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This is a pre-copyedited, author-produced version of an article accepted for publication in Cardiovascular Research (CVR) following peer review. The version of record Perrino, Ferdinandy, Bøtker, Brundel, Collins, Davidson, Den Ruijter, Engel, Gerdts, Girao, Gyöngyösi, Hausenloy, Lecour, Madonna, Marber, Murphy, Pesce, Regitz-Zagrosek, Sluijter, Steffens, Gollmann-Tepeköylü, Van Laake, Van Linthout, Schulz, Ytrehus. Improving translational research in sex-specific effects of comorbidities and risk factors in ischaemic heart disease and cardioprotection: Position paper and recommendations of the ESC Working Group on Cellular Biology of the Heart. Cardiovascular Research (CVR). 2021;117(2):367-385, is available online at: https://doi.org/10.1093/cvr/cvaa155. Ischaemic heart disease (IHD) is a complex disorder and a leading cause of death and morbidity in both men and women. Sex, however, affects several aspects of IHD, including pathophysiology, incidence, clinical presentation, diagnosis as well as treatment and outcome. Several diseases or risk factors frequently associated with IHD can modify cellular signalling cascades, thus affecting ischaemia/reperfusion injury as well as responses to cardioprotective interventions. Importantly, the prevalence and impact of risk factors and several comorbidities differ between males and females, and their effects on IHD development and prognosis might differ according to sex. The cellular and molecular mechanisms underlying these differences are still poorly understood, and their identification might have important translational implications in the prediction or prevention of risk of IHD in men and women. Despite this, most experimental studies on IHD are still undertaken in animal models in the absence of risk factors and comorbidities, and assessment of potential sex-specific differences are largely missing. This ESC WG Position Paper will discuss: (i) the importance of sex as a biological variable in cardiovascular research, (ii) major biological mechanisms underlying sex-related differences relevant to IHD risk factors and comorbidities, (iii) prospects and pitfalls of preclinical models to investigate these associations, and finally (iv) will provide recommendations to guide future research. Although gender differences also affect IHD risk in the clinical setting, they will not be discussed in detail here.

Publisher Copyright: © 2020, The Author(s). Severe blood disorders and cancer are the leading cause of death and disability from noncommunicable diseases in the global pediatric population and a major financial burden. The most frequent of these conditions, namely sickle cell disease and severe thalassemia, are highly curable by blood or bone marrow transplantation (BMT) which can restore a normal health-related quality of life and be cost-effective. This position paper summarizes critical issues in extending global access to BMT based on ground experience in the start-up of several BMT units in middle-income countries (MICs) across South-East Asia and the Middle East where close to 700 allogeneic BMTs have been performed over a 10-year period. Basic requirements in terms of support systems, equipment, and consumables are summarized keeping in mind WHO’s model essential lists and recommendations. BMT unit setup and maintenance costs are summarized as well as those per transplant. Low-risk BMT is feasible and safe in MICs with outcomes comparable to high-income countries but at a fraction of the cost. This report might be of assistance to health care institutions in MICs interested in developing hematopoietic stem cell transplantation services and strengthening context appropriate tertiary care and higher medical education.

Stroke, a vascular disease of the brain, is the #1 cause of disability and a major cause of death worldwide. Stroke has a major negative impact on the life of stroke-affected individuals, their families and the society. A significant proportion of stroke victims indicate that would have preferred death over their after-stroke quality of life. Mechanical thrombectomy (MT), opening the occluded artery using mechanical aspiration or a thrombus-entrapment device, is a guideline-mandated (class I, level of evidence A) treatment modality in patients with large vessel occlusion stroke. MT clinical benefit magnitude indicates that a universal access to this treatment strategy should be the standard of care. Today there is a substantial geographic variation in MT deliverability, with large-scale disparities in MT implementation. In many countries effective access to MT remains severely limited. In addition, many of the MT-treated patients are treated too late for a good functional outcome because of logistic delays that include transportations to remotely located, scarce, comprehensive stroke centres. Position Paper from the European Society of Cardiology Council on Stroke and European Association for Percutaneous Cardiovascular Interventions on interdisciplinary management of acute ischaemic stroke, developed with the support of the European Board of Neurointervention fills an important gap in systematically enabling interventional cardiologists to support stroke intervention in the geographic areas of unmet needs in particular. We review strengths and weaknesses of the document, and suggest directions for the next steps that are swiftly needed to deliver MT to stroke patients more effectively.

The pandemic of coronavirus disease (COVID)-19 is a global threat, causing high mortality, especially in the elderly. The main symptoms and the primary cause of death are related to interstitial pneumonia. Viral entry also into myocardial cells mainly via the angiotensin converting enzyme type 2 (ACE2) receptor and excessive production of pro-inflammatory cytokines, however, also make the heart susceptible to injury. In addition to the immediate damage caused by the acute inflammatory response, the heart may also suffer from long-term consequences of COVID-19, potentially causing a post-pandemic increase in cardiac complications. Although the main cause of cardiac damage in COVID-19 remains coagulopathy with micro- (and to a lesser extent macro-) vascular occlusion, open questions remain about other possible modalities of cardiac dysfunction, such as direct infection of myocardial cells, effects of cytokines storm, and mechanisms related to enhanced coagulopathy. In this opinion paper, we focus on these lesser appreciated possibilities and propose experimental approaches that could provide a more comprehensive understanding of the cellular and molecular bases of cardiac injury in COVID-19 patients. We first discuss approaches to characterize cardiac damage caused by possible direct viral infection of cardiac cells, followed by formulating hypotheses on how to reproduce and investigate the hyperinflammatory and pro-thrombotic conditions observed in the heart of COVID-19 patients using experimental in vitro systems. Finally, we elaborate on strategies to discover novel pathology biomarkers using omics platforms.

