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Correspondence | Open | Open Peer Review | Published: 30 April 2008
Methods of data collection and analysis for the economic evaluation alongside a national, multi-centre trial in the UK: Conventional ventilation or ECMO for Severe Adult Respiratory Failure (CESAR)
Mariamma M Thalanany1,
Miranda Mugford1,
Clare Hibbert2,
Nicola J Cooper3,
Ann Truesdale4,
Steven Robinson4,
Ravindranath Tiruvoipati5,6,
Diana R Elbourne4,
Giles J Peek5,
Felicity Clemens4,
Polly Hardy4,7,
Andrew Wilson3 &
The CESAR Trial Group
BMC Health Services Researchvolume 8, Article number: 94 (2008) | Download Citation
Extracorporeal Membrane Oxygenation (ECMO) is a technology used in treatment of patients with severe but potentially reversible respiratory failure. A multi-centre randomised controlled trial (CESAR) was funded in the UK to compare care including ECMO with conventional intensive care management. The protocol and funding for the CESAR trial included plans for economic data collection and analysis. Given the high cost of treatment, ECMO is considered an expensive technology for many funding systems. However, conventional treatment for severe respiratory failure is also one of the more costly forms of care in any health system.
Methods/Design
The objectives of the economic evaluation are to compare the costs of a policy of referral for ECMO with those of conventional treatment; to assess cost-effectiveness and the cost-utility at 6 months follow-up; and to assess the cost-utility over a predicted lifetime. Resources used by patients in the trial are identified. Resource use data are collected from clinical report forms and through follow up interviews with patients. Unit costs of hospital intensive care resources are based on parallel research on cost functions in UK NHS intensive care units. Other unit costs are based on published NHS tariffs. Cost effectiveness analysis uses the outcome: survival without severe disability. Cost utility analysis is based on quality adjusted life years gained based on the Euroqol EQ-5D at 6 months. Sensitivity analysis is planned to vary assumptions about transport costs and method of costing intensive care. Uncertainty will also be expressed in analysis of individual patient data. Probabilities of cost effectiveness given different funding thresholds will be estimated.
In our view it is important to record our methods in detail and present them before publication of the results of the trial so that a record of detail not normally found in the final trial reports can be made available in the public domain.
Trial Registrations
The CESAR trial registration number is ISRCTN47279827.
Extracorporeal Membrane Oxygenation (ECMO) was introduced into treatment of severe but potentially reversible respiratory failure in the 1970s. The technique involves placing patients on a life support circuit with a membrane oxygenator to temporarily take over the gas exchange function of e lung thereby allowing the lungs to rest and recover [1, 2]. The early reports of the use of ECMO in adult with severe respiratory failure were enthusiastic [3]. It soon became clear however, that although ECMO was effective and cost effective compared to conventional ventilation in newborns [4], the evidence was much less clear for the adult population. Many centres in the world use ECMO technology and have reported survival rates in excess of 50% in uncontrolled observational studies of patient outcomes [5, 6]. However, considerable improvements have also been reported in survival rates of conventionally treated patients with severe respiratory failure [7–9].
Given the high cost of treatment, ECMO is considered an expensive technology for many funding systems. However, conventional treatment for severe respiratory failure is also one of the more costly forms of care in any health system [10]. Differences in lengths of stay and types of care received by patients following either clinical pathway may result in different statistical distributions of cost for inpatient care. In addition, because appropriate care is provided in relatively few centres, the location of care and need for specialist transport for patients also affects the costs of care. Finally, if there is increased survival to discharge from hospital, then there will be more use of services in primary and community care, and requirement for help for recovering people at home. Thus the health service costs and the household costs might fall at any stage of the treatment and recovery, and in many different forms.
In addition to the costs of alternative forms of care, the economic choice depends on the value of the outcome gained. Uncertainty about the effectiveness of referral to an ECMO centre led to a trial to assess the costs and effectiveness of the new form of care funded by the NHS Health Technology Assessment programme. The protocol for the 'Conventional ventilation or ECMO for Severe Adult Respiratory failure (CESAR) Trial was published in 2006 [11]. This paper provides details of the methods used for the economic evaluation, mentioned in the protocol and conducted as an integral part of the CESAR trial.
Previous economic evaluations
A literature search failed to find any economic evaluation studies of adult ECMO. However, there have been a series of economic evaluations of ECMO in babies alongside the UK collaborative randomised trial of neonatal ECMO [12] which reported the estimated additional cost (UK 1994–95 price) of ECMO per additional surviving infant with no disability as £75,327 at one year of age. Follow-up at 4 and 7 years for the same study shows the incremental cost (UK 2001 & 2003 price) of neonatal ECMO to be £24,775 & £23,566 per disability-free life year gained [13, 14]. Similarly a retrospective cost-utility analysis [15] reports costs of USD 24,386 per quality adjusted life-year saved for 'salvage ECMO' in children. In all cases, in spite of the high cost of neonatal ECMO, the incremental cost per QALY was within health care funders' range of acceptable value for money. This remains a question in the case of adult ECMO.
The CESAR Trial
The CESAR trial [11] was designed to compare two alternative strategies for treating severe but potentially reversible respiratory failure: conventional ventilation, and transfer to a centre providing ECMO. In the UK, during the CESAR trial, ECMO is provided by Glenfield Hospital, Leicester, and conventional treatment by other UK hospitals capable of providing a high standard of care for ECMO eligible patients.
The primary outcome measure for the clinical evaluation is increase in survival at 6 months without severe disability ('confined to bed' and 'unable to wash or dress') at six months. Power calculations based on estimates of these outcomes from severe adult respiratory distress syndrome (ARDS) suggested a sample size of 180 would have sufficient power to detect a reduction in primary outcome by a third (based on 5% statistical significance, 2-sided test and 80% power). All ICUs in the UK were invited to take part in the trial and 148 units referred patients for consideration for entry to the trial. The participation of so many ICUs is necessary due to the small numbers of adults who suffer from the condition annually.
Economic questions about treatment of severe respiratory failure
The economic evaluation addresses the question of value for money of the alternative treatment options. The economic question asks "for patients with severe but potentially reversible respiratory failure, is ECMO cost-effective from the viewpoints of the NHS and society?" This question can be rephrased "is the additional cost of achieving an important gain in outcome within the range that the health funding system, or society, is willing to pay?"
The objectives of the economic evaluation are:
To compare the costs of a policy of referral for ECMO with those of conventional treatment.
To assess the cost-effectiveness of referral for ECMO compared with conventional treatment in terms of additional survival with and without disability at six months post-randomisation.
To assess the cost-utility of referral for ECMO compared with conventional treatment in terms of utility gain as measured by EQ5D at 6 months follow-up.
To assess the cost-utility of referral for ECMO compared with conventional treatment in terms of utility gain as measured by EQ5D, and other sources, over a predicted lifetime.
Design of the Economic Evaluation alongside the CESAR Trial
The design of this economic evaluation alongside the CESAR trial is based on published recommendations [for example, [16]]. This involves defining: the type of economic evaluation to be conducted; the comparator form of care; the perspective and time horizon for costs and outcomes; appropriate outcome measures for each perspective and type of evaluation; identification, measurement and valuation of resources; estimation of unit costs; and a plan for economic analysis, which includes decisions on discounting future costs and consequences, tackling uncertainties and presentation of results.
Type of economic evaluation
The first planned analysis is a cost effectiveness analysis (CEA) with increase in survival without severe disability at six months (the primary outcome in the CESAR trial) as the main outcome measure. A short term cost utility analysis (CUA) was also planned in which health benefits are quantified in terms of quality-adjusted life-years (QALYS), and measured using the instrument EQ-5D at 6 months. Lifetime CUA is planned using a decision model based on CESAR trial results and including additional data for predicted lifetime QALYs and health care costs.
The ideal comparator for any economic evaluation designed to assess the cost effectiveness in a particular context is the most commonly used treatment for the condition in that context. The CESAR trial was designed as a pragmatic comparison, where patients allocated to conventional care were receiving treatment that would be the normal form of care in the NHS. To ensure that the patients in the control group received as near as possible the best practice of care, the CESAR trial protocol specified aspects of service provision that must be considered, including facilities available at the participating ICUs, experience of treating such patients, and certain aspects of the clinical treatment protocol for ventilated patients. Full details are given in the CESAR trial protocol [11]. In general, however, the comparator group was intended to be representative of NHS care provision (in qualifying ICUs) for acute respiratory failure during the period of the trial.
Perspective or viewpoint for analyses
In the UK, the National Institute of Health and Clinical Excellence (NICE) proposes that applicants presenting economic analyses for NICE appraisals should take a NHS perspective [17]. However, there are aspects of public patient choice and valuation that may not be considered in such an analysis. Economic evaluators are guided to take a societal viewpoint if possible [16]. As the ECMO technology may be adopted for review by NICE or a similar agency in the UK, it was decided that the perspective for the CESAR trial should include both the NHS and societal perspectives. The latter viewpoint is important, as the results of this study are likely to have economic impacts other than through health care requirements if there is significantly increased survival of either able bodied or disabled adults. It is also anticipated that the results of the trial may provide useful information for a wider international audience where different ranges of services are provided within the health system.
Time horizon for economic evaluation
The follow-up duration for the CESAR trial is 6 months. This does not allow the full long term cost and benefits to be measured. However, it satisfies the recommendation of the American Thoracic Society for cost-effectiveness analyses of ICU therapies to have a minimum follow-up period of 6 months [10]. However, to meet our fourth objective, prediction and modelling long-term (lifetime) costs and benefits are also planned.
Outcome measures for economic evaluation
Survival without severe disability
Death of patients in the trial was recorded during the period of follow up whenever it occurred. Staff at the CESAR trial data management centre maintained contact with all centres with patients being treated within the CESAR trial ensuring complete reporting. For those discharged from hospital, contact was sought either through their home, or through their family doctors, if patients consented to be approached in either of these ways. Any further deaths would be reported in this way. Severe disability in survivors at six month was defined as those who were unable to care for themselves and were confined to bed: that is who had worst possible scores for the Euroqol EQ5D domains for self care and for mobility.
Quality adjusted life years (QALYs)
The calculation of QALYs was planned to be based on assessment of health related quality of life at six months from randomisation. The EQ-5D is a standardised instrument used for measuring health outcomes. Quality adjusted health utility weights for each patient are calculated for the CESAR trial using UK specific utility values for each patient's response to the EQ5D at 6 months. We could find no previous models for estimation of QALYs gained at 6 months in similar patients, and so they are estimated assuming that the value of the health state at trial entry was zero, and that over the months of survival, patients have experienced linearly increasing quality of life up to the level at 6 months.
