Similar to other Middle Eastern countries, breast cancer is the most common cancer among women in Qatar with increasing incidence and mortality rates. High mortality rates of breast cancer in the Middle Eastern countries are primarily due to delayed diagnosis of the disease. Thus screening and early detection of breast cancer are important in reducing cancer morbidity and mortality. With the aim of updating knowledge on existing interventions and developing effective intervention programs to promote breast cancer screening in Arabic populations in Qatar, this review addresses the question: What interventions are effective in increasing breast cancer knowledge and breast cancer screening rates in Arabic populations in Arabic countries and North America? Systematic literature review was performed to answer the proposed question. As the result of the search, six research studies were identified and appraised. From the findings, we infer several insights: (a) a language-appropriate and culturally sensitive educational program is the most important component of a successful intervention regardless of the study setting, (b) multi-level interventions that target both women, men, health care professionals, and/or larger health care system are more likely to be successful than single educational interventions or public awareness campaigns, and (c) more vigorous, personal and cognitive interventions that address psychosocial factors are likely to be more effective than less personal and informative interventions. This review has important implications for health care providers, intervention planners, and researchers.  Breast cancer is the most common cancer in women worldwide , 2. EachThese findings indicate that more emphasis on breast cancer screening (BCS) must be provided by health care workers and strategies to reinforce cancer screening need to be assumed by the health care system to increase early detection of breast cancer in Arabic women , 10. IntScreening and early detection of breast cancer are important in reducing cancer morbidity and mortality , 10, 11.In the Arabic women population, positive family history, young age, higher level of education, employment, knowledge of symptoms of breast cancer, and living in an urban area were positively associated with BCS . In addiThe Supreme Council of Health in Qatar  recognizOver the last few decades, numerous intervention strategies have been examined to promote BCS among ethnically diverse populations. A meta-analysis  of interFurthermore, theory-based interventions that were culturally tailored to provide educational materials that conform to cultural values, beliefs, and practices and involve key community members were shown to be more effective than non-tailored interventions . This fiAnother meta-analysis conducted in the United States focused on improving mammography rates in diverse populations; participants had a high school education or less, received a low income, were members of an ethnic minority group, were more than 60 years of age, or resided in rural or inner city areas . Thirty-Previously published literature reviews of interventions , 34, 37 Following the method for systematic review outlined by Polit and Beck , CINAHL,This review employed the following inclusion criteria: (1) the study provided an evaluation or description of a BCS program/educational intervention for Arabic women living in an Arabic region or in a Western multicultural society, (2) the study involved experimental, quasi-experimental, or longitudinal design, (3) the study sought to improve breast cancer knowledge and/or BCS rates in Arabic women. We defined Arabic women as women who speak Arabic and who live in Arab countries in the Middle East or North Africa, or Arab Americans and their descendants , 39. ExcThe search was limited to the following studies: (1) written in English; (2) published; (3) peer-reviewed to assure a high level of quality of evidence and endorse validity of the overall findings and conclusions. Databases were searched with no restriction on the start date until June 2012 due to limited numbers of published studies of Arabic women.A total of 81 studies were located as the result of the search—30 from CINAHL, Social Work Abstracts, SocINDEX, and Middle Eastern & Central Asian Studies and 51 from Medline (Ovid) & Cochrane Central Register of Controlled Trials. After screening the titles and abstracts of the studies brought up by the search, 73 studies were excluded from the review because they did not meet the inclusion criteria or they were duplicated across databases. The most common reason for exclusion was a lack of description or evaluation of an intervention, indicating that there are not many intervention studies in this area. Most of the excluded studies were qualitative, descriptive studies that explored barriers and challenges associated with BCS and biomedical intervention studies. The full paper was retrieved for analysis in eight studies. After reading the full text articles, two studies were excluded: one did not report a valid outcome measure and another was an instrumental study. Hence, a total of six studies were included in this review. In order to present reliable evidence of intervention effectiveness, quality assessments were conducted by the investigators following the criteria described in section 6.4 of the Data Collection Checklist from the Cochrane EPOC guidelines  Six studies were located in the search  database were contacted and invited to the PHC centers. Despite these intensive public awareness efforts and personal invitations to screening, results of the intervention were discouraging. Akhtar et al.  reportedThe recommendations offered by the authors in research studies appraised for this review can be summarized as the following: (a) educate the women and (b) tailor breast cancer screening interventions to the population’s unique needs.The significance of breast cancer education was underscored in all of the appraised studies. For example, Arshad et al.  showed tMost researchers agree that tailoring an intervention to a population’s educational, language, cultural, SES, employment, and health behavioral characteristics will increase its effectiveness. Cohen and Azaiza  concludeThis systematic review of six research studies that focused on Arabic women’s breast health behaviors presents an overview of strategies for BCS interventions and evaluates their effectiveness. The intervention studies varied in geographic area, study population, and target barriers. Unfortunately, there were too few studies to test whether or how the type of intervention employed impacted the findings. Intervention effectiveness was found to be dependent on the study setting, the historical, cultural, and demographical contexts of participants and their beliefs and attitudes about breast cancer and cancer screening, and the intervention methods employed.We infer several insights from this review. First, a language-appropriate and culturally sensitive (culture/place-specific) educational program is the most important component of a successful intervention to address psychosocial barriers, the disparity in knowledge and attitudes experienced by Arabic women, regardless of the study setting. Second, multi-level interventions that target general populations , health care professionals, and/or larger systems are more likely to be successful than single educational interventions or public awareness campaigns. Third, more vigorous, personal , and cognitive interventions are likely to be more effective than less personal  and informative interventions.Psychosocial factors are reported to have a strong influence on health protective and health maintenance behaviors and are very widely studied in cancer screening literature , 46, 47.Less evident insights that emerged during analysis of the studies suggested factors that can improve BCS rates in the Arabic population. (1) Offer free mammograms to ease the financial burden of screening services. All studies included in the review offered free mammograms and CBEs. (2) Increase the geographical area of the interventions to reach more women. Although home outreach, group transportation services, mobile screening facilities, and transit passes were not directly examined as independent variables, all studies assisted women participants to gain access to available screening services. (3) Employ a support person/liaison. Almost all studies attended to the socio-emotional barrier  by including female health personnel and assigning a female support person as a patient navigator. Patient navigators assisted with making appointments, calling women to encourage them to make appointments, ensuring that women had received mammogram results, accompanying the women to their appointments, and assisting them with interpretation, billing issues, and necessary follow-up care , 39. FurExcept for one study, all interventions were found to be effective either in improving cancer knowledge or increasing CBE/mammogram screening. However, as discussed for each study in the “This review has implications for health care providers and intervention planners. It is important to recognize that Arabic women have disparate levels of knowledge of and attitudes toward breast cancer regardless of the setting, education level, and SES status. Physicians and nurses can improve BCS by educating women about breast cancer and encouraging screening while acknowledging culturally-specific beliefs and practices and avoiding stereotyping. Social workers and community liaisons can bring women and health care systems together.Although we did not limit our search criteria to publication year and full-text articles, we were able to locate only recent articles with full-text. This probably reflects a shortage of breast cancer intervention studies in Arab populations. We did not search non-English research articles, gray literature, or unpublished studies, and might have overlooked studies with potential value. The credibility and strength of the results of a meta-analysis depends on the primary studies that comprise it. As discussed earlier, more than half of the primary studies did not involve randomization and/or control. Given methodological limitations of non-probability sampling and quasi-experimental design, researchers are strongly encouraged to explore alternative strategies to alleviate weakness and bias and provide methodological rigor in future studies.This review demonstrated the effectiveness and applicability of existing interventions to promote breast cancer screening in Arabic populations. We identified six themes: (1) provide language-appropriate and culturally sensitive educational programs to women; (2) employ multilevel interventions to maximize the synergic effect between each level of intervention; (3) deliver interventions that explore cognitive barriers personally (face-to-face or on the telephone); (4) offer free mammograms; (5) incorporate access-enhancing strategies; and (6) employ a support person  who can act as a mediator between women and the health care system and provide support and encouragement. Many more intervention and evaluation studies are needed in this area to develop culturally sensitive interventions and assess the cost-effectiveness and long-term sustainability of the programs.


