Although the painful shoulder is one of the most common dysfunctions of the locomotor apparatus, and is frequently treated both at primary healthcare centres and by specialists, little evidence has been reported to support or refute the effectiveness of the treatments most commonly applied. According to the bibliography reviewed, physiotherapy, which is the most common action taken to alleviate this problem, has not yet been proven to be effective, because of the small size of sample groups and the lack of methodological rigor in the papers published on the subject. No reviews have been made to assess the effectiveness of acupuncture in treating this complaint, but in recent years controlled randomised studies have been made and these demonstrate an increasing use of acupuncture to treat pathologies of the soft tissues of the shoulder. In this study, we seek to evaluate the effectiveness of physiotherapy applied jointly with acupuncture, compared with physiotherapy applied with a TENS-placebo, in the treatment of painful shoulder caused by subacromial syndrome .Randomised controlled multicentre study with blind evaluation by an independent observer and blind, independent analysis. A study will be made of 465 patients referred to the rehabilitation services at participating healthcare centres, belonging to the regional public health systems of Andalusia and Murcia, these patients presenting symptoms of painful shoulder and a diagnosis of subacromial syndrome . The patients will be randomised into two groups: 1) experimental (acupuncture + physiotherapy); 2) control (TENS-placebo + physiotherapy); the administration of rescue medication will also be allowed. The treatment period will have a duration of three weeks. The main result variable will be the change produced on Constant's Shoulder Function Assessment (SFA) Scale; as secondary variables, we will record the changes in diurnal pain intensity on a visual analogue scale (VAS), nocturnal pain intensity on the VAS, doses of non-steroid anti-inflammatory drugs (NSAIDs) taken during the study period, credibility scale for the treatment, degree of improvement perceived by the patient and degree of improvement perceived by the evaluator. A follow up examination will be made at 3, 6 and 12 months after the study period has ended. Two types of population will be considered for analysis: per protocol and per intention to treat.The discussion will take into account the limitations of the study, together with considerations such as the choice of a simple, safe method to treat this shoulder complaint, the choice of the control group, and the blinding of the patients, evaluators and those responsible for carrying out the final analysis. Instituto de Biomecánica at Valencia, which has estimated that 50% of sick leave is accounted for by muscle or bone injuries in the shoulder or neck.Painful shoulder is one of the most common complaints affecting the locomotor apparatus, and is frequently attended both at primary healthcare centres and by specialists. The annual incidence at primary healthcare centres is 1.2%  and withThe most common actions taken at present to relieve the symptoms of painful shoulder include steroid injections, physiotherapy, oral NSAIDs and "wait and see"; hardly any of these measures have been tested scientifically to demonstrate their effectiveness in this situation . AccordiThe most relevant bibliography we have examined comprises reviews of the question carried out by the Cochrane group in 2000, 2003 and 2004, together with certain systematic reviews by other authors. In general, the conclusions of the analysts in the Cochrane studies, and of other reviewers working for professional organisations, is that there is very little evidence to support or refute the effectiveness of the treatment commonly applied for the painful shoulder. Therefore, well-designed studies are necessary, using uniform methods of diagnosis and measurement to ensure the validity of the results obtained. We have also analysed other studies, with less backing than the above-mentioned opinions of expert reviewers, but with an acceptable methodology, that have concluded in favour of one or other mode of treatment, such as physiotherapy ,8 or theAcupuncture has been used to treat this type of medical problem in China for over 3000 years. At present, it is under consideration as a technique to be applied in Western medical practice for a great many complaints, especially for cases in which modern techniques are either of limited effectiveness or are unsuitable . AcupuncDos Hermanas "A" Health Centre, with the establishment of the Pain Treatment Unit, data have been compiled to obtain an initial evaluation of the reactions of patients who are given acupuncture treatment [Since the introduction of acupuncture techniques into primary healthcare at the reatment . Moreovereatment  as a preIn this article, we describe a randomised, blinded, multicentre study carried out with a sufficiently-large sample group, with systematised, uniform diagnostic criteria, homogeneous therapeutic interventions including the use of a placebo for the control group, follow up periods exceeding three months and validated measurement of results. We believe such a systematic approach is necessary to clearly describe the current context of treatment for the painful shoulder. In the study, we work on the hypothesis that the acupuncture of Tiaokou ST38, together with physiotherapy, can reduce pain and improve functionality in situations of subacromial syndrome  to a greater extent than does physiotherapy associated with a TENS-placebo treatment. The study began in March 2005 and the recruitment phase remains open.Randomised controlled multicentre study with blind evaluation by an independent observer and blind, independent analysis.Patients referred to the Rehabilitation services of the health centres participating in the study. These centres are part of the public health systems of the regions of Andalusia and Murcia (Spain). The patients presented chronic symptoms of subacromial syndrome  and were offered treatment with physiotherapy together with acupuncture or transcutaneous stimulus. They were informed of the characteristics of the study and of the techniques to be used, as well as of the possible risks . They were told they could leave the study at any moment, with no type of penalisation or loss of benefits to which they were entitled.Inclusion criteria• Patients with a clinical diagnosis of subacromial syndrome  with a case history > 3 months• Prior radiography, with normal results• Informed consent• Unilateral injuryExclusion criteria: surgery, luxations or fractures in the proximity of the shoulder; other severe direct or indirect traumas (in traction) observed in the anamnesis and clearly related to the onset of the current episode; hypocoagulates, generalised disorders of the musculoskeletal system or neurologic disorders, vascular trophic disorders in the lower limbs, lymphedema.The ethical validity of this study has been analysed and approved by the corresponding ethical and research committees at the healthcare centres involved. The study design takes into account the Principalism criteria of Beauchamp & Childress  and expressly guarantees the patient's right to privacy and informed decision-making. The study also complies with the norms for Good Clinical Practice and the Edinburgh 2000 revision of the Helsinki Declaration. All the patients who participate give their written, informed consent to the clinical research methods applied. During the development of the study, audits will be performed, according to the criteria of the Research and Ethics Committee and the healthcare centre's Quality Committee, independently of the external audits (research funding provider) that may be required.A patient may be withdrawn from the study at any time, either at will or by decision of the researcher. The reasons for interrupting participation in the study will be recorded on the summary page of the Digital Data Record (DDR). The following procedure is to be followed when a patient withdraws from the study:• Assess the relevant study variables• Record any adverse events• Evaluate the taking of rescue medication• Indicate the possible co-interventions carried out• Complete the DDR, record the date and reason for withdrawal.The patients will be assigned on a random basis to the two study groups: 1) experimental group treated with acupuncture plus physiotherapy; 2) control group, to be given the TENS placebo plus physiotherapy. Randomisation will be carried out in each digital data recording system. Every healthcare centre participating in the study has a specially-designed DDR based on a Dell Axim × 30 PDA; once a new patient's data are entered, the patient is randomly assigned a treatment code . This code is concealed from the evaluator. Each PDA system has three access codes, one for the study controller, one for the evaluator and one for the doctor carrying out the treatment, and only the latter has access to the treatment code. The research team will take the necessary measures to ensure the confidentiality of the patients taking part, including their deidentification within the databases constructed for the analysis.tiao-shan homolateral technique. This consists of the perpendicular insertion of a single-use sterile filiform acupuncture needle, 7.5 cm long, 30 gauge body diameter, using a guide-tube. The insertion is to be made, after sterilising the skin and with the patient in a prone position, at the Tiaokou point . While the needle is being manipulated, the patient should perform abduction and external and internal rotation exercises.Once a week, before the physiotherapy session, the doctors responsible for the treatment  will apply acupuncture at the Tiaokou ST38 point, following the The single-use sterile needles are manufactured by Cloud & Dragaon Radical Device Co., Ltd , according to EU norms, and are imported by Acupuncture Shop, Storegade 58, 6800 Vade (Denmark).Once a week, before the physiotherapy session, the doctors responsible for the treatment will apply the TENS placebo, which consists of placing two adhesive electrodes, one each on the front and