Wheelchairs for disabled children (≤18 years) can provide health, developmental and social benefits. World Health Organisation and United Kingdom Government reports demonstrate the need for improved access to wheelchairs both locally and internationally. The use of health economics within this field is lacking. Provision of wheelchairs based on cost-effectiveness evidence is not currently possible. We conducted the first systematic review in this field to incorporate evidence of effectiveness, service user perspectives, policy intentions and cost-effectiveness in order to develop a conceptual framework to inform future research and service development.We used an adapted EPPI-Centre mixed-method systematic review design with narrative summary, thematic and narrative synthesis. 11 databases were searched. Studies were appraised for quality using one of seven appropriate tools. A conceptual framework was developed from synthesised evidence.22 studies and 14 policies/guidelines were included. Powered wheelchairs appear to offer benefits in reduced need for caregiver assistance; improved communicative, personal-social and cognitive development; and improved mobility function and independent movement. From 14 months of age children can learn some degree of powered wheelchair driving competence. However, effectiveness evidence was limited and low quality. Children and parents placed emphasis on improving social skill and independence. Participation in wider society and development of meaningful relationships were key desired outcomes. Policy intentions and aspirations are in line with the perspectives of children and parents, although translation of policy recommendations into practice is lacking.There is a distinct lack of high quality effectiveness and economic evidence in this field. Social and health needs should be seen as equally important when assessing the mobility needs of disabled children. Disabled children and parents placed highest priority on independence and psychosocial outcomes of wheelchair interventions. Translation of policy and guidelines into practice is lacking and more effective implementation strategies are required to improve services and outcomes. Future research should focus on outcome measure development, developing economic evaluation tools and incorporating these into high quality studies to address known research gaps. The novel conceptual framework maps current gaps in evidence and outlines areas for development. It is estimated that between 10%  of the wIndependent mobility for disabled people and provision of assistive mobility technology (such as wheelchairs) to facilitate this is considered a human right, which calls for all countries to ensure that disabled people are able to access essential assistive mobility technology to promote mobility and independence . WithoutApproximately 5% of children worldwide (around 95 million children aged 14 or under) have a disability . Each diAppropriate wheelchair interventions are therefore a global imperative in order to reduce disability discrimination and promote equality.There are an estimated 770,000 children and young people under the age of 16 in the UK living with a disability . SeveralWheelchair interventions can have a range of positive impacts on the lives and health of disabled children and young people. In order to promote effective and equitable wheelchair services both in the UK and globally, better understanding of the effectiveness and cost-effectiveness of wheelchair interventions is needed. Likewise, the opinions of young wheelchair users and their families need to be taken into account to shape services. Social theories of disability state that disability exists as both a physical and social issue. Discrimination and positivist approaches to disability management pose more threat to equality than actual physical impairment .Health economics can play a specific role in the development of wheelchair services by providing essential data on the cost-effectiveness of different wheelchair interventions in both developing and developed countries. This would in theory facilitate better use of resources and greater coverage of services. At present the health economics toolbox is particularly poor when applied to disabilities and children. Development of health economics methodologies based on a social model of health would promote holistic evaluation of effectiveness and cost-effectiveness.In order to develop an appropriate set of economic tools it is important to explore existing effectiveness, service user opinion and economic evidence. The development of a conceptual framework from synthesised evidence could then be used to guide wheelchair service development in an evidence-based manner. No existing systematic reviews which address these important issues were found prior to conducting this review.To maintain clarity, we will define a number of key concepts and definitions as follows: the term “wheelchair service” is used to define any private, state or NFPO run service supplying wheelchairs to disabled people based upon assessment of mobility needs by a qualified professional. The term “wheelchair provision” is used to define the supply of a wheelchair intervention to a disabled person by a wheelchair service (as defined above). The term “wheelchair intervention” is used to define any wheelchair supplied to a disabled person by a wheelchair service (as defined above). The term “effectiveness” refers to all relevant clinical and non-clinical outcomes related to wheelchair use, such as (but not restricted to): cognitive, physical and behavioural development; functional mobility and motor skills; independence; educational achievement; social interaction; initiative development; physical and/or emotional well-being; and health-related quality of life. We do not use “effectiveness” to refer to biomechanical outcomes, such as propulsion patterns.The overarching aim was to explore current effectiveness evidence, service user perspectives, policy and cost-effectiveness evidence in order to develop a conceptual framework to inform future research and wheelchair service development in the UK, with international implications. Four objectives were developed to inform searching, management and interpretation of evidence:• to determine the effectiveness and cost-effectiveness of wheelchairs for disabled children and young people• to better understand service user, parent and professional perspectives regarding wheelchairs for disabled children and young people• to explore current UK policy, NFPO publication and clinical guideline recommendations and intentions regarding wheelchair provision for disabled children and young people• to determine if disabled children’s desired outcomes match with existing policy aspirations and effectiveness evidenceReview questions were formulated for each of the different aspects of this review, with additional questions developed to guide the overarching synthesis of evidence. See Figure An initial scoping search of the literature was conducted to refine the review scope, processes and keywords. A variety of quantitative, qualitative and policy literature was found, demonstrating the multi-faceted nature of wheelchair interventions. It was therefore decided that a mixed-method systematic review would be the most appropriate way to address the issues of interest. The review questions and a protocol were then developed to guide the review. Searches were conducted between January and April 2012.The review followed the University of York Centre for Research and Dissemination (York CRD) principles for conducting searches and extracting data . A themaAn adapted Evidence for Policy and Practice Information and Co-ordinating Centre (EPPI-centre) design and methodology for mixed-method evidence  was usedA full audit trail was recorded during each stage of the review to enable replicable methods and outcomes. During the screening process each study was screened independently by two reviewers. The second reviewer extracted data and appraised the quality of a selection of intervention studies (n = 5). The findings showed general consensus between the two reviewers, although full appraisal of inter-rater reliability was not conducted due to time constraints.Internet reference database searching was the main strategy for gathering studies. Inclusion and exclusion criteria were used to refine searches. Databases searched were Cochrane Collaboration Register and Library, Science Direct, CINAHL, Medline, ASSIA, PsychINFO, PubMed, Web of Science, DARE, NHS EED and HTA.RefWorks.As wheelchair interventions have developed significantly in recent times it was deemed appropriate to restrict the intervention, opinion and economic literature searches to the last 15 years (February 1997 to February 2012). Reference list and hand-searching supplemented electronic searching. Grey literature was also included to limit publication bias. Due to limited translation resources, only studies written or translated into English  were considered for inclusion. Search results were managed using the online bibliographic management program Policy and NFPO literature was not available on academic databases. It was identified through internet search engines , Department of Health/relevant NFPO websites and through hand-searching. Only UK policy/NFPO literature from the last 10 years (March 2002 to March 2012) was considered for inclusion to avoid obsolete literature being included in the review. Although international literature was included in the other streams, it was deemed too expansive to include all international policy in this review. Nonetheless, UK policy is evidence-based including international evidence.Search terms and keywords were a mixture of Medical Subject Heading (MeSH) and non-MeSH terms. A full list of search terms/keywords can be seen in Table Searches focused on manual and powered wheelchairs specifically due to the volume of recent inquiries in the UK into wheelchair services, their relatively high cost and the unique benefits they provide to disabled children. Economic evidence searches were carried out separately to the intervention/opinion searches in order increase specificity. A full list of inclusion/exclusion criteria can be found in Table Three stages of screening were used. For the initial screening process all identified study titles were assessed for relevance against the inclusion/exclusion criteria. A second screening process was used to assess relevance of studies by their abstract. When relevance was unclear the full study was obtained and reviewed. All studies that were considered relevant after initial and second screening were obtained in full and underwent a final screening process. In order to reduce bias a second researcher reviewed each study independently and consensus was reached regarding inclusion. A formal screening process was not required for the policy literature, as searches were conducted using search engines and searching of government and NFPO websites. Searching stopped once saturation had been reached and no new policy/guideline reports were found.Basic information  was collected for all studies. Additionally, evidence specific data extraction tools were made for the purpose of extracting