Breast and cervical cancers have emerged as major global health challenges and disproportionately lead to excess morbidity and mortality in low- and middle-income countries (LMICs) when compared to high-income countries. The objective of this paper was to highlight key findings, recommendations, and gaps in research and practice identified through a scoping study of recent reviews in breast and cervical cancer in LMICs.We conducted a scoping study based on the six-stage framework of Arskey and O’Malley. We searched PubMed, Cochrane Reviews, and CINAHL with the following inclusion criteria: 1) published between 2005-February 2015, 2) focused on breast or cervical cancer 3) focused on LMIC, 4) review article, and 5) published in English.Through our systematic search, 63 out of the 94 identified cervical cancer reviews met our selection criteria and 36 of the 54 in breast cancer. Cervical cancer reviews were more likely to focus upon prevention and screening, while breast cancer reviews were more likely to focus upon treatment and survivorship. Few of the breast cancer reviews referenced research and data from LMICs themselves; cervical cancer reviews were more likely to do so. Most reviews did not include elements of the PRISMA checklist.Overall, a limited evidence base supports breast and cervical cancer control in LMICs. Further breast and cervical cancer prevention and control studies are necessary in LMICs. As a global health priority, cancer is rapidly emerging as a visible and prevalent challenge differentially impacting low- and middle-income countries (LMICs) compared with high-income countries (HICs) –4. With Though considerable regional variation exists, the cumulative probability of breast cancer for women aged 15–79 years in less developed countries in 2010 was 3.8% (95% CI: 3.4–4.1), closer to 50% higher than the rate from 1980  . The cumTo date, a wide range of systematic and non-systematic literature reviews have been conducted examining breast and cervical cancer control in LMICs. The purpose of this paper was to conduct a scoping study assessing the current status of published evidence for best practices across the care continuum for breast and cervical cancer in LMICs and to identify common themes and gaps that could be addressed with future research and systematic reviews. Specifically, the guiding research question was what reviews have indicated best practice for prevention, screening, diagnosis, treatment, and survivorship for breast and cervical cancer in LMICs. Researchers often undertake such “scoping studies” to examine the extent, range, and nature of research activity and identify gaps in the existing literature . Given tA scoping study of breast and cervical cancer control in LMICs was conducted following the six-stage framework of Arskey and O’Malley  and the What reviews have indicated best practice for prevention, screening, diagnosis, treatment, and survivorship for breast and cervical cancer in LMICs?”)with the purpose of the scoping study . Our primary interest was to examine the range of reviews on breast and cervical cancers in LMICs and identify priority areas for future systematic reviews and future research where the research base is lacking.Following the recommendations of Levac et al. , we linkSearches in PubMed, Cochrane Review, and CINHAL were conducted with the following inclusion criteria: 1) published between 2005-February 2015, 2) focus on women with breast and cervical cancer, 3) focused on LMICs countries, 4) review article, and 5) published in English language. Subsequently, the search strategy for breast cancer reviews in PubMed included: ("Breast Neoplasms" (MeSH)) AND "Developing Countries" (MeSH); Filters: review; published in the last 10 years). For cervical cancer searches breast cancer was replaced by ). For details on MeSH subheadings please see Two members of the abstraction team reviewed each manuscript for two study selection criteria: 1) a focus on cervical and breast cancer in LMICs, and 2) reflected a literature review rather than empirical research itself. A third member of the abstraction team resolved discrepancies regarding which studies to include.The abstraction team consisted of eight of the authors. Two members of the abstraction team reviewed each manuscript. Items abstracted included: type of review , cancer care continuum , focus We include a descriptive numerical summary of the reviews and a qualitative thematic analysis by the synthesis team to summarize findings across the cancer care continuum. The synthesis team was divided into three groups focusing on: 1) cervical cancer; 2) breast cancer; and 3) general themes. Each group reviewed the abstraction tables for themes separately and then the entire team met and discussed the themes that emerged and how best to report the results. A second round of data abstraction occurred after our synthesis meeting to capture more information about the themes identified. We assessed whether studies were based on LMICs , the geographical focus of the review , whether methods  were described clearly . Finally to summarize and collate the topic areas of each review, the abstraction team determined if a review focused on technological/behavioral interventions and implementation science themes. Reviews were categorized by topic based on if they reviewed studies regarding the theme, made recommendations based on the theme, both, or neither. Reviews were labeled behavioral or technical intervention if the authors assessed that the reviewed studies included an intervention design that focused either on changing behaviors (e.g. education) or technical . In determining a review’s consideration of implementation science, we judged the inclusion of four major themes relying on Peters et al, 2009 : governaReporting in this analysis adheres to the PRISMA guidelines for reporting results of systematic reviews  22]. PR. PR22]. The manuscript was shared with the entire research team for feedback, insights, and editing.The search strategy implemented resulted in 62 reviews of cervical cancer and 34 reviews of breast cancer in LMIC settings that met our eligibility criteria . CervicaCervical cancer and breast cancer reviews also differed in their focus and content . CervicaThemes were identified if reviewed, recommended, or both, within a particular paper . Most resystematic reviews of the literature from LMICs around breast and cervical cancer is lacking overall, it is particularly absent on breast cancer where only six systematic reviews were identified [Development of the evidence base for best practice around breast and cervical cancer across the cancer prevention-survivorship continuum is of primary importance to inform cancer control strategies in LMICs. In this scoping study, roughly twice as many reviews were identified relating to cervical cancer compared with breast cancer in LMICs. While cervical cancer predominates in morbidity and mortality in some areas of the world (e.g. Sub-Saharan Africa), overall breast cancer is more prevalent in LMICs than cervical cancer . While sentified .Evidence-based best practice arises from quality systematic reviews . ProductWithout quality systematic reviews of breast and cervical cancer studies based on research and data from LMICs themselves or why the evidence reviewed is thought to be applicable to those countries, the evidence base will likely remain incomplete, poorly replicable, and potentially recommending inaccurate and inappropriate strategies. Additionally, reviews  commonly over-reached the data evaluated and included recommendations on issues not reviewed elsewhere in the published paper. This over-reaching was concentrated mostly on issues of governance and systems development, essential components of cancer control but frequently not the focus of empirical research .Areas of focus for the reviews included in this scoping study indeed reflect research priorities to date around breast and cervical cancer. Largely because of rapid advances in HPV testing, vaccination, and visual inspection, cervical cancer reviews are more focused on prevention and detection than other phases of the continuum; in fact, only a few cervical cancer reviews focused on survivorship. In contrast, breast cancer reviews were much less likely to focus on prevention and more likely to focus upon treatment and survivorship, topics where more global research has been completed. While the HPV vaccine has shifted the focus to prevention in cervical cancer, mammography has yet to spark this type of shift in breast cancer . In termrelevant to LMIC but instead only those that deal with studies in LMIC. Second, our search identified seven non-English studies that were not included in this review. Third, this study was not an exhaustive search across gray literature and all databases for review materials on breast and cervical cancer. In addition, gray literature was not the focus of this review only peer-reviewed and indexed articles as we wanted to best understand the gaps in systematic reviews on breast cancer and cervical cancer. Finally, our synthesis of the reviews was limited by the fact that most reviews were non-systematic reviews in cervical cancer and with a notable proportion of consensus statements in breast cancer without strong foundations in systematic methods. This study’s strengths, however, include a systematic methodology, a large and interdisciplinary collaborating team, and the juxtaposition of breast and cervical cancer literature together creating opportunity for comparison.This scoping study has limitations. First, with many similar assessments, the search strategy could be incomplete and miss papers in other sources or that were not coded with keywords used in this search. In a few instances, reviewers identified other papers not captured by the original search strategy. Further, search terms may not have identified all reviews In order to provide evidence-based options in LMIC around cervical and breast cancer that are scalable, research needs to arise from LMIC settings and needs to address implementation science. Further research in low-resource settings rather than extrapolating from high-resources settings is indicated by the scoping study, particularly around breast cancer control. In addition, few of the reviews considered in this scoping study research include research that draws from implementation science or makes recommendations based on implementation science. Future research is needed across all implementation science themes, but workforce capacity and community- or person-centeredness were especially under-considered in the reviews included in this scoping study.Demonstration is needed that shows existing therapies, diagnostic tests, and interventions developed elsewhere can be as effective and practical in LMIC areas through implementation-oriented research and assessments . ComplexS1 Data(XLSX)Click here for additional data file.S1 Table(PDF)Click here for additional data file.S1 Text(PDF)Click here for additional data file.


