INTRODUCTIONThe LIfestyle for BRAin Health (LIBRA) index yields a dementia risk score based on modifiable lifestyle factors and is validated in Western samples. We investigated whether the... Show moreINTRODUCTIONThe LIfestyle for BRAin Health (LIBRA) index yields a dementia risk score based on modifiable lifestyle factors and is validated in Western samples. We investigated whether the association between LIBRA scores and incident dementia is moderated by geographical location or sociodemographic characteristics.METHODSWe combined data from 21 prospective cohorts across six continents (N = 31,680) and conducted cohort-specific Cox proportional hazard regression analyses in a two-step individual participant data meta-analysis.RESULTSA one-standard-deviation increase in LIBRA score was associated with a 21% higher risk for dementia. The association was stronger for Asian cohorts compared to European cohorts, and for individuals aged ≤75 years (vs older), though only within the first 5 years of follow-up. No interactions with sex, education, or socioeconomic position were observed.DISCUSSIONModifiable risk and protective factors appear relevant for dementia risk reduction across diverse geographical and sociodemographic groups. Show less
Canney, M.; Induruwage, D.; Tang, M.L.; Pinho, N.A. de; Er, L.; Zhao, Y.S.; ... ; ISN INET-CKD Investigators 2023
Introduction: Despite recognized geographic and sex-based differences in hemoglobin in the general population, these factors are typically ignored in patients with chronic kidney disease (CKD) in... Show moreIntroduction: Despite recognized geographic and sex-based differences in hemoglobin in the general population, these factors are typically ignored in patients with chronic kidney disease (CKD) in whom a single therapeutic range for hemoglobin is recommended. We sought to compare the distribution of hemoglobin across international nondialysis CKD populations and evaluate predictors of hemoglobin.Methods: In this cross-sectional study, hemoglobin distribution was evaluated in each cohort overall and stratified by sex and estimated glomerular filtration rate (eGFR). Relationships between candidate predictors and hemoglobin were assessed from linear regression models in each cohort. Estimates were subsequently pooled in a random effects model.Results: A total of 58,613 participants from 21 adult cohorts (median eGFR range of 17-49 ml/min) and 3 pediatric cohorts (median eGFR range of 26-45 ml/min) were included with broad geographic representation. Hemoglobin values varied substantially among the cohorts, overall and within eGFR categories, with particularly low mean hemoglobin observed in women from Asian and African cohorts. Across the eGFR range, women had a lower hemoglobin compared to men, even at an eGFR of 15 ml/min (mean difference 5.3 g/l, 95% confidence interval [CI] 3.7-6.9). Lower eGFR, female sex, older age, lower body mass index, and diabetic kidney disease were all independent predictors of a lower hemoglobin value; however, this only explained a minority of variance (R-2 7%-44% across cohorts).Conclusion: There are substantial regional differences in hemoglobin distribution among individuals with CKD, and the majority of variance is unexplained by demographics, eGFR, or comorbidities. These findings call for a renewed interest in improving our understanding of hemoglobin determinants in specific CKD populations. Show less
AimsCombined anatomical and functional imaging enables detection of non-obstructive and obstructive coronary artery disease (CAD) as well as myocardial ischaemia. We evaluated sex differences in... Show moreAimsCombined anatomical and functional imaging enables detection of non-obstructive and obstructive coronary artery disease (CAD) as well as myocardial ischaemia. We evaluated sex differences in disease profile and outcomes after combined computed tomography angiography (CTA) and positron emission tomography (PET) perfusion imaging in patients with suspected obstructive CAD.Methods and resultsWe retrospectively evaluated 1948 patients (59% women) referred for coronary CTA due to suspected CAD during the years 2008–2016. Patients with a suspected obstructive lesion on coronary CTA (n = 657) underwent 15O-water PET to assess stress myocardial blood flow (MBF). During a mean follow-up of 6.8 years, 182 adverse events (all-cause death, myocardial infarction, or unstable angina) occurred. Women had more often normal coronary arteries (42% vs. 22%, P < 0.001) and