The effect of experimentally-induced sleep fragmentation and estradiol suppression on neurobehavioral performance and subjective sleepiness in pre-menopausal women.

STUDY OBJECTIVES: Menopause is associated with nighttime sleep fragmentation, declining estradiol and impaired cognition. In a model of pharmacologically-induced estradiol suppression mimicking menopause, we examined the impact of menopause-pattern sleep fragmentation on daytime neurobehavioral performance and sleepiness in premenopausal women. METHODS: Twenty premenopausal women completed two 5-night inpatient studies in the mid-to-late follicular phase (estrogenized) and after pharmacological estradiol suppression (hypo-estrogenized). During each study, participants had an uninterrupted 8-hour sleep opportunity for two nights, followed by three nights where sleep was experimentally fragmented to mimic menopause-pattern sleep disturbance, and during which the sleep opportunity was extended to prevent shortening of the sleep duration. Neurobehavioral performance and subjective sleepiness were measured using the Psychomotor Vigilance Task and Karolinska Sleepiness Scale (KSS). RESULTS: Compared to unfragmented sleep, sleep fragmentation increased attentional lapses (+0.6 lapses, p<0.05), slowed reaction time (+9.4 milliseconds, p<0.01), and increased daytime sleepiness (+0.5 KSS score, p<0.001). Estradiol suppression increased attentional lapses (+0.8; p<0.001) and reaction time (+12.3, p<0.01) but did not significantly affect daytime sleepiness. The effect of sleep fragmentation on neurobehavioral performance differed by estradiol state, such that the adverse effects of sleep fragmentation on attentional lapses (+0.9, trend p=0.06) and reaction time (+15, p<0.05) were observed only when estrogenized. CONCLUSIONS: Menopause-pattern sleep fragmentation and estradiol suppression worsened neurobehavioral performance and daytime sleepiness, even while sleep duration was not reduced. The adverse effects of sleep fragmentation in the context of an adequate sleep duration highlight the importance of sleep continuity as a vital aspect of good sleep health.

Effects of Sleep Fragmentation and Estradiol Decline on Cortisol in a Human Experimental Model of Menopause.

CONTEXT: Perturbations to the hypothalamic-pituitary-adrenal (HPA) axis have been hypothesized to increase postmenopausal cardiometabolic risk. Although sleep disturbance, a known risk factor for cardiometabolic disease, is prevalent during the menopause transition, it is unknown whether menopause-related sleep disturbance and estradiol decline disturb the HPA axis. OBJECTIVE: We examined the effect of experimental fragmentation of sleep and suppression of estradiol as a model of menopause on cortisol levels in healthy young women. METHODS: Twenty-two women completed a 5-night inpatient study during the mid-to-late follicular phase (estrogenized). A subset (n = 14) repeated the protocol after gonadotropin-releasing hormone agonist-induced estradiol suppression. Each inpatient study included 2 unfragmented sleep nights followed by 3 experimental sleep fragmentation nights. This study took place with premenopausal women at an academic medical center. Interventions included sleep fragmentation and pharmacological hypoestrogenism, and main outcome measures were serum bedtime cortisol levels and cortisol awakening response (CAR). RESULTS: Bedtime cortisol increased 27% (P = .03) and CAR decreased 57% (P = .01) following sleep fragmentation compared to unfragmented sleep. Polysomnographic-derived wake after sleep-onset (WASO) was positively associated with bedtime cortisol levels (P = .047) and negatively associated with CAR (P < .01). Bedtime cortisol levels were 22% lower in the hypoestrogenized state compared to the estrogenized state (P = .02), while CAR was similar in both estradiol conditions (P = .38). CONCLUSION: Estradiol suppression and modifiable menopause-related sleep fragmentation both independently perturb HPA axis activity. Sleep fragmentation, commonly seen in menopausal women, may disrupt the HPA axis, which in turn may lead to adverse health effects as women age.

Disruption of Sleep Continuity During the Perimenopause: Associations with Female Reproductive Hormone Profiles.

