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Purpose: All patients with metastatic breast cancer (MBC) expressing estrogen receptor-α (ESR1) will eventually develop resistance to endocrine therapies. In up to 40% of patients, this resistance is caused by activating mutations in the ligand-binding domain (LBD) of ESR1. Accumulating clinical evidence indicate adverse outcomes for these patients, beyond that expected by resistance to endocrine therapy. Here we aimed to study the role of ESR1 mutations in conferring chemoresistance in BC cells., Methods: MCF-7 cells harboring Y537S and D538G ESR1 mutations (mut-ER) were employed to study the response to chemotherapy drugs, paclitaxel and doxorubicin, using viability and apoptotic assay in vitro, and tumor growth in vivo. JNK/c-Jun/MDR1 pathway was studied using qRT-PCR, western-blot, gene-reporter and ChIP assays. MDR1 expression was analyzed in clinical samples using IHC., Results:  Cell harboring ESR1 mutations displayed relative chemoresistance compared to WT-ER, evidenced by higher viability and reduced apoptosis as well as resistance to paclitaxel in vivo. To elucidate the underlying mechanism, MDR1 expression was examined and elevated levels were observed in mut-ER cells, and in clinical BC samples. MDR1 is regulated by the c-Jun pathway, and we showed high correlation between these two genes in BC using TCGA databases. Accordingly, we detected higher JNK/c-Jun expression and activity in ESR1-mutated cells, as well as increased occupancy of c-Jun in MDR1 promoter. Importantly, JNK inhibition decreased MDR1 expression and restored sensitivity to chemotherapy., Conclusions: Taken together, these data indicate that ESR1 mutations confer chemoresistance through activation of the JNK/MDR1 axis. These finding suggest a novel treatment option for BC tumors expressing ESR1 mutations., Competing Interests: Declarations. Conflict of interest: The authors declare no potential conflicts of interest. Ethical approval: All procedures performed in studies involving human clinical samples were in accordance with a written informed consent obtained from the research subjects by the Tel Aviv Sourasky Medical Center, under an approved institutional review board (IRB) (0137–21-TLV). The experiments on animals were conducted in accordance with institutional guidelines of the Sourasky Medical Center in accordance with current regulations and standards of the institution Animal Care and Use Committee., (© 2024. The Author(s).)

Tuberculosis (TB) continues to be a major global health burden and kills over a million people annually. New immunization strategies are required for the development of an efficacious TB vaccine that can potentially induce sterilizing immunity. In this study, we first confirmed that a live vaccine strain of Mycobacterium smegmatis , previously designated as IKEPLUS, conferred a higher survival benefit than the Bacillus Calmette-Guerin (BCG) in a murine model of intravenous Mycobacterium tuberculosis (Mtb) infection. We have shown that there was a significant increase in the expression of the Rv0282 gene, which is encoded in the esx-3 locus, which played an important role in iron uptake when IKEPLUS was grown in both low zinc and iron-containing Sauton medium. We then confirmed using in vitro assays of biofilm formation that zinc plays a vital role in the growth and formation of M. smegmatis biofilms. IKEPLUS grown in low zinc media led to the better protection of mice after intravenous challenge with a very high dosage of Mtb. We also showed that various variants of IKEPLUS induced apoptotic cell-death of infected macrophages at a higher rate than wild-type M. smegmatis . We next attempted to determine if zinc containing ribosomal proteins such as rpmb2 could contribute to protective efficacy against Mtb infection. Since BCG has an established role in anti-mycobacterial efficacy, we boosted BCG vaccinated mice with rmpb2, but this did not lead to an increment in the protection mediated by BCG.

Monitoring the tumor margins of basal cell carcinomas is still a challenge in everyday clinical practice. Usually, the clinical margins of the tumor are marked by the naked eye or, even better, with dermoscopy before surgery and then examined in detail after the operation using histological examination. In order to achieve tumor freedom, several surgical steps are sometimes necessary, meaning that patients spend longer periods in hospital and the healthcare system is burdened more as a result. One way to improve this is the one-stop shop method, which requires precise diagnostics and margin marking before and during surgery so that tumor freedom can be achieved after just one surgery. For this reason, the current status of the diagnosis and treatment of basal cell carcinomas before and after surgery is to be examined following extensive literature research using devices and methods that have already been tested in order to determine how a simplified process of tumor margin control of basal cell carcinomas can be made possible both in vivo and ex vivo.

