Patient-centered change in the day-to-day impact of postmenopausal vaginal symptoms: results from a multicenter randomized trial.

BACKGROUND: Vulvovaginal symptoms, which include dryness, irritation, and pain with intercourse, are common among postmenopausal women and are associated with impaired sexual functioning and quality of life. Previous assessment of treatment strategies for these symptoms has been limited by a lack of sensitive patient-centered outcome measures that assess symptom impact on functional and quality-of-life domains. OBJECTIVE: We aimed to (1) examine change in the impact of postmenopausal vulvovaginal symptoms on multiple aspects of well-being and functioning in relation to vaginal estradiol and moisturizer treatment and (2) guide meaningful interpretation of scores on a structured-item questionnaire measure of condition-specific impact. STUDY DESIGN: Data were drawn from postmenopausal women who were enrolled in the Menopause Strategies: Finding Lasting Answers for Symptoms and Health Vaginal Health Trial (a 12-week, double-blind, placebo-controlled randomized trial of treatment for vulvovaginal symptoms) who were assigned to vaginal 10-µg estradiol tablet plus placebo gel (n=98), vaginal moisturizer plus placebo tablet (n=97), or dual placebo (n=94). At baseline and 12-week follow up, participants completed the Day-to-Day Impact of Vaginal Aging questionnaire to assess the impact of vaginal symptoms on 4 domains (activities of daily living, emotional well-being, sexual functioning, and body image), each on a 0-4 point scale. Day-to-Day Impact of Vaginal Aging sensitivity to change was assessed by the examination of the associations between change in Day-to-Day Impact of Vaginal Aging domain scores and vulvovaginal symptom severity from baseline to 12 weeks with analysis of covariance. Within-woman and between-group minimal clinically important improvement was assessed with the use of an anchor-based approach that relates change in Day-to-Day Impact of Vaginal Aging domain scores with self-reported benefit from treatment. RESULTS: Participants in all treatment arms (n=289) demonstrated reduced impact of vulvovaginal symptoms on all domains of well-being and functioning as assessed by Day-to-Day Impact of Vaginal Aging at 12-week follow up, with no significant differences in improvement between women who were assigned to either estradiol tablet or vaginal moisturizer compared with placebo. For all Day-to-Day Impact of Vaginal Aging domains, mean impact scores were reduced when participants reported symptom improvement (-0.3 to -0.8 point change in Day-to-Day Impact of Vaginal Aging scores for <2-point symptom severity change vs -0.4 to -1.6 point change in Day-to-Day Impact of Vaginal Aging scores for 2+ point symptom severity change; all P<.001). Minimal clinically important change in Day-to-Day Impact of Vaginal Aging domain scale scores, which are anchored to self-reported meaningful benefit from treatment at 12 weeks, ranged from -0.4 to -1.3 (within-woman) and -0.2 to -0.7 (between-group). Observed change and minimal clinically important difference were largest for the sexual functioning domain. CONCLUSION: The impact of vulvovaginal symptoms on day-to-day activities, sexual function, emotional well-being, and body image may be improved with low-dose vaginal estradiol, moisturizer, or topical placebo. The Day-to-Day Impact of Vaginal Aging questionnaire demonstrates sensitivity to change with treatment of vulvovaginal symptoms, particularly Day-to-Day Impact of Vaginal Aging scales that focus on symptom impact on sexual functioning and body image. Minimal clinically important improvement in the impact of vulvovaginal symptoms as measured by the Day-to-Day Impact of Vaginal Aging can be defined with the use of these measures.

Facebook advertising for recruitment of midlife women with bothersome vaginal symptoms: A pilot study.