CONTEXT: Nocturnal vasomotor symptoms (nVMS), depressive symptoms (DepSx), and female reproductive hormone changes contribute to perimenopause-associated disruption in sleep continuity. Hormonal changes underlie both nVMS and DepSx. However, their association with sleep continuity parameters resulting in perimenopause-associated sleep disruption remains unclear. OBJECTIVE: We aimed to determine the association between female reproductive hormones and perimenopausal sleep discontinuity independent of nVMS and DepSx. METHODS: Daily sleep and VMS diaries, and weekly serum assays of female reproductive hormones were obtained for 8 consecutive weeks in 45 perimenopausal women with mild DepSx but no primary sleep disorder. Generalized estimating equations were used to examine associations of estradiol, progesterone, and follicle stimulating hormone (FSH) with mean number of nightly awakenings, wakefulness after sleep onset (WASO) and sleep-onset latency (SOL) adjusting for nVMS and DepSx. RESULTS: Sleep disruption was common (median 1.5 awakenings/night, WASO 24.3 and SOL 20.0 minutes). More awakenings were associated with estradiol levels in the postmenopausal range (ß = 0.14; 95% CI, 0.04 to 0.24; P = 0.007), and higher FSH levels (ß [1-unit increase] = 0.12; 95% CI, 0.02 to 0.22; P = 0.02), but not with progesterone (ß [1-unit increase] = -0.02; 95% CI, -0.06 to 0.01; P = 0.20) in adjusted models. Female reproductive hormones were not associated with WASO or SOL. CONCLUSION: Associations of more awakenings with lower estradiol and higher FSH levels provide support for a perimenopause-associated sleep discontinuity condition that is linked with female reproductive hormone changes, independent of nVMS and DepSx.

Sleep Fragmentation and Estradiol Suppression Decrease Fat Oxidation in Premenopausal Women.

CONTEXT: Body fat gain associated with menopause has been attributed to estradiol (E2) withdrawal. Hypoestrogenism is unlikely to be the only contributing factor, however. OBJECTIVE: Given the links between sleep and metabolic health, we examined the effects of an experimental menopausal model of sleep fragmentation on energy metabolism. METHODS: Twenty premenopausal women (age 21-45 years) underwent a 5-night inpatient study during the mid-to-late follicular phase (estrogenized; n = 20) and the same protocol was repeated in a subset of the participants (n = 9) following leuprolide-induced E2 suppression (hypo-estrogenized). During each 5-night study, there were 2 nights of unfragmented sleep followed by 3 nights of fragmented sleep. Indirect calorimetry was used to assess fasted resting energy expenditure (REE) and substrate oxidation. RESULTS: Sleep fragmentation in the estrogenized state increased the respiratory exchange ratio (RER) and carbohydrate oxidation while decreasing fat oxidation (all P < 0.01). Similarly, in the hypo-estrogenized state without sleep fragmentation, RER and carbohydrate oxidation increased and fat oxidation decreased (all P < 0.01); addition of sleep fragmentation to the hypo-estrogenized state did not produce further effects beyond that observed for either intervention alone (P < 0.05). There were no effects of either sleep fragmentation or E2 state on REE. CONCLUSION: Sleep fragmentation and hypoestrogenism each independently alter fasting substrate oxidation in a manner that may contribute to body fat gain. These findings are important for understanding mechanisms underlying propensity to body fat gain in women across the menopause transition.

Enrollment of female participants in United States drug and device phase 1-3 clinical trials between 2016 and 2019.

BACKGROUND: Historically, females have been underrepresented in clinical trials evaluating the safety and efficacy of investigational drugs and devices. We assessed participation by sex in recent clinical trials. METHODS: We extracted data over a 4-year period (2016-2019) from ClinicalTrials.gov on US-based, pharmaceutical industry or government-funded Phase 1-3 clinical trials of drugs and devices. We included trials with adult cardiovascular, psychiatric, and cancer endpoints whose protocol planned to enroll both sexes. Average proportions of females enrolled per trial were described overall and by disease area. RESULTS: Across 1433 trials including 302,664 participants in our analysis, on average, 41.2% were female. Females were underrepresented compared with their proportion of the disease population in cardiovascular disease trials (41.9% female participants vs. 49% female population with cardiovascular disease). In psychiatry, where females comprise 60% of patients, the mean participation of females in clinical trials was 42.0%. Similarly, for cancer trials, where 51% of patients are female, only 41.0% of cancer clinical trial participants were female. For each therapeutic area analyzed, the participation of females in clinical trials fell short of the benchmark derived from national prevalence data. CONCLUSIONS: While the participation of females in clinical trials has improved compared to previous reports, sex-based gaps still persist between trial populations and those expected to use these drugs/devices based on distributions of diseases in the population. Given potential sex-based differences in treatment responses and toxicities, adequate inclusion of females in clinical trials remains critical.

