Fundamental neurochemistry review: Old brain stories - Influence of age and sex on the neurodegeneration-associated lipid changes.

Brain aging is a naturally occurring process resulting in the decline of cognitive functions and increased vulnerability to develop age-associated disorders. Fluctuation in lipid species is crucial for normal brain development and function. However, impaired lipid metabolism and changes in lipid composition in the brain have been increasingly recognized to play a crucial role in physiological aging, as well as in several neurodegenerative diseases. In the last decades, the role of sexual dimorphism in the vulnerability to develop age-related neurodegeneration has increased. However, further studies are warranted for detailed assessment of how age, sex, and additional non-biological factors may influence the lipid changes in brains. The aim of this work is to address the presence of sex differences in the brain lipid changes that occur along aging, and in the two most common age-related neurodegenerative disorders (Alzheimer's and Parkinson's diseases). We included the studies that assessed lipid-related alterations in the brain of both humans and experimental models. Additionally, we explored the influence of sex on lipid-lowering therapies. We conclude that sex exerts a notable effect on lipid modifications occurring with age and neurodegeneration, and in lipid-reducing interventions. Therefore, the application of sex as an experimental variable is strongly encouraged for future research in the field of precision medicine approach.

Sex- and Gender-Related Aspects in Pulmonary Hypertension.

Biological sex and sociocultural gender are emerging as pivotal modifiers of health and diseases. Sex-based differences exist in the development, pathogenesis, and management of individuals with pulmonary arterial hypertension (PAH). The interplay between gender domains (ie, identity, roles, relations, and institutionalized gender) and PAH has been barely investigated. The aim of this narrative review is to describe up-to-date evidence on the integration of sex and gender in PAH research, highlighting areas for future investigation.

Epidemiology of cerebral microbleeds and risk of adverse outcomes in atrial fibrillation: a systematic review and meta-analysis.

AIMS: The aim of this study is to perform a systematic review and meta-analysis on the epidemiology of cerebral microbleeds (CMBs) and the risk of intracranial haemorrhage (ICH) and ischaemic stroke (IS) in patients with atrial fibrillation (AF). METHODS AND RESULTS: PubMed and EMBASE databases were systematically searched from inception to 6 March 2021. All studies reporting the prevalence of CMBs and incidence of ICH and IS in AF patients with and without CMBs were included. Meta-analysis was conducted using random-effect models; odds ratios (ORs), 95% confidence intervals (CIs), and prediction intervals (PIs) were calculated for each outcome. Subgroup analyses were performed according to the number and localization of CMBs. A total of 562 studies were retrieved, with 17 studies finally included in the meta-analysis. Prevalence of CMBs in AF population was estimated at 28.3% (95% CI: 23.8-33.4%). Individuals with CMBs showed a higher risk of ICH (OR: 3.04, 95% CI: 1.83-5.06, 95% PI 1.23-7.49) and IS (OR: 1.78, 95% CI: 1.26-2.49, 95% PI 1.10-2.87). Patients with ≥5 CMBs showed a higher risk of ICH. Metaregression showed how higher of prevalence of diabetes mellitus in AF cohort is associated with higher prevalence of CMBs. CONCLUSIONS: Cerebral microbleeds are common in patients with AF, found in almost one out of four subjects. Cerebral microbleeds were associated with both haemorrhagic and thromboembolic events in AF patients. Moreover, the risk of ICH increased consistently with the burden of CMBs. Cerebral microbleeds may represent an important overlooked risk factor for both ICH and IS in adults with AF.

Prevalence, management and impact of chronic obstructive pulmonary disease in atrial fibrillation: a systematic review and meta-analysis of 4,200,000 patients.