Estimates of lifetime QALYs are predicted based on assumptions of gradual improvement of quality of life up to 2 years from randomization [18–22], and of predicted life expectancy based on age specific rates for the population of England and Wales. Age and sex specific life expectancy is calculated for each surviving patient in the trial using UK life tables [23]. It is assumed that, at 24 months post randomization, all surviving trial patients attained the same average life expectancy and health state as adults of similar age in the UK population. It is assumed that average health states for different age groups would be the same as those obtained from the 1996 Health survey for England [24].
Identifying resource use
For the CESAR trial relevant aspects of resource use were identified using expert advice (managers, medical, nursing and patient representatives all commented on the draft lists) and also considering the items included in the economic evaluation of neonatal ECMO [12]. A list of resource items important from one or more viewpoints is given in Table 1. This includes resource use associated with initial stay in intensive and high dependency care units at different levels of care (measured by number of organs supported – see below), use of ambulance transport, stays in other hospital wards before discharge, costs of visiting incurred by relatives whilst patients are in hospital, resource use after discharge up to six months, major changes in household, out-of-pocket expenses of patient and family, loss of paid and unpaid working time, changes in working time, and informal care.
Table 1 Items of resource use in the CESAR trial
Measuring resource use
Resource use data are collected prospectively for every trial participant at various points of his/her progress from recruitment to follow-up using a series of data forms and questionnaires. Some, but not all, of these are additional to the instruments planned for the CESAR trial management and clinical outcome data collection [11]. These instruments are:
Daily organ support form – completed by intensive care staff for each trial participant on a daily basis, and used to classify intensity of resources used during the intensive care ECMO/conventional treatment period.
Transport form (a) at trial entry – completed by Glenfield Hospital transport team to record transfer of trial participants to ECMO centre or conventional treatment centres.
Transport form (b) – completed by Glenfield transport team to record ambulance journey of participants returning either to the original recruiting hospital or another intensive care unit after ECMO.
Outcomes data sheet – completed by medical staff and records date on death of patient (if applicable), date of discharge, date of transfer to another hospital/home, use of ambulance for transfer etc.
Events Diary -to be completed and kept by every participant to document all services used from discharge to follow-up as an aide memoire to help them to answer questions at 6 months. This included information about informal help received as well as formal services.
Patient cost questionnaire at 6 month follow up – administered by trained interviewer at patient's home or by telephone to collect resource use data from discharge to follow-up, covering items recorded in (e) above.
GP proforma – completed by GPs to collect medication use of those patients who refuse the 6-month follow-up but give permission for use of GP records.
The Events Diary (e) and the Patient cost questionnaire (f) were piloted with five patients discharged from Glenfield Hospital ICU, and the GP proforma (g) piloted with 5 general practitioners. Interviewers were trained in the administration of the patient cost questionnaire (f). As it was anticipated that many Ambulance Trusts across UK may become involved in transporting trial patients, all ambulance trusts were contacted and agreement obtained to provide costs of patient journeys (including overhead & running costs) as and when it took place during the trial.
Two items of resource use not collected alongside the trial are: resource use associated with and following a patient's death in ICU, and cost incurred by relatives whilst visiting patients in intensive care/hospital stay. These items were excluded from the data collection from CESAR trial patients due to the practical difficulty of collecting data and due to the lack of a well-defined methodology available at the early stages of planning the CESAR trial. However, the cost of visiting patients in intensive care was thought likely to be an important social cost, and is being estimated by a separate study in a sample of CESAR centres and is described in more detail under "estimating unit costs" below.
Resource data collection for the economic evaluation
Following recruitment, the progress of all participants is tracked initially until their discharge from hospital so that resource use, and clinical progress, can be accurately measured and collected at each stage. During the intensive treatment period (ECMO or conventional ventilation) data are collected on number of days spent in each treatment mode, including daily information on number of organs supported and the level of critical care (ICU or HDU). After transfer to another hospital or another ward within the same hospital after the acute phase of the illness, resource use is measured as number of in-patient days up to discharge.
Details of all ambulance use related to transferring trial patients at recruitment are collected by the Glenfield transport team and details of all other ambulance journeys (for example transfer between hospitals) are collected by the relevant hospitals and sent to the research team. Data collected include date, time, origin and destination of journey, mode of transport (road ambulance, fixed wing aircraft, or helicopter), duration of journey, and distance travelled by patient.
After discharge from hospital, each participant is sent details of the forthcoming interview and the 'events diary' to record resource use. The patient is asked to give permission for one of a series of options to take place six months after trial entry: (1) face-to-face interview (2) telephone interview (3) postal questionnaire and (4) collection of resource use from GP records. Those patients still in hospital at six months if fit enough are asked to give permission to be interviewed at their hospital bedside using a very short resource use questionnaire.
Estimating unit costs
In order to estimate total cost of treatment for each trial participant, the respective quantities of resource use are multiplied by their corresponding unit costs. Some resources used by participants are in the form of actual costs (not charges) and do not need any valuation. For example, cost of ambulance journeys are obtained directly from the relevant ambulance service providers and incorporate all overhead and running costs. The unit costs of most items of resource use are obtained from nationally available sources [25, 26]. Use of medication is valued using the price of drugs listed in the British National Formulary [27]. Informal care is valued by the opportunity cost method suggested by Posnett & Jan [28]. Average cost per day of ICU and ECMO is obtained from a separate study and weighted/adjusted for each centre in the CESAR trial (see "Cost/day of ICU including ECMO unit care" below). Cost of visiting is also derived from a separate study (see "Costs of visiting patients in intensive care" below). Costs of private travel will be estimated using Automobile Association (AA) [28] motoring costs.
Valuation of informal care time
Informal time will be valued using weights suggested for Posnett & Jan's [29] scenarios: working time were output is replaced; working time where output is not replaced; non-work time of those in paid employment and those not in paid employment; and finally time for those not in paid employment where unpaid housework is not replaced. Average wage rates of men and women in the United Kingdom needed for estimating time costs is obtained from Office of National Statistics (ONS) [30].
Predicted future costs of lifetime care
It was assumed that survivors at 6 months would continue to have similar average daily costs of care as at the 6 months follow up point, until 24 months post randomization. At 24 months, the average health service expenditure for the surviving patients in the CESAR trial was assumed to be the same as that of similar age groups in the UK. The age groups used in predicting future costs and benefits were: 16–44 years, 45–64 years, 65–74 years and 75–84 years. Data on health services costs for these age groups have been published in the proceedings of Parliament [31]. The same age groups were used as the basis for estimating both patients' long-term costs and their benefits.
Price year, inflation, currency and discounting
Resources and costs will be measured in the year in which they occur using appropriate unit costs for each year of resource use. All costs are then revalued for analysis and reporting to 2005 UK values using health care inflation estimates.
The follow-up duration for the short term analyses is 6 months and therefore discounting is not necessary. For the lifetime estimates, costs and QALYs were discounted at 3.5%, based on UK Treasury guidelines [32].
Cost per day of ICU including ECMO unit care
The task of achieving a case-mix adjusted daily costs of ICU care was achieved through a prospective, observational, longitudinal multi-centre study (the 'Critical Care HRG study'), concurrent with the CESAR trial, involving a volunteer sample of 70 critical care units, where monthly data on critical care unit expenditure together with daily data on patients' organ support were collected for a two/three-month period [33]. The sample of participating critical care units had good geographical coverage in England with smaller numbers from Scotland and Northern Ireland, but none from Wales. An average daily cost of ICU was estimated by collecting data on the monthly expenditure of intensive care units and apportioning this sum by their monthly throughput of patients. Case-mix adjustment of this average daily cost was achieved by a weighting based on the number of organs supported on that day.
Data on patients' organ support requirements were collected on a daily basis by the critical care unit staff using specially designed data collection booklets. These data were collected for consecutive admissions during the study period. At the same time, the intensive care units and hospital finance departments were sent questionnaires to document their monthly expenditure on consumables (drugs and fluids, disposable equipment, nutritional products and blood and blood products), staff (consultant medical staff and other medical staff), clinical support services (radiology tests and laboratory services), professionals allied to medicine (physiotherapists, clinical pharmacists, dieticians, medical technical officers, information technologists, clinical and biomedical scientists, speech and language therapists, clinical psychologists and occupational therapists), support staff (personnel officers and directorate accountants) and specialised bed therapy. Data were also collected on the organizational characteristics of the intensive care units and the monthly number of patient days, number of staffed beds, number of patient admissions etc. An average daily cost was calculated using the following formula:
Σ Monthly expenditure on Staff + Consumables + Clinical Support Services Monthly number of patient days MathType@MTEF@5@5@+=feaafiart1ev1aaatCvAUfKttLearuWrP9MDH5MBPbIqV92AaeXatLxBI9gBaebbnrfifHhDYfgasaacPC6xNi=xI8qiVKYPFjYdHaVhbbf9v8qqaqFr0xc9vqFj0dXdbba91qpepeI8k8fiI+fsY=rqGqVepae9pg0db9vqaiVgFr0xfr=xfr=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@AB0A@
The average daily cost in critical care ICU had to be adjusted to reflect the severity of illness or degree of organ support required by patients. For this purpose, data provided by 46 critical care units in the Critical Care ICU HRG study [34] were used. Only those critical care units that supplied data on their expenditure, organ support and unit characteristics were included in this analysis. The aim was to develop an appropriate model from which estimates of daily case-mix adjusted costs could be determined.
Different ways of modelling the organ support and expenditure data were explored. The model of choice was informed by the Breusch-Pagan and Hausman specification tests [35] that favoured a random-effects model based on the number of organs supported on a daily basis; clustered to include 0–1 organ, 2 organs and = 3 organs. This model offered a simple and reproducible system of estimating case-mix adjusted costs of care. Daily organ support weights were 0.577 for 0–1 organ supported, 1.137 for 2 organs supported and 1.156 for = 3 organs supported [36]. These weights will be applied to average daily costs of patients participating in the CESAR trial. A total cost per patient of their ICU stay was calculated by weighting patients' average daily cost according to the number of organs supported on a daily basis and summing these daily costs for each patient.