less often abnormal stress MBF (9% vs. 28%, P < 0.001) than men. The annual adverse event rate was lower in women vs. men (1.2% vs. 1.7%, P = 0.02). Both in women and men, coronary calcification, non-obstructive CAD, and abnormal stress MBF were independent predictors of events. Abnormal stress MBF was associated with 5.0- and 5.6-fold adverse event rates in women and men, respectively. There was no interaction between sex and coronary calcification, non-obstructive CAD, or abnormal stress MBF in terms of predicting adverse events.ConclusionAmong patients evaluated for chronic chest pain, women have a lower prevalence of ischaemic CAD and a lower rate of adverse events. Combined coronary CTA and PET myocardial perfusion imaging predict outcomes equally in women and men. Show less
Panhuis, W.I.H.; Schoenke, M.; Siebeler, R.; Banen, D.; Pronk, A.C.M.; Streefland, T.C.M.; ... ; Kooijman, S. 2023
Circadian disruption (CD) is the consequence of a mismatch between endogenous circadian rhythms and behavior, and frequently occurs in shift workers. CD has often been linked to impairment of... Show moreCircadian disruption (CD) is the consequence of a mismatch between endogenous circadian rhythms and behavior, and frequently occurs in shift workers. CD has often been linked to impairment of glucose and lipid homeostasis. It is, however, unknown if these effects are sex dependent. Here, we subjected male and female C57BL/6J mice to 6-h light phase advancements every 3 days to induce CD and assessed glucose and lipid homeostasis. Within this model, we studied the involvement of gonadal sex hormones by injecting mice with gonadotropin-releasing hormone-antagonist degarelix. We demonstrate that CD has sex-specific effects on glucose homeostasis, as CD elevated fasting insulin levels in male mice while increasing fasting glucose levels in female mice, which appeared to be independent of behavior, food intake, and energy expenditure. Absence of gonadal sex hormones lowered plasma insulin levels in male mice subjected to CD while it delayed glucose clearance in female mice subjected to CD. CD elevated plasma triglyceride (TG) levels and delayed plasma clearance of TG-rich lipoproteins in both sexes, coinciding with reduced TG-derived FA uptake by adipose tissues. Absence of gonadal sex hormones did not notably alter the effects of CD on lipid metabolism. We conclude that CD causes sex-dependent effects on glucose metabolism, as aggravated by male gonadal sex hormones and partly rescued by female gonadal sex hormones. Future studies on CD should consider the inclusion of both sexes, which may eventually contribute to personalized advice for shift workers. Show less
Hack, R.J.; Cerfontaine, M.N.; Gravesteijn, G.; Tap, S.; Hafkemeijer, A.; Grond, J. van der; ... ; Oberstein, S.A.J.L. 2022
BACKGROUND: A retrospective study has shown that EGFr (epidermal growth factor-like repeat) group in the NOTCH3 gene is an important cerebral autosomal dominant arteriopathy with subcortical... Show moreBACKGROUND: A retrospective study has shown that EGFr (epidermal growth factor-like repeat) group in the NOTCH3 gene is an important cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) disease modifier of age at first stroke and white matter hyperintensity (WMH) volume. No study has yet assessed the effect of other known CADASIL modifiers, that is, cardiovascular risk factors and sex, in the context of NOTCH3 EGFr group. In this study, we determined the relative disease-modifying effects of NOTCH3 EGFr group, sex and cardiovascular risk factor on disease severity in the first genotype-driven, large prospective CADASIL cohort study, using a comprehensive battery of CADASIL clinical outcomes and neuroimaging markers. METHODS: Patients with CADASIL participated in a single-center, prospective cohort study (DiViNAS [Disease Variability in NOTCH3 Associated Small Vessel Disease]) between 2017 and 2020. The study protocol included a clinical assessment, neuropsychological test battery and brain magnetic resonance imaging on a single research day. Multivariable linear, logistic and Cox regression models were used to cross-sectionally assess the effect of CADASIL modifiers on clinical severity (stroke, disability, processing speed) and neuroimaging markers (WMH volume, peak width of skeletonized mean diffusivity, lacune volume, brain volume, cerebral microbleed count). RESULTS: Two hundred patients with CADASIL participated, of which 103 harbored a NOTCH3 EGFr 1-6 