Women In Clinical Studies Research Articles

Colorectal Cancer and Asbestos Exposure: A Women's Health Perspective.

Colorectal cancer (CRC) is considered a "man's disease". However, emerging data show that females may have a higher prevalence of certain risk factors. A potential causal role of asbestos in CRC carcinogenesis has been suggested. This relationship is controversial, and only a few studies have focused on exposed female populations. The aim of this study was to review the scientific literature related to asbestos-related CRC incidence and mortality rates in female populations to address gender bias in the existing research. A systematic review was performed following PRISMA statement. Fourteen studies reporting 92 cases in total were included. Most women were aged 50 years or older and were employed in occupational activities with high asbestos exposure (steel, textile, and asbestos-cement industry) for at least 10 years. In one single case, household asbestos exposure was reported. The colon was the primary location of the tumor in 47 out of 92 cases. Three women were also affected by synchronous or metachronous peritoneal mesotheliomas. This study revealed a general methodological "gender bias" in scientific research. A significantly higher representation of women in clinical studies is needed to clarify the link between asbestos exposure and the development of colorectal cancer.

Participation of women in clinical studies of atrial fibrillation in the Northern Netherlands.

Concerns exist of women underrepresentation in atrial fibrillation (AF) studies, potentially limiting the generalisability of study findings to women with AF. We assessed the participation of women in AF clinical studies performed at atertiary care centre in the Northern Netherlands. Eight AF clinical studies with screening logs were available for analysis. To identify sex-specific differences, patient inclusion and exclusion and reasons for exclusion were assessed. Participation-to-prevalence ratios (PPRs) were calculated to evaluate the representation of women in the studies relative to the AF sex distribution of the general population in the Netherlands (2019 Global Burden of Disease study). We included 1739 screened patients with AF in the analysis, of whom 722 (41.5%) were women. Of the patients screened, 161 (9%) were enrolled. Median age of screened patients was 69years (interquartile range (IQR): 61-77), and women were older than men (71years; IQR: 63-79 vs 68years; IQR: 60-75; p < 0.001). Women were not underscreened compared with men (PPR: 1.09; 95% confidence interval (CI): 1.08-1.10), disproportionally excluded (92% vs 90%; p = 0.10) or less willing to participate (17% vs 15%; p = 0.36). Women had an overall PPR of 1.05 (95% CI: 1.05-1.06) compared with the general AF population. At our tertiary hospital in the Northern Netherlands, women appeared to be well-represented in AF studies. The current study advocates for the adoption of amore comprehensive measure of equity, such as the PPR, and screening log evaluation to improve the generalisability of study findings to the entire clinical AF population.

System Genetics Analysis Reveals Sex Differences in Human Aortic Smooth Muscle Gene Expression.

Coronary artery disease (CAD) is one of the leading causes of death worldwide. The buildup of atherosclerotic plaque, including lipids and cellular waste, characterizes this disease. Smooth muscle cells (SMCs) can migrate and proliferate to form a fibrous cap that stabilizes the atherosclerotic plaque in response to plaque buildup. However, in some severe cases, the fibrous cap is unable to prevent plaque rupture, which can lead to a thrombotic event causing a stroke or myocardial infarction. Studies have been conducted to identify genes associated with this disease. However, the influence of sex on CAD risk is poorly understood due to the complexity of the disease and the lack of women in clinical studies. This study is investigated with a unique collection of human aortic smooth muscle cells (huASMCs) derived from 118 male and 33 female individuals who either underwent a heart transplant or were victims of motor vehicle accidents. In this investigation, we explore differentially expressed genes between males and females related to atherosclerosis using a unique RNAseq dataset of human aortic SMCs. Our study identified 8 genes (CHST1, DKK2, DLL4, EIF1AXP1, GALNT13, NOTCH4, SELL, SPARCL1) that exhibit sex-biased effects in SMCs. Of these, 6 genes were found in the Athero-Express dataset and 5 of them were associated with atherosclerosis-relevant phenotypes. We discovered a novel NOTCH4/DLL4 pathway that plays a role in the differential expression of these genes between males and females. This pathway is linked to coronary artery physiology and may play a role in the pathophysiology of coronary artery disease that differs between the sexes. Overall, this investigation shows that differentially expressed genes between males and females in human aortic SMCs exist.