appropriate findings from the different types of literature. Each tool was tailor made for a specific type of evidence, which allowed the extraction of data to be specific to each stream of evidence. See Table Summary measures could not be used across the intervention evidence due to differences in sample demographics, outcome measures and interventions  was incorporated into the thematic synthesis. For survey evidence that could not be line-by-line coded, narrative summary was used to form a structured narrative of results. These data were later synthesised with the thematic synthesis findings and incorporated into the appropriate descriptive themes.A final over-arching narrative synthesis was undertaken to draw together the results across the different streams of evidence. The framework developed by Oliver et al.  was usedA conceptual framework for developing cost-effective wheelchair services for children and young people was refined from the overarching synthesis of evidence. Findings from the different streams of evidence were interrogated, discussed, mapped, charted and refined through further discussion within the research team to build a deeper understanding. The most important findings were selected and integrated into a conceptual diagram. A programme theory for an evidence-based pathway through wheelchair services was developed which highlighted gaps in knowledge and current services.A full list of included studies can be found in Additional file Evidence could not be grouped and analysed using meta-analysis due to heterogeneity of samples, methodology, interventions and outcomes  -27; one Of the 10 studies, five looked specifically at children with cerebral palsy and orthopaedic disabilities ,25,27,29Only one randomised controlled trial (RCT) was found . The rem.Only four studies employed statistical analysis and sample sizes were small; several studies used a single case-study design. The single RCT  was of m1Quality appraisal of studies indicated that they were generally low quality ; interactions with family ; indoor play motor activities ; quality of interactive play ; and developmental level of symbolic play  .For children with orthopaedic disabilities aged 18 to 42 months PWCs also facilitate significant improvements in: interactions with family . Seven studies were related specifically to PWCs ,31-36 anMost of the participants were families of disabled children (child age range from 18 months to 18 years), although four studies also included professional participants  ,33,35,3912 descriptive themes were generated from line-by-line coding of the evidence  8,9,12,41,43,442. Joint-working and multi-agency approachThe need for joined-up working between health, social care, education and NFPOs was a recurrent theme throughout the literature, with a general aim to improve services and to extend the scope of provision ,14,15,453. Effective use and outcomesSeveral publications highlighted the need for wheelchairs to be useable in all places required in order to maximise effectiveness ,12,15. T4. Funding and procurementRecommendations included: ring-fenced budgeting for PWC provision ; improve5. Aftercare and informationMaintenance and review procedures need attention, with clear and defined minimum standards for reviews ,13,15. B6. Eligibility criteria and assessmentComprehensive access to multi-disciplinary assessments was of high priority ,15,43,457. Service user involvementRecommendations included: designing services around the needs of service users ,43,45; sTwo eligible studies exploring the cost-effectiveness of wheelchairs for disabled children were found. Due to the lack of evidence and the heterogeneity of data  it was not possible to synthesise the findings, therefore narrative summary was conducted.Neilson et al.  found thFrontier Economics  examinedThe majority of data were specifically about PWC provision and use, which is reflected in the over-arching synthesis. A number of additional findings were elicited from further synthesis of the entire integrated dataset:Intervention and opinion evidence shows that wheelchair provision can be beneficial for both the wheelchair user and their family, including parental independence ,37; reduAs use of a PWC requires family involvement it is important that the home environment and the ability to transport a wheelchair is assessed and facilitated where possible. The cost of maintenance, repairs and adaptations can be prohibitive for families ,38, thusEach service user may benefit from having a clear point of contact for any queries they may have ,13,15. SThe psychosocial needs of children using PWCs appear to be of highest priority for service users and their parents ,34,36-38It is of note that the majority of opinion evidence (n = 9) related to children aged under 14 years. This indicates that there may be a lack of evidence on key periods of transition, such as moving from child to adult services.Inefficiencies (such as long waiting times) need to be reduced ,37,38 anEvidence of effectiveness and validated clinical practice outcome measures are needed in all aspects of health services . The devOpinion evidence continually demonstrated the importance of independence and the subsequent perceived benefits to service users and families ,31,34,38The key benefits from provision of wheelchairs for service users and their families were lifestyle oriented, with a focus on social and independence effects. Policy and NFPO literature does take into account these wider benefits; recommendations highlight the need to set minimum standards for wheelchairs that are useable in all places required ,12,15 anPolicy and NFPO literature states that wheelchairs should be useable in all places they are required ,12,15, hHome adaptation with clear advice provided to all service users and families regarding funding and grant entitlements are also important factors that impact on health-related quality of life outcomes . Some faThe conceptual framework .The major contribution to knowledge from this novel mixed-method review comes from the synthesis of diverse evidence to form a new conceptual framework and programme theory for optimal wheelchair service provision for children.Within this overall context, the most important finding is that for children and young people wheelchairs offer more than mobility; they offer enhanced independence, social integration and participation in age-appropriate activities. It is therefore paramount that wheelchair interventions are seen as facilitators to a new way of life. Nonetheless, disabled children and parents can find the transition to wheelchair use a traumatic process that is not yet sufficiently understood. Being able to individually tailor support for children and parents, and being able to measure these wider lifestyle benefits, is therefore a priority. Further research is needed to address these significant gaps in current knowledge.UK policy and NFPO recommendations are reflective of the perspectives of young wheelchair users and their families, but there is a lack of effective translation of policy and evidence into practice. Although policy recommendations do correlate with the opinion evidence, the barriers to effective provision and use of wheelchairs have continued to prevail in UK NHS services over many years -14. The The translation of evidence and knowledge into practice is not simply a case of publishing guidelines and policy. Evidence based practice requires specific action and commitment from services, for instance through the implementation of a knowledge translation framework such as the Knowledge to Action Process . This knTranslation of evidence into practice is mitigated by the level of evidence, the context, the presence of facilitation and the success of implementation  . ServiceNew tools have been produced to facilitate adoption of evidence into practice that could help identify the problems of evidence translation in local contexts. For example, The NHS Institute for Innovation and Improvement  developeThe ‘Any Qualified Provider’ principle concerns the tendering process whereby any qualified provider can compete for NHS contracts that are awarded by the Department of Health in England. Approved providers may include state/private hospitals, charities, private organisations and certain retailers (e.g. private wheelchair suppliers). This allows patients to make informed decisions about their healthcare based on service attributes important to them, for instance how geographically close a service is or the quality of care provided. This principle promotes services that are developed around the holistic needs of the service user  as they There is a distinct lack of high-quality effectiveness and cost-effectiveness evidence within this field. Although many studies have used robust methods to explore bio-mechanical impacts of mobility interventions (which were not relevant for this review), these do not reflect the outcomes of services from a carer or service user perspective. The intervention evidence, although limited by quality, demonstrates that wheelchair interventions may have a range of positive effects beyond mobility. However these results should be viewed with caution due to the limited quality of evidence. More evidence is required to understand how effective interventions can be measured and achieved for all service users. This requires studies to use large sample sizes, robust methods and diverse outcome measures.The application of health economics could enable a better understanding of the cost-effectiveness of wheelchair interventions, and thus benefit service-commissioning and funding allocation, and enable these practices to be evidence-based and equitable. The limited economic evidence in this review may be considered best evidence in the field due to the lack of other research into the cost-effectiveness of wheelchairs for children and young people.Future research should focus on developing more appropriate outcome measures, health economic methods, and exploring the use of quality of life or capability measures to determine effectiveness from a more holistic perspective. Current wheelchair service outcome measures focus on clinical outcomes and service quality (e.g. QUEST ), which Designing high-quality research in this field has specific challenges, particularly if looking generally at wheelchair interventions across a range of disabilities. Mobility impairment can be as a result of many different conditions, and thus needs and interventions can be highly variable. This has implications for conducting large scale trials using clinical outcomes. Likewise, interventions are likely to be highly variable across different conditions. Health-related quality of life and capability measures would allow a universal outcome that reflects the wider benefits of such interventions, and therefore would be a more appropriate approach to understanding the effectiveness of various interventions.Although the use of QALYs can be contentious , it provAt present child and parent proxy versions of validated health-related quality of life measures do exist, for instance the Health Utilities Index (HUI) . HoweverIf wheelchair services in the UK and internationally were to adopt a single set of outcome