Hasil untuk "Diseases of the circulatory (Cardiovascular) system"

W. Frąk, Armanda Wojtasińska, Wiktoria Lisińska et al.

Cardiovascular diseases (CVDs) are disorders associated with the heart and circulatory system. Atherosclerosis is its major underlying cause. CVDs are chronic and can remain hidden for a long time. Moreover, CVDs are the leading cause of global morbidity and mortality, thus creating a major public health concern. This review summarizes the available information on the pathophysiological implications of CVDs, focusing on coronary artery disease along with atherosclerosis as its major cause and arterial hypertension. We discuss the endothelium dysfunction, inflammatory factors, and oxidation associated with atherosclerosis. Mechanisms such as dysfunction of the endothelium and inflammation, which have been identified as critical pathways for development of coronary artery disease, have become easier to diagnose in recent years. Relatively recently, evidence has been found indicating that interactions of the molecular and cellular elements such as matrix metalloproteinases, elements of the immune system, and oxidative stress are involved in the pathophysiology of arterial hypertension. Many studies have revealed several important inflammatory and genetic risk factors associated with CVDs. However, further investigation is crucial to improve our knowledge of CVDs progression and, more importantly, accelerate basic research to improve our understanding of the mechanism of pathophysiology.

Robert D Brook, Pia-Allison Roa, Phillip D Levy et al.

Background: Fine particulate matter <2.5 µm (PM2.5) air pollution increases cardio-pulmonary morbidity and mortality. To inform the public regarding local air quality and reduce short-term exposures to PM2.5, daily Air Quality Indices (AQIs) with activity guidance are issued across the United States (US). We aimed to estimate the cardio-pulmonary health benefits of the current AQI strategy. Methods: We estimated the number needed to treat (NNT) per county per day to avoid 1 atherosclerotic cardiovascular disease (ASCVD) or pulmonary event during each PM2.5 AQI action day (defined as a day with an AQI >100 for PM2.5) for 3 groups (healthy adults, ASCVD and pulmonary disease patients) in the US during 2022. The theoretical number of adverse events potentially prevented per county was estimated each day as the relevant county population divided by the corresponding NNT. These results were summed for all AQI action days among US counties to equal the potential total number of ASCVD and pulmonary events avoided nationwide. Results: There were 1081 AQI action days for PM2.5 (58.0 ± 32.4 µg/m3) across 236 counties in 2022, accounting for an estimated excess of 164 ASCVD and 3963 pulmonary events. Approximately 31 ASCVD and 796 pulmonary events could be theoretically avoided if all populations followed activity guidelines during every AQI action day. Conclusions: Daily AQI activity guidelines, as currently structured and implemented, likely prevent few cardio-pulmonary events per year in the US. Additional research is warranted to determine how to improve the overall approach to more effectively protect public health.

Rosa Lillo, Rosa Lillo, Alessio Cianci et al.

BackgroundTo date, only limited data are available on right atrium (RA) morphofunctional remodeling in Fabry disease (FD).PurposeWe aimed to investigate RA structural and functional remodeling in patients with FD vs. healthy controls using 2D speckle tracking echocardiography (STE) and to explore whether any differences exist in FD patients with and without left ventricular hypertrophy (LVH).MethodsWe prospectively enrolled patients with FD and controls matched for age, sex, and cardiovascular risk factors. Patients with FD were divided in two groups according to the presence/absence of LVH (LVH+: left ventricular wall thickness &gt;12 mm). All patients underwent standard echocardiography and STE analysis investigating the mechanics of all cardiac chambers, including RA reservoir, contractile and conduit strain.ResultsA total of 64 patients with FD (50% males; mean age 50 ± 17 years; 51.5% LVH+) and 64 control patients were included in the study. Focusing on right chambers, RA and right ventricular (RV) dimensions were similar between FD and controls. No differences were found for tricuspid annular plane systolic excursion (p = 0.073) and RV fractional area change (p = 0.461), while RV systolic Tissue Doppler velocity was reduced in patients with FD (p = 0.041). STE analysis revealed impaired strain values for all cardiac chambers in FD vs controls, specifically: left ventricular global longitudinal strain (LV-GLS, p &lt; 0.001), left atrial (LA) reservoir strain (p = 0.001), conduit strain (p = 0.012), and contractile strain (p &lt; 0.001), RV-GLS and RV free wall strain (p &lt; 0.001). Similarly, all RA strain phases were significantly reduced in patients with FD compared with control patients (RA reservoir 27.4 ± 11.1 vs. 41.9 ± 8.3%, p &lt; 0.001; RA contractile 9.9 ± 5.1 vs. 18.0 ± 4.9%, p &lt; 0.001; RA conduit 19.1 ± 8.1 vs. 24.1 ± 8.1%, p = 0.001). When comparing FD patients without LVH to controls, it was found that RA reservoir and contractile strains were significantly reduced in the former (p &lt; 0.001). In multivariable linear regression analyses, LA reservoir strain (p = 0.010) and LV-GLS (p = 0.044) emerged as independent correlates of RA mechanics after adjustments were made for RA dimensions, RV systolic function parameters and hypertrophy, and LV maximal wall thickness.ConclusionsIn FD impaired RA strain is a common finding. RA reservoir and contractile strains are reduced in FD patients even before LVH ensues, as compared to controls. LA reservoir strain and LV-GLS show an independent correlation with RA reservoir strain.