variant and 97 an EGFr 7-34 variant. NOTCH3 EGFr 1-6 group was the most important modifier of age at first stroke (hazard ratio, 2.45 [95% CI, 1.39-4.31]; P=0.002), lacune volume (odds ratio, 4.31 [95% CI, 2.31-8.04]; P=4.0x 10(-6)), WMH volume (B=0.81 [95% CI, 0.60-1.02]; P=1.1x 10(-12)), and peak width of skeletonized mean diffusivity (B=0.65 [95% CI, 0.44-0.87]; P=1.6x 10(-8)). EGFr 1-6 patients had a significantly higher WMH volume in the anterior temporal lobes and superior frontal gyri and a higher burden of enlarged perivascular spaces. After NOTCH3 EGFr group, male sex and hypertension were the next most important modifiers of clinical outcomes and neuroimaging markers. CONCLUSIONS: NOTCH3 EGFr group is the most important CADASIL disease modifier not only for age at first stroke and WMH volume but also strikingly so for a whole battery of clinically relevant disease measures such as lacune volume and peak width of skeletonized mean diffusivity. NOTCH3 EGFr group is followed in importance by sex, hypertension, diabetes, and smoking. Show less
Simple Summary Barrett's esophagus (BE) is the only known precursor lesion of esophageal adenocarcinoma (EAC). Endoscopic surveillance plays an important role in the timely detection of neoplastic... Show moreSimple Summary Barrett's esophagus (BE) is the only known precursor lesion of esophageal adenocarcinoma (EAC). Endoscopic surveillance plays an important role in the timely detection of neoplastic progression. However, the cost-effectiveness of current surveillance strategies is debatable. Previous studies have shown that male Barrett's patients have lower neoplastic progression risk than females. However, these studies do not provide a more practical translation of these sex disparities into different surveillance intervals. The current multicenter prospective cohort study aimed to evaluate sex differences in 868 BE patients; not only with respect to neoplastic progression risk, but also concerning the difference in time to detection of high-grade dysplasia (HGD)/EAC: time to neoplastic progression was estimated to be almost twice as low in males than in females. In contrast, the stage of neoplasia appeared to be higher in females. Our results can guide future discussions for sex-specific guidelines, supporting the implementation of neoplastic risk stratification per individual patient in BE surveillance. Recommendations in Barrett's esophagus (BE) guidelines are mainly based on male patients. We aimed to evaluate sex differences in BE patients in (1) probability of and (2) time to neoplastic progression, and (3) differences in the stage distribution of neoplasia. We conducted a multicenter prospective cohort study including 868 BE patients. Cox regression modeling and accelerated failure time modeling were used to estimate the sex differences. Neoplastic progression was defined as high-grade dysplasia (HGD) and/or esophageal adenocarcinoma (EAC). Among the 639 (74%) males and 229 females that were included (median follow-up 7.1 years), 61 (7.0%) developed HGD/EAC. Neoplastic progression risk was estimated to be twice as high among males (HR 2.26, 95% CI 1.11-4.62) than females. The risk of HGD was found to be higher in males (HR 3.76, 95% CI 1.33-10.6). Time to HGD/EAC (AR 0.52, 95% CI 0.29-0.95) and HGD (AR 0.40, 95% CI 0.19-0.86) was shorter in males. Females had proportionally more EAC than HGD and tended to have higher stages of neoplasia at diagnosis. In conclusion, both the risk of and time to neoplastic progression were higher in males. However, females were proportionally more often diagnosed with (advanced) EAC. We should strive for improved neoplastic risk stratification per individual BE patient, incorporating sex disparities into new prediction models. Show less
Men seem to have a higher intrinsic risk of venous thromboembolism (VTE) than women, regardless of age. To date, this difference has not been explained. By integrating state-of-the-art research... Show moreMen seem to have a higher intrinsic risk of venous thromboembolism (VTE) than women, regardless of age. To date, this difference has not been explained. By integrating state-of-the-art research presented at the International Society on Thrombosis and Haemostasis Congress of 2021 with the available literature, we address potential explanations for this intriguing risk difference between men and women. We discuss the role of exogenous and endogenous sex hormones as the most important known sex-specific determinants of VTE risk. In addition, we highlight clues on the role of sex hormones and VTE risk from clinical scenarios such as pregnancy and the polycystic ovary syndrome. Furthermore, we address new potential sex-specific risk factors and unanswered research questions, which could provide more insight in the intrinsic risk difference between men and women, such as body height and differences in body fat distribution, leading to dysregulation of metabolism and inflammation. Show less
