Role of sex and gender-related variables in development of metabolic syndrome: A prospective cohort study.

INTRODUCTION: The burden of metabolic syndrome (MetS) and its components has been increasing mainly amongst male individuals. Nevertheless, clinical outcomes related to MetS (i.e., cardiovascular diseases), are worse among female individuals. Whether these sex differences in the components and sequalae of MetS are influenced by gender (i.e., psycho-socio-cultural factors)) is a matter of debate.  Therefore, the purpose of this study was to determine the association between gender-related factors and the development of MetS, and to assess if the magnitude of the associations vary by sex. METHOD: Data from the Colaus/PsyColaus study, a prospective population-based cohort of 6,734 middle-aged participants in Lausanne (Switzerland) (2003-2006) were used. The primary endpoint was the development of MetS as defined by the Adult Treatment Panel III of the National Cholesterol Education Program. Multivariable models were estimated using logistic regression to assess the association between gender-related factors and the development of MetS. Two-way interactions between sex,  age and gender-related factors were also tested. RESULTS: Among 5,195 participants without MetS (mean age=51.3 ± 10.6, 56.1 % females), 27.9 % developed MetS during a mean follow-up of 10.9 years. Female sex (OR:0.48, 95 %CI:0.41-0.55) was associated with decreased risk of developing MetS. Conversely, older age, educational attainment less than university, and low income were associated with an increased risk of developing MetS. Statistically significant interaction between sex and strata of age, education, income, smoking, and employment were identified showing that the reduced risk of MetS in female individuals was attenuated in the lowest education, income, and advanced age strata. However, females who smoke and reported being employed demonstrated a decreased risk of MetS compared to males. Conversely smoking and unemployment were significant risk factors for MetS development among male adults. CONCLUSIONS: Gender-related factors such as income level and educational attainment play a greater role in the development of MetS in female than individuals. These factors represent novel modifiable targets for implementation of sex- and gender-specific strategies to achieve health equity for all people.

Sex differences in the perception of cardiovascular risk in familial hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia (FH), a common genetic condition, is characterized by elevated low-density lipoprotein cholesterol (LDL-C) and premature atherosclerotic cardiovascular disease (ASCVD). Recent data indicate an undertreatment of females with FH. OBJECTIVE: To characterize the role of sex in the perception of FH, its associated ASCVD risk and treatment. METHODS: A survey investigating for sex differences in the perception of FH was sent to 1073 patients with FH using a cross sectional study design. RESULTS: A total of 412 patients (51.9 % male) responded to the survey; mean age was 56.2 ± 14.4 years. There was a higher proportion of males with ASCVD than females (41.5 % vs. 16.5 %, respectively, p<0.001). Analyses of the survey responses showed that a majority of both males and females agreed that their risk of ASCVD is higher than healthy individuals of same age (70.8 % vs. 74.7 %, respectively, p = 0.434). Females were more concerned about having high LDL-C levels (67.5 % vs. 56.5 % in males, p = 0.024), especially those in secondary prevention programs. As for treatment of FH, approximately 75 % of both sex groups considered statins to be efficient in reducing the risk of myocardial infarction, but less than half of the females considered statins to be safe (44.8 % vs. 60.0 % in males, p = 0.003). No major sex differences were noted regarding the influence of the doctor in their understanding of FH as a disease. CONCLUSION: Overall, both males and females with FH were well informed about FH, although females were more concerned about having high LDL-C levels and they feared the safety of statins.

Importance of accounting for timing of time-varying exposures in association studies: Hydrochlorothiazide and non-melanoma skin cancer.

PURPOSE: Hydrochlorothiazide (HCTZ), a widely prescribed antihypertensive drug with photosensitising properties, has been linked with non-melanoma skin cancer (NMSC) risk. However, previous analyses did not fully explore if and how the impact of past HCTZ exposures accumulates with prolonged use and/or depends on time elapsed since exposures. Therefore, we used different models to more comprehensively assess how NMSC risk vary with HCTZ exposure, and explore how the results may depend on modeling strategies. METHODS: We used different parametric models with alternative time-varying exposure metrics, and the flexible weighted cumulative exposure model (WCE) to estimate associations between HCTZ exposures and NMSC risk in a population-based cohort of HCTZ users over 65 years old, in the province of Ontario, Canada. RESULTS: Among 3844 HCTZ users, 273 developed NMSC during up to 8 years of follow-up. In parametric models, based on all exposures, increased duration of past HCTZ use was associated with an increase of NMSC risk but cumulative dose showed no systematic association. Yet, WCE results suggested that only exposures taken 2.5-4 years in the past were associated with the current NMSC hazard. This finding led us to re-define the parametric models, which also confirmed that any HCTZ dose taken outside this time-window were not systematically associated with NMSC incidence. CONCLUSIONS: Our analyses illustrate how flexible modeling may yield new insights into complex temporal relationships between a time-varying drug exposure and risks of adverse events. Duration and recency of antihypertensive agents exposures must be taken into account in evaluating risk and benefits.