measures a wealth of data could be generated, which could be used to evaluate the holistic effectiveness of wheelchair interventions for children and young people. This data could be used to aid the development, supply and maintenance of wheelchairs. It would promote interventions that reflect the desires of service users and would allow outcomes to be measured appropriately from the perspective of the service user and the clinician. Furthermore, services could be structured around the needs of service users.Within a UK healthcare system context, the findings provide impetus for NICE to consider wheelchair services (both adult and child) a high priority. NICE provides national clinical guidelines on healthcare interventions, medication and new health technologies in order to ensure high quality and evidence based care for patients within the NHS . To dateNo major deviations from the protocol were noted. In the spirit of transparency, it is worth considering some potential limitations. The original aim was to understand wheelchair interventions more generally, however due to the general focus in the literature on PWC interventions, the findings have greater relevance to PWC. Over half of the intervention studies looked specifically at children with cerebral palsy. Furthermore, the intervention evidence was of low quality and at risk of bias, thus the findings must be viewed with caution.Although evidence included in this review may not be universally generalizable to all conditions, it still offers a better understanding of what benefits are afforded by wheelchair provision. More research may be needed to see if particular benefits from wheelchairs are universal across conditions.The lack of economic evidence highlights the issues of applying health economics to wheelchair provision for disabled children and justifies further research within this field. The lack of RCTs in this field highlights the ethical and methodological issues of wheelchair intervention studies in children. However, the study by Jones et al.  establisOnly evidence written or translated into English was included in this review, which may have excluded valuable research written in other languages.Wheelchairs offer varied benefits to disabled children in terms of health, development and social inclusion. At present NHS wheelchair services in the UK are not meeting all of children’s needs and service development is required.Findings derived from the evidence are relevant for NHS services and have some implications for wheelchair services globally. Wheelchair services have an invaluable role in promoting equality for disabled people. If these services can address disabling barriers for children at a young age, they may be able to facilitate more inclusion in education and society.There are important gaps in current knowledge regarding health economic methods and available outcome measures, which hinder further service development and research. Health economics has an important role in developing effective, efficient and equitable wheelchair services globally. The lack of economic evidence in this field highlights the lack of appropriate methods to measure cost-effectiveness. Establishing the cost-effectiveness of interventions is a priority to promote efficient services.Collaboration between countries on future research would allow the collection of a wealth of data regarding intervention effectiveness and cost-effectiveness. The use of universal and validated outcome measures across countries would have a distinct impact on the development of wheelchair services that promote social inclusion and independence.ASBI: Adaptive Social Behaviour Inventory; ASSIA: Applied Social Sciences Index and Abstracts; BDI: Battelle Developmental Inventory; CASP: Critical Appraisal Skills Programme; CEBMa: Center for Evidence-Based Management; CI: Confidence Interval; COPM: Canadian Occupational Performance Measure; CINAHL: Cumulative Index to Nursing and Allied Health Literature; DARE: Database of Abstracts of Reviews of Effects; ECI: Early Coping Inventory; EPIOC: Electric powered indoor/outdoor chair; EPPI-centre: Evidence for Policy and Practice Information and Co-ordinating Centre; GMFM: Gross Motor Functional Measure; HTA: Health Technology Assessment; HUI: Health Utilities Index; ICIS: Impact of Childhood Illness Scale; MATCH: Matching Assistive Technology & Child; MEDLINE: Medical Literature Analysis and Retrieval System Online; MeSH: Medical Subject Headings; NFPO: Not for profit organisation; NHS: National Health Service; NHS EED: National Health Service Economic Evaluation Database; NICE: National Institute for Health and Clinical Excellence; PEDI: Pediatric Evaluation of Disability Inventory; PedsQL: Pediatric Quality of Life Inventory; PSSC: Parental Stress and Support Checklist; PIQ: Performance Intelligence Quotient; PKBS: Preschool and Kindergarten Behaviour Scales; PLS-3: Preschool Language Scale-3; PPVT: Peabody Picture Vocabulary Tests; PWC: Powered wheelchair; QALY: Quality adjusted life year; QUEST: Quebec User Evaluation of Satisfaction with assistive Technology; RCT: Randomised controlled trial; SF36: Short Form 36; SS: Sample size; UK: United Kingdom; VIQ: Verbal Intelligence Quotient; WHO: World Health Organisation; York CRD: University of York Centre for Research and Dissemination.The authors have no financial or non-financial competing interests to declare.NB, JN, RTE and NH were responsible for the review conception and design and the development of the original review protocols. All authors were involved in reading and approving the manuscript. NB conducted the searches, quality appraisal, data extraction processes, analyses of evidence and synthesis of evidence, with support from JN, RTE and NH. JN provided evidence synthesis expertise and supervisory support.NB is a Health Economics PhD student at Bangor University, supervised by RTE, JN and NH. RTE is Professor of Health Economics at Bangor University. She has expertise in the economic evaluation alongside trials of complex public health and psychosocial interventions, and an interest in the health economics of disability. JN has experience in child health research, health services research with embedded health economics and evidence synthesis. NH is Director of the Bath Institute of Medical Engineering (Designability) and a visiting Professor from University of Bath. His recent research projects include the use of assistive technology to support home based rehabilitation following stroke and monitoring patterns of physical activity during rehabilitation.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6963/14/309/prepubIncluded studies and reports. Full list of included studies and reports, with details of study design, objectives, hypotheses, outcomes, measures, sample size, country, key findings and statistical evidence (where appropriate).Click here for fileQuality appraisal tools and outcomes. Full list of quality appraisal tools and quality appraisal outcomes for each intervention, opinion and economic evidence study.Click here for file


Cortisone is an injected anti-inflammatory drug that can cause painful side effects known as “steroid flares” which are caused by cortisone crystallizing at the injection site. We used molecular dynamics simulations and X-ray diffraction to study the interaction of cortisone with model lipid membranes made of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) at drug concentrations from 0 mol% to 50 mol%. Cortisone was found to partition in the lipid bilayer and locate in the hydrophilic to hydrophobic interface of the membranes. Cortisone strongly affects the integrity of the membrane, as quantified by a decreased membrane thickness, increased area per lipid, and decreased lipid tail order parameters. At cortisone concentrations of more than 20 mol%, signals from crystallized cortisone were observed. These crystallites are embedded in the bilayers and orient with the membranes. While the cortisone molecules align parallel to the bilayers at low concentrations, they start to penetrate the hydrophobic core at higher concentrations. Trans-membrane crystallites start to nucleate when the membrane thickness has decreased such that cortisone molecules in the different leaflets can find partners from the opposite leaflet resulting in a non-zero density of cortisone molecules in the bilayer center. We suggest that the lipid bilayer provides a site for cortisone crystallization. In the pharmaceutical industry, drugs are typically developed to interact directly with molecular targets, such as protein receptors, and these targets (or receptors) may be embedded in cell membranes1344Cortisone (17-hydroxy-11-dehydrocorticosterone) is a synthetic glucocorticoid used globally and listed under the World Health Organization’s Essential Medicines7Cortisone can be taken orally to treat general inflammation, although it is more commonly used to treat local joint inflammation by direct injection to the active site. Cortisone primarily acts by specifically binding to an intracytoplasmic nuclear receptor, forming a complex, which enters the nuclear membrane and interacts with basic transcription factors9111213μm sized cortisone crystals forming on the synovial membrane cause macrophages to collect at the cite of crystallization. The immune response, known as a flare, leads to the release of synovial fluid, swelling, and pain at the site of injection2122However, there are several severe side-effects of cortisone, which include muscle wasting, hyperglycemia, and steroid psychosis151619z-values of 10 Å < z < 19 Åz = 0 marks the bilayer center). In addition, MD simulations of cortisone show that it is able to localize in the head group-tail group interface of bilayer; however, dependent upon initial positionX-ray diffraction experiments have shown cortisol, the antiderivative of cortisone, which differs from cortisone only by a hydroxyl group in place of a ketone group, to localize within the bilayer at By combining MD simulations and high resolution X-ray diffraction we show that cortisone crystallizes inside of lipid membranes at high cortisone concentrations. Unsaturated 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) membranes were studied at cortisone concentrations between 0 and 50 mol%. Cortisone was found to partition in the lipid bilayers and to locate between the hydrophilic and hydrophobic regions, orienting parallel to the membranes. The presence of cortisone leads to a continuous thinning of the bilayers and an increase of the lipid area at concentrations of up to 20 mol%. At higher concentrations, cortisone was found to strongly penetrate the hydrophobic core and eventually nucleate in 2-dimensional crystallites inside the membranes. This mechanism may be related to the formation of steroid flares in cortisone therapy in biological tissue.We used MD simulations to identify the energetics and conformations of cortisone in the membranes, as well as the effects of cortisone on the structure of the lipid bilayer. A typical simulation snapshot for a concentration of 10 mol% cortisone is shown in First, we computed the potential of mean force (PMF) for a single cortisone molecule across the pure POPC membrane . The PMF−/Å3 corresponding