Bacterial Vaginosis in Postmenopausal Women.

Bacterial vaginosis (BV) is the most common vaginal infection worldwide, but most research has been conducted in premenopausal women. After menopause, endogenous estrogen production decreases, often leading to the genitourinary syndrome of menopause (GSM), characterized by vulvovaginal dryness and irritation. The estrogen-deficient postmenopausal state results in an elevated vaginal pH and depletion of vaginal lactobacilli. Use of traditional BV diagnostics (Amsel criteria, Nugent score) is difficult in post-menopausal women, especially those not on estrogen replacement therapy, as these methods were originally developed in premenopausal women. In this review, we discuss recent clinical data on BV in postmenopausal women, difficulties in diagnosis using traditional methods, the role of BV molecular diagnostics, and our current expert opinion for managing BV in this population. BV prevalence has been found to range between 2%-57% among postmenopausal women per Amsel and Nugent criteria. This is likely an over-estimate of the true prevalence due to limitations in these criteria which were only validated in pre-menopausal women. Despite increasing diagnostic options for BV in recent years, including highly sensitive and specific BV nucleic acid amplification tests (NAATs), the physiologic changes of menopause and limited inclusion of postmenopausal women in clinical studies, diagnosis is difficult in this population. Recent studies utilizing 16s rRNA gene sequencing suggest that the vaginal microbiota of premenopausal and postmenopausal women is quite different, even if BV is not present. Data also suggest that obese postmenopausal women have significantly lower rates of BV compared to non-obese postmenopausal women, although further research is needed in this area. Multiple treatment options exist for vaginal atrophy and BV in this population. Data are limited regarding optimal diagnostic approaches for BV in postmenopausal women; BV NAATs and 16s rRNA gene sequencing may have a role for diagnosing BV in symptomatic women although further studies are needed. Menopausal women with characteristic vaginal symptoms and an elevated vaginal pH should be initially treated for estrogen deficiency prior to considering a diagnosis of BV; subsequent treatment for BV should be driven by symptoms.

A targeted metabolic analysis of football players and its association to player load: Comparison between women and men profiles.

Professional athletes undertake a variety of training programs to enhance their physical performance, technical-tactical skills, while protecting their health and well-being. Regular exercise induces widespread changes in the whole body in an extremely complex network of signaling, and evidence indicates that phenotypical sex differences influence the physiological adaptations to player load of professional athletes. Despite that there remains an underrepresentation of women in clinical studies in sports, including football. The objectives of this study were twofold: to study the association between the external load (EPTS) and urinary metabolites as a surrogate of the adaptation to training, and to assess the effect of sex on the physiological adaptations to player load in professional football players. Targeted metabolic analysis of aminoacids, and tryptophan and phenylalanine metabolites detected progressive changes in the urinary metabolome associated with the external training load in men and women’s football teams. Overrepresentation analysis and multivariate analysis of metabolic data showed significant differences of the effect of training on the metabolic profiles in the men and women teams analyzed. Collectively, our results demonstrate that the development of metabolic models of adaptation in professional football players can benefit from the separate analysis of women and men teams, providing more accurate insights into how adaptation to the external load is related to changes in the metabolic phenotypes. Furthermore, results support the use of metabolomics to understand changes in specific metabolic pathways provoked by the training process.