Background and Purpose: In previous studies, women had a higher risk of rupture of intracranial aneurysms than men, but female sex was not an independent risk factor. This may be explained by a... Show moreBackground and Purpose: In previous studies, women had a higher risk of rupture of intracranial aneurysms than men, but female sex was not an independent risk factor. This may be explained by a higher prevalence of patient- or aneurysm-related risk factors for rupture in women than in men or by insufficient power of previous studies. We assessed sex differences in rupture rate taking into account other patient- and aneurysm-related risk factors for aneurysmal rupture. Methods: We searched Embase and Pubmed for articles published until December 1, 2020. Cohorts with available individual patient data were included in our meta-analysis. We compared rupture rates of women versus men using a Cox proportional hazard regression model adjusted for the PHASES score (Population, Hypertension, Age, Size of Aneurysm, Earlier Subarachnoid Hemorrhage From Another Aneurysm, Site of Aneurysm), smoking, and a positive family history of aneurysmal subarachnoid hemorrhage. Results: We pooled individual patient data from 9 cohorts totaling 9940 patients (6555 women, 66%) with 12 193 unruptured intracranial aneurysms, and 24 357 person-years follow-up. Rupture occurred in 163 women (rupture rate 1.04%/person-years [95% CI, 0.89-1.21]) and 63 men (rupture rate 0.74%/person-years [95% CI, 0.58-0.94]). Women were older (61.9 versus 59.5 years), were less often smokers (20% versus 44%), more often had internal carotid artery aneurysms (24% versus 17%), and larger sized aneurysms (>= 7 mm, 24% versus 23%) than men. The unadjusted women-to-men hazard ratio was 1.43 (95% CI, 1.07-1.93) and the adjusted women/men ratio was 1.39 (95% CI, 1.02-1.90). Conclusions: Women have a higher risk of aneurysmal rupture than men and this sex difference is not explained by differences in patient- and aneurysm-related risk factors for aneurysmal rupture. Future studies should focus on the factors explaining the higher risk of aneurysmal rupture in women. Show less
Background and Purpose:In previous studies, women had a higher risk of rupture of intracranial aneurysms than men, but female sex was not an independent risk factor. This may be explained by a... Show moreBackground and Purpose:In previous studies, women had a higher risk of rupture of intracranial aneurysms than men, but female sex was not an independent risk factor. This may be explained by a higher prevalence of patient- or aneurysm-related risk factors for rupture in women than in men or by insufficient power of previous studies. We assessed sex differences in rupture rate taking into account other patient- and aneurysm-related risk factors for aneurysmal rupture.Methods:We searched Embase and Pubmed for articles published until December 1, 2020. Cohorts with available individual patient data were included in our meta-analysis. We compared rupture rates of women versus men using a Cox proportional hazard regression model adjusted for the PHASES score (Population, Hypertension, Age, Size of Aneurysm, Earlier Subarachnoid Hemorrhage From Another Aneurysm, Site of Aneurysm), smoking, and a positive family history of aneurysmal subarachnoid hemorrhage.Results:We pooled individual patient data from 9 cohorts totaling 9940 patients (6555 women, 66%) with 12 193 unruptured intracranial aneurysms, and 24 357 person-years follow-up. Rupture occurred in 163 women (rupture rate 1.04%/person-years [95% CI, 0.89–1.21]) and 63 men (rupture rate 0.74%/person-years [95% CI, 0.58–0.94]). Women were older (61.9 versus 59.5 years), were less often smokers (20% versus 44%), more often had internal carotid artery aneurysms (24% versus 17%), and larger sized aneurysms (≥7 mm, 24% versus 23%) than men. The unadjusted women-to-men hazard ratio was 1.43 (95% CI, 1.07–1.93) and the adjusted women/men ratio was 1.39 (95% CI, 1.02–1.90).Conclusions:Women have a higher risk of aneurysmal rupture than men and this sex difference is not explained by differences in patient- and aneurysm-related risk factors for aneurysmal rupture. Future studies should focus on the factors explaining the higher risk of aneurysmal rupture in women. Show less
