Readmissions Among Patients Admitted With Acute Decompensated Heart Failure Based on Income Quartiles

ObjectiveTo determine the impact of socioeconomic status using median household income within the patient's community on rate of readmission among patients with heart failure (HF).Patients and MethodsWe derived a study cohort of patients who were admitted from January 1, 2013, through December 31, 2014, with congestive HF from the Healthcare Cost and Utilization Project National Readmission Database. Patients were stratified into quartiles according to the estimated median household income of residents in the patient's ZIP Code (quartile 1, lowest; quartile 4, highest). The primary outcome was 30-day readmission. We used univariate and multivariate models to compare patients with respect to baseline characteristics, income quartiles, and 30-day readmission.ResultsAbout 20% (110,152 of 546,841) of patients with an index HF admission were readmitted within the first 30 days. Patients in the lowest income quartile had a higher readmission rate compared with those in the highest income quartile (21.1% [35,422 of 167,625] vs 19.5% [20,771 of 106,353]; P<.001). Patients within the lowest income group had higher odds of readmission for cardiovascular causes compared with the highest income group (50.6% [17,923 of 35,422] vs 48.8% [10,136 of 20,771; P<.001). Readmissions within the lowest income group accounted for 30% of all rehospitalization-related costs at $715 million. Multivariate analysis confirmed a higher rate of 30-day readmission among patients in the lowest income group compared with those in the highest group (adjusted odds ratio, 1.11; 95% CI, 1.08-1.13).ConclusionOur study shows that patients in communities with the lowest quartile of income have a higher rate of readmission following the index HF admission with high associated costs. Readmission reporting and reimbursement adjustments should account for these socioeconomic inequalities.     

Inverse Association of Handgrip Strength With Risk of Heart Failure

ObjectiveTo evaluate the nature, magnitude, and specificity of the association between handgrip strength (HGS) and heart failure (HF) risk.Patients and MethodsHandgrip strength was assessed at baseline from March 1, 1998, to December 31, 2001, by use of a hand dynamometer in the Finnish Kuopio Ischemic Heart Disease prospective population-based cohort of 770 men and women aged 61 to 74 years without a history of HF. Relative HGS was obtained by dividing the absolute value by body weight. Hazard ratios (HRs) with 95% CIs were estimated with Cox regression models. We used multiple imputation to account for missing data.ResultsDuring a median (interquartile range) follow-up of 17.1 (11.3-18.3) years, 177 HF events were recorded. Handgrip strength was continually associated with risk of HF, consistent with a curvilinear shape. On adjustment for several established risk factors and other potential confounders, the HR (95% CI) for HF was 0.73 (0.59-0.91) per 1 SD increase in relative HGS. Comparing the top vs bottom tertiles of relative HGS, the corresponding adjusted HR was 0.55 (0.38-0.81). The association remained similar across several clinical subgroups. Imputed results were broadly similar to the observed results.ConclusionRelative HGS is inversely and continually associated with the future risk of HF in the general population. Studies are warranted to evaluate whether HGS may be a useful prognostic tool for HF in the general population and to determine whether resistance exercise training may lower the risk of HF.     

Association of Proton Pump Inhibitors With Higher Risk of Cardiovascular Disease and Heart Failure

ObjectiveTo examine associations of cumulative exposure to proton pump inhibitors (PPIs) with total cardiovascular disease (CVD; composed of stroke, coronary heart disease, and heart failure [HF]) and HF alone in a cohort study of White and African American participants of the Atherosclerosis Risk in Communities (ARIC) study.MethodsUse of PPIs was assessed by pill bottle inspection at visit 1 (January 1, 1987 to 1989) and up to 10 additional times before baseline (visit 5; 2011 to 2013). We calculated cumulative exposure to PPIs as days of use from visit 1 to baseline. Participants (n=4346 free of total CVD at visit 5; mean age, 75 years) were observed for incident total CVD and HF events through December 31, 2016. We used Cox regression to measure associations of PPIs with total CVD and HF.ResultsAfter adjustment for potential confounding variables, participants with a cumulative exposure to PPIs of more than 5.1 years had a 2.02-fold higher risk of total CVD (95% CI, 1.50 to 2.72) and a 2.21-fold higher risk of HF (95% CI, 1.51 to 3.23) than nonusers.ConclusionLong-term PPI use was associated with twice the risk of total CVD and HF compared with nonusers. Our findings are in concordance with other research and suggest another reason to be cautious of PPI overuse.     

