Public pressure has increasingly emphasized the need to ensure the continuing quality of care provided by health professionals over their careers. Health profession's regulatory authorities, mandated to be publicly accountable for safe and effective care, are revising their quality assurance programs to focus on regular evaluations of practitioner performance. New methods for routine screening of performance are required and the use of administrative data for measuring performance on quality of care indicators has been suggested as one attractive option. Preliminary studies have shown that community pharmacy claims databases contain the information required to operationalize quality of care indicators. The purpose of this project was to determine the feasibility of routine use of information from these databases by regulatory authorities to screen the quality of care provided at community pharmacies.Information from the Canadian province of Quebec's medication insurance program provided data on prescriptions dispensed in 2002 by more than 5000 pharmacists in 1799 community pharmacies. Pharmacy-specific performance rates were calculated on four quality of care indicators: two safety indicators (dispensing of contra-indicated benzodiazepines to seniors and dispensing of nonselective beta-blockers to patients with respiratory disease) and two effectiveness indicators (dispensing asthma or hypertension medications to non-compliant patients). Descriptive statistics were used to summarize performance.Reliable estimates of performance could be obtained for more than 90% of pharmacies. The average rate of dispensing was 4.3% (range 0 - 42.5%) for contra-indicated benzodiazepines, 15.2% (range 0 - 100%) for nonselective beta-blockers to respiratory patients, 10.7% (range 0 - 70%) for hypertension medications to noncompliant patients, and 43.3% (0 - 91.6%) for short-acting beta-agonists in over-use situations. There were modest correlations in performance across the four indicators. Nine pharmacies (0.5%) performed in the lowest quartile in all four of the indicators, and 5.3% (n = 95) performed in the lowest quartile on three of four indicators.Routinely collected pharmacy claims data can be used to monitor indicators of the quality of care provided in community pharmacies, and may be useful in future to identify underperforming pharmacists, measure the impact of policy changes and determine predictors of best practices. Although medications are a mainstay of modern medical treatment, their use is associated with both benefit and harm -3. PreveAs pharmacists have incorporated this role of minimizing DRM into their practice, university-based educational programs have been modified to emphasize these responsibilities and standards of practice have been revised ,12. IncrIndicators are being developed to conduct routine surveillance of the quality of care provided in community pharmacies . To maxiThe purpose of this project was to determine the feasibility of routine use of information from these databases by regulatory authorities to screen the quality of care provided at community pharmacies.This study was conducted in the Canadian province of Quebec where the Order of Pharmacists, the governmental regulatory authority responsible for licensing pharmacists, monitors the performance of more than 5000 community pharmacists in 1800 community pharmacies. These pharmacists serve a population of 7.4 million patients, of whom approximately 50% receive government support for payment of their medications via the publicly-funded insurance program . Similar to public and private insurance programs in the rest of the Canadian provinces and American states, medication-related data maintained by RAMQ for insured patients includes payments made for each dispensing of a reimbursable medication, the date, the name, strength, dosage form and quantity of the dispensed medication, and prescriber, pharmacist and pharmacy identification. Reimbursable medications include over 85% of medications available in Canada. In Quebec, medication supply policies support dispensing of chronic medications on a 30 day interval rather than encouraging a 90 day dispensing interval. Although this policy provides more opportunities for pharmacists to detect and intervene on medication use problems, dispensing on either a 30 day or 90 day interval provides regulatory authorities with the data required to measure performance on quality of care indicators.To assess the quality of care provided at community pharmacies, we used a random sample of 1.4 million patients who received medications from community pharmacies between January and December 2002. In addition to the routine medication-related information, for each dispensing a unique anonymized identifier was provided by RAMQ for each patient, prescriber and dispensing pharmacy. These unique identifiers were used to develop a longitudinal prescription history for each patient and a practice population for each pharmacy that could be used to measure quality of performance on each indicator on a pharmacy-specific basis. Ethics approval was obtained from the McGill Faculty of Medicine Institutional Review Board.The feasibility of using pharmacy claims data to evaluate performance was assessed by calculating pharmacy-specific performance on four quality of care indicators and determining whether results met requirements for use for high-stakes decisions by regulatory authorities . SpecifiThe Pharmacy Quality Alliance (PQA) in the United States has developed quality indicators for conditions where there are widely documented medication use problems, including noncompliance with anti-hypertensive medications, over-use of rescue inhalers in the treatment of asthma and use of contra-indicated/high risk medications . We usedNumber of dispensings was counted in the numerator and denominator because the number of dispensings provided the best measure of the opportunity for community pharmacists to detect and intervene on medication-use problems. For example, for the indicator evaluating non-compliance with anti-hypertensive medications, pharmacists had the opportunity to detect non-compliance each time a patient returned to the pharmacy for a refill of his/her medication. Therefore, each dispensing to a non-compliant patient represented an opportunity for intervention by the pharmacist.Pharmacy-specific performance on each quality indicator was calculated using dispensings of medications from all community pharmacies. All dispensings were included because pharmacists are expected to inquire about all prescription therapies including dispensings from other pharmacies. Operationally this meant that for the dispensing of concomitant non-selective beta-blockers and inhaled short acting beta agonists (SABA), the medications could be dispensed from two different pharmacies and the performance was attributed to the pharmacy dispensing the non-selective beta-blocker to the patient. For the over-use of SABA and non-compliance with anti-hypertensive medications, all SABA's and anti-hypertensives dispensed to the patient from all pharmacies were counted. As medication discontinuation and switching are not well documented in databases and are common in management of hypertension, the inclusion of all anti-hypertensives allowed us to eliminate the problems of over-estimation of non-compliance due to switching or changing dose of anti-hypertensive medications.To ensure stable estimates of performance we required pharmacists at each pharmacy to dispense the relevant medication to the at-risk population (i.e. denominator group) five or more times over the one year period . Such cuTo evaluate whether the performance on the quality indicator met the requirements established by regulatory authorities, we first determined the number of pharmacies where pharmacists provided the service frequently enough for reliable performance estimates to be calculated. We then used univariate statistics and the coefficient of variation to examine the distribution of the quality of performance across pharmacies. To determine if performance on one indicator influenced performance on another indicator, we estimated the Spearman Rank Order Correlation among indicators using the pharmacy as the unit of analysis. To estimate the proportion of pharmacies that would be in the worst-performing quartile in all indicators, and would likely be targeted for regulatory review, we cross tabulated performance by quartile on the four performance indicators.Our sample included 1,427,325 patients with an average age of 50 and a predominance of women  to a high of -0.13 (over-use of SABA and under-use of anti-hypertensive medications).Nine pharmacies performed in the lowest quartile on all four indicators, with an additional 95 pharmacies performing in the lowest quartile on three of four indicators. These pharmacies represent those that, in all likelihood, would be targeted for further evaluation by regulatory authorities. By contrast, three pharmacies were in the top quartile for all four indicators with another 79 pharmacies in the top quartile for three of four indicators. These pharmacies would be useful to determine predictors of best practice.This study evaluated all 1800 community pharmacists providing medications to 1.4 million people within the jurisdiction of one regulatory authority in Canada. We found that performance at community pharmacies could be measured on four quality of care indicators using pharmacy claims data. Over 85% of pharmacies provided services frequently enough to be reliably assessed on all four indicators. Proactive surveillance documented substantial variability in performance, with the best performance demonstrated on the indicator measuring rates of dispensing of contra-indicated benzodiazepines to the elderly, and the worst performance demonstrated on the dispensing of SABA to patients who were over-using this medication. Pharmacists at 5.3% (95/1799) of pharmacies underperformed on three of the four indicators.This study is the first to be done in Canada that uses routinely available claims data to evaluate performance at community pharmacies. The PQA in the United States has completed a series of demonstration projects using administrative data from limited numbers of pharmacies (25 to 85 community pharmacies) to evaluate and report on pharmacy-based performance on quality indicators measuring similar medication use-problems . SimilarComparison of our results with those from the demonstration projects is also difficult as the PQA indicators use patients as the unit of analysis where we elected to use dispensings as the unit of analysis. Although number of patients could have been used in our study, by doing so we would have been unable to detect differences in pharmacies where, for example, a patient was compliant for 11 of 12 dispensings as compared to a pharmacy where the patient was compliant for none of the 12 dispensings. If patients had been used as the unit of analysis, both patients would have been classified as non-compliant for the year and the performance of the two pharmacies considered to be equal. To