The REal Life EVidence AssessmeNt Tool (RELEVANT): development of a novel quality assurance asset to rate observational comparative effectiveness research studies Recommendations for the standardization of clinical outcomes used in allergen immunotherapy trials for allergic rhinoconjunctivitis: an EAACI Position Paper. Preventing food allergy: protocol for a rapid systematic review European Respiratory Society guidelines for the diagnosis of primary ciliary dyskinesia Ethical key issues and fundamental rights in paediatric research Re-orientation of clinical research in traumatic brain injury: report of an international workshop on comparative effectiveness research. Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia in Adults: An American Academy of Sleep Medicine Clinical Practice Guideline. Methods for Development of the European Commission Initiative on Breast Cancer Guidelines Acupuncture in treatment of stable asthma. EULAR recommendations for the management of knee osteoarthritis: report of a task force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT) Development and cross-sectional validation of the Childhood Asthma Control Test. Using real-world data for coverage and payment decisions: the ISPOR Real-World Data Task Force report. Patient related outcomes in a real life prospective follow up study: Allergen immunotherapy increase quality of life and reduce sick days World Allergy Organization-McMaster University Guidelines for Allergic Disease Prevention (GLAD-P): Probiotics Key Steps in Conducting Systematic Reviews for Underpinning Clinical Practice Guidelines: Methodology of the European Association of Urology. The European guideline on management of major bleeding and coagulopathy following trauma: fourth edition Double-blind, placebo-controlled study of Alternaria alternata immunotherapy: clinical efficacy and safety. European Respiratory Society guidelines for the management of adult bronchiectasis Development and pilot testing of a mobile health solution for asthma self-management: asthma action plan smartphone application pilot study. Quality standards for real-world research. Focus on observational database studies of comparative effectiveness. Introduction of Complementary Foods and the Relationship to Food Allergy Canadian Thoracic Society 2012 guideline update: diagnosis and management of asthma in preschoolers, children and adults. Montelukast for the high impact of asthma exacerbations in Venezuela: a practical and valid approach for Latin America?
Abstract Background Evidence from observational comparative effectiveness research ( CER ) is ranked below that from r and omized controlled trials in traditional evidence hierarchies . However , asthma observational CER studies represent an important complementary evidence source answering different research questions and are particularly valuable in guiding clinical decision making in real-life patient and practice setting s. Tools are required to assist in quality appraisal of observational CER to enable identification of and confidence in high- quality CER evidence to inform guideline development . Methods The REal Life EVidence AssessmeNt Tool ( RELEVANT ) was developed through a step-wise approach . We conducted an iterative refinement of the tool based on Task Force member expertise and feedback from pilot testing the tool until reaching adequate inter-rater agreement percentages . Two distinct pilots were conducted — the first involving six members of the Respiratory Effectiveness Group ( REG ) and European Academy of Allergy and Clinical Immunology ( EAACI ) joint Task Force for quality appraisal of observational asthma CER ;  the second involving 22 members of REG and EAACI membership . The final tool consists of 21 quality sub-items distributed across seven methodology domains : Background , Design , Measures , Analysis , Results , Discussion /Interpretation , and Conflict of Interest . Eleven of these sub-items are considered critical and named “ primary sub-items ” . Results Following the second pilot , RELEVANT showed inter-rater agreement ≥ 70 % for 94 % of all primary and 93 % for all secondary sub-items tested across three rater groups . For observational CER to be classified as sufficiently high quality for future guideline consideration , all RELEVANT primary sub-items must be fulfilled . The ten secondary sub-items further qualify the relative strengths and weaknesses of the published CER evidence . RELEVANT could also be applicable to general quality appraisal of observational CER across other medical specialties . Conclusions RELEVANT is the first quality checklist to assist in the appraisal of published observational CER developed through iterative feedback derived from pilot implementation and inter-rater agreement evaluation . Developed for a REG-EAACI Task Force quality appraisal of recent asthma CER , RELEVANT also has wider utility to support appraisal of CER literature in general ( including pre-publication ) . It may also assist in manuscript development and in educating relevant stakeholders about key quality markers in observational CER BACKGROUND Allergen immunotherapy ( AIT ) has been thoroughly documented in r and omized controlled trials ( RCTs ) . It is the only immune-modifying and causal treatment available for patients suffering from IgE-mediated diseases such as allergic rhinoconjunctivitis , allergic asthma and insect sting allergy . However , there is a high degree of clinical and method ological heterogeneity among the endpoints in clinical studies on AIT , for both subcutaneous and sublingual immunotherapy ( SCIT and SLIT ) . At present , there are no commonly accepted st and ards for defining the optimal outcome parameters to be used for both primary and secondary endpoints . METHODS As elaborated by a Task Force ( TF ) of the European Academy of Allergy and Clinical Immunology ( EAACI ) Immunotherapy Interest Group , this Position Paper evaluates the currently used outcome parameters in different RCTs and also aims to provide recommendations for the optimal endpoints in future AIT trials for allergic rhinoconjunctivitis . RESULTS Based on a thorough literature review , the TF members have outlined recommendations for nine domains of clinical outcome measures . As the primary outcome , the TF recommends a homogeneous combined symptom and medication score ( CSMS ) as a simple and st and ardized method that balances both symptoms and the need for antiallergic medication in an equally weighted manner . All outcomes , grouped into nine domains , are review ed . CONCLUSION A st and ardized and globally harmonized method for analysing the clinical efficacy of AIT products in RCTs is required . The EAACI TF highlights the CSMS as the primary endpoint for future RCTs in AIT for allergic rhinoconjunctivitis Background The European Academy of Allergy and Clinical Immunology is developing guidelines about how to prevent and manage food allergy . As part of the guidelines development process , a systematic review is planned to examine published research about the prevention of food allergy . This systematic review is one of seven inter-linked evidence syntheses that are being undertaken in order to provide a state-of-the-art synopsis of the current evidence base in relation to epidemiology , prevention , diagnosis and clinical management , and impact on