The Effects of Hyperglycemia on Early Endothelial Activation and the Initiation of Atherosclerosis.

It is well established that patients with diabetes have an increased risk of developing atherosclerotic cardiovascular disease. The earliest detectable sign of atherosclerosis initiation is endothelial cell activation. Activated endothelial cells express adhesion proteins, P-selectin, E-selectin, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1, which function to recruit monocytes to the subendothelial layer. This study examines the effect of hyperglycemia on endothelial cell activation and the initiation and progression of atherosclerosis. In vitro studies revealed that exposure of human aortic endothelial cells to elevated (30 mmol/L) glucose concentrations significantly increased the expression of P-selectin, E-selectin, and vascular cell adhesion molecule-1. In vivo studies showed that, before lesion development, 5-week-old hyperglycemic ApoE-/-Ins2+/akita mice had significantly increased expression of these adhesion proteins in the aortic sinus and increased macrophage infiltration, compared with normoglycemic ApoE-/- controls. At 25 weeks of age, ApoE-/-Ins2+/akita mice had significantly larger atherosclerotic plaques than ApoE-/- controls (0.022 ± 0.004 versus 0.007± 0.001 mm3; P < 0.05). Similar endothelial activation was observed in heterozygous ApoE+/-Ins2+/akita mice; however, detectable atherosclerotic lesions did not develop in the absence of dyslipidemia. Lowering blood glucose levels (by 55%) using a sodium-glucose cotransporter 2 inhibitor reduced endothelial activation. Together, these findings support a causative role for hyperglycemia in atherogenesis and highlight the importance of blood glucose regulation in preventing atherosclerotic cardiovascular disease.

Sex or Gender Reporting in Ophthalmology Clinical Trials Among US Food and Drug Administration Approvals, 1995 to 2022.

Importance: As critical determinants of scientific rigor, reproducibility, and equity, sex and gender should be considered in clinical trial design and reporting. Objective: To evaluate the accuracy of sex and gender reporting and extent of sex- and gender-based analysis in clinical trials associated with US Food and Drug Administration (FDA) drug approvals between January 1, 1995, and December 31, 2022. Design, Setting, and Participants: In this cross-sectional study of participants enrolled in FDA ophthalmology trials, the following trial documents were reviewed by pairs of independent reviewers in decreasing order of priority: peer-reviewed publication, ClinicalTrials.gov report, and FDA medical and statistical reviews. Trial protocols and supplementary materials were also reviewed. Main Outcome and Measures: The proportion of trials that correctly applied sex and gender terminology, reported the method of assessing sex or gender, and conducted sex- or gender-based data analysis; incorrect application of sex and gender terminology was defined as interchangeable use of sex- and gender-related terms without a clear justification. Results: Between 1995 and 2022, 34 ophthalmic drugs corresponding to 85 trials (34 740 participants) received FDA approval, of which 16 drugs (47.1%) corresponding to 32 trials (18 535 participants [37.6%]) were associated with peer-reviewed publications. Sixteen trials used sex and gender terminology correctly (19.5%). No trial reported how sex and gender were collected nor enrolled participants from sexual and gender identity minority populations. Most trials reported sex- and gender-disaggregated demographic data (96.5%), but few conducted sex- or gender-based analysis for data on dropout (1.2%), primary outcomes (28.2%), secondary outcomes (2.4%), and adverse events (9.4%). Erroneous sex and gender reporting was associated with later publication year (2008.5 vs 2001.0; median difference, 7.5; 95% CI, -6.0 to 11.0; P < .001) and higher journal influence metrics, including 2022 journal impact factor (13.7 vs 5.9; median difference, 7.8; 95% CI, -1.4 to 152.4, P < .001) and 2022 journal citation indicator (4.9 vs 2.1; median difference, 2.9; 95% CI, 0-20.0, P < .001). Conclusions and Relevance: In this observational study, over three-quarters of ophthalmology trials associated with FDA drug approvals conflated sex and gender and over two-thirds lacked sex- and gender-based analyses. More rigorous integration of sex and gender appears warranted for FDA, and presumably other trials, to improve their validity, reproducibility, and equity.

Sex Disparities in Operating Room use Among Cataract Surgeons: A 10-Year Retrospective Population-Based Analysis.