Internal validation of the average daily cost data collected was not performed, however external validation was possible using data collected by the Critical Care National Cost Block Programme [37]. Twenty-one intensive care units in this study (30%) contributed data to the Cost Block Programme for the financial year 2000–2001. Although the Cost Block Programme collected data for a different time period and using a different configuration of units, the similarity between the mean costs per patient day is striking, in particular, the costs of consumables and clinical support services. The study by Hibbert et al [33] had wider coverage of resources with respect to professionals allied to medicine and an in-built allowance for capital equipment, which may be responsible for a slightly higher mean costs per day (£1302, 2003 price year) compared to £1028 (2001 price year, £1119 inflated to 2003 price year) for the Cost Block Programme.
The completeness of the returned data was investigated by each resource item and expressed as a percentage of the number of responses divided by the total number of 18 possible responses which reflected the quantity of data sought from participating centres. Data on nursing and administrative staff together with drugs and fluids yielded the highest number of responses (77%). Data on clinical and biomedical scientists and clinical psychologists yielded the lowest number of responses at 14%.
Not all CESAR centres participated in the Critical Care HRG study. Separate visits or contacts by correspondence were made with all CESAR centres that did not participate in the ICU HRG costing study, including the ECMO centre, to collect the same expenditure data in order to estimate the daily cost in the same way. Forty hospitals recruited patients up until the 31st March 2005. Given that more than one hospital recruited, in some cases, more than one patient during each financial year and patients could have received treatment in both an ICU and an HDU, one hundred and sixteen cost questionnaires were sent out in total to account for this (58 for the ICU and combined ICU/High Dependency Units (HDUs) and 58 for the separate HDUs – where provided). The types of critical care units i.e. which of the participating critical care units had both an ICU and an HDU or operated as a combined ICU/HDU, were not known, so each critical care unit was sent two cost questionnaires for each financial year when a patient was recruited to the trial. Thirteen hospitals completed the expenditure questionnaires however, only 11 hospitals returned data on both their unit characteristics and expenditure, which were needed in order to apportion the expenditure data correctly (i.e. down to an average daily cost). In order to estimate average daily costs for each CESAR hospital for the financial year in which a patient/patients were treated, missing data were substituted with mean estimates obtained from the responding hospitals by financial year.
Figure 1 shows the whole process of estimating unit costs of ICU stay, derivation of weights for number of organs supported and how this feeds into the cost estimation in the trial. A fuller description of this part of the research is included in Clare Hibbert's PhD Thesis [36].
Unit cost flowchart for hospital critical care.
Costs of visiting patients in intensive care
A pilot study of the costs of visiting [38] was carried out in December 2001 at an ICU in the UK. The daily costs per visit estimated in the pilot study are shown in Table 2. The pilot study informed the methods for a multi-centre study in six intensive care units in the UK which are registered with the CESAR trial. The aim was to estimate the average cost of visiting patients in intensive care. All adults including primary carers visiting the intensive care units during a three-week duration were requested to complete a questionnaire that asked them about their time spent in visiting and travel, out-of-pocket expenses, employment status, loss of income etc. Data from this study will be used to estimate the average cost of visiting per day.
Table 2 Cost of time foregone, lost pay, out-of-pocket expenses per visit to ICU at UK 2005 prices
Analysis and reporting of costs and economic evaluation
Estimation of costs for each patient
Costs falling upon the health sector (health & social services), upon patients or their families, and other costs such as help from friends will be presented in total and disaggregated form. Resource use and unit costs described above will be used for to estimate mean, medians, standard deviations and ranges of costs for each patient in the CESAR trial.
Cost effectiveness analysis
Incremental cost-effectiveness ratio (ICER)
With the availability of patient level data on costs and effects it is possible to summarize uncertainty in the ICER as a confidence interval. As cost data are typically not normally distributed, non-parametric bootstrapping will be used to generate confidence intervals.
Cost utility analysis
Lifetime incremental cost-utility ratios will be estimated using bootstrap estimation methods [39, 40], and using data and simplifying assumptions described in previous paragraphs.
Sensitivity analysis and uncertainty
Sensitivity analysis based on testing specific assumptions and probabilistic analysis will be used to explore the uncertainty in the results [41, 42]. Items to be tested in sensitivity analyses are listed in Table 3. Primary analysis will be on complete case basis, where a complete case is defined as cases meeting the CESAR trial clinical effectiveness data analysis. Estimation of the key cost variables is based on between 40 and 50 data items representing different aspects of resource use from each participant. If any single item is missing, the cost variable will also be incomplete. We predict that the complete case analysis will contain a small proportion of the total number of trial participants and thus have a high potential for bias and imprecision. Any missing resource item values will be replaced with imputed values and re-analysed as part of the sensitivity analysis. Missing data will be imputed using Rubin's multiple imputation method [43] with SOLAS v3.20 (Statistical Solutions Inc, Co Cork, Eire).
Table 3 Items to test during sensitivity analysis
Generalising the results to different settings
It would be beneficial to health care decision makers if economic study results could be generalised from one setting to another as this would avoid having to repeat every study in every setting. Factors which may vary in different settings are: unit costs of resources, geographical variations in demography or epidemiology of disease, clinical practice patterns, incentives to health care professionals and availability of resources. To facilitate estimation of the transferability of economic data from the CESAR trial to other health care setting, such factors in the study population will be described, and resource use and prices reported separately.
The CESAR trial is the first RCT of adult ECMO with an economic evaluation incorporated into the design of the trial. The CESAR Trial was funded with full economic support from the design stages of the trial with funding for two part-time health economists which helped the economic research team to tackle many challenges in the design, methods, data collection, developing and piloting the economic questionnaire and planning the analysis. The trial protocol was developed in collaboration with health economists, who are members of the Trial Steering Committee, and an economics working group oversees the economic data collection and analysis.
Incorporation of economic evaluations within randomised controlled trials of medical therapies has been a growing trend in the past decade. Many health care systems in developed countries now use economic evaluations as a formal input to decisions about whether to fund new technologies. In the UK, economic evaluations play a key role in the technology appraisal process at the National Institute of Clinical Excellence (NICE) which makes decisions about a range of health technologies (NICE 2004).
Economic evaluations conducted alongside randomised trials are meant to inform decision-makers about the economic benefit of the technology under investigation. The information will shed the most light on the question of 'value for money' if the trial and the evaluation are properly designed, if appropriate data are collected and correctly analysed, and if the many sources of uncertainly surrounding these evaluations are adequately addressed. The past decade has seen a large increase in the number of published economic evaluations as well as improvements in economic evaluation techniques. However, much debate and confusion still persist among analysts, readers, and policy- makers concerning methods and the overall usefulness of CEA in resource allocation decision making. A number of potential reasons may account for this, among them political expediency, social preferences and systemic barriers to implementation. In addition, there are a number of more technical shortcomings associated with the generation of economic evidence including methodological inconsistency across completed economic evaluations and the limited generalisability or transferability of findings or settings beyond the location of the original study.
The economic evaluation methodology described in this paper aims to address these issues and guidelines and recommendations from more recent publications in methods for economics and trials [44] were used in the design and conduct of the evaluation and the planned analysis.
The CESAR Trial was funded with full economic support from the design stages of the trial with funding for three part-time health economists which helped the economic research team to tackle many challenges in the design, methods, data collection, developing and piloting the economic questionnaire and planning the analysis. The trial protocol was developed in collaboration with health economists, who were members of the trial steering group, and an economics working group including the trial manager and leaders have overseen the economic evaluation.
The strengths of the trial on which this economic evaluation was based are that it was randomised and controlled, pragmatic in design, and provided a vehicle for collecting a comprehensive set of data on resource use and clinical effectiveness. These provide a reliable basis for estimating the economic efficiency of ECMO for adults with severe respiratory failure. The study cost accounting was comprehensive and included most major health service cost items. Most unit costs used for valuation of reported resources used were from published national sources and where unit costs were unavailable rigorous methods were used for their estimation and the methods used clearly described. Unit costs for ICU stays were estimated for every centre that recruited a patient which was then weighted for each patient to reflect the level of care and number of organs supported during the acute phase of the illness. Very few resource items were excluded from the data collection process alongside the trial.
Presenting this methodology paper before the end of the trial is an attempt to make transparent the methods used for the evaluation, and to allay concern of manipulation of economics results. In our view it is important to record our methods in detail and present before publication of the results of the trial so that a record of detail not normally found in the final trial reports can be made available in the public domain.
There are aspects of the planned methods that may be seen as idealistic. In particular, our estimation of resource use after hospital discharge is based on patients' reports after a traumatic period in their lives of many different aspects of service use and personal costs. The aggregate cost variables are made up from a combination of this large number of reported items, many of which may be missing. Although complete case analysis is our primary method of analysis, we are conscious that this might be quite unrepresentative of the CESAR trial population. Our planned secondary approach is to use imputation of missing values to increase the numbers of patients for whom we can estimate costs. However, this also raises the question about how much detail we actually needed to collect from patients (or other sources). Previous researchers have attempted to establish reduced form resource use data for costing [45, 46] but have not arrived at any general rules for doing this. Subject to Steering Group approval, the data from this trial will be available for further analysis of this problem.
As a result of this publication of the methods for the economic evaluation in the CESAR trial prior to publication of the results, we shall be open to scrutiny for any changes to protocol in our reported data collection and analysis. By this means we hope to increase confidence in the results of the economic evaluation.
CEA:
CESAR:
Conventional Ventilation or ECMO for Severe Adult Respiratory Failure
CUA:
ECMO:
Extracorporeal membrane oxygenation
ICER:
Incremental Cost Effectiveness Ratio
NHS:
ONS:
Office of National Statistics
PSSRU:
Personal Social Services Research Unit
RCT:
Lewandowski K: Extracorporeal membrane oxygenation for severe acute respiratory failure. Critical Care. 2000, 4: 156-168. 10.1186/cc689.