rear surfaces of the leg that is homolateral to the affected shoulder. The electrodes are connected to a deactivated TENS apparatus, model 8016 M. The stimulation unit remains placed in front of the patient, such that the flashing of the diode simulating the stimulus is visible at all times. The patient remains in the same position for 20 minutes, after which the TENS unit is disconnected and the electrodes removed from the patient's body. The frequency of the sessions is the same as that for acupuncture.The physiotherapy sessions last 40 minutes each and consist of the following • Recentering of the humeral head • Diadynamic currents, diphase attached with positive pole at the point of greatest pain • Post-session cryotherapy (10 minutes).The patient is recommended to avoid any activity that may cause pain in the affected arm for the duration of the study. Ultrasound therapy was not included as an applicable technique because it has been shown to be ineffective in treating pathologies in this region .The daily physiotherapy sessions will follow those of acupuncture and the TENS placebo in the following way: first, a session of acupuncture or TENS placebo followed by the first one of physiotherapy; the next four sessions of physiotherapy to be applied on following consecutive days. The second acupuncture or TENS placebo session is applied prior to the sixth one of physiotherapy, and is followed by another four physiotherapy sessions during the next four consecutive days. The third and final acupuncture or TENS placebo session is applied prior to the eleventh one of physiotherapy, and is followed by another four physiotherapy sessions during the next four consecutive days, after which the final assessment is made. The acupuncture and the TENS placebo sessions take place in identical rooms.The patients are allowed to take analgesics and/or NSAIDs if they wish. If they do, this fact, and the daily dose taken, should be recorded in the digital data record (DDR).• Anti-inflammatory medication• If taken, the maximum dose allowed is 1 diclophenac pill (50 mg) three times a day for a maximum of 4 weeks.• Administration instructions: to be taken with meals, to alleviate possible gastric irritation.• Gastroprotective medication• Specific indications:• No past record of ulcers or risk factors such as anticoagulant therapy, association with corticoids, age > 60 years or severe baseline illness : NO GASTROPROTECTION• No past record of ulcers and risk factors such as anticoagulant therapy, association with corticoids, age > 60 years or severe baseline illness : GASTROPROTECTION with 200 μg misoprostol every 6 or 12 hours or 20 mg famitidine every 12 hours.• Past record of ulcers: GASTROPROTECTION with 20 mg omeprazole every 24 hours.• Contraindications: diclophenac should not be taken by patients allergic to it, to acetylsalicylic acid or other NSAIDs, by patients with a history of asthma, angiodema or rhinitis provoked by NSAIDs, by patients affected by porphyria or with a history of ulcers, coagulation pathologies or haemorrhages. Caution is advised for patients with kidney insufficiency, cardiac insufficiency, hypertension or liver insufficiency.For the sake of consistency, criteria of selective tension and mobility patterns that we b• Sociodemographic data• Age• Sex• Influence on the shoulder of the type of work performed • Background• Previous episodes of shoulder pain (number of episodes)• If previous episodes occurred, did they provoke sick leave? (No. of such events and their duration)• Current episode• Concomitant neck pain(yes/no)• Duration of the present episode (in months)• Previous treatment received for the same episode • Acute onset of the present episode (yes/no)• Direct cause • Is the affected shoulder the dominant one? (yes/no)• Constant's Shoulder Function Assessment (SFA) Scale• Pain intensity in the shoulder during the day, on a 10 cm Visual Analogue Scale (VAS)• Pain intensity in the shoulder during the night, on a 10 cm Visual Analogue Scale (VAS)• Analgesic and NSAID medication taken during the previous 2 weeks .At 3 weeks (T-1) after the start of the study, the results of the intervention will be assessed by an independent expert evaluator. The 3-month follow up will be performed by the same evaluator. An additional follow up will be carried out at 6 and 12 months after the final evaluation (by independent telephone interviewer), including the main result measurements. These are the change in the SFA score, with respect to baseline values, after the 15th physiotherapy session. This assessment will be made by an external rehabilitation specialist with no information regarding the treatment received by the patient. Constant's Shoulder Function Assessment (SFA) Scale has a maximum score of 100 points, including subjective and objective elements in a proportion of 35/65, respectively. The subjective parameters describe the degree of pain felt by the patient and his/her ability to carry out normal daily activities, as regards both the level of activity and the position of the arm. The objective parameters are based on the range of active compound movements that enable the arm to be moved to functionally relevant positions, using a goniometer to measure the rear and lateral elevation and the positioning of the hand in relation to the head and the trunk in order to assess the degree of rotation achieved. The score for the power exerted by the shoulder is based on the weight (in kg) the patient can raise in abduction, to a maximum of 11 kg. A total SFA score of 100 indicates a shoulder with perfect freedom of movement, no pain and normal functioning.After the first week of treatment, the level of confidence in the treatment is measured on a Treatment Credibility Scale (TCS) . This wa1. Are you confident this treatment will alleviate the pain you feel?2. Does the treatment seem a logical one?3. Would you recommend this treatment to a friend or relative who had the same problem?4. Do you think this treatment could be applied to other problems?After three weeks of treatment (T-1) (15 sessions of physiotherapy), the following secondary variables will be assessed by an independent evaluator:• Pain intensity in the shoulder during the day, on a 10 cm VAS (DPI-VAS)• Pain intensity in the shoulder during the night, on a 10 cm VAS (NPI-VAS)• Degree of improvement perceived by the patient (IPP)  • Degree of improvement perceived by the evaluator (IPE) • NSAIDs taken (NT)• Treatment Credibility Scale items 3 and 4• Adverse events (ADEV) of a traumatic nature that might distort the results of the evaluation.An independent evaluator and rehabilitation specialist will make the following assessments at 3 months after the treatment ends:• Score on Constant's Shoulder Function Assessment (SFA) Scale• Pain intensity in the shoulder during the day, on a VAS (DPI-VAS)• Pain intensity in the shoulder during the night, on a VAS (NPI-VAS)• Degree of improvement perceived by the patient (IPP)• Degree of improvement perceived by the evaluator (IPE)• NSAIDs taken (NT)• Adverse events (ADEV)• Subsequent episodes of shoulder pain, their duration and treatment applied.An independent evaluator will make the following assessments by telephone interview at 6 months after the treatment ends:• Score on Constant's Shoulder Function Assessment (SFA) Scale (only the subjective parameters)• Pain intensity in the shoulder during the day, on a VAS (DPI-VAS)• Pain intensity in the shoulder during the night, on a VAS (NPI-VAS)• Degree of improvement perceived by the patient (IPP)• NSAIDs taken (NT)• Adverse events (ADEV)• Subsequent episodes of shoulder pain, their duration and treatment applied.An independent evaluator will make the following assessments by telephone interview at 12 months after the treatment ends:• Score on Constant's Shoulder Function Assessment (SFA) Scale (only the subjective parameters)• Pain intensity in the shoulder during the day, on a VAS (DPI-VAS)• Pain intensity in the shoulder during the night, on a VAS (NPI-VAS)• Degree of improvement perceived by the patient (IPP)• NSAIDs taken (NT)• Adverse events (ADEV)• Subsequent episodes of shoulder pain, their duration and treatment applied.® operating system, and specially designed for the purposes of this study, with obligatory fields, validation rules and quality control for error avoidance; a 512 bit encoding system is incorporated to ensure the confidentiality of all the records. Furthermore, as additional functions, it will include a security analysis system with stored passwords, and functions for the export/import and synchronisation of the database content. Access to this PDA will be limited to THREE users: 1) the healthcare centre evaluator; 2) the doctor applying the treatments; 3) the study controller. Each will have a different access code.Data collection and recording will be carried out using an Dell Axim × 30 PDA, fitted with the WindowsThe data tables describing the characteristics of the study subjects and the results of each of the evaluations will be entered separately. Each record corresponding to an evaluation, after approval by the researcher responsible, will be stored such that further editing cannot be performed. A backup copy of the database will be encrypted in a 512 bit system and uploaded weekly by safe transmission system to a web server. The study controller will store on the central computer the data obtained from each of the participating healthcare centres and will include all the records in the central database. Similarly, the study controller will make a weekly printout of the updated tables from each of the healthcare centres; these documents will be stored securely and kept as an original record for purposes of inspection or auditing or in case of loss of digital data. Each PDA will be the responsibility of the corresponding researcher at each health centre.The sample size was predetermined for a level of significance of 0.05, a power of 0.80 and a final average score on Constant's SFA scale of 70 among the experimental group (standard deviation 17) and 65 among the control group (standard deviation 18), with a two-tailed test, according to data taken from Kleinhenz .For the purposes of the analysis, two types of population are to be considered:• Per intention to treat (ITT): this population will consist of all the randomised patients. Those taking part in the selection phase but not subsequently randomised for treatment will be excluded from this population. This will comprise the main population for analysis of the parameters of effectiveness.