Identifying Uncertainty in Environmental Risk Assessments: The Development of a Novel Typology and Its Implications for Risk Characterization

Environmental risk analysts need to draw from a clear typology of uncertainties when qualifying risk estimates and/or significance statements about risk. However, categorizations of uncertainty within existing typologies are largely overlapping, contradictory, and subjective, and many typologies are not designed with environmental risk assessments (ERAs) in mind. In an attempt to rectify these issues, this research provides a new categorization of uncertainties based, for the first time, on the appraisal of a large subset of ERAs, namely 171 peer-reviewed environmental weight-of-evidence assessments. Using this dataset, a defensible typology consisting of seven types of uncertainty (data, language, system, extrapolation, variability, model, and decision) and 20 related sub-types is developed. Relationships between uncertainties and the techniques used to manage them are also identified and statistically evaluated. A highly preferred uncertainty management option is to take no action when faced with uncertainty, although where techniques are applied they are commensurate with the uncertainty in question. Key observations are applied in the form of guidance for dealing with uncertainty, demonstrated through ERAs of genetically modified higher plants in the European Union. The presented typology and accompanying guidance will have positive implications for the identification, prioritization, and management of uncertainty during risk characterization.     

Engineered Heart Tissue: A Novel Tool to Study the Ischemic Changes of the Heart In Vitro

Background

Understanding the basic mechanisms and prevention of any disease pattern lies mainly on development of a successful experimental model. Recently, engineered heart tissue (EHT) has been demonstrated to be a useful tool in experimental transplantation. Here, we demonstrate a novel function for the spontaneously contracting EHT as an experimental model in studying the acute ischemia-induced changes in vitro.

Methodology/Principal Findings

EHT was constructed by mixing cardiomyocytes isolated from the neonatal rats and cultured in a ring-shaped scaffold for five days. This was followed by mechanical stretching of the EHT for another one week under incubation. Fully developed EHT was subjected to hypoxia with 1% O₂ for 6 hours after treating them with cell protective agents such as cyclosporine A (CsA) and acetylcholine (ACh). During culture, EHT started to show spontaneous contractions that became more synchronous following mechanical stretching. This was confirmed by the increased expression of gap junctional protein connexin 43 and improved action potential recordings using an optical mapping system after mechanical stretching. When subjected to hypoxia, EHT demonstrated conduction defects, dephosphorylation of connexin-43, and down-regulation of cell survival proteins identical to the adult heart. These effects were inhibited by treating the EHT with cell protective agents.

Conclusions/Significance

Under hypoxic conditions, the EHT responds similarly to the adult myocardium, thus making EHT a promising material for the study of cardiac functions in vitro.     

The Development of a Novel High Throughput Computational Tool for Studying Individual and Collective Cellular Migration

Understanding how cells migrate individually and collectively during development and cancer metastasis can be significantly aided by a computation tool to accurately measure not only cellular migration speed, but also migration direction and changes in migration direction in a temporal and spatial manner. We have developed such a tool for cell migration researchers, named Pathfinder, which is capable of simultaneously measuring the migration speed, migration direction, and changes in migration directions of thousands of cells both instantaneously and over long periods of time from fluorescence microscopy data. Additionally, we demonstrate how the Pathfinder software can be used to quantify collective cell migration. The novel capability of the Pathfinder software to measure the changes in migration direction of large populations of cells in a spatiotemporal manner will aid cellular migration research by providing a robust method for determining the mechanisms of cellular guidance during individual and collective cell migration.     

Cardioprotection by Aldosterone Receptor Antagonism in Heart Failure: 1. The Role of Aldosterone in Heart Failure

