The valuation tool user guide: monetizing Cradle to Cradle®

This User Guide outlines the object, scope and expected deliverables from the Valuation Tool component of the Cradle to Cradle ® C2C BIZZ project. It describes the compendium of subtools that have been developed comprising: i) overview of funding tools; ii) C2C investment appraisal tool; and iii) C2C value indexing tool. The underpinning methodologies, as well as their inherent strengths and limitations are also described. The C2C BIZZ project as a whole aims specifically to promote and enhance the implementation of C2C methods in business site development within North Western Europe (NWE) (PAD, p.14). It is intended to infuse C2C notions into conventional site development, restructuring and management. The primary focus of the project is on planning, building and managing of business sites with C2C credentials (PAD, p.18) using sites in Lille Metropole (La Lainiere), London (London Sustainable Industries Park) and Luxemburg (Ecoparc Windhof) as experimental fields. C2C BIZZ is not concerned with the internal operations and activities of occupiers or users of the developed site. Accordingly, the scope of the valuation tool is confined to the planning, building and management of C2C sites. The deliverable from this component is a compendium of subtools (see Figure 1 below) that may be used to analyse the financial performance of C2C credentials in business sites to aid the making of a business case for such developments and evaluating the financial incentives for particular C2C site development projects. This entire work is premised on the argument that the wider adoption of C2C principles within the built environment depends on the rate of uptake by the private sector. The private sector, being profit driven, are likely to engage in C2C site development if they are convinced of its capacity to contribute to their business goals which ultimately is a return on their investment. The tool development described in this document attempts to provide a framework for collating an evidence base that can assist in articulating the business case for C2C in business site developments

Regulation of pancreatic cancer aggressiveness by stromal stiffening

No abstract available

Could NICE guidance on the choice of blood pressure lowering drugs be simplified?

Reecha Sofat and colleagues argue that prescribing advice needs updating in the light of recent evidence that all classes of blood pressure lowering drugs are broadly equivalen

Cochrane corner: PCSK9 monoclonal antibodies for the primary and secondary prevention of cardiovascular disease

Introduction: Drug therapies targeted at the reduction of low-density lipoproteincholesterol (LDL-C) are mainstream in the treatment of cardiovascular disease (CVD) and particularly for the prevention of coronary heart disease. In patients who do not have a sufficient response to, or who do not tolerate traditional LDL-C-lowering therapies such as statins or ezetimibe, monoclonal antibodies (mAbs) against PCSK9 (PCSK9 inhibitors) may provide an alternative treatment. Non-mAb-based PCSK9 inhibitors such as inclisiran are also emerging but currently lack robust outcome data1 and their effects are not considered in the current review. In this synopsis, we summarise findings from a recent update of a Cochrane systematic review on the efficacy and safety of PCSK9 inhibitors.2 This article focuses on the effects on outcomes (CVD and total mortality), safety, and the quality of the evidence in studies of mAb PCSK9 inhibitors alirocumab and evolocumab. Most of the available studies compared PCSK9 mAb treatment against placebo (against a background of usual care including statin and or ezetimibe), with a smaller group of studies evaluating the effects of PCSK9 mAb directly against statins and/or ezetimibe (none of the trials compared PCSK9 exclusively against statin treatment). Methods: The following databases were systematically searched for suitable randomised controlled trials (RCTs): Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Web of Science, ClinicalTrials.gov and the International Clinical Trials Registry Platform. Parallel-group and factorial RCTs with at least 24 weeks of follow-up were eligible; due to discontinuation of bococizumab and RG7652, studies examining these mAbs were excluded in this update. Summary of findings The 24 selected randomised trials (60 997 participants, box 1) predominantly included high-risk patients, for example, by enrolling patients with non-optimal LDL-C concentration despite treatment with statins or ezetimibe, or with a history of CVD. The study sample included 1879 who had familial hypercholesterolaemia (FH) (22% of the alirocumab participants and 38% of the evolocumab participants who provided information on FH status), and 18 908 (31%) with a diagnosis of type 2 diabetes mellitus (T2DM) at baseline (32% in alirocumab and 34% evolocumab trials; out of participants with reported T2DM status). Of the included patients, 4590 had no history of CVD (10% of the alirocumab patients and 7% of the evolocumab participants). Alirocumab was evaluated in 18 trials and evolocumab in 6 trials. Comparisons were made against placebo in 18 trials, ezetimibe and/or statins in 6 trials. Tables 1 and 2 display the key results of the meta-analysis for both PCSK9 inhibitors compared with placebo and with statins and/or ezetimibe, respectively