Digital health is defined as the “use of information and communications technologies to improve human health, healthcare services, and wellness for individuals and across populations.”Today, everything is affected by the digital revolution – the impact of new technology on improving the health and well-being of individuals, communities, and populations is unprecedented. Recent technological achievements have revolutionized clinical practice, from prevention through diagnosis, monitoring to disease management, and enabled unprecedented public interest and engagement in self-management and well-being. Dozens of digital health projects have been conducted in Europe alone  and withHowever, the successful development, integration and implementation of new technology and methods require a radical shift from traditional and single-disciplinary academic and clinical approaches. In order to truly embrace these opportunities and transform healthcare and improve well-being, we need a new approach to science and health research. Only when investigated together, aimed at solving real-world problems, will health and technology be in a position to create results with significant impact on the delivery of clinical and social care and improve the well-being of individuals and populations.knowledge is the best enemy of disease – the application of what we know already will have a bigger impact on health and disease than any drug or technology likely to be introduced in the next decade” , have rapidly become established as the mainstream enhancing opportunities for personalized care, improving self-management, and bringing the desirable outcome: behavior change. Third, with over 4.55 billion people worldwide using a mobile phone in 2014, mHealth apps and interventions empower users in the developed world and are accelerating unprecedented access to best evidence and healthcare service in the low and middle income settings. Fourth, more than a decade ago, Sir Muir Gray forecasted that “ decade” . Better However, these challenges are only achievable through truly multi-disciplinary research collaborations.Frontiers in Public Health and Frontiers in ICT, champions this approach by providing a unique interdisciplinary publication venue for both professional communities, enabling the cross-fertilization and breeding of the next generation of versatile researchers who truly appreciate the language, methods, needs, and challenges of other disciplines. This momentum is creating the need for interdisciplinary health and public health computer science training. Closer partnerships between research and industry/start-ups bringing on board policy makers are essential to drive a real change.Intrinsically a multidisciplinary domain, digital health spans disciplines including computer science, engineering, information science, journalism, economy, clinical medicine, public health, epidemiology, and others. Technology and computer science investigate new frameworks and algorithms of excellent theoretical value, however, for successful digital health research. It is essential to address real-world medical challenges, solve clinical or public health problems, and recognize patients’ needs. Similarly, clinical IT solutions should improve management of conditions and delivery of care through utilization of cutting edge computer science solutions. This gap needs to be bridged by a joint multidisciplinary collaboration between healthcare professionals/medical scientists and computer scientists/engineers; so, both professions contribute to join research at equal levels. Thus, this Digital Health section, linked from Recent achievements in mobile technology and sensor/wearable devices have created real-time geo-located big data streams, facilitating context-aware social media communication and participatory systems that are radically changing the way we monitor populations with unprecedented opportunities for disease surveillance, early-warning, preparedness, and rapid response. Public health surveillance decision making is being revolutionized by the mining, analysis, and visualization of heterogeneous data sources, but must better leverage cutting-edge computer science to integrate with existing national and international surveillance systems . The potEnabled by the recent deployment of innovative medical devices, healthcare provision is being increasingly driven outside clinical settings to community and home and even further to care provision on-the-go . While iBy 2018, it is predicted that 75 million wireless-connected health and fitness devices will be shipped, up from 23 million in 2011 . Mobile Finally, novel approaches to human–computer interaction  and bettIt is estimated there are around 4.55 billion people worldwide using a mobile phone in 2014, of which about 1.75 billion are smartphone users . The useWhile mobile adoption is generally slowing, new users in the developing regions of Asia-Pacific and the Middle East and Africa will drive further increases  accelera“Knowledge is the enemy of disease, the application of what we know will have a bigger impact than any drug or technology likely to be introduced in the next decade” famously predicted Sir Muir Gray, Director of the UK NHS National Knowledge Service and NHS Chief Knowledge Officer over 10 years ago , based on problem-based learning (PBL) approaches that have been well established in medical education for decades. GBL has been enjoying unprecedented interest among researchers  impactinResearch on EPR, real time big data streams generated by social media, and increasingly popular tracking and wearable devices has demonstrated the potential to improve health outcomes and provide signals for early warning. Developments such as crowdsourcing, participatory surveillance, patients pledging to become “data donors,” and the ‘quantify self’ movement (where citizens share data through mobile device-connected technologies) have been significant game-changers in terms of data sharing. However, in the absence of transparent regulations and governance structures, and increasing exploiting of data collected via apps, searchers by industry, there are two strikingly disparate approaches to data ownership, responsibility over sharing and accountability.On one hand, traditionally risk adverse governments seem failing to communicate the advantages and opportunities arising from sharing anonymized patients data for research purposes to their citizens. In the UK, the failure in communication and lack of transparency over the control of data ownership resulted in loss of citizens’ trust and the backlash over the proposed implementation of care data initiative enabling large NHS patient data sharing , 46.On the other hand, citizens seem less concerned about their more accurate and potentially private health data being directly collected by major IT companies and MedTech manufactures through tracking/wearable devices and social media for data-driven marketing purposes. Recent study by Libert investigating top 50 search results for 2000 common diseases identified that a full 91% of servers made the user search available to outside companies – that included not only commercial sites but government organizations, universities, and non-profits too . As mediThird, population-level epidemiological datasets are also collected through surveillance systems. While notification of potential threats is enforced at international level through the International Health Regulations, IHR) and at European level with ECDC (EC Decision 2008/426/EC), countries remain in control of the datasets while surveillance population level data would be invaluable for scientific research, epidemic intelligence, and early-warning and risk assessment. Legal frameworks and operational procedures limiting the sharing of surveillance and epidemiological data between agencies and systems, as well as research organizations, are becoming openly challenged by open data initiatives in the public health domain. These could potentially enable almost real-time data sharing and faster response during emergencies, while opening new frontiers for data-driven interdisciplinary research.As the key challenge – transparent access to health data – remains pushed aside, scientific and healthcare communities must engage with the underlying political, human, and legal challenges to enable and facilitate transparent data access for research needs and large-scale integrations. As personal data are subject to industry-defined terms of conditions, much needed oversight and international government regulations are required to restore user control of personal data with implications for public policy supporting a balanced agenda that safeguards personal information, while enabling the use of data to improve health.Frontiers in Public Health will provide the ideal publication venue for world-class interdisciplinary research addressing these, and many more challenges arising in the future with curiosity, and the desire to transform healthcare and impact the health of citizens and populations globally. Through the cross-fertilization of ideas and growth of an involved and engaged multi-disciplinary research community, the innovative research published in the “Digital Health” section will contribute to transforming how care and public health are delivered and accessed over the next decade.The “Digital Health” section of The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Background: The analysis of eye movements (EM) by eye-tracking has been carried out for several decades to investigate mood regulation, emotional information processing, and psychomotor disturbances in depressive disorders.Method: A systematic review of all English language PubMed articles using the terms “saccadic eye movements” OR “eye-tracking” AND “depression” OR “bipolar disorders” was conducted using PRISMA guidelines. The aim of this review was to characterize the specific alterations of EM in unipolar and bipolar depression.Results: Findings regarding psychomotor disturbance showed an increase in reaction time in prosaccade and antisaccade tasks in both unipolar and bipolar disorders. In both disorders, patients have been reported to have an attraction for negative emotions, especially for negative pictures in unipolar and threatening images in bipolar disorder. However, the pattern could change with aging, elderly unipolar patients disengaging key features of sad and neutral stimuli. Methodological limitations generally include small sample sizes with mixed unipolar and bipolar depressed patients.Conclusion: Eye movement analysis can be used to discriminate patients with depressive disorders from controls, as well as patients with bipolar disorder from patients with unipolar depression. General knowledge concerning psychomotor alterations and affective regulation strategies associated with each disorder can also be gained thanks to the analysis. Future directions for research on eye movement and depression are proposed in this review. The study of eye movements (EM) in psychiatry and psychopathology began in 1908 based on the pioneer research of Allen Ross Diefendorf and Raymond Dodge. These authors were the first to study the ocular reaction in depression, mania, hebephrenic disease, epilepsy, and imbecile populations  population. Firstly, we describe the main eye-tracking paradigms, their characteristics and usefulness. Then, we present studies addressing unipolar and bipolar depression through the use of eye-tracking paradigms. Finally, we suggest perspectives for future research.A search of the literature was conducted in accordance with Preferred