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Aging; Arteriosclerosis; Hemodynamics Envelliment; Arteriosclerosi; Hemodinàmica Envejecimiento; Arteriosclerosis; Hemodinámica Arterial pulse waves (PWs) such as blood pressure and photoplethysmogram (PPG) signals contain a wealth of information on the cardiovascular (CV) system that can be exploited to assess vascular age and identify individuals at elevated CV risk. We review the possibilities, limitations, complementarity, and differences of reduced-order, biophysical models of arterial PW propagation, as well as theoretical and empirical methods for analyzing PW signals and extracting clinically relevant information for vascular age assessment. We provide detailed mathematical derivations of these models and theoretical methods, showing how they are related to each other. Finally, we outline directions for future research to realize the potential of modeling and analysis of PW signals for accurate assessment of vascular age in both the clinic and in daily life. This article is based upon work from COST Action “Network for Research in Vascular Ageing” (VascAgeNet, CA18216), supported by COST (European Cooperation in Science and Technology, www.cost.eu). This work was supported by British Heart Foundation Grants PG/15/104/31913 (to J.A. and P.H.C.), FS/20/20/34626 (to P.H.C.), and AA/18/6/34223, PG/17/90/33415, SPG 2822621, and SP/F/21/150020 (to A.D.H.); Kaunas University of Technology Grant INP2022/16 (to B.P.); European Research Executive Agency, Marie-Sklodowska Curie Actions Individual Fellowship Grant 101038096 (to S.P.); Istinye University, BAP Project Grant 2019B1 (to S.P.); “la Caixa” Foundation Grant LCF/BQ/PR22/11920008 (to A.G.); and National Institute for Health and Care Research Grant AI AWARD02499 and EU Horizon 2020 Grant H2020 848109 (to A.D.H.).

Context Data on long-term safety of growth hormone (GH) replacement in adults with GH deficiency (GHD) are needed. Objective We aimed to evaluate the safety of GH in the full KIMS (Pfizer International Metabolic Database) cohort. Methods The worldwide, observational KIMS study included adults and adolescents with confirmed GHD. Patients were treated with GH (Genotropin [somatropin]; Pfizer, NY) and followed through routine clinical practice. Adverse events (AEs) and clinical characteristics (eg, lipid profile, glucose) were collected. Results A cohort of 15 809 GH-treated patients were analyzed (mean follow-up of 5.3 years). AEs were reported in 51.2% of patients (treatment-related in 18.8%). Crude AE rate was higher in patients who were older, had GHD due to pituitary/hypothalamic tumors, or adult-onset GHD. AE rate analysis adjusted for age, gender, etiology, and follow-up time showed no correlation with GH dose. A total of 606 deaths (3.8%) were reported (146 by neoplasms, 71 by cardiac/vascular disorders, 48 by cerebrovascular disorders). Overall, de novo cancer incidence was comparable to that in the general population (standard incidence ratio 0.92; 95% CI, 0.83-1.01). De novo cancer risk was significantly lower in patients with idiopathic/congenital GHD (0.64; 0.43-0.91), but similar in those with pituitary/hypothalamic tumors or other etiologies versus the general population. Neither adult-onset nor childhood-onset GHD was associated with increased de novo cancer risks. Neutral effects were observed in lipids/fasting blood glucose levels. Conclusion These final KIMS cohort data support the safety of long-term GH replacement in adults with GHD as prescribed in routine clinical practice.

The effect of physical activity on breast cancer risk may be partly mediated by sex steroid hormones. This review synthesized and appraised the evidence for an effect of physical activity on sex steroid hormones. Systematic searches were performed using MEDLINE (Ovid), EMBASE (Ovid), and SPORTDiscus to identify experimental studies and prospective cohort studies that examined physical activity and estrogens, progestins, and/or androgens, as well as sex hormone binding globulin (SHBG) and glucocorti-coids in pre- and postmenopausal women. Meta-analyses were performed to generate effect estimates. Risk of bias was assessed, and the GRADE system was used to appraise quality of the evidence. Twenty-eight randomized controlled trials (RCT), 81 nonrandomized interventions, and six observational studies were included. Estrogens, progesterone, and androgens mostly decreased, and SHBG increased, in response to physical activity. Effect sizes were small, and evidence quality was graded moderate or high for each outcome. Reductions in select sex steroid hormones following exercise supports the biological plausibility of the first part of the physical activity-sex hormone-breast cancer pathway. The con-firmed effect of physical activity on decreasing circulating sex steroid hormones supports its causal role in preventing breast cancer.