create a more sensitive measure of performance we, therefore, elected to use the number of dispensings as the unit of analysis. Use of dispensings versus patients would also be anticipated to result in a greater variability in performance across pharmacies, whereas use of patients as the unit of analysis would provide an estimate of the impact of pharmacy services in the population. Both approaches will be useful to evaluate in the future.The results of our work have significant implications for regulatory authorities as the approach of using claims data to measure performance on quality of care indicators appears to be feasible and reveals substantial variability in the quality of care provided at community pharmacies. With greater demand for public accountability for the quality of health professional practice, regulatory authorities are moving from a passive complaints-based process for monitoring to proactive quality assurance. Currently, pharmacy regulatory authorities have adopted very resource-intensive processes such as on-site inspections or competence testing for assessing the quality of practice -30. GiveThe main strengths of this study are the large and representative population of pharmacies studied and the measurement of quality indicators in comparable populations. Limitations that should be considered in interpreting the results are that only four indicators were evaluated that may not be representative of a pharmacy's quality of care, and the relationship between performance on the indicator and patient outcome was not ascertained. We were also missing data such as treatment indication, and patient age, sex and socioeconomic status, all of which could influence the types of drugs prescribed and their utilization. In future it would be preferable to retrieve information on these patient-related characteristics to statistically adjust for differences in clientele served by different pharmacies. In addition to these patient characteristics that may affect pharmacy-specific performance, pharmacy-level characteristics have also been shown to relate to the quality of care provided in community pharmacies . Future Our results confirm that patients present to community pharmacies with evidence of well known medication use problems that are related to safe and effective use of medications. Patients at some pharmacies receive superior care and our methodologies could be used to evaluate the patient, pharmacy and prescriber-based characteristics that are associated with better care. There are many changes being made to the way services are being provided in community pharmacies such as regulation of pharmacy technicians, remote dispensing and deregulation of prescription medications. The utilization of pharmacy claims data provides unique opportunities to evaluate the influences of such policy changes.Routinely collected pharmacy claims data can be used to monitor indicators of quality of pharmacy services, and may be useful in future to identify potentially underperforming pharmacists, measure the impact of policy changes and to determine predictors of best practices.The authors declare that they have no competing interests.NW led the conception and design of the study, operationalized the indicators, led the analysis and interpretation of the data, prepared the manuscript and gave final approval of the version of the paper to be published. LT contributed to the conception of the indicators and their operationalization and revised the manuscript. SS completed the data analysis. LS and CVV contributed to the conception of the study and analysis of results and reviewed the manuscript for psychometric accuracy and applicability to assessment of practicing health care professionals. RT provided expertise in study design and operationalization of indicators, analysis and interpretation of the data and preparation of the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6963/11/12/prepub


Erythropoietin (EPO) is a 30.4 kDa glycoprotein produced by the kidney, and is mostly well-known for its physiological function in regulating red blood cell production in the bone marrow. Accumulating evidence, however, suggests that EPO has additional organ protective effects, which may be useful in the prevention or treatment of acute kidney injury. These protective mechanisms are multifactorial in nature and include inhibition of apoptotic cell death, stimulation of cellular regeneration, inhibition of deleterious pathways, and promotion of recovery.In this article, we review the physiology of EPO, assess previous work that supports the role of EPO as a general tissue protective agent, and explain the mechanisms by which it may achieve this tissue protective effect. We then focus on experimental and clinical data that suggest that EPO has a kidney protective effect. Erythropoietin (EPO) is a complex molecule, which regulates red blood cell production in the bone marrow. Recombinant human EPO (rHuEPO) is commercially available and is widely used for the treatment of anemia. In recent years, additional nonerythropoietic tissue/organ protective properties of EPO have become apparent, in particular for kidneys. In this article, we consider the evidence supporting EPO as a general tissue protective drug and discuss the potential mechanisms by which it may achieve this general effect. We then focus on the renal protective effects of EPO and the potential mechanisms through which it may confer this specific protection. Finally, we review the experimental studies and clinical trials of EPO in acute kidney injury (AKI)--discuss risks, lessons learned, and the need for further randomized studies in humans before any change in clinical practice is considered.EPO is a 30.4 kD glycoprotein and class I cytokine consisting of 165 amino acids .in vivo activity than receptor-binding affinity.The variable nature of the sialic acid content gives rise to EPO isoforms with differences in charge. As the number of sialic acid groups on the carbohydrate portion of EPO increase, so does its serum half-life, whereas receptor-binding capacity decreases -7. ClearEach EPO molecule has two EPO receptor (EPOR) binding sites. There are two affinities of the EPOR for EPO in solution: one of high and one of low affinity  .Approximately 90% of systemic EPO in adults is produced by peritubular interstitial fibroblasts in the renal cortex and outer medulla of the kidney. A feedback mechanism involving oxygen delivery to the tissues appears to regulate EPO production ,11.The EPO receptor (EPOR) is a 66 kD membrane glycoprotein typically consisting of 484 amino acids and 2 peptide chains; it belongs to a large cytokine and growth factor receptor family . BindingThe cytoplasmic domains of the EPOR contain a number of phosphotyrosines that are phosphorylated by the activation of a member of the Janus-type protein tyrosine kinase family (JAK2), which is bound to the common beta subunit of the EPOR . In addiThere are a number of common pathways through which EPO exerts its erythropoietic effects that also appear to confer tissue protection. EPO "classically" binds to two EPORs, which become joined as a homodimer and change. This activates JAK2, which is bound to the common beta subunit of the EPOR  and leadEPO classically signals through the "signal transducer and activator of transcription 5" (STAT-5) pathway. The STAT proteins are direct substrates of Janus kinases (JAKs), which results in tyrosine phosphorylation of the STATs as well as phosphorylation of the phosphatidylinositol 3-kinase (PI3K) and subsequent phosphorylation of Akt Figure .Akt  appears to contribute to the cell protection EPO confers Figure . ProteinEPO may be involved in modulation of cellular calcium homeostasis by increasing calcium influx . NuclearFinally, induction of heat shock protein 70 (HSP70) by EPO is related to renal protection in ischemic kidneys . HSP70 pThe principal physiological function of EPO is red blood cell production, which results from a tightly controlled proliferation and differentiation pathway . Early hEPO-binding to EPORs on erythroid progenitor cells leads to activation of the JAK2-STAT5 signaling pathway and phosphorylation of PI3K and Akt1   of EPO beyond erythropoiesis have been shown in the kidney in many animal and some clinical studies.The tissue protective or "pleiotropic" effects . For example, carbamylated EPO (CEPO) does not bind to the classical EPOR isoform and is devoid of hematopoietic activity; however, it can provide tissue protection in the kidney, supporting the existence of a heteroreceptor EPO isoform, which mediates tissue protection . It is cMany animal studies have shown that EPO administration protects kidney tissue from damage and improves renal function in ischemia-reperfusion (IR) and contrast-induced injury models of AKI Tables  and 2 2,28-52 inin vitro model performed by the same team, CEPO promoted more capillary formation than EPO and also appeared to protect the kidneys from IR injury by promotion of angiogenesis . EP. EP57]. The EARLYARF trial is the largest trial of EPO as a nephroprotective agent. However, it suffered from several important methodological limitations. First, it used poorly validated biomarkers as predictors of high risk for AKI. This approach, along with an untested cutoff value to trigger participant inclusion, resulted in the inclusion of a general critically ill cohort rather than only those at true high risk for AKI. The transient increase in urinary GGT and ALP seen in this trial, along with the uncertainty about the timing of the insult in a heterogeneous cohort, limited the ability to draw conclusions about the efficacy of early EPO administration. Importantly, the biomarkers selected to trigger protection against AKI by means of EPO therapy were very poor in predicting AKI with a receiver operating characteristic area under the curve of only 0.54. The decision to randomize was based solely on these biomarkers and did not take into account additional clinical factors that might assist in determining the risk of AKI.A second problem in this study relates to the inclusion of patients with likely volume-responsive prerenal AKI, which would likely reduce the study's power, to determine the true efficacy of EPO. Fractional sodium excretion was low in most randomized patients, suggesting intact renal sodium reabsorption. The exclusion or identification and separate treatment of patients with prerenal AKI may reduce their confounding effect on results.Third, serum creatinine measurements used for the baseline in the primary outcome were based on inconsistent criteria and timing. Some were taken before or around the time of ICU admission and others after adding additional confounders to the analysis. For the vast majority of patients, no creatinine measurement was available. Thus, the diagnosis of AKI was based on a retrospective (post-hoc) analysis using different criteria . These varying criteria can influence the accuracy of any assessment.Fourth, at randomization, approximately one third of patients had already met the criteria for AKI, suggesting that the intervention was relatively