Effects of Replacing Sedentary Time With Physical Activity on Mortality Among Patients With Heart Failure: National Health and Nutrition Examination Survey Follow-Up Study

A sedentary lifestyle is prevalent among patients with heart failure (HF) and is associated with poor prognosis and survival, possibly owing to the displacement of health-enhancing behaviors, such as physical activity (PA). However, there is limited evidence examining the displacement effects of reducing duration of sedentary time (ST) on clinical outcomes in patients with HF. The current study examined the theoretical effects of relocating ST with PA on all-cause and cardiovascular disease (CVD)-specific mortality risks in patients with HF. We analyzed 265 patients with HF who participated in the National Health and Nutrition Examination Survey from 2003 to 2006. Cox proportional hazards regression model was fitted to estimate mortality risks based on objectively measured ST well as time spent in light-intensity PA (LPA) and moderate- and vigorous-intensity PA (MVPA). The theoretical changes in the hazard ratio (HR) by replacing ST with LPA or MVPA were examined using isotemporal substitutional modeling. On average, patients with HF spent 70% of waking hours per day in ST (9.01 hours), followed by LPA (29%; 3.75 hours) and MVPA (1%; 0.13 hours). Ten-minute substitution of ST with LPA was associated with significantly lower all-cause and CVD-specific mortality risks (hazard ratio [HR]=0.93 for both). The mortality risks progressively decreased as more ST was relocated to LPA. The relocation effects of ST with MVPA were not statistically significant, possibly because of limited MVPA accrued in this clinical population. The current study provides empirical evidence about the potential health benefits of replacing a modest amount of ST with LPA among patients with HF.     

Hypertensive Diseases in Pregnancy and Kidney Function Later in Life: The Genetic Epidemiology Network of Arteriopathy (GENOA) Study

ObjectiveTo evaluate the relationship between hypertensive diseases in pregnancy and kidney function later in life.MethodsWe evaluated measured glomerular filtration rate (mGFR) using iothalamate urinary clearance in 725 women of the Genetic Epidemiology Network of Arteriopathy (GENOA) study. Women were classified by self-report as nulliparous (n=62), a history of normotensive pregnancies (n=544), a history of hypertensive pregnancies (n=102), or a history of pre-eclampsia (n=17). We compared adjusted associations among these four groups with mGFR using generalized estimating equations to account for familial clustering. Chronic kidney disease (CKD) was defined as mGFR of less than 60 mL/min per 1.73 m² or urinary albumin-creatinine ratio (UACR) greater than or equal to 30 mg/g.ResultsAmong women with kidney function measurements (mean age, 59±9 years, 52.9% African American), those with a history of hypertensive pregnancy had lower mGFR (–4.66 ml/min per 1.73 m²; 95% CI, -9.12 to -0.20) compared with women with a history of normotensive pregnancies. Compared with women with a history of normotensive pregnancies, women with a history of hypertensive pregnancy also had higher odds of mGFR less than 60 ml/min per 1.73 m² (odds ratio, 2.09; 95% CI, 1.21 to 3.60). Additionally, women with a history of hypertensive pregnancy had greater odds for chronic kidney disease (odds ratio, 4.89; 95% CI, 1.55 to 15.44), after adjusting for age, race, education, smoking history, hypertension, body mass index, and diabetes.ConclusionA history of hypertension in pregnancy is an important prognostic risk factor for kidney disease. To our knowledge, this is the first and largest investigation showing the association between hypertensive diseases in pregnancy and subsequent kidney disease using mGFR in a large biracial cohort.     