BACKGROUND: The MsFLASH (Menopause Strategies: Finding Lasting Answers for Symptoms and Health) Network recruited into five randomized clinical trials (n = 100-350) through mass mailings. The fifth trial tested two interventions for postmenopausal vulvovaginal symptoms (itching, pain, irritation, dryness, or pain with sex) and thus required a high level of sensitivity to privacy concerns. For this trial, in addition to mass mailings we pilot tested a social media recruitment approach. We aimed to evaluate the feasibility of recruiting healthy midlife women with bothersome vulvovaginal symptoms to participate in the Vaginal Health Trial through Facebook advertising. METHODS: As part of a larger advertising campaign that enrolled 302 postmenopausal women for the 12-week randomized, double-blind, placebo-controlled Vaginal Health Trial from April 2016 to February 2017, Facebook advertising was used to recruit 25 participants. The target population for recruitment by mailings and by Facebook ads included women aged 50-70 years and living within 20 miles of study sites in Minneapolis, MN and Seattle, WA. Design of recruitment letters and Facebook advertisements was informed by focus group feedback. Facebook ads were displayed in the "newsfeed" of targeted users and included a link to the study website. Response rates and costs are described for both online ads and mailing. RESULTS: Facebook ads ran in Minneapolis for 28 days and in Seattle for 15 days, with ads posted and removed from the site as needed based on clinic flow and a set budget limit. Our estimated Facebook advertising reach was over 200,000 women; 461 women responded and 25 were enrolled at a cost of US$14,813. The response rate per estimated reach was 0.22%; costs were US$32 per response and US$593 per randomized participant. The social media recruitment results varied by site, showing greater effectiveness in Seattle than in Minneapolis. We mailed 277,000 recruitment letters; 2166 women responded and 277 were randomized at a cost of US$98,682. The response rate per letter sent was 0.78%; costs were US$46 per response and US$356 per randomized participant. Results varied little across sites. CONCLUSION: Recruitment to a clinical trial testing interventions for postmenopausal vaginal symptoms is feasible through social media advertising. Variability in observed effectiveness and costs may reflect the small sample sizes and limited budget of the pilot recruitment study.

Early Pregnancy Hemoglobin A1C and Pregnancy Outcomes: A Population-Based Study.

OBJECTIVE: Women with prediabetes are identified from screening for overt diabetes in early pregnancy, but the clinical significance of prediabetes in pregnancy is unclear. We examined whether prediabetes in early pregnancy was associated with risks of adverse outcomes. STUDY DESIGN: We conducted a retrospective cohort study of pregnant women enrolled in Kaiser Permanente Washington from 2011 to 2014. Early pregnancy hemoglobin A1C (A1C) values, covariates, and outcomes were ascertained from electronic medical records and state birth certificates. Women with prediabetes (A1C of 5.7-6.4%) were compared with those with normal A1C levels (<5.7%) for risk of gestational diabetes mellitus (GDM) and other outcomes including preeclampsia, primary cesarean delivery, induction of labor, large/small for gestational age, preterm birth, and macrosomia. We used modified Poisson's regression to calculate adjusted relative risks (RRs) and 95% confidence intervals (CIs). RESULTS: Of 7,020 women, 239 (3.4%) had prediabetes. GDM developed in 48% of prediabetic women compared with 11% of women with normal A1C levels (adjusted RR: 2.8, 95% CI: 2.4-3.3). Prediabetes was not associated with all other adverse maternal and neonatal outcomes. CONCLUSION: Prediabetes in early pregnancy is a risk factor for GDM. Future research is needed to elucidate whether early intervention may reduce this risk.

Medication Adherence Does Not Explain Black-White Differences in Cardiometabolic Risk Factor Control among Insured Patients with Diabetes.

BACKGROUND: Among patients with diabetes, racial differences in cardiometabolic risk factor control are common. The extent to which differences in medication adherence contribute to such disparities is not known. We examined whether medication adherence, controlling for treatment intensification, could explain differences in risk factor control between black and white patients with diabetes. METHODS: We identified three cohorts of black and white patients treated with oral medications and who had poor risk factor control at baseline (2009): those with glycated hemoglobin (HbA1c) >8 % (n = 37,873), low-density lipoprotein cholesterol (LDL-C) >100 mg/dl (n = 27,954), and systolic blood pressure (SBP) >130 mm Hg (n = 63,641). Subjects included insured adults with diabetes who were receiving care in one of nine U.S. integrated health systems comprising the SUrveillance, PREvention, and ManagEment of Diabetes Mellitus (SUPREME-DM) consortium. Baseline and follow-up risk factor control, sociodemographic, and clinical characteristics were obtained from electronic health records. Pharmacy-dispensing data were used to estimate medication adherence (i.e., medication refill adherence [MRA]) and treatment intensification (i.e., dose increase or addition of new medication class) between baseline and follow-up. County-level income and educational attainment were estimated via geocoding. Logistic regression models were used to test the association between race and follow-up risk factor control. Models were specified with and without medication adherence to evaluate its role as a mediator. RESULTS: We observed poorer medication adherence among black patients than white patients (p < 0.01): 50.6 % of blacks versus 39.7 % of whites were not highly adherent (i.e., MRA <80 %) to HbA1c oral medication(s); 58.4 % of blacks and 46.7 % of whites were not highly adherent to lipid medication(s); and 33.4 % of blacks and 23.7 % of whites were not highly adherent to BP medication(s). Across all cardiometabolic risk factors, blacks were significantly less likely to achieve control (p < 0.01): 41.5 % of blacks and 45.8 % of whites achieved HbA1c <8 %; 52.6 % of blacks and 60.8 % of whites achieved LDL-C <100; and 45.7 % of blacks and 53.6 % of whites achieved SBP <130. Adjusting for medication adherence/treatment intensification did not alter these patterns or model fit statistics. CONCLUSIONS: Medication adherence failed to explain observed racial differences in the achievement of HbA1c, LDL-C, and SBP control among insured patients with diabetes.