Skin Cancer and Hydrochlorothiazide: Novel Population-Based Analyses Considering Personal Risk Factors Including Race/Ethnicity.

BACKGROUND: Hydrochlorothiazide, a common antihypertensive, has photosensitive properties, potentially increasing skin cancer risk. We evaluated melanoma and nonmelanoma skin cancer among hydrochlorothiazide users with 3 different cohorts as each allows assessment of different potential cofounders/effect modifiers, including race/ethnicity. METHODS: We built 3 cohorts using IBM MarketScan Research Databases: Commercial and Encounters (>3.5 million individuals, 2010-2018), a subcohort with health risk assessment respondents (415, 330), and Medicaid (509, 767, 2011-2017). Adults (aged 18+ years) entered the respective cohort with a first-filled prescription (cohort entry) for hydrochlorothiazide (the exposure of interest) or angiotensin-converting enzyme (ACE) inhibitors (the active comparator), with ≥12 months of continuous enrollment with medical/pharmacy coverage at baseline. We excluded those who used hydrochlorothiazide/ACE inhibitor (including fixed-dose combination products) 12 months before cohort entry and those with prior skin cancer, HIV, or organ transplant. We compared the risk for hydrochlorothiazide versus ACE inhibitor using multivariate proportional hazards regression. RESULTS: Baseline characteristics were similar, aside from more Black individuals among hydrochlorothiazide users (43.3% [95% CI, 43.0%-43.6%]) than ACE inhibitor users (28.1% [95% CI, 27.9%-28.3%]). The hazard ratio (95% CI) for nonmelanoma skin cancer related to hydrochlorothiazide (versus ACE inhibitor) was 0.96 (0.91-1.00) in the Commercial cohort, 1.01 (0.77-1.32) for the health risk assessment subcohort, and 1.33 (0.77-2.29) for Medicaid. For melanoma, the respective hazard ratios were 1.07 (0.95-1.20), 0.85 (0.43-1.67), and 0.93 (0.51-1.67), respectively. CONCLUSIONS: Our evaluation using 3 different approaches, including adjustment for race/ethnicity, did not establish a clear difference between hydrochlorothiazide and ACE inhibitor in terms of skin cancer risk.

Cardiovascular health through a sex and gender lens in six South Asian countries: Findings from the WHO STEPS surveillance.

Background: Sex and gender-based differences in cardiovascular health (CVH) has been explored in the context of high-income countries. However, these relationships have not been examined in low- and middle-income countries. The main aim of this study was to examine how sex and gender-related factors are associated with cardiovascular risk factors of people in South Asian countries. Methods: We conducted a retrospective analysis of the World Health Organization's "STEPwise approach to surveillance of risk factors for non-communicable disease" or "STEPS" from six South Asian countries, surveys conducted between 2014-2019. The main outcomes were CVH as measured by a composite measure of STEPS-HEART health index (smoking, physical activity, fruit and vegetable consumption, overweight/obesity, diabetes and hypertension), values ranging from 0 (worst) to 6 (best or ideal) and self-reported occurrence of cardiovascular disease (ie, heart attack and stroke). Multivariate linear and logistic regression models were performed. Multiple imputation with chained equations was performed. Results: The final analytic sample consisted of 33 106 participants (57.5% females). The mean STEPS-HEART index score in the South Asian population was 3.43 [SD: 0.92]. Female sex (ß: 0.05, 95% confidence interval (CI) = 0.01-0.08, P < 0.05) was significantly associated with better CVH compared to males. Being married (ßmale = -0.30, 95% CI = -0.37, -0.23 vs ßfemale = -0.23, 95% CI = -0.29, -0.17; P < 0.001) and having a household size ≥5 (ßmale = -0.15, 95% CI = -0.24, -0.06 vs ßfemale = -0.11, 95% CI = -0.16, -0.04; P < 0.01) were associated with poorer CVH, more so in males. Being married was also associated with high risk of CVD (ORmale = 2.54, 95% CI = 1.68-3.86, P < 0.001 vs ORfemale = 1.19, 95% CI = 0.84-1.68, P = 0.31), significant in males. Conclusions: Among the South Asian population, being female may be advantageous in having an ideal CVH. However, gender-related factors such as marital status and large household size were associated with poorer CVH and greater risk of CVD, regardless of sex.