Coronary heart disease (CHD) is the leading cause of death and disability worldwide. Despite current therapy, the morbidity and mortality for patients with CHD remains significant. The most important manifestations of CHD arise from acute myocardial ischaemia-reperfusion injury (IRI) in terms of cardiomyocyte death and its long-term consequences. As such, new therapeutic interventions are required to protect the heart against the detrimental effects of acute IRI and improve clinical outcomes. Although a large number of cardioprotective therapies discovered in pre-clinical studies have been investigated in CHD patients, few have been translated into the clinical setting, and a significant number of these have failed to show any benefit in terms of reduced myocardial infarction and improved clinical outcomes. Because of this, there is currently no effective therapy for protecting the heart against the detrimental effects of acute IRI in patients with CHD. One major factor for this lack of success in translating cardioprotective therapies into the clinical setting can be attributed to problems with the clinical study design. Many of these clinical studies have not taken into consideration the important data provided from previously published pre-clinical and clinical studies. The overall aim of this ESC Working Group Cellular Biology of the Heart Position Paper is to provide recommendations for optimizing the design of clinical cardioprotection studies, which should hopefully result in new and effective therapeutic interventions for the future benefit of CHD patients.

Introduction Every year there is an increase in the number of cases and deaths due to the majority of cancers. Currently, these diseases constitute the second cause of death in Poland and the USA. The number of cases of malignant neoplasms in Poland has more than doubled over the last three decades. According to the National Cancer Registry, in Poland about 95.5 people per thousand die every year from malignant neoplasms. Current epidemiological data on cancer is worrying because the World Health Organization predicts a significant increase in the incidence of cancer in the general population. This problem, which is significant on the global scale, demands the search for more effective prevention methods so that more and more attention is paid to both primary and secondary prevention. Prevention and early detection of cancer have become a priority for the national health policy of many European countries. Numerous studies around the world prove that reducing the risk of cancer is most effective through adopting a healthy lifestyle, avoiding exposure to carcinogens, combined with regular screening. Objective The aim of the study was to review knowledge on cancer prevention, including the latest research results. Conclusions Due to the systematic increase in the incidence of cancer, a strong emphasis should be placed on prevention. Preventive actions bring benefits not only to the individual, but are an important aspect of health policy. The importance of primary prevention in relation to healthy people has been demonstrated, including secondary prevention aimed at controlling risk factors in relation to persons exposed to them. The combination of these activities becomes an important element in maintaining the health of the individual, as well as society.

Objectives: The objective of the present study was to investigate the risk of death from non-malignant diseases in female pulp and paper workers in Norway. Methods: A total of 3143 women first employed between 1920–93 were included in the study cohort. Information about each cohort member was obtained from personnel record files in the mills in order to identify employment periods and job categories. Data on cause and date of death were added by linkage to the Cause of Death Register using unique personal identification numbers. The follow up period was 1951–2000. Standardised mortality ratios (SMRs) with 95% confidence intervals (95% CIs) were calculated using the national female mortality rates as reference. Poisson regression analysis was used to examine internal relations between the duration of employment in paper departments and the risk of death from selected causes. Relative risks (RRs) and 95% CIs were calculated. Results: The study showed a significantly increased risk for total non-malignant mortality (SMR = 1.14, 95% CI 1.05 to 1.24), mainly due to increased mortality from ischaemic heart disease (SMR = 1.22, 95% CI 1.03 to 1.43) and cerebrovascular diseases (SMR = 1.16, 95% CI 0.94 to 1.42). Analysis by department showed the highest risk of death in paper department workers with short term employment. Internal analyses showed a 5% and 9% increase in risk of dying from ischaemic heart disease and respiratory diseases, respectively, among paper department workers exposed to paper dust. The risk decreased with increasing duration of employment. Conclusion: The increased risk of ischaemic heart diseases and respiratory diseases seen among employees of paper departments may be related to exposure to paper dust.

International audience; Ischaemic heart disease (IHD) remains the leading cause of death and disability worldwide. As a result, novel therapies are still needed to protect the heart from the detrimental effects of acute ischaemia-reperfusion injury, in order to improve clinical outcomes in IHD patients. In this regard, although a large number of novel cardioprotective therapies discovered in the research laboratory have been investigated in the clinical setting, only a few of these have been demonstrated to improve clinical outcomes. One potential reason for this lack of success may have been the failure to thoroughly assess the cardioprotective efficacy of these novel therapies in suitably designed preclinical experimental animal models. Therefore, the aim of this Position Paper by the European Society of Cardiology Working Group Cellular Biology of the Heart is to provide recommendations for improving the preclinical assessment of novel cardioprotective therapies discovered in the research laboratory, with the aim of increasing the likelihood of success in translating these new treatments into improved clinical outcomes.

European journal of nuclear medicine and molecular imaging 43(4), 780-792 (2016). doi:10.1007/s00259-015-3259-3, Published by Springer-Verl., Heidelberg [u.a.]

Item does not contain fulltext There are large variations in the incidence, registration methods and reported causes of sudden cardiac arrest/sudden cardiac death (SCA/SCD) in competitive and recreational athletes. A crucial question is to which degree these variations are genuine or partly due to methodological incongruities. This paper discusses the uncertainties about available data and provides comprehensive suggestions for standard definitions and a guide for uniform registration parameters of SCA/SCD. The parameters include a definition of what constitutes an 'athlete', incidence calculations, enrolment of cases, the importance of gender, ethnicity and age of the athlete, as well as the type and level of sporting activity. A precise instruction for autopsy practice in the case of a SCD of athletes is given, including the role of molecular samples and evaluation of possible doping. Rational decisions about cardiac preparticipation screening and cardiac safety at sport facilities requires increased data quality concerning incidence, aetiology and management of SCA/SCD in sports. Uniform standard registration of SCA/SCD in athletes and leisure sportsmen would be a first step towards this goal.

