause hypogonadism, testosterone therapy may provide small improvements in sexual functioning and quality of life but little to no benefit for other common symptoms of aging. Long-term efficacy and safety are unknown. Primary Funding Source: American College of Physicians. (PROSPERO: CRD42018096585).

Lights on MsFLASH: a review of contributions.

OBJECTIVE: The Menopause Strategies: Finding Lasting Answers for Symptoms and Health clinical trials network was funded by the National Institutes of Health to find new ways to alleviate the most common, bothersome menopausal symptoms by designing and conducting multiple concurrent clinical intervention studies, accommodating a wide scope of populations and intervention strategies. METHODS: Trials were conducted in Boston, Indianapolis, Minneapolis, Oakland, Philadelphia, and Seattle, with the Data Coordinating Center in Seattle, and were designed with standardized eligibility criteria and endpoints. Primary outcomes focused on vasomotor symptoms, sleep quality and insomnia symptoms, and vaginal symptoms. Secondary outcomes included quality of life, sexual function, and mood. RESULTS: We completed five randomized clinical trials and three ancillary studies, testing nine interventions in over 1,300 women and collecting nearly 16,000 bio-specimens. Escitalopram, venlafaxine hydrochloride extended release, and low-dose estradiol diminished hot flashes by approximately 50% as compared with a 30% decrease by placebo. No benefits on vasomotor symptoms were observed with yoga or exercise compared with usual activity, nor with omega-3 supplementation compared with placebo. Cognitive behavioral therapy for insomnia reduced self-reported insomnia symptoms and improved overall sleep quality compared with menopause education control. We did not find significant benefit from a vaginal estradiol tablet or a vaginal moisturizer compared with placebo tablet and gel in diminishing the severity of vaginal symptoms. CONCLUSIONS: The MsFLASH trials contributed substantially to our understanding of bothersome menopausal symptom treatment. It is important that clinicians counseling women about available treatment options consider all therapies-both nonhormonal and hormonal.

Convergent-Divergent Validity and Correlates of the Day-to-Day Impact of Vaginal Aging Domain Scales in the MsFLASH Vaginal Health Trial.

INTRODUCTION: Clinical research and management of postmenopausal vaginal symptoms have been limited by the lack of validated measures for assessing symptom impact. AIM: To evaluate convergent-divergent validity of the Day-to-Day Impact of Vaginal Aging (DIVA) questionnaire among postmenopausal women with moderate-to-severe vulvovaginal symptoms and identify demographic and clinical factors associated with greater symptom impact. METHODS: We examined baseline data from postmenopausal women with moderate-to-severe vulvovaginal itching, pain, irritation, dryness, or pain with intercourse in a randomized trial of vaginal estradiol, moisturizer, or placebo. In addition to completing the DIVA questionnaire, participants rated the severity of their most bothersome vulvovaginal symptom, underwent assessment of vaginal pH and epithelial cytology, and completed other self-report measures including the Female Sexual Function Index (FSFI), Female Sexual Distress Scale (FSDS), and Patient Health Questionnaire-8 for depression (PHQ-8). MAIN OUTCOME MEASURE: The main outcome measures were the unadjusted correlations and multivariable-adjusted associations with 4 DIVA domain scales designed to assess symptom impact on day-to-day activities, sexual functioning, emotional well-being, and body image/self-concept on a scale of 0 to 4. RESULTS: Among 301 women, we detected moderately strong correlations between the DIVA emotional well-being scale and PHQ-8 scores (Pearson correlation coefficient [r] = 0.39) and strong correlations between the DIVA sexual functioning scale and FSFI and FSDS scores (r > 0.50). No significant correlations were detected between any DIVA scales and vaginal pH or epithelial cytology. In adjusted linear-regression analyses, greater vulvovaginal symptom severity was associated with worse DIVA scores for emotional well-being, sexual functioning, and self-concept/body image (average 0.3- to 0.5-point higher DIVA score for each 1-point difference in vulvovaginal symptom severity). Depression symptoms were associated with worse DIVA scores for activities of daily living and emotional well-being (0.2- to 0.4-point higher DIVA score for each 5- point worsening of PHQ-8 score). Women reporting recent sexual activity had lower symptom impact on sexual functioning and self-concept/body image domains (-0.3- to -0.4-point lower DIVA score with weekly sexual activity). CLINICAL IMPLICATIONS: Findings suggest that the impact of postmenopausal vaginal symptoms on functioning and well-being is greater in women with co-morbid depression symptoms and less frequent sexual activity, independent of symptom severity. STRENGTHS & LIMITATIONS: Strengths include the multicenter sample and wide array of measures. Results may not generalize to women with mild symptoms. CONCLUSION: Our results support the construct validity of the DIVA questionnaire for clinical practice and research and indicate that depression and lower frequency of sexual activity are markers of greater impact of postmenopausal vaginal symptoms on multiple dimensions of functioning and quality of life. Hunter MM, Guthrie KA, Larson JC, et al. Convergent-Divergent Validity and Correlates of the Day-to-Day Impact of Vaginal Aging Domain Scales in the MsFLASH Vaginal Health Trial. J Sex Med 2020;17:117-125.