Duplex–assisted internal carotid artery balloon angioplasty and stent placement: A novel approach to minimize or eliminate the use of contrast material

BackgroundCarotid artery balloon angioplasty and stenting (CBAS) is emerging as an acceptable alternative to carotid endarterectomy in selected high-risk patients. Conversely, patients with pre-existing renal impairment, diabetes, or both may be harmed by the nephrotoxic contrast agents required during CBAS. We attempted to limit or eliminate the use of contrast material during CBAS.MethodsEighteen patients with severe carotid stenoses (>70%) underwent CBAS at our institution over the last 12 months with duplex scan-assisted CBAS. Of these, 12 were primary procedures, and 6 were performed for carotid re-stenosis. Fourteen patients (78%) were neurologically asymptomatic. The average age of these patients was 75 ± 11 years (range, 44–92 years). Hypertension, chronic renal insufficiency (serum creatinine level ≥1.5 mg/dL), coronary artery disease, diabetes, and smoking were present in 89%, 67%, 59%, 33%, and 28% of patients, respectively. Preoperative duplex carotid mapping was performed in all cases. All procedures were performed with patients under local anesthesia and light sedation.ResultsAn ATL HDI 5000 scanner with the SonoCT feature was used. The common femoral artery was cannulated with a single-entry needle under direct ultrasound visualization. Fluoroscopy was used to assist passage of the guidewire into the aorta and the common carotid artery. In only four cases (22%) was an aortic arch angiogram obtained. Selective catheterization of the internal and external carotid arteries was performed under ultrasound guidance. The distal cerebral protection device (17 cases) was placed under fluoroscopic guidance. Balloon width and length were chosen according to ultrasound measurements. Balloon and stent deployment were successfully achieved with ultrasound guidance alone in all cases. Appropriate stent apposition and resolution of the stenosis was confirmed by duplex scanning in all cases. Five patients (28%) were noted to have low (<100 mL/min) internal carotid artery volume flow after stent deployment (range, 20–88 mL/min; mean ± SD, 50 ± 25 mL/min). The internal carotid artery volume flow increased immediately after Filterwire retrieval in all cases and ranged from 136 to 400 mL/min (mean, 245 ± 107 mL/min). This increase was statistically significant (P < .02). No ipsilateral strokes or deaths occurred during follow-up from 1 to 12 months (mean follow-up, 5 months).ConclusionsDuplex scan-assisted CBAS is feasible and may reduce the need for intra-arterial contrast injection in selected patients deemed at high risk for renal failure from nephrotoxic contrast material. Additional advantages include direct visualization of the puncture site, precise position of the balloon and stent, and B-mode and hemodynamic confirmation of the adequacy of the technique

Voltage Stability Analysis of Grid-Connected Wind Farms with FACTS: Static and Dynamic Analysis

Recently, analysis of some major blackouts and failures of power system shows that voltage instability problem has been one of the main reasons of these disturbances and networks collapse. In this paper, a systematic approach to voltage stability analysis using various techniques for the IEEE 14-bus case study, is presented. Static analysis is used to analyze the voltage stability of the system under study, whilst the dynamic analysis is used to evaluate the performance of compensators. The static techniques used are Power Flow, V–P curve analysis, and Q–V modal analysis. In this study, Flexible Alternating Current Transmission system (FACTS) devices- namely, Static Synchronous Compensators (STATCOMs) and Static Var Compensators (SVCs) - are used as reactive power compensators, taking into account maintaining the violated voltage magnitudes of the weak buses within the acceptable limits defined in ANSI C84.1. Simulation results validate that both the STATCOMs and the SVCs can be effectively used to enhance the static voltage stability and increasing network loadability margin. Additionally, based on the dynamic analysis results, it has been shown that STATCOMs have superior performance, in dynamic voltage stability enhancement, compared to SVCs

The Genetics of Primary Haemorrhagic Stroke, Subarachnoid Haemorrhage and Ruptured Intracranial Aneurysms in Adults