The MedSafer Study-Electronic Decision Support for Deprescribing in Hospitalized Older Adults: A Cluster Randomized Clinical Trial.

IMPORTANCE: Scalable deprescribing interventions may reduce polypharmacy and the use of potentially inappropriate medications (PIMs); however, few studies have been large enough to evaluate the impact that deprescribing may have on adverse drug events (ADEs). OBJECTIVE: To evaluate the effect of an electronic deprescribing decision support tool on ADEs after hospital discharge among older adults with polypharmacy. DESIGN, SETTING, AND PARTICIPANTS: This was a cluster randomized clinical trial of older (≥65 years) hospitalized patients with an expected survival of more than 3 months who were admitted to 1 of 11 acute care hospitals in Canada from August 22, 2017, to January 13, 2020. At admission, participants were taking 5 or more medications per day. Data analyses were performed from January 3, 2021, to September 23, 2021. INTERVENTIONS: Personalized reports of deprescribing opportunities generated by MedSafer software to address usual home medications and measures of prognosis and frailty. Deprescribing reports provided to the treating team were compared with usual care (medication reconciliation). MAIN OUTCOMES AND MEASURES: The primary outcome was a reduction of ADEs within the first 30 days postdischarge (including adverse drug withdrawal events) captured through structured telephone surveys and adjudicated blinded to intervention status. Secondary outcomes were the proportion of patients with 1 or more PIMs deprescribed at discharge and the proportion of patients with an adverse drug withdrawal event (ADWE). RESULTS: A total of 5698 participants (median [range] age, 78 [72-85] years; 2858 [50.2%] women; race and ethnicity data were not collected) were enrolled in 3 clusters and were adjudicated for the primary outcome (control, 3204; intervention, 2494). Despite cluster randomization, there were group imbalances, eg, the participants in the intervention arm were older and had more PIMS prescribed at baseline. After hospital discharge, 4989 (87.6%) participants completed an ADE interview. There was no significant difference in ADEs within 30 days of discharge (138 [5.0%] of 2742 control vs 111 [4.9%] of 2247 intervention participants; adjusted risk difference [aRD] -0.8%; 95% CI, -2.9% to 1.3%). Deprescribing increased from 795 (29.8%) of 2667 control to 1249 (55.4%) of 2256 intervention participants [aRD, 22.2%; 95% CI, 16.9% to 27.4%]. There was no difference in ADWEs between groups. Several post hoc sensitivity analyses, including the use of a nonparametric test to address the low cluster number, group imbalances, and potential biases, did not alter study conclusions. CONCLUSIONS AND RELEVANCE: This cluster randomized clinical trial showed that providing deprescribing clinical decision support during acute hospitalization had no demonstrable impact on ADEs, although the intervention was safe and led to improvements in deprescribing. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03272607.

Can synthetic data be a proxy for real clinical trial data? A validation study.