Background and Objectives: Nusinersen has shown significant functional motor benefit in the milder types of spinal muscular atrophy (SMA). Less is known on the respiratory outcomes in patients with nusinersen-treated SMA. The aim of this study was to describe changes in respiratory function in pediatric patients with SMA type 2 and 3 on regular treatment with nusinersen within the iSMAc international cohort and to compare their trajectory with the natural history (NH) data published by the consortium in 2020., Methods: This is a 5-year retrospective observational study of pediatric SMA type 2 and nonambulant type 3 (age ≤18 years) treated with nusinersen. The primary objective was to compare the slopes of decline in forced vital capacity % predicted (FVC% pred.), FVC, and age when FVC dropped below 60% between the treated patients and a control group from the natural history cohort. Data on peak cough flow and the use of noninvasive ventilation (NIV) and cough assist were collected., Results: Data were available for 69 treated patients, 53 were SMA type 2 and 16 type 3. The mean (SD) age at first injection was 8.5 (3.2) and 9.7 (3.7) years, respectively. The median (interquartile range) treatment duration was 1 (0.7; 1.9) and 1.2 (0.9; 1.9) years, respectively. At the time of the first nusinersen injection, 24 of 52 (46%) patients with SMA type 2 and 2 of 16 (13%) patients with SMA type 3 were on NIV. Forty-three of 53 (81%) and 4 of 16 (25%) patients used cough device. FVC% pred. in treated patients with SMA type 2 declined annually by 2.3% vs 3.9% in NH ( p = 0.08) and in treated patients with type 3 by 2.6% vs 3.4% NH ( p = 0.59). Patients treated reached FVC <60% later than untreated (12.1 vs 10 years, p = 0.05). A higher percentage of treated vs untreated patients maintained FVC% pred. equal/above their baseline after 12 (65% vs 36%) and 24 (50% vs 24%) months, respectively. NIV use among treated did not significantly change throughout 1-year follow-up., Discussion: This study included the largest real-world cohort of pediatric patients with milder SMA types. The results suggest a positive role of nusinersen in delaying the respiratory decline in patients treated longer than 1 year when compared with natural history. Larger cohorts and longer observation are planned., Classification of Evidence: This study provided Class III evidence that nusinersen slows progression for patients with SMA types 2 and 3 compared with a natural history cohort., Competing Interests: F. Trucco reports participation to Scientific Advisory Boards for Roche UK and teaching initiatives for Biogen, Avexis, Roche, and BREAS. D. Ridout, I. Hughes, Z. Zolkipli-Cunningham, and M. Main report no disclosures. M. Scoto reports participation in Scientific Advisory Boards and teaching initiatives for Avexis, Biogen, and Roche. She is involved as an investigator in clinical trials from Avexis, Biogen, and Roche. In addition, she is the co-principal investigator of the SMA REACH UK clinical network, partially funded by Biogen and Roche. F. Muntoni reports participation in Scientific Advisory Boards and teaching initiatives for Biogen, Roche, and Novartis. He is member of the Rare Disease Scientific Advisory Board for Pfizer. He is involved as an investigator in clinical trials from Novartis, Biogen, and Roche. In addition, he is the principal investigator of the SMA REACH UK clinical network, partially funded by Biogen and Roche. E. Mercuri reports participation in Scientific Advisory Boards and teaching initiatives for Biogen, Roche, Scholar Rock, and Novartis. He is involved as an investigator in clinical trials from Novartis, Biogen, Scholar Rock, and Roche. In addition, he is the principal investigator of the Italian registry participating in iSMAc, partially funded by Biogen, Roche, and Novartis. R. Finkel reports participation in Medical and Scientific Advisory Boards on SMA topics with Novartis, Biogen, Ionis, Roche, Cure SMA, SMA Europe, SMA REACH UK, SMA Foundation, and MDA. Finkel participates as an investigator in SMA-related clinical trials sponsored or supported by Novartis, Biogen, Ionis, Roche, and Scholar Rock. Dr. D. De Vivo reports participation as a consultant in Medical and Scientific Advisory Boards and as an investigator with Novartis, Biogen, Ionis, Roche, PTC, Santhera, Scholar Rock, Sanofi, GliaPharm, Fulcrum Therapeutics, Sarepta, NS Pharma, SMA Foundation, Cure SMA, DoD, NIH, Glut1 Deficiency Foundation, and Hope for Children Research Foundation. B. Darras has served as an ad hoc Scientific Advisory Board member for Novartis, Biogen, Cytokinetics, Vertex, Genentech, Roche, and Sarepta; Steering Committee chair for Roche; and Data Safety Monitoring Board member for Amicus Inc. He has no financial interests in these companies. He has received research support from the NIH/National Institute of Neurological Disorders and Stroke, the Slaney Family Fund for SMA, the Spinal Muscular Atrophy Foundation, CureSMA, and Working on Walking Fund and has received grants from Ionis Pharmaceuticals, Inc, for the ENDEAR, CHERISH, CS2/CS12 studies; from Biogen for CS11; and from Cytokinetics, Sarepta Pharmaceuticals, PTC Therapeutics, Fibrogen, and Summit. O. Mayer reports participation in Advisory Boards for Roche, Biogen, and PTC Therapeutics. He is participating in SMA REACH and iSMAC, partially funded by Biogen. C. Bruno reports participation in Scientific Advisory Boards on SMA topics with Novartis, Biogen, and Roche and participates as a principal investigator in SMA-related clinical trials sponsored by Novartis, Biogen, Ionis, and Roche. S. Messina reports participation in Scientific Advisory Boards and teaching initiatives for Novartis, Biogen, and Roche. She is involved as an investigator in clinical trials from Novartis, Biogen, Scholar Rock, and Roche. M. Pane reports participation in Scientific Advisory Boards and teaching initiatives for Novartis and Biogen. V.A. Sansone provides intellectual support in Advisory Boards and teaching activities for Biogen, Santhera, Sarepta, PTC, Dyne, Triplet, and Novartis. A. D'Amico reports participation in Scientific Advisory Board for Novartis, Roche, and Novartis and teaching initiatives for Biogen. She is also involved as an investigator in clinical trials from Novartis, Biogen, and Roche. In addition, she is an investigator of the Italian registry participating in iSMAc, partially funded by Biogen. E.S. Bertini reports participation in Scientific Advisory Boards for Novartis, Roche, Novartis, and PTC and teaching initiatives for Biogen. He is also involved as an investigator in clinical trials from Novartis, Biogen, Roche, and Novartis. In addition, he is an investigator of the Italian registry participating in iSMAc, partially funded by Biogen. C. Marini-Bettolo reports participation in Scientific Advisory Boards and teaching initiatives for Novartis, Biogen, and Roche. She is involved as an investigator in clinical trials from Novartis. In addition, she is principal investigator for the UK SMA patient registry funded by SMA UK. A. Childs reports participation in Advisory Boards for Novartis, Roche, Biogen, Santhera, and PTC Therapeutics. She is principal investigator for clinical trials supported by Sarepta, Santhera, and PTC Therapeutics. She is participating in SMA REACH and iSMAC, partially funded by Biogen. M. Ong reports participation in Advisory Boards or received consultation fees for Novartis, Roche, Biogen, and CSL Behring. She is participating in SMA REACH and iSMAC, partially funded by Biogen. Dr. A. Mayhew reports participation in Scientific Advisory Boards and teaching initiatives for Biogen and Roche. She is involved as an evaluator at site and acts as an independent consultant to train evaluators in clinical trials from Novartis, Biogen, and Roche. In addition, she is the principal investigator at Newcastle for the SMA REACH UK clinical network, partially funded by Biogen and by SMA UK. J. Montes reports participation as a consultant and on Scientific Advisory Boards for Biogen, Ionis, Roche, and Scholar Rock. G. Coratti reports consultant activities for Novartis, Biogen, Roche, Biologix, and Genesis Pharma. She is involved as a clinical evaluator in clinical trials from Novartis, Biogen, Scholar Rock, and Roche. R. De Sanctis reports consultant activities for Biogen and Roche. He is involved as a clinical evaluator in clinical trials from Novartis, Biogen, Scholar Rock, and Roche. L. Servais reports consultancy/board attendance/lectures for Novartis, Biogen, Roche, Scholar Rock, and BioHaven. A. Majumdar reports participation in Advisory Boards for Novartis, Roche, Biogen, Santhera, and PTC Therapeutics. He is principal investigator for clinical trials supported by Wave Therapeutics. He is participating in SMA REACH and iSMAC, partially funded by Biogen. D. Parasuraman reports participation in Advisory Boards for Roche, Biogen, Sarepta and has had support from PTC Therapeutics. He is principal investigator for clinical trials supported by Roche. He is participating in SMA REACH and iSMAC, partially funded by Biogen. V. Gowda reports participation in Advisory Boards or received consultation fees for Novartis, Roche, Biogen, PTC therapeutics, Wave Life Sciences, Pfizer, and Sarepta Therapeutics. She is participating in SMA REACH and iSMAC, partially funded by Biogen. FT, CB, EB, AD, EM, and MP are members of the ERN NMD (European Reference Networks). Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp., (© 2024 American Academy of Neurology.)