A double-blind, randomized, placebo-controlled trial of suvorexant for the treatment of vasomotor symptom-associated insomnia disorder in midlife women.

STUDY OBJECTIVES: The neuropeptide orexin promotes wakefulness, modulates thermoregulation, increases after menopause, and is normalized in women receiving estrogen therapy, suggesting a role for orexin antagonism as a treatment for the vasomotor symptom (VMS)-associated insomnia disorder. We tested the efficacy of the dual orexin receptor antagonist suvorexant for chronic insomnia related to nighttime VMS. METHODS: In a double-blind, placebo-controlled trial, 56 women with chronic insomnia associated with nighttime VMS, Insomnia Severity Index (ISI) scores ≥15, and >30 min of diary-rated wake after sleep-onset (WASO) were randomized to receive oral suvorexant 10-20 mg (n = 27) or placebo (n = 29) nightly for 4 weeks. Analysis of within-person change in ISI was adjusted for baseline ISI and race. RESULTS: Mean baseline ISI scores were 18.1 (95% CI, 16.8 to 19.4) and 18.3 (95% CI, 17.2 to 19.5) in the suvorexant and placebo groups, respectively (p = .81). The average 4-week ISI within-person decrease from baseline was greater on suvorexant (-8.1 [95% CI, -10.2 to -6.0]) compared to placebo (-5.6 [95% CI, -7.4 to -3.9], p = .04). Compared to placebo, nighttime diary-rated VMS frequency was significantly reduced with suvorexant (p < .01). While diary-rated WASO and total sleep time trended toward improvement on suvorexant, findings were not significant after adjustment for multiple comparisons. Daytime VMS and other sleep-related outcomes did not differ between groups. Suvorexant was well tolerated. CONCLUSION: These results suggest that suvorexant is likely a well-tolerated and efficacious treatment for VMS-associated insomnia disorder and reduces nighttime VMS. Antagonism of orexin receptors could provide a novel therapeutic option for midlife women with VMS-associated chronic insomnia. CLINICAL TRIAL INFORMATION: Efficacy of Suvorexant in the Treatment of Hot Flash-associated Insomnia, https://clinicaltrials.gov/ct2/show/NCT03034018, ClinicalTrials.gov Identifier: NCT03034018.

Brain-derived neurotrophic factor and mood in perimenopausal depression.

BACKGROUND: Previous work implicates high pro-inflammatory biomarkers in mood disturbance and low brain-derived neurotrophic factor (BDNF) levels in major depression. However, in hormonally-sensitive premenstrual dysphoric disorder (PMDD), BDNF levels are higher when mood is worse. Perimenopausal depression has not been studied to date. We evaluated whether BDNF and inflammatory cytokines predict mood symptoms across the menstrual cycle in hormonally-sensitive perimenopausal depression symptoms. METHODS: Data from 49 time points derived from mid-to-late follicular phase [M/L-FP] and peri­menstrual assessments of 14 perimenopausal women ages 38-52 with ovulatory menstrual cycles 24-35 days long across 1-2 cycles for mood symptoms, BDNF levels, cytokines, gonadal steroids. Depression was assessed with Montgomery-Åsberg Depression Rating Scale (MADRS), Beck Depression Inventory (BDI); irritability with Kellner Symptom Questionnaire Anger-Hostility subscale (SQ); overall psychological distress with Profile of Mood States (POMS). Mixed models were run on dependent measures of MADRS (primary endpoint) and other mood outcomes (BDI, POMS, SQ) with independent variables of interest (each biomarker, cycle phase), controlling for cycle number and participant. RESULTS: After FDR adjustment, BDNF levels showed consistent significant positive relationships to MADRS (ß=0.00053; p = 0.0028), POMS (ß=0.00153; p = 0.0394), SQ (ß=0.00053; p = 0.0067), and BDI (ß=0.00039; p = 0.0231). Cycle phase did not affect this relationship. No other biomarker consistently predicted affective symptom severity. LIMITATIONS: Small sample size and large number of comparisons. CONCLUSION: In women with perimenopausal depression symptoms, BDNF is elevated in association with more severe mood symptomatology, resembling the pattern in hormonally-sensitive PMDD and suggesting a hormonally-sensitive mood disorder biomarker profile distinct from that of major depression.