OBJECTIVES: There are increasing requirements to make research data, especially clinical trial data, more broadly available for secondary analyses. However, data availability remains a challenge due to complex privacy requirements. This challenge can potentially be addressed using synthetic data. SETTING: Replication of a published stage III colon cancer trial secondary analysis using synthetic data generated by a machine learning method. PARTICIPANTS: There were 1543 patients in the control arm that were included in our analysis. PRIMARY AND SECONDARY OUTCOME MEASURES: Analyses from a study published on the real dataset were replicated on synthetic data to investigate the relationship between bowel obstruction and event-free survival. Information theoretic metrics were used to compare the univariate distributions between real and synthetic data. Percentage CI overlap was used to assess the similarity in the size of the bivariate relationships, and similarly for the multivariate Cox models derived from the two datasets. RESULTS: Analysis results were similar between the real and synthetic datasets. The univariate distributions were within 1% of difference on an information theoretic metric. All of the bivariate relationships had CI overlap on the tau statistic above 50%. The main conclusion from the published study, that lack of bowel obstruction has a strong impact on survival, was replicated directionally and the HR CI overlap between the real and synthetic data was 61% for overall survival (real data: HR 1.56, 95% CI 1.11 to 2.2; synthetic data: HR 2.03, 95% CI 1.44 to 2.87) and 86% for disease-free survival (real data: HR 1.51, 95% CI 1.18 to 1.95; synthetic data: HR 1.63, 95% CI 1.26 to 2.1). CONCLUSIONS: The high concordance between the analytical results and conclusions from synthetic and real data suggests that synthetic data can be used as a reasonable proxy for real clinical trial datasets. TRIAL REGISTRATION NUMBER: NCT00079274.

Sex, Gender, and Cardiovascular Health in Canadian and Austrian Populations.

BACKGROUND: Evidence differentiating the effect of biological sex from psychosociocultural factors (gender) in different societies and its relation to cardiovascular diseases is scarce. We explored the association between sex, gender, and cardiovascular health (CVH) among Canadian (CAN) and Austrian (AT) populations. METHODS: The Canadian Community Health Survey (CCHS) (n = 63,522; 55% female) and Austrian Health Interview Survey (AT-HIS) (n = 15,771; 56% female) were analyzed in a cross-sectional survey design. The CANHEART/ATHEART index, a measure of ideal CVH composed of 6 cardiometabolic risk factors (smoking, physical activity, fruit and vegetable consumption, overweight/obesity, diabetes, and hypertension; range 0-6; higher scores reflecting better CVH) was calculated for both databases. A composite measure of psychosociocultural gender was computed for each country (range 0-1, higher score identifying characteristics traditionally ascribed to women). RESULTS: Median CANHEART 4 (interquartile range 3-5) and CAN gender scores 0.55 (0.49-0.60) were similar to median ATHEART 4 (3-5) and AT gender scores 0.55 (0.46-0.64). Although higher gender scores (CCHS: ß = -1.33, 95% confidence interval [CI] -1.44 to -1.22; AT-HIS: ß = -1.08, 95% CI -1.26 to -0.89)) were associated with worse CVH, female sex (CCHS: ß = 0.35, 95% CI (0.33-0.37); AT-HIS: ß = 0.60, 95% CI (0.55-0.64)) was associated with better CVH in both populations. In addition, higher gender scores were associated with increased prevalence of heart disease compared with female sex. The magnitude of this risk was higher in Austrians. CONCLUSIONS: These results demonstrate that individuals with characteristics typically ascribed to women reported poorer cardiovascular health and higher risk of heart disease, independently from biological sex and baseline CV risk factors, in both countries. Female sex exhibited better CV health and a lower prevalence of heart disease than male in both populations. However, gender factors and magnitude of gender impact varied by country.

The Importance of Gender to Understand Sex Differences in Cardiovascular Disease.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide. There is robust evidence of heterogeneity in underlying mechanism, manifestation, prognosis, and response to treatment of CVD between male and female patients. Gender, which refers to the socially constructed roles, behaviours, expressions, and identities of individuals, is an important determinant of CV health, and its consideration might help in attaining a broader understanding of the observed sex differences in CVD. Established risk factors such as hypertension, dyslipidemia, diabetes mellitus, obesity, and smoking are well known to contribute to CVD. However, despite the differences in CVD risk between male and female, most studies looking into the magnitude of effect of each risk factor have traditionally focused on male subjects. While biological sex influences disease pathophysiology, the psycho-socio-cultural construct of gender can further interact with this effect. Behavioural, psychosocial, personal, cultural, and societal factors can create, repress, or strengthen underlying biological CV health differences. Although mechanisms of action are largely unclear, it is suggested that gender-related factors can further exacerbate the detrimental effect of established risk factors of CVD. In this narrative review, we explore the current literature investigating the role of gender in CV risk and its impact on established risk factors as a fundamental step toward precision medicine.

Anticoagulant Use and the Risk of Thromboembolism and Bleeding in Postoperative Atrial Fibrillation After Noncardiac Surgery.