Shaik Jakeer, S. N, Seethi Reddy Reddisekhar Reddy

Abstract The investigation of the rheological properties of bio-magnetic nanofluid in the human circulatory system has attracted the attention of biomedical engineers, medical professionals and researchers in recent days to explore the potential of utilizing magnetic field in the diagnosis of cancer cells, thrombosis and cardiovascular diseases. The Eyring-Powell fluid model was employed in this investigation because it accurately captures the non-Newtonian features of blood owing to its shear thinning and stress relaxation qualities. The present study illustrates the importance of the induced magnetic field on Eyring-Powell nanofluid flow across three distinct geometries (stagnation point, plate, and wedge) with the presence of gyrotactic microorganisms. The investigation of different geometries provides essential information regarding their practical applications, such as the development of targeted therapies for localized drug delivery, the dissolution of blood clots to promote clot breakdown, the enhancement of drug delivery to specific regions, the prevention of biofilm formation on vessel walls, the promotion of improved blood flow, and the reduction of plaque for arterial health. The conversion of fluid transport equations into ordinary differential equations has been achieved through the utilization of appropriate self-similarity variables. The resulting equations have been solved with the use of the Runge-Kutta-Fehlberg (RKF) approach. The characteristics of numerous dimensionless parameters such as magnetic Prandtl number (Mmp=0.5,1.0,1.5), magnetic parameter (βmp=0.2,0.4,0.6), fluid parameters (ε,δ=0.0,0.5,1.0), chemical reaction parameter (Kr=0.0,0.5,1.0), Eckert number (Ec=1.0,2.0,3.2), Thermophoresis (NT=0.3,0.6,0.9), Brownian motion (NB=0.3,0.6,0.9), Biot number (Bi=0.5,1.0,1.5), bioconvective constant (σ1=0.0,1.0,2.0), bioconvective Schmidt number (Sb=0.1,0.3,0.5), Peclet number (Pe=0.1,0.3,0.5), temperature ratio (θw=1.0,2.0,3.0), Radiation (Rd=0.0,1.0,1.5), Schmidt number (Sc=1.0,2.0,3.0), and non-dimensional activation energy (E=0.0,0.5,1.0) are analyzed. The magnetic Prandtl number and the magnetic parameter both show a decrease with an increase in the induced magnetic field. The magnitude of concentration increases with the elevation of both the Bio convective constant and the Peclet number. The skin friction coefficient is increased to the higher values of the fluid parameter in all three geometries. Nusselt number and Sherwood number both increase to the higher values of the thermophoresis parameter across the plate, wedge, and stagnation point. The Peclet and bioconvective numbers increase the concentration of motile organisms across the plate, wedge, and stagnation point geometries.

Francesco Bardi, E. Gasparotti, E. Vignali et al.