Predictors of irritability symptoms in mildly depressed perimenopausal women.

OBJECTIVE: Irritability is a highly burdensome complaint, commonly, but not universally, linked with depressive symptoms. While increased variability in estradiol has been associated with depressive symptoms during perimenopause, more insight is needed into reproductive hormone dynamics and other factors that predispose perimenopausal women to irritable mood. METHODS: Among 50 mildly depressed perimenopausal women (mean (SD) age 48.4 (3.9) years), severity of irritability symptoms (on Symptom Questionnaire Hostility subscale, range 0-23) was assessed weekly for eight weeks, concurrent with potential predictors. Associations between these were examined using generalized estimating equating models. RESULTS: Most women (82.0%) reported having moderate to severe irritability at least once. However, the severity of irritability was highly variable from week-to-week (between-subject mean coefficient of variation [CV] 72.9% and within-subject mean CV 63.7%). In multivariate analyses, less variable serum estradiol levels (standardized ß within-person CV -0.23 95%CI [-0.32, -0.14], p < 0.001), greater depression severity (0.45 [0.35, 0.56], p < 0.001), younger age (-0.23, [-0.28, -0.09], p < 0.001), and more frequent vasomotor symptoms (0.14 [0.05, 0.23], p = 0.002) were associated with more irritability. Depression severity explained the largest portion of the variance in irritability, but still not more than 20.3%. Neither crude values, weekly change in, or variability of progesterone or FSH levels were associated with irritability. CONCLUSIONS: Irritability was highly prevalent among mildly depressed perimenopausal women. In contrast to depressive symptoms, decreased rather than increased variability in estradiol levels was associated with more irritability. This highlights that irritable mood can be disentangled from depressive symptoms in perimenopausal women and might be linked with different estradiol dynamics.

Predictors of increased risk for early treatment non-adherence to oral anti-estrogen therapies in early-stage breast cancer patients.

PURPOSE: Non-adherence to the oral anti-estrogen therapies (AET) tamoxifen and aromatase inhibitors in early-stage hormone receptor-positive breast cancer is associated with numerous negative clinical outcomes. Prior studies have identified that non-adherence is associated with psychological and menopause-related factors which are present during AET, but the presence of these characteristics prior to AET initiation has not been investigated. METHODS: Psychological and menopause symptoms (depression, generalized anxiety, insomnia, somatosensory amplification, hot flash frequency, and hot flash-related interference) were assessed pre-AET initiation as predictors of subsequent non-adherence in 73 participants (Mage = 55.0, SD = 10.1 years). Participants self-reported treatment adherence after three and 6 weeks on AET. Participants who did not initiate treatment were excluded from the analysis. RESULTS: Discriminant function analyses revealed that the hypothesized set of psychological and menopause symptoms at baseline (pre-AET) together statistically distinguished between those who were non-adherent (n = 19; 26.0%) from adherent (n = 54; 74.0%) at 6 weeks. Model classification accuracy was statistically significant (Wilks' ƛ = 0.782, χ2(6) = 15.50, p = 0.017) at the 6-week timepoint. Results were consistent at 3 weeks. Pre-AET psychological and menopause symptoms correctly classified 6-week treatment adherence 77.9% of the time. Depression contributed most to distinguishing between adherers and non-adherers. CONCLUSIONS: The presence of a composite profile of psychological and menopause symptoms prior to AET initiation may help to identify early treatment non-adherence. Results can be used to identify patients at risk for non-adherence and to guide psychological and symptom management interventions.

Hypothalamic-pituitary-adrenal axis, subjective, and thermal stress responses in midlife women with vasomotor symptoms.