Reporting Items for Systematic reviews and Meta Analyses  and erroneous anticipatory saccades , in each task, is listed below Table .In 1993, Sereno et al. investigated saccadic performance in affective disorder groups composed by depressed and bipolar patients. They found no difference between affective disorder, schizophrenic and control participants for RT and ER in gap and no-gap conditions. Harris et al.  obtainedIn unipolar and bipolar disorders, Harris et al.  found anIn their first study in 1995, Crawford et al. found no differences between BD, schizophrenic patients and HC in predictive saccade performances. In a second study, they investigated the impact of antipsychotic treatments on predictive saccadic performances in BD patients. Patients with BD treated with antipsychotics had more accurate saccades than non-treated BD when the target was visible or temporarily withdraw  and MDD, by using EM recording. Examining four different types of emotions , depressed patients did not differ from GAD patients or HC for RT and the direction of initial EM. However, Eizenman et al.  found anEye movement tasks are a useful tool to investigate cognitive and motor functioning, through exploration of both low  and high  levels of motor control. Varieties of processes such as automatic relocation of visual search, spatial working memory, prediction, and response suppression can be evaluated through eye tracking, and related to mood disorders.Unipolar depressed patients present psychomotor retardation expressed by an increase in RT in both prosaccade and antisaccade tasks  and the attentional maintenance bias, specific to depression  most sample sizes were relatively small, (ii) there is a great variability in the eye movement parameters studied, (iii) most of the studies included patients treated with psychotropic medication and rigorous control of the medication effects over EM was generally lacking.EM have been used to identify the characteristics of motor and cognitive alteration in MDD and BD. The psychomotor retardation specificity associated with each disorder helps us distinguish these two populations  , and to systematically account for medication effects and their potential combinations with the core perceptual-motor effects of each disorder. Moreover, the current state of the literature on EM and depression has permitted us to establish that (i) unipolar depressed patients have been characterized by psychomotor retardation and negative emotional bias, and (ii) bipolar depressed patients present psychomotor retardation, inhibition deficit and are attracted by negative emotions such as threat. All these data are clinically useful for (i) understanding the link between emotion regulation, cognition and mood disorders, (ii) differentiating unipolar and bipolar disorders, and (iii) evaluating therapeutic response.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Maternal psychological distress is one of the most common perinatal complications, affecting up to 25% of pregnant and postpartum women. Research exploring the association between prenatal and postnatal distress and toddler cognitive development has not been systematically compiled. The objective of this systematic review was to determine the association between prenatal and postnatal psychological distress and toddler cognitive development.Articles were included if: a) they were observational studies published in English; b) the exposure was prenatal or postnatal psychological distress; c) cognitive development was assessed from 13 to 36 months; d) the sample was recruited in developed countries; and e) exposed and unexposed women were included. A university-based librarian conducted a search of electronic databases  . We searched gray literature, reference lists, and relevant journals. Two reviewers independently evaluated titles/abstracts for inclusion, and quality using the Scottish Intercollegiate Guideline Network appraisal tool for observational studies. One reviewer extracted data using a standardized form.Thirteen of 2448 studies were included. There is evidence of an association between prenatal and postnatal distress and cognitive development. While variable effect sizes were reported for postnatal associations, most studies reported medium effect sizes for the association between prenatal psychological distress and cognitive development. Too few studies were available to determine the influence of the timing of prenatal exposure on cognitive outcomes.Findings support the need for early identification and treatment of perinatal mental health problems as a potential strategy for optimizing toddler cognitive development. Maternal mental health problems are among the most common morbidities in pregnancy and postpartum with up to 25% of women experiencing stress, depression, or anxiety ,2. The iHistorically, the main focus in perinatal mental health has been the adverse effects of postpartum depression. However, epidemiologic evidence of rates of prenatal anxiety and depression that are similar or greater than postnatal rates , new devInquiry regarding specific mechanisms linking maternal psychological distress to suboptimal child outcomes is in the early stages ,14. LongToddlerhood is considered to be a critical developmental period . It is aCognitive development is strongly dependent upon early experiences ,22. WhilThe objective of this systematic review was to summarize evidence on the relationship between prenatal and postnatal maternal psychological distress and cognitive development in toddlers. It extends the work of a previous systematic review that we conducted on the association between maternal psychological distress and infant development (birth to 12 months) . BecauseObservational studies of any type  were included in this review if they evaluated the association between the most common forms of maternal psychological distress and toddler cognitive development as characterized by: (a) stress, depression, or anxiety occurring during pregnancy or the postpartum period (1 year following birth); (b) an outcome measure of cognitive development from 13 months of age up to and including 36 months; (c) recruitment of participants from developed countries; (d) publication in English between January, 1990 and March, 2014; and (e) inclusion of women exposed and unexposed to prenatal and/or postnatal psychological distress. Studies were excluded if the initial measure of maternal distress was beyond 1 year postpartum, psychological distress was based on a physiologic measure , or the sole exposure was a pharmacologic treatment for maternal distress.Maternal psychological distress was defined as stress, depression, or anxiety occurring during the prenatal or postnatal period. We classified maternal distress as prenatal if it occurred during pregnancy, and postnatal if it occurred from delivery to one-year post-delivery.The trimesters of pregnancy were categorized as first (0–13 weeks gestation), second (>13 weeks–26 weeks), and third (>26 weeks–40+ weeks). The magnitude of effect was defined as small when the correlation (r) was 0.10–0.30 or the odds ratio (OR) was <1.7; as medium when r = 0.30–0.50 or OR>1.7 to 2.5; and as large when r ≥ 0.50 or OR>2.5 .A university-based librarian developed the search strategy. Five electronic databases  were searched. The main MeSH keywords were: pregnancy; postpartum period; depression; anxiety; psychological stress; mental health; child development; and cognitive. Reference lists of included articles and relevant reviews were examined and key journals were hand-searched. We also searched government sites and private agencies with information on child development for unpublished and gray literature . The search encompassed the period from January, 1990 to March, 2014. Two individuals independently reviewed each article’s title or abstract with resolution of disagreements through discussion and consensus. Reviewers coded each article as included or excluded based on inclusion criteria, and further coded excluded articles by reason for exclusion.http://methodology/checklists.html). The SIGN tool is widely used and recommended for quality appraisal of cohort, cross-sectional and case-control studies (http://www.sign.ac.uk/index.html). Each study was appraised based on six components: study design, potential for selection bias, confounders, withdrawals and dropouts, blinding , and measurement of exposures and outcomes. Based on an algorithm designed for the Quality Assessment Tool for Quantitative Studies , each component was defined as strong, moderate, or weak with an overall study quality assigned based on the total number of strong, moderate, or weak components. Studies were categorized as having an overall quality of strong if no components were designated as weak and at least four components were strong, moderate if one component was weak and less than four components were strong, and weak if a rating of weak was assigned to two or more components. Disagreements regarding quality ratings were resolved by consensus.Two independent reviewers appraised the quality of each article using the Scottish Intercollegiate Guideline Network (SIGN) tool for observational studies  and quality of the evidence . Authors were contacted regarding missing data. Completed data extraction forms are available from the authors.We planned a qualitative (descriptive) analysis of the findings and examined studies for the potential to conduct a meta-analysis. If heterogeneity across studies was low, we planned on conducting a fixed-effect meta-analysis. In the presence of heterogeneity, we intended on using a random-effects meta-analysis. This review was exempt from ethics review board approval.A total of 2,448 studies were captured by the search with 13 studies meeting inclusion criteria . The lisboth prenatal and postnatal distress as primary exposures). In terms of timing of exposure, one measured prenatal distress during the first trimester [Eight studies examined prenatal distress as the primary exposure ,29–35, arimester , one durrimester , one durrimester , and thrrimester ,33,34.Among the thirteen studies, three had overall quality ratings of strong ,32,35, nGiven that prenatal psychological distress is one of the strongest predictors of postnatal psychological distress, it should be considered when evaluating the influence of postnatal distress on child outcomes ,40. CurrA wide variety of instruments were used to measure maternal psychological distress in these studies, and all studies scored ‘strong’ in the subcategory of ‘measurement’ for using tools with demonstrated reliability and validity . All insOverall, ten of thirteen studies reported significant associations between maternal distress and cognitive development.Seven of the eight studies evaluating prenatal distress as a primary outcome reported significant associations—six with negative associations and one with a positive association . Among tAmong the studies with reported or calculable effect sizes, five of seven significant studies of prenatal distress and toddler cognitive development found medium effect sizes ,31,33,34Four of the six studies of postnatal distress ,30,37,38Specific types of distress and their timing of measurement are summarized in In terms of timing of exposure, significant relationships were found with cognitive development when maternal distress occurred in the first , second Among the 2,448 studies captured through the search, 13 studies were eligible for inclusion in this review. The small number of studies evaluating the association between maternal psychological distress and development in toddlers