Association of Anticoagulant Therapy With Risk of Fracture Among Patients With Atrial Fibrillation.

Importance: Warfarin is prescribed to patients with atrial fibrillation (AF) for the prevention of cardioembolic complications. Whether warfarin adversely affects bone health is controversial. The availability of alternate direct oral anticoagulant (DOAC) options now make it possible to evaluate the comparative safety of warfarin in association with fracture risk. Objective: To test the hypothesis that, among patients with nonvalvular AF, use of DOACs vs warfarin is associated with lower risk of incident fracture. Design, Setting, and Participants: This comparative effectiveness cohort study used the MarketScan administrative claims databases to identify patients with nonvalvular AF and who were prescribed oral anticoagulants from January 1, 2010, through September 30, 2015. To reduce confounding, patients were matched on age, sex, CHA2DS2-VASc (congestive heart failure, hypertension, age [>65 years = 1 point; >75 years = 2 points], diabetes, and previous stroke/transient ischemic attack [2 points], vascular disease) score, and high-dimensional propensity scores. The final analysis included 167 275 patients with AF. Data were analyzed from February 27, 2019 to September 18, 2019. Exposures: Warfarin and DOACs (dabigatran etexilate, rivaroxaban, and apixaban). Main Outcomes and Measures: Incident hip fracture, fracture requiring hospitalization, and all clinical fractures (identified using inpatient or outpatient claims) defined by International Classification of Diseases, Ninth Revision, Clinical Modification codes. Results: In the study population of 167 275 patients with AF (38.0% women and 62.0% men; mean [SD] age, 68.9 [12.5] years), a total of 817 hip fractures, 2013 hospitalized fractures, and 7294 total fractures occurred during a mean (SD) follow-up of 16.9 (13.7) months. In multivariable-adjusted, propensity score-matched Cox proportional hazards regression models, relative to new users of warfarin, new users of DOACs tended to be at lower risk of fractures requiring hospitalization (hazard ratio [HR], 0.87; 95% CI, 0.79-0.96) and all clinical fractures (HR, 0.93; 95% CI, 0.88-0.98), whereas the association with hip fractures (HR, 0.91; 95% CI, 0.78-1.07) was not statistically significant. When comparing individual DOACs with warfarin, the strongest findings were for apixaban (HR for hip fracture, 0.67 [95% CI, 0.45-0.98]; HR for fractures requiring hospitalization, 0.60 [95% CI, 0.47-0.78]; and HR for all clinical fractures, 0.86 [95% CI, 0.75-0.98]). In subgroup analyses, DOACs appeared more beneficial among patients with AF who also had a diagnosis of osteoporosis than among those without a diagnosis of osteoporosis. Conclusions and Relevance: In this real-world population of 167 275 patients with AF, use of DOACs-particularly apixaban-compared with warfarin use was associated with lower fracture risk. These associations were more pronounced among patients with a diagnosis of osteoporosis. Given the potential adverse effects of warfarin on bone health, these findings suggest that caution should be used when prescribing warfarin to patients with AF at high risk of fracture.

Prostate-Specific Antigen Levels During Testosterone Treatment of Hypogonadal Older Men: Data from a Controlled Trial.