PURPOSE: To evaluate sex differences in operating room (OR) time and case volumes among comprehensive cataract surgeons in Ontario, Canada's most populated province. DESIGN: Retrospective, population-based cohort study. METHODS: Physician billing data of active comprehensive cataract surgeons between 2010 and 2019 were analyzed to identify all cataract surgeries in this timeframe. The number of OR days and case volume were the primary outcomes. Data were stratified by surgeon sex and career stage. RESULTS: Between 2010 and 2019, approximately 1.05 million cataract surgeries were performed in Ontario. There were an average of 195 ± 3 comprehensive cataract surgeons per year, of which 39 ± 5 were female. The proportion of female surgeons increased from 16.8% of all surgeons in 2010 to 24.4% in 2019. The greatest proportion of male surgeons were in the late phase of their career, whereas the greatest proportion of female surgeons were in the early stage of their career. On average, male surgeons had 44.9 ± 1.90 OR days per year and females had 32 ± 1.90 OR days per year, resulting in female surgeons averaging 12.45 ± 1.90 fewer OR days per year. This OR distribution remained consistent across career stages. Average case volumes per OR day were similar across sexes, but male surgeons performed on average 172.7 ± 30.6 more surgeries per year. CONCLUSIONS: Despite performing similar average case volumes per OR day, female surgeons had less OR time compared to their male counterparts per year, and this remained consistent across career stages and over the 10-year period. Metrics for OR allocation and use should be well defined and transparent.

Recurrence of new-onset post-operative AF after cardiac surgery: detected by implantable loop recorders: A systematic review and Meta-analysis.

BACKGROUND: Atrial fibrillation (AF) is one of the most common complications after cardiac surgery. New-onset post-operative AF may signal an elevated risk of AF and associated outcomes in long-term follow-up. We aimed to estimate the rate of AF recurrence as detected by an implantable loop recorder (ILR) in patients experiencing post-operative AF within 30 days after cardiac surgery. METHODS: We searched MEDLINE, Embase and Cochrane CENTRAL to April 2023 for studies of adults who did not have known AF, experienced new-onset AF within 30 days of cardiac surgery and received an ILR. We pooled individual participant data on timing of AF recurrence using a random-effects model with a frailty model applied to a Cox proportional hazard analysis. RESULTS: From 8671 citations, 8 single-centre prospective cohort studies met eligibility criteria. Data were available from 185 participants in 7 studies, with a median follow-up of 1.7 (IQR: 1.3-2.8) years. All included studies were at a low risk of bias. Pooled AF recurrence rates following 30 post-operative days were 17.8% (95% CI 11.9%-23.2%) at 3 months, 24.4% (17.7%-30.6%) at 6 months, 30.1% (22.8%-36.7%) at 12 months and 35.3% (27.6%-42.2%) at 18 months. CONCLUSIONS: In patients who experience new-onset post-operative AF after cardiac surgery, AF recurrence lasting at least 30 s occurs in approximately 1 in 3 in the first year after surgery. The optimal frequency and modality to use for monitoring for AF recurrence in this population remain uncertain.

Associations between psychological distress and hair cortisol during pregnancy and the early postpartum: A meta-analysis.

Pregnancy and the early postpartum signify a period of high stress. Perinatal stress can include psychological distress (PD), such as anxiety, depression, and stress, as well as neuroendocrine stress, indexed by activation of the hypothalamic-pituitary-adrenal (HPA) axis and the production of the hormone cortisol. Elevated PD and cortisol levels during the perinatal period can have long-term implications for the mother and child. Methodological advances have enabled the sampling of cortisol from hair, to provide a retrospective marker of HPA axis activity over several months. Despite knowing that maternal PD and HPA activity during the perinatal period independently impact health and development, research to date is unclear as to the association between maternal PD and hair cortisol. The present meta-analysis included 29 studies to assess the strength of the relation between maternal PD and hair cortisol levels during pregnancy and the early postpartum period. Several sample and methodological factors were assessed as moderators of this effect. Analyses were conducted using multilevel meta-analysis. Results of the multilevel meta-analysis indicated that the overall effect size between PD and HCC was small but not significant z = 0.039, 95% CI [- 0.001, 0.079]. Moderator analyses indicated that the strength of the association between PD and hair cortisol was moderated by pregnancy status (i.e., effects were stronger in pregnant compared to postpartum samples), timing of HCC and PD measurements (i.e., effects were larger when PD was measured before HCC) and geographic location (i.e., effects were larger in North American studies). The findings advance our understanding of the link between PD and HPA activity during the perinatal period, a time of critical impact to child development.

Rhythm vs. Rate Control in Patients with Postoperative Atrial Fibrillation after Cardiac Surgery: A Systematic Review and Meta-Analysis.