Hemmila MR, Rowe SA, Boules TN, Miskulin J, McGillicuddy JW, Schuerer DJ, Haft JW, Swaniker F, Arbabi S, Hirschl RB, Bartlett RH: Extracorporeal life support for Severe Acute Respiratory Distress Syndrome in Adults. Annals of Surgery. 2004, 240: 595-607.
Hill JD, O'Brien TG, Murray JJ, Dontigny L, Bramson ML, Osborn JJ, Gerbode F: Prolonged extracorporeal oxygenation for acute post-traumatic respiratory failure (shock-lung syndrome). N Eng J Med. 1972, 286: 629-634.
UK Collaborative Trial Group: UK collaborative randomised trial of neonatal extracorporeal membrane oxygenation. Lancet. 1996, 348: 75-82. 10.1016/S0140-6736(05)66228-9.
Bartlett RH: Extracorporeal Life Support Registry Report 1995. ASAIO J. 1997, 43 (1): 104-7. 10.1097/00002480-199701000-00018.
Peek GJ, Moore HM, Moore N, Sosnowski AW, Firmin RK: Extracorporeal Membrane Oxygenation for Adult Respiratory Failure. Chest. 1997, 112: 759-764. 10.1378/chest.112.3.759.
Milberg JA, Davis DR, Steinberg KP, Hudson LD: Improved survival of patients with acute respiratory distress syndrome (ARDS). 1983–1993. JAMA. 1995, 273: 306-309. 10.1001/jama.273.4.306.
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Jardin F, Fellahi J-L, Beauchet A, Vieillard Baron A, Loubières Y, Page G: Improved prognosis of acute respiratory distress syndrome 15 years on. Intens Care Med. 1999, 25: 936-941. 10.1007/s001340050985.
American Thoracic Society: Understanding Costs and Cost-Effectiveness in Critical Care. Am J Respir Crit Care Med. 2002, 164: 540-550.
Peek GJ, Clemens F, Elbourne D, Firmin R, Hardy P, Hibbert C, Killer H, Mugford M, Thalanany M, Tiruvoipati R, Truesdale A, Wilson A: CESAR: Conventional ventilatory support vs extracorporeal membrane oxygenation for severe adult respiratory failure. BMC Health Services Research. 2006, 6: 163-10.1186/1472-6963-6-163.
Roberts T: Economic evaluation and randomised controlled trial of extracorporeal membrane oxygenation: UK collaborative trial. BMJ. 1998, 317: 911-916.
Petrou S, Edwards L: Cost effectiveness analysis of neonatal extracorporeal membrane oxygenation based on four year results from the UK Collaborative ECMO Trial. Arch Dis Child Fetal Neonatal Ed. 2004, 89: F263-F268. 10.1136/adc.2002.025635.
Petrou S, Bischof M, Bennett C, Elbourne D, Field D, McNally H: Cost-effectiveness of neonatal extracorporeal membrane oxygenation based on 7-year results from the United Kingdom Collaborative ECMO Trial. Pediatrics. 2006, 117: 1640-9. 10.1542/peds.2005-1150.
Mahle WT, Forbess JM, Kirshbom PM, Cuadrado AR, Simsic JM, Kanter KR: Cost-utility analysis of salvage cardiac extracorporeal membrane oxygenation in children. J Thorac Cardiovasc Surg. 2005, 129: 1084-90. 10.1016/j.jtcvs.2004.08.012.
Drummond MF, O'Brien B, Stoddart GL, Torrance GW: Methods for the economic evaluation of health care programmes. 1997, Oxford: Oxford University Press
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Angus DC, Musthafa AA, Clermont G, Griffin MF, Linde-Zwirble WT, Dremsizov TT, Pinsky MR: Quality-adjusted survival in the first year after the acute respiratory distress syndrome. Am J Respir Crit Care Med. 2001, 163: 1389-94.
Herridge MS, Cheung AM, Tansey CM, Matte-Martyn A, Diaz-Granados N, Al-Saidi F, Cooper AB, Guest CB, Mazer CD, Mehta S, Stewart TE, Barr A, Cook D, Slutsky AS, Canadian Critical Care Trials Group: One-year outcomes in survivors of the acute respiratory distress syndrome. N Engl J Med. 2003, 348: 683-93. 10.1056/NEJMoa022450.
Graf J, Wagner J, Graf C, Koch KC, Janssens U: Five-year survival, quality of life, and individual costs of 303 consecutive medical intensive care patients – a cost-utility analysis. Crit Care Med. 2005, 33: 547-55. 10.1097/01.CCM.0000155990.35290.03.
Rimachi R, Vincent JL, Brimioulle S: Survival and quality of life after prolonged intensive care unit stay. Anaesth Intensive Care. 2007, 35: 62-7.
Sznajder M, Aegerter P, Launois R, Merliere Y, Guidet B, CubRea : A cost-effectiveness analysis of stays in intensive care units. Intensive Care Med. 2001, 27: 146-53. 10.1007/s001340000760.
Government Actuary's Department: Life tables for the UK. 2007. Cited 29 Aug 2007, [http://www.gad.gov.uk/Demography_Data/Life_Tables/]
Department of Health: Health Survey for England 1996. [http://www.dh.gov.uk/en/Publicationsandstatistics/PublishedSurvey/HealthSurveyForEngland/Healthsurveyresults/DH_4001554]
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British National Formulary. 2005, [http://www.bnf.org/bnf/]
Automobile Association (AA) motoring costs. 2005, [http://www.theaa.com/motoring_advice/motoring_costs.html]
Posnett J, Jan S: Indirect cost in economic evaluation: The opportunity cost of unpaid inputs. Health Economics. 1996, 5: 13-23. 10.1002/(SICI)1099-1050(199601)5:1<13::AID-HEC182>3.0.CO;2-J.
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Treasury HM: The Green Book: appraisal and evaluation in central government. 2007, London: The Stationery Office
Hibbert CL, Coates EJ, Brazier JE, Morris J: A cost survey of 70 adult critical care units – results from volunteer sample in England, Scotland and Northern Ireland in 2003. Care of the Critically Ill. 2005, 21: 8-17.
Hibbert CL, Coates E, Brazier J, Morris J: Development of Healthcare Resource Groups for adult critical care. Report for the NHS Information Authority. 2004, London Department of Health
Sutton AJ, Abrams KR, Jones DR, Sheldon TA, Song F: Methods for meta-analysis in medical research. 2000, Chichester: John Wiley & Sons
Hibbert C: Development and application of a method for estimating case-mix adjusted costs of adult critical care units. PhD Thesis. 2007, Sheffield: University Sheffield
Dean JE, Edbrooke DL, Corcoran M: The critical care national cost block programme: implementing a standard costing methodology on a national scale. Care of the Critically Ill. 2002, 18: [http://www.mercs3510.fsnet.co.uk/Publications/publications.html]
Thalanany MM, Mugford M, Mitchell-Inwang C: Visiting adult patients in intensive care: the importance of relatives' travel and time costs. Intensive and Critical Care Nursing. 2006, 22: 40-8. 10.1016/j.iccn.2005.10.004.
Briggs AH: Statistical methods for cost-effectiveness research: A guide to current issues and future developments. Office of Health Economics London. 2003
Karlsson G, Johannesson M: The decision rules of cost-effectiveness analysis. PharmacoEconomics. 1996, 9: 113-120.
Glick HA, Briggs AH, Polsky D: Quantifying stochastic uncertainty and presenting results of cost-effectiveness analyses. Expert Rev of Pharmacoeconomics & Outcomes Res. 2001, 1: 25-36. 10.1586/14737167.1.1.25.
Fenwick E, O'Brien B, Briggs A: Cost-effectiveness acceptability curves: facts, fallacies and frequently asked questions. Health Economics. 2004, 13: 405-415. 10.1002/hec.903.
Rubin DB: Multiple Imputation for Nonresponse in Surveys. 1987, New York: John Wiley & Sons, Inc
McGuire A, Drummond M, Drummond M, (eds): Economic Evaluation in Health Care: Merging Theory with Practice. 2001, Oxford and New York: Oxford University Press
Knapp M, Beecham J: Reduced list costings: examination of an informed short cut in mental health research. Health Economics. 1993, 2: 313-322. 10.1002/hec.4730020404.
Whynes DK, Walker AR: On approximations in treatment costing. Health Economics. 1995, 4: 31-39. 10.1002/hec.4730040104.
The Trial (ISRCTN47279827) is funded by the NHS R&D Health Technology Assessment programme (HTA). The opinions expressed here are those of the author(s) and not necessarily those of the UK Government's Department of Health or the Sponsor.
CESAR is a collaborative study between the Glenfield Hospital, Leicester; Medical Statistics Unit, London School of Hygiene and Tropical Medicine; University of East Anglia, Norwich, University of Sheffield, and University of Leicester.
Grant holders of the project (ISRCTN47279827) are Giles Peek(Glenfield Hospital), Richard Firmin (Glenfield Hospital), Diana Elbourne (London School of Hygiene and Tropical Medicine (LSHTM), Miranda Mugford (University of East Anglia), Ann Truesdale (LSHTM), Andy Wilson (University of Leicester), Clare Hibbert, (University of Sheffield and RTI Health Solutions, Manchester) David Edbrooke (Royal Hallamshire Hospital Sheffield, Hillary Killer (Glenfield Hospital).
The economic evaluation team comprises Miranda Mugford (Professor of Health Economics), researchers Mariamma M Thalanany, Clare Hibbert, Lizzie Coates ( 2002–2004), Nicola Cooper, and Ann Raven (independent researcher 2000 – 2001), Diana Elbourne, Ann Truesdale, Steven Robertson (2001–2005) and Val Knights (clerical support 2001–2005).
Clinical Co-ordinating Centre at Glenfield Hospital organises the clinical advisory service, co-ordinates the activities of all clinical centres in the trial and comprises Giles Peek (cardio-thoracic surgeon), Richard Firmin (consultant surgeon), Ravindranath Tiruvoipati (CESAR clinical research fellow), Hilliary Killer (General Manager), and Nikki Jones (CESAR clinical research fellow 2001–2003).
Samantha Harris (research nurse, Glenfield Hospital) helped with piloting the memory aid and resource use questionnaire. Transport of patients at trial recruitment is organised by Gail Faulkner, Corrine McCullough (2001–2004), Jackie Redfern (2004–2005), Alan Sheward (2004–2005) and Megan Gratrix (2005–2006).
Data Co-ordination and statistical support is provided by Medical Statistics Unit, London School of Hygiene and Tropical Medicine under the direction of Diana Elbourne, and includes Ann Truesdale (Trial advisor), Pollyanna Hardy (Statistician 2001–2005), Felicity Clemens (statistician), Korotimi Diallo (Data Manager), Steven Robertson (Data Manager to 2005), Keith Tomlin (Database manager to 2004) and Andy King (programmer), Debbie Piercy (Clerical assistant and data entry clerk).
The 6-month follow-up team is co-ordinated by Dr Andy Wilson (University of Leicester) and interviewers Jo Sanderson (2002–2006) Paul Sinfield and Carolyn Tarrant.
The Trial Steering Committee meets every year and is responsible for approving any changes to protocol and monitors and supervises the trial towards achieving its objectives. Members include an independent chairperson, Professor David Field (Professor of Neonatal Medicine, Leicester Royal Infirmary), independent members Professor Nigel Webster (Professor of Anaesthesia and Intensive Care, Aberdeen Royal Infirmary), Professor Anne Tattersfield (Professor of Respiratory Medicine, Nottingham City Hospital), Wendy Nganasurian (lay member), Silvia Holden (lay member), and Dr John Scott (East Anglian Ambulance Trust). Members of the project management group are ex-officio. This represents all the different disciplines involved in the trial. Specialist working groups will advise the Steering Committee.
An earlier draft of the paper was presented at the 2nd Annual Meeting of the International Health Technology Assessment (HTAi) Conference in Rome in June 2005 and the abstract of the paper published as conference proceedings in the Italian Journal of Public Health, Italian Journal of Public Health, Year 3, Volume 2, number 2, summer 2005, supplement 1 p.159.
School of Medicine, Health Policy and Practice, University of East Anglia, Norwich, NR4 7TJ, UK
Mariamma M Thalanany
& Miranda Mugford
Health Economics & Decision Science, School of Health & Related Research, University of Sheffield, S1 4DA, UK
Clare Hibbert
Department of Health Sciences, University of Leicester, LE1 7RH, UK
Nicola J Cooper
& Andrew Wilson
London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK
Ann Truesdale
, Steven Robinson
, Diana R Elbourne
, Felicity Clemens
& Polly Hardy
Glenfield Hospital, Leicester, LE3 9QP, UK
Ravindranath Tiruvoipati
& Giles J Peek
Frankston Hospital, Victoria, 3199, Australia
Clinical Epidemiology and Biostatistics Unit, Royal Children's Hospital, Melbourne, Australia
Polly Hardy
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Correspondence to Miranda Mugford.
Thalanany MM – 1) made substantial contributions to conception and design of the economic evaluation in the CESAR trial 2) design of all economic questionnaires, 3) transport data collection 4) design and analysis of the cost of visiting study, 5) was involved in drafting the manuscript and 6) has given the final approval of the version to be published.
Mugford M – 1) responsibility for leading and co-ordinating all activities of the economic group, 2) made substantial contributions to conception and design; 2) was involved in revising the manuscript critically for important intellectual content; and 3) has given final approval of the version to be published.
Truesdale A, Elbourne D, Peek G, Clemens F, Cooper N, Hibbert C, Wilson A – 1) made substantial contributions to conception and design; 2) were involved in revising the manuscript critically for important intellectual content; and 3) have given final approval of the version to be published.
Robertson S, Hardy P, – 1) were involved in revising the manuscript critically for important intellectual content, 2) took part in data collection and analysis and 3) have given final approval of the version to be published.
Tiruvoipati R – Was involved in revising the manuscript critically for important intellectual content, 2) took part in data collection and 3) have given final approval of the version to be published.
Economic Evaluation
Critical Care Unit
Severe Respiratory Failure
Health Service Cost
Resource Item