OBJECTIVE: Dysregulated responses to experimental stress paradigms may indicate exposure to chronic stress. Vasomotor symptoms (VMS) are linked with diminished quality of life and psychological stress, but induced stress responsivity has received limited investigation. We examined whether women with and without VMS differ in their evoked hypothalamic-pituitary-adrenal axis, subjective, hemodynamic, and thermal stress responses. METHODS: A total of 37 midlife women (27 VMS+; 10 VMS-) completed 2 experimental stress paradigms: (1) Montreal Imaging Stress Task (MIST; computerized social-evaluative stressor) and (2) Quantitative Sensory Testing (QST; thermal stress task). Responses on a five-domain (range 0-50) Visual Analog Scale, salivary cortisol (hypothalamic-pituitary-adrenal axis), and hemodynamic indices (blood pressure, heart rate) were measured before and after each task to compare within-person change between groups. Thermal sensitivity was assessed on the QST. RESULTS: On the MIST, the VMS+ group showed a smaller cortisol release (0.01 vs 0.07 µg/dL; P = 0.046; corresponding to 54% vs 83% increases), and subjective stress response (21.2- vs 31.1-point Visual Analog Scale increase, P = 0.05; corresponding to 2427% vs 2863% increases) but no hemodynamic difference, compared to the VMS- group. The QST did not provoke stress responses via cortisol release or subjective report, but the VMS+ group tended to perceive heat at a higher temperature (38.5°C vs 36.4°C, P = 0.08). CONCLUSIONS: Women with VMS exhibited both diminished cortisol and subjective stress responses to the MIST, and reduced thermal sensitivity on QST compared to women without VMS. Dysregulated stress responsivity provides preliminary evidence suggesting that VMS may represent a chronic stress condition.

Impact of Estradiol Variability and Progesterone on Mood in Perimenopausal Women With Depressive Symptoms.

CONTEXT: Women are at increased risk for depressive symptoms during the menopause transition. Changes in estradiol secretion and presence of vasomotor symptoms (VMS) contribute to perimenopausal depressive symptoms, but links with progesterone have not been investigated. OBJECTIVE: To determine whether estradiol variability, ovulatory levels of progesterone, and VMS burden are independently associated with perimenopausal depressive symptomatology. DESIGN AND INTERVENTION: Depressive symptoms, serum levels of estradiol and progesterone, and VMS frequency were assessed weekly in an 8-week observational study. Association of mood with estradiol variability, ovulatory levels of progesterone, and VMS frequency were estimated using generalized estimating equation models. SETTING: Academic medical center. PATIENTS: Fifty unmedicated perimenopausal women with mild-to-moderate depressive symptoms (mean Montgomery-Åsberg Depression Rating Scale [MADRS] score 15.5 ± 5.3). MAIN OUTCOME MEASURE: Depressive symptoms (MADRS score). RESULTS: During the study, 90.0% of participants had varying estradiol levels, 51.1% had ovulatory progesterone levels, and 90% had VMS. Greater estradiol variability and absence of progesterone levels consistent with ovulation, but not VMS frequency, are associated with higher levels of depressive symptoms (ß = 0.11 [95% confidence interval (95% CI), 0.04 to 0.18; P = 0.001]; ß = -2.62 [95% CI, -4.52 to -0.71; P = 0.007], respectively), after accounting for higher body mass index, lifetime history of depression, and stressful life events. CONCLUSIONS: Increasing dysregulation of ovarian hormones, but not VMS, associates with more depressive symptom burden during perimenopause. These results suggest that perimenopausal mood instability is driven by the underlying hormonal dysregulation of the menopause transition involving changes in both estradiol and progesterone.

Cardiovascular reactivity and psychological hyperarousal in hot flash-associated insomnia disorder.