late in the process of injury for many. In addition, the trial size was small with clear limitations in statistical power.Fifth, in patients with early AKI (> 30%), measurement of the reduction in AKI stage and improved recovery should replace the use of development of AKI as an endpoint. RIFLE and AKIN classification systems can be used in this way.p < 0.05).Sixth, there were baseline differences between the study groups. For example, the EPO group were older and more likely to have sepsis . Exclusion of patients with hemoglobin >120 g/L from clinical trials of EPO minimizes the risk for thrombosis. Nonetheless, systematic assessment for thrombosis should be performed in any EPO trials of critically ill patients because they have an increased risk for thrombosis.Hypertension occurs in approximately 30% of patients who receive long-term EPO treatment and appears to involve increased endothelin release, upregulation of tissue renin and angiotensin production, changes in the balance of vasoactive substances (prostaglandin/prostacyclin/thromboxane), and an elevation of calcium by EPO (at least in chronic kidney disease) that impairs the vasodilating action of nitric oxide. It is advisable that patients with uncontrolled hypertension do not participate in trials of EPO in AKI.Carbamylated EPO, a cytoprotective, nonerythropoietic derivative of EPO may not exhibit the same risks as EPO and holds great interest as a future tissue-protective therapy. However, it requires further experimental testing before it can be safely evaluated in clinical trials.EPO-AKI and EPO-Biomarkers are the two components of the renal substudy of the EPO-TBI trial (NCT00987454). EPO-TBI is a trial of EPO as cerebral protection after traumatic brain injury, and the renal substudy assesses the effect of EPO on the development of acute kidney injury (AKI) and the response to treatment using multiple renal biomarkers with different time profiles in patients with traumatic brain injury. Having recently sustained a timed physical injury, this homogenous cohort lends itself to such a study. AKI will be classified using methods based on the RIFLE criteria. Baseline renal function will be taken from a consistent source for all patients. With a cohort of 606 patients, this will be the largest study of EPO to protect against AKI ever performed, increasing the probability of detecting a treatment effect. Furthermore, it will be the first EPO trial to incorporate active risk assessment for thrombotic episodes. Weekly intervals separate the doses of EPO (up to 3) in this trial to allow time for clearance and to avoid excessively high levels of EPO. In addition, patients with a known malignancy and/or uncontrolled hypertension will be excluded, thus minimizing risk to patients. In a paradoxical way, the EPO-TBI trial provides a unique opportunity to clarify the potential benefit of EPO as a kidney protective agent. This trial also may provide valuable insight into the mechanisms of EPO in AKI and pave the way for further dedicated large scale trials of EPO in AKI.Many experimental studies and a strong biological rationale support the notion that EPO may be an effective nephroprotective drug. Only two studies have assessed its efficacy in this regard: one study of patients who received elective coronary artery bypass grafting, and the other in a heterogeneous group of critically ill patients. The first showed benefit; the second did not. Thus, there is uncertainty as to whether the experimental benefits can be translated into clinical benefits. A study of EPO in TBI, however, is now underway and will randomize 606 patients to placebo or EPO. This study will offer a unique opportunity to study, in a larger and more homogeneous cohort, whether EPO does confer renal protection in patients at risk of AKI. Until such data are available or other studies emerge to provide more clinical data, EPO remains an attractive but unproven nephroprotective agent.RB is an investigator of a National Health and Medical Research Council/Victorian Neurotrauma Initiative funded clinical trial of Erythropoietin in Traumatic Brain Injury (NCT00987454).EM wrote the first draft of the manuscript. RB reviewed and modified the initial draft.


Spontaneous coronary artery dissection is an important yet rare cause of acute coronary syndrome. The available literature shows a higher risk factor for women, notably during pregnancy and puerperium. The incidence in postmenopausal women is exceedingly rare, and is more commonly seen in association with concurrent predisposing factors.We illustrate an extremely rare case of a 62-year-old post-menopausal woman presenting with an acute myocardial infarction secondary to spontaneous dissection of the left anterior descending artery. Subsequent investigations did not reveal the presence of any co-morbidities.To the best of our knowledge, our patient is one of the oldest documented cases of spontaneous coronary artery dissection on record, and is notable for having no known underlying risk factors for development of spontaneous coronary artery dissection.Given the paucity of literature on spontaneous coronary artery dissection, particularly in postmenopausal women, we believe this case will provide further insight into the clinical presentation and management of this rare entity.A 62-year-old previously healthy postmenopausal Hispanic woman presented with chest pain and was found to have an ST elevation myocardial infarction. Cardiac catheterization revealed a dissection in her left anterior descending artery. Revascularization was deferred; our patient received appropriate medical management and remained asymptomatic. A full panel of tests was done to exclude underlying connective tissue disorders and vasculitis. On subsequent follow-up, our patient continued to do well and all work-up was reported as negative.We describe the varied presentation and subsequent management of a case of spontaneous coronary artery dissection and highlight the importance of considering spontaneous coronary artery dissection as a differential diagnosis even in older, postmenopausal women.The consequences of a delay in diagnosis and appropriate management are associated with a high mortality and morbidity; hence we believe that reporting all cases of spontaneous coronary artery dissection, particularly in postmenopausal women, will add invaluable information to the limited literature on this rare condition. Spontaneous coronary artery dissection (SCAD) is a rare entity; the overall incidence on coronary angiographies is around 0.2% . The meaCoronary atherosclerosis and the peripartum period are most commonly associated with the development of SCAD . Other pThe clinical presentation of SCAD depends largely on the degree of compromise of myocardial blood flow, with most patients presenting with an acute coronary syndrome . UndiagnA review of the literature is remarkable for only a few reported cases of SCAD in postmenopausal women; its incidence in this particular subset of patients, in the absence of known predisposing factors, is exceedingly rare.We illustrate below the rare case of a 62-year-old healthy postmenopausal woman who presented with an acute myocardial infarction secondary to SCAD involving her left anterior descending artery, followed by a brief review of the literature on SCAD including the pathogenesis, treatment and prognosis.A 62-year-old previously healthy postmenopausal Hispanic woman without prior cardiac history presented to our emergency department with recurrent retrosternal chest pain. Our patient denied any illicit drug use, smoking or excessive alcohol consumption. She also denied any family history of heart disease. Of note, our patient reported that she had attained menopause around the age of 50 years; between the ages of 20 and 30 years, she had three full-term pregnancies resulting in the birth of her three children.An initial electrocardiogram was remarkable for ST elevations in the precordial leads Figure , with a Since it was first reported in 1931 .SCAD has been reported predominantly in young women, particularly during pregnancy and puerperium. The incidence in postmenopausal women is rare; a review of the existing literature is notable for only three other cases of SCAD in postmenopausal women above the age of 60 years . Of the Our patient was postmenopausal, without any associated significant atherosclerotic disease, severe hypertension or other co-morbidities; and at 62 years of age, our patient is one of the oldest documented cases of SCAD on record.The etiology of SCAD is likely multifactorial, the common insult being the weakening of the arterial wall, predisposing it to dissection. The proposed pathophysiologic mechanisms include inflammation and rupture of atherosclerotic plaques, enzymatic lysis of the arterial wall by peri-adventitial eosinophilic infiltrates in non-atherosclerotic vessels, changes in hormonal milieu associated with pregnancy and puerperium, presence of underlying vascular and connective tissue disorder, and mechanical weakening of the arterial wall caused by shear and stress associated with physical activity and cocaine use .In atherosclerotic arteries, plaque inflammation and rupture can cause disruption of the intimal medial junction resulting in an intimal flap and subsequent intramural hematoma formation . CoronarClinical presentations can span the clinical spectrum from unstable angina, to myocardial infarction and sudden cardiac death . There hThe literature on SCAD largely consists of case reports and case series; in the absence of clinical trials and guidelines, treatment decisions continue to be a challenge. Regardless of the management employed, the primary concern is to maintain the patency of the true lumen . For patPossible late complications include progression of the dissection and formation of pseudoaneurysms . PatientThe overall survival for patients with SCAD has been reported as around 90%, with no significant difference in outcome being reported regardless of the treatment modalities employed .SCAD is a fascinating clinical entity. Although our case report is not the first of its kind, it does bring forward an extraordinarily uncommon presentation of a rare disease process.Our patient’s age, absence of significant cardiac risk factors and lack of identifiable connective tissue disorder or vasculitis make her a rare case of SCAD; the etiology of the dissection remains a medical enigma.Given the rare incidence of SCAD in postmenopausal women, there is a relative dearth of information regarding the clinical presentation, diagnosis and management in postmenopausal women. We hope that this case report and the associated literature review will serve to provide valuable insight into this rare yet intriguing disease process.Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.CT is the consultant cardiologist responsible for the medical care of the patient, and read and edited the manuscript. VS provided the images, and read and approved the manuscript. SM completed the literature review and wrote the manuscript. All authors read and approved the final manuscript.