Background Cardiovascular diseases remain a leading cause of morbidity and mortality worldwide and require extensive investigation through in-vitro studies. Mock Circulatory Loops (MCLs) are advanced in-vitro platforms that accurately replicate physiological and pathological hemodynamic conditions, while also allowing for precise and patient-specific data collection. Particle Image Velocimetry (PIV) is the standard flow visualization technique for in-vitro studies, but it is costly and requires strict safety measures. High-power Light Emitting Diode illuminated PIV (LED-PIV) offers a safer and cheaper alternative. Methods In this study, we aim to demonstrate the feasibility of a Hybrid-MCL integrated with a LED-PIV system for the investigation of Abdominal Aortic Aneurysm (AAA) compliant phantoms. We considered two distinct AAA models, namely, an idealized model and a patient-specific one under different physiological flow and pressure conditions. Results The efficacy of the proposed setup for the investigation of AAA hemodynamics was confirmed by observing velocity and vorticity fields across multiple flow rate scenarios and regions of interest. Conclusion The findings of this study underscore the potential impact of Hybrid-MCL integrated with a LED-PIV system on enhancing the affordability, accessibility, and safety of in-vitro CVD investigations.

E. Konduracka, P. Rostoff

Acute exposure to air pollution is associated with an increasing risk of death and cardiovascular disorders. Nonetheless, the impact of chronic exposure to air pollution on the circulatory system is still debated. Here, we review the links of chronic exposure to outdoor air pollution with mortality and most common cardiovascular diseases, in particular during the coronavirus disease 2019 event (COVID-19). We found that recent studies provide robust evidence for a causal effect of chronic exposure to air pollution and cardiovascular mortality. In terms of mortality, the strongest relationship was noted for fine particulate matter, nitrogen dioxide, and ozone. There is also increasing evidence showing that exposure to air pollution, mainly fine particulate matter and nitrogen dioxide, is associated with the development of atherosclerosis, hypertension, stroke, and heart failure. However, available scientific evidence is not strong enough to support associations with cardiac arrhythmias and coagulation disturbances. Noteworthy, for some pollutants, the risk of negative health effects is high for concentrations lower than the limit values recommended by the European Union and Word Health Organization. Efforts to diminish exposure to air pollution and to design optimal methods of air pollution reduction should be urgently intensified and supported by effective legislation and interdisciplinary cooperation.

I. Y. Cho, H. Koo, Yoo Jin Um et al.

BACKGROUND While intellectual disability is associated with higher mortality rates due to circulatory diseases, it is unclear whether intellectual disability is associated with higher risk of myocardial infarction (MI) and stroke than the general population. OBJECTIVES We aimed to analyze the risk of cardiovascular diseases (CVD), specifically myocardial infarction (MI) and ischemic stroke, and death due to circulatory diseases in individuals with disability. METHODS This retrospective cohort study used data from the National Disability Registration System linked to the Korean National Health Insurance Service database. Individuals who underwent national health examinations in 2009 were followed until 2020. Cox-proportional hazard analyses were performed to estimate the risk of CVD, MI, ischemic stroke, and circulatory disease deaths with adjustment for covariates. RESULTS A total of 3642 individuals with intellectual disability (mean [SD] age 39.1 [12.6], 28.8 % female) and 3,889,794 individuals without intellectual disability (mean [SD] age 47.1 [13.9], 45.6 % female) were included. Compared to those without intellectual disability, those with intellectual disability had higher risk of CVD (adjusted hazard ratio [aHR] 1.71, 95 % confidence interval [CI] 1.45-2.02), ischemic stroke (aHR 2.21, 95 % CI 1.81-2.69), and death due to circulatory diseases (aHR 4.20, 95 % CI 3.24-5.45), and a non-significant risk for MI (aHR 1.24, 95 % CI 0.95-1.63) after full adjustment for covariates. CONCLUSIONS Individuals with intellectual disability were at increased risk of CVD, in particular ischemic stroke, and death due to circulatory diseases. Healthcare professionals should be aware of increased CVD risk in individuals with intellectual disability.

Galina V. Artamonova, Evgeny D. Bazdyrev, Sergey A. Makarov

HighlightsWe have identified regional peculiarities of traditional and non-traditional cardiovascular risk factors.We have defined and characterized clinical and organizational characteristics of the specialized care, prevention, and treatment of diseases of the circulatory system in the Kemerovo region - Kuzbass.Moreover, we have described the principles of innovative organizational models for improving care for patients with diseases of the circulatory system, focused on the needs of outpatient organizations. AbstractThe review presents the main research findings obtained at the Department of Optimization of Medical Care for Cardiovascular Diseases of the Research Institute for Complex Issues of Cardiovascular Diseases over the past 13 years of work. The uniqueness of the obtained data lies in the fact that we have identified regional peculiarities of cardiovascular risk factors in residents of an industrial region (using the Kemerovo region data). Data on monitoring of health and risk factors served as the basis for the development of innovative organizational models for improving care for patients with diseases of the circulatory system from the stage of primary care to tertiary care using a systematic and integrated approach, and situational analysis. Management decisions within models are based on international quality standards that reaffirm that risk-based management, the role of personnel and the work environment are the integral to the improvement of performance and the achievement of the main goals of medical organization. Using the project approach, we have implemented management tools for internal quality control and safety of patients and personnel.