In recent years, understanding of the role of aldosterone has expanded beyond the known classic effects of promoting renal sodium retention and potassium and magnesium loss. It is now well documented that aldosterone causes myocardial and perivascular fibrosis, blocks the myocardial uptake of norepinephrine, and increases plasminogen activator inhibitor levels. In conjunction with angiotensin II, aldosterone causes vascular damage, endothelial dysfunction, and decreased vascular compliance. Thus, the renin-angiotensin-aldosterone system (RAAS) plays a major role in the development of both hypertension and heart failure and is, therefore, a key target for therapeutic interventions. Commonly prescribed medications for control of hypertension and congestive heart failure are inhibitors of the RAAS, including angiotensin converting enzyme inhibitors (ACE-Is) and angiotensin II (A-II) receptor antagonists. A well-documented increase in aldosterone levels occurs over several months during chronic treatment with an ACE-I or an A-II receptor antagonist. Such suppression of circulating aldosterone, however, is transient, as exemplified by the term “escape” used to describe the phenomenon. This rebound of aldosterone even occurs when patients receive both an ACE-I and an A-II receptor antagonist. In addition, ACE-Is and A-II receptor antagonists are less effective in controlling blood pressure in the estimated 60% of hypertensive patients who are salt- (volume-) sensitive and more prone to hypertension-associated morbidity, such as black patients and type 2 diabetics. Thus, chronic and complete blockade of aldosterone action requires an aldosterone receptor antagonist. The Randomized Aldactone Evaluation Study (RALES) trial results in patients with severe heart failure (New York Heart Association class III or IV) and a left ventricular ejection fraction of no more than 35% showed that administration of a subhemodynamic dose of spironolactone (25 mg/day) as an add-on therapy to ACE-Is plus standard treatment resulted in a significant mortality reduction due to decreases in both death from progressive heart failure and sudden cardiac death. These findings support the pivotal role of aldosterone in the pathophysiology of progressive heart failure. Although it is an effective antialdosterone agent, widespread use of spironolactone in humans is limited by its tendency to produce undesirable sexual side effects. At standard doses, impotence and gynecomastia can be induced in men, whereas premenopausal women may experience menstrual disturbances. Data on a selective aldosterone receptor antagonist, eplerenone, show that it appears promising for the effective blockade of aldosterone and its harmful effects without the sexual disturbances of spironolactone. Recently, eplerenone was successfully introduced for the treatment of hypertension and heart failure. A growing number of experimental studies are finding a broader role for aldosterone in driving the pathophysiology of both heart failure and hypertension. When added to conventional therapy, aldosterone receptor blockers show benefits in addition to those conferred by ACE-Is and/or A-II receptor blockers.     

Waist Circumference as a Screening Tool for Cardiovascular Risk Factors: Evaluation of Receiver Operating Characteristics (ROC)

To evaluate the receiver operating characteristics (ROC) to determine the cutoffs of waist circumference as a potential population directed screening tool for hypercholesterolaemia (≥6.5 mmol/L), low high density lipoprotein cholesterol (<0.9 mmol/L), and hypertension (treated and/or systolic ≥160 and/or diastolic blood pressure ≥95 mmHg), in 2183 men and 2698 women aged 20 to 59 years selected at random from Dutch civil registries. Main outcome measures: Height, weight, body mass index (BMI), waist circumference, total plasma cholesterol and high density lipoprotein cholesterol concentrations, and blood pressure. Results: ROC curves showed that sensitivity equalled specificity at waist circumferences between 93–95 cm in men and 81–84 cm in women for identifying individual risk factors, and 92 cm in men and 81 cm in women for identifying those with at least one risk factor. Sensitivity and specificity were equal at levels between 61% to 69% for identifying individual risk factors, with positive predictions (56.8% in men and 37.8% in women) within 2% of those using previously defined ‘Action Level 1’ of waist circumference 94 cm in men and 80 cm in women (58.8% in men and 37.4% in women). Risk prediction by anthropometric methods was relatively low: ROC areas for identifying each risk factor by waist varied from 55% to 60%, and reached about 65% for identifying at least one risk factor. Height accounted for less than 03% of variance in waist circumference. Using BMI at 25 kg/m² gave similar prediction to waist, but its combination with waist did not improve predictive values. Conclusions: Measurement of waist circumference ‘Action Level 1’ at 94 cm (37 inches) in men and 80 cm (32 inches) in women could be adopted as a simpler valid alternative to BMI for health promotion, to alert those at risk of cardiovascular disease, and as a guide to risk avoidance by self-weight management     

Heart Failure in a Cohort of Patients with Chronic Kidney Disease: The GCKD Study

ConclusionsThe burden of self-reported and Gothenburg HF among patients with CKD is high. The proportion of patients who meet the criteria for Gothenburg HF in a European cohort of patients with moderate CKD is more than twice as high as the prevalence of self-reported HF. However, because of the shared signs, symptoms and medications of HF and CKD, the Gothenburg score cannot be used to reliably define HF in CKD patients. Our results emphasize the need for early screening for HF in patients with CKD.     

Limited Value of Cystatin-C over Estimated Glomerular Filtration Rate for Heart Failure Risk Stratification

Background

To compare the prognostic value of estimated glomerular filtration rate, cystatin-C, an alternative renal biomarker, and their combination, in an outpatient population with heart failure.Estimated glomerular filtration rate is routinely used to assess renal function in heart failure patients. We recently demonstrated that the Cockroft-Gault formula is the best among the most commonly used estimated glomerular filtration rate formulas for predicting heart failure prognosis.