Use of Nitrates and Risk of Cardiovascular Events in Patients With Heart Failure With Preserved Ejection Fraction

ObjectiveTo assess the association of nitrate use with cardiovascular events in patients with heart failure with preserved ejection fraction (HFpEF).Patients and MethodsPatient data were collected from the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist trial, which had been conducted at 233 sites in 6 countries from August 10, 2006, through January 31, 2012. The primary outcome was the occurrence of a major adverse cardiovascular event (cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke) or heart failure hospitalization. The association between nitrate use and cardiovascular risk was evaluated using Cox proportional hazards analysis. In addition, we verified the results using propensity score–matched patients.ResultsA total of 3417 patients with HFpEF were evaluated over a mean follow-up of 3.1 years, and 778 experienced a primary outcome event. The risk of primary outcome events was significantly higher in patients taking nitrates than in those not taking nitrates (hazard ratio [HR], 1.21; 95% CI, 1.01-1.46, P=.04). The risk of major adverse cardiovascular events was significantly higher in patients taking nitrates than in those not taking nitrates (HR, 1.32; 95% CI, 1.05-1.66, P=.01). Furthermore, the risk of hospitalization for heart failure was higher in patients taking nitrates (HR, 1.25; 95% CI, 0.99-1.60, P=.06), with propensity score–matched analyses revealing similar findings. In addition, a similar association was observed in various subgroups.ConclusionThis study reported that nitrate use in patients with HFpEF was associated with a significantly increased risk of cardiovascular events.     

Shift Work,Genetic Factors,and the Risk of Heart Failure: A Prospective Study of the UK Biobank

ObjectiveTo quantify the association of combined shift work and genetic factors with the incidence of heart failure (HF).Participants and MethodsThis study included 242,754 participants with complete shift work information in the UK Biobank. Participants were followed from baseline (2006 to 2010) through January 31, 2018. The association between shift work and HF incidence was investigated separately in males and females using a Cox proportional hazards model adjusted for covariates. In addition, we established a polygenic risk score and assessed whether shift work alters genetic susceptibility to HF.ResultsThe results showed a significant association of permanent night shift work with incident HF among females (hazard ratio, 2.25; 95% CI, 1.34 to 3.76; P=.002) after adjusting for age, and the association was attenuated in the fully adjusted model. Among men, we did not detect an association between shift work and HF. In addition, we observed that the association between the risk of HF and shift work was strengthened by high genetic risk. Permanent night shift work paired with high genetic risk, compared with low genetic risk, was suggested to be associated with the risk of HF in females (hazard ratio, 2.89; 95% CI, 1.05 to 7.94) but not in males.ConclusionShift work, particularly permanent night shift work, may increase the risk of HF in females, especially in those with high genetic risk.     

Risk Factors of Readmissions in Geriatric Rehabilitation Patients: RESORT

ObjectiveTo evaluate the risk factors associated with 30- and 90-day hospital readmissions in geriatric rehabilitation inpatients.DesignObservational, prospective longitudinal inception cohort.SettingTertiary hospital in Victoria, Australia.ParticipantsGeriatric rehabilitation inpatients of the REStORing Health of Acutely Unwell AdulTs (RESORT) cohort evalutated by a comprehensive geriatric assessment including potential readmission risk factors (ie, demographic, social support, lifestyle, functional performance, quality of life, morbidity, length of stay in an acute ward). Of 693 inpatients, 11 died during geriatric rehabilitation. The mean age of the remaining 682 inpatients was 82.2±7.8 years, and 56.7% were women.InterventionsNot applicable.Main Outcome MeasuresThirty- and 90-day readmissions after discharge from geriatric inpatient rehabilitation.ResultsThe 30- and 90-day unplanned all-cause readmission rates were 11.6% and 25.2%, respectively. Risk factors for 30- and 90-day readmissions were as follows: did not receive tertiary education, lower quality of life, higher Charlson Comorbidity Index and Cumulative Illness Rating Scale (CIRS) scores, and a higher number of medications used in the univariable models. Formal care was associated with increased risk for 90-day readmissions. In multivariable models, CIRS score was a significant risk factor for 30-day readmissions, whereas high fear of falling and CIRS score were significant risk factors for 90-day readmissions.ConclusionsHigh fear of falling and CIRS score were independent risk factors for readmission in geriatric rehabilitation inpatients. These variables should be included in hospital readmission risk prediction model developments for geriatric rehabilitation inpatients.     