reflects the relatively understudied nature of the preschool period compared to infancy and school-age , and ourThe findings of this review are consistent with a growing body of evidence that suggests that exposure to prenatal distress can negatively influence children’s development through complex biological pathways including neuroendocrine changes ,15,44–47We did not observe a pattern in the relationship between specific forms or timing of prenatal distress and cognitive development. The lack of a clear pattern may suggest that there is little specificity regarding the association between unique types of distress and cognitive development. However, the associations across heterogeneous types of distress may also reflect comorbidity of mental health problems  that is common in pregnant and postpartum women , but notOf importance, two studies examined the influence of chronicity of depression symptoms on cognitive development. Cornish et al. (2005), found that proportions of infants with sub-optimal MDI scores were similar in women with brief postpartum depression  and no depression (10%), whereas infants of mothers with chronic depression  were over 3 times more likely to have poor cognitive development . ConversOne of the unanticipated findings of this review was how few additional predictors of toddler cognitive development were significant once maternal mental health was considered in statistical models, although studies assessed a wide variety of demographic, socioeconomic, obstetrical, maternal behavior, neonatal and child factors. Within this context, the association between toddler development and maternal distress found in this review underscores its importance as an early life risk factor. Future research regarding the relationship between prenatal and postnatal distress and child development should address two key questions: 1) What protective prenatal influences and interventions lessen the impact of prenatal psychological distress on poor child outcomes; and 2) What postnatal influences and interventions minimize or reverse the adverse neurological sequelae of a sub-optimal intrauterine environment ? Notably, the research of the past two decades represented in this review largely explores intrauterine risk factors without also examining potential protective factors that occur during the prenatal or postnatal periods.This systematic review summarized evidence from observational studies published during the past 24 years on the association between maternal psychological distress and toddler cognitive development. However, the limitations of this review and the body of literature on which it was based should be acknowledged. The conclusions of the review are based on a small number of studies (n = 13). We did not include articles published in languages other than English or prior to 1990. The prevalent missing data related to maternal exposure , the inability to retrieve missing data, and the diversity in reporting of outcomes by continuous and dichotomous outcomes precluded meta-analysis. To address these limitations, future studies should report proportions of children with and without the outcome by maternal exposure. Several studies did not control for potential confounders that influence toddlers . Some potential for misclassification bias exists as a result of measuring maternal psychological distress at one time or with a single self-report instrument . Thus, wWhile based on a limited number of studies (n = 13), the conclusions of this review from primarily community-based studies point inevitably to consideration of early prenatal and postnatal detection and intervention of perinatal mental health problems on a population-level. Maternal mental health is a modifiable risk factor. Emerging evidence suggests that early intervention aimed at reducing maternal mental health problems in the prenatal and postnatal periods is effective at improving maternal mental health, maternal functioning, parenting, child cognitive development, and maternal-child interaction –52. The


The focus of this Research Topic is to bring new insights into central immune tolerance. To fulfill that, much has been discussed about the master in the regulation of tolerance, the autoimmune regulator (Aire) gene –3, the mIt includes 12 excellent contributions in the format of mini reviews or original research papers covering one or more of these aspects: promiscuous gene expression (PGE), epigenetics, miRNAs, association of the Aire gene and miRNAs, thymocyte–TEC interaction, coxsackievirus and type 1 diabetes, exosomes in the thymus, thymic crosstalk, thymic B cells, T cell development, chemokines and migration of T cells, miRNAs and the thymic atrophy, cell–cell interactions, and thymus ontogeny.Authors raised hypothesis, discuss concepts, and show open questions. The remaining important issues to resolve questions within the central tolerance research are briefly discussed below.The first mini review is authored by Olga Ucar and Kristin Rattay . They foAre the Eph/ephrins important for thymocyte–TEC interaction? This issue was reviewed by Javier Garcia-Ceca and cols . The matAnother stimulating mini review is authored by Hélène Michaux and cols  in whichOur group contributed with a mini review  focusingA very pertinent question raised by Gabriel Skogberg and cols  is on thThe thymic crosstalk, i.e., the reciprocal control by the close contact between TECs and thymocytes, which influences the differentiation of both types of cells was elegantly reviewed by Noëlla Lopes and cols . AuthorsThymus is an organ composed of different cell types including TECs, DCs, macrophages among other cell types, and of course thymocytes. Recently, researchers have identified an unexpected cell type formed by B cells, which may be originated from intrathymic B lymphopoiesis or immigration from the periphery. Tomoyoshi Yamano and cols  contribuThe regulation of T cell development is apparently well resolved; however, several unsolved questions remain. This important aspect is represented in this Research Topic through the mini review by Iris Caramalho and cols . AuthorsCell migration within the thymus is crucial for the central tolerance. Developing thymocytes migrate throughout the thymus being exposed initially to the cortex and then to the thymic medulla were they respectively undergo positive and negative selection. Chemokines represent key regulators for thymocyte migration. Zicheng Hu and cols  argue thTrypanosoma cruzi infection corresponds to an adequate mouse model to access this question. Leandra Linhares-Lacerda and cols (Thymic atrophy during senescence is widely recognized; however, poorly understood. In addition to the atrophy due to senescence, thymus involutes in response to a variety of stimuli including microbial infections. The mouse model of and cols  show resCellularity of mTECs is pivotal for cell–cell interactions within the thymus, which is required for central tolerance. Taishin Akiyama and cols  argue thThymus morphogenesis is a central point with many open questions. The mini review authored by Arnon Dias Jurberg and cols  addresseThis Research Topic provides an international and updated insight into the latest developments and open questions on the cellular and molecular bases of central tolerance induction.DM, EO and GP wrote the Editorial.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


In low- and middle-income countries (LMIC), determinants of women’s and children’s health are complex and differential vulnerability may exist to risk factors of perinatal distress and preterm birth. We examined the contribution of maternal perinatal distress on preterm birth and infant health in terms of infant survival and mother–infant interaction. A critical narrative and interpretive literature review was conducted. Peer-reviewed electronic databases , grey literature, and reference lists were searched, followed by a consultation exercise. The literature was predominantly from high-income countries. We identify determinants of perinatal distress and explicate changes in the hypothalamic–pituitary–adrenal axis, sympathetic, immune and cardiovascular systems, and behavioral responses resulting in pathophysiological effects. We suggest cultural–neutral composite measures of allostatic mediators  of maternal perinatal distress as objective indicators of dysregulation in body systems in pregnant women in LMIC. Understanding causal links of maternal perinatal distress to preterm birth in women in LMIC should be a priority. The roles of allostasis and allostatic load are considered within the context of the health of pregnant women and fetuses/newborns in LMIC with emphasis on identifying objective indicators of the level of perinatal distress and protective factors or processes contributing to resilience while facing toxic stress. We propose a prospective study design with multiple measures across pregnancy and postpartum requiring complex statistical modeling. Building research capacity through partnering researchers in high-income countries and LMIC and reflecting on unique ethical challenges will be important to generating new knowledge in LMIC. Both perinatal distress and preterm birth are world-wide problems that are especially burdensome in low- and middle- income countries (LMIC). Maternal prenatal and postnatal distress , collectively referred to as “perinatal distress,” may be significantly higher in LMIC than high income countries . The preStress, anxiety, or depression during pregnancy may contribute to preterm birth , 6. EverPerinatal distress may also adversely influence infant survival, behavior, and development through poor quality of maternal–infant interactions –21. A TaClinicians typically rely on self-report questionnaires to assess perinatal distress. While very useful, self-report is prone to bias or error . An alteA critical narrative and interpretive review  was undeWe searched peer-reviewed electronic databases including MEDLINE (1946–January 2013), Embase (1974–January 2013), Global Health (1910–January 2013), and Cumulative Index to Nursing and Allied Health Literature (CINHAL) (1990–January 2013). Grey literature , reference lists, and an existing network of experts in the area  were also used in identifying relevant publications. A conventional review technique using the search strategy and selection strategy detailed in Table Applying a precise review question or narrowing the search by assembling certain levels of evidence is restrictive when the intent of the literature review is also to generate a theory . ConsequAll types of studies were valued for their contribution, as they provided new ways of understanding our emergent conceptual framework and causal links between perinatal distress and preterm birth. Criteria for assessment included: (1) whether the study design was appropriate given the aim and objectives of the study; (2) appraisal of study reporting ; or (3) judgment about whether the study clarified what is known and what is not known, and informed the interpretation of concepts or the review in general . No papeTowards the end of the review, a group of stakeholders  from Pakistan, Kenya, Tanzania, and Canada were brought together to add additional insights and refine the conceptual framework. Terminology, such as perinatal distress, was clarified and a common understanding was developed of concepts. Essential elements of the framework were identified and revisions were made to better illustrate relationships between components. Through an iterative and consensus building process with feedback received from peer-reviewers of this manuscript, we present