BACKGROUND: An effective and safe oral anticoagulation (OAC) strategy for patients with new postoperative AF (POAF) after noncardiac surgery remains unclear. We aimed to determine the association between OAC use and 1) thromboembolic events and 2) major bleeding in patients with POAF after noncardiac surgery. METHODS: A retrospective cohort (1999-2015) was used to identify patients with new POAF after inpatient noncardiac surgery. Initiation of OAC was defined as prescription of an OAC within 30 days following hospital discharge. Times to first hospital admission or emergency department visit for a thromboembolic or major bleeding event were compared using Cox proportional hazards models. RESULTS: We identified 22,007 patients with new POAF after inpatient noncardiac surgery. The majority of patients had intermediate (CHA2DS2-VASc 2-3: 45%) to high (CHA2DS2-VASc ≥ 4: 42%) thromboembolic risk. During a mean follow-up of 4 years, a total of 1099 (5%) thromboembolic and 3250 (15%) bleeding events occurred. Compared with patients not on anticoagulation, anticoagulation did not reduce the risk for thromboembolic events (adjusted hazard ratio [aHR] 0.89, 95% CI 0.73-1.07). In patients initiated on anticoagulation, there was an association with a higher risk for major bleeding (aHR 1.14, 95% CI 1.04-1.25). CONCLUSIONS: In patients with new POAF after noncardiac surgery, anticoagulation was not associated with a reduction in long-term thromboembolic events; however, this was accompanied by an overall increased risk for major bleeding. Future prospective clinical studies are needed to better address the role for anticoagulation therapy in the setting of POAF after noncardiac surgery to understand the efficacy and safety of treatment.

Real-world analyses of therapy discontinuation of checkpoint inhibitors in metastatic melanoma patients.

The 'real-world' patient population of metastatic melanoma is not fully represented in clinical trials investigating checkpoint inhibitors. We described therapy discontinuation in an unselected population-based cohort of adults with metastatic melanoma who started therapy with pembrolizumab, nivolumab, or nivolumab/ipilimumab from January 2015 to August 2017. Therapy discontinuation was defined as a gap between doses beyond 120 days, and/or initiation of another cancer therapy. We estimated drug-specific rate ratios for therapy discontinuation adjusted for age, sex, comorbidities, health care use, and past cancer therapies. We included 876 metastatic melanoma patients initiating pembrolizumab (44.3%), nivolumab/ipilimumab (31.2%), and nivolumab (24.5%). At 12 months of follow-up, the probabilities of therapy discontinuation were 49.9% (95% confidence interval, CI 43.6-56.5) for pembrolizumab, 58.8% (95% CI 50.5-67.3) for nivolumab, and 59.2% (95% CI 51.7-66.8) for nivolumab/ipilimumab. Stratified analyses based on prior cancer therapy, brain metastases at baseline, and sex showed similar trends. In multivariable analyses, compared with pembrolizumab, patients starting nivolumab (rate ratio 1.38, 95% CI 1.08-1.77) or nivolumab/ipilimumab (rate ratio 1.30, 95% CI 1.02-1.65) were more likely to discontinue therapy. Our findings indicate frequent discontinuations of checkpoint inhibitors at one year. The lower discontinuation associated with pembrolizumab should be confirmed in further studies.

COVID-SAFER: Deprescribing Guidance for Hydroxychloroquine Drug Interactions in Older Adults.

BACKGROUND/OBJECTIVES: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes high morbidity and mortality in older adults with chronic illnesses. Several trials are currently underway evaluating the antimalarial drug hydroxychloroquine as a potential treatment for acute infection. However, polypharmacy predisposes patients to increased risk of drug-drug interactions with hydroxychloroquine and may render many in this population ineligible to participate in trials. We aimed to quantify the degree of polypharmacy and burden of potentially inappropriate medications (PIMs) that older hospitalized adults are taking that would interact with hydroxychloroquine. METHODS: We reanalyzed data from the cohort of patients 65 years and older enrolled in the MedSafer pilot study. We first identified patients taking medications with potentially harmful drug-drug interactions with hydroxychloroquine that might exclude them from participation in a typical 2019 coronavirus disease (COVID-19) therapeutic trial. Next, we identified medications that were flagged by MedSafer as potentially inappropriate and crafted guidance around medication management if contemplating the use of hydroxychloroquine. RESULTS: The cohort contained a total of 1,001 unique patients with complete data on their home medications at admission. Of these 1,001 patients, 590 (58.9%) were receiving one or more home medications that could potentially interact with hydroxychloroquine, and of these, 255 (43.2%) were flagged as potentially inappropriate by the MedSafer tool. Common classes of PIMs observed were antipsychotics, cardiac medications, and antidiabetic agents. CONCLUSION: The COVID-19 pandemic highlights the importance of medication optimization and deprescribing PIMs in older adults. By acting now to reduce polypharmacy and use of PIMs, we can better prepare this vulnerable population for inclusion in trials and, if substantiated, pharmacologic treatment or prevention of COVID-19. J Am Geriatr Soc 68:1636-1646, 2020.

