Associations of body composition measures and C2, a marker for small artery elasticity: The MESA.

ObjectiveLower C2, a continuous blood pressure waveform characteristic asserted to represent small artery elasticity, predicts future cardiovascular disease events. It is hypothesized that the paradoxical positive association between body mass index (BMI) and C2 may reflect muscle instead of excess fat.MethodsIn a multi-ethnic, community-living cohort of 1,960 participants, computed tomography scans of the abdomen were used to measure visceral adipose tissue (VAT) and total abdominal muscle tissue (TAMT), and applanation tonometry of the radial arteries was used to assess C2. The period cross-sectional associations between BMI, TAMT, and VAT with C2 were ascertained.ResultsThe mean age was 62 ± 9 years and 51% were male. After adjustments for age, gender, ethnicity, pack years smoking cigarettes, diabetes, hypertension, and total and HDL cholesterol, higher BMI (standardized beta = 0.09, P-value < 0.01) and more TAMT (standardized beta = 0.12, P-value < 0.01) were significantly associated with higher C2. In contrast, more VAT (standardized beta = -0.09, P-value < 0.01) was associated with lower C2.ConclusionsIn multivariable analysis, VAT, in contrast to TAMT and BMI, was associated with less compliant small arteries. Visceral fat may be a better marker for detrimental excess body fat than BMI

Higher leptin is associated with hypertension: the Multi-Ethnic Study of Atherosclerosis

Adipokines are secreted from adipose tissue, influence energy homeostasis and may contribute to the association between obesity and hypertension. Among 1897 participants enrolled in the Multi-Ethnic Study of Atherosclerosis, we examined associations between blood pressure and leptin, tumor necrosis factor-α (TNFα), resistin and total adiponectin. The mean age and body mass index (BMI) was 64.7 years and 28.1, respectively, and 50% were female. After adjustment for risk factors, a 1-s.d.-increment higher leptin level was significantly associated with higher systolic (5.0 mm Hg), diastolic (1.9), mean arterial (2.8) and pulse pressures (3.6), as well as a 34% higher odds for being hypertensive (P<0.01 for all). These associations were not materially different when the other adipokines, as well as BMI, waist circumference or waist-to-hip ratio, were additionally added to the model. Notably, the associations between leptin and hypertension were stronger in men, but were not different by race/ethnic group, BMI or smoking status. Adiponectin, resistin and TNFα were not independently associated with blood pressure or hypertension. Higher serum leptin, but not adiponectin, resistin or TNFα, is associated with higher levels of all measures of blood pressure, as well as a higher odds of hypertension, independent of risk factors, anthropometric measures and other selected adipokines

Hypertensive nephrosclerosis: wider kidney biopsy indications may be needed to improve diagnostics

Background Hypertensive nephrosclerosis is the presumed underlying cause in many end‐stage kidney disease (ESKD) patients, but the diagnosis is disputed and based on clinical criteria with low diagnostic accuracy. Objective To evaluate and improve the diagnostic process for nephrosclerosis patients. Methods We included adults from the population‐based HUNT study (n = 50 552), Norwegian CKD patients referred for kidney biopsy 1988–2012 (n = 7261), and unselected nephrology clinic patients (n = 193) used for matching. Decision tree analysis and ROC curve‐based methods of optimal cut‐offs were used to improve clinical nephrosclerosis criteria. Results Nephrosclerosis prevalence was 2.7% in the general population, and eGFR decline and risk for kidney‐related hospital admissions and ESKD were comparable to patients with diabetic kidney disease. In the biopsy cohort, current clinical criteria had very low sensitivity (0.13) but high specificity (0.94) for biopsy‐verified arterionephrosclerosis. A new optimized diagnostic algorithm based on proteinuria (155 mm Hg) and age (>75 years) only marginally improved diagnostic accuracy (sensitivity 0.19, specificity 0.96). Likewise, there were still false‐positive cases with treatable diagnoses like glomerulonephritis, interstitial nephritis and others (40% of all test positive). Decision curve analysis showed that the new criteria can lead to higher clinical utility, especially for patients considering the potential harms to be close to the potential benefits, while the more risk‐tolerant ones (harm:benefit ratio < 1:4) should consider kidney biopsy. Conclusion Further improvements of the current clinical criteria seem difficult, so risks and benefits of kidney biopsy could be more actively discussed with selected patients to reduce misclassification and direct treatment.publishedVersio