Outcomes of Athletes With Genetic Heart Diseases and Implantable Cardioverter-Defibrillators Who Chose to Return to Play

ObjectiveTo evaluate outcomes for athletes with a genetic heart disease (GHD) and an implantable cardioverter-defibrillator (ICD) after return-to-play (RTP) approval.Patients and MethodsWe conducted a retrospective review of athletes with GHD and an ICD who were evaluated and treated in Mayo Clinic’s Genetic Heart Rhythm Clinic between July 2000 and July 2020. Data on frequency of GHD-associated breakthrough cardiac events (BCEs), inappropriate shocks, and ICD-related complications were collected and analyzed.ResultsThere were 125 (57 [45.6%] female) GHD-positive athletes with an ICD (mean age at RTP was 19.8±11.6 years); 56 of 125 (44.8%) had long QT syndrome. Overall, 42 ventricular fibrillation–terminating ICD therapies were given to 23 athletes (18.4%) over an average follow-up of 3.6±3.5 years. Athletes with an ICD were more likely to experience a BCE during athletic follow-up (n=28 of 125, 22.4%) compared with those without an ICD (n=4 of 533, 0.8%; P<.0001). The BCE rate for athletes with ICDs was 6.3 events per 100 athlete-years of follow-up; this included 5.1 ventricular fibrillation–terminating events per 100 athlete-years compared with 0.3 BCEs per 100 patient-years for athletes without ICDs. In total, 6 (4.8%) athletes experienced at least one inappropriate shock (1.34 per 100 athlete-years) and 28 (29.6%) athletes had at least one other device-related complication (5.02 per 100 patient-years). However, none of these other complications occurred during sports.ConclusionThis 20-year single-center study provides the longest spanning retrospective review of outcomes for athletes with ICDs given RTP approval. For athletes with GHD and an ICD, no sports-associated deaths or reports of sports-related ICD damage occurred.     

Human Immunodeficiency Virus Infection and Variation in Heart Failure Risk by Age,Sex, and Ethnicity: The HIV HEART Study

ObjectivesTo evaluate the risk of heart failure (HF) linked to human immunodeficiency virus (HIV) infection, how risk varies by demographic characteristics, and whether it is explained by atherosclerotic disease or risk factor treatment.Patients and MethodsWe performed a retrospective cohort study of persons with HIV (PWHs) from January 1, 2000, through December 31, 2016, frequency-matched 1:10 to persons without HIV on year of entry, age, sex, race/ethnicity, and treating facility. We evaluated the risk of incident HF associated with HIV infection, overall and by left ventricular systolic function, and whether HF risk varied by demographic characteristics.ResultsAmong 38,868 PWHs and 386,586 matched persons without HIV, mean ± SD age was 41.4±10.8 years, with 12.3% female, 21.1% Black, 20.5% Hispanic, and 3.9% Asian/Pacific Islander. During median follow-up of 3.8 years (interquartile range, 1.4-9.0 years), the rate (per 100 person-years) of incident HF was 0.23 in PWHs vs 0.15 in those without HIV (P<.001). The PWHs had a higher adjusted HF rate (adjusted hazard ratio [aHR], 1.73; 95% confidence interval [CI], 1.57 to 1.91), which was only modestly attenuated after accounting for interim acute coronary syndrome events. Results were similar by systolic function category. The adjusted risk of HF in PWHs was more prominent for those 40 years and younger (aHR, 2.45; 95% CI, 1.92 to 3.03), women (aHR, 2.48; 95% CI, 1.90 to 3.26), and Asian/Pacific Islanders (aHR, 2.46; 95% CI, 1.27 to 4.74).ConclusionHIV infection increases the risk of HF, which varied by demographic characteristics and was not primarily mediated through atherosclerotic disease pathways or differential use of cardiopreventive medications.     

Worsening of Renal Function Among Hospitalized Patients With Acute Heart Failure: Phenotyping,Outcomes, and Predictors