Sex Differences in the Clinical Outcomes After Left Atrial Appendage Closure: A Systematic Review and Meta-Analysis

IntroductionLeft atrial appendage occlusion (LAAO) has emerged as a reasonable alternative to oral anticoagulation in a selective group of patients with atrial fibrillation (AF). While women are known to have higher risk of AF-related stroke, the impact of sex differences on the clinical outcomes of LAAO has not been well-studied. ObjectiveWe sought to perform a meta-analysis evaluating sex differences on the outcomes of patients undergoing LAAO. MethodsWe searched PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases (from inception to October 2021) for studies evaluating the impact of sex difference on LAAO procedural outcomes. We used a random-effects model to calculate risk ratio (RR) with 95% confidence intervals (CI). In-hospital all-cause mortality and ischemic stroke were the primary endpoints. In-hospital pericardial effusion/cardiac tamponade, major bleeding, technical success, device-related thrombus, and hospital length of stay were secondary outcomes. ResultsA total of 5 studies with 54,754 patients were included, of whom 22,461 (41%) were females. Female sex was associated with higher rates of in-hospital all-cause mortality (RR 2.18; 95% CI 1.46–3.26; P = 0.0001) and in-hospital ischemic stroke (RR 1.67; 95% CI 1.06–2.61; P = 0.03) when compared with males. Females had higher rates of in-hospital major bleeding (RR 1.93; 95% CI 1.40–2.67; P < 0.0001) and hospital length of stay >1 day (RR 1.38; 95% CI 1.33–1.45; P < 0.00001). There were no differences between females and males in terms of technical success (RR 1.00; 95% CI 1.00–1.00; P = 1.00) and device-related thrombus and (RR 0.94, 95% CI 0.31–2.82; P = 0.91). ConclusionWomen are more likely to experience worse periprocedural outcomes with longer hospital stay after LAA closure. Further efforts are needed to increase the participation of women in clinical studies and to assess these differences to properly address the discrepancy in outcomes between men and women.

Protect Pregnant and Lactating Women with COVID-19 Through Research, Not from Research.

Protect Pregnant and Lactating Women with COVID-19 Through Research, Not from Research.

Medicines in pregnancy.

Medicine use in pregnancy is extremely common, but there are significant knowledge gaps surrounding the safety, dosage and long-term effects of drugs used. Pregnant women have been purposively excluded from clinical trials of the majority of treatments for conditions that may occur concurrently with pregnancy. There is minimal information on the pharmacokinetics of many existing treatments and no systematic capture of long-term outcome data to help inform choices. Treatments commonly used in pregnancy are thus often old and untested, not optimised in dose, and prescribed off-label without adequate safety information. In addition, there has been a staggering lack of investment in drug development for obstetric conditions for decades. This is a major public health concern, and pregnancy complications are the leading cause of mortality in children under five years old globally, and health in pregnancy is a major determinant of women’s long-term health and wellbeing. There is an acute need for adequate investment and legislation to boost inclusion of pregnant women in clinical studies, capture high-quality information on medication use in pregnancy in general, and encourage new medicinal product development for obstetric conditions.

Count me in: using a patient portal to minimize implicit bias in clinical research recruitment.

Determine whether women and men differ in volunteering to join a Research Recruitment Registry when invited to participate via an electronic patient portal without human bias. Under-representation of women and other demographic groups in clinical research studies could be due either to invitation bias (explicit or implicit) during screening and recruitment or by lower rates of deciding to participate when offered. By making an invitation to participate in a Research Recruitment Registry available to all patients accessing our patient portal, regardless of demographics, we sought to remove implicit bias in offering participation and thus independently assess agreement rates. Women were represented in the Research Recruitment Registry slightly more than their proportion of all portal users (n = 194775). Controlling for age, race, ethnicity, portal use, chronic disease burden, and other questionnaire use, women were statistically more likely to agree to join the Registry than men (odds ratio 1.17, 95% CI, 1.12-1.21). In contrast, Black males, Hispanics (of both sexes), and particularly Asians (both sexes) had low participation-to-population ratios; this under-representation persisted in the multivariable regression model. This supports the view that historical under-representation of women in clinical studies is likely due, at least in part, to implicit bias in offering participation. Distinguishing the mechanism for under-representation could help in designing strategies to improve study representation, leading to more effective evidence-based recommendations. Patient portals offer an attractive option for minimizing bias and encouraging broader, more representative participation in clinical research.