Fibroblast Growth Factor–23 and Cardiac Structure and Function

Background: Fibroblast growth factor–23 (FGF‐23) is a phosphaturic factor previously associated with left ventricular hypertrophy and systolic dysfunction among individuals with chronic kidney disease. Whether FGF‐23 acts directly to induce left ventricular hypertrophy, potentially independent of its klotho coreceptor, remains uncertain. We investigated associations of FGF‐23 with cardiac structural abnormalities among individuals with a broad range of kidney function and explored potential biological mechanisms using cardiac magnetic resonance imaging and histology in klotho‐null mice, an established model of constitutively elevated FGF‐23. Methods and Results: Among 887 participants with coronary artery disease in the Heart and Soul Study, FGF‐23 was modestly associated with worse left ventricular ejection fraction (−1.0% per standard deviation increase in lnFGF‐23; standard error, 0.4%), but was not associated with the overall prevalence of concentric hypertrophy (odds ratio, 1.5; CI, 0.9 to 2.4) or eccentric hypertrophy (odds ratio, 1.1; CI, 0.9 to 1.3). FGF‐23 was only associated with concentric hypertrophy among individuals with diminished kidney function (eGFR <60 mL/min per 1.73 m2; odds ratio, 2.3; CI, 1.0 to 5.3; P‐interaction=0.28). Comparing klotho‐null with wild‐type mice, null mice did not have greater left ventricular mass (P=0.37) or a lower ejection fraction (P=0.94). Conclusions: Together, our results suggest that FGF‐23 is unlikely to have major effects on cardiovascular structure and function among patients free of substantial chronic kidney disease, and these effects may not be independent of the klotho coreceptor

Association of urinary uromodulin with kidney&nbsp;function decline and mortality: the&nbsp;health ABC study .

BackgroundUrine uromodulin (uUMOD) is a protein secreted by the kidney tubule. Recent studies have suggested that higher uUMOD may be associated with improved kidney and mortality outcomes.MethodsUsing a case-cohort design, we evaluated the association between baseline uUMOD levels and ≥&nbsp;30% estimated glomerular filtration rate (eGFR) decline, incident chronic kidney disease (CKD), rapid kidney function decline, and mortality using standard and modified Cox proportional hazards regression.ResultsThe median value of uUMOD was 25.8&nbsp;µg/mL, mean age of participants was 74 years, 48% were women, and 39% were black. Persons with higher uUMOD had lower prevalence of diabetes and coronary artery disease (CAD), and had lower systolic blood pressure. Persons with higher uUMOD also had higher eGFR, lower urinary albumin to creatinine ratio (ACR), and lower C-reactive protein (CRP). There was no association of uUMOD with &gt;&nbsp;30% eGFR decline. In comparison to those in the lowest quartile of uUMOD, those in the highest quartile had a significantly (53%) lower risk of incident CKD (CI 73%, 18%) and a 51% lower risk of rapid kidney function decline (CI 76%, 1%) after multivariable adjustment. Higher uUMOD was associated with lower risk of mortality in demographic adjusted models, but not after multivariable adjustment.ConclusionHigher levels of uUMOD are associated with lower risk of incident CKD and rapid kidney function decline. Additional studies are needed in the general population and in persons with advanced CKD to confirm these findings.


Femoral Artery Atherosclerosis Is Associated With Physical Function Across the Spectrum of the Ankle-Brachial Index: The San Diego Population Study.