• Per protocol: this population will consist of all the patients in the ITT population with no serious deviations from the protocol. This will comprise the secondary population for analysis.All the tests will be bilateral and carried out at a level of significance of α = 0.05. So as not to interrupt the study, no intermediate analyses are foreseen.To describe the different baseline characteristics of the patients, we shall use measures both of position  and of variability (standard deviation or interquartile range) for the continuous variables, while the others will be described via their frequency distributions, comparing the experimental and control groups. Moreover, a graphic analysis will be made, using smoothed versions of the histograms, boxes and other representations.For the principal result variable, the difference between the final value and the baseline Constant SFA score, measured in absolute terms, the experimental and control groups will be compared after adjusting by the baseline value and subsequently by other possible confounders. This analysis will be repeated in the follow ups at 3, 6 and 12 months. We will evaluate the effect of possible points of influence by repeating the model after exclusion of the observations with a large Cook-distance value. The assumptions of the model will be tested and reanalysed using a Q-Q plot diagram for the assumption of normality, and by comparing the studentised residuals versus the values of the independent variable for the assumption of constant variances.For the secondary result variables, the bivariate analysis will be performed using contingency tables analysed by ji-squared tests (for tables larger than 2 × 2), by ji-squared tests corrected for continuity, or Fisher's exact test (for 2 × 2 tables), for the categoric variables, and by simple linear regression for all other cases. Two-dimensional graphs will also be used.The multivariate analysis will depend on the nature of the response variable. When this is dichotomic, a binary logistic regression analysis will be made, and for this purpose we will establish the dummy variables needed for the categoric predictors. The inclusion of the "experimental group" or "control group" variable will be forced. The "forward procedure" method will be used to select the possible confounding variables in the model, and the entry criterion used will be the change in the likelihood ratio. The functional form of the continuous predictors will be studied via the corresponding statistical criteria, these being mainly graphic procedures.For continuous variables, a multiple linear regression model will be used, and the same model-selection criteria and diagnostic procedures as described above will be applied.Recruiting of the patients began in March 2005 and will continue until December 2005. Follow up is planned to end in March 2007.We believe that one of the most interesting features of this study is the fact that it introduces a neurostimulative technique, and one that is relatively simple to apply, into rehabilitative medicine. Nevertheless, we are also aware that this comprises one of its greatest difficulties, as this alternative treatment has been very little used, to date, in this field. The possibility of extending this clinical practice into rehabilitation services is one of the challenges we seek to overcome.It is very difficult to assess all the aspects that go to make up chronic pain, as it is such a subjective experience. This poses problems as regards finding theoretical models and appropriate measuring instruments, although the correct application of experts' recommendations will make it possible to standardise results for later analysis.There is little evidence to support or refute the effectiveness of the most common interventions to treat the painful shoulder. As well as the necessity to carry out further, well-designed clinical studies, we need to establish a uniform means of defining shoulder pathologies and of developing valid result measurements that are consistent and adaptable to changes in the population. The choice of a single type of pathology prevents us from extrapolating the possible results of research to all the situations in which painful shoulder is diagnosed. However, the fact of selecting a single diagnosis will ensure the specificity of the intervention and will enable us to evaluate particular aspects of the process.Dos Hermanas "A" Health Centre and on the comments made in the systematic reviews of the field made by the Cochrane Group.The clinical studies carried out to examine non conventional medical treatments such as acupuncture pose serious problems regarding the study design and possible bias. In selecting the variables to be examined in this study, we have taken into consideration the previous experience of the Pain Treatment Unit at the The placebo selected differs considerably from the acupuncture technique under study, but the intervention in itself is, in fact, difficult to disguise . The depAlthough the characteristics of the intervention prevent us from establishing a double blind design, we intend to blind the patients from the evaluator, and believe this simple blinding will make it possible to achieve sufficient control of possible bias.As with any other multicentre study, we are confronted with certain disadvantages, such as the loss of unity of judgement, with the participation of various researchers, or the reduced homogeneity of the sample group and the parallel increase in data dispersion. In order to overcome these problems, we have had to create very simple criteria for patient selection, to avoid possible subjectivity as concerns the different researchers. Additionally, we have laid great stress on the need to obtain a good level of communication between the different work groups, a condition that is sometimes essential to standardise criteria and to guarantee the internal validity of the study. The best way to achieve this communication is by means of frequent meetings, the coordination of which will be the responsibility of the study controller.The limited number of patients and the restrictions imposed on the study concerning the criteria for inclusion are counteracted by its extension to healthcare centres serving populations living in a different cultural situation, and to centres that are organised in different ways. Thus, the external validity of the study is safeguarded.COPD: Chronic Obstructive Pulmonary DiseaseDDR: Digital data recordGP: General PractitionerITT: Intention to treatNSAIDs: Non-steroid anti-inflammatory drugsPDA: Personal Digital AssistantSFA: Shoulder Function Assessment ScaleTCS: Treatment Credibility ScaleTENS: Transcutaneus Electric Nerve StimulationVAS: Visual analogue scaleThe author(s) declare that they have no competing interests.Conception and design: J. Vas. Revision of the different versions of the study protocol: J. Vas, E. Perea-Milla, C. Mendez, A. Herrera Galante, F. Madrazo, I. Medina, C. Ortega, V. Olmo, F. Perez Fernandez, L. Hernandez, J. M. Seminario, M. Brioso, F. Luna. Substantial contributions to the conception and design of the digital data record: I. Gordo, A. M. Godoy, C. Jiménez, M. A. Ruiz, J. Montes, A. Hidalgo, R. Gonzalez-Quevedo, P. Bosch, A. Vazquez, and J. V. Lozano. All authors have read and approved the final manuscript.Fundación Progreso y Salud (File No. 82045) from the recruitment phase until the short term evaluation, and by Consejeria de Salud de la Junta de Andalucia (File No. 136/04) for the long term follow up phases. The publishing of this article is funded by the IRYSS Network.The study protocol was developed in 2004 and is co-funded by The pre-publication history for this paper can be accessed here:HD Physiotherapy protocol ISRCTN28687220.doc Additional explicative document of the physiotherapy protocol for the patients included in the study.Click here for fileHD Table 1 ISRCTN28687220.doc Table 1. Examination protocolClick here for file


G Protein-Coupled Receptors (GPCRs) are a large and diverse family of membrane proteins whose members participate in the regulation of most cellular and physiological processes and therefore represent key pharmacological targets. Although several bioinformatics resources support research on GPCRs, most of these have been designed based on the traditional assumption that monomeric GPCRs constitute the functional receptor unit. The increase in the frequency and number of reports about GPCR dimerization/oligomerization and the implication of oligomerization in receptor function makes necessary the ability to store and access information about GPCR dimers/oligomers electronically.We present here the requirements and ontology (the information scheme to describe oligomers and associated concepts and their relationships) for an information system that can manage the elements of information needed to describe comprehensively the phenomena of both homo- and hetero-oligomerization of GPCRs. The comprehensive information management scheme that we plan to use for the development of an intuitive and user-friendly GPCR-Oligomerization Knowledge Base (GPCR-OKB) is the result of a community dialog involving experimental and computational colleagues working on GPCRs..Our long term goal is to disseminate to the scientific community organized, curated, and detailed information about GPCR dimerization/oligomerization and its related structural context. This information will be reported as close to the data as possible so the user can make his own judgment on the conclusions drawn for a particular study. The requirements and ontology described here will facilitate the development of future information systems for GPCR oligomers that contain both computational and experimental information about GPCR oligomerization. This information is freely accessible at  G Protein-Coupled