We are committed to fully satisfy all our customers.
To achieve maximum quality in our products, through working with high quality suppliers and having highly qualified personnel.
To achieve the requirements and expectations of all our customers.
To fully Comply with the legislation and regulations that are applicable to the company, as well as those commitments voluntarily adopted by it.
Every aspect of Clam Desarrollo S.L. is important, including personnel, suppliers, products, customer service, machinery etc, the involvement of each one is paramount to achieving our objectives.
To continue to improve the image of Clam Desarrollo S.L., distinguishing itself from the competition.
Help continuous improvement, establishing proactive actions aimed at achieving them.
The management of the company is committed to having this policy enacted, understood, implemented and maintained at all levels of the company.
Finally, with the implementation of the quality management system we will continue to improve all our processes, as well as the continuous satisfaction of our customers.


The flavorsome pumpkin and sunflower seeds for a waltz of good taste. The coconut flakes for a burst of coastal sea winds amid a small dash of coffee and sugar – here's a trail mix for someone who wants it all and then yet again, not to heavy either. Next time hunger strikes at 4, open a pack and have some more.
The mix is delicious, an energizer which can not just substitute a snack but keep away all the junk food blues. Perfect for a snack during travel or for hungry at four.


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text:
Боросиликатное стекло — силикатное стекло, где щелочные компоненты в исходном сырье заменены на оксид бора (B2O3). От обычного стекла отличается повышенной термической стойкостью и повышенной стойкостью к механическим повреждениям. Впервые синтезировано Отто Шоттом в 1887 году.