quality of life , which will be used to inform clinical recommendations . The aim of this systematic review will be to assess the effectiveness of approaches for the primary prevention of food allergy . Methods Seven bibliographic data bases will be search ed from their inception to September 30 , 2012 for systematic review s , r and omized controlled trials , quasi-r and omized controlled trials , controlled clinical trials , controlled before- and -after studies , interrupted time series and cohort studies . Cohort studies will be included due to an inability to r and omize with interventions such as breastfeeding . Studies that focused on the development of either food sensitization ( a proxy measure ) or food allergy will also be eligible for inclusion . Studies will be critically appraised using the Critical Appraisal Skills Program and Cochrane Risk of Bias tools , as appropriate . Discussion There is a lack of rigorous evidence to support recommendations about how to prevent the development of food allergy . It would appear that it is important to see the prevention of food allergy in the context of individual , family and wider factors that may influence its development . There is much left to learn about preventing food allergy , and this is a priority given the high societal and healthcare costs involved . This systematic review will help to further this learning The diagnosis of primary ciliary dyskinesia is often confirmed with st and ard , albeit complex and expensive , tests . In many cases , however , the diagnosis remains difficult despite the array of sophisticated diagnostic tests . There is no “ gold st and ard ” reference test . Hence , a Task Force supported by the European Respiratory Society has developed this guideline to provide evidence -based recommendations on diagnostic testing , especially in light of new developments in such tests , and the need for robust diagnoses of patients who might enter r and omised controlled trials of treatments . The guideline is based on pre-defined questions relevant for clinical care , a systematic review of the literature , and assessment of the evidence using the GRADE ( Grading of Recommendations , Assessment , Development and Evaluation ) approach . It focuses on clinical presentation , nasal nitric oxide , analysis of ciliary beat frequency and pattern by high-speed video-microscopy analysis , transmission electron microscopy , genotyping and immunofluorescence .  It then used a modified Delphi survey to develop an algorithm for the use of diagnostic tests to definitively confirm and exclude the diagnosis of primary ciliary dyskinesia ; and to provide advice when the diagnosis was not conclusive . Finally , this guideline proposes a set of quality criteria for future research on the validity of diagnostic methods for primary ciliary dyskinesia . International ERS guidelines recommend a combination of tests to diagnose  primary ciliary dyskinesia Purpose This article is aim ed at describing the methodology of “ ethical reasoning ” that finally led TEDDYNoE ( Task-force in Europe for Drug Development for the Young ) to propose the integration of international human rights law to develop coherent and exhaustive ethical recommendations on paediatric research at a European level . Methods A large number of ethical guidelines and texts of varying legal force existing in the field of clinical research and in particular related to paediatrics are analysed . Differences and non-coordinated implementation are pointed out . Results Differences , tensions or outright contradictions among the provisions of these texts can generate confusion leading to the adoption of different ethical st and ards across Europe . In this context , the real challenge is to ensure that each child involved in a clinical trial in the EU territory may rely directly on the same principles and rights . Taking international human rights law as the main starting point to develop a coherent framework for paediatric research that incorporates all the relevant ethical considerations and existing guidelines is a way of achieving this objective . Conclusions The implementation , at national and local level , of the “ European Ethical Recommendations ” ( Eudralex 2008 vol . 10 ) , based on international human rights law , seems to be the next step in facilitating a coordinated approach to the application of the Directive 2001/20/EC , as well as developing quality and ethically sound paediatric research During the National Neurotrauma Symposium 2010 , the DG Research of the European Commission and the National Institutes of Health/National Institute of Neurological Disorders and Stroke ( NIH/NINDS ) organized a workshop on  comparative effectiveness research  ( CER ) in traumatic brain injury ( TBI ) . This workshop review ed existing approaches to improve outcomes of TBI patients . It had two main outcomes : First , it initiated a process of re-orientation of clinical research in TBI . Second , it provided ideas for a potential collaboration between the European Commission and the NIH/NINDS to stimulate research in TBI . Advances in provision of care for TBI patients have result ed from observational studies , guideline development , and meta-analyses of individual patient data . In contrast , r and omized controlled trials have not led to any identifiable major advances . Rigorous protocol s and tightly selected population s constrain generalizability . The workshop addressed additional research approaches , summarized the greatest unmet needs , and highlighted priorities for future research . The collection of high- quality clinical data bases , associated with systems biology and CER , offers substantial opportunities . Systems biology aims to identify multiple factors contributing to a disease and addresses complex interactions . Effectiveness research aims to measure benefits and risks of systems of care and interventions in ordinary setting s and broader population s. These approaches have great potential for TBI research . Although not new , they still need to be introduced to and accepted by TBI research ers as instruments for clinical research . As with therapeutic targets in individual patient management , so it is with research tools : one size does not fit all INTRODUCTION The purpose of this guideline is to establish clinical practice recommendations for the pharmacologic treatment of chronic insomnia in adults , when such treatment is clinical ly indicated . Unlike previous meta-analyses , which focused on broad classes of drugs , this guideline focuses on individual drugs commonly used to treat insomnia . It includes drugs that are FDA -approved for the treatment of insomnia , as well as several drugs commonly used to treat insomnia without an FDA indication for this condition . This guideline should be used in conjunction with other AASM guidelines on the evaluation and treatment of chronic insomnia in adults . METHODS The American Academy of Sleep Medicine commissioned a task force of four experts in sleep medicine . A systematic review was conducted to identify r and omized controlled trials , and the Grading of Recommendations Assessment , Development , and Evaluation ( GRADE ) process was used to assess the evidence . The task force developed recommendations and assigned strengths based on the quality of evidence , the balance of