Introduction Hormonal contraception is a well-known risk factor for venous thromboembolism (VTE). APC resistance and impaired functions of protein S and TFPI are thought to play an important role in the pathogenesis of hormone-related VTE. It is unknown, whether women, who develop VTE during hormonal contraception possess a vulnerability in these pathways, making them susceptible to thrombosis. Materials and methods Plasma samples were obtained from 57 premenopausal women in average 15.3 years after hormone-associated VTE and from 31 healthy controls. Thrombin generation at high tissue factor (TF) in the absence and in the presence of activated protein C (APC) and at low TF without and with inhibiting anti-protein S- and anti-TFPI-antibodies was measured via calibrated automated thrombography. Results Women with previous hormone-related thrombosis had higher thrombin generation at low TF, higher APC resistance, protein S- and TFPI ratios, differences: 219.9 nM IIa.min (95%CI:90.4 to 349.3); 1.88 (95%CI:0.71 to 3.05); 0.13 (95%CI:0.01 to 0.26) and 0.19 (95%CI:0.08 to 0.30), respectively. Thrombin generation at high TF without APC did not differ between the groups. Smoking decreased thrombin generation at low TF by −222.6 nM IIa.min (95%CI: −381.1 to −64.1), the APC sensitivity ratio by −2.20 (95%CI: −3.63 to −0.77) and the TFPI ratio by −0.16 (95%CI: −0.29 to −0.03), but did not influence thrombin generation at high TF. Discussion We demonstrated impairment of the protein S/TFPI system and increased APC resistance in women with previous hormone-induced VTE. Smoking decreased thrombin generation at assay conditions, dependent on the function of the TFPI system.

Background: Cannabis legalization and use have risen globally. However, the association between cannabis use, eating behaviors and body weight among adolescents is yet unexplored. Objectives: This study examined the association between cannabis use, fast-food consumption, overweight and obesity in 28 countries using data from the 2010–2016 Global School-Based Student Health Survey. Methods: Multivariable logistic regression and meta-analysis were performed among a sample of 83,726 adolescents (48.7% females) aged 12–15 years, mean (SD) age of 13.8 (0.9) years. Results: The overall prevalence of cannabis use (in past 30 days) and fast-food consumption (in past 7 days) were 2.8% and 57.3% respectively. The overall prevalence of overweight and obesity was 14.7% and 4.2%, respectively. Cannabis use was significantly associated with fast-food consumption (OR = 1.33; 95%CI = 1.13–1.57) but not with overweight (OR = 0.95; 95%CI = 0.80–1.14) or obesity (OR = 1.16; 95%CI = 0.85–1.59). For obesity, there was a moderate level of between-country heterogeneity (I 2 = 51.9%) and significant positive associations with cannabis use were observed in Bahamas, Bangladesh, Namibia and Nepal. Conclusion: The results highlight the association between cannabis use and dietary risks, providing evidence for public health interventions on the interrelated nature of cannabis use and fast-food consumption.

Over the past 50 years, many countries around the world have faced an unchecked pandemic of obesity and type 2 diabetes (T2DM). As best practice treatment of T2DM has done very little to check its growth, the pandemic of diabesity now threatens to make health-care systems economically more difficult for governments and individuals to manage within their budgets. The conventional view has been that T2DM is irreversible and progressive. However, in 2016, the World Health Organization (WHO) global report on diabetes added for the first time a section on diabetes reversal and acknowledged that it could be achieved through a number of therapeutic approaches. Many studies indicate that diabetes reversal, and possibly even long-term remission, is achievable, belying the conventional view. However, T2DM reversal is not yet a standardized area of practice and some questions remain about long-term outcomes. Diabetes reversal through diet is not articulated or discussed as a first-line target (or even goal) of treatment by any internationally recognized guidelines, which are mostly silent on the topic beyond encouraging lifestyle interventions in general. This review paper examines all the sustainable, practical, and scalable approaches to T2DM reversal, highlighting the evidence base, and serves as an interim update for practitioners looking to fill the practical knowledge gap on this topic in conventional diabetes guidelines.