OBJECTIVES: Given the neurocognitive hyperarousal observed in patients with insomnia disorder and associations of nocturnal hot flashes with cardiovascular disease risk, we examined whether women with hot flash-associated insomnia disorder demonstrate exaggerated cardiovascular responsivity to acute stressors, and also a profile of psychological hyperarousal. METHODS: Peri and postmenopausal women with and without hot flash-associated insomnia disorder underwent assessments of cardiovascular autonomic responsivity to acute stress paradigms and psychological hyperarousal. Hemodynamic responses (heart rate, blood pressure) to nociceptive, social-evaluative, and cognitive stress paradigms were measured in the morning. Psychological hyperarousal was evaluated using questionnaires assessing daytime and presleep hyperarousal, anxiety, and sleep-related cognitions. RESULTS: Women (25 with and 15 without hot flash-associated insomnia) aged 53.4 ±â€Š4.8 years reported a range of insomnia symptoms. Resting-state hemodynamics were similar between groups. Heart rate and blood pressure responses to stress paradigms did not differ by group nor did they correlate with insomnia severity. Women with insomnia disorder had higher generalized anxiety disorder scores (mean 2.7 ±â€Š3.0 vs 1.0 ±â€Š1.4; P = 0.05) and sleep-related cognitions than those without insomnia (P ≤ 0.05). Insomnia symptom severity was moderately correlated with presleep and daytime hyperarousal, anxiety, and sleep-related cognition (all r ≥ 0.43). CONCLUSIONS: Though hot flash-associated insomnia is characterized by psychological hyperarousal before sleep and during the daytime, it does not relate to cardiovascular responsiveness to acute stressors. Our findings do not support the hypothesis that altered cardiovascular control is a potential mechanism by which hot flash-associated insomnia confers higher cardiovascular disease risk.

Occupational exposure to disinfectants and asthma control in US nurses.

Disinfectant use has been associated with adverse respiratory effects among healthcare workers. However, the specific harmful agents have not been elucidated. We examined the association between occupational exposure to disinfectants and asthma control in the Nurses' Health Study II, a large cohort of female nurses.Nurses with asthma were invited in 2014 to complete two questionnaires on their current occupation and asthma (response rate 80%). Asthma control was defined by the Asthma Control Test (ACT). Exposure to major disinfectants was evaluated by a job-task-exposure matrix (JTEM).Analyses included 4102 nurses with asthma (mean age 58 years). Asthma control was poor (ACT score 16-19) in 12% of nurses and very poor (ACT score ≤15) in 6% of nurses. Use of disinfectants to clean medical instruments (19% exposed) was associated with poorly (OR 1.37; 95% CI 1.05-1.79) and very poorly (OR 1.88, 95% CI 1.38-2.56) controlled asthma (ptrend=0.004, after adjustment for potential confounders). Using JTEM estimates, exposure to formaldehyde, glutaraldehyde, hypochlorite bleach, hydrogen peroxide and enzymatic cleaners was associated with poor asthma control (all ptrend<0.05); exposure to quaternary ammonium compounds and alcohol was not.Use of several disinfectants was associated with poor asthma control. Our findings suggest targets for future efforts to prevent worsening of asthma control in healthcare workers.

Determinants of disinfectant use among nurses in U.S. healthcare facilities.

BACKGROUND: Disinfectant use among healthcare workers has been associated with respiratory disorders, especially asthma. We aimed to describe disinfectants used by U.S. nurses, and to investigate qualitative and quantitative differences according to workplace characteristics and region. METHODS: Disinfectant use was assessed by questionnaire in 8,851 nurses. Hospital characteristics were obtained from the American Hospital Association database. RESULTS: Working in a hospital was associated with higher disinfectant use (OR: 2.06 [95%CI: 1.89-2.24]), but lower spray use (0.74 [0.66-0.82]). Nurses working in smaller hospitals (<50 beds vs. ≥200 beds) were more likely to use disinfectants (1.69 [1.23-2.32]) and sprays (1.69 [1.20-2.38]). Spray use was lower in the West than in the Northeast (0.75 [0.58-0.97]). CONCLUSION: Disinfectant use was more common among nurses working in smaller hospitals, possibly because they perform more diverse tasks. Variations in spray use by hospital size and region suggest additional targets for future efforts to prevent occupational asthma. Am. J. Ind. Med. 60:131-140, 2017. © 2016 Wiley Periodicals, Inc.

Epidemiology of Sarcoidosis in a Prospective Cohort Study of U.S. Women.