ObjectiveTo define clinical phenotyping and its associated outcome of worsening of renal function (WRF) in hospitalized acute heart failure (AHF) patients.Patients and MethodsLatent class analysis was performed in 113 AHF patients who developed WRF within 72 hours in the DOSE (Diuretic Optimization Strategies Evaluation) trial (from March 2008 to November 2009) and ROSE-AHF (Renal Optimization Strategies Evaluation in Acute Heart Failure) trial (from September 2010 to March 2013) to identify potential WRF phenotypes. Clinical characteristics and outcome (in-hospital and post-discharge) were compared between different phenotypes.ResultsTwo WRF phenotypes were identified by latent class analysis, which we named WRF minimally responsive to diuretics (WRF-MRD) and WRF responsive to diuretics (WRF-RD). Among the population, 58 (9.5%) developed WRF-MRD and 55 (9.0%) developed WRF-RD. Patients with WRF-MRD had more comorbidities than WRF-RD. In WRF-MRD, there were an early increase in serum creatinine, a smaller amount of net fluid loss and weight loss, and a higher rate of worsening or persistent heart failure over 72 hours. In contrast, for those with WRF-RD, they had faster in-hospital net fluid loss and weight loss and a better 60-day survival after discharge even compared with patients without WRF (P=.004). Furthermore, baseline chronic obstructive pulmonary disease, diabetes, and cystatin C were independent predictors of WRF-MRD, whereas serum hemoglobin and sodium predicted WRF-RD.ConclusionsAmong hospitalized AHF patients, we identified two phenotypes of WRF with distinct response to heart failure treatment, predictors, and short-term prognosis after discharge. The results could help early differentiation of WRF phenotypes in clinical practice.     

Association of Timing and Balance of Physical Activity and Rest/Sleep With Risk of COVID-19: A UK Biobank Study

Behavioral lifestyle factors are associated with cardiometabolic disease and obesity, which are risk factors for coronavirus disease 2019 (COVID-19). We aimed to investigate whether physical activity, and the timing and balance of physical activity and sleep/rest, were associated with SARS-CoV-2 positivity and COVID-19 severity. Data from 91,248 UK Biobank participants with accelerometer data and complete covariate and linked COVID-19 data to July 19, 2020, were included. The risk of SARS-CoV-2 positivity and COVID-19 severity—in relation to overall physical activity, moderate-to-vigorous physical activity (MVPA), balance between activity and sleep/rest, and variability in timing of sleep/rest—was assessed with adjusted logistic regression. Of 207 individuals with a positive test result, 124 were classified as having a severe infection. Overall physical activity and MVPA were not associated with severe COVID-19, whereas a poor balance between activity and sleep/rest was (odds ratio [OR] per standard deviation: 0.71; 95% confidence interval [CI], 0.62 to 0.81]). This finding was related to higher daytime activity being associated with lower risk (OR, 0.75; 95% CI, 0.61 to 0.93) but higher movement during sleep/rest being associated with higher risk (OR, 1.26; 95% CI, 1.12 to 1.42) of severe infection. Greater variability in timing of sleep/rest was also associated with increased risk (OR, 1.21; 95% CI, 1.08 to 1.35). Results for testing positive were broadly consistent. In conclusion, these results highlight the importance of not just physical activity, but also quality sleep/rest and regular sleep/rest patterns, on risk of COVID-19. Our findings indicate the risk of COVID-19 was consistently approximately 1.2-fold greater per approximately 40-minute increase in variability in timing of proxy measures of sleep, indicative of irregular sleeping patterns.     

Acute Pulmonary Embolism During Pregnancy and Puerperium: National Trends and In-Hospital Outcomes

ObjectiveTo investigate the trend and outcomes of acute pulmonary embolism (PE) during pregnancy and puerperium using a large national database.Patients and MethodsThe National Inpatient Sample was queried to identify pregnancy-related hospitalizations in the United States from January 1, 2007, through September 30, 2015. Temporal trends in the rates of acute PE and in-hospital mortality rates were extracted.ResultsAmong 37,524,314 hospitalizations, 6,333 patients (0.02%) had acute PE. The prevalence of comorbidities and risk factors such as hypertension, obesity, and smoking increased, but rates of acute PE did not change significantly (18.01 in 2007 vs 19.36 in 2015, per 100,000 hospitalizations, P_trends=.21). Advanced therapies were used in a small number of women (systemic thrombolysis: 2.4%, surgical pulmonary embolectomy: 0.5%, and inferior vena cava filter in 8.3%). Rates of in-hospital mortality were almost 200-fold higher among those who had acute PE (29.3 vs 0.13, per 1000 pregnancy-related, P<.001). The rate of in-hospital mortality did not change among women with acute PE (2.6% in 2007 vs 2.5% in 2015, P_trends=.74).ConclusionIn this contemporary analysis of pregnancy-related hospitalizations, acute PE was uncommon, but rates have not decreased over the past decade. Acute PE during pregnancy and puerperium was associated with high maternal mortality, and the rates of in-hospital mortality have not improved. Future studies to improve prevention and management of acute PE during pregnancy and puerperium are warranted.     