Kooij, M.K. van der; Dekkers, O.M.; Aarts, M.J.B.; Berkmortel, F.W.P.J. van den; Boers-Sonderen, M.J.; Groot, J.W.B. de; ... ; Kapiteijn, E. 2021
Simple Summary Melanoma is a malignant form of skin cancer. The overall survival of patients with advanced stages of disease were initially low. Fortunately, in recent years systemic treatment with... Show moreSimple Summary Melanoma is a malignant form of skin cancer. The overall survival of patients with advanced stages of disease were initially low. Fortunately, in recent years systemic treatment with immunotherapy has prolonged survival. We set out to answer the question whether men and women with advanced melanoma differ in prognostic factors, tumor-response to immunotherapy, and treatment-related adverse events. All patients in the Netherlands were registered between July 2013 and July 2018. We showed that although clinical and tumor characteristics differ, the safety profile of immunotherapy is comparable. Furthermore, overall, a 10% survival advantage for women was seen. Following immunotherapy there was no survival difference. Recent meta-analyses show conflicting data on sex-dependent benefit following systemic treatment for advanced melanoma patients. We examined the nationwide Dutch Melanoma Treatment Registry (July 2013-July 2018), assessing sex-dependent differences in advanced melanoma patients (stage IIIC/IV) with respect to clinical characteristics, mutational profiles, treatments initiated, grade 3-4 adverse events (AEs), treatment responses, and mortality. We included 3985 patients, 2363 men (59%) and showed that although men and women with advanced melanoma differ in clinical and tumor characteristics, the safety profile of immune checkpoint inhibition (ICI) is comparable. The data suggest a 10% survival advantage for women, mainly seen in patients >= 60 years of age and patients with BRAF V600 mutant melanoma. Following ICI there was no survival difference. Show less
Background: Emerging evidence shows sex differences in manifestations of vascular brain injury in memory clinic patients. We hypothesize that this is explained by sex differences in cardiovascular... Show moreBackground: Emerging evidence shows sex differences in manifestations of vascular brain injury in memory clinic patients. We hypothesize that this is explained by sex differences in cardiovascular function.Objective: To assess the relation between sex and manifestations of vascular brain injury in patients with cognitive complaints, in interaction with cardiovascular function.Methods: 160 outpatient clinic patients (68.8 +/- 8.5 years, 38% female) with cognitive complaints and vascular brain injury from the Heart-Brain Connection study underwent a standardized work-up, including heart-brain MRI. We calculated sex differences in vascular brain injury (lacunar infarcts, non-lacunar infarcts, white matter hyperintensities [WMHs], and microbleeds) and cardiovascular function (arterial stiffness, cardiac index, left ventricular [LV] mass index, LV mass-to-volume ratio and cerebral blood flow). In separate regression models, we analyzed the interaction effect between sex and cardiovascular function markers on manifestations of vascular brain injury with interaction terms (sex*cardiovascular function marker).Results: Males had more infarcts, whereas females tended to have larger WMH-volumes. Males had higher LV mass indexes and LV mass-to-volume ratios and lower CBF values compared to females. Yet, we found no interaction effect between sex and individual cardiovascular function markers in relation to the different manifestations of vascular brain injury (p-values interaction terms > 0.05).Conclusion: Manifestations of vascular brain injury in patients with cognitive complaints differed by sex. There was no interaction between sex and cardiovascular function, warranting further studies to explain the observed sex differences in injury patterns. Show less
J. dal; Skov, B.G.; Andersen, M.; Feldt-Rasmussen, U.; Feltoft, C.L.; Karmisholt, J.; ... ; Jorgensen, J.O.L. 2020