В состав оптических стёкол оксид бора вводят для того, чтобы повлиять на характер зависимости показателя преломления от длины волны света.

Коэффициент теплового расширения
У боросиликатного стекла коэффициент теплового расширения примерно в три раза меньше, чем у натрий-известкового стекла. Cреди стёкол этот коэффициент меньше только у кварцевого стекла (почти в 10 раз). Это позволяет стеклу не трескаться при резких изменениях температуры. Этим также обусловлено его применение в качестве противопожарного и в других случаях, когда необходима термическая стойкость. Поскольку коэффициент плотности у боросиликатной основы выше, чем у силикатных стекол, оно лучше защищено от риска физических повреждений. Этим достигается повышение химической стойкости и уменьшение коэффициента линейного теплового расширения — до 3,1 °C−1 при 20 °C у лучших отечественных образцов.

Использование
Художники по стеклу применяют боросиликатное стекло для изготовления различных композиций в пламени горелки. Из него выдуваются дорогостоящие декоративные художественные фужеры, бокалы, вазы, графины, фигурки и т. д. Также из него изготавливают ювелирные украшения, зачастую сочетая с драгоценными металлами.

В быту, для изготовления посуды для открытого огня, заварочных чайников. Применяется как материал для лабораторной посуды, а также для химической промышленности и других отраслей, например, в качестве материала теплообменника для тепловых электростанций. Также применяется для изготовления гитарных слайдов.

Также боросиликатное стекло может применяться для изготовления пипеток для ИКСИ, биопсии бластомера, которая проводится для проведения предимплантационной генетической диагностики с использованием в качестве генетического материала биопсийных клеток. Существует 3 варианта пипеток с внутренним диаметром от 4 мкм до 7,5 мкм. Длина пипетки составляет от 60 до 75 мм и имеет угол скоса 30°. Пипетки предназначены для одноразового использования.

Боросиликатные стёкла различных составов составляют значительную часть марок оптических стёкол. В частности, к классу боросиликатных относятся такие типы кроновых оптических стёкол как лёгкие (ЛК), обычные (К), тяжёлые (ТК) и баритовые кроны (БК), а также кронфлинты (КФ). В свою очередь в каждый из этих типов входят несколько различных марок стёкол, выпускаемых промышленностью.

Из боросиликатного стекла изготавливают не только линзы, но и зеркала для телескопов-рефлекторов. Причина этого в сочетании цены и малого коэффициента температурного расширения.
В начале XX века это был лучший материал для этих целей. В настоящее время лучшим материалом являются  и ситаллы, но они стоят дороже пирекса.

Из боросиликатного стекла с коэффициентом линейного теплового расширения 2,8 °C−1 производства фирмы Охара корпорейшн изготавливаются зеркала для Гигантского Магелланова телескопа (ГМТ).

Примечания

Стекло
Бор (элемент)

redpajama_set_name: RedPajamaWikipedia


Louis Vuitton, the largest luxury store in the world, with a house designed as a real walk located in Paris 8th arrondissement on the Champs Elysees near Arc de Triomphe, at the corner of the George V Avenue and facing the Fouquet's Restaurant. Inside no floors, a succession of gently sloping terraces that lead you to the center. It was in 1854 that the young Louis Vuitton created the house by making travel trunks. His fame will come thanks to the help of his heir, Georges Vuitton, who created in 1896 the famous monogrammed canvas to fight the counterfeit way.
We propose serveral hotels near Louis Vuitton in Paris.
Metro station: George V (line 1).
RER A station: Charles de Gaulle-Etoile at 350 meters.


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Please note: these templates were a part of a Something Wicked This Way Comes previously released under a brand Weekendays Digital Designs (Dagi's Temp-tations & Nom De Plume).
Something Wicked This Way Comes, the newest digital scrapbook tmeplates by Dagi's Temp-tations are arriving in store just in time to help you scrap your Halloween memories. With ghosts, spiders, bats and more, Something Wicked This Way Comes is full of spooky goodness that's sure to add just the right touch of cute and creepy to your Halloween scrapbook pages.


Professor Niemann is a 1993 graduate of our Law School and, after 22 years in private and corporate practice, has returned to serve as the inaugural Director of the Law School's Entrepreneurship Legal Clinic. During law school at MU, he was Student Bar Association President, Co-Chair of the Student-Faculty Relations Committee, a member of the Chancellor's Student Advisory Committee, and a member of the Law School Dean Search Committee.
Professor Niemann's early legal career began in St. Louis as a litigation associate at Evans & Dixon. He later transitioned from commercial litigation to corporate practice while working at Blumenfeld, Kaplan & Sandweiss. During his early legal career in St. Louis, Professor Niemann tried several cases and argued appeals in various state and federal courts, including oral argument before the U.S. Court of Appeals for the Eighth Circuit. His appellate brief in Duggan v. Zip Mail Services, Inc., 920 S.W.2d 200 (Mo.Ct.App. 1996) resulted in new precedent on Federal Arbitration Act pre-emption of Missouri's Uniform Arbitration Act and clarification of the "interstate commerce" exemption.
Prior to returning to Mizzou, Professor Niemann represented start-ups, early stage companies and other commercial clients in both law firm and in-house legal roles. His recent in-house experience spanned over 7 years at Assurant, a Fortune 300 multi-national company. After starting in Assurant's Government Relations Department in Miami, Florida, Professor Niemann soon transferred to Assurant's Atlanta office and served in general counsel roles for various business units. He spent his last years at Assurant as lead counsel for the Company's new product development team, helping innovators protect and commercialize their inventions while also managing their intellectual property portfolio.
Professor Niemann has served in numerous leadership roles for the Bar Association of Metropolitan St. Louis, including Young Lawyers' Division Chair, BAMSL Board and Executive Committee Member, and Distinguished Fellow of the St. Louis Bar Foundation. He received the BAMSL YLD Award of Merit in 1996. He has also held leadership positions with the American Bar Association, including Chair of the ABA Young Lawyers' Division Ethics & Professionalism Committee and Member of the ABA's Ethics 2000 Committee. Professor Niemann contributed to the ABA Journal Article "A Treacherous Path: Evolving Business Law Ethics Issues" (February 2000). He has been a featured speaker at numerous CLE and client education programs. He is also an ABA YLD Fellow.
Professor Niemann holds law licenses in Missouri, Georgia and Illinois, and has been admitted to practice before the U.S. Court of Appeals for the 8th Circuit, and the federal district courts for Eastern and Western Missouri and the Southern District of Illinois.


text:
(473137) 2015 KK3 es un asteroide perteneciente al cinturón de asteroides, descubierto el 12 de septiembre de 2007 por el equipo del Spacewatch desde el Observatorio Nacional de Kitt Peak, Arizona, Estados Unidos.