benefits and harms , and patient values and preferences . Literature review s are provided for those pharmacologic agents for which sufficient evidence was available to establish recommendations . The AASM Board of Directors approved the final recommendations . RECOMMENDATIONS The following recommendations are intended as a guideline for clinicians in choosing a specific pharmacological agent for treatment of chronic insomnia in adults , when such treatment is indicated . Under GRADE , a STRONG recommendation is one that clinicians should , under most circumstances , follow . A WEAK recommendation reflects a lower degree of certainty in the outcome and appropriateness of the patient-care strategy for all patients , but should not be construed as an indication of ineffectiveness . GRADE recommendation strengths do not refer to the magnitude of treatment effects in a particular patient , but rather , to the strength of evidence in published data . Downgrading the quality of evidence for these treatments is predictable in GRADE , due to the funding source for most pharmacological clinical trials and the attendant risk of publication bias ; the relatively small number of eligible trials for each individual agent ; and the observed heterogeneity in the data . The ultimate judgment regarding propriety of any specific care must be made by the clinician in light of the individual circumstances presented by the patient , available diagnostic tools , accessible treatment options , and re sources . We suggest that clinicians use suvorexant as a treatment for sleep maintenance insomnia ( versus no treatment ) in adults . ( WEAK ) . We suggest that clinicians use eszopiclone as a treatment for sleep onset and sleep maintenance insomnia ( versus no treatment ) in adults . ( WEAK ) . We suggest that clinicians use zaleplon as a treatment for sleep onset insomnia ( versus no treatment ) in adults . ( WEAK ) . We suggest that clinicians use zolpidem as a treatment for sleep onset and sleep maintenance insomnia ( versus no treatment ) in adults . ( WEAK ) . We suggest that clinicians use triazolam as a treatment for sleep onset insomnia ( versus no treatment ) in adults . ( WEAK ) . We suggest that clinicians use temazepam as a treatment for sleep onset and sleep maintenance insomnia ( versus no treatment ) in adults . ( WEAK ) . We suggest that clinicians use ramelteon as a treatment for sleep onset insomnia ( versus no treatment ) in adults . ( WEAK ) . We suggest that clinicians use doxepin as a treatment for sleep maintenance insomnia ( versus no treatment ) in adults . ( WEAK ) . We suggest that clinicians not use trazodone as a treatment for sleep onset or sleep maintenance insomnia ( versus no treatment ) in adults . ( WEAK ) . We suggest that clinicians not use tiagabine as a treatment for sleep onset or sleep maintenance insomnia ( versus no treatment ) in adults . ( WEAK ) . We suggest that clinicians not use  diphenhydramine  as a treatment for sleep onset and sleep maintenance insomnia ( versus no treatment ) in adults . ( WEAK ) . We suggest that clinicians not use  melatonin  as a treatment for sleep onset or sleep maintenance insomnia ( versus no treatment ) in adults . ( WEAK ) . We suggest that clinicians not use tryptophan as a treatment for sleep onset or sleep maintenance insomnia ( versus no treatment ) in adults . ( WEAK ) . We suggest that clinicians not use  valerian  as a treatment for sleep onset or sleep maintenance insomnia ( versus no treatment ) in adults . ( WEAK ) In December 2003 , the European Council identified best practice as key for ensuring development of high- quality cancer-screening programs . To support national policies on cancer control , the European Union institutions progressed several initiatives on cancer . The European Commission ( EC ) Initiative on Breast Cancer ( ECIBC ) is the most recent of these projects and the most implementation driven . Within this initiative , the European Guidelines for Breast Cancer Screening and Diagnosis ( in short , European Breast Guidelines ) are being developed ( http://ecibc.jrc.ec.europa.eu/ ) . Guidelines are approaches to generally improve prevention , diagnosis , treatment , and follow-up of diseases , overcoming inappropriate variations by providing recommendations for best care . The new era of guidelines promises recommendations that are based on the best available evidence summarized in systematic review s while providing the necessary flexibility needed to individualize decisions . The best methods for development of practice guidelines have experienced intense elaboration and attention during the past decades ( 17 ) . The impetus for this attention has been the change from expert- or consensus-based to evidence -based health care recommendations . Although this change in terminology should express the shift from un systematic development of guidelines to systematic and trustworthy recommendations , it is often misunderstood and misconstrued as meaning that experts are now meaningless in the process or as if consensus through discussion is a matter of the past . Neither is correct . Experts from various disciplines and consensus as a result of deliberation remain a mainstay of health care guideline development ( 810 ) . These experts are responsible for prioritization of questions that should be addressed in guidelines ; judgments that result from interpretation of evidence , including the rating of the certainty of the available evidence ; and decisions about how the judgments on the different criteria bear on recommendations . What has changed over time in guideline development are the rules , the structure and explicitness of the process , and the guideline product . Indeed , review s of guideline development methodology and how guidelines can be improved have led to more structured and documented processes that allow a reduction of bias and provide balanced views of appropriately composed guideline panels ( 2 , 5 , 6 ) . Core components for trustworthy guideline development ( 13 , 5 , 7 , 11 ) include that guidelines be developed by a knowledgeable , multidisciplinary panel of experts and representatives from key affected groups ; be based on a systematic review of the existing evidence ; consider important patient subgroups and patient preferences as appropriate ; be based on an explicit and transparent process that minimizes distortions , biases , and conflicts of interest ( 12 ) ; provide a clear explanation of the logical relationships between alternative care options and health outcomes and provide ratings of both the quality of evidence and the strength of the recommendations ( 1316 ) ; and be reconsidered and revised as appropriate when important new evidence warrants modifications . In addition , greater transparency in linking the considered research evidence and the recommendations , as well as the requirement of making structured expert judgments , represents a shift in the guideline development paradigm ( 5 , 11 , 1719 ) . At the same time , developing guidelines for a large number of member states and those that aim to adapt the guidelines poses challenges , such as the feasibility of implementing strategies that may exist in some member countries but not others ( for example , organized population -based screening in Italy but not Greece ) . Addressing these challenges