Cardiomyopathies are a heterogeneous group of heart muscle diseases and an important cause of heart failure (HF). Current knowledge on incidence, pathophysiology and natural history of HF in cardiomyopathies is limited, and distinct features of their therapeutic responses have not been systematically addressed. Therefore, this position paper focuses on epidemiology, pathophysiology, natural history and latest developments in treatment of HF in patients with dilated (DCM), hypertrophic (HCM) and restrictive (RCM) cardiomyopathies. In DCM, HF with reduced ejection fraction (HFrEF) has high incidence and prevalence and represents the most frequent cause of death, despite improvements in treatment. In addition, advanced HF in DCM is one of the leading indications for heart transplantation. In HCM, HF with preserved ejection (HFpEF) affects most patients with obstructive, and similar to 10% of patients with non-obstructive HCM. A timely treatment is important, since development of advanced HF, although rare in HCM, portends a poor prognosis. In RCM, HFpEF is common, while HFrEF occurs later and more frequently in amyloidosis or iron overload/haemochromatosis. Irrespective of RCM aetiology, HF is a harbinger of a poor outcome. Recent advances in our understanding of the mechanisms underlying the development of HF in cardiomyopathies have significant implications for therapeutic decision-making. In addition, new aetiology-specific treatment options (e.g. enzyme replacement therapy, transthyretin stabilizers, immunoadsorption, immunotherapy, etc.) have shown a potential to improve outcomes. Still, causative therapies of many cardiomyopathies are lacking, highlighting the need for the development of effective strategies to prevent and treat HF in cardiomyopathies.

Overdiagnosis is a growing problem worldwide. Overdiagnosis is the diagnosis of deviations, abnormalities, risk factors, and pathologies that in themselves would never cause symptoms (this applies only to risk factors and pathology), would never lead to morbidity, and would never be the cause of death. Overdiagnosis is often misinterpreted as overutilization or overtreatment. Overutilization, overtreatment, and overdiagnosis are interrelated but three distinct topics. Overutilization (establishment of standard practice that does not provide net benefit) does not have to lead to overdiagnosis or overtreatment, but the risk exists. Treatment of overdiagnosed conditions is one category of overtreatment. Another is when the best available evidence shows that the treatment has no beneficial effect. Overdiagnosis can be caused by overutilization and is nearly always followed by overtreatment. Treating an overdiagnosed condition cannot improve the patient’s prognosis, and therefore can only be harmful. At the individual level, we can never be sure if the person is overdiagnosed. However, experiences and thoughts of individuals who are most likely overdiagnosed can be explored in qualitative interviews, e.g. men with a small screening detected abdominal aortic aneurism. In longitudinal surveys, the degree and length of psychosocial consequences associated with overdiagnosis can be estimated. In high-quality RCTs, the magnitude of overdiagnosis can be quantified, and in cohort studies, we can find indications of overdiagnosis. Finally, we can conduct research about the consequences of overdiagnosis in at least eight different areas: financial strain, hassles/inconveniences, medical costs, opportunity costs, physical harms, psychological harms, societal costs and work-related costs.

Cardiac arrest is a common and treatable cause of death and disability. Each year ≈424 000 people experience emergency medical services (EMS)-assessed out-of-hospital cardiac arrest (OHCA) in the United States.1 The actual burden of OHCA is likely significantly higher because a substantial number go unassessed. In a prospective analysis of deaths in a US county, 5.6% of annual mortality was attributable to cardiac arrest.2 Many patients who suffer OHCA do not receive prompt cardiopulmonary resuscitation (CPR). Among those who receive CPR, a large number do not survive because of an inability to restore spontaneous circulation, or anoxic cerebral injury even after restoration of circulation. Nevertheless, when timely interventions are provided, a small proportion of patients (10.4% of all EMS-treated OHCA) recover to resume normal lives. The key therapeutic interventions that make the difference between life and death, metaphorically characterized as the 5 links in a chain of survival by the American Heart Association, include: (1) immediate recognition of cardiac arrest and activation of the EMS, (2) early CPR with emphasis on chest compression, (3) rapid defibrillation, (4) effective advanced life support, and (5) integrated postcardiac arrest care.3 Resuscitation science has undergone major advances since the origins of modern CPR >50 years ago.4 The field continues to be dynamic with emergence of new therapies such as therapeutic hypothermia5 and improvements in systems of care. However, many questions remain on issues such as optimum compression rate, efficacy of chest compression only CPR (CCCPR), dispatcher-assisted CPR, and benefits of postresuscitation measures such as hypothermia. A critical challenge also lies in the translation of resuscitation science into practice. To improve outcomes, each of the links in the chain of survival needs to be executed promptly and effectively. There remain several lacunae, which need to be overcome to develop an …

AMI : acute myocardial infarction ARVC : arrhythmogenic right ventricular cardiomyopathy BrS : Brugada syndrome CACS : coronary artery calcium score CAD : coronary artery disease ChD : Chagas heart disease CMR : cardiac magnetic resonance CPVT : catecholaminergic polymorphic ventricular tachycardia CTCA : computed tomography coronary angiography CV : cardiovascular DCM : dilated cardiomyopathy EAPCR : European Association for Cardiovascular Prevention and Rehabilitation HCM : hypertrophic cardiomyopathy LGE : late gadolinium enhancement LQTS : long QT syndrome LV/RV : left/right ventricle LVH : left ventricle hypertrophy NSVT : non-sustained ventricular tachycardia PPE : preparticipation evaluation PVC : premature ventricular contractions SCA/SCD : sudden cardiac arrest/death TTE : transthoracic echocardiography VF : ventricular fibrillation VT : ventricular tachycardia Sudden cardiac death (SCD) associated with athletic activity is a rare but devastating event. Victims are usually young and apparently healthy, and while many of these deaths remain unexplained, a substantial number of victims harbour an underlying and potentially detectable cardiovascular (CV) disease.1–4 The vast majority of these events are due to malignant tachyarrhythmias, usually ventricular fibrillation (VF) or ventricular tachycardia (VT) degenerating into ventricular fibrillation (VF), occurring in individuals with arrhythmogenic disorders (e.g. hypertrophic cardiomyopathy, arrhythmogenic cardiomyopathy, channelopathies). Intensive exercise training and competitive sport participation is a trigger that may favour insurgence of ominous ventricular tachyarrhythmias in predisposed individuals.5 Consequently, there is a great interest in early identification of at-risk individuals for whom appropriate treatment, followed or not by physical activity adjustment, may be implemented to minimize the risk of SCD. However, the role of pre-participation evaluation (PPE) in athletes as a feasible and efficient strategy to identify individuals at risk has remained controversial. …