Designación y nombre
Designado provisionalmente como 2015 KK3.

Características orbitales
2015 KK3 está situado a una distancia media del Sol de 2,783 ua, pudiendo alejarse hasta 2,928 ua y acercarse hasta 2,638 ua. Su excentricidad es 0,052 y la inclinación orbital 4,117 grados. Emplea 1696 días en completar una órbita alrededor del Sol.

Características físicas
La magnitud absoluta de 2015 KK3 es 16,5.

Véase también
 Lista de asteroides del (473101) al (473200)
 Cuerpo menor del sistema solar

Referencias

Asteroides del cinturón principal
Objetos astronómicos descubiertos por el Spacewatch
Objetos astronómicos descubiertos desde el Observatorio Nacional de Kitt Peak
Objetos astronómicos descubiertos en 2007
Wikiproyecto:Asteroides/Artículos de asteroides


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MYTECHMAG
Home Cyber Security How Cyber Security is Transforming?
How Cyber Security is Transforming?
Cybersecurity is continually evolving as security experts, and their adversaries develop and modify new techniques to their trade. Researchers, businesses, and professionals from the security community considered emerging trends in the field through the 8th semiannual UC Cyber Security Summit, hosted at UC Santa Barbara.
Speakers narrated topics such as creating, weaponizing, and detecting deep tricks, an issue of utmost importance, especially as the official race kicks into gear. They also addressed threats to essential infrastructure as well as phishing, the center of UC Santa Barbara's Cyber Security Awareness Month operations this year.
Giovanni Vigna, a teacher of computer science and director of the campus' Center for CyberSecurity and co-director of the Security Lab, addressed the keynote address, discussing how artificial intelligence is transforming the security landscape. According to Vigna, identifying threats and managing network security is demanding and time-consuming. People are looking to AI to automate and organize their efforts while also expanding their range.
AI can efficiently classify computer activity and even learn to organize it, streamlining this monotonous work, he explained. It makes anomaly detection available at a scale, scope, and efficiency unthinkable when the concept was developed in the 1980s. It can even allow security authorities to go on the offensive: proactively accumulating intel and developing tools to combat attacks their network hasn't encountered yet.
But AI is not a clear-cut answer to our security challenges. Malicious actors are well recognized for running insidious false-flag attacks that can involve AI. "What's more, the adversary can contaminate the dataset from which you're learning," Vigna said, like setting out decoys. As an analogy, he mentioned the antics of those who designate inanimate objects like people in pictures they post on Facebook. This compromises the data the company's software utilizes to learn.
Combining AI into cybersecurity doesn't change the fact that security workers still require to keep their methods safe from attackers. Machine learning addresses this even more crucial and more difficult. Researchers have reported a flaw that allows an individual to keep what a system has learned. It's a procedure for reverse engineering, and AI algorithm based on the answers it presents. "If I can question you as an oracle about what you think about my data and what you have studied, then I can steal anything you ever learned," stated Vigna.
"In my lab, we're concentrating on machine learning in many different ways, and not only to expose stuff," he added. "For example, we use machine learning to distinguish which parts of the code are more prone to restrain vulnerabilities." The use of AI will not end the difficulty of cybersecurity. AI is just another tool, and its consequences will be only as good or as bad as the intentions of the individuals operating it. "The bad guys are utilizing artificial intelligence, too," Vigna showed out.
He also suggested that the security community tends to assume that unusual activity communicates with malicious activity. But this isn't essentially the case. Some attacks look innocuous, while others, the regular maintenance, look suspicious. Connecting AI anomaly detection with systems set up by humans to differentiate good and bad actions appears to offer the best of both procedures. Humans are still a vital part of cybersecurity. "You can promote the level of discourse using artificial intelligence, but certain choices still require humans to interpret and build a context to fully address the threat," Vigna replied. We're the ones who make the distinction judgments about what our software wins.
Previous articleLesser-Known Cyber Security Threats That are Growing
Next articleIoT & Cyber Security: Measures to Take!
Cyber Security for Small Businesses is Important Now
Top Alarming Cyber Security Facts for 2020
Top Cyber Security Trends That Will Affect Your Business in 2020
Balancing Security Assurance and Throughput: High Footfall Screening
How Deep Learning can Sense Cyber Threats Even Before it Takes Place?
A Standard Approach to Managing Cybersecurity Threats
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Virginia entices locals to go green by offering numerous time- and money-saving, green driver incentives. These perks include alternative fuel vehicle (AFV) emissions test exemptions for electric cars and hybrids, high occupancy vehicle (HOV) lane access for clean-fuel vehicles, state and federal tax incentives, discounted electric vehicle (EV) charging rates, fuel-efficient auto insurance discounts, and more.
These eco-friendly driver incentives and related green vehicle laws are subject to change. In addition to referencing this page, periodically check in with your local VA Department of Motor Vehicles branch and the government's Alternative Fuels Data Center.
Get the full scoop through Air Check Virginia and our pages on green vehicle laws and smog checks. If necessary, locate the nearest inspection center using our locator widget at the bottom of the page.
If you drive a qualifying clean-fuel vehicle, you may apply for clean special fuel vehicle plates through the Virginia DMV. The benefit: You may use certain VA high occupancy vehicle (HOV) lanes, regardless of the number of passengers in your vehicle.
Virginia issues three types of clean special fuel plates. Each comes with a specific HOV lane occupancy-requirement exemption. The date on your DMV plate application receipt determines the type of clean fuel plate you'll receive.
On or after July 1, 2011—Exemption from the occupancy requirements of any HOV lane, excluding those in the I-95/395 corridor and I-66 corridor.
Between July 1, 2006 and June 30, 2011—Exemption from the occupancy requirements of any HOV lane, excluding those in the I-95/395 corridor.
Before July 1, 2006—Statewide exemption from the occupancy requirement of any HOV lane.
Keep in mind, if Virginia issues you clean special fuel plates before July 1, 2011, you may only renew or transfer these to a new purchase that also qualifies as a clean vehicle.
Check that your vehicle made the list of qualifying clean fuel vehicles.
Download and complete the License Plate Application (VSA 10), including the vehicle identification number (VIN) and title number.
The DMV Special Registration Work Center will then review your application, then mail you notification of whether you qualify. If so, it will also mail you your clean special fuel license plates and a payment invoice (if applicable). These plates cost $25 annually in addition to your regular registration fees.
For full details, consult the DMV's page on Clean Special Fuel Vehicles/Plates.
Virginia and the federal government offer tax breaks on alternative fuels and alternative fuel vehicles. Read the following subsections below for more info.
If you have questions on taking advantage of certain tax incentives, consider consulting a tax professional, the Virginia Department of Taxation, or your local IRS Taxpayer Assistance Center.
Sold and delivered to a government entity (to also be exclusively used by the government entity)—excluding anyone operating under contract with said entity.
Sold and delivered to a 501(3)(c) nonprofit, charitable organization —that exclusively offers charitable, long-distance, advanced life-support to Virginia's low-income medical patients—to operate an aircraft.
Produced by the owner (or lessee) of an agricultural operation when he uses it exclusively for the farm or as fuel in the producer's motor vehicles.
Refer to Virginia Code (58.1-2250) for specifics.
For full details on these tax breaks for eco-friendly vehicle owners, consult the Tax Incentive Information Center.
Dominion offers two electric vehicle pricing plans as part of its pilot program for plug-in electric vehicles. Read on to learn how you can save some extra green.
Dominion offers a rate reduction to customers who charge their electric vehicles during an 8-hour off-peak period. To take advantage of the Electric Vehicle Pricing Plan, you must have an additional meter installed specifically for your EV.
Although Dominion provides additional meters for free, you might incur installation costs. Plus, the EV Pricing Plan comes with an additional service charge. For more info, check outDominion's EV Pricing Plan Details and FAQs, or call (866) 366-4357.
Dominion offers a whole-house pricing plan called the EV + Home Pricing Plan that aims to get customers to use appliances during off-peak hours as much as possible. For the purposes of this plan, view your EV as a separate appliance.
The plan entails exchanging your current meter for a new one that records energy usage in timed intervals. This allows for a recharging your electric vehicle and using other appliances during a pricing period that costs you less.
For more info, check out Dominion's EV + Home Pricing Plan Details, FAQs, and recharging tips , or call (866) 366-4357.
If your current auto insurance carrier doesn't reward eco-friendly driving, find one that does. Compare auto insurance rates online and save some green for going green.
Virginia grants an extension on state weight limits for natural gas vehicles and vehicles either equipped with an auxiliary power unit (APU) or idle reduction technology. Read on for details.
Bi-fuel vehicle that uses natural gas.
Vehicle converted to run on natural gas.
Find out the full details in the Virginia Code (46.2-1129.2).
Virginia extends the state weight limits for vehicles that reduce emissions either using an auxiliary power unit or idle reduction technology. Specifically, such a vehicle may exceed gross, single axle, tandem axle, or bridge formula weight limits by a maximum of 550 lbs. (in total) to compensate for the extra weight of the equipment.
For specifics, consult the Virginia Code (46.2-1129.1).
Use this form to order OR transfer license plates through the VA Department of Motor Vehicles.