to bulk water. The maximum in density at In order to compare the simulations to our X-ray scattering data (see below), we further computed electron density profiles from equilibrium simulations at various cortisone concentrations. Further insight into cortisone conformations is given by the density purely from cortisone molecules in 2 at 0% cortisone up 105 Å2 at 50% cortisone. The lipid area for the pure POPC bilayer is in good agreement with the experimental value of 68.3 Å2 To quantify the effect of cortisone on the structure of membrane, we computed the area per phospholipid Highly oriented, multi-lamellar membrane stacks were prepared on silicon wafers and the molecular structure was studied using high resolution X-ray diffraction imaging. By using oriented membranes, the in-plane structure Two-dimensional X-ray intensity maps for cortisone concentrations of 0, 2, 5, 10, 35 and 50 mol% cortisone are shown in Electron density profiles dz = 48 Å, the head group distance to The lamellar spacing, −1, 1.12 Å−1, and 1.17 Å−1 agree well with the [100], [102], [103] reflections observed from crystallized cortisonea = 7.31 Å and c = 22 Å. The presence of these peaks suggests the formation of crystallized cortisone at high concentrations.In-plane diffraction is shown in −1 and 1.17 Å−1 were integrated along the azimuthal angle ϕ from 10° < ϕ <60° ( ϕ <10 was not included due to the effect of absorption). The results for 35 mol% and 50 mol% cortisone are presented in f = 0.96 and crystals from the 50 mol% sample show f = 0.64. While a perfect orientation has f = 1, randomly oriented crystallites would result in f = 0.25. The cortisone crystals, therefore, have a preferred orientation along To determine the orientation of the cortisone structures with respect to the bilayers, the peaks at The interaction of cortisone with model POPC bilayers was studied using MD simulations and X-ray diffraction. In both, experiment and simulation, cortisone was found to strongly interact with the lipid bilayer. X-ray and neutron diffraction experiments have previously reported conformational changes in lipid bilayers with the introduction of drugs and hormones303132313233A membrane bound state for cortisone was found in MD simulations and X-ray diffraction experiments at low cortisone concentrations. The simulations observed a minima in the PMF for cortisone across the bilayer, with a strong preference to avoid entering the bilayer center. Simulations and experiments observe cortisone in the hydrophilic to hydrophobic interface with the hydrophobic face in contact with the lipid tails. By positioning into the interfacial region of the bilayer, cortisone causes a decrease in the bilayer thickness and an increase in the area per lipid molecule.Additional scattering features were observed at 20 mol% cortisone, indicating the presence of crystallized cortisone within the membranes. These cortisone crystals are oriented with the membrane; the corresponding crystal lattices are forming perpendicular to the membrane plane. During the simulations, however, no evidence for cortisone crystallization was observed, neither from visual inspection of the trajectories nor from computed X-ray intensity maps , suggestThe process of cortisone crystallite formation is illustrated in The corresponding structure of a membrane with embedded crystallite is shown in μm in diameter, and the average lipid has an area of 65 Å2, and a membrane/water partition coefficient of 200, then 100 mg of cortisone could result in up to 109 cells obtaining cortisone/plasma membrane lipid concentrations of ~20 mol%. Therefore, cortisone is likely present in the elevated concentrations studied here. A cortisone flare is a reaction of the body to a cortisone injection, typically 24–48 hours after the injection has been administered. In about 5% of the cases, cortisone is found to crystallize and cause pain around the soft tissue along with the joint lining, in conjunction with strong pain. A flare is typically treated by resting the inflamed area.Cortisone is often used to treat inflammation of the joints to function as inflammation reducing agents, which in turn reduces pain in the joints. It is used in the treatment of bursitis, tendonitis, and arthritis in the form of local injections in the knee, shoulder, elbow or back, or systemic injections for inflammation all over the body. Up to 100 mg of cortisone are commonly injected during an anti-inflammatory treatmentIn our simulations and experiments, the lipid bilayer was found to serve as a 2-dimensional substrate for cortisone accumulation and crystallization As cortisone is believed to cross the membrane by free diffusion or membrane mediated endocytosis, the steroid can bind to both the inner and outer leaflet of the plasma membrane, thereby initiating crystallization in the manner outlined in Steroid flares, commonly observed after cortisone injection, have been attributed to the formation of microcrystalline corticosteroid. In this study, we show that crystallized cortisone is observed in POPC model membranes at high cortisone concentration. By combining molecular dynamics simulations and X-ray diffraction, we present a potential mechanism for the nucleation of cortisone flares, where the steroid crystals nucleate within the 2-dimensional plane of the lipid membrane.Cortisone partitions into the head group-tail group interfacial region of the bilayers at low cortisone concentrations, aligning parallel to the membranes. Increasing cortisone concentration results in an increased area per lipid, a decreasing membrane width, and more disordered lipid tails. At concentrations of more than 20 mol% cortisone, the formation of crystalized cortisone inside the hydrophobic membrane core was observed. These crystals form when the membrane thickness has decreased such that cortisone molecules in the different leaflets can find partners from the opposite leaflet, resulting in a non-zero density of cortisone molecules in the bilayer center. The corresponding crystallites orient with the membranes.2). 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine,  and Cortisone  were mixed at the desired molecular ratio and dissolved in a 1:1 mixture of chloroform /2,2,2-trifluoroethanol (TFE) (Sigma). The final solution concentration was 16 mg/mL.Highly-oriented multi lamellar membranes were prepared on single-side polished silicon wafers  provided circular flow and even distribution. The samples was allowed to dry for 20 minutes on the tilting incubator.The wafers were placed in 1,2-dichloromethane  within a closed Pyrex dish. Wafers were cleaned by sonication for 30 minutes, which resulted in a hydrophobic silicon surface. The wafers were then removed and rinsed three times thoroughly with alternating methanol and 18.2 MΩ·cm water. The wafers were then dried with pressurized nitrogen gas 2O) to prevent lipid peroxidation, prior to the X-ray scattering experiments37The samples were then placed in a vacuum for ~24 hours at 298 K to allow for the evaporation of trace solvent. Wafers were stored in a glove box . This beam geometry provides optimal illumination of the membrane samples to maximize the scattered signal. By using highly-oriented stacks, the in-plane Out-of-plane and in-plane X-ray scattering data was obtained using the Biological Large Angle Diffraction Experiment (BLADE) in the Laboratory for Membrane and Protein Dynamics at McMaster University. BLADE uses a 9 kW  CuK−1 < qz < 0.3 Å−1 were integrated to enhance the data quality.As in-plane features are usually orders of magnitude weaker than the pronounced out-of-plane features, slices 0.03 Åρ(z), is approximated by a 1-dimensional Fourier analysis31The out-of-plane structure of the membrane was determined using specular reflectivity. The relative electron density, N is the highest order of the Bragg peaks observed in the experiment. The integrated peak intensities, Once an analytical expression for ρ(z) = 0.26 e−/Å3. The curves were then scaled until the total number of electrons within the lipid unit cell across a membrane leaflet, For POPC and POPC + 5 mol% cortisone, the calculated electron densities, ρw = 0.33 e−/Å3. For pure POPC and POPC with 5 mol% cortisone, 20 and 21 water molecules per POPC were calculated, respectively. Therefore, for the POPC sample, the integral over the lipid unit cell is assumed to contain one POPC molecule and 20 water molecules. For the 5 mol% cortisone sample, the integral number of electrons over a lipid unit cell in the bilayer is assumed to contain a full lipid molecule, 21 water molecules, and 5% of a cortisone molecule. The procedure follows that outlined by Alsop et al.The total number of electrons includes contributions from POPC, cortisone, and water molecules. The number of water molecules per lipid was calculated by calculating the approximate volume of water, Parameters for POPC were taken from the SLipids force fields43http://memgen.uni-goettingen.de)The lipid membrane simulation systems were generated with the web server MemGen . Each umbrella simulation was carried out for 80 ns. The temperature was set to 300 K through a stochastic dynamics integrator x-y plane only, but keeping the box dimension in z-direction fixed. After removing the first 10 ns for equilibration, the PMFs were computed with the weighted histogram analysis method (WHAM)T the temperature.A harmonic umbrella potential acting on the center of mass of the solute was applied .


There are many clinical intervention strategies for treating tarsal tunnel syndrome. The role of conservative versus surgical interventions at various stages of the disease process remains unclear, and there is a need for a structured, step-wise approach in treating patients with this syndrome based on derived empirical evidence. This narrative review attempts to analyse the literature to date, for the long-term purpose of developing a clinical treatment algorithm.Cochrane Library 2013), the databases of EMBASE, AMED, MEDLINE, CINAHL, Physiotherapy evidence database (PEDRO), Biomed Central, Science Direct and Trip Database (1972 to the present). Authors and experts within the field of lower-limb orthopaedics were contacted to discuss applicable data. Subject-specific criteria searches utilizing the following key terms were performed across all databases:The literature searches that have been incorporated in compiling a comprehensive review of this condition have included: the Cochrane Neuromuscular Group's Specialised Register, Central Register of Controlled trials and Methodology Register  for the treatment of this condition in both adults and children. According to our review, there is limited high-level robust evidence to guide and refine the clinical management of tarsal tunnel syndrome. Requirements for small-scaled randomized controlled trials in groups with homogenous etiology are needed to analyze the effectiveness of specific treatment modalities.It is necessary that further research endeavours be pursued for the clinical understanding, assessment and treatment of Tarsal tunnel syndrome. Accordingly, a structured approach to managing patients who have been correctly diagnosed with this condition should be formulated on the basis of empirical evidence where possible.