AIM: Prevalence of chronic obstructive pulmonary disease (COPD) in atrial fibrillation (AF) patients is unclear, and its association with adverse outcomes is often overlooked. Our aim was to estimate the prevalence of COPD, its impact on clinical management and outcomes in patients with AF, and the impact of beta-blockers (BBs) on outcomes in patients with COPD. METHODS AND RESULTS: A systematic review and meta-analysis was conducted according to international guidelines. All studies reporting the prevalence of COPD in AF patients were included. Data on comorbidities, BBs and oral anticoagulant prescription, and outcomes (all-cause death, cardiovascular (CV) death, ischaemic stroke, major bleeding) were compared according to COPD and BB status. Among 46 studies, pooled prevalence of COPD was 13% [95% confidence intervals (CI) 10-16%, 95% prediction interval 2-47%]. COPD was associated with higher prevalence of comorbidities, higher CHA2DS2-VASc score and lower BB prescription [odds ratio (OR) 0.77, 95% CI 0.61-0.98]. COPD was associated with higher risk of all-cause death (OR 2.22, 95% CI 1.93-2.55), CV death (OR 1.84, 95% CI 1.39-2.43), and major bleeding (OR 1.45, 95% CI 1.17-1.80); no significant differences in outcomes were observed according to BB use in AF patients with COPD. CONCLUSION: COPD is common in AF, being found in 13% of patients, and is associated with increased burden of comorbidities, differential management, and worse outcomes, with more than a two-fold higher risk of all-cause death and increased risk of CV death and major bleeding. Therapy with BBs does not increase the risk of adverse outcomes in patients with AF and COPD.

Determinants of perceived health and unmet healthcare needs in universal healthcare systems with high gender equality.

BACKGROUND: Patient attitudes about health and healthcare have emerged as important outcomes to assess in clinical studies. Gender is increasingly recognized as an intersectional social construct that may influence health. Our objective was to determine potential sex differences in self-reported overall health and access to healthcare and whether those differences are influenced by individual social factors in two relatively similar countries. METHODS: Two public health surveys from countries with high gender equality (measured by UN GII) and universal healthcare systems, Canada (CCHS2014, n = 57,041) and Austria (AT-HIS2014, n = 15,212), were analysed. Perceived health was assessed on a scale of 1 (very bad) to 4 (very good) and perceived unmet healthcare needs was reported as a dichotomous variable (yes/no). Interactions between sex and social determinants (i.e. employment, education level, immigration and marital status) on outcomes were analysed. RESULTS: Individuals in both countries reported high perceived health (Scoring > 2, 85.0% in Canada, 79.9% in Austria) and a low percentage reported unmet healthcare needs (4.6% in Canada, 10.7% in Austria). In both countries, sex and several social factors were associated with high perceived health, and a sex-by-marital status interaction was observed, with a greater negative impact of divorce for men. Female sex was positively associated with unmet care needs in both countries, and sex-by-social factors interactions were only detected in Canada. CONCLUSIONS: The intersection of sex and social factors in influencing patient-relevant outcomes varies even among countries with similar healthcare and high gender equality.

Public perceptions and behavioural responses to the first COVID-19 pandemic wave in Italy: results from the iCARE study.

BACKGROUND: Italy was the first European country to be affected by COVID-19. Considering that many countries are currently battling the second wave of the pandemic, understanding people's perceptions and responses to government policies remain critical for informing on-going mitigation strategies. We assessed attitudes towards COVID-19 policies, levels of adherence to preventive behaviours, and the association between COVID-19 related concerns and adherence levels. METHODS: We recruited a convenience sample of Italian individuals from an international cross-sectional survey (www.icarestudy.com) from 27 March to 5 May 2020. Multivariate regression models were used to test the association between concerns and the adoption of preventive measures. RESULTS: The survey included 1332 participants [female (68%), younger than 25 (57%)] that reported high awareness (over 96%) and perceived importance (88%) of policies. We observed varied levels of adherence to: hand-washing (96%), avoiding social gatherings (96%), self-isolation if suspected or COVID-19 positive (77%). Significantly lower adherence to self-isolation was reported by individuals with current employment. High levels of concerns regarding health of other individuals and country economy were reported. Only health concerns for others were significantly associated with higher adherence to hand-washing behaviour. CONCLUSIONS: In order to inform current/future government strategies, we provide insights about population's responses to the initial pandemic phase in Italy. Communication approaches should consider addressing people's concerns regarding the health of other individuals to motivate adherence to prevention measures. Provision of social and economic support is warranted to avoid unequal impacts of governmental policies and allow effective adherence to self-isolating measures.

Sex and Gender-Related Issues in Heart Failure.

Understanding the role of sex- and gender-related factors, when dealing with a global growing epidemic such as heart failure, is a much needed and unmet goal for health care providers and scientists in order to design targeted strategies, aimed at improving both clinical and patient reported outcomes measures in women and men with heart failure. The present review provides an overview of the current available evidence on sex- and gender-related differences in heart failure.