requires considerations that extend beyond strictly clinical efforts in guideline development and mastering the many factors that influence recommendations and their implementation . This article describes the rationale , methods , and processes the ECIBC has adopted to develop the European Breast Guidelines in the context of evolving international st and ards . It also describes an innovative approach to presenting , disseminating , and accelerating implementation of recommendations . Guideline Methodology and Development To adhere to the core requirements for guideline development , the EC has taken several steps . First , it selected , via an open call ( https://ecibc.jrc.ec.europa.eu/ guidelines -team ) , a panel with broad representation of expertise , knowledge , and background , which includes patients , health care professionals , epidemiologists , guideline method ologists , and others ( Appendix ) . These individuals voluntarily participate in the ECIBC and compose the guidelines development group ( GDG ) . Second , it ensured that all recommendations were supported by systematic review s of the evidence conducted by independent scientists from Cochrane Iberoamricathe systematic review team (SRT)following st and ard Cochrane Collaboration methods ( 20 , 21 ) . Third , because this is a women-centered initiative , we included women advocates in the GDG as full voting guideline group members . We separately considered important subgroups of women during recommendation development ( for example , different age groups ) , and we specifically focused on evidence that supports best ways of communicating this information to women to inform their decisions . Fourth , we applied EC conflict of interest rules ( http://ecibc.jrc.ec.europa.eu/rules ) , which are consistent with international recommendations , and used GRADE ( Grading of Recommendations Assessment , Development and Evaluation ) Evidence to Decision ( EtD ) frameworks to minimize the influence of competing interests on the recommendations ( 12 , 17 , 18 ) . These EtD frameworks help guideline panels use evidence in a structured , transparent way to inform decisions with a series of criteria , such as anticipated harms and benefits of the options considered , the certainty of the evidence for those effects , and the costs and feasibility of the options , to help them reach their decision . Fifth , using the GRADE approach to guideline development and its EtD frameworks , we focused our questions and recommendations on outcomes that matter to women and provided a rating of the certainty or quality of evidence and the strength of recommendations that is widely accepted as the reference st and ard ( Figures 1 and 2 ) . Sixth , our evidence review s are up to date when the recommendations are formulated , and we engage in international stakeholder feedback to ensure that recommendations remain timely and relevant to public health and clinical practice . The ECIBC is committed to review ing and updating the recommendations as required when new evidence becomes available . The general process is explained in Figure 3 and is based on the Guidelines International NetworkMcMaster Guideline Development Checklist ( https://hei grade .mcmaster.ca/ guideline -development/using-checklist ) ( 5 ) . Figure 1 . According to GRADE , certainty , quality , strength of evidence , or confidence in the estimate of effect is determined on the basis of a systematic review of the evidence for each outcome ( based on the domains risk of bias , indirectness , imprecision , inconsistency , and publication bias that lower certainty and , usually only for nonr and omized studies , large effects , doseresponse relations and opposing plausible residual confounding that may increase the certainty ) . For recommendations , the overall certainty is determined across outcomes based on the lowest certainty outcome among those critical for decision making for the specific context . The guidelines development group applies the GRADE Evidence -to-Decision frameworks to make recommendations that are made available on the European Commission Web site . ( Reproduced from reference 15 , with permission from Schnemann HJ . ) . GRADE = Grading of Recommendations Assessment , Development and Evaluation . Figure 2 . GRADE EtD frameworks . The GRADE EtD frameworks as available in the GRADE pro software ( www . grade pro.org ) . They help with structuring the entire guideline process into 4 sections and support the conduct of guideline group meetings , presentation , and implementation . They clarify the perspective that is taken by the guideline panel or decision maker and the type of question that is asked in the question section . The section on assessment includes the criteria if the problem is a priority , the balance of health benefits and harms , values and preferences related to the outcomes , cost , re sources and cost-effectiveness , equity , acceptability , and feasibility . Conclusions provide the decision or recommendation with a justification and implementation , as well as research considerations . The presentation function supports the conduct of guideline group meetings and facilitates the output of EtD frameworks to other implementation tools , such as Web sites , h and -held apps , and interactive decision aids . EtD = Evidence to Decision ; GRADE = Grading of Recommendations Assessment , Development and Evaluation ; HTA = health technology assessment ; PICO = population , intervention , comparators , and outcomes . Figure 3 . Approach to guideline development used by the European Commission Initiative on Breast Cancer . The European Commission JRC has oversight of the organization , budgeting , planning , and training . The JRC also manages conflicts of interest , documents all aspects of the work , and manages the membership and group processes . The guideline development group and JRC formulate the questions and work with the systematic review team on identifying and assessing the evidence . The guidelines development group is responsible for developing the recommendations . The JRC is responsible for most other aspects as described in the figure under dissemination , implementation , and updating . JRC = Joint Research Centre ; PICO = population , intervention , comparator , and outcomes . ( Reproduced with adaptation to the JRC process from Previous studies of acupuncture in asthma have reported conflicting results , some cl aim ing benefit for some patients . We conducted a r and omized , double-blind ( patient and evaluator ) study in 23 non-smoking asthmatics ( 10 M ; 13 F ) aged 43 + /- 15 years with forced expiratory volume in 1 s ( FEV1 ) 59 + /- 16 % pred . After initial assessment ( respiratory function tests and Asthma Quality Life Question naire ) patients were r and omized to receive either ' real ' or ' sham ' acupuncture . The measurements were repeated within 1 h and after 2 weeks . Patients were recording peak expiratory flow rate ( PEFR ) throughout the period of the study . After 2 weeks patients who received ' real ' treatment on the first visit received ' sham ' treatment and vice versa . The measurements were again repeated within 1 h and after 2 weeks . There was no improvement in any aspects of respiratory function measured after either form of acupuncture . Despite this there was a significant improvement in