Female Sexual Function Index Short Version: A MsFLASH Item Response Analysis.

The Female Sexual Function Index (FSFI) is a psychometrically sound and popular 19-item self-report measure, but its length may preclude its use in studies with multiple outcome measures, especially when sexual function is not a primary endpoint. Only one attempt has been made to create a shorter scale, resulting in the Italian FSFI-6, later translated into Spanish and Korean without further psychometric analysis. Our study evaluated whether a subset of items on the 19-item English-language FSFI would perform as well as the full-length FSFI in peri- and postmenopausal women. We used baseline data from 898 peri- and postmenopausal women recruited from multiple communities, ages 42-62 years, and enrolled in randomized controlled trials for vasomotor symptom management. Goals were to (1) create a psychometrically sound, shorter version of the FSFI for use in peri- and postmenopausal women as a continuous measure and (2) compare it to the Italian FSFI-6. Results indicated that a 9-item scale provided more information than the FSFI-6 across a spectrum of sexual functioning, was able to capture sample variability, and showed sufficient range without floor or ceiling effects. All but one of the items from the Italian 6-item version were included in the 9-item version. Most omitted FSFI items focused on frequency of events or experiences. When assessment of sexual function is a secondary endpoint and subject burden related to questionnaire length is a priority, the 9-item FSFI may provide important information about sexual function in English-speaking peri- and postmenopausal women.

Is heart rate variability associated with frequency and intensity of vasomotor symptoms among healthy perimenopausal and postmenopausal women?

OBJECTIVE: Research has suggested that the autonomic nervous system (ANS) is involved in the experience of vasomotor symptoms (VMS) during menopause. We examined the relationship of VMS intensity and heart rate variability (HRV), a measure of ANS function. METHODS: Women (n = 282) were recruited from three American states for a clinical trial of yoga, exercise, and omega-3 fatty acid supplements for VMS. To be eligible, women had to report at least 14 VMS per week, with some being moderate to severe. Sitting electrocardiograms were recorded for 15 min using Holter monitors at both baseline and 12-week follow-up. Time and frequency domain HRV measures were calculated. Women completed daily diary measures of VMS frequency and intensity for 2 weeks at baseline and for 1 week at the follow-up assessment 12 weeks later. Multivariable linear regression was used to assess the relationship between VMS and baseline HRV measures and to compare change in HRV with change in VMS over the 12 weeks. RESULTS: Baseline HRV was not associated with either VMS frequency or intensity at baseline. Change in HRV was not associated with change in VMS frequency or intensity across the follow-up. INTERPRETATION: Heart rate variability (HRV) was not associated with basal VMS frequency or intensity in perimenopausal and postmenopausal women experiencing high levels of VMS. Autonomic function may be associated with the onset or presence of VMS, but not with the number or intensity of these symptoms.

Trends in diabetes incidence among 7 million insured adults, 2006-2011: the SUPREME-DM project.

An observational cohort analysis was conducted within the Surveillance, Prevention, and Management of Diabetes Mellitus (SUPREME-DM) DataLink, a consortium of 11 integrated health-care delivery systems with electronic health records in 10 US states. Among nearly 7 million adults aged 20 years or older, we estimated annual diabetes incidence per 1,000 persons overall and by age, sex, race/ethnicity, and body mass index. We identified 289,050 incident cases of diabetes. Age- and sex-adjusted population incidence was stable between 2006 and 2010, ranging from 10.3 per 1,000 adults (95% confidence interval (CI): 9.8, 10.7) to 11.3 per 1,000 adults (95% CI: 11.0, 11.7). Adjusted incidence was significantly higher in 2011 (11.5, 95% CI: 10.9, 12.0) than in the 2 years with the lowest incidence. A similar pattern was observed in most prespecified subgroups, but only the differences for persons who were not white were significant. In 2006, 56% of incident cases had a glycated hemoglobin (hemoglobin A1c) test as one of the pair of events identifying diabetes. By 2011, that number was 74%. In conclusion, overall diabetes incidence in this population did not significantly increase between 2006 and 2010, but increases in hemoglobin A1c testing may have contributed to rising diabetes incidence among nonwhites in 2011.