We developed an evidence-based practice guideline to support occupational safety and health (OSH) professionals in assessing the risk due to lifting and in selecting effective preventive measures for low back pain (LBP) in the Netherlands. The guideline was developed at the request of the Dutch government by a project team of experts and OSH professionals in lifting and work-related LBP. The recommendations for risk assessment were based on the quality of instruments to assess the risk on LBP due to lifting. Recommendations for interventions were based on a systematic review of the effects of worker- and work directed interventions to reduce back load due to lifting. The quality of the evidence was rated as strong (A), moderate (B), limited (C) or based on consensus (D). Finally, eight experts and twenty-four OSH professionals commented on and evaluated the content and the feasibility of the preliminary guideline. For risk assessment we recommend loads heavier than 25 kg always to be considered a risk for LBP while loads less than 3 kg do not pose a risk. For loads between 3–25 kg, risk assessment shall be performed using the Manual handling Assessment Charts (MAC)-Tool or National Institute for Occupational Safety and Health (NIOSH) lifting equation. Effective work oriented interventions are patient lifting devices (Level A) and lifting devices for goods (Level C), optimizing working height (Level A) and reducing load mass (Level C). Ineffective work oriented preventive measures are regulations to ban lifting without proper alternatives (Level D). We do not recommend worker-oriented interventions but consider personal lift assist devices as promising (Level C). Ineffective worker-oriented preventive measures are training in lifting technique (Level A), use of back-belts (Level A) and pre-employment medical examinations (Level A). This multidisciplinary evidence-based practice guideline gives clear criteria whether an employee is at risk for LBP while lifting and provides an easy-reference for (in)effective risk reduction measures based on scientific evidence, experience, and consensus among OSH experts and practitioners. Lifting is an activity that is common during work. In a European study on working conditions, 35% of the employees reported manual lifting or carrying of loads on a regular basis. Despite automation, European workers are equally exposed to lifting and carrying as they did 10 years ago . In the In the last ten years, comprehensive literature overviews concerning health risks, especially low back pain (LBP), due to lifting have been published -8. DespiLBP - after flu – is the second most important reason for sick leave and is responsible for 15% of the annual number of sick leave days in the Netherlands . Of thesAlthough knowledge is gained about the possible work-related causes and prevention of LBP, we seem to make little progress in preventing this important work-related complaint. This slow progress is not for want of trying . For exaIn order to answer these three questions in the best possible way, the Dutch Government granted a project on the development of an evidence-based practice guideline to support occupational safety and health (OSH) professionals in the Netherlands in their decision making whether lifting at work can be considered a risk factor for LBP and, consequently, which interventions can be recommended. This practice guideline should be based on the best available scientific evidence, integrated with the expertise of OSH professionals and taking into account the values and preferences of employers and employees ,25. ThisThe practice guideline was developed by a project team of OSH experts and practitioners and is based on:1) an evaluation of the quality of methods for risk assessment of workplaces that involve lifting;2) the results of a systematic review of the effects of interventions for reducing biomechanical loading of the back due to lifting;3) an evaluation of the feasibility of the draft guideline by external peer reviewers and a practice test on feasibility of the draft by OSH professionals..This paper provides an overview of the main findings and recommendations. For detailed information we refer to the Dutch background document of the multidisciplinary practice guideline (In Dutch: nvab.artsennet.nl/Richtlijnen/NVABrichtlijnen-en-procedurele-leidraden/Richtlijn-Tillen.htm)The project team consisted of nine persons, experts and practitioners in the development and implementations of clinical practice guidelines and/or lifting and work-related LBP. All members are authors of this paper. The group met nine times in various compositions during a period of 12 months to discuss all relevant documents, evidence reports, and specific recommendations. Consensus was reached on all decisions regarding evidence reports and the specific recommendations.th 2011) and Medline (1945-November 8th 2011) for systematic reviews regarding the quality of risk assessments methods for physical workload. The search terms are listed in Table A systematic search was performed in OVID SP, and the same time in Embase , B (moderate), C (limited) and D (consensus) .http://osha.europa.eu/en/topics/msds/slic/handlingloads/19.htm). This method was not described in the review by Takala et al. [The project team selected observation methods above self-reports to assess the risks of physical work load due to lifting. The main reason was that observation methods used by trained OSH professionals would result in more valid assessments . Takala a et al. , becausea et al. . Therefoa et al.  and the a et al.  to assesa et al.   of trunk muscles, trunk postures or time lifting as valid measures of load. The reasons were threefold. First, a recent health impact assessment on the effect of lifting devices demonstrated that the impact of this intervention could only be evaluated properly by estimating the reduction in exposure to lifting activities and, subsequently, determine the influence of this reduction in exposure on the decrease in occurrence in LBP . Second,In our systematic review of the effects of interventions, we included any study that evaluated the effect on low back load or LBP due to lifting at work in a field experiment. We did not include laboratory experiments because it is difficult to translate such results to practice. We made a distinction between measures directed at the worker like the use of back-belts or directed at the work situation like the use of lifting devices.th 2011) and Medline (1945-November 8th 2011) for reviews and primary studies regarding the efficacy of interventions to reduce low back load or LBP due to lifting. The search terms are listed in Table We performed a systematic search with OVID SP in Embase , the vertical lifting distance (Level B), the horizontal lifting distance and sliding friction (Level A), and a better contact factor (Level C), can reduce the load on the low back. This is in line with the risk factors from the NIOSH lifting equation  and the We also considered the evidence for the organizational factors lifting teams, team lifting, job content and duration and regulations Table . Well-stEight experts and twenty-four OSH professionals, with at least two of all the participating professional associations commented on and evaluated the content and the feasibility of the preliminary guideline. Thirteen topics were evaluated such as whether the goal of the practice guideline was clearly formulated, whether the procedure to assess the risk of lifting was feasible in practice, and whether the recommendations for interventions were clearly formulated and feasible in practice. On all these topics the comments of the experts and OSH professionals helped to improve the feasibility of the guideline.We developed a practice guideline to support occupational safety and health professionals in assessing the risk due to lifting and in selecting effective preventive measures for low back pain. This practice guideline is based on the best available scientific evidence and should be used by occupational safety and health professionals taking into account the values and preferences of workers and employers. Providing evidence-based guidance for risk assessment and lifting interventions will improve the quality of preventive practice and increase the impact of occupational health and safety advice. We strongly advise societies and associations of health professionals to support implementation of this guideline into daily practice by active education of their members in order to optimize successful health strategies to reduce the impact of lifting on low back pain among high risk groups of workers.The authors declare that they have no competing interests.A core group of the project team consisting of JV, ML, AB and CH did the preparatory work on the basis of the project request of the Dutch Government and made a proposal for the clinical questions. These clinical questions were discussed with the other members of the project team consisting of PK, BV, LE, NVR, MVDW. Next, the core group performed the systematic literature search, performed the critical appraisal and wrote the evidence report draft, wrote the draft of the preliminary guideline and managed the external peer review and practice test of the preliminary guideline. All authors were involved in the revision of the draft guideline. PK drafted this manuscript. All authors were involved in reading and revision of the manuscript. All authors read and approved the final manuscript.


Sitting for more than 8 h a day has been shown to negatively impact health and mortality while standing is the recommended healthier alternative. Home-based standing programs are commonly recommended for adults who cannot stand and/or walk independently. The aim of this systematic review is to review effectiveness of home-based standing programs for adults with neurological conditions including stroke and spinal cord injury; and to provide dosage guidelines to address body structure and function, activity and participation outcomes.Eight electronic databases were searched, including Cochrane Library databases, MEDLINE, CINAHL and EMBASE. From 376 articles, 36 studies addressing impact of a standing intervention on adults with sub-acute or chronic neurological conditions and published between 1980 and September 2015 were included. Two reviewers independently screened titles, reviewed abstracts, evaluated full-text articles and rated quality and strength of evidence. Evidence level was rated using Oxford Centre for Evidence Based Medicine Levels and quality evaluated using a domain-based risk-of-bias rating. Outcomes were divided according to ICF components, diagnoses and dosage amounts from individual studies. GRADE and the Evidence-Alert Traffic-Lighting system were used to determine strength of recommendation and adjusted in accordance with risk-of-bias rating.Stronger evidence supports the impact of home-based supported standing programs on range of motion and activity, primarily for individuals with stroke or spinal cord injury while mixed evidence supports impact on bone mineral density. Evidence for other outcomes and populations is weak or very weak.Standing should occur 30 min 5 times a week for a positive impact on most outcomes while 60 min daily is suggested for mental function and bone mineral density.The online version of this article (doi:10.1186/s12891-015-0813-x) contains supplementary material, which is available to authorized users. Sitting for more than 8 h per day has been shown to increase mortality  while stSupported standing devices such as standers, tilt-tables or standing wheelchairs allow the user to attain and maintain a standing or partial-standing position and commonly stabilize hips, knees and ankles through posterior heel, anterior knee and posterior hip supports and/or straps. A systematic review  supporteSupported standing programs have been integrated into clinical practice for over 50 years –19 and yThe Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)  statemenBibliographies of electronically retrieved studies and review articles were manually searched to identify additional publications. Both authors independently read all titles and abstracts and agreed on articles to be retrieved full text. Following independent full-text review, both agreed to studies meeting inclusion criteria. Differences of opinion were