Receptors (GPCRs) are among the largest and most diverse protein families in mammalian genomes, and constitute the largest single family of therapeutic targets for drug treatment. They are integral membrane proteins with a central common core made of seven transmembrane helices connected by intracellular and extracellular loops Figure . The priThe traditional view of GPCR function had focused on the assumption that monomeric receptors participated in ligand binding and signal transduction processes Figure . SpecifiThe physiological relevance of GPCR oligomerization is largely accepted nowadays, especially in light of the discovered functional implications of GPCR association that include pharmacological diversity, G-protein coupling specificity, downstream signaling amplification or attenuation, and/or internalization  stores computational and experimental information about GPCR oligomerization, and b) allows browsing, visualization and structured querying of its contents. Such a system would foster and support productive and quantitative communication and collaboration between computational and experimental scientists, but is not currently available in any form. To best serve the broad GPCR community by providing a comprehensive and reliable  GPCR oligomerization information system, it is important that opinions from GPCR experts in both experimental and computational fields are given due consideration. This manuscript describes the result of a community dialog we initiated to identify the requirements for a comprehensive GPCR oligomerization information system and to design an ontology (information scheme) to represent such information. The GPCR oligomerization ontology that we present here is a formal description of the information concepts required to describe GPCR oligomerization and of the relationships between these concepts. As such, this ontology allows the organization of information in a formal way, a prerequisite to supporting many of the requirements that potential users identified for the future GPCR oligomerization information system (see Information System Requirements below).An information system devoted to homo- and hetero-oligomers of GPCRs requires the capability to store, and allow browsing, visualization and structured querying of a specialized set of heterogeneous data. To facilitate the implementation of a comprehensive information system focused on GPCR oligomerization, it is important to make informed decisions about the specific usages the information system will support and what type of information must be stored and queried. Thus, in a first step towards developing such a system, we have obtained system requirements – a list of features essential to the finished information system – from experts in the GPCR oligomerization field, and have developed an ontology to represent the results of GPCR oligomerization studies . The system requirements and ontology constitute a comprehensive information management scheme for a GPCR oligomerization information system and can be used to guide the fine design and implementation of such a system. Throughout the ontology and this manuscript we define the word 'protomer' to refer to a protein which is a constituent part of an oligomer. In contrast, we reserve the word 'monomer' for stand-alone GPCR proteins.In the following sections, we report the system requirements that have been identified for a comprehensive GPCR oligomerization information system. Each requirement describes a high-level feature that an information system for GPCR oligomers must include to be useful, and explains how this feature will support studies of GPCR oligomers.The repository will complement the scientific literature by offering a unified view of the data and/or conclusions published in different articles. One of the most daunting obstacles encountered when directly searching the literature is the existence of varying monomer/oligomer naming schemes or different residue numbering conventions. This makes it extremely difficult to locate articles of interest using current text searching methods. A useful GPCR oligomerization information system should make it possible to bypass this problem by supporting the creation of unified views by aggregating data along different axes. In an information system for GPCR oligomers, aggregation could be done at the level of the oligomer or structural domain, so that obtaining the list of small molecules that were shown to bind an oligomer would be possible even if the information was originally published in five articles where the same oligomer was referred to by three different names. The GPCR oligomerization information system should therefore eliminate the common problems encountered when searching the literature with current text searching methods. A GPCR information system should also provide links to the primary literature for each fact or interpretation offered.Native oligomeric complexes of GPCRs that satisfy any or all of the rules recently stipulated by NC-IUPHAR  should aThere is a rich compendium of established and experimental bioinformatics resources designed to support GPCR research  the experimental procedure used to characterize the oligomer, e.g., Fluorescence Resonance Energy Transfer (FRET), Bioluminescence Resonance Energy Transfer (BRET), Time Resolved FRET (TR-FRET), cross-linking, co-immunoprecipitation, co-expression of fragments or modified protomers, Atomic Force Microscopy (AFM), or use of dimer-specific antibodies (for a complete review see ); ii) thScientific publications contain descriptions of experimental results and of the methods used to produce them. In contrast, it is not unusual for the interpretation of the data presented in a manuscript to be challenged in follow-up publications, as more experimental data become available. Because various interpretations of the data are often the object of debate until a consensus is reached, the information system will be most helpful if it stores the experimental data. In the case of conflicting data, all experimental results will be reported, with the appropriate reference.A detailed information system about GPCR oligomers should include information about the experimental method  and/or the specific type of modeling procedure  should be stored and detailed as completely as possible. Results from several computational techniques, including molecular dynamics simulations , should cis- or trans-activation; vii) possible structural rearrangement at the interface upon activation; viii) GPCR-G-protein stoichiometry. Although most of this information derives from paradigms of G protein-dependent signaling, inferences from G-protein independent pathways will also be incorporated as more detailed information becomes available.The user should receive detailed information when available about i) activated protomer(s) within the oligomer; ii) the activating ligands; iii) single or multiple occupancy of binding sites; iv) types of conformational change within each protomer; v) symmetric/asymmetric functioning; vi) The user will find beneficial the following information: i) role of oligomerization in maturation and cell-surface delivery; ii) ligand regulation (and characterization of the ligand as agonist or antagonist); iii) cross-modulation of signaling/binding; iv) negative/positive cooperativity; v) attenuation/potentiation of signaling in G protein-dependent and independent pathways; vi) G-protein specificity; vii) internalization (for a recent review see ). By seaRecent evidence for compounds that can selectively activate hetero-oligomers but not homo-oligomers suggests that GPCR hetero-oligomers can be used as models in the development of new therapies , as wellin vivo effects of hetero-oligomer specific ligands as well as reported in vivo phenotypical changes  in knock-out animals should be available to the user.One of the main requirements for the recognition and acceptance of GPCRs multimeric receptors recently defined by NC-IUPHAR  is a firThe requirements presented in the previous section call for the management of various types of information about the oligomers, their structural domains, or their binding ligands. Because each of these information types relates to one or more other information types, and because the relationship between such types can become complex, it is necessary to specify precisely the information type relationships that the information system will support. To achieve this, we have created a formal ontology for a comprehensive GPCR oligomerization information system currently under development in our laboratories. The term ontology is commonly used in bioinformatics to denote various types of ways to organize biological information (from the directed acyclic graph of the "Gene Ontology" to frame-based systems). Here, we consider that an ontology is the result of making choices to represent a specific aspect of reality, e.g., a biological entity such as a GPCR oligomer within an information system, database, or knowledge representation system, in order to make it amenable to certain types of computations (we therefore follow the definition of an ontology given in ). ChoiceoligomerName of type String that stores the name of the Oligomer. The Oligomer concept also has a protomers attribute that lists the specific protein types that form the oligomer. The ontology does not track the exact stoichiometric subunit composition of oligomers because most of the time this information is not known. Instead the ontology records what types of GPCRs are known or predicted to participate in that instance of Oligomer. For instance, to indicate that the δ-opioid receptor is predicted to oligomerize with the μ-opioid receptor, an instance of the Oligomer concept is created with a protomers attribute that references these two GPCRs. The protomers attribute is of type Collection<Protein>, a notation that indicates that this attribute can contain a number of instances of the Protein concept. The number of Protein instances that can participate in the relation defined by the protomers attribute is specified on the arrow from Oligomer to Protein. This is an example of an association between one concept and another, where one concept can have multiple instances of the other concept. In a UML diagram, such multiplicities of association are indicated at the start of the arrow between the two concepts. In this case, the notation 1..