Placebo improvement in pharmacologic treatment of menopausal hot flashes: time course, duration, and predictors.

OBJECTIVES: To characterize the time course, duration of improvement, and clinical predictors of placebo response in treatment of menopausal hot flashes. METHODS: Data were pooled from two trials conducted in the Menopausal Strategies: Finding Lasting Answers to Symptoms and Health network, providing a combined placebo group (n = 247) and a combined active treatment group (n = 297). Participants recorded hot flash frequency in diaries twice daily during treatment (Weeks 0-8) and subsequent follow-up (Weeks 9-11). The primary outcome variable was clinically significant improvement, defined as a 50% or greater decrease in hot flash frequency from baseline and calculated for each week in the study. Subgroups were defined a priori using standard clinical definitions for significant improvement and partial improvement. Clinical and demographic characteristics of the participants were evaluated as predictors of improvement. RESULTS: Clinically significant improvement with placebo accrued each treatment week, with 33% significantly improved at Week 8. Of placebo responders who were improved at both Weeks 4 and 8, 77% remained clinically improved at Week 11 after treatment ended. Independent predictors of significant placebo improvement in the final multivariable model were African American race (odds ratio [OR] = 5.61, 95% confidence interval [CI] = 2.41-13.07, p < .001), current smokers (OR = 2.30, 95% CI = 1.05-5.06, p = .038), and hot flash severity in screening (OR = 1.45, 95% CI = 1.00-2.10, p = .047). CONCLUSIONS: Clinically significant improvement with placebo accrued throughout treatment with a time course similar to improvement with active drug. A meaningful number of participants in the placebo group sustained a clinically significant response after stopping placebo pills. The results suggest that nonspecific effects are important components of treatment and warrant further studies to optimize their contributions in clinical care.

Use of statins and antihypertensive medications in relation to risk of long-standing persistent atrial fibrillation.

BACKGROUND: After an initial episode of atrial fibrillation (AF), patients may develop long-standing persistent or permanent AF. OBJECTIVE: We evaluated whether use of statins, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or ß-blockers is associated with lower risk of long-standing persistent AF after an initial AF episode. METHODS: We conducted a population-based inception cohort study of participants enrolled in Group Health, aged 30 to 84 years, with newly diagnosed AF in 2001-2004. We included only participants whose initial AF episode terminated within 6 months of onset. We ascertained the primary outcome of long-standing persistent AF from medical records, electrocardiograms, and administrative data. We determined time-varying medication use from Group Health pharmacy data. RESULTS: Among 1317 participants with incident AF, 304 developed long-standing persistent AF. Our study suggests that current statin use versus never use may be associated with lower risk for long-standing persistent AF. However, the association was not statistically significant when adjusted for age, sex, cardiovascular risk factors, and current use of antiarrhythmic medication (hazard ratio [HR] = 0.77; 95% CI = 0.57, 1.03). In lagged analyses intended to reduce healthy user bias, current statin use 1 year prior versus never use 1 year prior was not associated with risk for long-standing persistent AF (HR = 0.91; 95% CI = 0.67, 1.24). ACE inhibitor, ARB, and ß-blocker use were not associated with risk for long-standing persistent AF. CONCLUSIONS: Current statin use may confer protection that wanes after discontinuing use. Alternatively, healthy user bias or chance may explain the association. The association of statin use with long-standing persistent AF warrants further investigation.

Variants near FOXE1 are associated with hypothyroidism and other thyroid conditions: using electronic medical records for genome- and phenome-wide studies.