Retinal microcirculation reflects retinal perfusion abnormalities and retinal arterial structural changes at relatively early stages of various cardiovascular diseases. Wall-to-lumen ratio (WLR) may represent the earliest step in hypertension-mediated organ damage.Our objective was to compare functional and structural parameters of retinal microcirculation in a randomly selected urban population sample, in hypertensive and normotensive individuals., Design and Method: A total of 398 randomly selected individuals from an urban population aged 25-65 years, residing in Pilsen, Czech Republic, were screened for major cardiovascular risk factors. Retinal microcirculation was assessed using scanning laser Doppler flowmetry, with data evaluable in 343 patients. Complete data were available for 342 individuals divided into four groups based on blood pressure and control status of hypertension: normotensive individuals ( n  = 213), treated controlled hypertensive individuals ( n  = 30), treated uncontrolled hypertensive individuals ( n  = 26), and newly detected/untreated hypertensive individuals ( n  = 73)., Results: There was a tendency to higher wall thickness in treated but uncontrolled hypertensive patients (compared to normotensive and treated controlled hypertensive individuals). WLR was significantly increased in treated but uncontrolled hypertensive patients as well as in individuals with newly detected thus untreated hypertension or in patients with known but untreated hypertension. There was no difference in WLR in treated, controlled hypertensive patients compared with normotensive individuals., Conclusion: Our results show that an increased WLR, reflecting early vascular damage, was found in newly detected individuals with hypertension and in untreated hypertensive patients, reflecting early hypertension-mediated vascular damage. Early initiation of hypertension treatment may be warranted., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: We aimed to evaluate the prognostic impact of renal insufficiency and fluctuation of glomerular filtration observed during hospitalization for heart failure (HF)., Methods: We followed 3,639 patients hospitalized for acute HF and assessed the mortality risk associated with moderate or severe renal insufficiency, either permanent or transient., Results: After adjustment, severe renal failure defined as estimated glomerular filtration (eGFR) &lt;30 mL/min indicates ≈60% increase in 5-year mortality risk. Similar risk also had patients with only transient decline of eGFR to this range. In contrast, we did not observe any apparent mortality risk attributable to mild/moderate renal insufficiency (eGFR 30-59.9 mL/min), regardless of whether it was transient or permanent., Conclusion: Even transient severe renal failure during hospitalization indicates poor long-term prognosis of patients with manifested HF. In contrast, only moderate renal insufficiency observed during hospitalization has no additive long-term mortality impact., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Aim: We determined the long-term role of increased RDW (red blood cell distribution width) detected during cardiac decompensation. Methods: We followed 3697 patients [mean age 71.4 years (±SD 10.1), 59.1% males] hospitalized for acute heart failure (HF) and assessed the five-year all-cause mortality risk associated with tertiles of RDW. Results: Patients with RDW in the top tertile showed roughly twofold higher 5-year mortality risk than those in the bottom tertile. The association remained significant not only after adjustments for potential covariates but even if we excluded patients who deceased during the first year of follow-up [HRR 1.76 (95% CIs :1.42-2.18), p  < 0.0001]. Conclusion: The high degree of anisocytosis represents an independent predictor of poor prognosis in HF patients, even long-term after an acute manifestation.

Tuberculosis (TB) continues to be a major global health burden and kills over a million people annually. New immunization strategies are required for the development of an efficacious TB vaccine that can potentially induce sterilizing immunity. In this study, we first confirmed that various strains of the IKEPLUS vaccine confer a higher survival benefit than BCG in a murine model of intravenous Mycobacterium tuberculosis (Mtb) infection. We have shown that there was a significant increase in the expression of the Rv0282 when IKEPLUS was grown in low zinc and iron containing Sauton medium. We confirmed on biofilm assays that zinc plays a vital role in the growth and formation of Mycobacterium smegmatis ( M. smegmatis ) biofilms. IKEPLUS grown in low zinc media led to better protection of mice after intravenous challenge with very high dosage of Mtb. We also showed that various variants of IKEPLUS induced apoptotic cell-death of infected macrophages at a higher rate than wild type M. smegmatis . We next attempted to determine if zinc containing ribosomal proteins such as rpmb2 could contribute to protective efficacy against Mtb infection. Since BCG has an established role in anti-mycobacterial efficacy, we boosted BCG vaccinated mice with rmpb2 but this did not lead to an increment in the protection mediated by BCG.

Background: Severe hypercholesterolemia is associated with an increase in the risk of developing atherosclerotic cardiovascular disease. The aim of this analysis was to assess longitudinal trends in severe dyslipidemia (defined as total cholesterol > 8 mmol/L or LDL-cholesterol > 5 mmol/L) in a representative population sample of the Czech Republic and to analyze the longitudinal trends in the basic characteristics of individuals with severe dyslipidemia. Methods: Seven independent cross-sectional surveys were organized in the Czech Republic to screen for major cardiovascular risk factors (from 1985 to 2015-2018). A total of 20,443 randomly selected individuals aged 25-64 years were examined. Results: The overall prevalence of severe dyslipidemia was 6.6%, with a significant downward trend from the fifth survey onwards (2000/2001). Over the study period of 30+ years, the individuals with severe dyslipidemia became older, increased in BMI, and did not change their smoking habits. Total cholesterol and non-HDL-cholesterol decreased significantly in both sexes throughout the duration of the study. Conclusions: Despite a significant improvement in lipids in the Czech Republic from 1985, substantially contributing to the decline in cardiovascular mortality, the number of individuals with severe dyslipidemia remained high, and in most cases, they were newly detected during our screening examinations and were thus untreated.

Background: We analyzed the prescription and dosage of essential pharmacotherapy in chronic heart failure (HF) at the time of discharge from the hospitalization for cardiac decompensation and how it may have influenced the prognosis of the patients., Methods: We followed 4097 patients [mean age 70.7, 60.2% males] hospitalized for HF between 2010 and 2020. The vital status we ascertained from the population registry, other circumstances from the hospital information system., Results: The prescription of beta-blockers (BB) was 77.5% (or only 60.8% of BB with evidence in HF), 79% of renin-angiotensin system (RAS) blockers, and 45.3% of mineralocorticoid receptor antagonists (MRA). Almost 87% of patients were treated with furosemide at the time of discharge, while only ≈53% of patients with ischemic etiology of HF took a statin. The highest target dose of BB was recommended in ≈11% of patients, RAS blockers in ≈ 24%, and MRA in ≈ 12% of patients. In patients with concomitant renal insufficiency, the prescription of BB and MRA was generally less frequent and on a significantly lower dosage. In contrast, the opposite was true for the RAS blocker (however statistically insignificant). In patients with EF ≤ 40%, the prescription of BB and RAS blockers were more frequent but in a significantly lower dosage. On the contrary, MRAs were recommended in these patients more often and in higher doses. In terms of mortality risk, patients treated only with a reduced dose of RAS blockers showed a 77% higher risk of death within one year (or 42% within five years). A significant relationship was also found between mortality and the recommended dose of furosemide., Conclusions: The prescription and dosage of essential pharmacotherapy are far from optimal, and in the case of RAS blockers, this affected the patient's prognosis as well.

Purpose: Compared to unattended office blood pressure (uOBP), attended office blood pressure (aOBP) is higher. It is not known, however, to what extent distance between physician and patient influences blood pressure (BP) values., Materials and Methods: Participants were stable hypertensive patients, followed in the university hospital-based out-patient center. During a session, automated office BP was measured three times after a pre-set five-minute pause, using the Omron 907 device; both aOBP and uOBP were done, in a random order. Simultaneously, beat-to-beat BP measurement was performed using the Finapress device. During aOBP, some participants were in close contact with the physician while others were in loose contact where the doctor was sitting in the room about 2.5 m apart. One year later, the second session with the same protocol was organized, but the close and loose contact were interchanged. The data were analyzed using a paired t -test., Results: Complete data were collected in 32 patients, baseline uOBP was 122.8 ± 14.8/69.5 ± 11.7 mmHg. Systolic and diastolic aOBP with close contact was higher by 4.6 ± 6.9 and 1.9 ± 3.4 mmHg ( p  < 0.0007 and 0.0039, respectively), while aOBP with loose contact was not different from uOBP. Beat-to-beat BP increased during aOBP by 6.5 ± 8.5/3.3 ± 4.8 mmHg. The increase persisted during all the three aOBP measurements ( p  < 0.0001 for all systolic and diastolic BP values); the results were similar for close and loose contact. The peak increase during uOBP was of similar magnitude as during aOBP but it lasted shorter: it reached the significance level of p  < 0.0001 only during the first uOBP measurement., Conclusions: Compared to uOBP, aOBP values were higher with close, but not with loose contact between physician and patient. These differences were, however, not detected by beat-to-beat BP measurement.