Degenerative changes of lumbar spine anatomy resulting in the encroachment of neural structures are often regarded progressive, ultimately necessitating decompressive surgery. However the natural course is not necessarily progressive and the efficacy of a variety of nonsurgical interventions has also been described. At present there is insufficient data to compare surgical and nonsurgical interventions in terms of their relative benefit and safety. Previous attempts failed to provide clear clinical recommendations or to distinguish subgroups that substantially benefit from a certain treatment strategy. We present the design of a randomized controlled trial on (cost-) effectiveness of surgical decompression versus prolonged conservative treatment in patients with neurogenic intermittent claudication caused by lumbar stenosis.The aim of the Verbiest trial is to evaluate the effectiveness of prolonged conservative treatment compared to decompressive surgery. The study is a multi-center randomized controlled trial with two parallel groups design. Patients (age over 50) presenting to the neurologist or neurosurgeon with at least 3 months complaints of neurogenic intermittent claudication and considering surgical treatment are eligible for inclusion. Participants are randomly allocated to either prolonged conservative treatment, receiving further treatment from their general practitioner and physical therapist, or allocated to surgery and operated within 4 weeks. Primary outcome measure is the functional assessment of the patient as measured by the Zurich Claudication Questionnaire at 24 months of follow-up. Data is analyzed according to the intention to treat principle.With a cost-effectiveness analysis the trade off between the costs of prolonged conservative treatment and delayed surgery in a smaller number of patients are compared with the current policy of surgical management. As surgery is expected to be inevitable in certain subgroups of patients, the distinction of and classification by predictive patient characteristics is most relevant to clinical practice.NTR2216Netherlands Trial Register (NTR):  Lumbar stenosis is defined as a reduction in the diameter of the spinal canal, lateral nerve canals, or neural foramina. Most frequently lumbar stenosis is the result of a degenerative disease process and consequently involves multiple levels of the lumbar spine or sites of lumbar stenosis. Degenerative lumbar stenosis is caused by bone hypertrophy, osteoarthritis of facet joints, ligamentous hypertrophy, disc protrusion, spondylolisthesis alone or any combination of these elements. Central canal stenosis results in compression of the cauda equina. Lateral recess stenosis and neuro foraminal stenosis result in encroachment of the nerve root. Degenerative spinal stenosis most commonly affects the L3-L4, and L4-L5 segments to cause cauda equina compression ,2.Symptoms related to lumbar stenosis range from numbness, fatigue to actual pain of the buttocks, thighs, and legs. Back pain and muscle weakness are also frequently reported. Symptoms may radiate from the buttocks to the distal lower extremities and are often accompanied with paraesthesias. In contrast to sciatica symptoms are generally bilateral and localized poorly . A pathoDegenerative lumbar stenosis is the most common reason for lumbar surgery in elderly people . Taking Although the condition is frequently diagnosed and various surgical and nonsurgical interventions for individuals with neurogenic intermittent claudication are widely accepted in clinical practice, there is limited evidence to support many of them, especially in terms of their relative benefit and risk compared with other options -11. The In a randomized controlled trial (RCT) comparing the effectiveness of early surgery to prolonged conservative treatment among patients with sciatica, early surgery favored a better short-term outcome compared to prolonged conservative management . HoweverVarious studies observing the natural course of neurogenic intermittent claudication report improvement of symptoms and conclude that expectant observation could be an alternative to surgical treatment ,17-21. ILimited evidence is available regarding the efficacy for nonsurgical treatments in the treatment of lumbar stenosis ,10. NonsTwo previous RCTs comparing the effectiveness of surgery to nonsurgical treatment of degenerative lumbar stenosis have been performed ,24. WeinAt present there is still a paucity of high quality evidence to justify the timing of surgery and useful clinical parameters to identify subjects for the most appropriate treatment strategy are lacking. The primary goal of this study is to assess the (cost-) effectiveness of a policy of conventional surgical intervention as compared to prolonged conservative management in the treatment of degenerative lumbar stenosis. Further, patient characteristics and clinical findings are evaluated to define subgroups that substantially benefit from one of the two proposed treatment strategies.The study is designed as a multi-center RCT with two parallel groups. The multi-center design is necessary to accrue the required amount of patients and obtain generalizable results. The trial is conducted in the hospitals, which previously collaborated in the Sciatica trial . The medPatients presenting to the neurologist or neurosurgeon in the participating hospitals with at least 3 months complaints of neurogenic intermittent claudication and considering surgical treatment are eligible for inclusion. The duration of these complaints is one of the main (a priori defined) factors to be evaluated for a possible treatment-effect-modification. Inclusion and exclusion criteria are listed in Table General practitioners and physical therapists in the vicinity of the participating hospitals have been informed at the start of the trial. They are directly involved as they provide primary care for subjects allocated to prolonged conservative treatment. Secondly, general practitioners are asked to refer potentially eligible patients with neurogenic intermittent claudication to the outpatient clinics for evaluation by the neurologist.Conservative management is a prolonged nonsurgical treatment policy conducted by the general practitioner. The general practitioner provides additional information about the condition's causes, symptoms and treatment options. Further, the efficacy of the prescribed pain medication is reviewed and if necessary alterations are made, taking into account possible contra-indications in the elderly. Subjects are advised to stay active and if possible return to work and/or their leisure activities. The general practitioner prescribes physical therapy, which consists of active exercises to guide the patient in upgrading his or her activities according to an agreed time schedule. The guide is time, not the intensity of the pain. The protocol for the individual exercise therapy supervised by a physical therapist includes education, stretching, strengthening and conditioning exercises . EducatiAfter induction of general endotracheal anaesthesia the patient is positioned prone or in knee-chest position. The level on which to operate is determined through anatomical landmarks and confirmed by fluoroscopy. After a midline posterior skin and subcutaneous tissue incision centered at the interspinous level to be decompressed, the dissection goes through the dorsolumbar fascia. The multifidi are detached from both sides of the spinous processes and laminar attachments. Paraspinal muscles are than retracted laterally. The interspinous ligament is resected to enable the removal of the inferior aspect of the cranial lamina and the superior aspect of the caudal lamina. Subsequent a flavectomy is performed. The decompression is extended laterally with an undercutting of the medial aspect of the facet joints and if necessary an extensive foraminotomy is performed. In case of severe bony stenosis a complete laminectomy is performed. No transpedicular fixation of the spine is performed during the first surgery. Hospital admission is 2 to 4 days, including the day of surgery. During the post-operative period the patients are mobilized accompanied by a physical therapist, starting 3 hours after surgery. If the patient regains the physical ability to manage basis activities of daily living, the patient is discharged. At home the patients visit their own physical therapist who guides them and provides exercises. If possible patients gradually resume their daily activities and work if applicable. The patient is allowed to resume all activities in case no physical limitations are present.Clinical data is collected during consecutive follow-up visits to the outpatient clinics at baseline and at 12, 26, 52, 104, 260 weeks after randomization. Subjects fill in questionnaires at selected time points which are returned during the outpatient clinic visits or by mail  provides information about the total amount, the frequency, the intensity, and the duration of physical activity [Allocation to prolonged conservative treatment may possibly result in subjects becoming less active. As the activity level decreases, situations as walking/standing that give rise to symptoms of neurogenic intermittent claudication diminish and possibly result in symptom/pain relief. Although physical activity, disability and symptom severity are assessed during follow-up examinations, typically the reliability and validity of the measurement of habitual physical activity by questionnaires is low . A contiactivity -33. Furtactivity .The RMDQ is one of the most frequently used functional disability questionnaires for back-related conditions. The RMDQ was originally designed as a back condition specific questionnaire but is also widely used for patients with sciatica and neurogenic intermittent claudication ,35,36. TThe SF-36 is generic health survey questionnaire that measures overall health status, functional status and health-related quality of life ,39. The Perceived recovery is assessed with a seven-point likert scale varying from 'completely recovered' to 'worse than ever'. The scales are completed by the patient, the research nurse and the neurosurgeon.The pain intensity experienced by the patient during the past week is assessed on a horizontal 100 millimeters scale varying from 0 millimeter, "no pain", to 100 millimeters 'the worst pain