We repurposed existing genotypes in DNA biobanks across the Electronic Medical Records and Genomics network to perform a genome-wide association study for primary hypothyroidism, the most common thyroid disease. Electronic selection algorithms incorporating billing codes, laboratory values, text queries, and medication records identified 1317 cases and 5053 controls of European ancestry within five electronic medical records (EMRs); the algorithms' positive predictive values were 92.4% and 98.5% for cases and controls, respectively. Four single-nucleotide polymorphisms (SNPs) in linkage disequilibrium at 9q22 near FOXE1 were associated with hypothyroidism at genome-wide significance, the strongest being rs7850258 (odds ratio [OR] 0.74, p = 3.96 × 10(-9)). This association was replicated in a set of 263 cases and 1616 controls (OR = 0.60, p = 5.7 × 10(-6)). A phenome-wide association study (PheWAS) that was performed on this locus with 13,617 individuals and more than 200,000 patient-years of billing data identified associations with additional phenotypes: thyroiditis (OR = 0.58, p = 1.4 × 10(-5)), nodular (OR = 0.76, p = 3.1 × 10(-5)) and multinodular (OR = 0.69, p = 3.9 × 10(-5)) goiters, and thyrotoxicosis (OR = 0.76, p = 1.5 × 10(-3)), but not Graves disease (OR = 1.03, p = 0.82). Thyroid cancer, previously associated with this locus, was not significantly associated in the PheWAS (OR = 1.29, p = 0.09). The strongest association in the PheWAS was hypothyroidism (OR = 0.76, p = 2.7 × 10(-13)), which had an odds ratio that was nearly identical to that of the curated case-control population in the primary analysis, providing further validation of the PheWAS method. Our findings indicate that EMR-linked genomic data could allow discovery of genes associated with many diseases without additional genotyping cost.

Menopausal quality of life: RCT of yoga, exercise, and omega-3 supplements.

OBJECTIVE: The purpose of this study was to determine the efficacy of 3 nonhormonal therapies for the improvement of menopause-related quality of life in women with vasomotor symptoms. STUDY DESIGN: We conducted a 12-week 3 × 2 randomized, controlled, factorial design trial. Peri- and postmenopausal women, 40-62 years old, were assigned randomly to yoga (n = 107), exercise (n = 106), or usual activity (n = 142) and also assigned randomly to a double-blind comparison of omega-3 (n = 177) or placebo (n = 178) capsules. We performed the following interventions: (1) weekly 90-minute yoga classes with daily at-home practice, (2) individualized facility-based aerobic exercise training 3 times/week, and (3) 0.615 g omega-3 supplement, 3 times/day. The outcomes were assessed with the following scores: Menopausal Quality of Life Questionnaire (MENQOL) total and domain (vasomotor symptoms, psychosocial, physical and sexual). RESULTS: Among 355 randomly assigned women who average age was 54.7 years, 338 women (95%) completed 12-week assessments. Mean baseline vasomotor symptoms frequency was 7.6/day, and the mean baseline total MENQOL score was 3.8 (range, 1-8 from better to worse) with no between-group differences. For yoga compared to usual activity, baseline to 12-week improvements were seen for MENQOL total -0.3 (95% confidence interval, -0.6 to 0; P = .02), vasomotor symptom domain (P = .02), and sexuality domain (P = .03) scores. For women who underwent exercise and omega-3 therapy compared with control subjects, improvements in baseline to 12-week total MENQOL scores were not observed. Exercise showed benefit in the MENQOL physical domain score at 12 weeks (P = .02). CONCLUSION: All women become menopausal, and many of them seek medical advice on ways to improve quality of life; little evidence-based information exists. We found that, among healthy sedentary menopausal women, yoga appears to improve menopausal quality of life; the clinical significance of our finding is uncertain because of the modest effect.

Intensification of antihyperglycemic therapy among patients with incident diabetes: a Surveillance Prevention and Management of Diabetes Mellitus (SUPREME-DM) study.

PURPOSE: Antihyperglycemic medication intensification practices among patients with incident diabetes are incompletely understood. We characterized the first intensification the year after oral antihyperglycemic medication initiation among incident diabetes patients. METHODS: This retrospective cohort study across 11 US health systems included adults identified with incident diabetes between 2005 and 2009 who started oral antihyperglycemic monotherapy or combination therapy within 6 months after diabetes identification. We determined intensification, defined as increased index medication dosage, addition of another oral medication, or switch to/addition of insulin 31-365 days after initial antihyperglycemic dispensing. Cox regression was used to assess intensification for patient, temporal, and system covariates, adjusting for glycosylated hemoglobin (HbA1c) as a time-dependent variable. RESULTS: Among 41,233 patients, 33.5% and 45.3% had treatment intensified within 6 and 12 months, respectively. This first intensification was most often with increased index medication dosage (78%), least often with insulin (<1%). HbA1c% was strongly associated with intensification (adjusted hazard ratios [HR] 1.59, 3.62, 4.44, and 5.52 for HbA1c 6.5% to <7%, 7% to <7.5%, 7.5 to <8%, and ≥8%, respectively, all P < 0.001, compared with HbA1c < 6.5%). In patients initially on monotherapy, age modified the HbA1c effect: at HbA1c < 7%, the HR differed little between middle-aged and older patients; at HbA1c ≥ 7%, the HR decreased with older age (e.g., age 40-49 years and HbA1c ≥ 8%: HR 8.14; age ≥ 80 years and HbA1c ≥ 8%: HR 4.44; compared with age ≥ 80 years and HbA1c < 6.5%). Within 1 year, 84.3% achieved HbA1c < 8%; 65.1% achieved HbA1c < 7%. CONCLUSIONS: Clinicians appear to be applying treatment intensification guidelines and individualizing therapy by considering patient age, achieving glycemic control among most incident diabetes patients.