Objectives: Vitamin K deficiency consistently associates with worse clinical outcome in COVID-19 patients. However, whether this is due to increased expenditure during inflammation or poor vitamin K status prior to infection remained unknown., Methods: Dp-ucMGP levels of 128 individuals were measured for the post-MONICA study and were compared to SARS-CoV-2 PCR testing results., Results: Dp-ucMGP levels prior to COVID-19 infection were not significantly different comparing PCR-negative, PCR-positive and not hospitalized, and PCR-positive and hospitalized patients., Conclusion: In this study, we demonstrate normal vitamin K status prior to infection in SARS-CoV-2 positive patients, supporting the theory of increased utilisation during disease., Competing Interests: Declaration of competing interest RJ declares application of a patent on vitamin K in COVID-19., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Hypertension is the most common cardiovascular disease which substantially increases cardiovascular morbidity and mortality. Despite the broad availability of antihypertensive medication, control of hypertension is not satisfactory worldwide., Objective: The study aim was to assess longitudinal trends in blood pressure, prevalence, awareness, treatment, and control of hypertension in a representative population sample of the Czechia from 1985 to 2016/2017, focusing on sex differences., Methods: A total of 7,606 men and 8,050 women aged 25-64 years were screened for major CV risk factors in seven independent cross-sectional surveys run consistently in the same six country districts of the Czechia between 1985 and 2016/2017. The population samples were randomly selected., Results: Over a study period of 31/32 years, there was a significant decline in systolic and diastolic blood pressure in both sexes, whereas the prevalence of hypertension decreased only in women. There was an increase in hypertension awareness in both sexes over the entire study period with consistently higher rates in women. The proportion of individuals treated with antihypertensive drugs increased significantly in both sexes throughout the study, again with consistently higher rates in women. Control of hypertension increased significantly over the study period with consistently higher rates in women. The age-adjusted trends in blood pressure, prevalence, awareness, and treatment of hypertension were significantly different in men and women, always in favor of women. The age-adjusted trends in control of hypertension in treated patients were equally poor in both sexes., Conclusion: There are significant differences in longitudinal trends in blood pressure, prevalence, awareness, treatment, and control of hypertension between men and women, always in favor of women except for the control of hypertension in treated patients, where it is equally poor in both sexes., Competing Interests: 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., (Copyright © 2022 Cífková, Bruthans, Strilchuk, Wohlfahrt, Krajčoviechová, Šulc, Jozífová, Eremiášová, Pudil, Linhart, Widimský, Filipovský, Mayer, Škodová and Lánská.)

Data on monkeypox in children and adolescents aged <18 years are limited (1,2). During May 17–September 24, 2022, a total of 25,038 monkeypox cases were reported in the United States, † primarily among adult gay, bisexual, and other men who have sex with men (3). During this period, CDC and U.S. jurisdictional health departments identified Monkeypox virus (MPXV) infections in 83 persons aged <18 years, accounting for 0.3% of reported cases. Among 28 children aged 0–12 years with monkeypox, 64% were boys, and most had direct skin-to-skin contact with an adult with monkeypox who was caring for the child in a household setting. Among 55 adolescents aged 13–17 years, most were male (89%), and male-to-male sexual contact was the most common presumed exposure route (66%). Most children and adolescents with monkeypox were non-Hispanic Black or African American (Black) (47%) or Hispanic or Latino (Hispanic) (35%). Most (89%) were not hospitalized, none received intensive care unit (ICU)–level care, and none died. Monkeypox in children and adolescents remains rare in the United States. Ensuring equitable access to monkeypox vaccination, testing, and treatment is a critical public health priority. Vaccination for adolescents with risk factors and provision of prevention information for persons with monkeypox caring for children might prevent additional infections., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

Brain tumors comprise over 100 types of masses, differing in the following: location; patient age; molecular, histological, and immunohistochemical characteristics; and prognosis and treatment. Glioma tumors originate from neuroglia, cells supporting the brain. Palladin, a structural protein widely expressed in mammalian tissues, has a pivotal role in cytoskeletal dynamics and motility in health and disease. Palladin is linked to the progression of breast, pancreatic, and renal cancers. In the central nervous system, palladin is involved in embryonic development, neuronal maturation, the cell cycle, differentiation, and apoptosis. However, the role of palladin in brain tumors is unknown. In this work, we explored palladin's role in glioma. We analyzed clinical data, along with bulk and single-cell gene expression. We then validated our results using IHC staining of tumor samples, together with qRT-PCR of glioma cell lines. We determined that wild-type palladin-4 is overexpressed in adult gliomas and is correlated with a decrease in survival. Palladin expression outperformed clinically used prognostic markers and was most prominent in glioblastoma. Finally, we showed that palladin originates from the malignant cell population. Our findings indicate that palladin expression might be linked to adult glioma progression and is associated with prognosis., Competing Interests: The authors declare no conflict of interest.

Background and Aims: Leptin is an adipocyte-derived peptide involved in energy homeostasis and body weight regulation. The position of leptin in cardiovascular pathophysiology remains controversial. Some studies suggest a detrimental effect of hyperleptinemia on the cardiovascular (CV) system, while others assume the role of leptin as a neutral or even protective factor. We have explored whether high leptin affects the mortality and morbidity risk in patients with stable coronary heart disease., Methods and Results: We followed 975 patients ≥6 months after myocardial infarction or coronary revascularization in a prospective study. All-cause or cardiovascular death, non-fatal cardiovascular events (recurrent myocardial infarction, stroke, or any revascularization), and hospitalizations for heart failure (HF) we used as outcomes. High serum leptin concentrations (≥18.9 ng/mL, i.e., 4th quartile) were associated with worse survival, as well as with a higher incidence of fatal vascular events or hospitalizations for HF. Even after full adjustment for potential covariates, high leptin remained to be associated with a significantly increased 5-years risk of all-cause death [Hazard risk ratio (HRR) 2.10 (95%CIs:1.29-3.42), p < 0.003], CV death [HRR 2.65 (95%CIs:1.48-4.74), p < 0.001], and HF hospitalization [HRR 1.95 (95% CIs:1.11-3.44), p < 0.020]. In contrast, the incidence risk of non-fatal CV events was only marginally and non-significantly influenced [HRR 1.27 (95%CIs:0.76-2.13), p = 0.359]., Conclusions: High leptin concentration entails an increased risk of mortality, apparently driven by fatal CV events and future worsening of HF, on top of conventional CV risk factors and the baseline status of left ventricular function., Competing Interests: Declaration of competing interest None., (Copyright © 2022 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Aims: We analyzed the mortality risk and its predictors in patients hospitalized for heart failure (HF)., Methods: Patients discharged from hospitalization for acute decompensation of HF in 2010-2020 and younger than 86 years were followed (n=4097). We assessed the incidence and trends of all-cause death, its main predictors, and the pharmacotherapy recommended at discharge from the hospital., Results: The 30 days all-cause mortality was in discharged patients 3.2%, while 1-year 20.4% and 5-years 55.4%. We observed a modest trend to decreased 1-year mortality risk over time. Any increase of year of hospitalization by one was associated with about 5% lower risk in the fully adjusted model. Regarding predictors of 1-year mortality risk, a positive association was found for age over 65, history of malignancy, and peak brain natriuretic peptide during hospitalization ≥10times higher than normal concentration. In contrast, as protective factors, we identified LDL ≥1.8 mmol/L, treatment with beta-blockers, renin-angiotensin axis blockers, statins, and implanted cardioverter in the same regression model. The ejection fraction category and primary etiology of HF (coronary artery disease vs. others) did not significantly affect the mortality risk in a fully adjusted model., Conclusions: Despite advances in cardiovascular disease management over the last two decades, the prognosis of patients hospitalized for heart failure remained highly unfavorable., Competing Interests: The authors report no conflicts of interest in this work.