CONTEXT: Prostate-specific antigen (PSA) changes during testosterone treatment of older hypogonadal men have not been rigorously evaluated. DESIGN: Double-blinded, placebo-controlled trial. SETTING: Twelve US academic medical centers. PARTICIPANTS: Seven hundred ninety hypogonadal men ≥65 years of age with average testosterone levels ≤275 ng/dL. Men at high risk for prostate cancer were excluded. INTERVENTIONS: Testosterone or placebo gel for 12 months. MAIN OUTCOMES: Percentile changes in PSA during testosterone treatment of 12 months. RESULTS: Testosterone treatment that increased testosterone levels from 232 ± 63 ng/dL to midnormal was associated with a small but substantially greater increase (P < 0.001) in PSA levels than placebo treatment. Serum PSA levels increased from 1.14 ± 0.86 ng/mL (mean ± SD) at baseline by 0.47 ± 1.1 ng/mL at 12 months in the testosterone group and from 1.25 ± 0.86 ng/mL by 0.06 ± 0.72 ng/mL in the placebo group. Five percent of men treated with testosterone had an increase ≥1.7 ng/mL and 2.5% of men had an increase of ≥3.4 ng/mL. A confirmed absolute PSA >4.0 ng/mL at 12 months was observed in 1.9% of men in the testosterone group and 0.3% in the placebo group. Four men were diagnosed with prostate cancer; two were Gleason 8. CONCLUSIONS: When hypogonadal older men with normal baseline PSA are treated with testosterone, 5% had an increase in PSA ≥1.7 ng/mL, and 2.5% had an increase ≥3.4 ng/mL.

Association of Disease Definition, Comorbidity Burden, and Prognosis With Hip Fracture Probability Among Late-Life Women.

IMPORTANCE: Advanced age is associated with lower use of drug treatment to prevent fractures, but concerns about comorbidities and prognosis increase the complexity of managing osteoporosis in this age group. OBJECTIVE: To determine the association of disease definition, number of comorbidities, and prognosis with 5-year hip fracture probabilities among women who are 80 years and older. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study (4 US sites) included 1528 community-dwelling women identified as potential candidates for initiation of osteoporosis drug treatment. MAIN OUTCOMES AND MEASURES: Women were contacted every 4 months to ascertain vital status and hip fracture. Five-year hip fracture probability was calculated accounting for competing mortality risk. Participants were classified into 2 distinct groups based on disease definition criteria proposed by the National Bone Health Alliance: with osteoporosis (n = 761) and without osteoporosis but at high fracture risk (n = 767). Comorbid conditions were assessed by self-report. Prognosis was estimated using a mortality prediction index. All analysis was performed between March 2018 and January 2019. RESULTS: The study had 1528 participants, all of whom were women, with a mean (SD) age of 84.1 (3.4) years. During follow-up, 125 (8.0%) women experienced a hip fracture and 287 (18.8%) died before experiencing this event. Five-year mortality probability was 24.9% (95% CI, 21.8-28.1) among women with osteoporosis and 19.4% (95% CI, 16.6-22.3) among women without osteoporosis but at high fracture risk. In both groups, mortality probability similarly increased with more comorbidities and poorer prognosis. In contrast, 5-year hip fracture probability was 13.0% (95% CI, 10.7-15.5) among women with osteoporosis and 4.0% (95% CI, 2.8-5.6) among women without osteoporosis but at high fracture risk. The difference was most pronounced among women with more comorbidities or worse prognosis. For example, among women with 3 or more comorbid conditions, hip fracture probability was 18.1% (95% CI, 12.3-24.9) among women with osteoporosis vs 2.5% (95% CI, 1.3-4.2) among women without osteoporosis but at high fracture risk. CONCLUSIONS AND RELEVANCE: Women 80 years and older who have osteoporosis, including those with more comorbidities or poorer prognosis, have a high 5-year probability of hip fracture despite accounting for competing mortality risk. In contrast, among women without osteoporosis but at high fracture risk, competing mortality risk far outweighs hip fracture probability, especially among those with more comorbidities or worse prognosis.

Depressive Symptoms and Total Healthcare Costs: Roles of Functional Limitations and Multimorbidity.