Background: The genetic basis of haemorrhagic stroke has proved difficult to unravel, partly hampered by the small numbers of subjects in any single study. A meta-analysis of all candidate gene association studies of haemorrhagic stroke (including ruptured subarachnoid haemorrhage and amyloid angiopathy-related haemorrhage) was performed, allowing more reliable estimates of risk.Methods: A systematic review and meta-analysis of all genetic studies in haemorrhagic stroke was conducted. Electronic databases were searched until and including March 2007 for any candidate gene in haemorrhagic stroke. Odds ratio (OR) and 95% confidence intervals (CI) were determined for each gene disease association using fixed and random effect models.Results: Our meta-analyses included 6,359 cases and 13,805 controls derived from 55 case-control studies, which included 12 genes (13 polymorphisms). Statistically significant associations with haemorrhagic stroke were identified for those homozygous for the ACE/I allele (OR, 1.48; 95% CI, 1.20-1.83; p = 0.0003) and for the 5G allele in the SERPINE1 4G/5G polymorphism (OR, 1.42; 95% CI, 1.03-1.96; p = 0.03). In addition, both epsilon 2 and epsilon 4 alleles of APOE were significantly associated with lobar haemorrhage (OR, 1.81; 95% CI, 1.26-2.62; p = 0.002 and OR, 1.49; 95% 1.08-2.05; p = 0.01 respectively). Furthermore, a significant protective association against haemorrhagic stroke was found for the factor V Leiden mutation (OR, 0.30; 95% CI, 0.10-0.87; p = 0.03).Conclusion: Our data suggests a genetic contribution to some types of haemorrhagic stroke, with no overall responsible single gene but rather supporting a polygenic aetiology. However, the evidence base is smaller compared to ischaemic stroke. Importantly, for several alleles previously found to be associated with protection from ischaemic stroke, there was a trend towards an increased risk of haemorrhagic stroke

PCSK9 monoclonal antibodies for the primary and secondary prevention of cardiovascular disease.

BACKGROUND: Despite the availability of effective drug therapies that reduce low-density lipoprotein (LDL)-cholesterol (LDL-C), cardiovascular disease (CVD) remains an important cause of mortality and morbidity. Therefore, additional LDL-C reduction may be warranted, especially for patients who are unresponsive to, or unable to take, existing LDL-C-reducing therapies. By inhibiting the proprotein convertase subtilisin/kexin type 9 (PCSK9) enzyme, monoclonal antibodies (PCSK9 inhibitors) may further reduce LDL-C, potentially reducing CVD risk as well. OBJECTIVES: Primary To quantify short-term (24 weeks), medium-term (one year), and long-term (five years) effects of PCSK9 inhibitors on lipid parameters and on the incidence of CVD. Secondary To quantify the safety of PCSK9 inhibitors, with specific focus on the incidence of type 2 diabetes, cognitive function, and cancer. Additionally, to determine if specific patient subgroups were more or less likely to benefit from the use of PCSK9 inhibitors. SEARCH METHODS: We identified studies by systematically searching the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and Web of Science. We also searched Clinicaltrials.gov and the International Clinical Trials Registry Platform and screened the reference lists of included studies. We identified the studies included in this review through electronic literature searches conducted up to May 2016, and added three large trials published in March 2017. SELECTION CRITERIA: All parallel-group and factorial randomised controlled trials (RCTs) with a follow-up time of at least 24 weeks were eligible. DATA COLLECTION AND ANALYSIS: Two review authors independently reviewed and extracted data. When data were available, we calculated pooled effect estimates. MAIN RESULTS: We included 20 studies with data on 67,237 participants (median age 61 years; range 52 to 64 years). Twelve trials randomised participants to alirocumab, three trials to bococizumab, one to RG7652, and four to evolocumab. Owing to the small number of trials using agents other than alirocumab, we did not differentiate between types of PCSK9 inhibitors used. We compared PCSK9 inhibitors with placebo (thirteen RCTs), ezetimibe (two RCTs) or ezetimibe and statins (five RCTs).Compared with placebo, PCSK9 inhibitors decreased LDL-C by 53.86% (95% confidence interval (CI) 58.64 to 49.08; eight studies; 4782 participants; GRADE: moderate) at 24 weeks; compared with ezetimibe, PCSK9 inhibitors decreased LDL-C by 30.20% (95% CI 34.18 to 26.23; two studies; 823 participants; GRADE: moderate), and compared with ezetimibe and statins, PCSK9 inhibitors decreased LDL-C by 39.20% (95% CI 56.15 to 22.26; five studies; 5376 participants; GRADE: moderate).Compared with placebo, PCSK9 inhibitors decreased the risk of CVD events, with a risk difference (RD) of 0.91% (odds ratio (OR) of 0.86, 95% CI 0.80 to 0.92; eight studies; 59,294 participants; GRADE: moderate). Compared with ezetimibe and statins, PCSK9 inhibitors appeared to have a stronger protective effect on CVD risk, although with considerable uncertainty (RD 1.06%, OR 0.45, 95% CI 0.27 to 0.75; three studies; 4770 participants; GRADE: very low). No data were available for the ezetimibe only comparison. Compared with placebo, PCSK9 probably had little or no effect on mortality (RD 0.03%, OR 1.02, 95% CI 0.91 to 1.14; 12 studies; 60,684 participants; GRADE: moderate). Compared with placebo, PCSK9 inhibitors increased the risk of any adverse events (RD 1.54%, OR 1.08, 95% CI 1.04 to 1.12; 13 studies; 54,204 participants; GRADE: low). Similar effects were observed for the comparison of ezetimibe and statins: RD 3.70%, OR 1.18, 95% CI 1.05 to 1.34; four studies; 5376 participants; GRADE: low. Clinical event data were unavailable for the ezetimibe only comparison. AUTHORS' CONCLUSIONS: Over short-term to medium-term follow-up, PCSK9 inhibitors reduced LDL-C. Studies with medium-term follow-up time (longest median follow-up recorded was 26 months) reported that PCSK9 inhibitors (compared with placebo) decreased CVD risk but may have increased the risk of any adverse events (driven by SPIRE-1 and -2 trials). Available evidence suggests that PCSK9 inhibitor use probably leads to little or no difference in mortality. Evidence on relative efficacy and safety when PCSK9 inhibitors were compared with active treatments was of low to very low quality (GRADE); follow-up times were short and events were few. Large trials with longer follow-up are needed to evaluate PCSK9 inhibitors versus active treatments as well as placebo. Owing to the predominant inclusion of high-risk patients in these studies, applicability of results to primary prevention is limited. Finally, estimated risk differences indicate that PCSK9 inhibitors only modestly change absolute risks (often to less than 1%)