Background: Stroke represents an essential part of the burden of cardiovascular diseases. Despite specific mortality from cerebrovascular diseases decreasing in the Czech Republic since the 80s, the trends in case fatality and individual risk of patients who suffered from stroke remain questionable. In patients hospitalized for ischemic stroke, we evaluated the mortality trends in the last two decades., Methods: 9076 patients (mean age 71.8, 51.9% males) hospitalized for ischemic stroke between 2003 and 2019 were followed. The vital status we ascertained up to 31.12.2020, other circumstances from the hospital information system Results: In total, 5583 patients died during follow-up. The in-hospital fatality was 9.1%, 30-day mortality 14.2%, and 1-year mortality 28.4%. In patients hospitalized from 2003 to 2015, the 5-year mortality was 49.8%. No significant changes were noted for in-hospital fatality, 30-days, 1-year mortality, as well as 5-years mortality risk across more extensive periods (2003-07, 2008-11, 2012-15 and 2016-19). As expected, any decade of patient´s age was associated with about two-fold higher mortality risk. Intravenous thrombolysis, as part of initial management, markedly increased over time (from 2.4% in 2003-07 to 48.1% in 2016-19). However, this procedure affected beneficially only 1-year mortality risk, while regarding 5-years mortality was its effect neutral., Conclusions: Despite favorable trends in cerebrovascular events from a population perspective, the individual prognosis of patients who have suffered a stroke remains very poor.

Background: Fabry disease (FD) is a multi-organ disorder associated with severe physical and psychological impairments, particularly in adulthood. To date, comprehensive data on the psychological burden of FD are lacking. The present study assessed quality of life (QOL) in a representative cohort of adults with FD., Methods: Patient-reported outcome measures were retrospectively analyzed in 86 adults with FD (49.6±16.6 years; 62.8% female) and compared to adults with congenital heart defects (ACHD) which is another lifelong disease and affliction. QOL was assessed using the European Quality of Life 5 Dimensions 5 Levels questionnaire (EQ-5D-5L)., Results: Subjects affected by FD reported an overall reduced QOL (EQ-VAS: 71.8±20.0). Most frequently reported complaints occurred within the dimensions pain/discomfort (69.7%), daily activities (48.9%) and anxiety/depression (45.4%). Compared to ACHD, individuals with FD scored significantly lower in the areas of pain/discomfort, usual activities and mobility (all P<0.05). Older age and female sex were particularly associated with diminished QOL (P=0.05)., Conclusions: Patients with FD are at high risk for impaired QOL. They require additional support to cope with disease-related challenges. Increased attention should be directed towards improving their subjective well-being to potentially increase their QOL and long-term health outcomes., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cdt.amegroups.com/article/view/10.21037/cdt-22-215/coif). The series “Current Management Aspects in Adult Congenital Heart Disease (ACHD): Part V” was commissioned by the editorial office without any funding or sponsorship. HK served as the unpaid guest editor of the series. CA and SF report grants/contracts received from AMICUS. CK reports payment or honoraria, support for attending meetings/travel received from AMICUS, Chiesi, Sanofi and Takeda. CK served on the Advisory Board for AMICUS, Chiesi, Sanofi and Takeda. The authors have no other conflicts of interest to declare., (2022 Cardiovascular Diagnosis and Therapy. All rights reserved.)

The need for increased testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19), has resulted in an increase of testing facilities outside of traditional clinical settings and sample handling by individuals without appropriate biohazard and biocontainment training. During the repatriation and quarantine of passengers from the Grand Princess cruise ship at a US military base, biocontainment of a potentially infectious sample from a passenger was compromised. This study describes the steps taken to contain the spill, decontaminate the area, and discusses the needs for adequate training in a biohazard response.

Objectives: Before community transmission of COVID-19 was recognized in the United States, cruise ship passengers with high risk for exposure to SARS-CoV-2 were repatriated and quarantined. We describe cases of influenza-like illness (ILI) among responders., Methods: We reviewed situation reports and responder illness reports to characterize ill responders, including illness onset date, symptoms, fever, diagnostic tests, potential breaches in PPE use, and return to work status., Results: Among 339 responders, nine (3%) reported ILI. No breaches in PPE were reported. Three responders with ILI were tested for both SARS-CoV-2 infection and influenza A; none tested positive for SARS-CoV-2 infection and two tested positive for influenza A., Conclusions: Despite an outbreak of ILI among responders, none were diagnosed with COVID-19, suggesting preventive measures in place might have been sufficient to prevent responders from SARS-CoV-2 exposure., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 American College of Occupational and Environmental Medicine.)

The Democratic Republic of the Congo (DRC) declared an Ebola virus disease (EVD) outbreak in North Kivu in August 2018. By June 2019, the outbreak had spread to 26 health zones in northeastern DRC, causing >2,000 reported cases and >1,000 deaths. On June 10, 2019, three members of a Congolese family with EVD-like symptoms traveled to western Uganda's Kasese District to seek medical care. Shortly thereafter, the Viral Hemorrhagic Fever Surveillance and Laboratory Program (VHF program) at the Uganda Virus Research Institute (UVRI) confirmed that all three patients had EVD. The Ugandan Ministry of Health declared an outbreak of EVD in Uganda's Kasese District, notified the World Health Organization, and initiated a rapid response to contain the outbreak. As part of this response, UVRI and the United States Centers for Disease Control and Prevention, with the support of Uganda's Public Health Emergency Operations Center, the Kasese District Health Team, the Superintendent of Bwera General Hospital, the United States Department of Defense's Makerere University Walter Reed Project, and the United States Mission to Kampala's Global Health Security Technical Working Group, jointly established an Ebola Field Laboratory in Kasese District at Bwera General Hospital, proximal to an Ebola Treatment Unit (ETU). The laboratory consisted of a rapid containment kit for viral inactivation of patient specimens and a GeneXpert Instrument for performing Xpert Ebola assays. Laboratory staff tested 76 specimens from alert and suspect cases of EVD; the majority were admitted to the ETU (89.3%) and reported recent travel to the DRC (58.9%). Although no EVD cases were detected by the field laboratory, it played an important role in patient management and epidemiological surveillance by providing diagnostic results in <3 hours. The integration of the field laboratory into Uganda's National VHF Program also enabled patient specimens to be referred to Entebbe for confirmatory EBOV testing and testing for other hemorrhagic fever viruses that circulate in Uganda., Competing Interests: The authors have declared that no competing interests exist.