Objective Data on sex differences in acromegaly at the time of diagnosis vary considerably between studies.Design A nationwide cohort study including all incident cases of acromegaly (1978-2010, n ... Show moreObjective Data on sex differences in acromegaly at the time of diagnosis vary considerably between studies.Design A nationwide cohort study including all incident cases of acromegaly (1978-2010, n = 596) and a meta-analysis on sex differences in active acromegaly (40 studies) were performed.Method Sex-dependent differences in prevalence, age at diagnosis, diagnostic delay, pituitary adenoma size, insulin-like growth factor 1 (IGF-I) and growth hormone (GH) concentrations were estimated.Results The cohort study identified a balanced gender distribution (49.6% females) and a comparable age (years) at diagnosis (48.2 CI95% 46.5-49.8 (males) vs. 47.2 CI95% 45.5-48.9 (females), p = 0.4). The incidence rate significantly increased during the study period (R-2 = 0.42, p < 0.01) and the gender ratio (F/M) changed from female predominance to an even ratio (SR: 1.4 vs. 0.9, p = 0.03). IGF-I-SDS was significantly lower in females compared to males, whereas neither nadir GH nor pituitary adenoma size differed between males and females.In the meta-analysis, the weighted percentage female was 53.3% (CI95% 51.5-55.2) with considerable heterogeneity (I-2 = 85%) among the studies. The mean age difference at diagnosis between genders was 3.1 years (CI95% 1.9-4.4), and the diagnostic delay was longer in females by 0.9 years (CI95% -0.4 to 2.1). Serum IGF-I levels were significantly lower in female patients, whereas nadir GH, and pituitary adenoma size were comparable.Conclusion There are only a minor sex differences in the epidemiology of acromegaly at the time of diagnosis except that female patients are slightly older and exhibit lower IGF-I concentrations and a longer diagnostic delay. Show less
OBJECTIVES This study is to determine the management and clinical outcomes of patients investigated with coronary computed tomography angiography (CCTA)-derived fractional flow reserve (FFRCT)... Show moreOBJECTIVES This study is to determine the management and clinical outcomes of patients investigated with coronary computed tomography angiography (CCTA)-derived fractional flow reserve (FFRCT) according to sex.BACKGROUND Women are underdiagnosed with conventional ischemia testing, have lower rates of obstructive coronary artery disease (CAD) at invasive coronary angiography (ICA), yet higher mortality compared to men. Whether FFRCT improves sex-based patient management decisions compared to CCTA alone is unknown.METHODS Subjects with symptoms and CAD on CCTA were enrolled (2015 to 2017). Demographics, symptom status, CCTA anatomy, coronary volume to myocardial mass ratio (V/M), lowest FFRCT values, and management plans were captured. Endpoints included reclassification rate between CCTA and FFRCT management plans, incidence of ICA demonstrating obstructive CAD ($50% stenosis) and revascularization rates.RESULTS A total of 4,737 patients (n = 1,603 females, 33.8%) underwent CCTA and FFRCT. Women were older (age 68 +/- 10 years vs. 65 +/- 10 years; p < 0.0001) with more atypical symptoms (41.5% vs. 33.9%; p < 0.0001). Women had less obstructive CAD (65.4% vs. 74.7%; p < 0.0001) at CCTA, higher FFRCT (0.76 +/- 0.10 vs. 0.73 +/- 0.10; p < 0.0001), and lower likelihood of positive FFRCT <= 0.80 for the same degree stenosis (p < 0.0001). A positive FFRCT <= 0.80 resulted in equal referral to ICA (n = 510 [54.5%] vs. n = 1,249 [56.5%]; p = 0.31), but more nonobstructive CAD (n = 208 [32.1%] vs. n = 354 [24.5%]; p = 0.0003) and less revascularization (n = 294 [31.4%] vs. n = 800 [36.2%]; p < 0.0001) in women, unless the FFRCT was #0.75 where revascularization rates were similar (n = 253 [41.9%] vs. n = 715 [46.4%]; p = 0.06). Women have a higher V/M ratio (26.17 +/- 7.58 mm(3)/g vs. 24.76 +/- 7.22 mm(3)/g; p < 0.0001) that is associated with higher FFRCT independent of degree stenosis (p < 0.001). Predictors of revascularization included stenosis severity, FFRCT, symptoms, and V/M ratio (p < 0.001) but not female sex (p = 0.284).CONCLUSIONS FFRCT differs between the sexes, as women have a higher FFRCT for the same degree of stenosis. In FFRCT-positive CAD, women have less obstructive CAD at ICA and less revascularization, which is associated with higher V/M ratio. The findings suggest that CAD and FFRCT variations by sex need specific interpretation as these differences may affect therapeutic decision making and clinical outcomes. (Assessing Diagnostic Value of Non-invasive FFRCT in Coronary Care [ADVANCE]; NCT02499679) (C) 2020 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. Show less