* indicates that an instance of Oligomer may have one or more Protein instances in its attribute protomers, where the 1 indicates that an Oligomer must have at least one Protein associated with it, and the * indicates that there can be more than one Proteins associated with the Oligomer. Similarly, it is possible (for example in the association from Protein to Oligomer), that a Protein may not be a part of any Oligomer at all, or may be a component of many different Oligomers. In this case, the notation reads 0..*  ExternalReference instances. The literatureReferences attribute allows citations and other outside references to be attached to a particular Oligomer instance. The ExternalReference concept performs this function because its three attributes  allow the identification of published material and external database links associated with that Oligomer instance. For example, an ExternalReference instance whose attributes are {externalID = 10926528, resourceType = PubMed and otherReferenceInfo = ""} refers to an article in PubMed whose primary identifier is 10926528. This information is sufficient to identify the article describing the crystal structure of rhodopsin -O-phenylethyl ester (OPE), the effect was also reduced . This change would also be stored as measuredEffect = DECREASED. When the antagonist [(D-Trp30)CCK-26-32]-O-phenylethyl ester (D-Trp-OPE) was used, the measuredEffect was UNCHANGED -enkephalin (DAMGO), only induced the internalization of μ-opioid, not of sst2A. These three results would be stored as 1) d = TRUE .ligandUnderTest), b) the property of ligand action, indicating whether the ligand is an agonist, partial agonist, antagonist, neutral antagonist or inverse agonist (ligandProperty), c) the protomer (or protomers) that the ligand is observed to bind (protomersBound), d) the measured change in ligand affinity to the oligomer compared to the protomer (affinityChange), and e) the presence of demonstrated ligand binding crosstalk  – see section 6.4. The helper concept MeasuredVariation records if the affinity was: INCREASED, DECREASED, NOT CHANGED, or NOT_TESTED.The concept LigandBinding encodes differences in the binding of a given ligand to the Oligomer with respect to the protomer. This concept is defined by the following attributes: a) the ligand tested in the pharmacological assay  enkephalin (DPDPE) (ctively) . The infceptor). .GPCRs mostly signal through heterotrimeric G proteins although increasing evidence suggests that GPCRs may also function in a G-protein-independent manner. In this section we only refer to classical G protein-dependent signaling pathways, although the ontology can incorporate information about G protein-independent signaling pathways as well.molecule) that belongs to a pathway (in attribute pathway) downstream of the receptor has been tested (the type of assay can be described in the attribute measurementType). The attribute changeInMeasurement records either how the output of the assay differs from the monomer to the oligomer or the effect that different cross-talk ligands have on specific ligand-mediated signaling processes . For instance, if the levels of cAMP are tested, and the corresponding assay reports that cAMP levels are higher for the oligomer than for the monomer, then changeInMeasurement will have the value INCREASED. The attribute activatingLigand records which ligand was used to activate the receptor. The attribute isDesensitized is used to report the loss of responsiveness of the protomer to the continuing or increasing dose of activatingLigand. The attribute isPhosphorylated contains information about whether the GPCR receptor is phosphorylated or not. Further, the attribute signalingXTalk indicates if the signal transduction change corresponds to crosstalk between signaling pathways mediated by the protomers of the Oligomer (see section 6.4). Finally, changes in G-protein specificity are accounted by the attribute gProteinType. This attribute is part of the Signaling concept rather than Oligomer as the G-protein specificity is dependent on the ligand.GPCR oligomers can signal through different pathways than a GPCR monomer. The Signaling concept makes it possible to encode such differences in downstream signal transduction. Encoding of this concept assumes that a molecule  Phe-Phe-OH) (=ligandB) produces a two-fold increase in binding affinity (changeInProtomerA = INCREASED) of the μ-opioid agonist DAMGO (= ligandA). Figure An example of bindingXTalk  can be seen in the treatment of cells or native membranes containing both μ-opioid  of compounds such as MDAN-19 and MDAN-16 to either δ – or μ-opioid receptors, but has no effect on MDAN-21 potency [ligandA = MDAN21, protomerA = μ-receptor, ligand B = NTI, protomerB = δ-receptor, changeInProtomerA = UNCHANGED, or MDAN16, protomerA = μ-receptor, ligand B = NTI, protomerB = δ-receptor, changeInProtomerA = DECREASED.Similarly, for signalingXTalk,  potency . This MDcolocalizationEnvironment) will be indicated by the isColocalized attribute. Specific functional properties for the GPCR oligomers identified in native tissue  will be stored via the inVivoPhenotypicChange attribute. As the use of knock out animals or RNAi technology may also provide key information on the existence of GPCR oligomers in vivo, this information will be stored as well using the geneKnockoutResponse attribute.A growing body of evidence refers to the existence of GPCR oligomers in native tissue. This information is extremely important as it relates to the physiological relevance of the GPCR oligomer under study. Whether or not all protomers of an oligomer are identified in the same cell or within the same subcellular compartments .The case of GABAhe brain , we willr GABAB1  or GABABBAB1 [B2  in mice As data about GPCR oligomerization accumulate in the scientific literature, it becomes appropriate to create an electronic repository to facilitate the browsing, searching and integration of relevant data. However, the construction of such a resource is not trivial because the resource should offer information about many various aspects of GPCR oligomerization and how these aspects interrelate. To enable the construction of a GPCR oligomerization information system that is as complete and responsive to the needs of the GPCR community as possible, we have gathered the requirements of such a system from experimental and computational experts in the GPCR field. Based on an interdisciplinary dialog, we have created an ontology that formalizes information concepts and concept relationships required to store the different aspects of GPCR oligomerization in an electronic repository. These concepts are formally defined in the OWL language, a W3C standard for ontology exchange  recognizE. coli metabolic pathways could be stored electronically [Many ontologies proposed under the OBO consortium can be reused in a variety of applications  require curators to read and interpret a manuscript to extract information that will be added to the database. A more collaborative strategy could be proposed where structured information would be embedded in articles in such a way that the extraction of information can be automated and will not require human interpretation. The advantage of this strategy is that the structured information would be reviewed at the same time as the manuscript and that it would solve the problem of information extraction from the literature. The ontology described in this manuscript would support such a strategy because it is possible to automatically generate a structured language from an ontology that could be used to encode information for embedding in a manuscript. We note that while this strategy is possible, there are still a number of sociological barriers to its widespread use. In the meantime, the GPCR-OKB ontology presented here will be useful to database designers and curators who need to manage information about GPCR oligomerization.We have presented the requirements and ontology of an information system designed to manage the elements of information necessary to describe the phenomena of both homo- and hetero-oligomerization of GPCRs in a data-driven manner. The elements of information supported by the GPCR Oligomerization ontology include: i) links to other databases with information about GPCR protomers, ii) information about the experimental details of methods used to study GPCR oligomers, iii) experimental evidence for and computational predictions of the specific residues at oligomeric interfaces, iv) structural models of oligomers deduced from experiments or computer simulation studies; v) information about potential mechanisms of activation of GPCR oligomers; vi) information about functional roles of GPCR oligomers and the various phenotypical changes that occur compared to the individual subunits; vii) novel compounds that are proposed to selectively target GPCR oligomers; viii) the possible physiological relevance of GPCR oligomers.The requirements and ontology described in this manuscript will facilitate the development of future GPCR oligomerization information systems that will integrate data generated by experimental and computational studies of GPCR oligomerization. The one under current development in our laboratories (GPCR-OKB) will be continually curated and maintained..The ontology for GPCR-OKB is available at LS participated in the conceptual design of the ontology, created corresponding diagrams, and wrote the manuscript. MM helped to choose examples from the literature to illustrate the different attributes of the ontology, and participated in ontology design and manuscript drafting. MB, LD, SRG, MJL, GM, RN, KP, MP, JPP, and GV contributed to the manuscript draft with constructive criticism and helpful comments/suggestions. JAJ participated in requirement analysis, and helped refine the ontology design. FC and MF conceived the study, coordinated its design, and helped to draft the manuscript. All authors read and approved final manuscript.