The MedSafer Study: A Controlled Trial of an Electronic Decision Support Tool for Deprescribing in Acute Care.

OBJECTIVES: Polypharmacy is common, costly, and harmful for hospitalized older adults. Scalable strategies to reduce the burden of potentially inappropriate medications (PIMs) are needed. We sought to leverage medication reconciliation in hospitalized older adults by pairing with MedSafer, an electronic decision support tool for deprescribing. DESIGN: This was a nonrandomized controlled before-and-after study. SETTING: The study took place on four internal medicine clinical teaching units. PARTICIPANTS: Subjects were aged 65 years and older, had an expected prognosis of 3 or more months, and were taking five or more usual home medications. INTERVENTION: In the baseline phase, patients received usual care that was medication reconciliation. Patients in the intervention arm also had a "deprescribing opportunity report" generated by MedSafer and provided to their in-hospital treating team. MEASUREMENTS: The primary outcome was ascertained at the time of hospital discharge and was the proportion of patients who had one or more PIMs deprescribed. RESULTS: A total of 1066 patients were enrolled, and deprescribing opportunities were present for 873 (82%; 418 during the control and 455 during the intervention phases, respectively). The proportion of patients with one or more PIMs deprescribed at discharge increased from 46.9% in the control period to 54.7% in the intervention period with an adjusted absolute risk difference of 8.3% (2.9%-13.9%). Not all classes of drugs in the intervention arm were associated with an increase in deprescribing, and new PIM starts were equally common in both arms of the study. CONCLUSION: Using an electronic decision support tool for deprescribing, we increased the proportion of patients with one or more PIMs deprescribed at hospital discharge as compared with usual care. Although this type of intervention may help address medication overload in hospitalized patients, it also underscores the importance of powering future trials for a reduction in adverse drug events. TRIAL REGISTRATION: NCT02918058. J Am Geriatr Soc 67:1843-1850, 2019.

Flexible Modeling of the Association Between Cumulative Exposure to Low-Dose Ionizing Radiation From Cardiac Procedures and Risk of Cancer in Adults With Congenital Heart Disease.

Adults with congenital heart disease are increasingly being exposed to low-dose ionizing radiation (LDIR) from cardiac procedures. In a recent study, Cohen et al. (Circulation. 2018;137(13):1334-1345) reported an association between increased LDIR exposure and cancer incidence but did not explore temporal relationships. Yet, the impact of past exposures probably accumulates over years, and its strength may depend on the amount of time elapsed since exposure. Furthermore, LDIR procedures performed shortly before a cancer diagnosis may have been ordered because of early symptoms of cancer, raising concerns about reversal causality bias. To address these challenges, we combined flexible modeling of cumulative exposures with competing-risks methodology to estimate separate associations of time-varying LDIR exposure with cancer incidence and all-cause mortality. Among 24,833 patients from the Quebec Congenital Heart Disease Database, 602 had incident cancer and 500 died during a follow-up period of up to 15 years (1995-2010). Initial results suggested a strong association of cancer incidence with very recent LDIR exposures, likely reflecting reverse causality bias. When exposure was lagged by 2 years, an increased cumulative LDIR dose from the previous 2-6 years was associated with increased cancer incidence, with a stronger association for women. These results illustrate the importance of accurate modeling of temporal relationships between time-varying exposures and health outcomes.

Circulating MicroRNAs Implicate Multiple Atherogenic Abnormalities in the Long-Term Cardiovascular Sequelae of Preeclampsia.