A mortality cohort study was undertaken among Polish pulp and paper workers. This paper concentrates on neoplasms mortality among men and women employed continuously for at least one year in the factory producing sulphate pulp, paper board and paper products. A retrospective observation carried out till 31 December 1995 covered 10,460 workers employed during the years 1968-1990. The cohort accessibility was 99%. Cancer risk was evaluated on the basis of standardized mortality ratio (SMR) calculated according to the person-years method. The general population of Poland was the reference population. The results of a 23-year cohort observation, published earlier, showed a lowered overall mortality from all causes and from all malignant neoplasms, and a significant excess of death from peritoneum and prostate cancer among pulp mill male subcohort. The conclusion was drawn that a 'young' cohort and relatively short follow-up period might have affected the results. The results presented in this paper, obtained after further five years of observation showed in the male cohort an excess of deaths from cancer of respiratory tract and peritoneum (lung SMR = 122, nasal cavities SMR = 587, peritoneum SMR = 562). An approximate correction for smoking habits resulted in only 4 decreased risk estimates for lung cancer, indicating a small positive confounding effect of smoking in this material. In female cohort an excess of brain cancer was found (SMR = 355). Only the excess mortality from cancers of nose, lung and peritoneum was coherent with the exposure to higher concentrations of wood dust, pulp, paper and board dust. It may support a hypothesis that these factors as well as dust pollutants, not yet identified in this study, may be considered as one of the risk factors contributing to the incidence of neoplasms of these sites.

A cohort study was designed to evaluate the risk of death from malignant neoplasms among pulp and paper workers. This paper presents the evaluation of death risk among workers engaged only in the production of paper, paperboard and paper products. The cohort study covered 1,322 males and 1,914 females employed for, at least, one year in a big pulp and paper mill during the period 1968-90. The study of exposure to harmful factors revealed that concentrations of paper and paperboard dusts in this mill exceeded hygienic standards. The analysis of death risk by causes and gender of those under study was based on standardized mortality rate (SMR) calculated using the method of person-year observation. The general population of Poland was used as reference. The results do not confirm excess mortality from lung, stomach and hematopoietic cancers in paper mill workers reported by other authors. However, an elevated risk of bladder cancer in males (SMR = 491, two deaths) and brain cancer in females (SMR = 353, two deaths) was observed. Both SMR values were not statistically significant. Because of small number of deaths, risk according to exposure and latency was not evaluated.

Mortality among workers in the Polish pulp and paper industry was evaluated in retrospective cohort study of 10460 workers who had been employed continuously for at least one year between 1968 and 1990 in the factory producing sulphate pulp, paper, board and paper products. A standardized mortality ratio (SMR) analysis was used to compare death rates for the exposure group with Polish national rates. For all the subjects death due to all causes and all malignant neoplasms were lower than the number expected. The only significantly increased risks were those of malignant neoplasm of brain among women (4 cases, SMR = 318) and of retroperitoneum and peritoneum among men (2 cases, SMR = 659), exposed to high level of wood dust and irritant sulphur compounds. The authors could not find any etiological explanation of the excessive mortality from brain and peritoneum cancers.

Each year in the United States, approximately 800 000 men and women are affected by stroke, which equates to one incident of stroke every 40 seconds.1 Stroke is the fourth leading cause of death nationally and is one of the foremost contributors to functional disability.2 The cost to the US healthcare system is substantial. Specifically, in 2010 medical treatment for stroke cost approximately $54 billion and is expected to exceed $1 trillion by 2050.3 The burden of stroke is not limited to US alone; mortality from stroke is responsible for ~9% of all deaths worldwide and is the second most common cause of death following ischemic heart disease.4 While the overall risk of stroke has declined by 25% in the last decade,5 disability from stroke is now emerging as a major public health problem, particularly in the elderly, as we observe an increase in aging of the population. Accordingly, in this month’s topic review in Circulation: Cardiovascular Quality and Outcomes , we concentrate on contemporary issues around stroke and transient ischemic attack (TIA). Significant knowledge and practice gaps continue to exist across the continuum of stroke care. First, risk factor modification for stoke remains suboptimal. The most important modifiable risk factor for prevention of stroke is hypertension (HTN), with the lowering of blood pressure associated with a more than 25% reduction in the relative risk (RR) of stroke.6,7 Modification of other risk factors such as diabetes, hypercholesterolemia, smoking cessation and atrial fibrillation (AF),8 have also been shown to reduce the incidence of stroke.9 However, appropriate identification of patients at risk and ensuring adherence to prevention strategies presents many challenges. For example, numerous patients with HTN are not on therapy and many of those who are treated have suboptimal blood pressure …

The American College of Medical Toxicology and the National Association of Medical Examiners convened an expert panel to generate evidence-based recommendations for the practice of death investigation and autopsy, toxicological analysis, interpretation of toxicology findings, and death certification to improve the precision of death certificate data available for public health surveillance. The panel finds the following: 1. A complete autopsy is necessary for optimal interpretation of toxicology results, which must also be considered in the context of the circumstances surrounding death, medical history, and scene findings. 2. A complete scene investigation extends to reconciliation of prescription information and pill counts. 3. Blood, urine, and vitreous humor, when available, should be retained in all cases. Blood from the femoral vein is preferable to blood from other sites. 4. A toxicological panel should be comprehensive and include opioid and benzodiazepine analytes, as well as other potent depressant, stimulant, and anti-depressant medications. 5. Interpretation of postmortem opioid concentrations requires correlation with medical history, scene investigation, and autopsy findings. 6. If death is attributed to any drug or combination of drugs (whether as cause or contributing factor), the certifier should list all the responsible substances by generic name in the autopsy report and on the death certificate. 7. The best classification for manner of death in deaths due to the misuse or abuse of opioids without any apparent intent of self-harm is "accident." Reserve "undetermined" as the manner for the rare cases in which evidence exists to support more than one possible determination.