Heart failure with preserved ejection fraction (HFpEF) is a condition with increasing incidence, leading to a health care problem of epidemic proportions for which no curative treatments exist. Consequently, an urge exists to better understand the pathophysiology of HFpEF. Accumulating evidence suggests a key pathophysiological role for coronary microvascular dysfunction (MVD), with an underlying mechanism of low-grade pro-inflammatory state caused by systemic comorbidities. The systemic entity of comorbidities and inflammation in HFpEF imply that patients develop HFpEF due to systemic mechanisms causing coronary MVD, or systemic MVD. The absence or presence of peripheral MVD in HFpEF would reflect HFpEF being predominantly a cardiac or a systemic disease. Here, we will review the current state of the art of cardiac and systemic microvascular dysfunction in HFpEF (Graphical Abstract), resulting in future perspectives on new diagnostic modalities and therapeutic strategies.

Heart failure with preserved ejection fraction (HFpEF) is a condition with increasing incidence, leading to a health care problem of epidemic proportions for which no curative treatments exist. Consequently, an urge exists to better understand the pathophysiology of HFpEF. Accumulating evidence suggests a key pathophysiological role for coronary microvascular dysfunction (MVD), with an underlying mechanism of low-grade pro-inflammatory state caused by systemic comorbidities. The systemic entity of comorbidities and inflammation in HFpEF imply that patients develop HFpEF due to systemic mechanisms causing coronary MVD, or systemic MVD. The absence or presence of peripheral MVD in HFpEF would reflect HFpEF being predominantly a cardiac or a systemic disease. Here, we will review the current state of the art of cardiac and systemic microvascular dysfunction in HFpEF (Graphical Abstract), resulting in future perspectives on new diagnostic modalities and therapeutic strategies.

Background Migraine has been associated with several diseases. This population-based prospective Finnish postal survey Health and Social Support Study explored whether self-reported migraine predicted incident hypertension independently in a working-age population by utilizing two data sources: the baseline survey from the year 1998 in combination with the follow-up survey data from the years 2003 and 2012 with linkage to the national Social Insurance Institution registry data of the special reimbursement medication for hypertension from 1999 to 2013. The survey follow-up reached until the second follow-up in the year 2012. The register follow-up also included the year 2013. Methods The present population-based prospective cohort study, utilizing two different data sources, included 8593 respondents (22.7% response rate) who participated in 1998, 2003, and 2012 but who did not report hypertension at the baseline in 1998, and whose responses could be linked with the Social Insurance Institution registry data from the beginning of 1999 to the end of 2013. The multivariable logistic regression analysis was based on the combined two data sets. Results A significant association of self-reported migraine and incident hypertension (odds ratio 1.37; 95% confidence interval 1.20–1.57) prevailed in the multiple logistic regression analysis adjusted for central socio-demographic and health behaviour variables. Conclusion Extra attention should be paid to prevention and control of hypertension in working-age migraine patients.