Cardiac mapping is a broad term that covers several modes of mapping such as body surface , endocarNewer mapping systems have revolutionized the clinical electrophysiology laboratory in recent years and have offered new insights into arrhythmia mechanisms. They are aimed at improving the resolution, three-dimensional spatial localization, and/or rapidity of acquisition of cardiac activation maps. These systems use novel approaches to accurately determine the three-dimensional location of the mapping catheter and local electrograms are acquired using conventional, well-established methods. Recorded data of the catheter location and intracardiac electrogram at that location are used to reconstruct in real-time a representation of the three-dimensional geometry of the chamber, color-coded with relevant electrophysiological information.However, these mapping systems are very expensive and not required for the commoner clinical arrhythmias like atrioventricular nodal reentry (AVNRT), accessory pathway mediated tachycardia  and typical atrial flutter. The purpose of this article is to discuss the possible contribution of newer cardiac mapping system to treat various arrhythmias.Myocardial potentials are reconstructed from data acquired by recording cavity potential from an array of electrodes sitting in the blood pool within the cardiac chamber and not in endocardial contact. Inverse- solution methods are applied to these non-contact signals in order to reconstruct endocardial potentials from the raw cavity potentials.Cardiac chamber geometry is established.Site(s) critical for maintenance of reentry circuit(s) are identified.Ablation catheter is navigated to critical site(s).Endocardial Solutions (ESI) system is used for clinical non-contact intracardiac mapping. It can display high-resolution color maps of endocardial activation in the intact beating heart . The eleA catheter locator system is central to steps 1 and 3 while the inverse solution for reconstructing endocardial electrograms is central to step 2. A 'locator' signal emitted from the mapping/ablation catheter allows its position to be determined relative to the electrode array. It can be used to construct the three-dimensional computer model of the endocardium  by moving the conventional catheter around the cardiac chamber, thus building a series of co-ordinates for the endocardium. Reconstructed electrograms are then superimposed onto the virtual endocardium to produce isopotential maps.Electrogram reconstruction has been validated by comparing the morphology and timing of reconstructed electrograms with contact electrograms from the same endocardial location (as indicated by the catheter location system). The accuracy of electrogram reconstruction is good, but decreases with increasing distance between the electrode array and the endocardium and this becomes significant for distances >34 mm.The main advantage of this system is that it requires only one beat to reconstruct a complete activation map, which potentially allows mapping of hemodynamically unstable arrhythmias. However, the distance between the endocardial wall and the balloon center and the spatial complexity of the activation patterns influences the accuracy of the electrogram reconstruction negatively. This will affect the reliability when mapping for example, dilated LVs or complex reentrant circuits -7.The technology is based on a catheter location system, which determines a mapping catheter's position and attitude within an ultra low magnetic field emitted from radiators positioned under the operating table.The catheter resembles a standard 7- or 8- Fr deflectable catheter with a 4-mm tip and proximal 2-mm ring electrodes. The location sensors lie just proximal to the tip electrode, totally embedded within the catheter. The three location sensors are located orthogonally to each other. The locator pad is placed beneath the operating table and includes three coils that generate ultralow magnetic fields, which decay as a function of the distance from their sources. When the catheter is moved within this magnetic field, the currents generated represent movement in three dimensions. The resolution of the location capabilities of the system has been previously been shown to be <1 mm in both in vitro and in vivo studies [The reference catheter is introduced and placed inside the coronary sinus or in the right ventricle. The mapping/ ablation catheter is introduced and placed in the chamber being mapping. The mapping system determines the location and orientation of both the mapping and reference catheters. The location of the mapping catheter is gated to a fiducial point in the cardiac cycle and recorded relative to the location of the fixed reference catheter at that time, thus compensated for both subject and cardiac motion. By moving the catheter inside the heart, the system continuously analyzes its location and presents it to the user, thus enabling navigation without the use of fluoroscopy.The mapping catheter is dragged over the endocardium, sequentially acquiring the location of its tip together with the local electrogram when the catheter is in stable contact with the wall. By sampling the location of the catheter together with the local electrogram from a plurality of endocardial sites, the three-dimensional anatomy of the chamber is reconstructed in real-time. The local activation time is then color-coded and superimposed on the anatomical map with red indicating early-activated sites, blue and purple late activated areas, and yellow and green areas intermediate activation times ,4,5.The stability of the catheter and contact is evaluated at every site by examining the following criteria: 1) local activation time stability, which is defined as the difference in ms between the local activation calculated from two consecutive beats; 2) location stability, defined as the distance in mm between two consecutive gated locations; 3) morphological superpositioning of the intracardaic electrogram recorded on two consecutive beats; and 4) cycle length stability, defined as the difference between the cycle length of the last beat and the median cycle length during the procedure.The three-dimensional geometry of the chamber is generated using a modified "star" reconstruction algorithm. The sets of points from endocardial surface are used for geometrical reconstruction. It is recommended to map each chamber in a different reconstruction bin ('chamber setup"), when mapping more than one chamber, which can be simultaneously displayed.The electroanatomical maps can be presented in either two or three dimensions as activation, isochronal, propagation, or voltage maps. The activation maps display the local activation time color-coded overlaid on the reconstructed three-dimensional geometry ,4,5. TheThe capabilities of the CARTO system to associate relevant electrophysiological information with the appropriate spatial location in the heart and to accurately determine the three-dimensional location and orientation of the ablation catheter may be of great value in guiding ablation. The technology enables one to perform the mapping procedure and to potentially define the mechanism underlying the arrhythmia, to design an ablation strategy, and finally to return accurately to the desired site for the delivery of RF energy.The CARTO nonfluoroscopic electroanatomic mapping system enhances our ability to analyze and ablate the arrhythmia in following ways: 1) it allows us to associate the intracardiac electrogram with the reconstructed three-dimension anatomy (electroanatomic mapping), which helps to determine the site of arrhythmia origin, its mechanism, and the importance of particular cardiac structures in sustaining the arrhythmia circuit. Knowledge of the arrhythmia mechanism and circuit  is critical in planning arrhythmia ablation. Thus, macroreentrant tachyarrhythmias, such as incisional atrial tachycardia, are best mapped using the CARTO system ,9) CatheThe system is limited to point-to-point mapping strategy. Thus, if the arrhythmias are non-sustained or quickly change to a different morphology or mechanism, e.g., atrial tachycardia degenerates to atrial fibrillation, mapping of such arrhythmias will be difficult to complete and the procedure is likely to take considerable time.Simultaneous mapping of multiple points has been performed using 64 -pole endocardial basket catheter , which can be deployed percutaneously. Current designs of basket arrays consist of a series of equally spaced electrode pairs mounted on eight flexible splines (A-H), and each spline contains eight 1.5 mm electrodes with 3-mm spacing, which can be straightened and advance from a percutaneous sheath into the cardiac chamber of interest so that the splines deploy and are apposed against the endocardium  It provides simultaneous, multiple, stable recordings for most of the endocardial surface. Depending on the location of the arrhythmogenic substrate a complete coverage of the reentry circuit is possible. 2) In addition to multiple simultaneous recordings, the basket catheter provides stable, multiple pacing sites distributed throughout the chamber where it is deployed. Thus, the entrainment of arrhythmias could be remarkably facilitated. 3) The color-coded animation images simplify the analysis of multielectrode recordings and help in establishing the relationship between activation patterns and anatomic structures. 4) In patients with atrial flutter, mapping with a basket catheter provides the unique ability of recording from both the sides of the Tricuspid valve and Inferior vena cava (TV-IVC) isthmus simultaneously. 5) It allows high density mapping from infrequent ectopic beats. 