Iwaki, H.; Blauwendraat, C.; Leonard, H.L.; Makarious, M.B.; Kim, J.J.; Liu, G.Q.; ... ; Nalls, M.A. 2020
Background Previous studies reported various symptoms of Parkinson's disease (PD) associated with sex. Some were conflicting or confirmed in only one study. Objectives We examined sex associations... Show moreBackground Previous studies reported various symptoms of Parkinson's disease (PD) associated with sex. Some were conflicting or confirmed in only one study. Objectives We examined sex associations to PD phenotypes cross-sectionally and longitudinally in large-scale data. Methods We tested 40 clinical phenotypes, using longitudinal, clinic-based patient cohorts, consisting of 5946 patients, with a median follow-up of 3.1 years. For continuous outcomes, we used linear regressions at baseline to test sex-associated differences in presentation, and linear mixed-effects models to test sex-associated differences in progression. For binomial outcomes, we used logistic regression models at baseline and Cox regression models for survival analyses. We adjusted for age, disease duration, and medication use. In the secondary analyses, data from 17 719 PD patients and 7588 non-PD participants from an online-only, self-assessment PD cohort were cross-sectionally evaluated to determine whether the sex-associated differences identified in the primary analyses were consistent and unique to PD. Results Female PD patients had a higher risk of developing dyskinesia early during the follow-up period, with a slower progression in activities of daily living difficulties, and a lower risk of developing cognitive impairments compared with male patients. The findings in the longitudinal, clinic-based cohorts were mostly consistent with the results of the online-only cohort. Conclusions We observed sex-associated contributions to PD heterogeneity. These results highlight the necessity of future research to determine the underlying mechanisms and importance of personalized clinical management. (c) 2020 International Parkinson and Movement Disorder Society Show less
Background Women are more susceptible than men to several forms of pulmonary hypertension, but have better survival. Sparse data are available on chronic thromboembolic pulmonary hypertension ... Show moreBackground Women are more susceptible than men to several forms of pulmonary hypertension, but have better survival. Sparse data are available on chronic thromboembolic pulmonary hypertension (CTEPH). Methods We investigated sex-specific differences in the clinical presentation of CTEPH, performance of pulmonary endarterectomy (PEA), and survival. Results Women constituted one-half of the study population of the European CTEPH registry (N = 679) and were characterized by a lower prevalence of some cardiovascular risk factors, including prior acute coronary syndrome, smoking habit, and chronic obstructive pulmonary disease, but more prevalent obesity, cancer, and thyroid diseases. The median age was 62 (interquartile ratio, 50-73) years in women and 63 (interquartile ratio, 53-70) in men. Women underwent PEA less often than men (54% vs 65%), especially at low-volume centers (48% vs 61%), and were exposed to fewer additional cardiac procedures, notably coronary artery bypass graft surgery (0.5% vs 9.5%). The prevalence of specific reasons for not being operated, including patient ' s refusal and the proportion of proximal vs distal lesions, did not differ between sexes. A total of 57 (17.0%) deaths in women and 70 (20.7%) in men were recorded over long-term follow-up. Female sex was positively associated with long-term survival (adjusted hazard ratio, 0.66; 95% confidence interval, 0.46-0.94). Short-term mortality was identical in the two groups. Conclusions Women with CTEPH underwent PEA less frequently than men, especially at low-volume centers. Furthermore, they had a lower prevalence of cardiovascular risk factors and were less often exposed to additional cardiac surgery procedures. Women had better long-term survival. Show less