Growth during intrauterine life, infancy, childhood, and adolescence has a powerful effect on morbidity and mortality at each of these stages of life and the effects persist for the remainder of the individual’s life. For many decades, it has been recognized that infectious diseases have been the leading cause of death in children under the age of 5 in developing countries. It is only in recent years that the potentiating effects of undernutrition on infectious diseases have been recognized. Data analyzed from developing countries showed that more than half of child deaths were attributed to the potentiating effects of undernutrition and, of these, 80% were attributable to mildmoderate undernutrition rather than severe undernutrition. Thus, high rates of undernutrition in young infants are of great concern. Increasing rates of being overweight and obese in later childhood and adolescence in developed countries have been noted for several decades. However, in low- and middle-income countries (LMIC), where high rates of undernutrition in young infants still exist, this has only become the focus of attention in more recent years giving rise to the concept of a double burden of malnutrition in LMIC. (Published: 24 January 2013) Citation: Glob Health Action 2013, 6 : 19785 - http://dx.doi.org/10.3402/gha.v6i0.19785

Cardiovascular disease (CVD) in women has been historically understudied. For many years, heart disease had been thought to be primarily a “man’s disease.” Consequently, women have been significantly under-represented in longitudinal studies of disease history and in clinical trials. High-quality data from women at the extremes of age, with multiple co-morbidities, and from racial and ethnic minorities have been particularly rare. In order to increase awareness of cardiovascular prevention among women, in 1999 the American Heart Association (AHA) published its first women-specific clinical recommendations for the prevention of CVD.1 In 2004, the AHA and multiple other collaborating organizations subsequently sponsored “Evidence-Based Guidelines for Cardiovascular Disease Prevention in Women,” which underwent updates in 2007 and 2011. As a result of these and other related initiatives, the rate of public awareness of CVD as the leading cause of death among US women has increased from 30% in 1997 to 54% in 2009.2 CVD-associated death among US women has declined significantly over this time period.3,4 Yet substantial work still needs to be done to improve women’s cardiovascular health. CVD remains the number one killer among women.4 As the obesity epidemic continues, we are actually finding increases in coronary heart disease (CHD) death among young women 35 to 54 years of age.2 Morbidity and mortality from stroke and hypertension remain high.4 In addition, substantial outcomes disparities continue for women from racial and ethnic minorities.4 We have therefore dedicated our topic summaries in this issue of Circulation: Cardiovascular Quality and Outcomes to CVD in women. We have included only those studies where authors provided a convincing a priori reason to study a particular disease process or clinical intervention in women and reported primary endpoints that were sex-specific. We have included articles on the representation of women …

Cardiovascular disease (CVD) is the leading cause of death in women, and knowledge of the clinical consequences of atherosclerosis and CVD in women has grown tremendously over the past 20 years. Research efforts have increased and many reports on various aspects of ischaemic heart disease (IHD) in women have been published highlighting sex differences in pathophysiology, presentation, and treatment of IHD. Data, however, remain limited. A description of the state of the science, with recognition of the shortcomings of current data, is necessary to guide future research and move the field forward. In this report, we identify gaps in existing literature and make recommendations for future research. Women largely share similar cardiovascular risk factors for IHD with men; however, women with suspected or confirmed IHD have less coronary atherosclerosis than men, even though they are older and have more cardiovascular risk factors than men. Coronary endothelial dysfunction and microvascular disease have been proposed as important determinants in the aetiology and prognosis of IHD in women, but research is limited on whether sex differences in these mechanisms truly exist. Differences in the epidemiology of IHD between women and men remain largely unexplained, as we are still unable to explain why women are protected towards IHD until older age compared with men. Eventually, a better understanding of these processes and mechanisms may improve the prevention and the clinical management of IHD in women.

Mortality among workers in the Finnish pulp and paper industry was evaluated in a retrospective cohort study of 3520 workers who had been employed continuously for at least one year between 1945 and 1961. Six subcohorts were formed according to six work areas: sulphite, sulphate, paper, and board mills, maintenance department, and power plant. National mortality rates were used for comparison. The mortality of a cohort of 1290 sawmill workers was also studied in order to have a socially, geographically, and occupationally similar group without the exposures typical of the pulp and paper industry for comparison. Smoking habits were surveyed. Mortality was followed up until 31 December 1981. Overall mortality for the entire cohort did not differ from that expected (1044 obs, 1029.4 exp, SMR 101), but there was an excess of deaths from diseases of the circulatory system among the men (489 obs, 404.9 exp, SMR 121). This was due to the excess of deaths from ischaemic heart disease found among the men at the sulphite, sulphate, and paper mills, maintenance department, and power plant, but not at the sawmill. The existing smoking data did not explain this finding and it may therefore be associated with occupational exposures.

The different studies published and indexed in Medline and in the Spanish Medical Index (IME) from 1984 up to 1998 (IME: 1971-1996) are reviewed. To start with, an assessment was made of the number of publications put out which have to do with the impact of pollution on human health as well as the percentage thereof which analyze the mortality as a health indicator. Afterward, the original works published within the January 1994-June 1998 period were reviewed in detail. Most of the original articles are combined time series studies which analyze, on a single-day basis, the relationship between the levels of pollution and the mortality for non-accidental causes. Other original articles were also summarized based on an approach other than the time series one, highlighting different cohort studies which relate the levels of pollution to the mortality on an individual level and which confirm the findings of prior ecological studies. The pollutants analyzed most often are the different types of particles, although studies are also common regarding the impact of sulfur dioxide, nitrogen dioxide, ozone and carbon monoxide. The method of analysis most used is the Poisson regression, into which different confusion variables bearing an impact thereon such as seasonality and tendency, temperature and relative humidity and day of the year are basically added. In the studies reviewed, the positive significant findings prevail, being consistent especially for particles, which is the pollutant most analyzed. The articles studying other pollutants, although fewer in number, also indicate a significant relationship between pollution levels and the mortality.

Cause specific mortality was analysed among 883 white male workers from a paper company in Berlin, New Hampshire. Subjects were assigned to different exposure groups on the basis of their having worked in the pulp mill, the paper mill, or elsewhere in the paper company. A standardised mortality ratio (SMR) analysis was used to compare death rates for each of the exposure groups with United States national rates. For all the subjects, deaths due to all causes, all malignant neoplasms, and lung cancer were close to the number expected and excesses were noted for cancers of the digestive system and leukaemia. Among pulp mill workers, the number of cancers of the digestive system was raised and the SMR for pancreatic cancer was especially high (SMR = 305, 95% CI = 98-712). Among paper mill workers, more deaths were due to leukaemia and cancers of the digestive system than expected. These results are consistent with the findings from other studies that employment in pulp and paper mills is associated with excess mortality due to digestive and lymphopoietic cancers.