Risk of Hematologic Malignancies in Elderly Patients With Ankylosing Spondylitis: A Cohort Study and Systematic Review

ObjectiveTo examine the risk of hematologic malignancies in older adults with ankylosing spondylitis (AS).Patients and MethodsWe used US Medicare data from January 1, 1999, to December 31, 2010, to identify a population-based cohort of beneficiaries with AS. We also included beneficiaries with inflammatory bowel disease (IBD) as disease controls and beneficiaries without AS or IBD as unaffected controls. We excluded those treated with tumor necrosis factor inhibitors in this period. We followed up each group for new diagnosis claims for hematologic malignancies until September 30, 2015.ResultsWe included 12,451 beneficiaries with AS, 234,905 with IBD, and 10,975,340 unaffected controls, with a mean follow-up of 9.9, 9.3, and 8.0 years, respectively. We identified 297 hematologic malignancies in the AS group, 4538 malignancies in the IBD group, and 128,239 malignancies in unaffected controls. The standardized incidence ratio in AS vs unaffected controls was 1.39 (95% CI, 1.05 to 1.61) for non-Hodgkin lymphoma, 1.50 (95% CI, 1.17 to 1.92) for chronic lymphocytic leukemia, and 1.52 (95% CI, 1.12 to 2.06) for multiple myeloma. Risks of acute myeloid leukemia and chronic myeloid leukemia were not elevated in AS, and there were too few cases of Hodgkin lymphoma to compute risks. Risks were comparable to those of beneficiaries with IBD. We also performed a systematic literature review of the risk of hematologic malignancy in AS, focusing on age associations, which have not been previously examined. We identified 21 studies in the systematic literature review, which included mainly young or middle-aged patients. Results suggested that AS was largely not associated with an increased risk of hematologic malignancies. Two cohort studies reported an increased risk of multiple myeloma in AS.ConclusionThe risks of non-Hodgkin lymphoma, chronic lymphocytic leukemia, and multiple myeloma are increased among elderly patients with AS.     

Artificial Intelligence Application in Graves Disease: Atrial Fibrillation,Heart Failure and Menstrual Changes

ObjectiveTo study the utility of artificial intelligence (AI)–enabled electrocardiograms (ECGs) in patients with Graves disease (GD) in identifying patients at high risk of atrial fibrillation (AF) and heart failure with reduced ejection fraction (HFrEF), and to study whether AI-ECG can reflect hormonal changes and the resulting menstrual changes in GD.Patients and MethodsPatients diagnosed with GD between January 1, 2009, and December 31, 2019, were included. We considered AF diagnosed at 30 days or fewer before or any time after GD and de novo HFrEF not explained by ischemia, valve disorder, or other cardiomyopathy at/after GD diagnosis. Electrocardiograms at/after index condition were excluded. A subset analysis included females younger than 45 years of age to study the association between ECG-derived female probability and menstrual changes (shorter, lighter, or newly irregular cycles).ResultsAmong 430 patients (mean age, 50±17 years; 337 (78.4%) female), independent risk factors for AF included ECG probability of AF (hazard ratio [HR], 1.5; 95% CI, 1.2 to 1.6 per 10%; P<.001), older age (HR, 1.05; 95% CI, 1.03 to 1.07 per year; P<.001), and overt hyperthyroidism (HR, 3.9; 95% CI, 1.2 to 12.7; P=.03). The C-statistic was 0.85 for the combined model. Among 495 patients (mean age, 52±17 years; 374 (75.6%) female), independent risk factors for HFrEF were ECG probability of low ejection fraction (HR, 1.4; 95% CI, 1.1 to 1.6 per 10%; P=.001) and presence of AF (HR, 8.3; 95% CI, 2.2 to 30.9; P=.002), and a C-statistic of 0.89 for the combined model. Lastly, of 72 females younger than 45 years, 30 had menstrual changes at time of GD and had a significantly lower AI ECG–derived female probability [median 77.3; (IQR 57.9 to 94.4)% vs. median 97.7 (IQR 92.4 to 99.5)%, P<.001].ConclusionAI-enabled ECG identifies patients at risk for GD-related AF and HFrEF and was associated with menstrual changes in women with GD.