Objective: The aim of this study is to look at the relationship between hyperthyrotropinemia and anthropometric measurements as well as cardiometabolic risk factors in obese children and adolescents. Materials and Methods: A total of 100 patients with isolated hyperthyrotropinemia and 124 patients with normal thyroid functions, between 10 and 18 years of age, were included in the study. Anthropometric and blood pressure measurements and biochemical parameters were recorded. Non-high-density lipoprotein cholesterol, total cholesterol/high-density lipoprotein cholesterol, and triglyceride/high-density lipoprotein cholesterol ratios were calculated. Results: The subjects' mean age was 12.6 +/- 1.9 years and their mean body mass index was 29.8 +/- 4 kg/m2. The isolated hyperthyrotropinemia group had considerably greater levels of triglyceride, non-high-density lipoprotein cholesterol, and the triglyceride/high-density lipoprotein cholesterol ratio. Higher prevalences of hypertriglyceridemia and increased triglyceride/ high-density lipoprotein cholesterol ratio were found in the group with isolated hyperthyrotropinemia. Thyroid-stimulating hormone had a statistically significant positive relationship with triglyceride, non-high-density lipoprotein cholesterol, total cholesterol/high-density lipoprotein cholesterol ratio, and triglyceride/high-density lipoprotein cholesterol ratio, as well as an inverse relationship with high-density lipoprotein cholesterol. Thyroid-stimulating hormone was positively correlated with triglyceride and triglyceride/high-density lipoprotein cholesterol ratio in both females and males; however, only in females, thyroid-stimulating hormone was positively correlated with non-high-density lipoprotein cholesterol and total cholesterol/highdensity lipoprotein cholesterol ratio. The triglyceride/high-density lipoprotein cholesterol ratio, as well as the rates of hypertriglyceridemia were higher in children with isolated hyperthyrotropinemia in the female subgroup. Male children with isolated hyperthyrotropinemia had significantly higher triglyceride levels in comparison with males with normal thyroid-stimulating hormone. Conclusion: The present study suggested that isolated hyperthyrotropinemia is associated with the deterioration of lipid metabolism, especially in females. Since dyslipidemia is accepted as a cardiovascular disease risk factor, isolated hyperthyrotropinemia might negatively influence cardiovascular functions in obese children and adolescents.

IntroductionPreeclampsia, an endothelial disorder of pregnancy, predisposes to remote cardiovascular diseases (CVD). Whether there is an accelerated effect of aging on endothelial decline in former preeclamptic women is unknown. We investigated if the arterial aging regarding endothelial-dependent and -independent vascular function is more pronounced in women with a history of preeclampsia as compared to women with a history of solely normotensive gestation(s).MethodsData was used from the Queen of Hearts study (ClinicalTrials.gov Identifier NCT02347540); a large cross-sectional study on early detection of cardiovascular disease among young women (≥18 years) with a history of preeclampsia and a control group of low-risk healthy women with a history of uncomplicated pregnancies. Brachial artery flow-mediated dilation (FMD; absolute, relative and allometric) and sublingually administered nitroglycerine-mediated dilation (NGMD; absolute and relative) were measured using ultrasound. Cross-sectional associations of age with FMD and NGMD were investigated by linear regression. Models were adjusted for body mass index, smoking, antihypertensive drug use, mean arterial pressure, fasting glucose, menopausal state, family history of CVD and stress stimulus during measurement. Effect modification by preeclampsia was investigated by including an interaction term between preeclampsia and age in regression models.ResultsOf the 1,217 included women (age range 22–62 years), 66.0% had a history of preeclampsia and 34.0% of normotensive pregnancy. Advancing age was associated with a decrease in relative FMD and NGMD (unadjusted regression coefficient: FMD: −0.48%/10 years (95% CI:−0.65 to −0.30%/10 years), NGMD: −1.13%/10 years (−1.49 to −0.77%/10 years)) and increase in brachial artery diameter [regression coefficient = 0.16 mm/10 years (95% CI 0.13 to 0.19 mm/10 years)]. Similar results were found when evaluating FMD and NGMD as absolute increase or allometrically, and after confounder adjustments. These age-related change were comparable in former preeclamptic women and controls (p-values interaction ≥0.372). Preeclampsia itself was independently associated with consistently smaller brachial artery diameter, but not with FMD and NGMD.ConclusionIn young- to middle-aged women, vascular aging in terms of FMD and NGMD was not accelerated in women after preeclampsia compared to normotensive pregnancies, even though former preeclamptic women consistently have smaller brachial arteries.

The effect of physical activity on breast cancer risk may be partly mediated by sex steroid hormones. This review synthesized and appraised the evidence for an effect of physical activity on sex steroid hormones. Systematic searches were performed using MEDLINE (Ovid), EMBASE (Ovid), and SPORTDiscus to identify experimental studies and prospective cohort studies that examined physical activity and estrogens, progestins, and/or androgens, as well as sex hormone binding globulin (SHBG) and glucocorticoids in pre- and postmenopausal women. Meta-analyses were performed to generate effect estimates. Risk of bias was assessed, and the GRADE system was used to appraise quality of the evidence. Twenty-eight randomized controlled trials (RCT), 81 nonrandomized interventions, and six observational studies were included. Estrogens, progesterone, and androgens mostly decreased, and SHBG increased, in response to physical activity. Effect sizes were small, and evidence quality was graded moderate or high for each outcome. Reductions in select sex steroid hormones following exercise supports the biological plausibility of the first part of the physical activity–sex hormone–breast cancer pathway. The confirmed effect of physical activity on decreasing circulating sex steroid hormones supports its causal role in preventing breast cancer. See related reviews by Lynch et al., p. 11 and Drummond et al., p. 28