the final conceptual framework see Fig. .Fig. 3PePerinatal mental health of women living in LMIC, particularly mental health during pregnancy, received little attention until 2002. LMIC were represented in only 8 and 15 % of the pregnant- and post-partum related studies, respectively compared to 90 % of high income countries . A systepregnancy-related anxiety, which relates to the women’s fears about the infant’s health, delivery, her own health and survival during the birthing experience, and the impending responsibility of providing for the child [general anxiety and preterm birth , th, thpregnh e.g., , 48). In. Inpregnh .Chronic stress differs from acute stress, in that the threat or demand is long-lived, and often without resolution [Episodic stressors include catastrophic events, such as natural disasters , and manmade calamities , have shown varied impacts on pregnancy outcomes from no detected effect  stressors. solution . The chrsolution . A studysolution . Neighbosolution . Episodit , to lowt , the body responds to perinatal distress  by producing multisystem physiologic responses through the production of hormonal and neurotransmitter mediators , 56, 57.The brain coordinates the interconnected set of neuroendocrine and behavioral responses to perinatal distress , 61. CorPathologic levels of cortisol can increase the production of placental corticotropin-releasing hormone (CRH) in a dose response relationship . Placent), represent the primary effects in response to dysregulation of cortisol [Total cholesterol, and high-density lipoprotein  of stress, have been implicated in the pathway to preterm birth. A systematic review examining the association between inflammatory cytokines and risk of spontaneous preterm birth in asymptomatic women concluded that the maternal–fetal interface, rather than systemic inflammation, plays a major role . PregnanImmunosuppression of cellular and humoral immune activity resulting from dysregulation of neuroendocrine mediators, is either site specific   or systeImmunoglobulin G, an antibody that crosses the placenta, is critical in protecting the infant from infection in the neonatal period. Lower transplacental ratios of immunoglobulin G have been reported in preterm infants . High leIncreased blood pressure and heart rate represent a disease state or disorders resulting from allostatic load, as a consequence of secondary outcomes and primary mediator of stress . CardiovThere is empirical support (approximately 60 studies) for an association between increased allostatic load and negative health consequences of stress  . NotablyAllostatic load or overload exerts its influence on biological indices or mediators of the HPA axis and sympathetic–adrenal–medullary systems involving a complex interplay between the mother and fetus , 59. TheIn addition to activating the HPA axis, and sympathetic, immune and cardiovascular systems, psychosocial health during pregnancy has been linked to negative maternal health behavior  . Maternap = 0.015) in Pakistani mothers of preterm infants than Pakistani mothers of full-term infants [Our pilot data suggests that the odds of depression are 2.7 times greater  across many systems at the same time and the temporal effects of the risk(s). The use of the conceptual framework of allostatic load to examine the etiologic contributions of perinatal distress on pregnancy and infant outcomes will necessitate longitudinal study designs with multiple time points , and multiple measures of data collection .Although for our purpose we have focused on the negative pregnancy outcome of preterm birth, the conceptual model can be used to investigate pathways for positive pregnancy outcomes. A positive health focus may facilitate population level interventions directed at promoting mental health during pregnancy or “salutogenesis” within the context of their social, cultural, and political environment . In LMICBuilding research capacity will be essential to addressing the under-representation of pregnancy and post-partum related studies in LMIC. Facilitating partnerships between researchers in high-income countries and LMIC to identify and resolve unique challenges related to ethical conduct of research will be important to generating new knowledge in LMIC. Key among these challenges is the communication and understanding of informed consent . Since wAside from these ethical issues, studies involving blood sampling for allostatic load parameters need to critically consider the available laboratory infrastructure. Study procedures including procurement of laboratory samples, storage, transportation and processing may create technical and logistical difficulties. Establishing standard procedures, training and supervision of local researchers to develop research capacity, and assisting with knowledge transfer may mitigate logistical issues and ensure adherence to study protocols , 103. FuPregnant women in LMIC have been a neglected population in studies on perinatal distress and pregnancy and infant outcomes. Given inequities in determinants of health and the social, cultural, and political contexts of childbearing women in LMIC, these women may experience differential vulnerability to risk factors for perinatal distress and poor pregnancy outcomes. Prospective studies with multiple biological and psychosocial measures of stress, depression or depressive symptoms and its antecedents , state and trait anxiety, and pregnancy-related anxiety may add new knowledge and enhance our understanding about the etiologic contributions of psychosocial processes to preterm birth. A theoretical framework of allostatic load will enable researchers to concurrently examine social, environmental, and genetic antecedents of stress-related vulnerability and physiological  and behavioral responses that influence not only pregnancy outcomes of women in LMIC but also the life trajectories of health and wellness of the fetuses/infants  . Interre


In 2001, the Institute of Medicine’s (IOM) report, “Exploring the Biological Contributions to Human Health: Does Sex Matter?” advocated for better understanding of the differences in human diseases between the sexes, with translation of these differences into clinical practice. Sex differences are well documented in the prevalence of cardiovascular (CV) risk factors, the clinical manifestation and incidence of cardiovascular disease (CVD), and the impact of risk factors on outcomes. There are also physiologic and psychosocial factors unique to women that may affect CVD risk, such as issues related to reproduction.The Society for Women’s Health Research (SWHR) CV Network compiled an inventory of sex-specific strategies and methods for the study of women and CV health and disease across the lifespan. References for methods and strategy details are provided to gather and evaluate this information. Some items comprise robust measures; others are in development.To address female-specific CV health and disease in population, physiology, and clinical trial research, data should be collected on reproductive history, psychosocial variables, and other factors that disproportionately affect CVD in women. Variables related to reproductive health include the following: age of menarche, menstrual cycle regularity, hormone levels, oral contraceptive use, pregnancy history/complications, polycystic ovary syndrome (PCOS) components, menopause age, and use and type of menopausal hormone therapy. Other factors that differentially affect women’s CV risk include diabetes mellitus, autoimmune inflammatory disease, and autonomic vasomotor control. Sex differences in aging as well as psychosocial variables such as depression and stress should also be considered. Women are frequently not included/enrolled in mixed-sex CVD studies; when they are included, information on these variables is generally not collected. These omissions limit the ability to determine the role of sex-specific contributors to CV health and disease. Lack of sex-specific knowledge contributes to the CVD health disparities that women face.The purpose of this review is to encourage investigators to consider ways to increase the usefulness of physiological and psychosocial data obtained from clinical populations, in an effort to improve the understanding of sex differences in clinical CVD research and health-care delivery for women and men. Despite cardiovascular disease (CVD) being a major health-care burden and the leading cause of death in women and men in the USA, marked disparities in cardiovascular health persist between the sexes , 2. IndeThe recognition of sex differences in the pathophysiology and the expression of human disease, including CVD, led to the NIH mandate to include both women and men in clinical studies and trials and to analyze data by sex . HoweverThe purpose of this review is to highlight variables that may contribute to our understanding of CVD in women Table . We willPopulation research provides a unique opportunity to gather information that allows comparison of both traditional and novel CVD risk factors by sex. Previous reviews from our group and others have discussed sex and gender differences in CVD risk but have not provided guidelines for the collection of data that could expand beyond traditional risk factors –18. For Altered menstrual patterns are a readily identifiable indicator of potential hypoestrogenism and other neurohormonal alterations. However, the causes of altered menstrual patterns are many and include both ovarian and nonovarian causes. Common ovarian causes include the following: (1) polycystic ovary syndrome, sometimes referred to as hyperandrogenic anovulation; (2) premature ovarian insufficiency which is due to reduced or accelerated loss of oocytes and is often accompanied by autoimmune disorders such as juvenile diabetes and autoimmune thyroiditis and by chromosomal abnormalities such as 45,XO or 46,XX/45,XO mosaicism or microdeletions within the long arm of the X chromosome; (3) stress-induced hypogonadism, which is accompanied by a constellation of neuroendocrine aberrations including hypercortisolism and hypothalamic hypothyroidism; (4) syndromal psychiatric syndromes such as depression, schizophrenia, and eating disorders, including anorexia nervosa and bulimia, which may alter neuroendocrine function and result in hypothalamic hypogonadism; (5) other systemic medical conditions and disorders including thyroidal conditions, hyperprolactinemia, and adrenal disorders to name but a few; (6) environmental and other unintentional exogenous hormonal exposures; (7) hormone use such as oral contraceptives; (8) drug use and abuse, including alcohol, marijuana, and opiates; (9) medications including antipsychotics and neuroleptics, selective estrogen receptor modulators , and aromatase inhibitors; and (10) food-based phytoestrogens.Women with eating disorders also often have severe nutritional compromise and significant hypercortisolemia, which may further accelerate CVD risk. There is a paucity of studies on the long-term health of women with all forms of hypothalamic hypogonadism. Greater investigative attention has been given to women with polycystic ovary syndrome due to accompanying features of metabolic syndromeSex differences in the molecular and physiological responses to common hormones such as cortisol and thyroid hormones likely contribute to differences in risk for stress-induced cardiovascular disease to as great an extent as hypogonadism. While stressors produce hypothalamic hypogonadism in both women and men, with attendant reductions in sex-specific hormones such as estradiol and progesterone in