BACKGROUND: Postoperative atrial fibrillation (POAF) is the most common complication after cardiac surgery; it is associated with morbidity and mortality. We undertook this review to compare the effects of rhythm vs. rate control in this population. METHODS: We searched MEDLINE, Embase and CENTRAL to March 2023. We included randomized trials and observational studies comparing rhythm to rate control in cardiac surgery patients with POAF. We used a random-effects model to meta-analyze data and rated the quality of evidence using GRADE. RESULTS: From 8,110 citations, we identified 8 randomized trials (990 patients). Drug regimens used for rhythm control included amiodarone in four trials, other class III anti-arrhythmics in one trial, class I anti-arrhythmics in four trials and either a class I or III anti-arrhythmic in one trial. Rhythm control compared to rate control did not result in a significant difference in length of stay (mean difference -0.8 days; 95% CI -3.0 to +1.4, I2 = 97%), AF recurrence within 1 week (130 events; risk ratio [RR] 1.1; 95%CI 0.6-1.9, I2 = 54%), AF recurrence up to 1 month (37 events; RR 0.9; 95%CI 0.5-1.8, I2 = 0%), AF recurrence up to 3 months (10 events; RR 1.0; 95%CI 0.3-3.4, I2 = 0%) or mortality (25 events; RR 1.6; 95%CI 0.7-3.5, I2 = 0%). Effect measures from seven observational studies (1428 patients) did not differ appreciably from those in randomized trials. CONCLUSIONS: Although atrial fibrillation is common after cardiac surgery, limited low-quality data guide its management. Limited available evidence suggests no clear advantage to either rhythm or rate control. A large-scale randomized trial is needed to inform this important clinical question.

Risk Scores for Prediction of Postoperative Atrial Fibrillation After Cardiac Surgery: A Systematic Review and Meta-Analysis.

Postoperative atrial fibrillation (POAF) is a common complication after cardiac surgery and is associated with poor clinical outcomes. The objective of this systematic review and meta-analysis was to assess the performance of risk scores to predict POAF in cardiac surgery patients. We searched MEDLINE, Embase, and Cochrane CENTRAL for studies that developed/evaluated a POAF risk prediction model. Pairs of reviewers independently screened studies and extracted data. We pooled area under the receiver operating curves (AUCs), sensitivity and specificity, and adjusted odds ratios from multivariable regression analyses using the generic inverse variance method and random effects models. Forty-three studies (n = 63,847) were included in the quantitative synthesis. Most scores were originally developed for other purposes but evaluated for predicting POAF. Pooled AUC revealed moderate POAF discrimination for the EuroSCORE II (AUC 0.59, 95% confidence interval [CI] 0.54 to 0.65), Society of Thoracic Surgeons (AUC 0.60, 95% CI 0.56 to 0.63), EuroSCORE (AUC 0.63, 95% CI 0.58 to 0.68), CHADS2 (AUC 0.66, 95% CI 0.57 to 0.75), POAF Score (AUC 0.66, 95% CI 0.63 to 0.68), HATCH (AUC 0.67, 95% CI 0.57 to 0.75), CHA2DS2-VASc (AUC 0.68, 95% CI 0.60 to 0.75) and SYNTAX scores (AUC 0.74, 95% CI 0.71 to 0.78). Pooled analyses at specific cutoffs of the CHA2DS2-VASc, CHADS2, HATCH, and POAF scores demonstrated moderate-to-high sensitivity (range 46% to 87%) and low-to-moderate specificity (range 31% to 70%) for POAF prediction. In conclusion, existing clinical risk scores offer at best moderate prediction for POAF after cardiac surgery. Better models are needed to guide POAF risk stratification in cardiac surgery patients.

The Effect of Testosterone on Cardiovascular Disease and Cardiovascular Risk Factors in Men: A Review of Clinical and Preclinical Data.

Cardiovascular disease (CVD) is the leading cause of death worldwide. The effects of testosterone, the primary male sex hormone, on cardiovascular risk have been of special interest due to the increased risk of CVD in men. Although it is well established that testosterone levels decline and cardiovascular mortality increases with age, the association between testosterone and CVD remains unclear. Observational and randomized studies on the effects of endogenous and exogenous testosterone have produced conflicting data, and meta-analyses have been inconclusive, suggesting significant study heterogeneity. Despite a lack of adequately powered randomized controlled trials, large observational studies in the early 2010s led to advisories on the use of testosterone replacement therapy. Similar advisories have been mandated for certain types of androgen deprivation therapy. Additional research suggests that testosterone shortens the heart-rate-corrected QT interval, improves glycemic control, induces vasodilation, is prothrombotic, and has anti-obesity effects, whereas associations with atherosclerosis and inflammation are less clear. Despite inconclusive evidence on cardiovascular risk and inconsistencies among clinical practice guidelines, millions of men continue to use testosterone replacement and androgen deprivation therapy. In addition to summarizing clinical and preclinical data, this review provides insight on potential mechanisms of action of testosterone on CVD, applications of this knowledge to clinical settings, and avenues for future research.