Obesity and metabolic syndrome (O&MS) due to the worldwide obesity epidemic affects children at all stages of chronic kidney disease (CKD) including dialysis and after kidney transplantation. The presence of O&MS in the pediatric CKD population may augment the already increased cardiovascular risk and contribute to the loss of kidney function. The Pediatric Renal Nutrition Taskforce (PRNT) is an international team of pediatric renal dietitians and pediatric nephrologists who develop clinical practice recommendations (CPRs) for the nutritional management of children with kidney diseases. We present CPRs for the assessment and management of O&MS in children with CKD stages 2–5, on dialysis and after kidney transplantation. We address the risk factors and diagnostic criteria for O&MS and discuss their management focusing on non-pharmacological treatment management, including diet, physical activity, and behavior modification in the context of age and CKD stage. The statements have been graded using the American Academy of Pediatrics grading matrix. Statements with a low grade or those that are opinion-based must be carefully considered and adapted to individual patient needs based on the clinical judgment of the treating physician and dietitian. Research recommendations are provided. The CPRs will be periodically audited and updated by the PRNT. Supplementary Information The online version contains supplementary material available at 10.1007/s00467-021-05148-y.

Bleeding and thrombosis are major clinical problems with high morbidity and mortality. Treatment modalities for these diseases have improved in recent years, but there are many clinical questions remaining and a need to advance diagnosis, management, and therapeutic options. Basic research plays a fundamental role in understanding normal and disease processes, yet this sector has observed a steady decline in funding prospects thereby hindering support for studies of mechanisms of disease and therapeutic development opportunities. With the financial constraints faced by basic scientists, the ISTH organized a basic science task force (BSTF), comprising Scientific and Standardization Committee subcommittee chairs and co-chairs, to identify research opportunities for basic science in hemostasis and thrombosis. The goal of the BSTF was to develop a set of recommended priorities to build support in the thrombosis and hemostasis community and to inform ISTH basic science programs and policy making. The BSTF identified three principal opportunity areas that were of significant overarching relevance: mechanisms causing bleeding, innate immunity and thrombosis, and venous thrombosis. Within these, five fundamental research areas were highlighted: blood rheology, platelet biogenesis, cellular contributions to thrombosis and hemostasis, structure-function protein analyses, and visualization of hemostasis. This position paper discusses the importance and relevance of these opportunities and research areas, and the rationale for their inclusion. These findings have implications for the future of fundamental research in thrombosis and hemostasis to make transformative scientific discoveries and tackle key clinical questions. This will permit better understanding, prevention, diagnosis, and treatment of hemostatic and thrombotic conditions. ispartof: JOURNAL OF THROMBOSIS AND HAEMOSTASIS vol:20 issue:6 pages:1496-1506 ispartof: location:England status: published

The safety considerations of food-based solutions for vitamin D deficiency prevention, such as fortification and supplementation, are critical. On the basis of collective data from 20 randomized controlled trials (RCTs) and 20 national healthy surveys, as well as prospective cohort studies (PCSs) across the ODIN project (“Food-based solutions for optimal vitamin D nutrition and health through the life cycle”, FP7-613977), we analyzed the potential safety issues arising from vitamin D intakes and/or supplementation. These adverse consequences included high serum 25-hydroxyvitamin D (S-25(OH)D) concentrations (>125 nmol/L), high serum calcium concentrations, and vitamin D intakes in excess of the tolerable upper intake levels (ULs). In the RCTs (n = 3353, with vitamin D doses from 5–175 µg/day), there were no reported adverse effects. The prevalence of high S-25(OH)D was 125 nmol/L were rare in the RCTs and PCSs, and no associated adverse effects were observed.