OBJECTIVES: Depressive symptoms can be both a cause and a consequence of functional limitations and medical conditions. Our objectives were to determine the association of depressive symptoms with subsequent total healthcare costs in older women after accounting for functional limitations and multimorbidity. DESIGN: Prospective cohort study (Study of Osteoporotic Fractures [SOF]). SETTING: Four US sites. PARTICIPANTS: A total of 2508 community-dwelling women (mean age = 79.4 years) participating in the SOF year 10 (Y10) examination linked with their Medicare claims data. MEASUREMENTS: At Y10, depressive symptoms were measured using the 15-item Geriatric Depression Scale (GDS) and functional limitations were assessed by number (range = 0-5) of impairments in performing instrumental activities of daily living. Multimorbidity was ascertained by the Elixhauser method using claims data for the 12 months preceding the Y10 examination. Total direct healthcare costs, outpatient costs, acute hospital stays, and skilled nursing facility during the 12 months following the Y10 examination were ascertained from claims data. RESULTS: Annualized mean (SD) total healthcare costs were $4654 ($9075) in those with little or no depressive symptoms (GDS score = 0-1), $7871 ($14 534) in those with mild depressive symptoms (GDS score = 2-5), and $9010 ($15 578) in those with moderate to severe depressive symptoms (GDS score = 6 or more). After adjustment for age, site, self-reported functional limitations, and multimorbidity, the magnitudes of these incremental costs were partially attenuated (cost ratio = 1.34 [95% confidence interval {CI} = 1.14-1.59] for those with mild depressive symptoms, and cost ratio = 1.29 [95% CI = 0.99-1.69] for those with moderate to severe depressive symptoms vs women with little or no depressive symptoms). CONCLUSION: Depressive symptoms were associated with higher subsequent healthcare costs attributable, in part, to greater functional limitations and multimorbidity among those with symptoms. Importantly, even mild depressive symptoms were associated with higher healthcare costs. J Am Geriatr Soc 67:1596-1603, 2019.

Impact of Competing Risk of Mortality on Association of Cognitive Impairment With Risk of Hip Fracture in Older Women.

Previous studies examining the association of cognitive impairment and dementia with fracture outcomes in older adults have usually used standard approaches that did not take into account the competing risk of mortality. However, ignoring mortality may not provide accurate estimates of risk of fracture because dementia in older adults strongly predicts death, making mortality a competing risk. A total of 1491 women (mean age 87.6 years) participating in the prospective Study of Osteoporotic Fractures (SOF) Year 20 exam were cognitively assessed and followed to ascertain vital status (deaths verified by death certificates) and hip fractures (confirmed by radiographic reports). Cognitive status was categorized as normal, mild cognitive impairment (MCI), or dementia, based on a standardized evaluation. Absolute probability of hip fracture by category of cognitive function was estimated using traditional Kaplan-Meier method and cumulative incidence function accounting for competing mortality risk. Risk of hip fracture by cognitive function category was determined using conventional Cox proportional hazards regression and subdistribution hazards models with death as a competing risk. During an average follow-up of 5.6 years, 139 (9.3%) women experienced a hip fracture and 990 (66.4%) died before experiencing this outcome. Among women with dementia, the risk of hip fracture was 11.7% (95% confidence interval [CI] 7.3-17.2) at 5 years and 18.6% (95% CI 9.1-30.9) at 10 years using traditional survival analysis versus 7.9% (95% CI 5.1-11.6) at 5 years and 8.8% (95% CI 5.8-12.8) at 9.8 years using a competing risk approach. Results were similar for women with MCI. Women with MCI and dementia have a higher risk of hip fractures than women with normal cognition. However, not taking into account the competing risk of mortality significantly overestimates the risk of hip fracture in women in the ninth and tenth decades of life with cognitive impairment. © 2018 American Society for Bone and Mineral Research.

Effects of vaginal estradiol tablets and moisturizer on menopause-specific quality of life and mood in healthy postmenopausal women with vaginal symptoms: a randomized clinical trial.