PMU46 TRIAL SEPARATION - IS THERE A TRUE GENDER DISPARITY IN CLINICAL TRIALS?

The gender imbalance in clinical studies has been widely discussed with women underrepresented in trial populations and becoming a growing concern. However, there may be several mitigating factors such as ability to recruit, gender-specific diseases, incidence variations and genetic predispositions. To drive a change in gender bias in this aspect of clinical research, more incisive analyses are required to define the true difference and understand the root causal relationship. This research aims to assess the current state of the gender disparity in pivotal clinical trials supporting recent FDA (Food and Drug Administration) CDER (Center for Drug Evaluation and Research) novel drug approvals. Publicly-available FDA CDER Drug Trial Snapshots were used to identify the gender split in participants of key trials supporting novel drug approvals between 01/01/2014-31/12/2018. For the 172 novel drugs approved by the FDA between 2014 to 2018, there were 106,894 (49.4%) male subjects, and 109,600 (50.6%) female subjects in total. In terms of specific therapy areas, for the 50 novel oncology drugs, there were 9,201 (45.4%) male subjects and 11,066 (54.6%) female subjects. For the 9 novel cardiovascular drugs, there were 33,721 (55.8%) male subjects, and 26,683 (44.2%) female subjects. However, there are a number of women-specific diseases which had zero male subjects in the trials such as ovarian cancer and bacterial vaginosis. There are also rare hereditary genetic diseases which had zero female trial subjects such as Duchenne muscular dystrophy and hemophilia A. Despite the inherent mitigating factors, the gender disparity remains unclear with women well-represented, underrepresented, or overrepresented in trials of novel drugs depending on the therapy area. Recruitment and retention of women in clinical studies is a key challenge requiring further research to defining the true gender differences in clinical trials and also to develop strategies to overcome these differences.

A review of clinical studies involving pregnant women registered in the Clinical Trials Registry of India.

Context and Aims:Pregnant women undergo physiological changes which influence the efficacy as well as safety of medications used. Very few drugs are tested and approved for medical conditions during pregnancy, and less pharmacokinetic data are available to form clinical treatment guidelines. There was no data available regarding the type of research studies conducted in pregnancy in India. Hence, we conducted this study to analyze the type of research studies in pregnancy registered in the Clinical Trials Registry of India (CTRI).Subjects and Methods:Following exemption from review by the Institutional Ethics Committee, all studies in pregnant women registered in CTRI from its inception in July 2007 to June 2018 were reviewed. Data were captured with respect to geographical distribution, trimester of pregnancy, study designs used, therapy area, and funding.Statistical Analysis Used:The variables were analyzed using descriptive statistics using SPSS version 16.0.Results:Out of a total of 14,911 studies in CTRI, a total of 285 (1.91%) studies involved pregnant women. Of these studies, 199 (69.8%) were interventional, whereas 86 (30.1%) were observational. Of all the interventional studies, 119 (60%) tested drugs, 47 (24%) tested a nondrug intervention, and the rest were nutraceuticals, Ayurveda, Yoga and Naturopathy, Unani, Siddha, and Homeopathy, and vaccines. Postgraduate theses constituted 140 (49.1%) studies, 79 (27.7%) were academic projects, 27 (9.4%) were government-funded studies, and only 16 (5.6%) were pharmaceutical-sponsored studies. The most commonly studied therapy area was anesthesia, followed by hypertension and induction of labor.Conclusions:This study depicts underrepresentation of pregnant women in clinical studies and more evidence needs to be generated with respect to drug safety and pharmacokinetics.