Mortality among workers in the Finnish pulp and paper industry was evaluated in a retrospective cohort study of 3520 workers who had been employed continuously for at least one year between 1945 and 1961. Six subcohorts were formed according to six work areas: sulphite, sulphate, paper, and board mills, maintenance department, and power plant. National mortality rates were used for comparison. The mortality of a cohort of 1290 sawmill workers was also studied in order to have a socially, geographically, and occupationally similar group without the exposures typical of the pulp and paper industry for comparison. Smoking habits were surveyed. Mortality was followed up until 31 December 1981. Overall mortality for the entire cohort did not differ from that expected (1044 obs, 1029.4 exp, SMR 101), but there was an excess of deaths from diseases of the circulatory system among the men (489 obs, 404.9 exp, SMR 121). This was due to the excess of deaths from ischaemic heart disease found among the men at the sulphite, sulphate, and paper mills, maintenance department, and power plant, but not at the sawmill. The existing smoking data did not explain this finding and it may therefore be associated with occupational exposures.

Background The second coronavirus disease (COVID-19) epidemic wave in the UK progressed aggressively and was characterised by the emergence and circulation of variant of concern alpha (VOC 202012/01). The impact of this variant on in-hospital COVID-19-specific mortality has not been widely studied. We aimed to compare mortality, clinical characteristics, and management of COVID-19 patients across epidemic waves to better understand the progression of the epidemic at a hospital level and support resource planning. Methods We conducted an analytical, dynamic cohort study in a large hospital in South London. We included all adults (≥ 18 years) with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who required hospital admission to COVID-19-specific wards between January 2020 and March 2021 (n = 2701). Outcome was COVID-19-specific in-hospital mortality ascertained through Medical Certificate Cause of Death. Results In the second wave, the number of COVID-19 admissions doubled, and the crude mortality rate dropped 25% (1.66 versus 2.23 per 100 person-days in second and first wave, respectively). After accounting for age, sex, dexamethasone, oxygen requirements, symptoms at admission and Charlson Comorbidity Index, mortality hazard ratio associated with COVID-19 admissions was 1.62 (95% CI 1.26, 2.08) times higher in the second wave. Conclusions Although crude mortality rates dropped during the second wave, the multivariable analysis suggests a higher underlying risk of death for COVID-19 admissions in the second wave. These findings are ecologically correlated with an increased circulation of SARS-CoV-2 variant of concern 202012/1 (alpha). Availability of improved management, particularly dexamethasone, was important in reducing risk of death.

Background and aim Pneumonia remains one of the most frequent death causes worldwide. Among the etiological factors S. pneumoniae-causing lobar pneumonia plays a leading role. According to current textbook knowledge at least three sequential stages of lobar pneumonia are distinguished: congestion, red hepatization and gray hepatization. However, there are no detailed data supporting this stage concept. There are also controversial views on its etiology. In this study, the lung changes in lobar pneumonia were related to the cause and duration of the disease. In addition, the complications of the disease were evaluated. PCR studies verified the etiology of pneumonia. Material and methods Lobar pneumonia was analyzed in 252 post mortem cases examined in a large hospital in Irkutsk. The pathology, etiology of pneumonia, course of disease and cause of death were recorded and correlated to its clinical course and duration. In the second part of the study, the results in 95 patients were analyzed in detail and related to PCR findings. Results Most patients were adult men of low social status who showed signs of severe alcoholism. Lobar pneumonia was observed in 85% of the patients, while the remaining patients showed sublobar (“lobular”, focal) lung involvement. Histologically, three patterns of inflammation were observed, which in most patients occurred concurrently in different parts of the involved lobe: “congestion”, characterized by serous exudation with multiple cocci (41% of cases), “red hepatization” (41% of cases) and “gray hepatization” (100% of cases). The latter pattern was subdivided into three subgroups according to the ratio of fibrin—neutrophils and the presence of macrophages. The mean number of different histological patterns observed per patient was 3.8. There was no correlation between the inflammatory patterns and the duration of the disease. In 23% of the patients, the cause of death was of pulmonary origin, while the remaining patients died of extrapulmonary complications (i.e. acute heart failure 26%, acute vascular insufficiency 15% purulent meningitis 11–24.3%. In 29/95 patients (20 with lobar and 9 with focal pneumonia) pneumococcal etiology of pneumonia was established by PCR. Conclusion Lobar pneumonia is a distinct clinico-pathological entity caused by S. pneumoniae, demonstrated by PCR testing and/or cytological examinations. Bacteriologic studies frequently give falsenegative results. Lobar pneumonia is characterized by three main histopathological patterns (congestion or microbeous edema, and red and gray hepatization) which usually occur side by side and not in chronological order. Early death is often related to heart failure and septic shock, while meningitis is a frequent complication later in the course.

Children are known to be better protected from COVID-19 than adults, but their susceptibility patterns and the risk relative to other diseases are insufficiently defined. Here, we found that the COVID-19 mortality rate is U-shaped in childhood: it initially decreases, reaching the minimum at the ages 3-10 years, and then increases throughout life. All-cause mortality and mortality from other diseases, such as pneumonia and influenza, show a similar pattern; however, childhood mortality rates from COVID-19 are considerably lower than from other diseases, with the best relative protection achieved at the youngest ages. Consistent with this, the fraction of COVID-19 deaths among all deaths increases as a function of age throughout childhood and the entire life. We discuss implications of the elevated postnatal COVID-19 risk and lower childhood COVID-19 mortality compared to other diseases.