I can imagine' ,41. BackCost-effectiveness is expressed as cost per QALY, based on the QALY difference between the surgery and prolonged conservative treatment group. QALYs are estimated by using mean health state values during consecutive follow-up assessments with the EuroQol-5 D. The EuroQol-5 D is a generic health related quality of life questionnaire frequently used for investigating cost-effectiveness ,43. TreaThe neurosurgeon and research nurse systematically record direct and indirect surgical complications and re-operation incidence. In case of failure of prolonged conservative management considerations for delayed surgery are reviewed.The success rate of both treatments is determined through perceived recovery and by applying the concept of MCID on the self reported functional disability scores. Derived from previous studies the estimated success rate of surgical management is 60% ,24,44 anDifferences between treatment groups at baseline are assessed using univariate analyses to check for a balanced randomization. In case of substantial differences that induce confounding of the main treatment effect, both an uncorrected and a corrected (multivariate) analysis are presented. Data analysis is performed according to the intention to treat principle. The primary hypothesis using the primary outcome measure is a comparison of the average ZCQ over a period of 24 months. All continuous outcome measures are assessed with a repeated-measures analysis of variance with a first-order autoregressive covariance matrix. Differences between treatment groups are assessed by computing both the main effect of the treatment and the interaction between treatment and time in a mixed linear model. The area under curve for the ZCQ scores and secondary treatment outcome variables during the follow-up period are compared both implicitly using the repeated measurements approach. A Kaplan-Meier survival analysis is used to estimate the proportion of patients reporting recovery as a function of time elapsed from randomization. The average difference is characterized by a Hazard Ratio derived from a Cox Proportional Hazards model and the accompanying likelihood ratio test.Table One covariate is pre-specified as a primary effect-modifier: duration of complaints at randomization. This covariate is clinically crucial since it allows the estimation of a possible "timing-of-surgery" effect by using the natural variability among patients with respect to the duration of complaints at the moment of the decision to perform surgery or to postpone it. Therefore each of the main analyses is accompanied with an extension to test for "duration-of-complaints" * "treatment" interaction. This interaction is tested at the nominal 5% level within the primary analysis. If the interaction is not significant, the primary analysis of this trial defaults to the standard model with main effects. If the interaction is significant, it follows that a fortiori a treatment effect exists (and it varies with the duration of complaints). The model without the interaction still gives the overall (average) effect of the main hypothesis with its associated confidence interval. For the remaining 11 variables in Table Data is stored via the internet-based secure data management system "ProMISe" of the department of Medical Statistics and Bio Informatics. The analyses are carried out using appropriate statistical software .It has been previously suggested that conservative management should be the initial treatment of degenerative lumbar stenosis and decompressive surgery is appropriate to consider only in case of intolerable pain or disability. Despite these recommendations the overall observed clinical improvement after surgery is disappointing and a substantial proportion of surgical candidates managed conservatively may still report improvement. Taken in to account the unexplained large geographic variation of surgery rates for lumbar stenosis and the long-term narrowing of the relative benefit of surgery compared to conservative management, another critical appraisal of indications for surgery is necessary.ITT: intention to treat; MCID: minimal clinically important difference; MMSE: mini-mental state examination; RMDQ: Roland Morris disability questionnaire; MRI: magnetic resonance imaging; QALY: quality-adjusted life year; RCT: randomized controlled trial; SF-36: short form 36; SPPB: short physical performance battery; SWT: shuttle walking test; VAS: visual analogue scale; ZCQ: Zurich claudication questionnaire.The authors declare that they have no competing interests.GO is the coordinator and principal investigator and drafted the manuscript. WP, PL, BK, SB and RB designed the study protocol. RB is responsible for the statistical analysis and data storage using the ProMISe data management system. CV is involved in the implementation of the trial in the participating hospitals, PL and SB consulted on the protocol for physical therapy, JE consulted on the protocol for the general practitioners. All authors participated in the study design and coordination. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2474/12/57/prepub


Improving the lifestyle of overweight and obese adults is of increasing interest in view of its role in several chronic diseases. Interventions aiming at overweight or weight-related chronic diseases suffer from high drop-out rates. It has been suggested that Motivational Interviewing and more frequent and more patient-specific coaching could decrease the drop-out rate. 'BeweegKuur' is a multidisciplinary lifestyle intervention which offers three programmes for overweight persons. The effectiveness and the cost-effectiveness of intensively guided programmes, such as the 'supervised exercise programme' of 'BeweegKuur', for patients with high weight-related health risk, remain to be assessed. Our randomized controlled trial compares the expenses and effects of the 'supervised exercise programme' with those of the less intensively supervised 'start-up exercise programme'.The one-year intervention period involves coaching by a lifestyle advisor, a physiotherapist and a dietician, coordinated by general practitioners (GPs). The participating GP practices have been allocated to the interventions, which differ only in terms of the amount of coaching offered by the physiotherapist. Whereas the 'start-up exercise programme' includes several consultations with physiotherapists to identify barriers hampering independent exercising, the 'supervised exercise programme' includes more sessions with a physiotherapist, involving exercise under supervision. The main goal is transfer to local exercise facilities. The main outcome of the study will be the participants' physical activity at the end of the one-year intervention period and after one year of follow-up. Secondary outcomes are dietary habits, health risk, physical fitness and functional capacity. The economic evaluation will consist of a cost-effectiveness analysis and a cost-utility analysis. The primary outcome measures for the economic evaluation will be the physical activity and the number of quality-adjusted life years. Costs will be assessed from a societal perspective with a time horizon of two years. Additionally, a process evaluation will be used to evaluate the performance of the intervention and the participants' evaluation of the intervention.This study is expected to provide information regarding the additional costs and effects of the 'supervised exercise programme' in adults with very high weight-related health risk.ISRCTN46574304ISRCTN:  People who are overweight are at higher risk of developing type 2 diabetes mellitus, cardiovascular disease and certain types of cancer . In addise BMI > 0 kg/m2 [0 kg/m2) .Not only overweight but also physical inactivity have been associated with chronic diseases like type 2 diabetes and cardiovascular disease -7. InterRecently, a multidisciplinary combined lifestyle intervention for type 2 diabetes patients, called 'BeweegKuur', has been developed by the Netherlands Institute for Sport and Physical Activity (NISB) ,19. Its Care providers using 'BeweegKuur' offer three programmes, differing in the amount of support. The 'independent exercise programme' is intended for overweight and obese individuals without comorbidities, while the 'start-up exercise programme' and the 'supervised exercise programme' are both intended for adults with overweight or obesity who suffer from comorbidities or are morbidly obese. An earlier study showed that the amount of support required to achieve lifestyle changes increases with the severity of overweight and the presence of comorbidities . AdditioLess intensively supervised programmes have been shown to be effective and cost-effective for people with type 2 diabetes or an increased risk of developing type 2 diabetes ,13,17. TThe present study is a clustered, multi-centre, randomized controlled trial evaluating the effectiveness and cost-effectiveness of the 'supervised exercise programme' versus the less intensively supervised 'start-up exercise programme' for patients with very high weight-related health risk. Thirty Dutch GP practices, each collaborating with a practice nurse, a physiotherapist and a dietician, have been randomly assigned to the control or experimental condition. In experimental practices, participants will take part in the 'supervised exercise programme', while participants in a control practice will take part in the 'start-up exercise programme'. Clinical outcome measurements take place at baseline, after 12 months (the end of the intervention period) and after 24 months . The study is funded by The Netherlands Organization for Health Research and Development .To reduce the risk of contamination between participants, and the risk of bias at the level of the professionals involved, entire practices have been allocated to the control or experimental condition. Prior to randomization, all practices have been matched pair wise based on size and location in an urban or rural area, to create two equivalent samples of 15 practices. In each pair, one practice has been randomized to the control condition, while the other was randomized to the experimental condition. To reduce the risk of contamination within a region, practices in the same region were allocated to the same condition as the first practice in that region that was randomized.2) combined