Methodology/Principal Findings

A total of 879 consecutive patients (72% men, age 70.4 years [P_25–75 60.5–77.2]) were studied. The etiology of heart failure was mainly ischemic heart disease (52.7%). The left ventricular ejection fraction was 34% (P_25–75 26–43%). Most patients were New York Heart Association class II (65.8%) or III (25.9%). During a median follow-up of 3.46 years (P_25–75 1.85–5.05), 312 deaths were recorded. In an adjusted model, estimated glomerular filtration rate and cystatin-C showed similar prognostic value according to the area under the curve (0.763 and 0.765, respectively). In Cox regression, the multivariable analysis hazard ratios were 0.99 (95% CI: 0.98–1, P = 0.006) and 1.14 (95% CI: 1.02–1.28, P = 0.02) for estimated glomerular filtration rate and cystatin-C, respectively. Reclassification, assessed by the integration discrimination improvement and the net reclassification improvement indices, was poorer with cystatin-C (−0.5 [−1.0;−0.1], P = 0.024 and −4.9 [−8.8;−1.0], P = 0.013, respectively). The value of cystatin-C over estimated glomerular filtration rate for risk-stratification only emerged in patients with moderate renal dysfunction (eGFR 30–60 ml/min/1.73 m², chi-square 12.9, P<0.001).

Conclusions/Significance

Taken together, the results indicate that estimated glomerular filtration rate and cystatin-C have similar long-term predictive values in a real-life ambulatory heart failure population. Cystatin-C seems to offer improved prognostication in heart failure patients with moderate renal dysfunction.     

Mobile Application-Based Seoul National University Prostate Cancer Risk Calculator: Development,Validation, and Comparative Analysis with Two Western Risk Calculators in Korean Men

Objectives

We developed a mobile application-based Seoul National University Prostate Cancer Risk Calculator (SNUPC-RC) that predicts the probability of prostate cancer (PC) at the initial prostate biopsy in a Korean cohort. Additionally, the application was validated and subjected to head-to-head comparisons with internet-based Western risk calculators in a validation cohort. Here, we describe its development and validation.

Patients and Methods

As a retrospective study, consecutive men who underwent initial prostate biopsy with more than 12 cores at a tertiary center were included. In the development stage, 3,482 cases from May 2003 through November 2010 were analyzed. Clinical variables were evaluated, and the final prediction model was developed using the logistic regression model. In the validation stage, 1,112 cases from December 2010 through June 2012 were used. SNUPC-RC was compared with the European Randomized Study of Screening for PC Risk Calculator (ERSPC-RC) and the Prostate Cancer Prevention Trial Risk Calculator (PCPT-RC). The predictive accuracy was assessed using the area under the receiver operating characteristic curve (AUC). The clinical value was evaluated using decision curve analysis.

Results

PC was diagnosed in 1,240 (35.6%) and 417 (37.5%) men in the development and validation cohorts, respectively. Age, prostate-specific antigen level, prostate size, and abnormality on digital rectal examination or transrectal ultrasonography were significant factors of PC and were included in the final model. The predictive accuracy in the development cohort was 0.786. In the validation cohort, AUC was significantly higher for the SNUPC-RC (0.811) than for ERSPC-RC (0.768, p<0.001) and PCPT-RC (0.704, p<0.001). Decision curve analysis also showed higher net benefits with SNUPC-RC than with the other calculators.

Conclusions

SNUPC-RC has a higher predictive accuracy and clinical benefit than Western risk calculators. Furthermore, it is easy to use because it is available as a mobile application for smart devices.     

Effect of an Aldosterone Antagonist (Spironolactone) on Patients with Severe Congestive Heart Failure

Spironolactone was evaluated as a diuretic in the therapy of six patients with chronic severe congestive heart failure, during which metabolic balance studies were performed. Two of the patients showed a clear-cut although moderate diuresis and natriuresis in response to spironolactone in the presence of other diuretics. Two patients had slight unsustained responses and two showed no response. No significant change in potassium excretion was observed. A decrease in the serum sodium level was noted in four patients, associated with a rise in serum potassium. Urinary aldosterone excretion was normal or low in all patients and showed no correlation with the diuretic response to spironolactone.It is concluded that spironolactone has definite but limited usefulness in the therapy of some but not all patients with chronic congestive heart failure.     

PCI术前AMI伴左心衰竭患者死亡的高危因素分析

目的:探讨PCI术前AMI伴左心衰竭患者死亡的高危因素.方法:回顾总结53例AMI伴左心衰患者,其中包括13例死亡病例.40例行PCI术的存活病例为对照组.将其临床特征及入院24小时内检测的血红蛋白(Hb)、血肌酐(Cr)、血氧饱和度(SaO2)、心肌坏死标志物,包括肌红蛋白(MYO),肌酸激酶同工酶(CK-MB),肌钙蛋白I(cTnI)和部分神经内分泌指标,包括肾素活性(PRA),血管紧张素Ⅱ(AngⅡ),醛固酮(ALD),肾上腺素(E).去甲肾上腺素(NE)进行对比研究.结果:死亡组在年龄、性别、Hb、Cr、SaO2、CK-MB、eTnI方面与存活组比较差别有显著性(P<0.05).结论:年龄偏大,多合并高血压病和糖尿病,早期发生低氧血症,以多支病变为特点的大面积心肌梗死患者易发生心功能不全,如同时合并肾功能不全、贫血的患者死亡风险高.