Introduction Tobacco is the leading cause of death and disease in India. This study examines the effect of training intervention in behavioral counseling on intention to quit tobacco in primary healthcare settings in India. The intervention included training to improve behavioral counseling practices of primary care physicians (PCPs) based on the 5As approach to increase patients' motivation to quit tobacco. Methods A quasi-experimental design was used for the study. The intervention consists of training of primary care physicians in the behavioral intervention in tobacco cessation. The intervention was conducted in twelve districts of two states in India (Rajasthan and Odisha) in 2016-2017. Four districts were randomly sampled for the study. A total of 1314 participants (intervention and control) were recruited for the study in the baseline and end-line surveys, respectively. Intention to quit in 30 days was the primary outcome measure. Difference-in-difference (DiD) logistic regression models were used separately for smokers and smokeless tobacco users to estimate the odds of intention to quit. Analysis was done in STATA Version 14. Results The intervention and time variable had a significantly positive influence on the intention to quit tobacco among smokers. Smokers in the intervention districts had higher odds of intention to quit (OR=9.82; 95% CI: 1.67-57.72) compared to smokers in the control districts. Smokeless tobacco (SLT) users had higher odds of intention to quit (OR=3.06; 95% CI: 1.35-6.98) in the end-line survey compared to baseline survey. Conclusions Our findings indicate that building capacity in behavioral intervention in primary care settings can help increase the intention to quit among smokers. The observed difference in intention to quit between smokers and SLT users suggests the need of tailored counseling interventions for SLT users. There is a need for further research to design and evaluate training and behavioral interventions for SLT and dual (smoking and SLT) users in primary care settings in low- and middle-income countries.

Aim The authors set out to evaluate the correlations between three of the main morphological aortic parameters (aortic diameter, intima, and media thickness) and the cause of death. Materials and methods Study group included 28 people died of a cardiovascular (CV) disease and 62 people died of a noncardiovascular (NCV) disease. Four aortic cross-sections (base, cross, thoracic, abdominal) were collected during autopsy from the selected cases, fixed in 10% buffered formalin and photographed together with a calibrating ruler. Then, they were processed using the classical histopathological (HP) technique (formalin fixation and paraffin embedding), stained with Hematoxylin-Eosin (HE) and Orcein, and the obtained histological slides were transformed into virtual slides. Aortic diameters were determined on calibrated photos using a custom-made software, developed in MATLAB (MathWorks, USA). Intima and media thicknesses were determined on virtual slides using a dedicated image analysis software. Results and discussions The most frequent CV causes of death were the ischemic heart diseases and the most frequent NCV causes of death were the inflammatory diseases. Aortic diameter decreased from the aortic origin till the aortic end, with larger values in women than in men and in CV diseases than in NCV diseases. The difference in the remodeling of the aortic diameter between the two groups is smaller towards the abdominal region. Intima thickness increased from the aortic origin till the aortic end and was larger especially in women died of CV diseases, whereas in men there were some shifts at the extremities of the aorta. The difference in the remodeling of the intimal thickness between the two groups is extremely variable. Media was thicker in almost all of its segments in CV group than in NCV. It was a divergent evolution of the correlation degree trends in the two groups. Conclusions The three morphological parameters of the aorta (diameter, intima, and media thicknesses) are more or less influenced by the pathological status that caused patient's death by the patient's sex and by the topographic region where the measurement was made.

Drug overdose remains a leading cause of death in the US, with growing rates attributable to illicit fentanyl use. Recent HIV outbreaks among people who inject drugs (PWID) and service disruptions from COVID-19 have renewed concerns on HIV resurgence. We examined the relationship between fentanyl use and three injection-related HIV risk behaviors among PWID in Baltimore City (BC) and Anne Arundel Country (AAC), Maryland. PWID (N = 283) were recruited to the study through targeted sampling at street-based locations in BC and AAC from July 2018 to March 2020. Receptive syringe sharing (RSS) [adjusted odds ratio (AOR): 2.8, 95% confidence interval (CI): 1.2-6.3] and daily injecting (AOR: 1.9, 95% CI: 1.0-3.6) were associated with injecting fentanyl and cocaine together. Fentanyl availability and COVID-19 bring new HIV prevention challenges, particularly among those who inject fentanyl with cocaine, highlighting the importance to expand and sustain harm reduction, prevention, and treatment services for PWID to reduce HIV and overdose burden.

Postmortem computed tomography (PMCT) is integrated into the evaluation of decedents in several American medical examiner offices and medicolegal death investigative centers in many other countries. We retrospectively investigated the value of PMCT in a series of firearm homicide cases from a statewide centralized medical examiner’s office that occurred during 2016. Autopsies were performed or supervised by board‐certified forensic pathologists who reviewed the PMCT scans prior to autopsy. PMCT scans were re‐evaluated by a forensic radiologist blinded to the autopsy findings and scored by body region (head–neck, thoracoabdominal, and extremities). Injury discrepancies were scored using a modified Goldman classification and analyzed with McNemar’s test. We included 60 males and 20 females (median age 31 years, range 3–73). Based on PMCT, 56 (79.1%) cases had injuries relevant to the cause of death in a single body region (24 head–neck region, 32 thoracoabdominal region). Out of these 56 cases, 9 had a missed major diagnosis by PMCT outside that region, including 6 extremity injuries visible during standard external examination. Yet all had evident lethal firearm injury. We showed that PMCT identifies major firearm injuries in homicide victims and excludes injuries related to the cause of death in other regions when a single body region is injured. Although PMCT has a known limited sensitivity for soft tissue and vascular pathology, it can be combined with external examination to potentially reduce or focus dissections in some of these cases depending on the circumstances and medicolegal needs.

Introduction: Falls are a leading cause of death among Chinese oldest olds. However, studies on Chinese community-dwelling older adults are lacking. We aimed to identify the associations of falls and severe falls with blood pressure and frailty among Chinese community-dwelling oldest olds. Methods: Cross-sectional analyses were conducted with 6,595 community-dwelling oldest olds (aged ≥80 years) from 22 Chinese provinces from the Chinese Longitudinal Health and Longevity Study (CLHLS). Systolic BP (SBP) and diastolic BP (DBP) were measured twice at participants’ homes, and a 38-item frailty index was used to assess the frailty status of participants. Falls and severe falls were confirmed through face-to-face interviews. Multivariate logistic regression was used to investigate the associations of BP and frailty with falls and severe falls. Results: The mean participant age was 91.0 years, and 56.1% were female. In total, 24.2% participants had a history of fall and 8.3% had a history of severe falls. The multivariate-adjusted odds ratio (OR) for falls among the oldest old with SBP ≥140 mm Hg compared to those with an SBP of 120–129 mm Hg was 1.20 (95% confidence interval [CI], 1.01–1.44). The adjusted OR for falls among frail participants compared to robust participants was 1.39 (95% CI, 1.02–1.89). DBP and pre-frailty were not associated with falls after multivariate adjustment. SBP, DBP, and frailty status were not associated with severe falls after multivariate adjustment. Conclusions: SBP and frailty but not DBP and pre-frailty are associated with increased odds of falls among Chinese community-dwelling oldest olds.