resolved at all stages through discussion and consensus without the need to involve a third reviewer.The initial search included all primary source studies including adults aged 19 years or older, with a neurological diagnosis, participating in a supported standing intervention. A stander was defined as a device that stabilized the hips, knees and ankles. A standing intervention was defined as being positioned above 60°  for at least 10 min for a minimum of five sessions within a 2-week period. Studies that used additional interventions such as functional electrical stimulation or whole body vibration were excluded unless there was also a supported standing only phase in the study. Studies where participants engaged in only one or two sessions of standing in total, or that were primarily investigating physiological responses to being tilted from supine to upright in less than 10 min were excluded. Patients in the acute phase immediately following onset or injury have different considerations to those able to engage in active rehabilitation or with chronic conditions, and those populations were excluded. To meet inclusion criteria, studies needed to be published in English, in a peer-reviewed journal and provide clear information on standing dosage.Data were extracted independently by both authors, and consensus on content of tables and ratings achieved through discussion. Quality assessment of Evidence Level 1–4 studies was completed using a domain-based risk-of-bias approach . DomainsOutcomes were divided into International Classification of Functioning (ICF)  componenThe PRISMA  flowcharOutcomes were divided into ICF  componenIn one high quality randomized controlled trial , standinThis outcome has only been studied in the SCI population with descriptive evidence providing the strongest support for positive benefits, particularly for higher dose standing, started early and continued in the long-term. One cross-sectional study reported significantly higher BMD in the proximal femur and lumbar spine with highest BMD at proximal femur in those standing using long-leg braces . AnotherIn two case-series designs, adults in a nursing home  and subjIncreased resting skin temperature and decreased skin temperature reactivity have been linked to development of pressure sores. In subjects with SCI, a single session of standing resulted in temperature decreases at two sites as well as altered reactivity of skin temperature at all sites except the right calf . SurveysA stander that enabled patients with SCI to move their trunks and perform supported exercises while standing, resulted in a positive increase in heart rate . Two surA follow-up interview of adults with chronic SCI or MS, showed that 67 % continued to stand and felt healthier because of it. This suggests a positive psychological impact  despite Residents of a nursing home with a variety of neurological diagnoses who stood and exercised regularly in a standing box, showed statistically significant improvement in their anal wink reflex . Other eA positive trend for gross motor function, trunk control and significant improvement in balance for individuals with stroke was found following standing intervention . Yet a sModerate to high quality evidence supports the positive impact of standing on ROM and activity for adults with neurological conditions. The strongest evidence, resulting from level II moderate or high quality studies, supports impact on ROM for adults with stroke and SCI. Strong evidence from a high quality randomized study, and other lower quality studies, also support the benefit of supported standing on activity outcomes such as standing symmetry and ability to maintain a stable standing position for the sub-acute and chronic stroke population. Strong evidence also supports the addition of task-specific training to tilt-table standing for improvement in gait, functional activity and muscle strength in the sub-acute stroke population.Evidence supporting impact on ROM for the sub-acute SCI population is supported by moderate quality level II evidence as well as lower quality studies. However, evidence supporting impact on activity outcomes such as activities of daily living, independence and transfers is merely supported by case study or survey evidence. One study including those with long-standing SCI or MS  stands oEvidence for impact on BMD is somewhat mixed with descriptive evidence mainly suggesting benefits for early initiation of higher-dose standing programs. There is conflicting evidence however, with one longitudinal study suggesting benefits for only some participants . A weaknLow evidence level intervention studies support improvements in muscle strength and spasticity/tone. Adult user input and expert opinion support impact on mental function, pain and sensory, cardiopulmonary and respiratory, bowel, urinary, and skin function. Older studies suggest that standing can increase bladder pressure  and decrContradictory evidence was found regarding impact on cardio-respiratory function with orthostatic hypotension being a problem for those with SCI . FrequenA number of higher-level intervention designs were identified, addressing activity, spasticity and muscle tone, strength, BMD and ROM outcomes. Eight level II studies , 56–58 iOnly two other systematic reviews on use of passive standing were identified in the search , 13. GliThis review was limited by the complexities of the electronic search. Terms such as stander or standing generate a high number of citations that are difficult to narrow down. Studies published in other languages or grey literature may have been missed. This review covered a long period of time (over 30 years) where reporting standards have changed, and some studies lacked detail about the intervention making it challenging to compare studies. Unfortunately, the bulk of studies identified achieved low-quality ratings and also included low numbers of participants resulting in low strength of recommendation. The low evidence level and disparate populations limited ability to combine results and to draw strong conclusions.However, this review does help to establish the current evidence level, adds strength of recommendation and identifies dosage guidelines for different populations and specific ICF components. The strongest evidence supports impact on ROM and activity with SCI and stroke populations. Low evidence level studies support improvements in BMD, strength and spasticity. Adult user input and expert opinion support improvements in mental, pain and sensory, cardiopulmonary and respiratory, bowel, urinary, and skin function. Overall little information on dosage was provided, the majority of articles lacked specifics about how the standing program was implemented and no study measured actual weight bearing or muscle activity. Future research studies may benefit from use of the TIDieR checklist  to ensurWhile additional high-quality research studies would be beneficial for all outcomes, the need is particularly high for the majority of body structure and function outcomes, in particular BMD, cardio-respiratory, pain, skin, bowel and bladder function. The largest number of high-level studies was completed with sub-acute stroke patients and yet evidence for effectiveness for most outcomes is limited. Further high-level and longer-term research is warranted with this population in particular. Although there has been an extensive amount of cross-sectional and observational research conducted with the sub-acute and chronic SCI population, stronger intervention research is also warranted.There was a notable disconnect between the qualitative and quantitative data identified in this review. In one study, no change was found on the objective measures, while a significant proportion of subjects reported an improvement in bowel function . While sFuture research studies should explore optimal angle of standing, possible benefits of abduction and type of stander. For adults who are dependent for transfers, standing programs require considerable time and resource commitment. Lack of attendant help has been cited as a reason for discontinuing standing . Use of Stronger evidence underpins the impact of supported standing programs on ROM and activity for stroke and SCI populations with mixed evidence supporting impact on BMD. Evidence for other outcomes is weak or very weak. Dosage data suggests that use of a standing device should occur for 30 min 5 times a week for positive impact on most outcomes such as self-care and standing balance, ROM, cardio-respiratory, strength, spasticity, pain, skin and bladder and bowel function while 60 min 4–6 times a week may be required for positive impact on BMD and mental function. While therapists can recommend with some confidence the use of a supported standing intervention to impact on ROM and activity outcomes, the evidence is less certain for other outcomes. Outcomes should be measured to ensure effectiveness for individual clients.


Microeconomic evaluations of public health programmes such as immunisation typically only consider direct health benefits and medical cost savings. Broader economic benefits around childhood development, household behaviour, and macro-economic indicators are increasingly important, but the evidence linking immunization to such benefits is unclear.A conceptual framework of pathways between immunisation and its proposed broader economic benefits was developed through expert consultation. Relevant articles were obtained from previous reviews, snowballing, and expert consultation. Articles were associated with one of the pathways and quality assessed using modified Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria.We found 20 studies directly relevant to one or more pathways. Evidence of moderate quality from experimental and observational studies was found for benefits due to immunisation in improved childhood physical development, educational outcomes, and equity in distribution of health gains. Only modelling evidence or evidence outside the immunization field supports extrapolating these benefits to household economic behaviour and macro-economic indicators.Innovative use of experimental and observational study designs is needed to fill evidence gaps around key pathways between immunisation and many of its proposed economic benefits.The online version of this article (doi:10.1186/s12916-015-0446-9) contains supplementary material, which is available to authorized users. Investment in immunisation programmes in both developed and developing countries has dramatically increased over the past two decades . This isHowever, many cost-effectiveness studies only consider direct health benefits and medical cost savings, although some consider a few wider benefits such as indirect (herd) protection and care-related productivity gains. However, economists have argued that improvements in health lead to economic growth through longer-term mechanisms such as decreasing fertility, strengthening macroeconomic stability, and improving educational outcomes , 6. MoreTo address this gap, we constructed a conceptual framework that captures causal pathways linking vaccines to their proposed benefits and conducted a rapid review of the validity and strength of evidence behind each pathway. Our aim is to inform research into filling knowledge gaps in this area, as well as to strengthen evidence-based advocacy and decision making about vaccination.Two authors of this report (MJ and RH) facilitated expert consultations during vaccine meetings convened by the World Health Organization in Toronto (13–14 July 2011), Geneva (28–29 June 2012), Sydney (10–11 July 2013), and Bangkok Unexplained heterogeneity or inconsistency of results P <0.1)Imprecision of results Randomized controlled trials were given a default quality rating of ‘high’. They were downgraded by one level for any of the following that apply and by two levels for any factor regarded as severe, up to a maximum of three:Observational studies that were methodologically sound with no obvious bias were regarded as providing ‘high’ quality evidence for the existence of pathways being evaluated if they were able to demonstrate very large effects, ‘moderate’ quality evidence if the effect sizes were large, and ‘low’ quality evidence if there were small or no effects. Observational studies that were not methodologically sound were by