Morinda citrifolia leaf enhanced performance by improving angiogenesis, mitochondrial biogenesis, antioxidant, anti-inflammatory & stress responses

Morinda citrifolia fruit, (noni), enhanced performances in athletes and post-menopausal women in clinical studies. This report shows the edible noni leaves water extract enhances performance in a weight-loaded swimming animal model better than the fruit or standardized green tea extract. The 4weeks study showed the extract (containing scopoletin and epicatechin) progressively prolonged the time to exhaustion by threefold longer than the control, fruit or tea extract. The extract improved (i) the mammalian antioxidant responses (MDA, GSH and SOD2 levels), (ii) tissue nutrient (glucose) and metabolite (lactate) management, (iii) stress hormone (cortisol) regulation; (iv) neurotransmitter (dopamine, noradrenaline, serotonin) expressions, transporter or receptor levels, (v) anti-inflammatory (IL4 & IL10) responses; (v) skeletal muscle angiogenesis (VEGFA) and (v) energy and mitochondrial biogenesis (via PGC, UCP3, NRF2, AMPK, MAPK1, and CAMK4). The ergogenic extract helped delay fatigue by enhancing energy production, regulation and efficiency, which suggests benefits for physical activities and disease recovery.

Toward Sex-Specific Guidelines for Cardiac Resynchronization Therapy?

An important treatment for patients with heart failure is cardiac resynchronization therapy (CRT). Even though only 20% of women were included in clinical trials for CRT, a benefit has been shown in recent studies for subgroups of women compared to their male counterparts. Given this low inclusion rate of women in clinical studies, professional society guideline-based CRT recommendations, such as those by the American College of Cardiology Foundation (ACCF)/American Heart Association (AHA)/Heart Rhythm Society (HRS), may not truly represent the best treatment for women, especially since most of the reports that showed this greater benefit in women were published after the latest guidelines. Despite having research and multiple publications regarding sex-specific heart failure outcomes and response to CRT, the ACCF/AHA/HRS guidelines have not yet been updated to account for the recent information regarding the differences in benefit for women and men with similar patient characteristics. This review discusses the physiology behind CRT, sex-specific characteristics of heart failure, and cardiac electrophysiology and summarizes the current sex-specific literature to encourage consideration of CRT guidelines for women and men separately.

Recruitment and retention of pregnant women into clinical research trials: an overview of challenges, facilitators, and best practices.

Pregnant women are a vulnerable group who are needed in clinical research studies to advance prevention and treatment options for this population. Yet, pregnant women remain underrepresented in clinical research. Through the lens of the socioecological model, we highlight reported barriers and facilitators to recruitment and retention of pregnant women in studies that sought their participation. We trace historical, policy-based reasons for the exclusion of pregnant women in clinical studies to present-day rationale for inclusion of this group. The findings highlight why it has been difficult to recruit and retain this population over time. A body of literature suggests that integrative sampling and recruitment methods that leverage the influence and reach of prenatal providers will overcome recruitment challenges. We argue that these strategies, in combination with building strong engagement with existing community-based organizations, will enable teams to more effectively promote and retain pregnant women in future longitudinal cohort studies.

HIV Study Shines Spotlight on Women

EVEN AS THE RESEARCH COMMUNITY has drawn criticism for frequently overlooking women in clinical studies, one historic initiative focusing solely on women for the past 15 years has gathered an abundance of biomedical and psychosocial data related to the effects of HIV in infected females. The resulting data set has fueled hundreds of published analyses, examining such topics as factors in treatment adherence and links between mental health and survival in HIV-infected women. The Women’s Interagency HIV Study (WIHS,pronounced“wise”)isthelargest prospective multicenter cohort study of HIV-positive and at-risk HIV-negative women in the United States (http://state piaps.jhsph.edu/wihs/). It also is reportedly the longest ongoing disease progression study of HIV infection in women. WIHS investigators hope to shed light on how HIV infection, treatment, environmental factors, and host genetic factors interact to determine the course of HIV disease in a heterogeneous population of women. “We want to come up with research findings that can be put into practice to impact the management and treatment of women infected with HIV,” said Monica Gandhi, MD, MPH, associate professor of medicine in the Divisions of HIV/AIDS and Infectious Diseases at the University of California, San Francisco. She is an investigator on epidemiological and clinical studies in the WIHS cohort.