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Best Buy is dedicated to always offering the best value to our customers. We will match the price, at the time of purchase, on a Low Price Guarantee product if you find the same item at a lower price at a Designated Major Online Retailer or at a local retail competitor's store.
If you find a qualifying lower price online, call 1-888-BEST BUY and direct a customer service agent to the web site with the lower price, or when visiting a Best Buy store, one of our employees will assist you.
On qualifying products, Best Buy will then verify the current price to complete the price match.
Chromecast is the easy way to enjoy online video and music on your TV. Plug it into any HDTV and control it with your existing Android smartphone or tablet, iPhone®, iPad®, or laptop. No remotes required. Cast your favorites from Netflix, YouTube, HBO GO, Hulu Plus, Pandora, Google Play Movies & TV, Google Play Music, and Chrome* to your TV with the press of a button.
Chromecast supports Netflix, YouTube, HBO GO, Hulu Plus, Pandora, Google Play Movies & TV, Google Play Music and Chrome*. Chromecast will automatically update to work with a growing number of apps.
Chromecast taps into the same app and browsing experience you're familiar with on your smartphone, tablet, and laptop, so there's nothing new to learn. Just open a supported app, press the cast icon, then sit back and enjoy.
Browse for what to watch, control playback, and adjust the volume using the smartphone, tablet, or laptop you already know how to use.
Chromecast works with Android smartphones and tablets, iPhone® and iPad® devices, Chrome (for both Windows and Mac®), and Chromebook Pixel. Support for other Chromebooks coming soon.
Switch to another app, open a new browser tab, or let your device go into sleep mode while you continue to watch your favorites on the TV, all without draining the battery on your smartphone, tablet or laptop.
With Chromecast, cast a Chrome browser tab with anything from photos to music to video from your Windows or Mac laptop or Chromebook Pixel to your TV at home.
Get started in 3 easy steps: Plug Chromecast into your TV, connect it to Wi-Fi, then cast videos and more from your smartphone, tablet, or laptop to your TV.
Chromecast is designed to plug directly into the back of your TV, slipping out of view. It's a small device in its category, making it easy to set up on any TV in your house.
Friends and family can use your Chromecast with their phones and tablets without having to set up anything, as long as they're connected to the Wi-Fi network at your house.
Chromecast supports up to 1080p video resolution, so you won't lose picture quality from high-def sources.
*Casting from Chrome feature is currently in beta.
Posted by: msagent99 from Irving, TX on 03/03/2014It kept Me From Buying A Smart Tv Just To Search The Internet On My Television.
Posted by: jonrambo414 from on 03/02/2014streams netflix from my computer to hdtv. worked fine out of the box and have had no problems.
Posted by: trappgod from Schaumburg on 03/02/2014This is perfect to use with my friends asks family. For what the product is, the price is perfect.
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Best 35 bucks I ever spent.
Posted by: cstanley523 from emmaus, pa on 03/02/2014This is the best 35 bucks I ever spent. Easy to setup, does everything I wanted it to do. I have had no issues streaming to my tv.
Posted by: bluescorpion from Lakewood, CO on 03/02/2014I'm glad I got this accessory. It is easy way to enjoy online video and music on your TV. Plug it into any HDTV and control it with your existing Android smartphone or tablet, smart TV, or laptop.
Up to 6% back in rewards with the My Best Buy™ Credit Card.
Online prices and selection generally match our retail stores, but may vary. Prices and offers are subject to change. © 2014 Best Buy. All rights reserved. BEST BUY, the BEST BUY logo, the Tag Design, MY BEST BUY, and BESTBUY.COM are trademarks of Best Buy and its affiliated companies.


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Jubilejny (biał. Юбілейны, ros. Юбилейный) – osiedle na Białorusi, w obwodzie mińskim, w rejonie mińskim, w sielsowiecie Siennica.

Przypisy

Bibliografia

Wsie w rejonie mińskim
Sielsowiet Siennica


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RealOp Investments
504 Rhett St. | Suite 200, Greenville SC 29601
504 Rhett St. | Suite 200, Greenville, SC 29601 864.416.7265
Copyright © 2021 RealOp Investments, LLC | Designed & Developed by The Ghost Runner
Megan Crawford
Megan received her Bachelor's degree in Business Administration from the University of South Carolina Upstate. Before joining RealOp Investments, Megan worked at NAI Real Estate as a property accountant. At NAI Megan helped with the various accounting needs for over forty properties, which included financial monthly reports, owner distributions and lease administration. As a staff accountant at RealOp, Megan assists in accounting functions for property management and financial reporting.
864.416.7265 ext.115 | Email Me
Laura Moats
CPA | Controller
Laura received her Bachelor's degree in Accounting and her Master's of Accountancy from the University of West Florida, and is a licensed CPA in both Florida and South Carolina. Before joining RealOp Investments in 2016, Laura worked for Regency Centers in Jacksonville, FL in various roles in property accounting and joint venture reporting.
She also has experience in both internal audit and public accounting. As Controller for RealOp, Laura manages corporate accounting and oversees the accounting functions for property management, asset management, and development.
864.416.7265 | Email Me
Cheyenne Miranda
Lease Administrator | Property Management
Cheyenne is completing her Bachelor's Degree in Communications from Coastal Carolina University with a minor in Public Health. She joined RealOp Investments in 2016, and currently serves as the Lease Administrator for RealOp's property management division, where she manages all aspects of our client's leases, renewals, amendments and move outs as well as a variety other matters to help ensure the delivery of a best in class service to our clients and tenants.
Vice President | Property Management
Gina oversees and provides property management services for RealOp and its client's office and industrial assets. Prior to joining RealOps in 2017, she managed office and retail portfolios of up to one million square feet with NAI Earle Furman, The Furman Company (CBRE), and Highwoods Properties.
Gina received her Bachelor's Degree from The University of North Carolina at Wilmington with a major in Economics and is a candidate to receive her CPM designation (Certified Property Manager) from the Institute of Real Estate Management.
Summer Johnson
Summer earned a Bachelor's Degree in Psychology from Clemson University. Prior to joining RealOp Investments in 2013, she excelled in various retail operations. As VP of Property Management, Summer provides property management services for her assigned portfolio and oversees operations of the Charleston office.
Amy M. Wood
Senior Vice President | Property Management
Amy earned her Bachelor's Degree in Business Administration from Peirce College and earned her CPM (Certified Property Manager) designation from the Institute of Real Estate Management. She has more than 20 years of industry experience and a commercial portfolio history in excess of 3.0 million square feet.
As Senior Vice President of Property Management, Amy manages all property management functions and oversee all activity at the ROI Property Managers entity level.
Amanda Redmond
Associate | Investment Management
Before joining RealOp Investments in 2016, Amanda enjoyed a diverse real estate background, having spent more than 15 years with NAI Earle Furman and EOS Real Estate Management. As an Associate for the Investment Management Team, Amanda assists in the overall management of the portfolio, portfolio risk, vendor management, financial reporting and asset disposition.
W. Chip Hunt
Vice President | Investment Management
Chip received his undergraduate degree from Wofford College with a major in Business Economics and also received a Masters in Real Estate Development from Clemson University.
Before joining RealOp Investments, he was a senior analyst within asset management for Piedmont Office Realty Trust, the fourth largest office real estate investment trust in the United States. As the Director of Investment Management, he manages ongoing operations and strategic execution for owned assets.
Patrick Pennell
Project Manager | Development
Patrick received his Bachelor's Degree in Construction Engineering and Management from Virginia Tech. Before joining RealOp Investments in early 2017, Patrick served a Development Manager for Johnson Development and Associates in Spartanburg, SC. As a Project Manager for RealOp, he manages design, permitting, and construction of current and future development projects.
Ralph Settle
Vice President | Development
Ralph received his undergraduate degree from Wofford College with a major in Business Economics and also received a Masters in Real Estate Development from Clemson University. Before joining RealOp Investments in 2015, Ralph served as Director of Development for Johnson Development Associates. As VP of Development, he manages all aspects of RealOp Development, including: sourcing and underwriting, site selection and acquisition, management and procurement of tenant relationships, construction management and vendor management.
864.416.7262 ext. 114 | Email Me