women and testosterone in men, the events that trigger stressful reactions differs between sexes and comparable stressors elicit different types or different magnitude responses in men and women . Women mFindings from the Women’s Ischemic Syndrome Evaluation (WISE) study suggest that endogenous estrogen deficiency in young women may be a potent risk factor for atherosclerosis. While both primary ovarian insufficiency due to reduced oocyte count and/or accelerated atresia and acquired, stress-induced, ovulatory disruption result in estrogen deficiency, the latter is the most prevalent and most studied in premenopausal women. Premenopausal women with stress-induced suppression of the central drive of gonadotropic-releasing hormone (GnRH) may develop anovulation and amenorrhea or continue to have menstrual cycles but with reduced estradiol and progesterone secretion. Not only does stress have the potential to cause hypoestrogenemia, it also increases cortisol, which blocks estrogen action. Hypoestrogenemia of hypothalamic origin (defined as estradiol <184 pmol/l (50 pg/ml), FSH <10 IU/l, and luteinizing hormone <10 IU/l) was the most powerful independent predictor of angiographic coronary artery disease (CAD) such that in women with suspected ischemia, those with hypothalamic hypogonadism were at sevenfold  increased risk of obstructive atherosclerotic CAD at coronary angiography . ExtensiRecognizing and diagnosing the cause of altered menstrual cycle function is rarely straightforward. The association between hypogonadism and cardiovascular disease may vary according to the etiology. In addition, alterations in cyclic ovarian function may affect nonreproductive tissues .The first step in detecting altered ovarian function is to screen for alterations in or persistently abnormal menstrual bleeding patterns. There are many causes of abnormal uterine bleeding. An evaluation of abnormal uterine bleeding (AUB) must determine the presence or absence of endometrial and cervical polyps, fibroids, malignancy, coagulopathy, endometrial infection, adhesions, and scarring, and exogenous exposure, known and unknown, to hormones and hormonal mimetics . Once thStrategies exist for characterizing alterations in gonadal function, but most of the strategies require serial blood or urine samples taken across a defined time frame often defined pragmatically as the interval between the day of first menstrual bleeding and the day of the next first menstrual bleeding. When menstrual cycles occur with predictable regular intervals, a single blood sample that is appropriately timed can allow gonadal function to be estimated . For insIn the systemic circulation, sex hormone-binding globulin (SHBG) binds sex steroids with greater affinity for testosterone than estrogen. This buffering mechanism keeps hormonal excursions within a given range. This mechanism does not seem to operate in the cerebrospinal fluid (CSF). Hormones, especially cortisol, in CSF are not protein bound to any significant degree, thus if hormone levels are measured in CSF, it should be recognized that these are free (bioactive) levels .One potential way to mitigate the problems associated with the determination of circulating hormones is to assess such hormone concentrations in conjunction with measurement of menstrual patterns including interval between bleeding episodes and perceived flow . One precautionary note is that measurement of hormones in the circulation, urine, or saliva may not be reflective of the active hormone level at the tissue or cellular level because of the local metabolism of the sex steroids. Many organs outside of the reproductive organs contain receptors for sex steroids and the exact action of sex steroids upon the various tissues of relevance are determined by tissue-specific mechanisms that may themselves differ in males and females . FurtherDebate continues as to whether menopausal status impacts CVD, e.g., whether observed relations are predominantly due to aging , to periPremenopausal, less than 3 months of amenorrhea and no increase in menstrual irregularity in the past year; Early perimenopausal, less than 3 months of amenorrhea with some increase in menstrual irregularity; Late perimenopausal, between 3 and 11 months of amenorrhea; Postmenopausal, 12 or more consecutive months of amenorrhea with no medical cause other than menopause. SWAN classifies women who have had a hysterectomy or a bilateral salpingo-oophorectomy (BSO) as surgical menopausal, a separate category from women who are naturally postmenopausal. The term “hysterectomy” needs to be carefully defined as the removal of the uterus only with preservation of the ovarian tissue as not the same as the removal of the uterus and one or two ovaries when residual ovarian function is a relevant variable. The WISE study developed an algorithm using menstrual, surgical, and reproductive history with serum hormone assays [Menopausal status can be defined by changes in a woman’s menstrual bleeding as in the Massachusetts Women’s Health Study , the Stue assays . In 2011e assays  suggestee assays , 50. Thee assays –58. Thercorrelative data of reproductive health with CVD, data are lacking regarding whether reproductive complications cause CVD. Even if the associations of pregnancy complications with CVD do not prove to be causal, they can serve as useful early warnings of rate of progression of subclinical to symptomatic CVD. For example, both the American Heart Association (AHA) and American College of Obstetricians and Gynecologists (ACOG) guidelines now include a history of preeclampsia as a CVD risk factor [One of the most obvious sex differences for medical research is pregnancy. While parity has been extensively studied with respect to CVD, newer research is beginning to link several pregnancy complications to increased CVD risk. While there is abundant k factor , 60. TheThe connections between pregnancy complications and CVD outcomes have been reviewed elsewhere . In brieMedical records remain the “gold standard” for characterizing a woman’s pregnancy history. Yet they have several drawbacks, including the expense of collecting and abstracting records. Primary among these is the difficulty of obtaining prenatal records for older cohorts of women, i.e., women assessed after age 60 who had pregnancies in their twenties, who are at the highest risk of CVD events over the next few years. It can be challenging to retrieve 40-year-old records, but this challenge should be reduced in the future with the use of electronic medical records.A second difficulty is that some pregnancy complications, such as preeclampsia or the indications for an induced labor, may be recorded in part in the outpatient prenatal setting and in part in the labor and delivery records of hospitals. Finally, obstetric practice in the detection, definition, and recording of details regarding pregnancy complications has changed over time. For example, standardized testing for gestational diabetes was not routine in the USA until the 1970s, the criteria for preeclampsia and gestational diabetes have evolved over the years, and the basis of gestational dating has shifted from menstrual dating to fetal ultrasound examination. These variations in practice create challenges both for abstracting medical records for primary exposure data and for deriving a consistent definition for validation studies of birth registry data and maternal recall data. A priority goal of practical investigation is to optimize data collection of pregnancy complications relative to future CVD.The vast national birth registries that were established in the 1960s and 1970s have been the foundation of our understanding of the links between pregnancy history and CVD. In Scandinavia, the use of a national health identification number permits the broad-scale linking of pregnancy history to CVD hospital admissions and mortality data . The natGiven the lack of availability of medical records or the limited data fields in birth registries, investigators may wish to query mothers about their pregnancy histories. Indeed, for many pregnancy variables, maternal recall may be a truer “gold standard” than often-incomplete medical records. This may be particularly true of lifestyle factors such as smoking or drinking alcohol during pregnancy. More debatable is the ability of women to recall salient clinical details. For example, a recent review of studies of maternal recall of preeclampsia showed modest sensitivity and low predictive values of positive maternal recall compared with medical records, though specificity was high . ClearlyEach study will have to take into account the best ways to collect data on pregnancy history, depending on the age of their cohort and the availability and quality of records and registries. The HUNT studies—a longitudinal series of clinical CVD exams in Norway—have been able to link registry data to the clinical examinations . The NurOne emerging risk of pregnancy relates to persistent fetal microchimerism . During pregnancy, fetal and maternal cells pass across the placenta from the fetus to the mother and vice versa. These stem cells persist in the blood or tissues for decades or for the entire life of the individual . Male feUltimately, pregnancy history—including the pregnancy complications, spontaneous abortion, stillbirth, and fertility—is likely to give us new insight into sex differences in CVD. The results may prove to be clinically useful tools for illuminating new therapies and identifying the many women who might benefit from CVD preventive interventions and care tailored to their reproductive history.Polycystic ovary syndrome (PCOS) is a common condition that affects approximately 5 % of women of reproductive age in the USA , 80 and There remains incomplete consensus of the definition of PCOS. There are three overlapping criteria for this disorder: (1) the NIH criteria developed in 1990 at a NIH conference held to create both a working definition of the disorder and diagnostic criteria ; (2) theWhile the etiology of PCOS is multifactorial and involves excess androgen secretion by ovaries and adrenal glands (primarily androstenedione), genetic, epigenetic factors, and environmental factors, such as insulin resistance/diabetes and obesity, there is insufficient robust prospective data to clearly determine whether these abnormalities increase the incidence of cardiovascular events or other diabetic complications , 92. SomAcquired, stress-induced, ovulatory disruption is the most prevalent cause of estrogen deficiency in premenopausal women and is discussed in detail above in “The lifetime prevalence of depressive disorders in women is approximately double that of men . The incA biological susceptibility hypothesis has been suggested to account for sex differences in the prevalence of mood disorders , 106. ThNeurotransmitter systems involved in the control of mood and behavior include the following: glutamate, gamma-aminobutyric acid (GABA), acetylcholine (ACh), serotonin (5-HT), dopamine (DA), noradrenaline (NA), and neuropeptides. Sex steroids modulate the production, uptake, and clearance of these neurotransmitters. Declining levels of estrogen in women have been associated with postpartum and post-menopausal depression, and the cyclical variations of estrogens and progesterone may be what triggers premenstrual symptoms in women .2 receptors [Estrogen has been described as a 5-HT, NA, and ACh agonist and also modulates DAeceptors –114. TheAs mood disorders occur in both women and men, the assumption is that there must be a unified basis for their development. This common underlying cause is believed to be related to genetic predisposition. Multiple stressful life events cause biochemical changes in numerous neuroendocrine and neuroanatomical systems. As genetics determine in part how one interprets and responds to stressful life events, one may be genetically predisposed to respond in a way that leads to the development of mood disorders. The higher prevalence of mood disorders in women could be explained by an increased exposure to stressful life events, an increased vulnerability due to genetic predisposition to these events, modulation of the neuroendocrine system by fluctuating gonadal hormones, or a combination of these factors . AccordiSeveral validated and user-friendly instruments are available for the assessment and measurement of depression, anxiety, PTSD, and a history of childhood trauma. These are summarized below.The Center for Epidemiologic Studies Depression Scale (CES-D)  is a sel“During the past month, have you often been bothered by feeling down, depressed, or hopeless?”