BACKGROUND: Women who have had preeclampsia (PE) are at increased risk for premature cardiovascular disease (CVD). The underlying pathophysiology of this risk remains unclear, but potentially involves subclinical vascular damage or dysfunction. Alterations in the levels of circulating microRNAs may be implicated, as they are known to play pervasive roles in vascular biology. We investigated whether levels of circulating microRNAs are altered between women with premature acute coronary syndrome (ACS), with and without a history of PE. METHODS: Women with premature ACS (age ≤ 55 years) were categorized based on a prior history of PE or normotensive pregnancy. Relative plasma levels of 372 microRNAs were initially assessed by polymerase chain reaction array in a subset of subjects (n = 12-13/group) matched for age, chronic hypertension, dyslipidemia, and smoking status. Candidate microRNAs were then validated in a larger cohort of ACS patients (n = 176). RESULTS: MicroRNAs previously linked to angiogenesis (miR-126-3p), inflammation (miR-146a-5p), and cholesterol metabolism (miR-122-5p) were significantly decreased in women with prior PE compared to women with prior normotensive pregnancy (P = 0.002, 0.017, and 0.009, respectively), even after adjustment for chronic hypertension. CONCLUSIONS: Circulating levels of miR-126-3p, -146a-5p, and -122-5p were significantly decreased in women with premature ACS who reported prior PE compared to those with prior normotensive pregnancy. These data provide novel insight into potential pathways that may contribute to the increased risk of CVD following PE.

Prolonged hypothalamic-pituitary-adrenal axis activation after acute coronary syndrome in the GENESIS-PRAXY cohort.

Background Glucocorticoid excess has been linked with cardiovascular disease. Little is known about the long-term cortisol response in patients after acute coronary syndrome. Design The objective of this study was to describe the distribution of salivary cortisol in the post-acute phase of acute coronary syndrome and to describe the association of late-night salivary cortisol with cardiovascular risk factors. Methods We used late-night salivary cortisol measurements post-discharge to estimate hypothalamic-pituitary-adrenal axis activity in 309 patients aged 18-55 years enrolled in the GENESIS-PRAXY study from January 2009-April 2013. We evaluated hypothalamic-pituitary-adrenal axis activity and its association with hypertension, dyslipidemia, diabetes, smoking, family history, prior acute coronary syndrome, psychiatric diseases, acute coronary syndrome severity, as well as mortality and rate of rehospitalization at 12 months. Results Persistently elevated late-night salivary cortisol>2.92 nmol/l was seen in 99 (32.0%) patients: within the range of what may be seen in Cushing's disease. Elevated late-night salivary cortisol was associated with previous acute coronary syndrome (13.3% vs 24.2%, p = 0.02), peripheral vascular disease (3.8% vs 13.1%, p = 0.002), and smoking (32.9% vs 46.5% p = 0.02). Elevated late-night salivary cortisol was associated with higher hemoglobin A1c values (5.6 ± 3.0 vs 6.1 ± 2.9, p = 0.008) and lower high density lipoprotein values (0.94 ± 0.53 vs 0.86 ± 0.50, p = 0.01). There were no differences in psychiatric symptom scores, acute coronary syndrome severity or mortality, and rate of rehospitalization at 12 months. Conclusions Many patients post-acute coronary syndrome have prolonged, marked activation of the hypothalamic-pituitary-adrenal axis. Late-night salivary cortisol co-associates with several cardiovascular risk factors. Further studies are needed to confirm the exact role of hypothalamic-pituitary-adrenal axis activity in the pathophysiology of cardiovascular disease.

Sex and gender considerations in transplantation research: protocol for a scoping review.

BACKGROUND: Despite the growing appreciation of the importance of sex and gender considerations in transplantation research, there is currently no framework or good practice guidelines for the appropriate handling of sex and gender issues in human allotransplantation research. METHODS: We will conduct a scoping review to synthesize the evidence on how matters of sex and gender have been handled in human allotransplantation research. We will survey the literature discussing sex and gender in relation to transplantation, including adult and pediatric patients, hematopoietic and solid organ transplant recipients as well as organ donors. We will search MEDLINE and Embase for literature discussing sex and gender in relation to transplantation. Two reviewers will independently evaluate the eligibility of all identified titles and abstracts for inclusion in the full text review, as well as data extraction. Descriptive data and information on how sex and gender have been considered in human transplantation research will be reported. DISCUSSION: This scoping review will be an important stepping stone towards the development of good practice guidelines on study design and analysis considerations when handling sex and gender issues in human transplantation research. This scoping review can also help identify methodological issues that restrict the translation of transplantation research findings into clinical practice related to underestimation of sex/gender differences. This review will ultimately identify major gaps, inform donor-recipient selection, guide personalized interventions, and prioritize research recommendations in human transplantation research.