Low-grade endotoxemia and platelet activation in cirrhosis.

Patients with cirrhosis may display impaired or enhanced platelet activation, but the reasons for these equivocal findings are unclear. We investigated if bacterial lipopolysaccharide (LPS) is implicated in platelet activation. In a cross-sectional study, conducted in an ambulatory care clinic and hospital, comparing 69 cirrhosis patients and 30 controls matched for sex, age, and atherosclerotic risk factors, serum levels of LPS, soluble cluster of differentiation 40 ligand and p-selectin (two markers of platelet activation), and zonulin (a marker of gut permeability) were investigated. Ex vivo and in vitro studies were also performed to explore the effect of LPS on platelet activation. Compared to controls, cirrhosis patients displayed higher serum levels of LPS (6.0 [4.0-17.5] versus 57.4 [43.4-87.2] pg/mL, P < 0.0001), soluble cluster of differentiation 40 ligand (7.0 ± 2.2 versus 24.4 ± 13.3 ng/mL, P < 0.0001), soluble p-selectin (14.2 ± 4.05 versus 33.2 ± 15.2 ng/mL, P < 0.0001), and zonulin (1.87 ± 0.84 versus 2.54 ± 0.94 ng/mL, P < 0.006). LPS significantly correlated with zonulin (r = 0.45, P < 0.001). Ex vivo studies showed that platelets from cirrhosis patients were more responsive to the agonists independently from platelet count; this phenomenon was blunted by incubation with an inhibitor of Toll-like receptor 4. In vitro study by normal platelets showed that LPS alone (50-150 pg/mL) did not stimulate platelets but amplified platelet response to the agonists; Toll-like receptor 4 inhibitor blunted this effect. CONCLUSION: LPS may be responsible for platelet activation and potentially contributes to thrombotic complications occurring in cirrhosis. (Hepatology 2017;65:571-581).

The impact of gender in cardiovascular medicine: Lessons from the gender/sex-issue in heart failure.

Heart Failure (HF) is a major healthcare issue, given its high prevalence and incidence, the rate of comorbidities, the related high health-care costs and its poor outcome. In the last years mounting evidence revealed several differences between men and women affected by this clinical condition. Apart from the well-known difference in phenotype (HF with reduced ejection fraction (HFrEF) occurs more commonly in men, and HF with preserved ejection fraction (HFpEF) is more frequent in women) other relevant sex-related issues dwell upon epidemiology, presentation, risk stratification and management. These differences shed new lights on the possibility to consider HF as a prototype of the impact of gender/sex issue in cardiovascular medicine. A call for action and future strategies might help in the achievement of a cleaver patient-care.

Gut-derived endotoxin stimulates factor VIII secretion from endothelial cells. Implications for hypercoagulability in cirrhosis.

BACKGROUND & AIMS: Patients with cirrhosis display enhanced blood levels of factor VIII, which may result in harmful activation of the clotting system; however, the underlying mechanism is unknown. METHODS: We performed a cross-sectional study in patients with cirrhosis (n=61) and matched controls (n=61) comparing blood levels of factor VIII, von Willebrand factor (vWf), lipopolysaccharide (LPS) and positivity for Escherichia coli DNA. Furthermore, we performed an in vitro study to investigate if LPS, in a concentration range similar to that found in the peripheral circulation of cirrhotic patients, was able to elicit factor VIII secretion from human umbilical vein endothelial cells (HUVEC). RESULTS: Patients with cirrhosis displayed higher serum levels of LPS (55.8 [42.2-79.9] vs. 23.0 [7.0-34.0]pg/ml, p<0.001), factor VIII (172.0 [130.0-278.0] vs. 39.0 [26.0-47.0]U/dl, p<0.0001), vWf (265.0 [185.0-366.0] vs. 57.0 [48.0-65.0]U/dl, p<0.001) and positivity for Escherichia coli DNA (88% vs. 3%, p<0.001, n=34) compared to controls. Serum LPS correlated significantly with factor VIII (r=0.80, p<0.001) and vWf (r=0.63, p<0.001). Only LPS (beta-coefficient=0.70, p<0.0001) independently predicted factor VIII levels. The in vitro study showed that LPS provoked factor VIII and vWf release from HUVEC via formation and secretion of Weibel-Palade bodies, a phenomenon blunted by pre-treating HUVEC with an inhibitor of Toll-like receptor 4. CONCLUSIONS: The study provides the first evidence that LPS derived from gut microbiota increases the systemic levels of factor VIII via stimulating its release by endothelial cells. Lay summary: Cirrhosis is associated with thrombosis in portal and systemic circulation. Enhanced levels of factor VIII have been suggested to play a role but the underlying mechanism is still unclear. Here we show that patients with cirrhosis display a concomitant increase of factor VIII and lipopolysaccharide (LPS) from Escherichia coli and suggest that LPS contributes to the release of factor VIII from endothelial cells.