Les maladies cardiovasculaires (MCV) sont la principale cause de décès dans le monde. Les effets de la testostérone, principale hormone sexuelle masculine, sur le risque cardiovasculaire ont suscité un intérêt particulier en raison du risque accru de MCV chez les hommes. S'il est bien établi que le taux de testostérone diminue et que la mortalité cardiovasculaire augmente avec l'âge, l'association entre la testostérone et les MCV demeure obscure. Les études d'observation et à répartition aléatoire sur les effets de la testostérone endogène et exogène ont donné des données contradictoires, et les méta-analyses n'ont pas été concluantes, laissant entrevoir une hétérogénéité importante des études. Malgré un manque d'essais comparatifs à répartition aléatoire, de vastes études d'observation réalisées au début des années 2010 ont conduit à formuler des avis sur l'utilisation du traitement de substitution de la testostérone. Des avis similaires ont été demandés pour certains types de traitements antiandrogéniques. D'après d'autres recherches, la testostérone raccourcirait l'intervalle QT corrigé en fonction de la fréquence cardiaque, améliorerait la maîtrise glycémique, provoquerait une vasodilatation, exercerait un effet prothrombotique et aurait des effets anti-obésité; en revanche, le lien avec l'athérosclérose et l'inflammation est moins claire. Malgré des preuves peu concluantes sur le risque cardiovasculaire et des incohérences quant aux directives de pratique clinique, des millions d'hommes continuent de recourir à des traitements de substitution de la testostérone et antiandrogéniques. En plus de résumer les données cliniques et précliniques, cette analyse donne un aperçu des modes d'action potentiels de la testostérone sur les MCV, des applications de ces connaissances en contexte clinique et des pistes de recherches futures.

Parental Mental Health and Hostility Are Associated With Longitudinal Increases in Child Internalizing and Externalizing Problems During COVID-19.

Children are at high risk for negative COVID-19 related outcomes. The present longitudinal study assessed (1) changes in child internalizing and externalizing problems from before to during the pandemic and (2) whether parent mental health (depression, anxiety, stress) or parenting behavior during COVID-19 were associated with changes in child mental health problems. Sixty eight mother-child dyads participated in this study. Children were approximately five years-old at the time of enrollment and were between the ages of 7-9 years old at the time of the follow-up survey. Parenting behavior, parental depression, anxiety, perceived stress and child internalizing and externalizing problems were measured using validated questionnaires. Children experienced greater internalizing (t = 6.46, p < 0.001) and externalizing (t = 6.13, p < 0.001) problems during the pandemic compared to before the pandemic. After taking into account child gender and COVID-related stressors, parental hostility was uniquely associated with greater changes in externalizing problems (ß = 0.355, SE = 0.178, p < 0.05), while maternal anxiety was associated with greater increases in internalizing problems (ß = 0.513, SE = 0.208, p < 0.05). Findings highlight the need for mental health supports for families to limit the impact of the COVID-19 pandemic on child and parent mental health.

Sodium-Glucose Co-Transporter Inhibitors and Atrial Fibrillation: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Background Sodium-glucose co-transporter (SGLT) inhibitors reduce cardiovascular outcomes including mortality in several populations; however, their effect on atrial fibrillation/flutter (AF) remains unclear. Our objective was to determine whether SGLT inhibitors reduce AF and whether a history of AF modifies the effect of SGLT inhibitors on the composite of heart failure hospitalization or cardiovascular death. Methods and Results We searched MEDLINE, Embase, and CENTRAL to March 2021. Pairs of reviewers identified randomized controlled trials that compared an SGLT inhibitor with placebo or no therapy. We pooled data using RevMan 5.4.1, assessed risk of bias using the Cochrane tool, and determined the overall quality of evidence using Grades of Recommendation, Assessment, Development and Evaluation. Thirty-one eligible trials reported on AF events (75 279 participants, mean age 62 years, 35.0% women). Moderate quality evidence supported a lower risk of serious AF events with SGLT inhibitors (1.1% versus 1.5%; risk ratio 0.75 [95% CI, 0.66-0.86]; I2=0%). A similar reduction in total AF events was also noted with SGLT inhibitors. Three trials reported on heart failure hospitalization/cardiovascular death stratified by a baseline history of AF (18 832 participants, mean age 66 years, 38.1% women); in patients with a history of AF, SGLT inhibitors resulted in a lower risk in the composite of heart failure hospitalization or cardiovascular death (hazard ratio, 0.70 [95% CI, 0.57-0.85]; I2=0%)-similar to the effect estimate for patients without AF, P value for interaction: 1.00. Conclusions SGLT inhibitors may reduce AF events and likely reduce heart failure hospitalization/cardiovascular death to a similar extent in patients with and without AF.