Liver metastasis is a leading cause of death in patients with colorectal cancer (CRC). Increasing evidence demonstrates that competing endogenous RNA (ceRNA) networks play important roles in malignant cancers. The purpose of this study was to identify molecular markers and build a ceRNA network as a significant predictor of colorectal liver metastases (CRLM). By integrated bioinformatics analysis, we found that apolipoprotein C1 (APOC1) was upregulated in CRLM and associated with prognosis in patients with CRC and thereby established an APOC1-dependent ceRNA network. By survival analysis, expression analysis, and correlation analysis of each element in the ceRNA network, we identified that ZEB1-AS1, miR-335-5p and APOC1 regulated each other. We further experimentally confirmed that ZEB1-AS1 promoted a CRC progression via regulating the expression of miR-335-5p that controlled the expression of APOC1. Our findings indicate that the ZEB1-AS1-miR-335-5p-APOC1 ceRNA regulatory network is significantly valuable for better prognosis of patients with CRC and as a new therapeutic target for the treatment of CRLM.

IntroductionCOVID-19 deaths are commoner among care-home residents, but the mortality burden has not been quantified.MethodsCare-home residency was identified via a national primary care registration database linked to national mortality data. Life expectancy was estimated using Makeham-Gompertz models, to (i) describe yearly life expectancy from Nov 2015 to Oct 2020 (ii) compare life expectancy (during 2016-2018) between care-home residents and the wider Scottish population and (iii) apply care-home life expectancy estimates to COVID-19 death counts to estimate years of life lost (YLL).ResultsAmong care-home residents, life expectancy in 2015/16 to 2019/20 ranged from 2.7 to 2.3 years for women and 2.3 to 1.8 years for men. Life expectancy was lowest in 2019/20. Age-sex specific life expectancy in 2016-2018 in care-home residents was lower than in the Scottish population (10 and 2.5 years in those aged 70 and 90 respectively). Rather than using national life tables, applying care-home specific life expectancies to COVID-19 deaths yields, mean YLLs for care-home residents were 2.6 and 2.2 for women and men respectively, with total care-home resident YLLs of 3,560 years in women and 2,046 years in men. In people aged over-70, approximately half of deaths and a quarter of YLL attributed to COVID-19 were accounted for by the 5% of over-70s who were care-home residents.ConclusionPrioritising care-home residents for vaccination is justified not only in terms of total deaths, but also in terms of years of life lost.Research in contextEvidence before this studyWe searched PubMed to 1st December 2020, with the terms (“nursing home” OR “care-home” OR “long-term care” OR “residential care”) AND (“mortality” OR “life expectancy” OR “length of stay”). We also searched for studies specific to the impact of the COVID-19 pandemic on those living in care-homes. We restricted our search to publications in English. Usual care-home life expectancy, in a UK context, has not previously been defined. One systematic review of length of stay was identified, which found significant heterogeneity in factors and associations. The impact of COVID-19 on excess mortality among care-home residents was noted, but the impact on life expectancy was not reported. Studies evaluating life expectancy among older people in the COVID-19 pandemic have not taken account of residency in their estimates.Added value of this studyUsing Scottish national representative linked data we describe the usual life expectancy of older adults (aged ≥70 years) living in care-homes, compared to older people living elsewhere. Deaths among care-home residents account for a considerable proportion of all mortality in older adults, around 19% for men and 30% for women. Life expectancy in care-home residents during the pandemic fell by almost 6 months, from 2.7 to 2.3 years in men and 2.1 to 1.8 years in women. In total, over 5,600 Years of Life were Lost (YLL) by care-home residents in Scotland who died with COVID-19. Around half of COVID-19 deaths and a quarter of YLL in those aged 70 years and over occurred among care-home residents. During the COVID-19 pandemic a smaller proportion of deaths among care-home residents occurred in hospitals.Implications of all the available evidencePrioritising the 5% of older adults who are care-home residents for vaccination against COVID-19 is justified both in terms of total deaths and total years of life lost. Individual and societal planning for care needs in older age relies on understanding usual care-home life expectancy and patterns of mortality. Understanding life expectancy may help clinicians, residents and their families make decisions about their health care, facilitating more informed discussions around their priorities and wishes. Population-wide estimates of YLL and burden of disease should take account of residency status, given the significant differences between life expectancy of those living in care-homes from their peers in other settings.

Features of the deaths caused by COPD (chronic obstructive pulmonary disease) in cancer patients remained a controversial issue. This study aimed to characterize the demographic characteristics and mortality rates of the deaths from COPD in patients with cancer. In total, 7,846,370 cancer patients aged 40 years or older in the United States were identified from the Surveillance, Epidemiology, and End Results database (1975-2016). Mortality rates and SMRs (standardized mortality ratios) adjusted by age, race, sex, and calendar year were calculated to investigate the risk of COPD deaths in cancer survivors and to compare it with the general population. A total of 119,228 COPD deaths in patients with cancer were recorded, with a mortality rate of 261.5/100,000 person-years, nearly two-fold that of the general population (SMR, 2.17; 95% CI [confidence interval], 2.16-2.18). The proportion of cancer survivors dying from COPD increased from 0.9% in 1975 to 3.4% in 2016. Patients with lung cancer had a higher overall risk (SMR, 9.23; 95% CI, 9.12-9.35) than those with extrapulmonary malignancies. Among all extrapulmonary sites, laryngeal (SMR, 5.54; 95% CI, 5.34-5.75) and esophageal cancers (SMR, 4.33; 95% CI, 4.04-4.63) had the highest SMR. The risk of death from COPD increased with follow-up time.