Gender related differences in treatment and response to statins in primary and secondary cardiovascular prevention: The never-ending debate.

Statins are a main curbstone in the prevention of cardiovascular disease (CVD), pandemic in 21st century. CVD displays evident sex and gender differences, not only in clinical manifestation and outcomes but also in pharmacological treatment. Whether statin therapy should be differentially prescribed according to sex is a matter of debate. Aside a different pharmacological action, statins are not proven to be less effective in one gender comparing to the other, nor to be less safe. Nevertheless, up to date evidence shows that statins have not been adequately tested in women, especially in primary prevention trials. Since data-lacking, making a treatment decision on women is potentially harmful, although female individuals represent the majority of the population and they have a greater lifetime CVD risk. Therefore, adequately powered randomized control trials with longer follow-up are warranted to establish if a benefit on CV events and mortality prevention exists in both sexes. The aim of the present review is to summarize the sex and gender differences in statin use: it raises concerns and updates perspectives towards an evidence-based and sex-tailored prevention of CVD management.

Adverse outcomes in patients with atrial fibrillation and peripheral arterial disease: a report from the EURObservational research programme pilot survey on atrial fibrillation.

AIMS: Peripheral arterial disease (PAD) is highly prevalent in general population. Data on the prevalence of symptomatic PAD in patients with atrial fibrillation (AF) are limited, and the impact of PAD on adverse outcomes in AF patients is controversial. Our aims were: (i) to define the prevalence of symptomatic PAD in European AF patients and describe its associated clinical risk factors and (ii) to establish the relationship of PAD to adverse events in AF, especially all-cause death. METHODS AND RESULTS: Atrial fibrillation patients enrolled in the EORP-AF Pilot study with data about PAD status were included in this analysis. Event rates were determined at 1-year follow-up. Peripheral arterial disease was recorded in 328 (11%) patients. Age (P < 0.0001), hypertension (P = 0.0059), diabetes mellitus (P = 0.0001), chronic heart failure (P < 0.0001), previous stroke/transient ischaemic attack (P = 0.0060), and antiplatelet drug treatment (P = 0.0001) were associated with the presence of PAD, while female gender was inversely associated (P = 0.0002). Peripheral arterial disease patients had higher absolute rates of both cardiovascular (CV) and all-cause death (both P < 0.0001). On Kaplan-Meier analysis, risk of all-cause death was higher in PAD patients compared with those without PAD (P < 0.0001), but PAD did not emerge as an independent risk factor for mortality on Cox regression analysis. A lower risk of all-cause death was associated with the prescription of statins (P = 0.0019), angiotensin-converting enzyme inhibitors (P = 0.0008), and calcium-channel blockers (P = 0.0071). CONCLUSION: Peripheral arterial disease is prevalent in 11% of AF patients and related to various atherosclerotic risk factors. Even if PAD is associated with higher risk of all-cause death on univariate analysis, this risk was significantly lowered and was no longer evident after adjusting for the use of CV prevention drugs.

Asymptomatic peripheral artery disease and antiplatelet management.

Peripheral arterial disease (PAD) is a hallmark of generalized atherosclerosis. Depending on the specific diagnostic criteria that are being used, the prevalence of PAD may be as high as 30 % in the population of people 70 or more years old. Unfortunately, although PAD is prevalent and has many important consequences for patients, it is often under-detected and under-treated by primary care physicians. The aim of this review is to provide an overview of the available literature on epidemiology and antiplatelets management of PAD patients. In particular, we focus on the "hidden" side of PAD burden, the asymptomatic patients, who are at high risk of negative cardiovascular outcomes. Identification of such PAD patients is therefore an important clinical goal to reduce mortality and morbidity and reduce the social cost of atherosclerotic disease. Early screening of PAD and an evidence-based antithrombotic approach are also discussed as potential strategies to counteract the negative impact of such condition in general population, as well as, in patients with other cardiovascular diseases.