with the following serious related comorbidities: sleep apnoea, arthritis, cardiovascular disease and/or type 2 diabetes; or (2) being morbidly obese (BMI 35-40 kg/m2) but without these related serious comorbidities. In addition, participants should currently fail to meet the Dutch norm for healthy physical activity , have to be sufficiently motivated to change their physical activity level and dietary behaviour (to be judged subjectively by the LSA during intake) and have to give their informed consent.Inclusion of participants started in July 2010. Inclusion criteria are (1) being overweight or obese . The LSA screens the patients for eligibility. Exclusion criteria are serious mobility limitations precluding participation in the intervention programme, such as severe cardiac failure, serious angina pectoris and rheumatoid arthritis. Pregnancy is also an exclusion criterion. The GP decides whether patients should be excluded.Although it is not possible to blind the professionals, randomization at the level of GP practices decreases the risk of contamination among the professionals. Participants are not aware of the allocation of their practice to the experimental or control condition.To identify effects of observer bias, clinical measurements that might be affected  will be repeated by a researcher blinded for the randomization of the practices and the baseline characteristics of the participants. Repeated measurements will be done for 20 participants in five randomly chosen control and five randomly chosen experimental practices.After inclusion, participants have several consultations with the LSA, dietician and physiotherapist during a one-year intervention period. The number of consultations differs per programme table .The LSA has a key role in supporting the participants and is the point of contact between the participants and the other health care providers in the 'BeweegKuur' programme. Following an individual intake to set personal goals, participants will have five individual consultations with the LSA to discuss progress in terms of behavioural change, roughly once every 10 weeks, during the one-year intervention period. Consultations with the dietician will consist of nutritional recommendations, education, coping with high-risk situations, checking dietary behaviour and fellow-sufferer contact. Advice will be based on various Dutch guidelines for diabetes, overweight and obesity -27. AfteThe physiotherapist will provide coaching to enable participants to exercise unsupervised in local exercise facilities. Coaching by the physiotherapist will be initiated by setting out personal goals and identifying barriers hampering engagement in physical activity. Coaching will consist of supervised exercise to overcome any barriers identified and increase physical capacity. Two or three sessions of supervised exercise per week will be planned over a period of 12 weeks. After these 12 weeks, the physiotherapist will evaluate whether the participant is able to exercise without supervision. The coaching period can be extended by four weeks if the participant does not seem able to exercise independently in local facilities. In all, the physiotherapist's coaching will take 12 to 16 weeks. After coaching by the physiotherapist has ended, the five follow-up consultations with the LSA and three or four follow-up consultations with the physiotherapist are planned, to help participants adopt and continue independent exercise activities. Both the LSA and the physiotherapist will help the participant find suitable existing exercise facilities during the entire intervention period.The number of consultations and the characteristics of the guidance provided by the LSA and the dietician in the control condition are the same as in the experimental condition. However, participants of the 'start-up exercise programme' will only have six consultations with the physiotherapist, which are planned during the first two months of the intervention period. The consultations with the physiotherapist consist of identifying barriers to physical activity and drawing up a plan to remain physically active without supervision by health care providers. If deemed necessary by the physiotherapist, participants can exercise under supervision during these meetings to overcome barriers to physical activity. Progress and complications relating to the exercise plan will be discussed in consultations with the physiotherapist from approximately two months after the start of the intervention. Additionally, participants will be coached in the adoption and maintenance of independent exercise activities during the five follow-up consultations with the LSA during and after the two months of guidance by the physiotherapist.Clinical assessments will be done by the 'BeweegKuur' health care providers (LSA or physiotherapist) in their own practice. After the baseline measurement, three different measurement intervals will be used, depending on the variable to be measured: (A) 3 months, (B) 6 months and (C) 12 months . The IPAQ short form will be included in the participants' questionnaire every six months, and consists of questions concerning the time spent on physical activity at specific intensities and the number of days on which this happened. Median values of activity categories will be calculated and expressed as metabolic equivalent (MET) minutes per week. The self-administered IPAQ short form has been reported to be sufficiently valid and reliable for use in developed countries .Accelerometry offers an objective way to assess physical activity. The CAM is a tri-axial accelerometer developed and manufactured by Maastricht Instruments. The CAM software is able to distinguish between sedentary behaviour, standing and activity, and has been validated for adults in laboratory conditions . The devThe short version of the Fat Food questionnaire will be included in the questionnaire sent to the participants every six months . The lenBody composition  will be measured with a tetrapolar bioelectrical impedance device (OMRON BF511). Blood samples will be taken to analyse fasting glucose (mmol/L), HbA1c (% or mmol/L), total cholesterol (mmol/L), HDL (mmol/L), triglycerides (mmol/L) and creatinin (μmol/L). Systolic and diastolic blood pressure, resting heart rate and BMI will also be measured.Peripheral neuropathy is related to functional capacity in type 2 diabetes patients . DiabetiThe participant's aerobic capacity will be estimated using the sub-maximal Åstrand cycle test ,37. The The economic evaluation will compare costs and effects of the 'supervised exercise programme' with those of the 'start-up exercise programme'. The economic evaluation will be performed from a societal perspective, which implies that all relevant costs and outcomes will be taken into account, regardless of who pays the costs and who benefits from the effects. A time horizon of two years will be used.Both a cost-effectiveness analysis (CEA) and a cost-utility analysis (CUA) will be done. The CEA will present clinical outcomes in terms of physical activity measured by means of accelerometry and the short version of the IPAQ . The CUAProgramme costs, health care costs, patient and family costs as well as loss of productivity will be assessed. Volumes of healthcare use, loss of productivity and other expenses will be identified by means of three-monthly self-administered questionnaires. Cost valuation will use the Dutch manual for cost analysis in health care research , while rA process evaluation will be used to gain insight into reach and the attendance rates of the target population, implementation fidelity, delivered intervention dose, and participant perception of the intervention  in orderThe intended sample size is based on the amount of MVPA in minutes per week. An increase of 50 minutes of MVPA per week by participants in the 'supervised exercise programme', as compared to participants in the 'start-up exercise programme' will be considered a clinically meaningful increase in MVPA. The standard deviation of MVPA in this population has been reported to be 120 minutes/week . A samplAllocation to the conditions, however, will take place at the level of GP practices, so clustering of patients within these practices should be taken into account. Assuming an intra-cluster correlation of 5%, and a total of 20 participants per practice, a total sample of 24 practices (n = 480) will be needed. As practices may also drop out of this study, we will include and allocate an additional six practices to account for this potential drop-out. The choice of six practices is completely arbitrary. This results in a projected total sample of 600 participants divided over 30 practices.Baseline characteristics  of both participants and clusters will be analysed by means of descriptive statistics. Statistical analyses will be performed according to the intention-to-treat principle, while additional analyses will be done using the per-protocol principle.Differences between outcomes in the control and intervention groups at different time points will be assessed using multi-level analyses. This type of analysis takes into account the longitudinal nature of the data, as well as the impact of cluster randomization.Differences in costs and effects will be presented as incremental cost-effectiveness ratios (ICERs). ICERs represent the differences in mean costs between the experimental and control interventions in the numerator and the difference in mean effects between the two groups in the denominator. Sensitivity analysis will be used to assess the robustness of the assumptions made in our base case analysis.Outcomes of the process evaluation will be studied by means of descriptive statistics.The aim of this study is to determine whether the 'supervised exercise programme' of the 'BeweegKuur' intervention has positive effects on physical activity levels compared to the less intensively supervised 'start-up exercise programme' in a population of overweight and obese adults with very high weight-related health risk, and to assess the difference in costs involved between the two lifestyle programmes. The risk of chronic diseases is known to decrease if overweight or obese persons achieve a more physically active lifestyle. This might also reduce health care expenses. Therefore, an improved lifestyle resulting from an intervention like 'BeweegKuur' is