RATIONALE: Sarcoidosis is a systemic granulomatous and inflammatory disorder that most often involves the lungs but also affects many other organs. Data on sarcoidosis from large epidemiological studies remain scarce. OBJECTIVES: To evaluate the baseline prevalence and 22-year incidence of sarcoidosis and their associations with demographic and geographic characteristics in a large cohort of U.S. women. METHODS: The Nurses' Health Study II is a prospective cohort study of U.S. female nurses enrolled in 1989 (aged 25-44 yr, n = 116,430). Data on major illnesses were collected through biennial questionnaires (1989-2011). Cases were identified by the nurses' self-report of physician-diagnosed sarcoidosis. Associations of demographic and geographic characteristics with sarcoidosis were evaluated by logistic regression and Cox models. MEASUREMENTS AND MAIN RESULTS: A total of 377 sarcoidosis cases were identified. The baseline prevalence was 100/100,000 women. The average annual incidence rate was 11/100,000 during 2,275,028 person-years of follow up. Incidence rate increased with age (P = 0.003), from 9 to 15/100,000 in women aged less than 35 to 55 or more years, respectively. Black women had a higher prevalence (odds ratio, 5.24; 95% confidence interval, 2.87-9.55) and incidence (hazard ratio, 3.80; 95% confidence interval, 2.31-6.24) than white women. Across U.S. regions, more than twofold differences were observed in sarcoidosis prevalence and incidence, with consistently higher rates in the Northeast. CONCLUSIONS: We provide recent national data on the epidemiology of sarcoidosis among U.S. women. Important differences in prevalence and incidence were observed across U.S. regions. Large epidemiological studies are needed to better understand the causes of the observed demographic and geographic differences in sarcoidosis.

Design and Conduct of an Internet-Based Preconception Cohort Study in North America: Pregnancy Study Online.

BACKGROUND: We launched the Boston University Pregnancy Study Online (PRESTO) to assess the feasibility of carrying out an Internet-based preconception cohort study in the US and Canada. METHODS: We recruited female participants age 21-45 and their male partners through Internet advertisements, word of mouth, and flyers. Female participants were randomised with 50% probability to receive a subscription to FertilityFriend.com (FF), a web-based programme that collects real-time data on menstrual characteristics. We compared recruitment methods within PRESTO, assessed the cost-efficiency of PRESTO relative to its Danish counterpart (Snart-Gravid), and validated retrospectively reported date of last menstrual period (LMP) against the FF data. RESULTS: After 99 weeks of recruitment (2013-15), 2421 women enrolled; 1384 (57%) invited their male partners to participate, of whom 693 (50%) enrolled. Baseline characteristics were balanced across randomisation groups. Cohort retention was similar among those randomised vs. not randomised to FF (84% vs. 81%). At study enrollment, 56%, 22%, and 22% couples had been trying to conceive for < 3, 3-5, and ≥ 6 months, respectively. The cost per subject enrolled was $146 (2013 US$), which was similar to our companion Danish study and half that of a traditional cohort study. Among FF users who conceived, > 97% reported their LMP on the PRESTO questionnaire within 1 day of the LMP recorded via FF. CONCLUSIONS: Use of the Internet as a method of recruitment and follow-up in a North American preconception cohort study was feasible and cost-effective.

Asthma history, job type and job changes among US nurses.

OBJECTIVES: Nurses are at increased risk of occupational asthma, an observation that may be related to disinfectants exposure. Whether asthma history influences job type or job changes among nurses is unknown. We investigated this issue in a large cohort of nurses. METHODS: The Nurses' Health Study II is a prospective study of US female nurses enrolled in 1989 (ages 24-44 years). Job status and asthma were assessed in biennial (1989-2011) and asthma-specific questionnaires (1998, 2003). Associations between asthma history at baseline (diagnosis before 1989, n=5311) and job type at baseline were evaluated by multinomial logistic regression. The relations of asthma history and severity during follow-up to subsequent job changes were evaluated by Cox models. RESULTS: The analytic cohort included 98 048 nurses. Compared with nurses in education/administration (likely low disinfectant exposure jobs), women with asthma history at baseline were less often employed in jobs with likely high disinfectant exposure, such as operating rooms (odds ratio 0.73 (95% CI 0.63 to 0.86)) and emergency room/inpatient units (0.89 (0.82 to 0.97)). During a 22-year follow-up, nurses with a baseline history of asthma were more likely to move to jobs with lower exposure to disinfectants (HR 1.13 (1.07 to 1.18)), especially among those with more severe asthma (HR for mild persistent: 1.13; moderate persistent 1.26; severe persistent: 1.50, compared with intermittent asthma, p trend: 0.004). CONCLUSIONS: Asthma history was associated with baseline job type and subsequent job changes among nurses. This may partly reflect avoidance of tasks involving disinfectant use, and may introduce bias in cross-sectional studies on disinfectant exposure and asthma in nurses.