Impact of Sex and Gender on Metabolic Syndrome in Adults: A Retrospective Cohort Study From the Canadian Primary Care Sentinel Surveillance Network.

OBJECTIVE: Metabolic syndrome (MetS), a cluster of 5 interconnected factors, is the main contributor to cardiovascular disease. Although sex- and gender-related elements have been linked to MetS and its components, this association has not been explored among Canadians with or without MetS. In this study, we aimed to identify sex and gender differences in characteristics of MetS in the Canadian population. METHODS: This retrospective cohort study used data from the Canadian Primary Care Sentinel Surveillance Network (CPCSSN) database. The CPCSSN contains de-identified electronic health records of >1.5 million Canadians (2010-2019). Individuals 35 to 75 years of age who had a primary care encounter formed the study sample (N=37,813). Multiple logistic regression models were used to estimate adjusted odds ratios for sex and gender differences among Canadians with and without MetS, which was the primary outcome variable. RESULTS: The estimated prevalence of MetS was 41.9%. The risk of developing MetS was significantly lower among females compared with males (odds ratio 0.73, 95% confidence interval 0.70 to 0.76). However, the risk was higher in females who used antidepressants (odds ratio 1.53, 95% confidence interval 1.42 to 1.65). An equal distribution of deprivation indexes was observed between males and females with MetS, with risk slightly higher for those with material deprivation. Females were found to be the most socially deprived. CONCLUSIONS: This study provides important sex- and gender-specific differences in MetS among Canadians. Targeting sex- and gender-specific risk factors could assist in reversing the trend of adverse cardiovascular outcomes associated with MetS.

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.

A Focus on the Pathophysiology of Adrenomedullin Expression: Endothelitis and Organ Damage in Severe Viral and Bacterial Infections.

Adrenomedullin (ADM) is a peptide hormone produced primarily in the adrenal glands, playing a crucial role in various physiological processes. As well as improving vascular integrity and decreasing vascular permeability, ADM acts as a vasodilator, positive inotrope, diuretic, natriuretic and bronchodilator, antagonizing angiotensin II by inhibiting aldosterone secretion. ADM also has antihypertrophic, anti-apoptotic, antifibrotic, antioxidant, angiogenic and immunoregulatory effects and antimicrobial properties. ADM expression is upregulated by hypoxia, inflammation-inducing cytokines, viral or bacterial substances, strength of shear stress, and leakage of blood vessels. These pathological conditions are established during systemic inflammation that can result from infections, surgery, trauma/accidents or burns. The ability to rapidly identify infections and the prognostic, predictive power makes it a valuable tool in severe viral and bacterial infections burdened by high incidence and mortality. This review sheds light on the pathophysiological processes that in severe viral or bacterial infections cause endothelitis up to the development of organ damage, the resulting increase in ADM levels dosed through its more stable peptide mid-regional proadrenomedullin (MR-proADM), the most significant studies that attest to its diagnostic and prognostic accuracy in highlighting the severity of viral or bacterial infections and appropriate therapeutic insights.

Sex- and Gender-Based Analysis on Norepinephrine Use in Septic Shock: Why Is It Still a Male World?

Sex and gender are fundamental health determinants and their role as modifiers of treatment response is increasingly recognized. Norepinephrine is a cornerstone of septic shock management and its use is based on the highest level of evidence compared to dopamine. The related 2021 Surviving Sepsis Campaign (SCC) recommendation is presumably applicable to both females and males; however, a sex- and gender-based analysis is lacking, thus not allowing generalizable conclusions. This paper was aimed at exploring whether sex- and gender-disaggregated data are available in the evidence supporting this recommendation. For all the studies underpinning it, four pairs of authors, including a woman and a man, extracted data concerning sex and gender, according to the Sex and Gender Equity in Research guidelines. Nine manuscripts were included with an overall population of 2126 patients, of which 43.2% were females. No sex analysis was performed and gender was never reported. In conclusion, the present manuscript highlighted that the clinical studies underlying the SCC recommendation of NE administration in septic shock have neglected the likely role of sex and gender as modifiers of treatment response, thus missing the opportunity of sex- and gender-specific guidelines.