expected to have major positive consequences at both individual and societal level.Increasing adherence to lifestyle interventions is crucial. The proposed solutions  might decrease the drop-out rate, thereby increasing the possible effects of the intervention and decreasing health care expenses. Nevertheless, these solutions require extra time investment by health care providers, raising intervention costs, so examining the cost-effectiveness of lifestyle interventions in primary care is of great social interest. The economic evaluation will provide insight into the cost-effectiveness regarding the effects on quality of life and physical activity, to support decisions concerning insurance coverage of the 'BeweegKuur' intervention and similar lifestyle interventions.Objectively measuring physical activity levels enables accurate conclusions to be drawn about the direct effects of the intervention. Moreover, this will afford new insights into physical activity and inactivity patterns in an overweight population with very high weight-related health risk.This study aims to gain insight into the cost-effectiveness of the 'supervised exercise programme' compared to the 'start-up exercise programme', in order to inform decision and policy makers about the implementation of 'BeweegKuur' in primary care in the Netherlands. In addition, the process evaluation will provide detailed information about the feasibility of implementing these two interventions and the degree of satisfaction of participants, and will also provide some insight into the mechanisms by which the components of the intervention exert their effects.The authors declare that they have no competing interests.BB is the investigator for the effect evaluation and wrote most of the present manuscript. MH is the investigator for the economic evaluation, wrote the design of the economic evaluation and helped draft the present manuscript. EV contributed to the design of the trial and supervises the methodology. NS supervises the clinical part of the study. SK developed the design of the trial and provides advice on process evaluation. HS is the principal investigator, developed the design of the study. All authors have read and approved the final version of the manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/11/815/prepub


The concept of resilience has captured the imagination of researchers and policy makers over the past two decades. However, despite the ever growing body of resilience research, there is a paucity of relevant, comprehensive measurement tools. In this article, the development of a theoretically based, comprehensive multi-dimensional measure of resilience in adolescents is described.Extensive literature review and focus groups with young people living with chronic illness informed the conceptual development of scales and items. Two sequential rounds of factor and scale analyses were undertaken to revise the conceptually developed scales using data collected from young people living with a chronic illness and a general population sample.The revised Adolescent Resilience Questionnaire comprises 93 items and 12 scales measuring resilience factors in the domains of self, family, peer, school and community. All scales have acceptable alpha coefficients. Revised scales closely reflect conceptually developed scales.It is proposed that, with further psychometric testing, this new measure of resilience will provide researchers and clinicians with a comprehensive and developmentally appropriate instrument to measure a young person's capacity to achieve positive outcomes despite life stressors. Resilience has been variously defined as positive developmental outcomes in the face of adversity or stress ,2; beingprocess by which individuals draw on personal characteristics and resources in their environment to enable them to successfully negotiate adversity [Early research identified resilience as a characteristic of the individual , and condversity ,7-10. AsA range of factors commonly associated with resilient outcomes have been widely studied and described. While the literature around the concept of resilience is increasing, there have been few attempts to synthesise current research findings into useful measurement tools. The issue with most current measures of resilience is their limited focus, for example, only addressing individual characteristics -13. OtheAn ecological-transactional model ,19 was uA detailed literature review in each of the five domains  was suppEmotion regulation and control beliefs: Positive emotion regulation skills involve processes by which positive emotionality is maximised or negative emotionality, emotional lability and inappropriate affect minimised. Significant associations have been reported between positive emotion regulation and resilience [The family, peer, school and community domain conceptual scales are self explanatory but some discussion is merited for the individual domain. silience ,31, concsilience -34. A posilience -38. For silience .what was happening and why, the meaning behind events. Adolescents identified this as an important factor in their resilience.This was a strong theme arising from the focus groups that was not identified in resilience literature review. Chronically ill adolescents described the importance of having the time and space to think things through, to work out Social skills have been described as the interpersonal behaviours needed to develop and deepen supportive personal relationships  and haveA positive sense of the future can be conceptualised as "expectations of attaining specific objectives  in later developmental periods"  while opProblem solving abilities have been linked to resilient children compared to their non-resilient peers ,37,51-53A large item pool for each scale was written according to the guiding principals for item development as described by Kline  and StreParticipants were recruited through Government and Catholic secondary schools, chronic illness support groups, and hospital clinics. Participation required written parent and participant consent.School students were given a letter explaining the purpose and procedure of the study and parent and participant consent forms. Students who returned signed consent forms completed the paper ARQ questionnaire during class time.Chronic illness support group members and hospital clinic patients were sent a letter explaining the purpose and procedure of the study, consent forms and the ARQ questionnaire. Completed consent forms and questionnaires were returned separately in the reply paid envelopes provided. After three weeks, reminder letters and replacement forms and questionnaires were sent to all nonrespondents.Ethics approval was granted from Swinburne University, The Royal Children's Hospital, Department of Education, Employment and Training ethics committees and the Catholic Education Office.Never, 2 Not often, 3 Sometimes, 4 Most of the time and 5 All the time. Higher scores indicate greater resilience. A space was available at the end of each domain for participants to write comments regarding items or the questionnaire.The ARQ is a pen and paper questionnaire with scales in five domains: individual, family, peers, school and community. Items comprise statements with a five point Likert response scale labelled: 1 Questionnaire items were deleted or revised if they were: identified by respondents as difficult to understand; considered by the researcher to have poor face validity; or endorsed by less than 20% or more than 80% of respondents ,27.Factor and reliability analyses were used to guide the construction of scales and selection of the best items. Factor analyses were conducted within each domain with maximum likelihood extraction and oblimin rotation to accommodate possible correlation between factors . InitialTwo samples completed the pilot ARQ. 1) A convenience sample of year 9 students attending Catholic schools in Victoria, Australia. Eleven of the 45 schools invited agreed to participate and 330 of the 1031 eligible students (32% response rate) completed the pilot ARQ . Factors closely reflected the conceptually developed scales and explained the majority of the variance in all solutions with the exception of the individual and community domains, where the most revision occurred .emotion regulation factor scale appeared more focussed on negative cognition, due in part to the positive emotion regulation items loading on the optimism/positive future expectation factor scale. Therefore, it was decided to:In the individual domain the six factor scales resembled the six conceptually derived scales . Revision of these scales therefore focused on developing scales that tapped more discrete constructs by drawing on the sense of community and social capital literature . The. TheconnFollowing this process, the pilot ARQ was revised to create the ARQ-Revision 1 (ARQ-Rev1) which was comprised of six scales and 79 items in the individual domain, and two scales each in the family (20 items), peer (11 items), school (15 items) and community (15 items) domains. Whilst the ARQ-Rev1 was relatively long , being over inclusive at this stage of development facilitated selection of the best items and scales in the second phase of data collection and revision described in Study 2.1. A total of 451 of 982 eligible students (50% response rate) completed the questionnaire during class time. Students had a mean age of 13.9 years  , emotional insight, empathy/tolerance and social skills. The scales contained six to eight items and, as shown in Table empathy and social skills scales with the intention of improving scale reliability. The items were written as described in the method section above, drawing on the conceptual underpinning of the scale and taking into account items that had failed to perform in the previous two revisions.The five factors were used to construct scales following the steps described in the method. Following this revision process the individual domain consisted of the five scales connectedness and availability and was labelled accordingly  indicating that adolescents' scores on family connectedness will generally correspond to their scores on the availability scale. Similarly, the factor analysis in the peer domain closely replicated the ARQ-Rev1 peer connectedness and availability scales  taps into the ability to form and maintain friendships. The