AQLQ and parallel reduction in the usage of bronchodilators . We concluded that in some patients acupuncture could be useful in improving quality of life and reducing the need for using bronchodilators either by having a placebo effect or that the exact site of needle puncture on the chest is unimportant BACKGROUND Osteoarthritis ( OA ) is the most common joint disease encountered throughout Europe . A task force for the EULAR St and ing Committee for Clinical Trials met in 1998 to determine the method ological and logistical approach required for the development of evidence based guidelines for treatment of knee OA . The guidelines were restricted to cover all currently available treatments for knee OA diagnosed either clinical ly and /or radiographically affecting any compartment of the knee . METHODS The first stage was the selection of treatment modalities to be considered . The second stage comprised a search of the electronic data bases Medline and Embase using a combination of subject headings and keywords . All European language publications in the form of systematic review s , meta-analyses , r and omised controlled trials , controlled trials , and observational studies were included . During stage three all the relevant studies were quality scored . The summary statistics for vali date d outcome measures , when available , were recorded and , where practical , the numbers needed to treat and the effect size for each treatment were calculated . In the fourth stage key clinical propositions were determined by expert consensus employing a Delphi approach . The final stage ranked these propositions according to the available evidence . A second set of propositions relating to a future research agenda was determined by expert consensus using a Delphi approach . RESULTS Over 2400 English language publications and 400 non-English language publications were identified . Seven hundred and forty four studies presented outcome data of the effects of specific treatments on knee OA . Quantitative analysis of treatment effect was possible in only 61 studies . Recommendations for the management of knee OA based on currently available data and expert opinion are presented . Proposals for a future research agenda are highlighted . CONCLUSIONS These are the first clinical guidelines on knee OA to combine an evidence based approach and a consensus approach across a wide range of treatment modalities . It is apparent that certain clinical propositions are supported by substantial research based evidence , while others are not . There is thus an urgent need for future well design ed trials to consider key clinical questions BACKGROUND For children younger than 12 years old with asthma , there are several quality -of-life instruments , clinical diaries , and question naires assessing symptoms ; however , a vali date d tool for assessing asthma control is currently lacking . OBJECTIVE To develop and vali date the  Childhood Asthma Control Test  ( C-ACT ) , a self-administered tool for identifying children aged 4 - 11 years whose asthma is inadequately controlled . METHODS A 21-item question naire was administered to 343 patients with asthma and their caregivers , r and omly assigning 75 % ( n = 257 ) for development and cross-sectional validation of the tool and 25 % ( n = 86 ) to a confirmatory sample . Stepwise logistic regression was used to reduce the 21 items to those best able to discriminate control as defined by the specialist 's rating of asthma control . RESULTS Seven items were selected from regression analyses of the development sample to comprise the C-ACT . The scores of each item were summed for a total score ( 0 - 27 ) , with lower scores indicating poorer control . Summed scores discriminated between groups of patients differing in the specialists ' rating of asthma control ( F = 36.89 ; P < .0001 ) , the need for change in patients ' therapy ( F = 20.07 ; P < .0001 ) , and % predicted FEV(1 ) ( F = 2.66 ; P = .0494 ) . A score of 19 indicated inadequately controlled asthma ( specificity 74 % , sensitivity 68 % ) . These analyses were confirmed in the confirmatory sample . CONCLUSION The C-ACT is a vali date d tool to assess asthma control and identify children with inadequately controlled asthma . CLINICAL IMPLICATION S The C-ACT can be valuable in clinical practice and research based on its validation , ease of use , input from the child and caregiver , and alignment with asthma guidelines OBJECTIVES Health decision-makers involved with coverage and payment policies are increasingly developing policies that seek information on " real-world " ( RW ) outcomes . Motivated by these initiatives , the International Society for Pharmacoeconomics and Outcomes Research ( ISPOR ) created a Task Force on Real-World Data to develop a framework to assist health-care decision-makers in dealing with RW data , especially related to coverage and payment decisions . METHODS Task Force cochairs were selected by the ISPOR Board of Directors . Cochairs selected chairs for four working groups on : clinical outcomes , economic outcomes , patient-reported outcomes , and evidence hierarchies . Task Force members included representatives from academia , the pharmaceutical industry , and health insurers . The Task Force met on several occasions , conducted frequent correspondence and exchanges of drafts , and solicited comments on three drafts from a core group of external review ers and from the ISPOR membership . RESULTS We defined RW data as data used for decision-making that are not collected in conventional r and omized controlled trials ( RCTs ) . We considered several characterizations : by type of outcome ( clinical , economic , and patient-reported ) , by hierarchies of evidence ( which rank evidence according to the strength of research design ) , and by type of data source ( supplementary data collection alongside RCTs , large simple trials , patient registries , administrative cl aims data base , surveys , and medical records ) . Our report discusses eight key issues : 1 ) the importance of RW data ; 2 ) limitations of RW data ; 3 ) the fact that the level of evidence required depends on the circumstance ; 4 ) the need for good research practice s for collecting and reporting RW data ; 5 ) the need for good process in using RW data in coverage and reimbursement decisions ; 6 ) the need to consider costs and benefits of data collection ; 7 ) the ongoing need for modeling ; and 8) the need for continued stakeholder dialogue on these topics . CONCLUSIONS Real-world data are essential for sound coverage and reimbursement decisions . The types and applications of such data are varied , and context matters greatly in determining the value of a particular type in any circumstance . It is critical that policymakers recognize the benefits , limitations , and method ological challenges in using RW data , and the need to consider carefully the costs and benefits of different forms of data collection in different situations Background One fourth of the adult population in Europe suffer from respiratory allergy . Subcutaneous-allergen-specific-immunotherapy ( SCIT ) has long-term disease modifying effect on disease specific Health-Related Quality of Life ( HRQoL ) . The purpose of this study was to assess the effect of SCIT on alternative disease outcomes in patients with grass-pollen and /or house dust mite induced allergic rhino-conjunctivitis and /or an asthma diagnosis . Focus was on expressing outcomes in terms of generic quality of life ( Quality -Adjusted-Life-Years ( QALY ) ) and reductions in sick days . Methods The study was a multi-centre study with prospect i ve follow-up . 