Aim: We explored whether matrix Gla protein (MGP, natural calcification inhibitor) and sclerostin (glycoprotein responsible for osteoblast differentiation) interact in terms of mortality risk in coronary patients. Methods: 945 patients after myocardial infarction and/or coronary revascularization were followed in a prospective study. All-cause death, fatal or nonfatal cardiovascular events and heart failure hospitalizations were registered. Results: Either high desphospho-uncarboxylated MGP (dp-ucMGP) or high sclerostin were independently associated with 5-year all-cause/cardiovascular mortality. However, we observed an additional mortality risk in the coincidence of both factors. Concomitantly high dp-ucMGP (≥884 pmol/l) plus sclerostin (≥589 ng/l) were associated with increased all-cause mortality risk compared with 'normal' concentration s of both factors (HRR 3.71 [95% CI: 2.07-6.62, p < 0.0001]), or if only one biomarker has been increased. A similar pattern was observed for fatal, but not for nonfatal cardiovascular events. Conclusion: Concomitantly high MGP and sclerostin indicate increased mortality risk, which probably reflects their role in cardiovascular calcifications.

Purpose: Liddle syndrome is a hereditary form of arterial hypertension caused by mutations in the genes coding of the epithelial sodium channel - SCNN1A, SCNN1B and SCNN1G. It is characterised by early onset of hypertension and variable biochemical features such as hypokalaemia and low plasma concentrations of renin and aldosterone. Phenotypic variability is large and, therefore, LS is probably underdiagnosed. Our objective was to examine a family suspected from Liddle syndrome including genetic testing and evaluate clinical and biochemical features of affected family members., Materials and Methods: Thirteen probands from the Czech family, related by blood, underwent physical examination, laboratory tests, and genetic testing. Alleles of SCNN1B and SCNN1G genes were examined by PCR amplification and Sanger sequencing of amplicons., Results: We identified a novel mutation in the β-subunit of an epithelial sodium channel coded by the SCNN1B gene, causing the nonsense mutation in the protein sequence p.Tyr604*. This mutation was detected in 7 members of the family. The mutation carriers differed in the severity of hypertension and hypokalaemia which appeared only after diuretics in most of them; low aldosterone level (< 0.12 nmol/l) was, however, present in all., Conclusions: This finding expands the spectrum of known mutations causing Liddle syndrome. Hypoaldosteronemia was 100% sensitive sign in the mutation carriers. Low levels are observed especially in the Caucasian population reaching 96% sensitivity. Assessment of plasma aldosterone concentration is helpful for differential diagnosis of arterial hypertension., Condensed Abstract: Liddle syndrome is a hereditary form of arterial hypertension caused by mutations in the genes encoding the epithelial sodium channel's α-, β- and γ-subunit. It is usually manifested by early onset of hypertension accompanied by low potassium and aldosterone levels. We performed a physical examination, laboratory tests and genetic screening in 13 members of a Czech family. We found a new mutation of the SCNN1B gene which encodes the β-subunit of the epithelial sodium channel. We describe the variability of each family member phenotype and point out the relevance of using aldosterone levels as a high sensitivity marker of Liddle syndrome in Caucasians.

Selective serotonin reuptake inhibitors (SSRIs) are currently the first-line antidepressant drug treatment for major depressive disorder (MDD). Treatment-resistant depression (TRD), defined as failure to achieve remission despite adequate treatment, affects ~30% of persons with MDD. The current recommended treatment for TRD is electroconvulsive therapy (ECT), while ketamine is an experimentally suggested treatment. This study aimed to elucidate the transcriptional differences in peripheral blood mononuclear cells (PBMC) between individuals with TRD and a control group without a psychiatric illness; and between patients with TRD, treated with either standard antidepressant drugs alone, or in combination with ECT or ketamine. Additionally, PBMC transcriptomics were compared between treatment responders, following completion of their treatment protocols. Total RNA was extracted from PBMC of the TRD group at two time points, and RNA and miRNA expression were profiled. Multiple mRNAs and miRNAs were found to be modified, with two protein coding genes, FKBP5 and ITGA2B, which are up- and downregulated, respectively; and several miRNAs have shown changes following successful ECT treatment. Further analysis demonstrated the direct functional regulation of ITGA2B by miR-24-3p. Our findings suggest that PBMC expression levels of FKBP5, ITGA2B, and miR-24-3p should be further explored as tentative ECT response biomarkers., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aims: Studies on the incidence, acute and subsequent mortality from myocardial infarction are limited mostly to selected clinical cohorts and populations and cover relatively short periods. Our aim was to describe and analyse long-term trends on a national scale., Methods: Acute myocardial infarction (AMI) was defined by the International Classification of Diseases (ICD)10; codes I21 and I22. Our natiowide 1994-2016 data on AMI mortality were obtained from the official mortality statistics (Czech Bureau of Statistics), data on morbidity (hospitalizations) from the National Register of Hospitalizations (Institute for Health Information and Statistics). For further analyses, data from the Czech EUROASPIRE I-V and Czech IMPACT studies were used., Results: Over the 1994-2016 period the total number of AMI cases per year decreased from 34,084 to 19,015, that of patients hospitalized for AMI from 22,373 to 15,419, the total number of deaths due to AMI from 14,834 to 4,673, in those treated because of AMI from 3,794 to 1,137, and hospital fatality in patients treated for AMI decreased from 17% to 7.5%. Over the years 1997-2016, the one-year all-cause mortality rate after AMI declined from 25.1 to 17.9%, cardiovascular (CV) mortality from 22.3 to 14.2%, five-year all-cause mortality from 41.7 to 34%, and CV mortality from 34.1 to 23.6%., Conclusion: The Czech Republic has witnessed a pronounced decrease in AMI incidence and fatality and, consequently, long-term mortality. The decreasing incidence and improving course of AMI are due to progress in primary prevention, in acute coronary care and interventional cardiology, and in secondary coronary heart disease (CHD) prevention.

Aim: Although uric acid has antioxidant effects, hyperuricemia has been established as an indicator of increased cardiovascular mortality in various patient populations. Treatment of asymptomatic hyperuricemia in patients with acute myocardial infarction (MI) is not routinely recommended, and the efficacy of such treatment in terms of cardiovascular risk reduction remains doubtful. Materials & methods: In a prospective cohort study, we followed 5196 patients admitted for a MI between 2006 and 2018. We assessed the relationship between baseline uricemia and the incidence of all-cause death and cardiovascular mortality and the effect of long-term allopurinol treatment. Hyperuricemia was defined as serum uric acid >450 μmol/l in men and >360 μmol/l in women. Results: In the entire cohort, the 1-year all-cause and cardiovascular mortality rates were 8 and 7.4%, and the 5-year rates were 18.3 and 15.3%, respectively. Using a fully adjusted model, hyperuricemia was associated with a 70% increased risk of both all-cause death and cardiovascular mortality at 1 year, and the negative prognostic value of hyperuricemia persisted over the 5-year follow-up (for all-cause death, hazard risk ratio = 1.45 [95% CI: 1.23-1.70] and for cardiovascular mortality, hazard risk ratio = 1.52 [95% CI: 1.28-1.80], respectively). Treatment of asymptomatic hyperuricemia with allopurinol did not affect mortality rates. Conclusion: Hyperuricemia detected in patients during the acute phase of an MI appears to be independently associated with an increased risk of subsequent fatal cardiovascular events. However, hyperuricemia treatment with low-dose allopurinol did not prove beneficial for these patients.