Tracking Inclusion of Women in Clinical Studies

Tracking Inclusion of Women in Clinical Studies

Targeting Gender Difference in the Introduction of New Drugs for Diabetes Mellitus and Metabolic Disorders

This review summarizes the important issue of gender difference in drug response as regards the therapeutic aspect of drugs utilized for diabetes mellitus and related disorders. Although, gender differences have been individuated both in experimental and clinical setting their role in clinical practice is not yet completely investigated. Indeed, they are involved in pharmacodinamyc and pharmacokinetics of antidiabetic drugs but the lack of a gender analysis and the reduced enrollement of women in clinical studies contributes widely to this uncertainty. Since sex is a fundamental biological variable that cannot be discounted, gender differences in pharmacology has to be considered in order to improve drug safety efficacy and to optimize medical therapy both in diabetic men and women also considering the higher incidence, the worst outcome and the higher mortality for cardiovascular diseases of diabetic women in comparison with diabetic men. New drugs, as well as new patents which are considered in this review, need to take into account these recommendations. Keywords: Diabetes mellitus, metabolic disorders, Akt phosphorylation, glucagons like peptide 1 and 2, DPP IV inhibitors, ATP potassium channel blockers, Insulin, Metformin

Gender Differences in Acute Coronary Syndrome

Acute coronary syndrome (ACS) is common in women, yet we have less sex-specific data in women than in men as a result of lower enrollment in clinical trials and low rates of sex-specific reporting. Women are generally older with more comorbidities when diagnosed with ACS. Women with ACS are less likely than men to be referred for invasive evaluation and procedures and are more likely to have normal coronary arteries when they are referred for coronary angiography. For reasons that are not well understood, women have higher rates of bleeding complications compared with men. This higher bleeding rate is consistently seen in many trials. There are 3 major randomized, controlled trials that compared early invasive therapy with conservative strategy for ACS. Two of these trials found higher rates of myocardial infarction (MI) and death at 1 year in women treated with early invasive strategy, whereas the third trial found a reduction in the composite end point of rehospitalization, MI, and death at 180 days in women treated with early invasive strategy. Sex differences have also been seen in glycoprotein (GP) IIb/IIIa use in women with an increase in death and MI noted for GP use in women with ACS. Continued and increased numbers of women in clinical studies of ACS as well as increased rates of sex-specific reporting will allow us to offer optimal quality care for women and men with ACS.

Reflections on a Decade of Experience in Implementing a Center for Women's Health at an Academic Medical Center

On the 10th anniversary of the establishment of a Center for Women's Health (CWH) program, the opportunity to share the successes and limitations in developing a centralized approach to women's healthcare is provided. The development of the CWH at the Columbia University Medical Center, New York-Presbyterian Hospital was prompted by concerns that the health status for women is worse than for men in terms of disability, morbidity, and chronic illness. Moreover, women move through cycles of health and illness differently from men, and gender inequalities in research design and implementation and underrepresentation of women in clinical studies contributed to knowledge gaps concerning women's health, possibly leading to suboptimal care. The goal in developing a program was (1) to provide outstanding medical care to women based on prevention and treatment of unique aspects of women's health, (2) to develop professional training and multidisciplinary educational programs promoting knowledge, understanding, and credible scientific efforts, and (3) to foster collaborative research and communication among researchers, practitioners, policymakers, and organizations. In this paper, the clinical and educational programmatic activities and lessons learned are described.

Sex, digitalis, and the sodium pump.

Foxglove and its constituents therapeutic agent digitalis have been used for centuries for the treatment of heart failure. All digitalis-like cardiotonic steroids enhance heart contraction through a mechanism involving the inhibition of the Na(+),K(+)- ATPase. Recently, Rathore and colleagues reported that sex-based differences may exist in the efficacy of digoxin for the treatment of heart failure. The authors of the study found that female patients exhibited increased risk of death associated with digoxin therapy, whereas male patients appeared to have no increased risk of death related to digoxin therapy. Blaustein and colleagues delve into the report and discuss possible explanations for these findings, suggest alternative ones, and advocate for enrolling greater numbers of women in clinical studies.