Wenpeng Shi, Atik Rohmana Maftuhatul Fuad, Yanhong Li et al.

Biodegradable polymers are expected to be an alternative to plastics. Because of its high biocompatibility, poly (lactic-co-glycolic acid) (PLGA) is widely used in medicine. It has been reported that micro-nano plastics can be accumulated in the circulatory system and cause tissue injury. With the increasing environmental exposure of degradable polymer nanoparticles (NPs), the impact of this risk factor on cardiovascular disease deserves attention. Thus, we aim to study the harmful effect of PLGA NPs on the process of vascular stenosis which is a typical pathological feature of cardiovascular diseases. We establish a mouse vascular stenosis model with intravenously injecting of PLGA NPs for 2 weeks. This model leads to a significant narrowing of the left common carotid artery which is characterized by the increasing intima area and focal stenosis. We observe that PLGA NPs accelerate stenosis progression by inducing inflammation and impairing vascular function. It promotes the proliferation of smooth muscle cells and causes abnormal collagen distribution. The combination of wall shear stress and PLGA NPs uptake speed up endothelial cell damage, decrease endothelial permeability and cell migration capacity. Our results suggest that PLGA NPs may pose a risk in cardiovascular stenosis which inspire us to concern the biodegradable polymeric materials in our living especially the clinic applications. Graphical Abstract

Yu. Ganzhula, Zh. Borykbay, V. Tkachev et al.

Introduction. The health of centenarians is a major focus in global studies. Dyslipidemia is directly linked to the risk of cardiovascular diseases, which pose a growing burden on healthcare due to the increasing elderly population. Studying the lipid profiles of centenarians is important for preventing circulatory system diseases and promoting healthy aging. This research aims to compare the prevalence of dyslipidemia in centenarians (median age 96 [95-97]) with elderly individuals (median age was 69 [64 – 74]) in the Republic of Kazakhstan and examine potential predictors of dyslipidemia in the centenarian group. Methods. The study involved 46 centenarians (study group) and 82 elderly individuals (control group). Statistical analysis was used to process the data, including blood markers and demographic variables, to identify factors contributing to dyslipidemia. Results and conclusion. The prevalence of hypercholesterolemia in centenarians was 32.6% (15 people - 3 men; 12 women), with elevated LDL levels in 4.3% (2 women). In the control group, hypercholesterolemia prevalence was 29.3% (24 people - 6 men; 18 women) and elevated triglycerides in 6.1% (3 women; 2 men). The study and control groups were compared based on their lipid profile characteristics, which showed similarities as indicated by all p-values being above 0.05: Cholesterol (p=0.348), HDL (p=0.975), LDL (p=0.161), and Triglycerides (p=0.159). Decreased physical activity was a predictor of dyslipidemia in centenarians. Excessive cholesterol levels were significantly higher among women than men in both groups. The primary factor for dyslipidemia was low physical activity, with other predictors having no significant impact on the lipid profiles of centenarians. This factor should be considered when assessing cardiovascular disease risks and all-cause mortality.

José Nunes de Alencar

Satoshi Higa

G. Bkaily, D. Jacques

The vascular endothelium plays a vital role during embryogenesis and aging and is a cell monolayer that lines the blood vessels. The immune system recognizes the endothelium as its own. Therefore, an abnormality of the endothelium exposes the tissues to the immune system and provokes inflammation and vascular diseases such as atherosclerosis. Its secretory role allows it to release vasoconstrictors and vasorelaxants as well as cardio-modulatory factors that maintain the proper functioning of the circulatory system. The sealing of the monolayer provided by adhesion molecules plays an important role in cardiovascular physiology and pathology.