Association of marital/partner status with hospital readmission among young adults with acute myocardial infarction.

INTRODUCTION: Despite evidence supporting the benefits of marriage on cardiovascular health, the impact of marital/partner status on the long-term readmission of young acute myocardial infarction (AMI) survivors is less clear. We examined the association between marital/partner status and 1-year all-cause readmission and explored sex differences among young AMI survivors. METHODS: Data were from the VIRGO study (Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients), which enrolled young adults aged 18-55 years with AMI (2008-2012). The primary end point was all-cause readmission within 1 year of hospital discharge, obtained from medical records and patient interviews and adjudicated by a physician panel. We performed Cox proportional hazards models with sequential adjustment for demographic, socioeconomic, clinical, and psychosocial factors. Sex-marital/partner status interaction was also tested. RESULTS: Of the 2,979 adults with AMI (2002 women [67.2%]; mean age 48 [interquartile range, 44-52] years), unpartnered individuals were more likely to experience all-cause readmissions compared with married/partnered individuals within the first year after hospital discharge (34.6% versus 27.2%, hazard ratio [HR] = 1.31; 95% confidence interval [CI], 1.15-1.49). The association attenuated but remained significant after adjustment for demographic and socioeconomic factors (adjusted HR, 1.16; 95% CI, 1.01-1.34), and it was not significant after further adjusting for clinical factors and psychosocial factors (adjusted HR, 1.10; 95%CI, 0.94-1.28). A sex-marital/partner status interaction was not significant (p = 0.69). Sensitivity analysis using data with multiple imputation and restricting outcomes to cardiac readmission yielded comparable results. CONCLUSIONS: In a cohort of young adults aged 18-55 years, unpartnered status was associated with 1.3-fold increased risk of all-cause readmission within 1 year of AMI discharge. Further adjustment for demographic, socioeconomic, clinical, and psychosocial factors attenuated the association, suggesting that these factors may explain disparities in readmission between married/partnered versus unpartnered young adults. Whereas young women experienced more readmission compared to similar-aged men, the association between marital/partner status and 1-year readmission did not vary by sex.

Sex and gender-based analysis and diversity metric reporting in acute care trials published in high-impact journals: a systematic review.

OBJECTIVE: To characterise sex and gender-based analysis (SGBA) and diversity metric reporting, representation of female/women participants in acute care trials and temporal changes in reporting before and after publication of the 2016 Sex and Gender Equity in Research guideline. DESIGN: Systematic review. DATA SOURCES: We searched MEDLINE for trials published in five leading medical journals in 2014, 2018 and 2020. STUDY SELECTION: Trials that enrolled acutely ill adults, compared two or more interventions and reported at least one clinical outcome. DATA ABSTRACTION AND SYNTHESIS: 4 reviewers screened citations and 22 reviewers abstracted data, in duplicate. We compared reporting differences between intensive care unit (ICU) and cardiology trials. RESULTS: We included 88 trials (75 (85.2%) ICU and 13 (14.8%) cardiology) (n=111 428; 38 140 (34.2%) females/women). Of 23 (26.1%) trials that reported an SGBA, most used a forest plot (22 (95.7%)), were prespecified (21 (91.3%)) and reported a sex-by-intervention interaction with a significance test (19 (82.6%)). Discordant sex and gender terminology were found between headings and subheadings within baseline characteristics tables (17/32 (53.1%)) and between baseline characteristics tables and SGBA (4/23 (17.4%)). Only 25 acute care trials (28.4%) reported race or ethnicity. Participants were predominantly white (78.8%) and male/men (65.8%). No trial reported gendered-social factors. SGBA reporting and female/women representation did not improve temporally. Compared with ICU trials, cardiology trials reported significantly more SGBA (15/75 (20%) vs 8/13 (61.5%) p=0.005). CONCLUSIONS: Acute care trials in leading medical journals infrequently included SGBA, female/women and non-white trial participants, reported race or ethnicity and never reported gender-related factors. Substantial opportunity exists to improve SGBA and diversity metric reporting and recruitment of female/women participants in acute care trials. PROSPERO REGISTRATION NUMBER: CRD42022282565.