“During the past month, have you often been bothered by little interest or pleasure in doing things?”The two-question case-friendly instrument for depression is as good as six previously validated longer questionnaires in detecting depression in primary care , 131. ItThe importance of assessing fluctuations in mood symptoms as a risk factor for CVD seems to be even more relevant in patients with bipolar disorder –135 as wThe State-Trait Anxiety Inventory (STAI) is a self-rating instrument asking about current/recent symptoms of anxiety (state) as well as how anxious the person is in general (trait) , 138. ItSeveral questionnaires are available for assessing PTSD. The one that includes both current and lifetime symptoms is the Clinician-Administered PTSD Scale (CAPS-1) . It can The Childhood Trauma Questionnaire (CTQ) is the most widely used screening tool for childhood emotional, physical, and sexual abuse as well as emotional and physical neglect –148.There are important physiological sex differences in CVD with implications for outcomes and therapies, including coronary microvascular dysfunction, heart failure with preserved ejection fraction (HFpEF), Takotsubo cardiomyopathy, mortality due to drugs such as digoxin and QT-prolonging medications, and post-myocardial infarction (MI) depression, to name a few , 149. A Up to 40 % of women with signs and symptoms of myocardial ischemia presenting for invasive coronary angiography have no obstructive epicardial CAD. These women have been considered “low risk,” yet data obtained from angiographic studies demonstrate that this group includes a subgroup of patients at higher risk of adverse cardiac events . Recent 2+ [A large body of evidence supports the role of traditional CVD risk factors with endothelial-dependent dysfunction and an associated adverse prognosis in women , 161. Ho2+ , while f2+ . BecauseDiabetes mellitus is a relatively greater risk factor for CVD in women compared to men , 171. DiWomen suffer disproportionately from autoimmune disorders compared to men. A rise in C-reactive protein (CRP) is noted in girls but not in boys at puberty . High leOverall, traditional CVD risk factors associated with coronary microvascular dysfunction account for <20 % of the observed variability in WISE women . TherefoClinically, cardiovascular biomarkers are substances that are measured most typically in the bloodstream when CVD is present and help diagnose, risk stratify, monitor, and assist in the management of people with suspected acute coronary syndrome (ACS), acute MI , and heaIn 2007, the National Academy of Clinical Biochemistry (NACB) and International Federation of Clinical Chemistry (IFCC) committee recommended that sex-specific reference limits should be used in clinical practice for some cardiac biomarkers , yet to The most commonly used biomarkers in CVD stratification, cardiac troponin I (cTnI), and cardiac troponin T (cTnT) have been shown to have significantly different mean concentrations between men and women, suggesting the need for establishment of sex-specific ranges . In a 20Heart failure has emerged as a new CVD epidemic related in part to effective therapies for acute coronary syndromes and myocardial infarction that have reduced ischemic heart disease mortality but have increased the number of patients living with ischemic cardiomyopathy. In addition, heart failure is prevalent in older individuals, a growing segment of the population. However, half of patients hospitalized for heart failure have normal left ventricular ejection fraction –188. HeaThere is currently no effective therapy that has been shown to reduce mortality in patients with HFpEF. This may be due in part to under-representation of women in heart failure clinical trials and to a lack of understanding of sex-specific heart failure pathophysiology. Cardiac remodeling differs between men and women , 196, anTransient systolic and diastolic dysfunction occurring in the absence of coronary atherosclerotic disease was first described in 1990 in Japan. The disorder has a significant female preponderance. The International Takotsubo Registry published data from 25 cardiovascular centers in nine countries, including Europe and USA, showing that 89.8 % of patients were women with a mean age of 66.8 years . PatientDeath due to CVD in females emerged rapidly as an epidemic in 1984 and persists today , 203 desWomen (minority women in particular) are underrepresented in cardiovascular clinical trials  Fig. 2)2). BasicIn 1986, the National Institutes of Health (NIH) established a policy for inclusion of women in clinical research, and the 1987 NIH guide encouraged the inclusion of minorities in clinical research studies. Congress transformed what previously had been policy into Public Law in the NIH Revitalization Act of 1993 (PL 103-43), which reinforced existing NIH policies but with four major differences, including (1) inclusion of women and ethnic minorities, (2) valid representation of same, (3) precludes cost exclusion, and (4) initiates recruitment and retention activities  . Adults sed risk .Outcomes of cardiovascular clinical trials emphasize mortality benefit, with inattention to outcomes valued by many elderly patients—independence, decreased symptoms, improved functional capacity, and decreased hospitalizations. Clinical trials in elderly patients must incorporate indices of physical and cognitive function, consider comorbidities and polypharmacy, and address outcomes desired and valued by elderly patients .While women have been, and remain under-represented in clinical trials , a greatIn the Food and Drug Administration Safety and Innovation Act (Public Law No. 112-144) signed into law 9 July 2012 required demographic data and analysis of sex, age, race, and ethnicity to be posted in a report on the FDA website within a year of enactment and an action plan to be developed. In December 2011, the FDA issued a “Draft Guidance for Industry and Food and Drug Administration staff,” on “Evaluation of Sex Differences in Medical Device Clinical Studies.” This FDA document addresses the scope of the problem, the importance of considering sex differences, barriers to enrollment of women, and recommendations for achieving representative enrollment. This guide recommends for the disease or condition for which the device is intended to treat or diagnose: sex-specific prevalence, sex-specific diagnosis and treatment patterns; identification of proportions of women included in past studies for the target indications; and identification of any known clinically significant sex differences in outcomes related to either safety or effectiveness. The recommendation was that this information be included in the study and submission documents for (1) new or ongoing studies, (2) completed studies (marketing application stage), and (3) post-market studies (PHS 522 PS stage). In addition, altering pre-market investigational paradigms regarding sex-based data were encouraged by alignment of regulatory requirements and enhancement of business incentives for this purpose . IncludeAnother suggestion with broad implications was the consideration of a new policy allowing extensions in patent duration for additional research in women such as those granted for new pediatric indications, which have been highly successful in encouraging research on medications in children. Advocacy groups were encouraged to add technical expertise to better address these issues within their current missions. Finally, strategies to increase awareness of the problem among investigators, industry, and regulators have been endorsed, including requiring investigators to complete continuing medical education on sex differences in disease, multidisciplinary forums such as those held by the Drug Information Agency, educational seminars with FDA leadership, and increased use of existing NIH online educational materials .http://www.cdisc.org) to allow tracking of recruitment, analyzing data across clinical trials that alone do not have sufficient numbers of women for meaningful analyses, and analyzing of adverse events. Recently, the FDA has embarked on an ambitious bioinformatics modernization effort that includes an effort to harmonize with the standards being used in exchange of Electronic Health Records, which may improve our ability to detect important sex differences [Improving the accessibility of new and existing data for review and for incorporation into meta-analyses is needed . AE and ferences .A variable for male or female is usually collected in clinical study datasets. We advise that a clear definition of the term is provided for each study. Sex is the biologic variable and gender a self-declared variable encompassing psychosocial and cultural attributes. A primary consideration for sex-specific analyses is that if sex or gender is an a priori secondary analysis, then the enrolled cohort of women should be sufficiently powered for comparative analysis of the primary aim. Without this a priori planning, all reported sex and gender comparisons should include a post hoc statistical power calculation. In treatment trials, differential procedural effectiveness and complications as well as adherence to guideline-directed lifestyle and medical therapy should be reported as clinical management recommendations are often suboptimal among women as compared to men. Appendices reporting a more detailed analysis by sex/gender, including subsets  should be included for all major observational and clinical trials. Consideration should also be given to targeted population strata of women of diverse race and ethnicity as these subsets report the highest morbid and fatal event rates. In many cases, adjusted analyses are presented that control for clinical and comorbid covariates that may minimize sex differences. It is recommended that absolute rates of morbid and fatal event rates also be included with adjusted analyses. Care should be taken when women are matched to subsets of men by a priori chosen criteria . Matching women to men may select a subset of atypical females and minimize unique sex-specific differences. If matching is performed, details as to how the selected women compared to the whole subset of females should be provided as well as additional sex stratified analyses.Efforts to develop and use sex-specific information regarding women have increased over the last two decades, and while there is still a great need for more data, the evidence base has increased. We encourage investigators to consider these variables that have impact on women’s CVD risk and outcomes when designing studies. Table