Background: To compare four automated immunoassays for the measurement of 25(OH)-vitamin D (25-OHD) and to assess the impact on the results obtained from a healthy population., Methods: We analysed 100 serum samples on Unicel DxI 800 (Beckman Coulter), Architect i1000 (Abbott), Cobas e411 (Roche) and Liaison XL (DiaSorin). Passing-Bablok regression and Bland-Altman plots were used for method comparison. In order to categorise the obtained values, results were categorised into the following groups: 0-25 nmol/L, 25-50 nmol/L, 50-75 nmol/L and above 75 nmol/L and compared. The percentage of samples below 75 nmol/L, and below 50 nmol/L was then calculated for every method., Results: According to paired comparisons, each method differs from others (p<0.0001) except Cobas vs Architect, which do not show a statistically significant difference (p=0.39). The strongest correlation was found between Liaison and Architect (ρ=0.94, p<0.0001). The percentage of samples below the recommended value of 75 nmol/L were: 70% (Architect), 92% (Liaison), 71% (Cobas) and 89% (Unicel). The percentage of samples below the value of 50 nmol/L were: 17% (Architect), 55% (Liaison), 28% (Cobas) and 47% (Unicel)., Conclusions: The observed differences stem from the use of different analytical systems for 25-OHD concentration analysis and can result in different outcomes. The recommended values should be established for each assay in accordance with the data provided by the manufacturer or in the laboratory, in accordance with proper standardisation., Competing Interests: Conflict of Interest: The authors stated that they have no conflicts of interest regarding the publication of this article., (2021 Jindra Windrichova, Pavel Broz, Radka Fuchsova, Ondrej Topolcan, Ladislav Pecen, Otto Mayer, Radek Kucera, published by CEON/CEES.)

The Hopi Tribe is a sovereign nation home to ~7500 Hopi persons living primarily in 12 remote villages. The Hopi Tribe, like many other American Indian nations, has been disproportionately affected by COVID-19. On 18 May 2020, a team from the US Centers for Disease Control and Prevention (CDC) was deployed on the request of the tribe in response to increases in COVID-19 cases. Collaborating with Hopi Health Care Center (the reservation's federally run Indian Health Service health facility) and CDC, the Hopi strengthened public health systems and response capacity from May to August including: (1) implementing routine COVID-19 surveillance reporting; (2) establishing the Hopi Incident Management Authority for rapid coordination and implementation of response activities across partners; (3) implementing a community surveillance programme to facilitate early case detection and educate communities on COVID-19 prevention; and (4) applying innovative communication strategies to encourage mask wearing, hand hygiene and physical distancing. These efforts, as well as community adherence to mitigation measures, helped to drive down cases in August. As cases increased in September-November, the improved capacity gained during the first wave of the pandemic enabled the Hopi leadership to have real-time awareness of the changing epidemiological landscape. This prompted rapid response coordination, swift scale up of health communications and redeployment of the community surveillance programme. The Hopi experience in strengthening their public health systems to better confront COVID-19 may be informative to other indigenous peoples as they also respond to COVID-19 within the context of disproportionate burden., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Stiffening of large arteries, clinically manifesting as increased aortic pulse wave velocity (PWV), is an inevitable outcome of aging. Among other mechanisms, impaired glucose metabolism plays an important role, leading to the deposition of advanced glycation end products (AGEs). This process is counterbalanced by the circulating soluble receptor for AGEs (sRAGE). We investigated the association between arterial stiffness on one side and multiple circulating biomarkers and the degree of skin deposition of AGEs on the other. In a cross-sectional design, 867 participants based on a general population sample (Czech post-MONICA studies) were examined. PWV was measured by SphygmoCor device (AtCor Medical Ltd.), while skin AGEs were measured using a dedicated autofluorescence method (AGE Reader mu ® ). To quantify the circulating status of AGEs, carboxymethyl lysine (CML) and sRAGE concentrations were assessed by ELISA, along with conventional glucose metabolism indicators. When analyzing the whole sample using multiple linear or logistic regression models and after adjustment for potential covariates, a significant association with PWV was found for fasting glycemia, HbA1c, sRAGE, skin AGEs, and the skin AGE-to-sRAGE ratio. Among these parameters, stepwise models identified the strongest association for the skin AGEs and AGE-to-sRAGE ratio, and this was also true when diabetic subjects were excluded. In contrast, neither CML nor its ratio relative to sRAGE showed any association with arterial stiffness. In conclusion, skin AGEs along with their ratio relative to sRAGE were closely associated with arterial stiffness and is a better indicator of the current status of deposited AGEs than other relevant factors.

Advanced glycation end products (AGEs) are involved in several pathophysiologic processes in vascular diseases, including progressive loss of elasticity of the vessel wall (arterial stiffness). Circulating soluble receptors for AGEs (sRAGE) act as a decoy and counterbalanced the harmful properties of AGEs as the natural protective factor. We compared the role of circulating or skin-deposed AGEs and sRAGE regarding the natural course of arterial stiffening. In a prospective cohort study, we longitudinally followed 536 general population-based subjects (subsample of Czech post-MONICA study). Aortic pulse-wave velocity (PWV) was measured twice (at baseline and after ~8 years of follow-up) using a SphygmoCor device (AtCor Medical Ltd), and the intraindividual change in PWV per year (∆PWV/year) was calculated. Concentrations of sRAGE and carboxymethyl lysine (circulating AGEs) were assessed at the follow-up visit by ELISA, while skin AGEs were measured using the autofluorescence-based device AGE Reader. Using multiple regressions, we found significant association between ∆PWV/year as a dependent variable, and both, sRAGE and skin AGEs as independent ones (each on its own model). However, the closest associations to ∆PWV/year were found for the ratio of these two factors (skin AGEs/sRAGE) [β coeff = 0.0747 (SE 0.0189), p < 0.0001]. In a categorized manner, subjects with skin AGEs/sRAGE ratio ≥ 3.3 showed about twofold higher risk having ΔPWV/year ≥ 0.2 m/s [adjusted odds ratio was 2.09 (95% CI: 1.35-3.22), p = 0.001]. In contrast, neither circulating AGEs nor circulating AGEs/sRAGE showed any significant relation to ΔPWV/year. In conclusion, skin AGEs/sRAGE ratio seems to be a more sensitive biomarker of vascular aging than these single factors themselves or circulation status of AGEs.