default considered be ‘low’ quality evidence, regardless of effect size.Most studies reviewed were based around models rather than traditional epidemiological designs involving primary data collection. There are no GRADE criteria for quality assessment of modelling studies. In order to account for the existence of such studies as part of the evidence base, we expanded the categories of studies in GRADE to include modelling studies but kept them in a separate category from empirical studies. Table Figure After review and screening for duplications, 93 unique journal articles from the original reviews were included in the initial study. Of these, 23 were identified as being exempt from or not appropriate for evidence quality review for reasons such as being commentaries rather than analyses. Evidence quality grades for the remaining studies are shown in Table Evidence that immunization improves non-utility capabilities No experimental studies were reviewed that directly provided evidence of the impact of immunization on the physical development of children via reduced morbidity. A single observational study by Bloom et al. , found nOne randomised trial of moderate quality by Canning et al. , provideEvidence that immunization produces productivity gains via improvements in non-utility capabilities (strength of evidence = modelling)By improving human capital in the form of increased physical, cognitive, and educational skills of children, immunization may have an impact on future workforce productivity and hence labour income of households as well as overall economic growth. In one modelling study, Bloom et al.  proposedIn Bangladesh, Bishai et al.  found thTwo recent modelling studies also addressed the impact of rotavirus immunization programmes on equity. Rheingans et al.  modelledNo observational or experimental studies were found that provided direct evidence of interaction effects between immunization and other health interventions on economic outcomes. However, two modelling studies have explored the interaction between immunization and other health interventions from a cost-effectiveness perspective, showing mixed results. Jeuland et al.  examinedex ante valuations of vaccines that did not yet exist would match ex post valuations in a future context. Further, while they provide evidence that significant private economic benefits exist to households, it is not possible to distinguish among the various pathways that may contribute to those benefits.Several observational studies –32 used Two mechanisms have been proposed by which immunization may reduce household financial vulnerability: firstly, through overall changes in labour earnings or savings behaviour, and secondly by reducing the risk from specific health shocks. None of the reviewed studies provided direct empirical evidence for either of these pathways. However, Verguet et al.  has propIf labour income rises, all else equal, we expect that households will be able to increase consumption, savings, and investment in human capital (such as education). Even in the absence of evidence for longer-term increases in labour income due to improved human capital, we would expect changes in immediate household consumption, savings, and investment because of increased disposable income as a result of reduced health expenditure and lost wages. However, no experimental, observational, or modelling studies were found that directly examine the effect of immunization on changes to household consumption, saving, or investment behaviour.As the risk of childhood mortality and morbidity decreases and survival rates increase, households may also be expected to produce fewer children and invest more in their health . HoweverOne modelling study  considerNo empirical studies were found that estimated the effects of vaccination in mitigating the short-term macroeconomic consequences of an infectious disease outbreak. However, several modelling studies have examined the impact of vaccination  in the context of an influenza pandemic. Using a computable general equilibrium model, Smith et al.  estimateWe found no studies of any kind directly examining the impact that vaccination may have on long-term macro-economic indicators such as national income, growth, or foreign direct investment. However, outside the field of vaccination, there were several studies examining the relationship between improved health in general and such indicators. In a longitudinal cross-country study, Alsan et al.  found a We have developed a conceptual framework of the pathways between vaccines and their proposed benefits, and assessed the strength of evidence behind each pathway. Our framework builds on previous lists of benefits , 10, 11,We obtained mixed results from this assessment of the validity and strength of evidence behind conceptual pathways linking immunization programmes with their proposed benefits. There is indisputable evidence that vaccines bring ‘narrow’ benefits related to health outcomes, health care cost savings, and protection against productivity losses directly related to the illness episode at the level of individual vaccinees and at the community level via herd protection. There is also some limited experimental or at least observational evidence that vaccines bring wider benefits at the household level in the form of improved non-utility capabilities and equity in the distribution of health gains by wealth quintile . However, there is only modelling evidence to support extrapolating these benefits to meso-level household economic behaviour , as well as macro-level economic indicators  that might logically follow.To incorporate modelling evidence, we expanded the traditional GRADE criteria to include a category for such studies. There was a gradient in the robustness of evidence from the modelling studies we reviewed due to variation both in the quality of input data  and the way the data were handled . However, we did not attempt to assess the quality of modelling evidence. Although there do exist some frameworks for assessing the quality of mathematical models in health –44, nonede novo systematic review. Previous reviews also found that there were few studies examining many of the potential broader economic benefits of vaccination [Our objective was to conduct a rapid review of the literature in order to validate a conceptual framework that evolved out of a consultative process. Since several systematic and narrative reviews in the area had previously been carried out, we opted to conduct a review of existing reviews with additional expert consultation, rather than a cination –11. The One limitation is that we focused on the vaccine-specific literature only, and did not explore the wider literature on the relationship between health in general  and broader economic benefits. Since vaccines improve health, it may be reasonable to assume that the downstream relationship between health and its economic benefits also apply to vaccines. Herein, we have taken a conservative approach by ignoring any evidence relating to pathways in which immunization programmes were not the ultimate cause.Conversely, vaccines are only one component of health systems that contribute to economic benefits. For instance, recent modelling work found that vaccines only avert around 27 % of childhood diarrhoea and pneumonia deaths, so remaining mortality reductions come from other interventions such as nutrition, case management, and hygiene . The benAnother limitation is that our framework does not consider the special benefits of maternal vaccination, including improved maternal and child health outcomes following vaccines such as influenza. Further, our framework has focused on the broader economic benefits of vaccination. However, the broader economic costs of vaccination are also of increasing interest to decision making. These include costs related to addressing adverse effects following immunisation and vaccine hesitancy at a societal level.The absence of evidence from interventional studies to support many of the proposed pathways does not imply evidence for the absence of such relationships. Many vaccines have proven health and economic benefits and are being routinely used in most countries, so experimental designs that deny vaccines to a proportion of participants may be considered unethical. Furthermore, associations between interventions and long-term economic behaviour at the household or macroeconomic level are expensive and time-consuming to investigate experimentally. Conditions for well-controlled ‘natural’ experiments are also rare. Hence, the use of designs that would be considered robust in the medical literature may be less common in the economics literature. Similarly, assumptions about human behaviour  may be well-accepted in in the economics literature without the need for empirical justification, but this is not the case in the medical literature. This may explain the decrease in availability of experimental or even observational evidence as we move from health-related outcomes to economic outcomes at either the household or the macro-economic level.The present study highlights the importance of collecting data about such behaviour wherever possible in order to strengthen the evidence base behind the potential broader economic impacts of vaccination. For instance, some of the outcomes for which we did not find experimental evidence (such as household choices around consumption and savings) could be routinely incorporated into clinical effectiveness trials of vaccines or into standard demographic and health surveys, should suitable data collection instruments be developed. In the interim, innovative analyses of historical observational datasets may provide evidence that would be considered more robust than models whose assumptions are not driven by data. There is a need to design the requisite methods and initiate the relevant studies as soon as possible given the increasing importance of broader economic indicators of vaccine impact in informing investment decisions about vaccines.


Idiopathic pulmonary fibrosis (IPF) is a rare fibrotic interstitial lung disease with a relentlessly progressive course and fatal outcome. Guidelines summarizing the current evidence and providing evidence-based recommendations for the treatment of rare diseases such as IPF are important since individual physicians often have limited experience. Nevertheless, the available evidence is often scarce and, therefore, evidence-based recommendations are prone to being vague or with low confidence, thus creating uncertainty instead of guidance. Moreover, the effect of guidelines themselves on clinical practice has not been sufficiently evaluated. On the other hand, expert opinion may be biased and lead to the misinterpretation of evidence, resulting in misleading recommendations and a potential harm to patients. This editorial focuses on the advantages and disadvantages of evidence-based guidelines and professional experience in the context of a rare disease such as IPF and tries to assess the optimum combination of both approaches.http://dx.doi.org/10.1186/s12916-016-0562-1 and http://dx.doi.org/10.1186/s12916-016-0563-0Please see related commentary articles:  Over 20 years ago, evidence-based medicine began to replace medical practices based on tradition, anecdotes, and theoretical reasoning through empirical evidence from clinical trials . The fouIPF treatment guideline development is an archetypal example to examine the positive and negative impacts of evidence-based guidelines. The 2011 ATS/ERS/JRS/ALAT guideline is an excellent summary of the available evidence and provides and implements a new definition of IPF . By upgrAs indicated by Rochwerg et al. , evidencEvidence-based guidelines summarize the available evidence using a comprehensive literature research approach and provide unbiased recommendations reflecting this evidence. However, this emphasis on methodology eventually results in a lack of practicability and guidance in areas with a dearth of evidence. The empirical approach based on expert advice can provide guidance, especially in areas with little or no formal evidence, but is vulnerable to biased recommendations. Thus, both approaches may adversely affect patients. A synthesis of these potentially complementary approaches seems appropriate to provide optimal guidance in the treatment of all patients.