Association of body mass index, diabetes, hypertension, and blood pressure levels with risk of permanent atrial fibrillation.

BACKGROUND: After an initial episode of atrial fibrillation (AF), AF may recur and become permanent. AF progression is associated with higher morbidity and mortality. Understanding the risk factors for permanent AF could help identify people who would benefit most from interventions. OBJECTIVE: To determine whether body mass index (BMI), diabetes, hypertension, and blood pressure levels are associated with permanent AF among people whose initial AF episode terminated. DESIGN: Population-based inception cohort study. PARTICIPANTS: Enrollees in Group Health, an integrated health care system, aged 30-84 with newly diagnosed AF in 2001-2004, whose initial AF terminated within 6 months and who had at least 6 months of subsequent follow-up (N = 1,385). MAIN MEASURES: Clinical characteristics were determined from medical records. Permanent AF was determined from medical records and ECG and administrative databases. Permanent AF was defined as AF present on two separate occasions 6-36 months apart, without any documented sinus rhythm between the two occasions. Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs). KEY RESULTS: Five-year cumulative incidence of permanent AF was 24 %. Compared with normal BMI (18.5-24.9 kg/m(2)), BMI levels of 25.0-29.9 (overweight), 30.0-34.9 (obese 1), 35.0-39.9 (obese 2), and ≥ 40.0 kg/m(2) (obese 3) were associated with HRs of permanent AF of 1.26 (95 % CI: 0.92, 1.72); 1.35 (0.96, 1.91); 1.50 (0.97, 2.33); and 1.79 (1.13, 2.84), adjusted for age, sex, diabetes, hypertension, blood pressure, coronary heart disease, valvular heart disease, heart failure, and prior stroke. Diabetes, hypertension, and blood pressure were not associated with permanent AF. CONCLUSIONS: For people whose initial AF episode terminates, benefits of having lower BMI may include a lower risk of permanent AF. Risk of permanent AF was similar for people with and without diabetes or hypertension and across blood pressure levels.

Initial antihyperglycemic drug therapy among 241 327 adults with newly identified diabetes from 2005 through 2010: a surveillance, prevention, and management of diabetes mellitus (SUPREME-DM) study.

BACKGROUND: Among adults with incident diabetes, data are lacking about first antihyperglycemic initiation and whether medication choice aligns with recommendations. OBJECTIVE: To identify predictors of initiating any antihyperglycemic, and specifically sulfonylurea versus metformin. METHODS: This retrospective cohort study included 241 327 patients from 11 US health systems, 2005 through 2010. Assessments included antihyperglycemic initiation within 6 months of diabetes identification, first medication initiated, and initiation predictors. RESULTS: Only 40.3% (n = 97 350) started any antihyperglycemic; 75.2% (n = 73 221) started metformin. Glycosylated hemoglobin (HbA1c) predicted initiating any antihyperglycemic (HbA1c >9%, relative risk [RR] = 3.94, 95% CI = 3.82, 4.07, vs HbA1c >6.5%-7%). Age modified the HbA1c effect: at higher HbA1c, likelihood of starting antihyperglycemics differed little across ages; at lower HbA1c, older patients were less likely to start antihyperglycemics (P < .001). Individuals with elevated serum creatinine (SCr) were more likely to started on sulfonylurea (SCr = 1.4-2, RR = 2.21 [2.05, 2.39]; SCr >2, RR = 2.75 [2.30, 3.29] vs normal SCr), particularly as HbA1c increased: patients with HbA1c 8%-9% and SCr >2 were 5.59 times (2.94, 10.65) more likely to start sulfonylurea versus those with HbA1c >6.5%-7% and normal SCr. Age predicted sulfonylurea initiation (20-39 years, RR = 0.87 [0.79, 0.95]; ≥ 80 years, RR = 2.41 [2.20, 2.65] vs 50-59 years). CONCLUSIONS: Among adults with incident diabetes, metformin was generally the first antihyperglycemic initiated. However, 59.7% did not start any antihyperglycemic at diabetes identification. HbA1c and age predict antihyperglycemic initiation; SCr and age predict sulfonylurea initiation.