248 patients were initiated on SCIT .  The disease specific Rhino-conjunctivitis Quality of Life Question naire ( RQLQ ) and two generic ( HRQoL ) instruments 15D and EQ-5D were used at baseline and at follow-up . The outcome measures included change in ; disease severity , RQLQ-scores , number of days with symptoms- and number of sick days per year and finally changes in generic HRQoL and thus , QALY . Disease severity was assessed by specialist doctors ; severity of rhino-conjunctivitis was classified according to the Allergic Rhinitis and its Impact on Asthma ( ARIA ) and asthma severity according to the Global Initiative for Asthma ( GINA guideline ) . The remaining outcome measures were assessed by the patients in question naires at baseline and at follow-up . An intension to treat approach was applied . For missing items imputation of sample mean base-line values or follow-up values were used after specified criteria . The effect of SCIT on rhino-conjunctivitis and /or asthma diagnoses was analysed at follow-up using three logistic regression models . Results The disease severity showed significantly improved disease control . Mean RQLQ-score was reduced from 3.02 at baseline to 2.00 at follow-up . Average annual days with symptoms were reduced from 189 to 145 days whilst annual sick days were reduced from 3.7 to 1.2 days . The 15D-score increased from 0.83 to 0.86 and the EQ-5D-score from 0.70 to 0.77 , which indicated an annual gain per patient of 0.03 - 0.06 QALY . Conclusions Allergic patients suffering from rhino-conjunctivitis alone or rhino-conjunctivitis and asthma experience significantly increased HRQoL and they gain 0.03 - 0.06 QALY , when treated with SCIT for one year . Trial registration The study was registered at Clinical Trials.gov with the identifier : NCT01486498 Background Prevalence of  allergic diseases in infants , whose parents and siblings do not have allergy , is approximately 10 % and reaches 20–30 % in those with an allergic first-degree relative . Intestinal microbiota may modulate immunologic and inflammatory systemic responses and , thus , influence development of sensitization and allergy . Probiotics have been reported to modulate immune responses and their supplementation has been proposed as a preventive intervention . Objective The World Allergy Organization ( WAO ) convened a guideline panel to develop evidence -based recommendations about the use of probiotics in the prevention of allergy . Methods We identified the most relevant clinical questions and performed a systematic review of r and omized controlled trials of probiotics for the prevention of allergy . We followed the Grading of Recommendations Assessment , Development and Evaluation ( GRADE ) approach to develop recommendations . We search ed for and review ed the evidence about health effects , patient values and preferences , and re source use ( up to November 2014 ) . We followed the GRADE evidence -to-decision framework to develop recommendations . Results Currently available evidence does not indicate that probiotic supplementation  reduces the risk of developing allergy in children . However , considering all critical outcomes in this context , the WAO guideline panel determined that there is a likely net benefit from using probiotics result ing primarily from prevention of eczema . The WAO guideline panel suggests : a ) using probiotics in pregnant women at high risk for having an allergic child ; b ) using probiotics in women who breastfeed infants at high risk of developing allergy ; and c ) using probiotics in infants at high risk of developing allergy . All recommendations are conditional and supported by very low quality evidence . Conclusions WAO recommendations about probiotic supplementation for prevention of allergy are intended to support parents , clinicians and other health care professionals in their decisions whether to use probiotics in pregnancy and during breastfeeding , and whether to give them to infants CONTEXT The findings of systematic review s ( SRs ) and meta-analyses ( MAs ) are used for clinical decision making . The European Association of Urology has committed increasing re sources into the development of high quality clinical guidelines based on such SRs and MAs . OBJECTIVE In this paper , we have summarised the process of conducting SRs for underpinning clinical practice guidelines under the auspices of the European Association of Urology Guidelines Office . EVIDENCE ACQUISITION The process involves explicit methods and the findings should be reproducible . When conducting a SR , the essential first step is to formulate a clear and answerable research question . An extensive literature search lays the foundation for evidence synthesis . Data are extracted independently by two review ers and any disagreements are resolved by discussion or arbitration by a third review er . EVIDENCE SYNTHESIS In SRs , data for particular outcomes in individual r and omised controlled trials may be combined statistically in a meta- analysis to increase power when the studies are similar enough . Biases in studies included in a SR/MA can lead to either an over estimation or an under estimation of true intervention effect size , result ing in heterogeneity in outcome between studies . A number of different tools are available such as Cochrane Risk of Bias assessment tool for r and omised controlled trials . In circumstances where there is too much heterogeneity , or when a review has included nonr and omised comparative studies , it is more appropriate to conduct a narrative synthesis . The GRADE tool for assessing quality of evidence strives to be a structured and transparent system , which can be applied to all evidence , regardless of quality . A SR not only identifies , evaluates , and summarises the best available evidence , but also the gaps to be targeted by future studies . CONCLUSIONS SRs and MAs are integral in developing sound clinical practice guidelines and recommendations . PATIENT SUMMARY Clinical practice guidelines should be evidence based , and systematic review s and meta-analyses are essential in their production . We have discussed the key steps of conducting systematic review s and meta-analyses in this paper Background Severe trauma continues to represent a global public health issue and mortality and morbidity in trauma patients remains substantial . A number of initiatives have aim ed to provide guidance on the management of trauma patients . This document focuses on the management of major bleeding and coagulopathy following trauma and encourages adaptation of the guiding principles to each local situation and implementation within each institution . Methods The pan-European , multidisciplinary Task Force for Advanced Bleeding Care in Trauma was founded in 2004 and included representatives of six relevant European professional societies . The group used a structured , evidence -based consensus approach to address scientific queries that served as the basis for each recommendation and supporting rationale . Expert opinion and