Acquiring and Modeling of Si Solar-Cell Transient Response to Pulsed X-Ray

We report on the acquisition and modeling of the transient response of a commercial silicon (Si) solar cell using a benchtop pulsed X-ray source. The solar-cell transient output to the X-ray pulses was acquired under the dark and steady-state light illumination to mimic the practical operation of a solar cell under different light illumination levels. A solar-cell circuit model was created to develop a fundamental understanding of the transient current/voltage response of solar cell at read-out circuit level. The model was validated by a good agreement between the simulation and experimental results. It was found that the solar-cell resistance ( $R$ ) and capacitance ( $C$ ) depend on the light illumination, and the resulting variation in $RC$ time constant significantly affects the solar-cell transient response. Thus, the solar cell produced different transient signals under different illumination intensities in response to the same X-ray pulse. The experimental data acquired in this work proves the feasibility of using solar panels for prompt detection of nuclear detonations, which also builds a practical mode of X-ray detection using a low-cost self-powered detector

Hypoxia induces dilated cardiomyopathy in the chick embryo: mechanism, intervention, and long-term consequences

Background: Intrauterine growth restriction is associated with an increased future risk for developing cardiovascular diseases. Hypoxia in utero is a common clinical cause of fetal growth restriction. We have previously shown that chronic hypoxia alters cardiovascular development in chick embryos. The aim of this study was to further characterize cardiac disease in hypoxic chick embryos. Methods: Chick embryos were exposed to hypoxia and cardiac structure was examined by histological methods one day prior to hatching (E20) and at adulthood. Cardiac function was assessed in vivo by echocardiography and ex vivo by contractility measurements in isolated heart muscle bundles and isolated cardiomyocytes. Chick embryos were exposed to vascular endothelial growth factor (VEGF) and its scavenger soluble VEGF receptor-1 (sFlt-1) to investigate the potential role of this hypoxia-regulated cytokine. Principal Findings: Growth restricted hypoxic chick embryos showed cardiomyopathy as evidenced by left ventricular (LV) dilatation, reduced ventricular wall mass and increased apoptosis. Hypoxic hearts displayed pump dysfunction with decreased LV ejection fractions, accompanied by signs of diastolic dysfunction. Cardiomyopathy caused by hypoxia persisted into adulthood. Hypoxic embryonic hearts showed increases in VEGF expression. Systemic administration of rhVEGF165 to normoxic chick embryos resulted in LV dilatation and a dose-dependent loss of LV wall mass. Lowering VEGF levels in hypoxic embryonic chick hearts by systemic administration of sFlt-1 yielded an almost complete normalization of the phenotype. Conclusions/Significance: Our data show that hypoxia causes a decreased cardiac performance and cardiomyopathy in chick embryos, involving a significant VEGF-mediated component. This cardiomyopathy persists into adulthood

Evaluation of sub-acute changes in cardiac function after cisplatin-based combination chemotherapy for testicular cancer

Long-term cardiovascular morbidity is increasingly observed in chemotherapy-treated testicular cancer survivors, but little is known of early sub-clinical changes in cardiac function. We prospectively evaluated cardiac function in testicular cancer patients by echocardiography. Systolic (Wall Motion Score Index) and diastolic (E/A-ratio and Tissue Velocity Imaging (TVI)) parameters, and serum levels of N-Terminal pro-Brain Natriuretic Peptide (NT-proBNP) were assessed before the start of chemotherapy and 1 year later. Echocardiography data were compared with an age-matched group of healthy controls. Forty-two patients treated with bleomycin, etoposide and cisplatin were evaluated (median age 27 years, range 18–50). Systolic function and E/A-ratio did not change, whereas the median TVI decreased (12.0 vs 10.0 cms−1; P=0.002). Median levels of NT-proBNP increased (5 vs 18 pmoll−1, P=0.034). Compared with controls, TVI before the start of chemotherapy was not significantly different. In conclusion, we found that at a median of 10 months after cisplatin-based treatment for testicular cancer, TVI decreased significantly, indicating a deterioration of diastolic cardiac function. Serum levels of NT-proBNP increased. The prognostic significance of these changes for future cardiovascular morbidity is not clear

Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction

Background The angiotensin receptor-neprilysin inhibitor sacubitril-valsartan led to a reduced risk of hospitalization for heart failure or death from cardiovascular causes among patients with heart failure and reduced ejection fraction. The effect of angiotensin receptor-neprilysin inhibition in patients with heart failure with preserved ejection fraction is unclear. Methods We randomly assigned 4822 patients with New York Heart Association (NYHA) class II to IV heart failure, ejection fraction of 45% or higher, elevated level of natriuretic peptides, and structural heart disease to receive sacubitril-valsartan (target dose, 97 mg of sacubitril with 103 mg of valsartan twice daily) or valsartan (target dose, 160 mg twice daily). The primary outcome was a composite of total hospitalizations for heart failure and death from cardiovascular causes. Primary outcome components, secondary outcomes (including NYHA class change, worsening renal function, and change in Kansas City Cardiomyopathy Questionnaire [KCCQ] clinical summary score [scale, 0 to 100, with higher scores indicating fewer symptoms and physical limitations]), and safety were also assessed. Results There were 894 primary events in 526 patients in the sacubitril-valsartan group and 1009 primary events in 557 patients in the valsartan group (rate ratio, 0.87; 95% confidence interval [CI], 0.75 to 1.01; P=0.06). The incidence of death from cardiovascular causes was 8.5% in the sacubitril-valsartan group and 8.9% in the valsartan group (hazard ratio, 0.95; 95% CI, 0.79 to 1.16); there were 690 and 797 total hospitalizations for heart failure, respectively (rate ratio, 0.85; 95% CI, 0.72 to 1.00). NYHA class improved in 15.0% of the patients in the sacubitril-valsartan group and in 12.6% of those in the valsartan group (odds ratio, 1.45; 95% CI, 1.13 to 1.86); renal function worsened in 1.4% and 2.7%, respectively (hazard ratio, 0.50; 95% CI, 0.33 to 0.77). The mean change in the KCCQ clinical summary score at 8 months was 1.0 point (95% CI, 0.0 to 2.1) higher in the sacubitril-valsartan group. Patients in the sacubitril-valsartan group had a higher incidence of hypotension and angioedema and a lower incidence of hyperkalemia. Among 12 prespecified subgroups, there was suggestion of heterogeneity with possible benefit with sacubitril-valsartan in patients with lower ejection fraction and in women. Conclusions Sacubitril-valsartan did not result in a significantly lower rate of total hospitalizations for heart failure and death from cardiovascular causes among patients with heart failure and an ejection fraction of 45% or higher. (Funded by Novartis; PARAGON-HF ClinicalTrials.gov number, NCT01920711.

Advanced glycation end-products, a pathophysiological pathway in the cardiorenal syndrome

The prevalence of heart failure (HF) is increasing. A distinction is made between diastolic HF (preserved left ventricular ejection fraction (LVEF)) and systolic HF (reduced LVEF). Advanced glycation end-products (AGEs) are crystallized proteins that accumulate during ageing, but are particularly increased in patients with diabetes mellitus and in patients with renal failure. Through the formation of collagen crosslinks, and by interaction with the AGE-receptor, which impairs calcium handling and increases fibrosis, AGE-accumulation has pathophysiologically been associated with the development of diastolic and renal dysfunction. Interestingly, diastolic dysfunction is a frequent finding in elderly patients, diabetic patients and in patients with renal failure. Taken together, this suggests that AGEs are related to the development and progression of diastolic HF and renal failure. In this review, the role of AGEs as a possible pathophysiological factor that link the development and progression of heart and renal failure, is discussed. Finally, the role of AGE intervention as a possible treatment in HF patients will be discussed

Application of a Key Events Dose-Response Analysis to Nutrients: A Case Study with Vitamin A (Retinol)

The methodology used to establish tolerable upper intake levels (UL) for nutrients borrows heavily from risk assessment methods used by toxicologists. Empirical data are used to identify intake levels associated with adverse effects, and Uncertainty Factors (UF) are applied to establish ULs, which in turn inform public health decisions and standards. Use of UFs reflects lack of knowledge regarding the biological events that underlie response to the intake of a given nutrient, and also regarding the sources of variability in that response. In this paper, the Key Events Dose-Response Framework (KEDRF) is used to systematically consider the major biological steps that lead from the intake of the preformed vitamin A to excess systemic levels, and subsequently to increased risk of adverse effects. Each step is examined with regard to factors that influence whether there is progression toward the adverse effect of concern. The role of homeostatic mechanisms is discussed, along with the types of research needed to improve understanding of dose-response for vitamin A. This initial analysis illustrates the potential of the KEDRF as a useful analytical tool for integrating current knowledge regarding dose-response, generating questions that will focus future research efforts, and clarifying how improved knowledge and data could be used to reduce reliance on UFs