Seyed Mahdi Emami Meybodi, Nafiseh Soleimani, Abolfazl Yari et al.

L. Rodríguez, Diego Méndez, Hector Montecino et al.

In terms of safe and healthy food, beans play a relevant role. This crop belongs to the species of Phaseolus vulgaris L., being the most consumed legume worldwide, both for poor and developed countries, the latter seek to direct their diet to healthy feeding, mainly low in fat. Phaseolus vulgaris L. stands out in this area—an important source of protein, vitamins, essential minerals, soluble fiber, starch, phytochemicals, and low in fat from foods. This species has been attributed many beneficial properties for health; it has effects on the circulatory system, immune system, digestive system, among others. It has been suggested that Phaseolus vulgaris L. has a relevant role in the prevention of cardiovascular events, the main cause of mortality and morbidity worldwide. Conversely, the decrease in the consumption of this legume has been related to an increase in the prevalence of cardiovascular diseases. This review will allow us to relate the nutritional level of this species with cardiovascular events, based on the correlation of the main bioactive compounds and their role as cardiovascular protectors, in addition to revealing the main mechanisms that explain the cardioprotective effects regulated by the bioactive components.

B. Das

Cardiopulmonary exercise testing (CPET) is the clinical standard for children with congenital heart disease (CHD), heart failure (HF) being assessed for transplantation candidacy, and subjects with unexplained dyspnea on exertion. Heart, lung, skeletal muscle, peripheral vasculature, and cellular metabolism impairment frequently lead to circulatory, ventilatory, and gas exchange abnormalities during exercise. An integrated analysis of the multi-system response to exercise can be beneficial for differential diagnosis of exercise intolerance. The CPET combines standard graded cardiovascular stress testing with simultaneous ventilatory respired gas analysis. This review addresses the interpretation and clinical significance of CPET results with specific reference to cardiovascular diseases. The diagnostic values of commonly obtained CPET variables are discussed using an easy-to-use algorithm for physicians and trained nonphysician personnel in clinical practice.

A. Sehgal, B. Allison, F. Crispi et al.

Epidemiologists have long documented higher risk of adult-onset cardiovascular diseases (CVD) such as stroke, hypertension and coronary artery disease) and mortality from circulatory causes in low birth weight cohorts (poor in utero substrate supply). Utero-placental insufficiency and in utero hypoxemic state induced alterations in arterial structure and compliance are important initiating factors for adult-onset hypertension. The mechanistic links between fetal growth restriction and CVD include decreased arterial wall elastin/collagen ratio, endothelial dysfunction and heightened renin-angiotensin-aldosterone-system (RAAS). Systemic arterial thickness on fetal ultrasound and vascular changes in placental histopathology in growth restricted cohorts indicate fetal/developmental origins of adult-onset circulatory diseases. Similar findings of impaired arterial compliance have been noticed across age-groups (neonates through to adults). Such changes augment what occurs as 'normal arterial ageing', resulting in accelerated arterial ageing. Data from animal models suggest that hypoxemia-associated vascular adaptations enacted in utero are region specific, reflecting long-term vascular pathology. In this review we explore the influence of birthweight and prematurity on blood pressure and arterial stiffness, demonstrating impaired arterial dynamics in growth restricted cohorts across age-groups, explain how early arterial ageing influences adult-onset CVDs, describe pathophysiology data from experimental models and finally, discuss interventions which may influence ageing by way of altering various cellular and molecular mechanisms of arterial ageing. Age-appropriate interventions which have noted efficacy include prolonged breastfeeding and high polyunsaturated fatty acids dietary intake. Targeting the RAAS seems a promising approach. New data indicates activation of Sirtuin 1 and maternal resveratrol may have beneficial effects.