OBJECTIVE: Compare the effects of a vaginal estradiol tablet and a vaginal moisturizer, each to placebo, on menopause-related quality of life and mood in postmenopausal women with moderate-severe vulvovaginal symptoms. METHODS: A total of 302 postmenopausal women enrolled in a 12-week, double-blind, placebo-controlled randomized trial were assigned to vaginal 10 µg estradiol tablet plus placebo gel (n = 102), vaginal moisturizer plus placebo tablet (n = 100), or dual placebo (n = 100). We measured change from randomization to 12 weeks in total score of the Menopause-Specific Quality of Life (MENQOL) questionnaire. We also evaluated the four MENQOL domains, depressive symptoms as measured by the Patient Health Questionnaire 8, and anxiety symptoms as measured by the Generalized Anxiety Disorder (GAD-7) questionnaire. RESULTS: Treatment with vaginal estradiol resulted in significantly greater improvement in total MENQOL scores compared to dual placebo (mean difference between arms -0.3 at 12 weeks (95% confidence interval [CI] -0.5, 0.0; P = 0.01). A statistically significant group mean difference favoring vaginal estradiol was observed for the MENQOL sexual function domain (-0.4 at 12 weeks; 95% CI -1.0, 0.1; P = 0.005), but not for any of the other domains. Treatment with vaginal moisturizer did not provide greater improvement compared to placebo in total MENQOL scores (mean difference 0.2 at 12 weeks; 95% CI -0.1, 0.4; P = 0.38) or in any of the MENQOL domains. Neither treatment group showed improvement compared with placebo in the Patient Health Questionnaire 8 or Generalized Anxiety Disorder Questionnaire . CONCLUSIONS: Treatment with low-dose vaginal estradiol, but not vaginal moisturizer, modestly improved menopause-related quality of life and sexual function domain scores in postmenopausal women with moderate-severe vulvovaginal symptoms.

Effects of Mobility and Cognition on Maintenance of Independence and Survival Among Women in Late Life.

Background: We examined the effects of mobility and cognition on maintenance of independence among women in late life. Methods: Prospective 5-year study of 1,010 independent community-dwelling women (mean age 88.0 years) participating in the Study of Osteoporotic Fractures Year 20 examination (2006-2008). Mobility, ascertained by walk speed, was categorized as good (≥0.9 m/s), intermediate (>0.6 m/s to <0.9 m/s), or poor (≤0.6 m/s). Cognitive status, adjudicated based on neuropsychological tests, was classified as normal or impaired (mild cognitive impairment or dementia). Loss of independence was defined as being unable to perform ≥2 activities of daily living or nursing home residence at 5-year follow-up. Possible outcomes were alive and independent, alive and dependent, and deceased. Results: Four hundred and twenty-three (41.9%) participants were independent at follow-up, whereas 208 (20.6%) were alive but dependent; 379 (37.5%) had died. Compared to women with good mobility, those with slow walk speed were less likely to be independent (risk ratio, [RR] 0.40, 95% confidence interval [CI] 0.29-0.52), after controlling for cognition and other risk factors. Similarly, those with impaired cognition were less likely to be independent, after controlling for walk speed and other risk factors (RR 0.60, 95% CI 0.49-0.71). Women with slow walk speed and impaired cognition were 6-fold less likely to be independent at follow-up compared to those with good walk speed and normal cognition (RR 0.15, 95% CI 0.08-0.23). Conclusions: Both mobility and cognition are associated with maintenance of independence among the oldest old of women even after accounting for each other and other conventional predictors.

Antidepressant Use and Cognitive Outcomes in Very Old Women.

Background: Antidepressant use is very common in the elderly, but the effects of antidepressants on cognition in the elderly are controversial with some studies suggesting harm and others protection. We aimed to investigate the association between different antidepressant use and change in cognition and risk of mild cognitive impairment (MCI) or dementia in very old women. Methods: We examined 1,234 community-dwelling women (mean age 83.2 years) from the Study of Osteoporotic Fractures. Baseline antidepressant use was reported and verified by medication containers, and medications were coded with computerized dictionary. Cognitive status (normal, MCI, or dementia) was adjudicated by an expert clinical panel 5 years later. Change in a short-form Mini-Mental State Examination and Trails B were evaluated over 5 years. Results: Eleven per cent of the women were taking antidepressants. Users of selective serotonin reuptake inhibitors (SSRIs) had the greatest cognitive decline over 5 years, after adjustment for demographics, medical comorbidities, benzodiazepine use, and baseline cognition. Multivariable logistic regression shows that the users of SSRIs were more than twice (OR = 2.69, 95% CI = 1.64-4.41) and trazodone users more than three times (3.48, 1.12-10.81) as likely to develop MCI or dementia compared with the nonusers. Further adjustment for baseline cognition or depressive symptoms did not appreciably alter the results, and the association remained after excluding women with high depressive symptoms. The use of tricyclic antidepressants or other antidepressants was not significantly associated with cognitive outcomes. Conclusions: The use of antidepressants, especially SSRIs and trazodone, was associated with an increased risk of cognitive impairment 5 years later among the oldest old women.