Biomarkers of progestin therapy resistance and endometrial hyperplasia progression.

OBJECTIVE: We sought to identify biomarkers associated with progestin therapy resistance and persistence/progression of endometrial hyperplasia. STUDY DESIGN: We performed a nested case-control study among women with complex (n = 73) and atypical (n = 41) hyperplasia treated with oral progestin, followed up 2-6 months for persistence/progression. We evaluated index endometrial protein expression for progesterone receptor isoform A, progesterone receptor isoform B (PRB), PTEN, Pax-2, and Bcl-2. Odds ratios and 95% confidence intervals (CIs) were estimated. RESULTS: Among women with atypical hyperplasia, high PRB expression was associated with 90% decreased risk of persistence/progression (95% CI, 0.01-0.8). High expression of progesterone receptor A and PRB suggested decreased risk of persistence/progression (odds ratio, 0.1; 95% CI, 0.02-1.0). These findings were not observed among women with complex hyperplasia. No associations were found with PTEN, Pax-2, and Bcl-2 protein expression. CONCLUSION: PRB expression shows promise as a biomarker of progestin response. Further research is warranted to understand how PRB expression may guide treatment decisions.

PAX2 loss by immunohistochemistry occurs early and often in endometrial hyperplasia.

Immunohistochemical markers to assist in the diagnosis and classification of hyperplastic endometrial epithelial proliferations would be of diagnostic use. To examine the possible use of PAX2 as a marker of hyperplastic endometrium, cases of normal endometrium, simple and complex hyperplasia without atypia, atypical hyperplasia, and International Federation of Gynecology and Obstetrics (FIGO) grade 1 endometrioid carcinomas were stained for PAX2. Two hundred and six endometrial samples were available for interpretation of PAX2 staining. The percentage of cases with complete PAX2 loss (0% of cells staining) increased with increasing severity of hyperplasia: 0% of normal proliferative and secretory endometrium (n=28), 17.4% of simple hyperplasia (n=23), 59.0% of complex hyperplasia (n=83), 74.1% of atypical hyperplasia (n=54), and 73.3% of FIGO grade 1 endometrioid cancers (n=15). Partial loss of PAX2 expression did occur in normal endometrium (17.9%) but in smaller proportions of tissue and was less frequent than in simple hyperplasia (47.8% with partial loss), complex hyperplasia (32.5%), atypical hyperplasia (22.2%), and FIGO grade 1 carcinomas (20.0%). Uniform PAX2 expression was rare in complex (8.4%) and atypical hyperplasia (3.7%) and carcinoma (6.7%). When evaluating loss of PAX2 in histologically normal endometrium adjacent to lesional endometrium in a given case, statistically significant differences in staining were observed for simple hyperplasia (P=0.011), complex hyperplasia (P<0.001), atypical hyperplasia (P<0.001), and FIGO grade 1 endometrioid cancer (P=0.003). In summary, PAX2 loss seems to occur early in the development of endometrial precancers and may prove useful in some settings as a diagnostic marker in determining normal endometrium from complex and atypical hyperplasia and low-grade carcinomas. However, it is not useful in distinguishing between these diagnostic categories.

Learning health care systems: leading through research: the 18th Annual HMO Research Network Conference, April 29-May 2, 2012, Seattle, Washington.

The Health Maintenance Organization Research Network (HMORN), a consortium of 19 health care delivery systems with integrated research centers, held their 18th annual conference in Seattle, Washington from April 29 to May 2, 2012. Group Health Research Institute hosted the conference, "Learning health care systems: Leading through research". The 2012 theme was chosen to reflect the critical role of collaboration among researchers, clinicians and health systems to improve health care nationally. Over 500 researchers and health care professionals participated in this conference. Representatives from the NCI, NHLBI, NIMH, and PCORI met with researchers to advance the quality and breadth of public domain research in HMOs. In this article we summarize information about the HMORN and its 18th annual conference.

Evaluating components of dental care utilization among adults with diabetes and matched controls via hurdle models.