Effects of Sacubitril-Valsartan, versus Valsartan, in Women Compared to Men with Heart Failure and Preserved Ejection Fraction: Insights from PARAGON-HF

Unlike heart failure with reduced ejection fraction, there is no approved treatment for heart failure with preserved ejection fraction (HFpEF), the predominant phenotype in women. Therefore, there is a greater heart failure therapeutic deficit in women, compared with men. In a pre-specified subgroup analysis, we examined outcomes according to sex in the PARAGON-HF trial which compared sacubitril-valsartan and valsartan in patients with HFpEF. The primary outcome was a composite of first and recurrent hospitalizations for heart failure and death from cardiovascular causes. We also report secondary efficacy and safety outcomes. Overall, 2479 women (51.7%) and 2317 men (48.3%) were randomized. Women were older, had more obesity, less coronary disease, and lower estimated glomerular filtration rate and NT-proBNP levels than men. For the primary outcome, the rate ratio for sacubitril-valsartan versus valsartan was 0.73 (95% CI 0.59-0.90) in women and 1.03 (0.84-1.25) in men; P interaction=0.017. The benefit from sacubitril-valsartan was due to reduction in heart failure hospitalization. The improvement in NYHA class and renal function with sacubitril-valsartan was similar in women and men, whereas the improvement in KCCQ-CSS was less in women than in men. The difference in adverse events, between sacubitril-valsartan and valsartan, was similar in women and men. As compared with valsartan, sacubitril-valsartan seemed to reduce the risk of heart failure hospitalization more in women than in men. While the possible sex-related modification of the effect of treatment has several potential explanations, the present study does not provide a definite mechanistic basis for this finding. URL: https://clinicaltrials.gov Unique Identifier: NCT01920711

Animal Models of Dyssynchrony

Cardiac resynchronization therapy (CRT) is an important therapy for patients with heart failure and conduction pathology, but the benefits are heterogeneous between patients and approximately a third of patients do not show signs of clinical or echocardiographic response. This calls for a better understanding of the underlying conduction disease and resynchronization. In this review, we discuss to what extent established and novel animal models can help to better understand the pathophysiology of dyssynchrony and the benefits of CRT

Global Differences in Heart Failure With Preserved Ejection Fraction The PARAGON-HF Trial

Background: Heart failure with preserved ejection fraction (HFpEF) is a global public health problem with important regional differences. We investigated these differences in the PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in HFpEF), the largest and most inclusive global HFpEF trial. Methods: We studied differences in clinical characteristics, outcomes, and treatment effects of sacubitril/valsartan in 4796 patients with HFpEF from the PARAGON-HF trial, grouped according to geographic region. Results: Regional differences in patient characteristics and comorbidities were observed: patients from Western Europe were oldest (mean 75 +/- 7 years) with the highest prevalence of atrial fibrillation/flutter (36%); Central/Eastern European patients were youngest (mean 71 +/- 8 years) with the highest prevalence of coronary artery disease (50%); North American patients had the highest prevalence of obesity (65%) and diabetes (49%); Latin American patients were younger (73 +/- 9 years) and had a high prevalence of obesity (53%); and Asia-Pacific patients had a high prevalence of diabetes (44%), despite a low prevalence of obesity (26%). Rates of the primary composite end point of total hospitalizations for HF and death from cardiovascular causes were lower in patients from Central Europe (9 per 100 patient-years) and highest in patients from North America (28 per 100 patient-years), which was primarily driven by a greater number of total hospitalizations for HF. The effect of treatment with sacubitril-valsartan was not modified by region (interaction P>0.05). Conclusions: Among patients with HFpEF recruited worldwide in PARAGON-HF, there were important regional differences in clinical characteristics and outcomes, which may have implications for the design of future clinical trials. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01920711