Factors associated with study completion in patients with premature acute coronary syndrome.

BACKGROUND: Factors associated with study completion in younger adults are not well understood. This study sought to describe psychosocial, clinical, and demographic features associated with completion of a study of men and women with premature acute coronary syndrome. METHODS: As part of the GENdEr and Sex determInantS of cardiovascular disease: From bench to beyond-Premature Acute Coronary Syndrome (GENESIS-PRAXY) study, demographic, psychosocial, and clinical variables were assessed in 1213 patients hospitalized for acute coronary syndrome (≤ 55 years; 30% women). Patients were followed for 12 months. Dropouts withdrew from the study or were lost to follow-up after 12 months; completers were still enrolled after 12 months. RESULTS: Of 1213 patients initially enrolled, 777 (64.1%) completed 12-month follow-up. Fully adjusted models suggested that being older (OR = 1.04, 95% CI [1.01, 1.06]), higher subjective social status within one's country (OR = 1.11, 95% CI [1.01, 1.22]), being free of type II diabetes, (OR = 0.66, 95% CI [0.45, 0.97]), non-smoking status (OR = 0.70, 95% CI [0.51, 0.95]) and being free of depression (OR = 1.52, 95% CI [1.11, 2.07]) were independently associated with study completion. CONCLUSIONS: Recruitment/retention strategies targeting individuals who smoke, are younger, have low subjective social status within one's country, have diabetes, or have depression may improve participant follow-up in cardiovascular cohort studies.

Markers of Vascular Dysfunction After Hypertensive Disorders of Pregnancy: A Systematic Review and Meta-Analysis.

Women with prior hypertensive disorders of pregnancy (HDP) are at twice the risk of cardiovascular disease compared with women with prior normotensive pregnancy, possibly because of sustained vascular dysfunction after delivery. The aim of this systematic review and meta-analysis is to summarize evidence of vascular dysfunction at least 3 months after HDP. Articles in all languages were retrieved from principal databases. Studies included were observational, with HDP as the main exposure and measurements of vascular dysfunction via imaging modalities or serum biomarkers as the main outcome, assessed at least 3 months postpartum. We pooled results of modalities reported in >3 studies using a random effects model. Of 6109 potentially relevant studies, 72 were included that evaluated 10 imaging modalities and 11 serum biomarkers in 8702 women. There was evidence of vascular dysfunction in women post HDP compared with women with prior normal pregnancy when measured by carotid-femoral pulse wave velocity (0.64 m/s [0.17-1.11]), carotid intima-media thickness (0.025 mm [0.004-0.045]), and augmentation index (5.48% [1.58-9.37]), as well as mean levels of soluble fms-like tyrosine kinase (6.12 pg/mL [1.91-10.33]). Between-groups differences in measures of vascular dysfunction were more pronounced when assessments were performed in younger women (<40 years) or closer to the index pregnancy for almost all modalities. In conclusion, pooled data from studies evaluating vascular imaging suggest that some vascular dysfunction persists after HDP as compared with women with prior normal pregnancy.

Prevalence of Cancer in Adults With Congenital Heart Disease Compared With the General Population.

The prevalence rate of cancer among adult patients with congenital heart disease (CHD) in North America has not been previously described. The Quebec adult CHD database was used to determine the prevalence rate of cancer among adult patients with CHD measured as the number of adults with CHD and cancer alive in 2005 per 1,000 adults with CHD. This prevalence rate was compared with the prevalence rate of cancer in the general population of adults in Canada. Types of cancer among the CHD group were described by gender and age. Adult patients with CHD had a 1.6 to 2 times higher prevalence of cancer at 2, 5, and 10 years for both men and women. Overall, men had a greater prevalence of total cancers in all-time durations than did women. Breast, colon, and prostate cancer were the most common cancers reported in adults with CHD. In conclusion, we observed an increased prevalence of cancer among the adult CHD population of Quebec compared with the general Canadian population.