T. Kossova

This article aims to investigate economic factors that determine the mortality rate from cardiovascular diseases in Russian regions. Independent variables are socio-economic factors, including the level of well-being, characteristics of the health care system in the region, level of alcohol consumption as a characteristic of the lifestyle of the population, as well as the directions of state policy for prevention and treatment of cardiovascular diseases, and alcohol and tobacco control initiatives. These factors are the focus of several social programs currently being implemented in Russia. The objective of this study is to identify the degree of sensitivity of the mortality rate from circulatory system diseases to changes in each of the factors considered. This will help to guide public policies aimed at improving population health.The empirical component of the study is based on the data from the Federal State Statistics Service of Russia (for the period from 2005 to 2019), as well as regional budgets and territorial compulsory health insurance funds. Panel data model with fixed effects was evaluated, and the elasticity of mortality from circulatory system diseases to changes in the formed set of factors. The paper shows that an increase in health care costs leads to a decrease in mortality from circulatory system diseases. With that, the sensitivity of this indicator to a one percent change in factors of well-being and lifestyle, including the volume of alcohol consumption, is higher than the sensitivity to a one percent change in health care expenditures. The article revealed the presence of a statistically significant relationship between changes in the legislation, which led to a significant increase in the availability of expensive medical care, and a decrease in mortality from circulatory system diseases. The findings are relevant for those reforming the health care system and can serve as a guideline for developing parameters of government healthcare programs.

Lawrence A Leiter, David G Kallend, Wolfgang Koenig et al.

Therapeutic Area: ASCVD/CVD Risk Factors Background: Excessive bodyweight, often associated with dyslipidemia, may affect the pharmacology of drugs. Inclisiran, a small interfering RNA targeting PCSK9 hepatic mRNA, is an effective LDL-C lowering agent with twice-yearly subcutaneous dosing (after the initial and 3-month doses). The aim of this analysis was to assess the efficacy and safety of inclisiran in patients with heterozygous familial hypercholesterolemia, atherosclerotic cardiovascular disease (ASCVD) or ASCVD risk equivalent across body mass index (BMI) strata. Methods: In this post hoc analysis from ORION-9 (NCT03397121), ORION-10 (NCT03399370) and ORION-11 (NCT03400800), eligible patients were randomized 1:1 to receive 300 mg inclisiran sodium (equivalent to 284 mg inclisiran) or placebo at baseline, Day 90 and 6-monthly thereafter. Analysis was stratified by baseline BMI: <25, 25–<30, 30–<35 or ≥35 kg/m2. Percentage change in atherogenic lipids from baseline at Day 510 was evaluated. Safety was assessed over 540 days. Results: Baseline demographic and clinical characteristics including atherogenic lipid levels were mostly balanced between treatment arms and across BMI strata (Table). Percentage change in atherogenic lipids from baseline at Day 510 was significantly greater with inclisiran vs placebo within each BMI stratum (Table). Treatment-emergent adverse events (TEAE) and treatment-emergent serious adverse events were generally similar between treatment arms and were reported more frequently with increasing BMI strata (data not shown). Clinically relevant TEAEs at the injection site were reported more frequently with inclisiran vs placebo similarly across strata, but all were mild or moderate. Conclusion: Twice-yearly dosing with inclisiran (after the initial and 3-month doses) provided effective and sustained lipid lowering in patients, irrespective of their baseline BMI, and was generally well tolerated.

Aseel Alsouqi, Serpil Muge Deger, Melis Sahinoz et al.

Background Sodium (Na+) stored in skin and muscle tissue is associated with essential hypertension. Sodium magnetic resonance imaging is a validated method of quantifying tissue stores of Na+. In this study, we evaluated tissue Na+ in patients with elevated blood pressure or stage I hypertension in response to diuretic therapy or low Na+ diet. Methods and Results In a double‐blinded, placebo‐controlled trial, patients with systolic blood pressure 120 to 139 mm Hg were randomized to low sodium diet (<2 g of sodium), chlorthalidone, spironolactone, or placebo for 8 weeks. Muscle and skin Na+ using sodium magnetic resonance imaging and pulse wave velocity were assessed at the beginning and end of the study. Ninety‐eight patients were enrolled to undergo baseline measurements and 54 completed randomization. Median baseline muscle and skin Na+ in 98 patients were 16.4 mmol/L (14.9, 18.9) and 13.1 mmol/L (11.1, 16.1), respectively. After 8 weeks, muscle Na+ increased in the diet and chlorthalidone arms compared with placebo. Skin sodium was decreased only in the diet arm compared with placebo. These associations remained significant after adjustment for age, sex, body mass index, systolic blood pressure, and urinary sodium. No changes were observed in pulse wave velocity among the different groups when compared with placebo. Conclusions Diuretic therapy for 8 weeks did not decrease muscle or skin sodium or improve pulse wave velocity in patients with elevated blood pressure or stage I hypertension. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02236520.