current clinical practice were also considered , particularly in areas in which r and omised clinical trials have not or can not be performed . Existing recommendations were reconsidered and revised based on new scientific evidence and observed shifts in clinical practice ; new recommendations were formulated to reflect current clinical concerns and areas in which new research data have been generated . This guideline represents the fourth edition of a document first published in 2007 and up date d in 2010 and 2013 . Results The guideline now recommends that patients be transferred directly to an appropriate trauma treatment centre and encourages use of a restricted volume replacement strategy during initial resuscitation . Best- practice use of blood products during further resuscitation continues to evolve and should be guided by a goal -directed strategy . The identification and management of patients pre-treated with anticoagulant agents  continues to pose a real challenge , despite accumulating experience and awareness . The present guideline should be viewed as an educational aid to improve and st and ardise the care of the bleeding trauma patients across Europe and beyond . This document may also serve as a basis for local implementation . Furthermore , local quality and safety management systems need to be established to specifically assess key measures of bleeding control and outcome . Conclusions A multidisciplinary approach and adherence to evidence -based guidance are key to improving patient outcomes . The implementation of locally adapted treatment algorithms should strive to achieve measureable improvements in patient outcome Allergen-specific immunotherapy ( ASIT ) with fungal extracts has been beset by safety and efficacy problems , which result mainly from qualitative and quantitative variations . Little has been published on the safety and efficacy of these extracts . The objective was to analyze the safety and efficacy of ASIT with an Alternaria alternata extract . A total of 28 patients were selected with rhinitis and /or bronchial asthma because of Alternaria allergy and monosensitization to molds . The patients were r and omized to an active ASIT or placebo group , both groups on a conventional immunotherapy schedule ( increasing weekly doses until maintenance dose and then monthly doses ) . Adverse reactions were classified with the European Academy of Allergology and Clinical Immunology system . Clinical efficacy was analyzed for a year with symptom/medication diary cards , peak expiratory flow ( PEF ) measures , clinical severity score , severity of symptoms ( visual analog scale ) , subjective evaluation of treatment by the patient and the physician , and a quality of life question naire . Twenty-three patients completed the study ; all reached the established maintenance dose with only two mild adverse reactions in the whole sample . Significant improvements were found after 6 months in respiratory symptoms in the active treatment group , and in all symptoms in both groups . PEF increased significantly in the active treatment group but not in the placebo group . The severity of asthma decreased in the active treatment group , and the severity of rhinitis decreased in both groups . Visual analog scale scores for severity of symptoms improved in all phases in the active treatment group , but only after 12 months in the placebo group . Physicians judged the disease course as significantly better in the active treatment group . ASIT with the A. alternata extract was safe , with clinical improvements after one year of treatment Bronchiectasis in adults is a chronic disorder associated with poor quality of life and frequent exacerbations in many patients . There have been no previous international guidelines . The European Respiratory Society guidelines for the management of adult bronchiectasis describe the appropriate investigation and treatment strategies determined by a systematic review of the literature . A multidisciplinary group representing respiratory medicine , microbiology , physiotherapy , thoracic surgery , primary care , methodology and patients considered the most relevant clinical questions ( for both clinicians and patients ) related to management of bronchiectasis . Nine key clinical questions were generated and a systematic review was conducted to identify published systematic review s , r and omised clinical trials and observational studies that answered these questions . We used the GRADE approach to define the quality of the evidence and the level of recommendations . The result ing guideline addresses the investigation of underlying causes of bronchiectasis , treatment of exacerbations , pathogen eradication , long term antibiotic treatment , anti-inflammatories , mucoactive drugs , bronchodilators , surgical treatment and respiratory physiotherapy . These recommendations can be used to benchmark quality of care for people with bronchiectasis across Europe and to improve outcomes . The publication of the first ERS guidelines for bronchiectasis BACKGROUND Collaborative self-management is a core recommendation of national asthma guidelines ; the written action plan is the knowledge tool that supports this objective . Mobile health technologies have the potential to enhance the effectiveness of the action plan as a knowledge translation tool . OBJECTIVE To design , develop and pilot a mobile health system to support asthma self-management . METHODS The present study was a prospect i ve , single-centre , nonr and omized , pilot preintervention-postintervention analysis . System design and development were guided by an expert steering committee . The network included an agnostic web browser-based asthma action plan smartphone application ( SPA ) . Subjects securely transmitted symptoms and peak flow data daily , and received automated control assessment , treatment advice and environmental alerts . RESULTS Twenty-two adult subjects ( mean age 47 years , 82 % women ) completed the study . Biophysical data were received on 84 % of subject days ( subject day = 1 subject × 1 day ) . Subjects viewed their action plan current zone of control on 54 % and current air quality on 61 % of subject days , 86 % followed self-management advice and 50 % acted to reduce exposure risks . A large majority affirmed ease of use , clarity and timeliness , and 95 % desired SPA use after the study . At baseline , 91 % had at least one symptom criterion for uncontrolled asthma and 64 % had ≥2 , compared with 45 % ( P=0.006 ) and 27 % ( P=0.022 ) at study close . Mean Asthma Quality of Life Question naire score improved from 4.3 to 4.8 ( P=0.047 ) . CONCLUSIONS A dynamic , real-time , interactive , mobile health system with an integrated asthma action plan SPA can support knowledge translation at the patient and provider levels Real-world research can use observational or clinical trial design s , in both cases putting emphasis on high external validity , to complement the classical efficacy r and omized controlled trials ( RCTs ) with high internal validity . Real-world research is made necessary by the variety of factors that can play an important a role in modulating effectiveness in real life but are often tightly controlled in RCTs , such as comorbidities and concomitant treatments , adherence , inhalation technique , access to care , strength of