BackgroundThe ankle-brachial index (ABI) is inadequate to detect early-stage atherosclerotic disease, when interventions to prevent functional decline may be the most effective. We determined associations of femoral artery atherosclerosis with physical functioning, across the spectrum of the ABI, and within the normal ABI range.Methods and resultsIn 2007-2011, 1103 multiethnic men and women participated in the San Diego Population Study, and completed all components of the summary performance score. Using Doppler ultrasound, superficial and common femoral intima media thickness and plaques were ascertained. Logistic regression was used to assess associations of femoral atherosclerosis with the summary performance score and its individual components. Models were adjusted for demographics, lifestyle factors, comorbidities, lipids, and kidney function. In adjusted models, among participants with a normal-range ABI (1.00-1.30), the highest tertile of superficial intima media thickness was associated with lower odds of a perfect summary performance score of 12 (odds ratio=0.56 [0.36, 0.87], P=0.009), and lower odds of a 4-m walk score of 4 (0.34 [0.16, 0.73], P=0.006) and chair rise score of 4 (0.56 [0.34, 0.94], P=0.03). Plaque presence (0.53 [0.29, 0.99], P=0.04) and greater total plaque burden (0.61 [0.43, 0.87], P=0.006) were associated with worse 4-m walk performance in the normal-range ABI group. Higher superficial intima media thickness was associated with lower summary performance score in all individuals (P=0.02).ConclusionsFindings suggest that use of femoral artery atherosclerosis measures may be effective in individuals with a normal-range ABI, especially, for example, those with diabetes mellitus or a family history of peripheral artery disease, when detection can lead to earlier intervention to prevent functional declines and improve quality of life

Mechanisms of action of the SGLT2 inhibitor canagliflozin on tubular inflammation and damage:A post-hoc mediation analysis of the CANVAS trial

AIMS: Exposure of tubular cells to albumin stimulates pro-inflammatory pathways including the release of Monocyte Chemoattractant Protein-1 (MCP-1) which may result in interstitial fibrosis and tubular damage reflected by increased urinary kidney injury molecule-1 (KIM-1). SGLT2 inhibition reduces urine albumin-creatinine ratio (UACR) and small studies suggest it also reduces MCP-1 and KIM-1. We hypothesised that the reduction in KIM-1 observed with the SGLT2 inhibitor canagliflozin is mediated through its effect on UACR and MCP-1. To test this hypothesis, we assessed the proportion of effect of canagliflozin on KIM-1 mediated through its effects on MCP-1 and UACR in patients with type 2 diabetes and albuminuric kidney disease. MATERIAL AND METHODS: KIM-1 and MCP-1 were measured in urine samples of the CANVAS trial at baseline and week 52 with the Mesoscale QuickPlex SQ 120 platform. KIM-1 and MCP-1 were standardized by urinary creatinine. The proportion of mediated effect of canagliflozin through UACR and MCP-1/Cr on KIM-1/Cr was estimated with G-computation. RESULTS: In total, 763 (17.6% of total cohort) patients with micro- or macroalbuminuria were included. Baseline characteristics were well balanced between the canagliflozin and placebo group. At year 1, canagliflozin compared to placebo reduced UACR, MCP-1/Cr, and KIM-1/Cr by 40.4% (95%CI 31.0, 48.4), 18.1% (95%CI 8.9, 26.4), and 30.9% (95%CI 23.0, 38.0), respectively. The proportion of the effect of canagliflozin on KIM-1/Cr mediated by its effect on UACR and in turn on MCP-1/Cr was 15.2% (95%CI 9.4, 24.5). CONCLUSION: Canagliflozin reduces urinary KIM-1 suggesting decreased tubular damage. This effect was partly mediated through a reduction in MCP-1, indicative of reduced tubular inflammation, which was in turn mediated by a reduction in UACR. This post-hoc analysis suggest that urinary albumin leakage may lead to tubular inflammation and induction of injury, and provide mechanistic insight for how canagliflozin may ameliorate tubular damage, but further research is required to confirm these findings. This article is protected by copyright. All rights reserved