Early life stress (ELS) is considered a major risk factor for developing psychopathology. Increasing evidence points towards sex-dependent dysregulation of the hypothalamic-pituitary-adrenal (HPA)... Show moreEarly life stress (ELS) is considered a major risk factor for developing psychopathology. Increasing evidence points towards sex-dependent dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis as a contributing mechanism. Additionally, clinical studies suggest that the mineralocorticoid receptor (MR) may further confer genetic vulnerability/resilience on a background of ELS. The link between ELS, sex and the HPA axis and how this interacts with MR genotype is understudied, yet important to understand vulnerability/resilience to stress. We used the early life-limited nesting and bedding model to test the effect of ELS on HPA properties in adult female and male mice carrying a forebrain-specific heterozygous knockout for MR. Basal HPA axis activity was measured by circadian peak and nadir corticosterone levels, in addition to body weight and weight of stress-sensitive tissues. HPA axis reactivity was assessed by mapping corticosterone levels after 10 min immobilization. Additionally, we measured the effects of ELS on steroid receptor [MR and glucocorticoid receptor (GR)] levels in the dorsal hippocampus and medial prefrontal cortex (mPFC) with western blot. Finally, behavioral reactivity towards a novel environment was measured as a proxy for anxiety-like behavior. Results show that HPA axis activity under rest conditions was not affected by ELS. HPA axis reactivity after immobilization was decreased by ELS in females and increased, at trend-level in males. This effect in females was further exacerbated by low expression of the MR. We also observed a sex*ELS interaction regarding MR and GR expression in the dorsal hippocampus, with a significant upregulation of MR in males only. The sex-dependent interaction with ELS was not reflected in the behavioral response to novel environment and time spent in a sheltered compartment. We did find increased locomotor activity in all groups after a history of ELS, which attenuated after 4 h in males but not females regardless of condition. Our findings support that ELS alters HPA axis functioning sex-dependently. Genetic predisposition to low MR function may render females more susceptible to the harmful effect of ELS whereas in males low MR function promotes resilience. We propose that this model may be a useful tool to investigate the underlying mechanisms of sex-dependent and genetic vulnerability/resilience to stress-related psychopathology. Show less
Luijtgaarden, M.W.M. van de; Caskey, F.J.; Wanner, C.; Chesnaye, N.C.; Postorino, M.; Janmaat, C.J.; ... ; EQUAL Study Investigators 2019
Background The epidemiology and prognosis of chronic kidney disease (CKD) differ by sex. We aimed to compare symptom prevalence and the clinical state in women and men of >= 65years of age with... Show moreBackground The epidemiology and prognosis of chronic kidney disease (CKD) differ by sex. We aimed to compare symptom prevalence and the clinical state in women and men of >= 65years of age with advanced CKD receiving routine nephrology care.Methods The European QUALity study on treatment in advanced chronic kidney disease (EQUAL) study follows patients from six European countries of >= 65years of age years whose estimated glomerular filtration rate (eGFR) dropped to <= 20mL/min/1.73m(2) for the first time during the last 6 months. The Dialysis Symptom Index was used to assess the prevalence and severity of 33 uraemic symptoms. Data on the clinical state at baseline were collected from medical records. Prevalence was standardized using the age distribution of women as the reference.Results The results in women (n=512) and men (n=967) did not differ with age (77.0 versus 75.7years) or eGFR (19.0 versus 18.5). The median number of symptoms was 14 [interquartile range (IQR) 9-19] in women, and 11 (IQR 7-16) in men. Women most frequently reported fatigue {39% [95% confidence interval (CI) 34-45]} and bone/joint pain [37% (95% CI 32-42)] as severe symptoms, whereas more men reported difficulty in becoming sexually aroused [32% (95% CI 28-35)] and a decreased interest in sex [31% (95% CI 28-35)]. Anaemia [73% (95% CI 69-77) versus 85% (95% CI 82-87)] was less common in women than in men, as were smoking history and cardiovascular comorbidity. However, a diagnosis of liver disease other than cirrhosis, psychiatric disease and mild malnutrition were more common among women.Conclusions Women in secondary care with an incident eGFR <= 20mL/min/1.73m(2) reported a higher symptom burden, while their clinical state was considered similar or even more favourable as compared with men. Show less
Severs, M.; Spekhorst, L.M.; Mangen, M.J.J.; Dijkstra, G.; Lowenberg, M.; Hoentjen, F.; ... ; Fidder, H.H. 2018