Critical appraisal of CRP measurement for the prediction of coronary heart disease events: new data and systematic review of 31 prospective cohorts.

BACKGROUND: Non-uniform reporting of relevant relationships and metrics hampers critical appraisal of the clinical utility of C-reactive protein (CRP) measurement for prediction of later coronary events. METHODS: We evaluated the predictive performance of CRP in the Northwick Park Heart Study (NPHS-II) and the Edinburgh Artery Study (EAS) comparing discrimination by area under the ROC curve (AUC), calibration and reclassification. We set the findings in the context of a systematic review of published studies comparing different available and imputed measures of prediction. Risk estimates per-quantile of CRP were pooled using a random effects model to infer the shape of the CRP-coronary event relationship. RESULTS: NPHS-II and EAS (3441 individuals, 309 coronary events): CRP alone provided modest discrimination for coronary heart disease (AUC 0.61 and 0.62 in NPHS-II and EAS, respectively) and only modest improvement in the discrimination of a Framingham-based risk score (FRS) (increment in AUC 0.04 and -0.01, respectively). Risk models based on FRS alone and FRS + CRP were both well calibrated and the net reclassification improvement (NRI) was 8.5% in NPHS-II and 8.8% in EAS with four risk categories, falling to 4.9% and 3.0% for 10-year coronary disease risk threshold of 15%. Systematic review (31 prospective studies 84 063 individuals, 11 252 coronary events): pooled inferred values for the AUC for CRP alone were 0.59 (0.57, 0.61), 0.59 (0.57, 0.61) and 0.57 (0.54, 0.61) for studies of 10 years follow up, respectively. Evidence from 13 studies (7201 cases) indicated that CRP did not consistently improve performance of the Framingham risk score when assessed by discrimination, with AUC increments in the range 0-0.15. Evidence from six studies (2430 cases) showed that CRP provided statistically significant but quantitatively small improvement in calibration of models based on established risk factors in some but not all studies. The wide overlap of CRP values among people who later suffered events and those who did not appeared to be explained by the consistently log-normal distribution of CRP and a graded continuous increment in coronary risk across the whole range of values without a threshold, such that a large proportion of events occurred among the many individuals with near average levels of CRP. CONCLUSIONS: CRP does not perform better than the Framingham risk equation for discrimination. The improvement in risk stratification or reclassification from addition of CRP to models based on established risk factors is small and inconsistent. Guidance on the clinical use of CRP measurement in the prediction of coronary events may require updating in light of this large comparative analysis