European medical device regulation is under scrutiny and will be re-regulated with stricter rules concerning requirements for clinical evidence for high-risk medical devices. It is the aim of this study to analyse the differences between Europe and USA in dealing with risks and benefits of new cardio-vascular devices.Since no information is available on clinical data used by the Notified Body for CE-marking, data from Austrian pre-reimbursement assessments close to European market approval were used as proxy and compared with clinical data available at time of market approval by FDA in the USA.10 cardio-vascular interventions with 27 newly CE approved medical devices were analysed. The time lag between market authorisation in Europe and in the USA is 3 to 7 years. Only 7 CE-marked devices also hold a FDA market approval, 7 further devices are in FDA approved ongoing efficacy trials. For 4 of the CE-marked devices the FDA market application or the approval-trial was either suspended due to efficacy or safety concerns or the approval was denied. Evidence available at time of CE-marking are most often case-series or small feasibility RCTs, while large RCTs and only in rare cases prospective cohort studies are the basis of FDA approvals. Additionally, the FDA often requires post-approval studies for high-risk devices.Market authorisation based on mature clinical data deriving from larger RCTs and longer follow-ups do not only change the perspective on the risk-benefit ratio, but also secures real patient benefit and safety and assures payers of investing only in truly innovative devices. Because of several market withdrawals due to unsafe or ineffective devices, European medical device regulation is under scrutiny and will be re-regulated with stricter rules concerning requirements for clinical evidence for class III (active) and class IIb (inactive) implantable medical devices . The criwhere the devices are approved and what the decentralised NBs receive as application information, the actual clinical evidence can only be speculated via clinical studies published after the CE mark was issued.It is well known that new medical devices, including all high-risk cardio-vascular devices, receive the European market approval (CE/ Conformité Européenne mark) several years prior to USA market authorisation . Due to Still, because of pressure from physician groups wishing to offer patients early access to innovative medicine and from manufacturers wishing early market expansion, applications for coverage of those newly CE marked devices are submitted to reimbursement institutions only several months later . In a reThe aim of this study is to analyse what evidence was available for cardio-vascular devices at the time of CE marking using the evidence presented in the Austrian assessments as a proxy, and to compare this data with the data available at the time of FDA (Food and Drug Administration) approval. Thereby, we intend to challenge the argument that earlier provision of new devices is always of benefit to the patient.new medical devices, we excluded those assessments that dealt with a) interventions where no new (defined by us as max. 3–5 years prior to assessment) CE marked products were available at the time of assessment, b) expansion of established indications (new interventions) with already existing products, and c) cerebro-vascular interventions.Since no information is available on clinical data used by the NB for CE marking and because the Austrian pre-reimbursement assessments are rather close to CE marking, we assumed that the clinical evidence – provided by the manufacturer – used for CE mark could be considered a subset of the one used for the assessments produced for deciding on including the interventions in the hospital benefit catalogue. For this study we assumed the evidence is the same. Out of all pre-reimbursement assessments we selected those that dealt with cardio-vascular interventions. Since the intention of the analysis was to concentrate on the level of evidence of From the included assessments (published between 2006 and 2014) we extracted information on a) intervention, b) devices, c) indication and d) best available evidence in terms of number and types of studies and number of study participants. Furthermore, we searched for publicly available online information on CE marking (spring 2014) and, in cases of missing information, contacted the manufacturers directly, rather than consulting the NANDO (New Approach Notified and Designated Organisations) Database.In the USA, new high-risk devices typically undergo a premarket approval (PMA) process based on an efficacy trial . DevicesNext, we assigned the levels of clinical evidence according to the Oxford Centre for Evidence-based Medicine hierarchy: 1: SR (systematic review) or MA  based on several high quality RCTs ; 2: at least 1 RCT of high quality; 3: CTs  without randomisation; 4: prospective case–control and cohort studies; 5: case reports and retrospective case series .Finally, we compared the market authorisation status and the level of evidence available around the time of market authorisation between Europe and the USA. Moreover, we analysed in more detail the differences between Europe and the USA in dealing with clinical evidence and with risk-benefit evaluations.Between 2008 and 2014, 15 (out of 48) pre-reimbursement assessments dealt with cardio-vascular interventions. From those, assessments on 10 cardio-vascular interventions were finally included into the analysis according to the pre-defined criteria (Table ®) due to safety concerns. 12 CE marked cardio-vascular devices are neither PMA-approved, nor hold an IDE status (yet), meaning that they are produced solely for the European market or the IDE will be applied for at a later stage. For 1 device (CYPHER® Select), marketing was discontinued in Europe.For the 10 cardio-vascular interventions analysed, 27 newly approved CE marked medical devices were available  cardio-devices holding European and US licences, the time lag between market authorisation in Europe and in the USA amounted to 3 to 7 years.st generation). Non-randomised controlled studies (level 3) or prospectively planned registries (level 4) were seldom available. On the contrary, IDE-accepted RCTs (level 2) or – in some rare medical conditions – prospective case series or cohort studies (level 3 and 4) were the basis for FDA approval decisions in most cases  or 2  and 656 patients  respectively. This type of clinical data was not available at the time of European market authorisation. Follow-up data from post-approval studies on inoperable and extreme risk patients is required by the FDA for both devices. No such requirements were defined at the time of EU market authorisation.he risks . Therefohe risks ; these sEarly approval in Europe and later demonstration of inefficacy in RCT: Symplicity™ received CE marking in 2008 based on a safety study (SYMPLICITY HTN-1). In 2014, the FDA approval study (SYMPLICITY HTN-3) failed to meet its primary efficacy endpoint [endpoint . As a coEarly approvals in Europe and safety concerns in the USA: Three different devices were approved for percutaneous left atrial appendage closure for the prevention of thromboembolic events in patients with atrial fibrillation in Europe between 2005 and 2013; none of them holds a PMA status. WATCHMAN® LAA Closure Technology was denied PMA in 2009 due to safety concerns. The FDA Circulatory System Devices Panel concluded  that although short-term efficacy had been demonstrated by the data available from the PROTECT AF trial, longer term efficacy had not been adequately demonstrated due to the lack of available long-term data [erm data . In lateerm data .Devices of unknown value: Optimizer™ received the CE mark in 2007 based on a feasibility trial , as well as stenotic lesions in the iliac and infrainguinal arteries, but the IDE application was suspended in 2012 due to problems concerning drug adhesion to the balloon and the according safety concerns [For PTA  of peripheral arteries with drug- eluting balloon (DEB), 6 devices received the CE mark between 2009 and 2013. Only one of these (Lutonix DCB™) also received PMA in 2014; another  is expected to be approved by the FDA in 2015 or later. One of the DEBs, concerns .Devices of critical risk-benefit-ratio: MitraClip® received CE marking in 2008 on the basis of case series (EVEREST I); PMA followed in 2013. Although an RCT (EVEREST II), a prospectively planned registry (EVEREST II HRR) and a “Real World Expanded Multi-center Study” (REALISM HR) were submitted, FDA approval was cautious, with 5 votes to 3 on whether the benefits outweigh the risks and 4 votes to 5 on whether there is a reasonable assurance of efficacy.A detailed analysis of the efficacy and safety assessments of individual devices seems to be more informative than the levels of evidence per se. Several differences in dealing with the evidence on benefit-risk ratios could be identified and the following patterns have appeared:Two devices for the endovascular repair of aortic aneurysms received CE marking in 2005 and 2013. Only one is also approved in the USA (2012); the other (Ventana™) holds an IDE, but the trial was suspended and enrolment was stopped because of a higher than expected number of re-interventions .which NB gave market authorisation on the basis of what type of clinical evidence.Recent publications showed that cardiovascular devices receiving PMA (between 2000 and 2007) are often (63%) based on non-randomised studies that lack adequate strength and may be prone to bias , that efBecause of the earlier market authorisation and the lack of requirements other than the performance evaluation of medical devices in Europe , the clinical evidence available at the time of pre-reimbursement assessments is naturally lower than some years later for market authorisation in the USA , 50, 51.Symplicity™ and Watchman®. Others are less visible, but still there: For Optimizer™ (CE marked in 2007), no convincing evidence on efficacy has been demonstrated so far. In the case of Cotavance™ (CE marked in 2011), steps towards FDA approval were suspended due to problems concerning drug adhesion to the balloon. For Ventana™ (CE marked 2013), enrolment into a trial was stopped because of a higher than expected number of re-interventions. There may even be more examples we are not aware of. Further general deficiencies are well described by Fraser et al. [Based on our experiences from 7 years of pre-reimbursement assessments , our stu® and HD Mesh Ablator® for the treatment of Atrial Fibrillation (AF) were not included in this analysis.This study has shortcomings: The biggest limitation is the fact that no data on the clinical evidence for the CE marking are available; we therefore had to rely on the information on available clinical studies derived from the Austrian pre-reimbursement assessments. Nevertheless, we think it is plausible that less rather than more clinical data were available at an earlier stage, though probably not all published. Additionally, only the devices for specific indications mentioned in the pre-reimbursement applications were assessed, meaning that other cardio-devices posing problems after CE marking such as ProRhytmOur conclusions are that good clinical evidence at the time of market authorisation not only secures real patient benefit and safety, but also assures payers of investing only in truly innovative devices. In addition, good clinical evidence might ease market access for manufacturers and make coverage in  benefit catalogues more predictable. There is a strong need for stricter device regulation in Europe and compulsory, long-term follow-up in order not to expose European patients to (often) premature experimental devices.CW/Claudia Wild is director of the LBI-HTA and trained in communications and social medicine; IZ/Ingrid Zechmeister is deputy director of the LBI-HTA and trained in health economics; JE/Judit Erdos is research assistant at LBI-HTA and trained in International Health Care Management.


Juvenile Idiopathic Arthritis (JIA) is one of the most common chronic pediatric rheumatic diseases (PRD). As is the case for most PRD's, evidence-based guidelines are sparse and management is based to great extent on physician’s experience. Moreover, there are differences between nations regarding availability and financing of biological therapies. Consequently, treatment regimens differ throughout Europe. In 2012, a European initiative called SHARE (Single Hub and Access point for pediatric Rheumatology in Europe) was launched to optimize and disseminate diagnostic and management regimens in Europe for children and young adults with rheumatic diseases.To provide evidence based recommendations for diagnosis and treatment of JIA.Evidence based recommendations were developed using the European League Against Rheumatism (EULAR) standard operating procedure . An expeThe literature search yielded 4723 articles, of which 174 were considered relevant. The included articles were scored for validity and level of evidence. Recommendations were formulated based on the valid papers and were discussed and adjusted where needed during the consensus meeting. In total, 10 recommendations for diagnosis and 31 for treatment were accepted with more than 80% agreement. Topics covered for diagnosis and for treatment are shown in Table The SHARE initiative provides recommendations for diagnosis and treatment of JIA and thereby facilitates improvement and uniformity of care throughout Europe. In the subsequent phase of the project, best practices identified from literature will be completed with the ‘experts opinion’ in order to formulate diagnostic and management guidelines as best practices for care of JIA patients throughout Europe.S. Vastert Consultant for: Novartis, V. Boom: None Declared, A. Ravelli: None Declared, A. Martini: None Declared, H. Foster: None Declared, N. Wulffraat Grant / Research Support from: Abbvie, GSK, Roche, Consultant for: Novartis, Genzyme, Roche, Pfizer.