Retinal microcirculation reflects retinal perfusion abnormalities and retinal arterial structural changes at relatively early stages of various cardiovascular diseases. Our objective has been to establish reference values for major functional and structural parameters of retinal microcirculation in a randomly selected urban population sample. A total of 398 randomly selected individuals from an urban population aged 25 to 65 years, resident in Pilsen, Czech Republic, were screened for major cardiovascular risk factors. Retinal microcirculation was assessed using scanning laser Doppler flowmetry (SLDF), with data evaluable in 343 patients. Of this number, complete data were available for 256 individuals free from manifest cardiovascular disease, diabetes and drug treatment for hypertension and/or dyslipidemia, constituting the reference value population. Juxtapapillary retinal capillary blood flow has increased significantly with age whereas vessel and luminal diameters have decreased. No sex differences in retinal microcirculation parameters have been found. Therefore, reference values for retinal microcirculation parameters have been established by age groups. Unattended automated office systolic BP, after adjusting for age, correlated significantly with wall-to-lumen ratio (WLR) and wall thickness (WT). Moreover, after adjusting for age and mean BP, a positive relationship has been found between carotid femoral pulse wave velocity and WT, WLR and wall cross-sectional area, indicating the interaction between micro- and macro-vasculature. In conclusion, our study is the first to provide reference values of retinal microcirculation parameters in a random Caucasian population sample. Our results have shown that, at the population level, the first structural changes in retinal microcirculation are those in lumen diameters. Of note, a close relationship between BP and vascular remodeling of retinal arterioles and between aortic stiffness and WLR of retinal arterioles suggests an interaction between micro- and macro-vasculature., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background and Aims: Matrix Gla protein (MGP) is a natural inhibitor of vascular calcification critically dependent on circulating vitamin K status. Growth differentiation factor 15 (GDF-15) is a regulatory cytokine mainly of the inflammatory and angiogenesis pathways, but potentially also involved in bone mineralization. We sought to determine whether these two circulating biomarkers jointly influenced morbidity and mortality risk in patients with chronic coronary heart disease (CHD)., Methods and Results: 894 patients ≥6 months after myocardial infarction and/or coronary revascularization at baseline were followed in a prospective study. All-cause and cardiovascular mortality, non-fatal cardiovascular events (myocardial infarction, stroke, any revascularization), and hospitalization for heart failure (HF) were followed as outcomes. Desphospho-uncarboxylated MGP (dp-ucMGP) was used as a biomarker of vitamin K status. Both, increased concentrations of dp-ucMGP (≥884 pmol/L) and GDF-15 (≥1339 pg/mL) were identified as independent predictors of 5-year all-cause or cardiovascular mortality. However, their coincidence further increased mortality risk. The highest risk was observed in patients with high dp-ucMGP plus high GDF-15, not only when compared with those with "normal" concentrations of both biomarkers [HR 5.51 (95% CI 2.91-10.44), p < 0.0001 and 6.79 (95% CI 3.06-15.08), p < 0.0001 for all-cause and cardiovascular mortality, respectively], but even when compared with patients with only one factor increased. This pattern was less convincing with non-fatal cardiovascular events or hospitalization for HF., Conclusions: The individual coincidence of low vitamin K status (high dp-ucMGP) and high GDF-15 expression predicts poor survival of stable CHD patients., Competing Interests: Declaration of competing interest None., (Copyright © 2020 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Aim: We analyzed the mortality risk of myocardial infarction (MI) patients according to renal function, observed during hospitalization. Materials & methods: Patients hospitalized for MI between 2006 and 2018 were followed (n = 5659). We divided the sample into four groups by estimated glomerular filtration (eGFR) [ml/min]: normal functions (lowest eGFR during hospitalization >60); transiently moderate insufficiency (lowest eGFR >30 and ≤60, highest >60); permanently moderate insufficiency (highest eGFR >30 and ≤60); severe insufficiency (highest and lowest eGFR ≤30). Results: Permanently moderate renal insufficiency indicates increased 5-years all-cause mortality (hazard risk ratio: 2.27 [95% CIs: 1.87-2.75], p < 0.0001), but a similar risk was found in patients with the only transient decline of renal functions (hazard risk ratio: 2.08 [95% CIs: 1.70-2.55], p < 0.0001). Both moderate insufficiency subgroups (transient/permanent) did not statistically differ regarding mortality risk. Conclusion: Even just fluctuation of eGFR toward moderate insufficiency during hospitalization represents an important prognostic indicator in MI patients.

Objectives: Impaired glucose metabolism represents one the most important cardiovascular risk factors, with steeply raising prevalence in overall population. We aimed to compare mortality risk of impaired fasting glycaemia (IFG) and overt diabetes mellitus (DM) in patients with coronary heart disease (CHD)., Study Design: prospective cohort study METHODS: A total of 1685 patients, 6-24 months after myocardial infarction and/or coronary revascularization at baseline, were followed in a prospective cohort study. Overt DM was defined as fasting glucose ≥ 7 mmol/L and/or use of antidiabetic treatment, while IFG as fasting glucose 5.6-6.99 mmol/L, but no antidiabetic medication. The main outcomes were total and cardiovascular mortality during 5 years of follow-up., Results: During follow-up of 1826 days, 172 patients (10.2%) deceased, and of them 122 (7.2%) from a cardiovascular cause. Both exposures, overt DM (n=623, 37.0% of the whole sample) and IFG (n=436, 25.9%) were associated with an independent increase of 5-year total mortality, compared to normoglycemic subjects [fully adjusted hazard risk ratio (HRR) 1.63 (95%CI: 1.01-2.61)]; p=0.043 and 2.25 (95%CI: 1.45-3.50); p<0.0001, respectively]. In contrast, comparing both glucose disorders one with each other, no significant differences were found for total mortality [HRR 0.82 (0.53-1.28); p=0.33]. Taking 5-years cardiovascular mortality as outcome, similar pattern was observed [HRR 1.96 (95%CI: 1.06-3.63) and 3.84 (95%CI: 2.19-6.73) for overt DM and IFG, respectively, with HRR 0.63 (95%CI: 0.37-1.07) for comparison of both disorders]., Conclusions: Impaired fasting glycaemia adversely increases mortality of CHD patients in the same extent as overt DM., Competing Interests: These are no conflicts of interest to disclose., (Thieme. All rights reserved.)

Adiponectin has several beneficial properties, namely, on the level of glucose metabolism, but paradoxically, its high concentrations were associated with increased mortality. We aimed to clarify the impact of high serum adiponectin on mortality and morbidity in patients with stable coronary artery heart disease (CAD). A total of 973 patients after myocardial infarction and/or coronary revascularization were followed in a prospective cohort study. All-cause and cardiovascular (CV) death, non-fatal cardiovascular events, and hospitalizations for heart failure (HF) were registered as outcomes. High serum adiponectin levels (≥8.58 ng/ml, i. e., above median) were independently associated with increased risk of 5-year all-cause, CV mortality or HF [with HRR 1.57 (95% CI: 1.07-2.30), 1.74 (95% CI: 1.08-2.81) or 1.94 (95% CI: 1.20-3.12), respectively] when adjusted just for conventional risk factors. However, its significance disappeared if brain natriuretic peptide (BNP) was included in a regression model. In line with this, we observed strong collinearity of adiponectin and BNP. Additionally, major adverse cardiovascular event (i. e., CV death, non-fatal myocardial infarction or stroke, coronary revascularization) incidence risk was not associated with high adiponectin. In conclusion, the observed inverse association between adiponectin concentrations and mortality risk seems to be attributable to concomitantly increased BNP, rather than high adiponectin being a causal factor., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

On June 3, 2020, a woman aged 73 years (patient A) with symptoms consistent with coronavirus disease 2019 (COVID-19) (1) was evaluated at the emergency department of the Hopi Health Care Center (HHCC, an Indian Health Services facility) and received a positive test result for SARS-CoV-2, the virus that causes COVID-19. The patient's symptoms commenced on May 27, and a sibling (patient B) of the patient experienced symptom onset the following day. On May 23, both patients had driven together and spent time in a retail store in Flagstaff, Arizona. Because of their similar exposures, symptom onset dates, and overlapping close contacts, these patients are referred to as co-index patients. The co-index patients had a total of 58 primary (i.e., direct) and secondary contacts (i.e., contacts of a primary contact); among these, 27 (47%) received positive SARS-CoV-2 test results. Four (15%) of the 27 contacts who became ill were household members of co-index patient B, 14 (52%) had attended family gatherings, one was a child who might have transmitted SARS-CoV-2 to six contacts, and eight (30%) were community members. Findings from the outbreak investigation prompted the HHCC and Hopi Tribe leadership to strengthen community education through community health representatives, public health nurses, and radio campaigns. In communities with similar extended family interaction, emphasizing safe ways to stay in touch, along with wearing a mask, frequent hand washing, and physical distancing might help limit the spread of disease., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.