connectedness scale had excellent reliability; however, the reliability of the three item availability scale fell below the target range of 0.7 - 0.9. Therefore five new items were written to create an eight-item scale with the intention of improving reliability.In the family domain, the two factor solution closely replicated the ARQ-Rev1 scales of supportive environment and connectedness scales  contains items related to an adolescents' feelings of commitment and connection to school both social and academically. Four new items were added to the connectedness scale to make an eight-item scale, with the intention of balancing the scale with positive items and improving the reliability coefficient.The factor analysis in the school domain closely replicated the ARQ-Rev1 community domain. The data consistently identified a single factor, seemingly addressing general community connectedness  and who are positively engaged with their family, peers, school and community environments. Arguably, such adolescents are more likely to show resilient outcomes in times of adversity. Conversely, the ARQ can identify adolescents who show poor engagement in all or some of these areas and who may be vulnerable in the face of adversity.problem solving scale failed to form a unique factor, with items loading on the social skills and emotional insight factors, and was ultimately subsumed into these two scales. This may reflect poor construct operationalisation or be a true reflection of the adolescent experience. Resilience literature supports the latter, reporting significant positive associations between problem solving skills and both social skills and emotion regulation in childhood, adolescence and adulthood [The ARQ scales identified in the factor analyses show notable conceptual similarity to the constructs initially proposed for measurement (drawn from the resilience literature and focus groups). However some scales were not supported by the statistical analysis. For example, the dulthood ,33,63-65negative cognition factor was unexpected and without precedence in other resilience measures. Many of the negative cognition items were negatively worded and were intended to gauge deficits in self efficacy, confidence and optimism/hope. Few resilience measures have included negative items as they generally assess possession of a resource rather than a deficit. This factor appears to address a sense of helplessness and low internal locus of control. Children identified in the Rochester Child Resilience Project as stress-affected [negative cognition scale defines vulnerable adolescents, such that high scores on this scale would be expected to be associated with low resilience. Further testing and comparison with other measures of resilience will add to the understanding of this scale.The identification of the affected  evidenceconnectedness will generally correspond to their scores on the availability scale. It may therefore be preferable to use only one of these two scales. However, the items loaded cleanly on separate factors in the analysis, suggesting the scales tapped into different constructs. Further investigation, including tests of construct validity, will allow an informed decision to be made as to whether to retain both scales or to retain one scale and decrease of the length of the measure - a desirable goal in scale development.The two family scales were highly correlated indicating that adolescents' scores on family The ARQ is at an early stage of development and further psychometric testing is necessary. For example, the comparison of ARQ scores and relevant sub-scales with other resilience measures, and comparison of sub-scales with gold standard measures of similar concepts such as coping and social support will provide evidence of criterion validity. Examination of ARQ scores for identified stress-resilient and stress-affected populations will indicate how well the ARQ discriminates between populations. Focus groups and administration of the questionnaire to over 500 adolescents in total have shown the questionnaire to be easy for adolescents to understand and complete. The factor and scale analyses revealed a stable factor structure that was conceptually convincing and true to the original intent of the measure. While the ARQ is presented as a functional measure of resilience in adolescents, evidence of scale and test-retest reliability, criterion validity and sensitivity to change will enhance understanding of and confidence in the measure's psychometric properties.The ARQ has been developed to identify adolescents who have personal characteristics associated with resilience, and who are positively engaged with their family, peers, school and community environments. Such adolescents are more likely to show resilient outcomes in times of adversity. Conversely, the ARQ can identify adolescents who show deficits or poor engagement in all or some of these areas, who may be vulnerable in the face of adversity. The availability of developmentally appropriate, multidimensional measurement tools will facilitate resilience researchers in their 'central mission' as described by Luthar and Brown "... to illuminate processes that significantly mitigate the ill effects of various adverse life conditions as well as those that exacerbate these, and thus to derive specific directions for interventions and social policies" .capacity to achieve positive outcomes despite life stressors.The ARQ was developed in response to a distinct lack of measurement tools in resilience research generally and for adolescents in particular. Greater scientific rigour and consistency in measurement tools and approaches will contribute to improved understanding of the complex processes involved in resilient responses to adversity. The availability of standard measures in resilience research, such as the ARQ, will make comparisons across studies and risk groups possible. With further psychometric testing, this new measure of resilience will provide researchers and clinicians with a comprehensive and developmentally appropriate instrument to measure a young person's The authors declare that they have no competing interests.DG participated in the design of the studies, coordinated and carried out data collection, performed the statistical analysis and drafted the manuscript. LB participated in the design of the studies, advised on data analysis and revised the manuscript. CO conceived of the study, participated in design, led the focus groups and revised the manuscript. SB participated in the design of the studies, was the principal supervisor of the doctoral thesis upon which this article was based and revised the manuscript. SS participated in the design of the study and revised the manuscript. All authors read and approved the final manuscript.1With the exception of one rural school where an unforeseen school event determined that year 7 classes were unavailable at the prearranged time and all year nine students were surveyed instead. We were unable to arrange another time due to school commitments and ethics requirements prohibited the substitution of another year level.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2288/11/134/prepubStudy 1 Factor solution individual domain. Study 1 output describing factor analysis of the individual domain. Output includes the initial statistics for the six-factor solution with oblimin rotation, and the rotated factor loadings with the original conceptual scales, and factor developed scales described.Click here for fileStudy 1 Factor solution family domain. Study 1 output describing factor analysis of the family domain. Output includes the initial statistics for the two-factor solution with oblimin rotation, and the rotated factor loadings with the original conceptual scales, and factor developed scales described.Click here for fileStudy 1 Factor solution peer domain. Study 1 output describing factor analysis of the peer domain. Output includes the initial statistics for the two-factor solution with oblimin rotation, and the rotated factor loadings with the original conceptual scales, and factor developed scales described.Click here for fileStudy 1 Factor solution school domain. Study 1 output describing factor analysis of the school domain. Output includes the initial statistics for the two-factor solution with oblimin rotation, and the rotated factor loadings with the original conceptual scales, and factor developed scales described.Click here for fileStudy 1 Factor solution community domain. Study 1 output describing factor analysis of the community domain. Output includes the initial statistics for the two-factor solution with oblimin rotation, and the rotated factor loadings with the original conceptual scales, and factor developed scales described.Click here for fileStudy 2 Factor solution individual domain. Study 2 output describing factor analysis of the individual domain. Output includes the initial statistics for the five-factor solution with oblimin rotation, and the rotated factor loadings with the original conceptual scales, and factor developed scales described.Click here for fileStudy 2 Factor solution family domain. Study 2 output describing factor analysis of the family domain. Output includes the initial statistics for the two-factor solution with oblimin rotation, and the rotated factor loadings with the original conceptual scales, and factor developed scales described.Click here for fileStudy 2 Factor solution peer domain. Study 2 output describing factor analysis of the peer domain. Output includes the initial statistics for the two-factor solution with oblimin rotation, and the rotated factor loadings with the original conceptual scales, and factor developed scales described.Click here for fileStudy 2 Factor solution school domain. Study 2 output describing factor analysis of the school domain. Output includes the initial statistics for the two-factor solution with oblimin rotation, and the rotated factor loadings with the original conceptual scales, and factor developed scales described.Click here for fileStudy 2 Factor solution community domain. Study 2 output describing factor analysis of the community domain. Output includes the initial statistics for the two-factor solution with oblimin rotation, and the rotated factor loadings with the original conceptual scales, and factor developed scales described.Click here for file