Оптимизация продвижения производственно-сервисного предприятия в Интернет-среде

Актуальность работы связана с прогрессирующей популярностью социальных медиа как площадки для продвижения бизнеса, что в свою очередь обусловлено ростом пользователей социальных сетей и их большим маркетинговым потенциалом. Объект исследования – продвижение в интернет-среде. Предмет исследования - SMM как один из элементов комплекса интернет-маркетинга. Цель ВКР – разработка проектных рекомендаций по продвижению торгово-монтажной компании в социальных сетях. Новизна и практическая значимость работы: разработанные проектные рекомендации могут быть реализованы на практике, что позволит оптимизировать продвижение компании в интернет-среде, повысить количество лидов, расширить аудиторию компании и увеличить ее лояльность.The relevance of the work is associated with the progressive popularity of social media as a platform for promoting business, which in turn is due to the growth of users of social networks and their great marketing potential. The object of research is promotion in the Internet environment. The subject of research is SMM as one of the elements of the Internet marketing complex. The purpose of WRC – development of project recommendations for the promotion of trade and installation company in social networks

Genetically Elevated Fetuin-A Levels, Fasting Glucose Levels, and Risk of Type 2 Diabetes: The Cardiovascular Health Study*

OBJECTIVE Fetuin-A levels are associated with higher risk of type 2 diabetes, but it is unknown if the association is causal. We investigated common (>5%) genetic variants in the fetuin-A gene (AHSG) fetuin-A levels, fasting glucose, and risk of type 2 diabetes. RESEARCH DESIGN AND METHODS Genetic variation, fetuin-A levels, and fasting glucose were assessed in 2,893 Caucasian and 542 African American community-living individuals 65 years of age or older in 1992–1993. RESULTS Common AHSG variants (rs4917 and rs2248690) were strongly associated with fetuin-A concentrations (P < 0.0001). In analyses of 259 incident cases of type 2 diabetes, the single nucleotide polymorphisms (SNPs) were not associated with diabetes risk during follow-up and similar null associations were observed when 579 prevalent cases were included. As expected, higher fetuin-A levels were associated with higher fasting glucose concentrations (1.9 mg/dL [95% CI, 1.2–2.7] higher per SD in Caucasians), but Mendelian randomization analyses using both SNPs as unbiased proxies for measured fetuin-A did not support an association between genetically predicted fetuin-A levels and fasting glucose (−0.3 mg/dL [95% CI, −1.9 to 1.3] lower per SD in Caucasians). The difference between the associations of fasting glucose with actual and genetically predicted fetuin-A level was statistically significant (P = 0.001). Results among the smaller sample of African Americans trended in similar directions but were statistically insignificant. CONCLUSIONS Common variants in the AHSG gene are strongly associated with plasma fetuin-A concentrations, but not with risk of type 2 diabetes or glucose concentrations, raising the possibility that the association between fetuin-A and type 2 diabetes may not be causal

Population-Based Limits of Urine Creatinine Excretion

Introduction: The validity of a timed urine collection is typically judged by measurement of urine creatinine excretion, but prevailing limits may be unreliable. We sought to empirically derive population-based limits of excretion for evaluating the validity of a timed urine collection. Methods: Covariate and 24-hour urine data were obtained from 3582 participants in the Chronic Renal Insufficiency Cohort (CRIC) study, 814 participants in the Modification of Diet in Renal Disease (MDRD) study, 1010 participants in the Jackson Heart Study (JHS), and 8536 participants in the Prevention of Renal Vascular End Stage Disease (PREVEND) study. Weight, height, age, sex, and serum creatinine concentrations were evaluated as potential predictors of urine creatinine excretion using Akaike Information Criteria, R-squared values, and deviance. Bias and precision of the fitted models were assessed by analyses of residuals. Agreement between 24-hour creatinine clearance and 125I-iothalamate clearance was assessed before and after exclusion of potentially invalid urine samples. Results: A best-fitting model to predict 24-hour urine creatinine excretion among the 9199 discovery cohort members included sex-specific terms for weight, height, and age (R-squared = 0.328). This model had a median bias of +4.3 mg creatinine/day (95% confidence interval −5.6, +13.3 mg/day) in 4599 validation cohort members, and 82% of observed values were within 30% of predicted model. Serum creatinine concentrations only marginally improved model precision but reduced bias in persons with advanced chronic kidney disease (CKD). Conclusion: The limits of urine creatinine excretion derived here represent the most valid and representative data for appraising the adequacy of a timed urine collection