doctor-caregiver communication , and socio-economic and other organizational factors . Real-world studies belong to two main categories : pragmatic trials and observational studies , which can be prospect i ve or retrospective . Focusing on comparative data base observational studies , the process aim ed at ensuring high- quality research can be divided into three parts : preparation of research , analyses and reporting , and discussion of results . Key points include a priori planning of data collection and analyses , identification of appropriate data base(s ) , proper outcomes definition , study registration with commitment to publish , bias minimization through matching and adjustment processes accounting for potential confounders , and sensitivity analyses testing the robustness of results . When these conditions are met , observational data base studies can reach a sufficient level of evidence to help create guidelines ( i.e. , clinical and regulatory decision-making ) OBJECTIVES : To address questions regarding breastfeeding , complementary feeding , allergy development , and current infant-feeding recommendations . METHODS : This was a nested , case-control within a cohort study in which mothers of 41 infants diagnosed with food allergy by the age of 2 years ( according to double-blind , placebo-controlled food challenge ) and their 82 age-matched controls kept prospect i ve food diaries of how their infants were fed in the first year of life . RESULTS : Infants who were diagnosed with food allergy by the time they were 2 years of age were introduced to solids earlier ( ≤16 weeks of age ) and were less likely to be receiving breast milk when cow ’s milk protein was first introduced into their diet . CONCLUSIONS : This study supports the current American Academy of Pediatrics ’ allergy prevention recommendations and the European Society of Pediatric Gastroenterology , Hepatology and Nutrition recommendations on complementary feeding to not introduce solids before 4 to 6 months of age . It also supports the American Academy of Pediatrics ’ breastfeeding recommendations that breastfeeding should continue while solids are introduced into the diet and that breastfeeding should continue for 1 year , or longer , as mutually desired by mother and infant BACKGROUND In 2010 , the Canadian Thoracic Society ( CTS ) published a Consensus Summary for the diagnosis and management of asthma in children six years of age and older , and adults , including an up date d Asthma Management Continuum . The CTS Asthma Clinical Assembly subsequently began a formal clinical practice guideline up date process , focusing , in this first iteration , on topics of controversy and ⁄or gaps in the previous guidelines . METHODS Four clinical questions were identified as a focus for the up date d guideline : the role of noninvasive measurements of airway inflammation for the adjustment of anti-inflammatory therapy ; the initiation of adjunct therapy to inhaled corticosteroids ( ICS ) for uncontrolled asthma ; the role of a single inhaler of an ICS⁄long-acting beta(2)-agonist combination as a reliever , and as a reliever and a controller ; and the escalation of controller medication for acute loss of asthma control as part of a self-management action plan . The expert panel followed an adaptation process to identify and appraise existing guidelines on the specified topics . In addition , literature search es were performed to identify relevant systematic review s and r and omized controlled trials . The panel formally assessed and grade d the evidence , and made 34 recommendations . RESULTS The up date d guideline recommendations outline a role for inclusion of assessment of sputum eosinophils , in addition to st and ard measures of asthma control , to guide adjustment of controller therapy in adults with moderate to severe asthma . Appraisal of the evidence regarding which adjunct controller therapy to add to ICS and at what ICS dose to begin adjunct therapy in children and adults with poor asthma control supported the 2010 CTS Consensus Summary recommendations . New recommendations for the adjustment of controller medication within written action plans are provided . Finally , priority areas for future research were identified . CONCLUSIONS The present clinical practice guideline is the first up date of the CTS Asthma Guidelines following the Canadian Respiratory Guidelines Committee 's new guideline development process . Tools and strategies to support guideline implementation will be developed and the CTS will continue to regularly provide up date s reflecting new evidence Background Asthma affects mainly Venezuela ’s urban and poor majority . Exacerbations bring about a high dem and in health services , thus becoming a significant public health problem . In general , asthma control programs ( GINA ) with use of inhaled steroid medications have proven effective , although their implementation in real life remains cumbersome . Montelukast could be a useful and practical tool for these deprived socioeconomic sectors . Methods This real-life pilot study was conducted in a prospect i ve , double blinded , placebo-controlled manner with r and omized and parallel groups . Asthmatics that had never used leukotriene modifiers were recruited and followed-up every three months . The main outcome was the number of exacerbations meriting use of nebulized bronchodilators  administered by the health care system . Results Eighty-eight asthmatic patients were enrolled , between children and adults . Groups were comparable in : demographic data , previous use of other medications , ACT scores , pulmonary functions ( Wright Peak Flow meter ) , allergy status ( Skin Prick Test ) as well as adherence to the prescribed Montelukast treatment . By an intention to treat ( ITT ) , a total of 64 patients were included for analysis . For the three and six months time points the difference between placebo and Montelukast was found to be significant ( p < 0.03 and p < 0.04 , respectively ) . Such trends continued for the rest of the year , but without statistical significance , due to patient attrition . Conclusions This real-life pilot study shows that a simplified strategy with oral Montelukast was practical and effective in controlling exacerbations in an asthmatic population of a vulnerable community from Caracas . Such an approach reinforces the role of primary care in asthma treatment
Results Although highlighting a general lack of high- quality real-life effectiveness observational research on these clinical ly important topics , the analysis provided insights into how identified observational studies might inform asthma guidelines developers and clinicians .
Overall , RELEVANT appeared reliable and easy to use by expert review ers .
Conclusions Using such quality appraisal tools is m and atory to assess whether specific observational real-life effectiveness studies can be used to inform guideline development and /or decision-making in clinical practice
Abstract Introduction A Task Force was commissioned jointly by the European Academy of Allergy and Clinical Immunology ( EAACI ) and the Respiratory Effectiveness Group ( REG ) to develop a  quality assessment tool for real-life observational research to identify high- quality real-life asthma studies that could be considered within future guideline development .