BACKGROUND: About one-third of adults with diabetes have severe oral complications. However, limited previous research has investigated dental care utilization associated with diabetes. This project had two purposes: to develop a methodology to estimate dental care utilization using claims data and to use this methodology to compare utilization of dental care between adults with and without diabetes. METHODS: Data included secondary enrollment and demographic data from Washington Dental Service (WDS) and Group Health Cooperative (GH), clinical data from GH, and dental-utilization data from WDS claims during 2002-2006. Dental and medical records from WDS and GH were linked for enrollees continuously and dually insured during the study. We employed hurdle models in a quasi-experimental setting to assess differences between adults with and without diabetes in 5-year cumulative utilization of dental services. Propensity score matching adjusted for differences in baseline covariates between the two groups. RESULTS: We found that adults with diabetes had lower odds of visiting a dentist (OR = 0.74, p < 0.001). Among those with a dental visit, diabetes patients had lower odds of receiving prophylaxis (OR = 0.77), fillings (OR = 0.80) and crowns (OR = 0.84) (p < 0.005 for all) and higher odds of receiving periodontal maintenance (OR = 1.24), non-surgical periodontal procedures (OR = 1.30), extractions (OR = 1.38) and removable prosthetics (OR = 1.36) (p < 0.001 for all). CONCLUSIONS: Patients with diabetes are less likely to use dental services. Those who do are less likely to use preventive care and more likely to receive periodontal care and tooth-extractions. Future research should address the possible effectiveness of additional prevention in reducing subsequent severe oral disease in patients with diabetes.

Urinary cadmium and mammographic density in premenopausal women.

Mammographic density (MD), a strong marker of breast cancer risk, is influenced by genetic, environmental, and hormonal factors. Cadmium, a persistent and widespread environmental pollutant, has been associated with risk of breast cancer, and laboratory evidence suggests cadmium is a carcinogen in the breast. We investigated the hypothesis that cadmium exposure is associated with higher MD. In a cross-sectional study of MD and urinary cadmium concentration, percentage MD (MD%) and Breast Imaging-Reporting and Data Systems (BI-RADS®) density category were determined from screening mammograms of 190 premenopausal women ages 40-45 years. Women completed a health questionnaire, and the cadmium content of spot urine samples was measured with inductively coupled plasma mass spectrometry and corrected for urine creatinine. Urinary cadmium concentrations are thought to reflect exposure to cadmium during a period of 20-30 years. Multivariable linear regression and logistic regression were used to estimate the strength of association between urinary cadmium and mammographic breast density. Adjusted mean MD% among women in the upper tertile of creatinine-corrected urinary cadmium was 4.6% higher (95% CI: -2.3 to 11.6%) than in women in the lowest cadmium tertile. Each twofold increase in urinary cadmium was associated with higher odds of MD% in the upper tertile (OR: 1.29, 95% CI: 0.82-2.02) or a BI-RADS category rating of "extremely dense" (OR: 1.75, 95% CI: 1.14-2.70). Stronger associations were observed among nulliparous women, and current or former smokers. Exposure to cadmium may be associated with increased breast density in premenopausal women.

Ascertainment of warfarin and aspirin use by medical record review compared with automated pharmacy data.

PURPOSE: Automated pharmacy databases are increasingly available for assessing medication use, but research on the validity of these data is incomplete. This study aimed to measure agreement on warfarin and aspirin use between medical records and automated pharmacy data among patients with newly detected atrial fibrillation (AF). METHODS: Patients with newly detected AF (n = 1953) were previously identified in a cohort study at Group Health (GH) in Washington State. Medical records were reviewed for information on risk factors and medication use, as well as clinical care during the 6 months after AF onset. Medication data were also obtained from the GH pharmacy database. We determined the sensitivity, specificity, and positive predictive value (PPV) as measures of the validity of the GH pharmacy database as compared with medical records for warfarin and aspirin use during the first 6 and 3 months after AF onset. We also calculated the κ statistic. RESULTS: For warfarin use, in comparison with the medical record review, the sensitivity, specificity, and PPV for the GH pharmacy database were excellent, and agreement was almost perfect in the 3- and 6-month periods after AF onset (κ = 0.92 and 0.93, respectively). For aspirin use, the GH pharmacy database had low sensitivity but high specificity, and agreement was only fair for these two periods (κ = 0.28 and 0.31, respectively). CONCLUSIONS: The GH pharmacy database is a valuable source of data for pharmacoepidemiologic research on warfarin use among patients with AF. However, the database cannot be recommended for assessment of aspirin use. Copyright © 2010 John Wiley & Sons, Ltd.