6)By mapping the precise location, the number of RF ablations may be reduced substantially. Basket catheters do not at all points orient themselves towards the endocardium in the shape expected of them and this may vitiate our judgment. Basket catheters have a relatively large area near the shaft without electrodes, therefore during mapping some part of endocardium is not in contact with the basket. The quality of recordings is critically dependent on proper selection of basket size. There is a potential risk of thrombo-embolism with left sided mapping.Two reference catheters and one mapping/ablation catheter are introduced percutaneously using subclavian and /or femoral approach. One reference catheter is positioned in the coronary sinus, and the other in the right ventricular (RV) apex. For ablation purpose, a 7F, 4-mm tip bidirectional steerable cooled ablation catheter  is used . The cooBecause dimensional and structural characteristics of the catheter are known, it is possible to construct a real-time 3D graphic representation of the catheters, including the position of the electrodes and the transducer. As one of the transducers is positioned distal to the deflection point of the shaft of the catheter, it is possible to display the curvature of the catheter as well. Furthermore, the real-time position management system graphically displays the beat-to-beat movement of the tip of the catheters.The 3D real-time position management and mapping system (Cardiac Pathways) uses ultrasound-ranging techniques to determine the position of a mapping/ ablation catheter relative to two reference catheters. The mapping system consists of an acquisition module and an ultrasound transmitter and receiver unit, both connected to a SPARC 20 computer . The system is capable of simultaneously processing (1) seven position management catheters, (2) 24 bipolar/48 unipolar electrogram signals, (3) 12- lead ECG and (4) two pressure signals. Signals are sampled at 3kHz per channel with a resolution of 14 bits. The high-pass filters are set at 30 Hz and the low-pass filters at 500 Hz. Electrograms and catheter positions are stored on optical disk. The original position of the reference catheters can be displayed on the real- time window, thereby allowing repositioning of catheters after displacement .The real-time display of the catheter tip and the possibility of on-line retrieving previous positions and curves of a catheter facilitate repositioning of a catheter at previously marked sites. Use of this system may result in reduced fluoroscopy time. Routine application of the real-time position management system requires only the use of special catheters; no additional catheters or skin electrodes are needed. As any type of catheter containing ultrasound transducers can be "tracked" within the reference frame and used to locate positions, it is possible to position, for example, two catheters simultaneously in the RA and the LA to create lesions using this guidance system. This may be useful in case of the creation of linear lesions in atrial fibrillation patients . The abiThe limitation of this system is occasional failure of ultrasound transducers, requiring replacement of a catheter. Secondly, a "Voltage map" cannot be obtained unlike the other systems described.RF ablation has become first-line therapy for many tachyarrhythmias. It has a high short-term success rate, low complication rate, and results in improved quality of life compared with other treatments. One concern is the potential effect of radiation exposure to both patient and medical personnel especially during long procedures. The newer mapping system may be helpful in this regard. Mapping systems does reduce fluoroscopic time for ablation without compromising efficacy or safety. The procedure time however may be even longer with the newer mapping systems.These newer mapping systems are useful tool for guiding catheter ablation of unstable arrhythmias  and complex atrial arrhythmias. The newer mapping systems at present are not cost-effective for developing countries. Since the special catheters used for nonfluoroscopic mapping are relatively expensive than the conventional catheters, they should not be used with due consideration, especially for arrhythmias that are relatively simple and easy to ablate, such as AVNRT, preexcitation syndrome, or AV nodal junctional ablation.Furthermore, these systems are continually being refined and the maps obtained from these systems are not ideal yet. The learning curve with the operators with this new and rapidly advancing technology is also an issue. Currently, these systems remain an adjunct to the conventional methods of mapping to guide catheter ablation. More research and study is required to define the primary indications for their usage.


The aim of this study was to develop and evaluate a pedagogical tool to enhance the understanding of a checklist that evaluates reports of nonpharmacological trials (CLEAR NPT).Paired randomised controlled trial.Clinicians and systematic reviewers.We developed an Internet-based computer learning system (ICLS). This pedagogical tool used many examples from published randomised controlled trials to demonstrate the main coding difficulties encountered when using this checklist.Randomised participants received either a specific Web-based training with the ICLS (intervention group) or no specific training.The primary outcome was the rate of correct answers compared to a criterion standard for coding a report of randomised controlled trials with the CLEAR NPT.Between April and June 2006, 78 participants were randomly assigned to receive training with the ICLS (39) or no training (39). Participants trained by the ICLS did not differ from the control group in performance on the CLEAR NPT. The mean paired difference and corresponding 95% confidence interval was 0.5 (−5.1 to 6.1). The rate of correct answers did not differ between the two groups regardless of the CLEAR NPT item. Combining both groups, the rate of correct answers was high or items related to allocation sequence (79.5%), description of the intervention (82.0%), blinding of patients (79.5%), and follow-up schedule (83.3%). The rate of correct answers was low for items related to allocation concealment (46.1%), co-interventions (30.3%), blinding of outcome assessors (53.8%), specific measures to avoid ascertainment bias (28.6%), and intention-to-treat analysis (60.2%).Although we showed no difference in effect between the intervention and control groups, our results highlight the gap in knowledge and urgency for education on important aspects of trial conduct. Background: A key part of the practice of evidence-based medicine  involves appraising the quality of individual research papers. This process helps an individual to understand what has been done in a clinical research study, and to decipher the strengths, limitations, and importance of the work. Several tools already exist to help clinicians and researchers to assess the quality of particular types of study, including randomised controlled trials. One of these tools is called CLEAR NPT, which consists of a checklist that helps individuals to evaluate reports of nonpharmacological trials . The researchers who developed CLEAR NPT also produced an Internet-based computer learning system to help researchers use CLEAR NPT correctly. They wanted to evaluate to what extent this learning system helped people use CLEAR NPT and, therefore, carried out a randomised trial comparing the learning system to no specific training. A total of 78 health researchers were recruited as the “participants” in the trial, and 39 were randomised to each trial arm. Once the participants had received either the Internet training or no specific training, they used CLEAR NPT to evaluate reports of nonpharmacological trials. The primary outcome was the rate of “correct” answers that study participants gave using CLEAR NPT.What the trial shows: The researchers found that the results on the primary outcome (rate of correct answers given by study participants) did not differ between the study arms. The rate of correct answers for individual items on the checklist also did not seem to differ between individuals receiving Internet training and those receiving no specific training. When looking at the scores for individual items, combined between the two study arms, participants scored highly on their appraisal of some aspects of trial design (such as generation of randomisation sequences and descriptions of blinding and the intervention) but poorly on other items .Strengths and limitations: Key strengths of this study include the randomised design and that the trial recruited enough participants to test the primary hypothesis. The failure to find a significant difference between study arms in this trial was likely not due to a lack of statistical power. One limitation of the study is that the group of researchers who participated were already fairly experienced in assessing trial quality at the start, and this may explain why no additional effect of the computer-based learning system was seen. It is possible that the training system may have some benefit for individuals who are less experienced in evaluating trials. A further possible limitation may be that there was a small imbalance at randomisation, with slightly more experienced researchers being recruited into the arm receiving no specific training. This imbalance might have underestimated the effect of the training system.Contribution to the evidence: The researchers here report that this study is the first they are aware of that evaluates a computer-based learning system for improving assessment of the quality of reporting of randomised trials. The results here find that this particular tool did not improve assessment. However, the results emphasise that training should be considered an important part of the development of any critical appraisal tools. Assessing the quality of reports of randomised controlled trials (RCTs) is particularly important for clinicians' critical appraisal of the health-care literature and for systematic reviewers . In factQuality assessment is often achieved by the use of checklists or scales, such as the Veerhagen list or the Jadad scale –12. In tReproducibility issues have been raised regardless of the chosen quality tool , becauseTo improve the understanding of the CLEAR NPT, we developed an Internet-based computer learning system (ICLS). This pedagogical tool offers, through the use of practical examples from RCTs, a problem-based approach to solving the main coding difficulties encountered when using the CLEAR NPT. We chose a Web-based tool as it is more feasible than face-to-face meetings and can be tailored to individuals' answers. To evaluate the impact of the ICLS on proper coding with the CLEAR NPT, we carried out an RCT comparing ICLS to no specific training.The ICLS was developed in three steps: construction, design, and validation.To develop the ICLS, we identified difficulties encountered when using the CLEAR NPT  and selected passages from RCTs that could be include in the ICLS.For this purpose, we selected a panel of reports of RCTs assessing NPT .Two reviewers, one involved in the elaboration of the CLEAR NPT (IB) and one using the CLEAR NPT for the first time (LF), independently assessed these reports using the CLEAR NPT items. A meeting followed in which the ratings were compared. This session allowed for the identification of disagreement and difficulties in understanding CLEAR NPT items. According to the difficulties in understanding CLEAR NPT items for this panel, the two reviewers selected specific passages that were either adequately reported, inadequately reported, or a frequent cause for disagreement.Although reviewers can be non-native English speakers, the computer learning system was written in English. In fact, most papers included in systematic reviews and meta-analyses are published in English. Consequently, it seemed logical to use the same language in the learning system.We designed a computer program following the model of a knowledge-based expert system –23. The The computer learning system was validated by one of the authors (PR) who confirmed the validity of the answers and pathways of the ICLS. The ICLS was also tested by a group of three people who had never used CLEAR NPT.We designed an RCT comparing two groups of participants receiving either the user's guide and specific training with the ICLS (intervention group) or a user's guide with no specific training (control group) to assess the impact of the ICLS. In France, the submission of a trial to an ethics committee is defined according to the public health law of August 2004, which requires the submission of protocols for review by an ethics committee only if the trial involves patients, and if the treatment is not administered in clinical practice but involves a specific treatment or specific investigation. Trials aimed at educating medical doctors or reviewers are not required to submit the protocol to an ethics committee. Participants in our study were previously informed of the trial, they could withdraw from the trial if they wished, and they were informed of the results of the trial upon completion.n = 430) were selected for their knowledge of quality assessment. HTAi is an international society for the promotion of health technology assessment and holds international conferences and forums. Members are involved in the field of evaluation, and some perform systematic reviews; (2) directors of Evidence-based Practice Centers (EPC) (n = 13) who develop systematic reviews and technology assessments on topics relevant to clinical, social science/behavioral, economic, and other healthcare organization and delivery issues; and (3) corresponding authors of meta-analyses of NPT published between 1 January 2004 and 3 March 3 2006 (n = 100).Members from three different categories of participants were invited by e-mail to participate in the RCT: (1) Members of Health Technology Assessment international (HTAi) . This design allowed for assessing reviewers' understanding of several articles. A smaller panel would decrease the variability of the results. However, the quality of reporting of the trial is a critical issue in quality assessment, and we would not have been able to formulate conclusions on the basis of a smaller panel.The paired randomisation procedure was centralized and performed by means of a computer-generated list stratified on the degree of expertise in the field of meta-analysis by a statistician of the epidemiology department performing the trial.The investigators did not have access to this procedure. Participants were considered “experts” if they had been involved in the publication of a meta-analysis indexed in PubMed.The randomisation was implemented on the Web site by a computer scientist (LR). Participants could not foresee their assignment until the beginning of the intervention. They received a personal log-in account number by e-mail that directed them to an appropriate Web page depending on their randomisation group. Each pair of participants assessed one report of a randomised trial. A waiting list of participants who agreed to be randomised was compiled to replace withdrawals.Participants in both groups received an e-mail containing the CLEAR NPT checklist and the user's guide. For each item in the CLEAR NPT, the user's guide explained its meaning and how to score it. The checklist and user's guide are detailed in Texts The control group received only the user's guide and was asked to assess one report of a randomised trial using the CLEAR NPT, whereas the experimental group was directed to the ICLS and also assessed one report of a randomised trial after completing the training.Participants could not be blinded to their randomisation group because of obvious differences in terms of intervention.New England Journal of Medicine, the Journal of the American Medical Association, Lancet, Annals of Internal Medicine, BMJ, Annals of Surgery, British Journal of Surgery, Annals of Surgical Oncology, Archives of General Psychiatry, American Journal of Psychiatry, Journal of Clinical Psychiatry, Physical Therapy, Supportive Care in Cancer, and Archives of Physical Medicine and Rehabilitation.To evaluate the performance of participants in using CLEAR NPT, we selected a panel of RCTs by searching PubMed for all RCTs assessing NPTs published between 1 January 2005 and 31 March 2006, in the following journals: A total of 200 reports were identified. Among these, some reports were randomly selected to be evaluated. Half of these reports assessed a surgical procedure, and half assessed another NPT such as rehabilitation, psychotherapy, or devices. The selected articles are described in Three reviewers  independently assessed the selected reports. All discrepancies were discussed, and the user's guide was consulted to obtain a consensus for appropriate answers for each item of the CLEAR NPT. This consensus was considered as the criterion standard.At the end of the training program, participants had to assess one of the selected reports of an RCT using the CLEAR NPT and complete a qualitative assessment of the ICLS. The primary outcome was the rate of correct answers on the ten main items of each group for the final assessment compared to the criterion standard. Secondary outcomes were the rate of correct answers for each item and a qualitative assessment of the ICLS by the survey participants, completed after fulfilling the training program.A sample size of 38 pairs will have 85% statistical power to detect a difference in means of 10% , assuming a standard deviation of differences of 20%, using a paired Student's t-test with a 0.05 two-sided significance level.p-value ≤ 0.05 was considered statistically significant, and all tests were two-sided. Statistical analyses involved the use of SAS 9.1 .The mean rate of correct answers of participants to the criterion standard was compared by a paired Student's t-test. The “per item rate” of correct answers to the criterion standard was compared by use of a McNemar test for paired dichotomous data and with Yates correction when appropriate. A n = 3), not understanding the program (n = 1), not completing the survey after five reminders (n = 4), and not finishing the training (n = 1).A total of 78 participants completed the final assessment and were analysed.Between April and June 2006, 78 participants were recruitedBaseline characteristics are described in Results on the primary outcome results are reported in Regardless of the CLEAR NPT checklist item considered, the rate of correct answers did not differ between the two groups . OverallTo our knowledge this study is the first to develop and evaluate a computer learning system to improve the understanding of a checklist for assessing the quality of reporting of RCTs. Moher et al. reported an annotated bibliography of scales and checklists developed to assess quality . Only a Some factors can be offered to explain the lack of efficacy of the ICLS. First, most of the participants had been involved in the publication of at least one meta-analysis. Consequently, this population has some level of expertise in quality assessment and probably needs more specific training than naïve participants. Consequently, we should probably assess the impact of the ICLS on inexperienced participants to determine its effect on the performance of this population.Second, the ICLS trained participants similarly for each item of the checklist. However, our results highlighted that lack of reproducibility concerned only some items of the checklist. Items related to the allocation sequence generation, description of interventions, blinding of patients or healthcare providers, and follow-up schedule were well rated, with more than 80% correct answers. These items probably need little or no training for proper scoring. Consequently, the ICLS could be tailored and provide more training on various examples for items with low understanding.Third, some examples of RCTs used to question and train a reviewer when using the CLEAR NPT might not be adequate. In fact, some examples with a high rate of correct answers were probably less informative, whereas other examples with a low rate of correct answers were probably more valuable for educating reviewers.Finally, because participants were not blinded to the aim of the study, we cannot exclude the risk of bias with participants in the control group relying on the user's guide with more attention than they would do in usual practice.Although the ICLS had no significant impact on RCT reviewers' performance, most assessment tools do not have any instructions in how to use the quality assessment scale –12, wherThe reproducibility of the items specific to the CLEAR NPT could probably be improved upon with a modification of the wording of these items. The item “Was participants adherence assessed quantitatively?” could be clarified with the following wording “Was participants adherence reported quantitatively in the results section?”. Furthermore, the item on co-interventions, which requires that the description of the co-intervention be provided in the results section not only in the methods section, could be modified as follows: “Were all other treatments or care as described in the results section the same in each randomised group?”Our results show that the item “Was the treatment allocation concealed?” had fewer than 50% of correct answers. These results are probably linked to the lack of consistency of the definition of allocation concealment. Pildal et al.  recognizBlinding of the outcome assessors was also poorly rated. These results concerned mainly trials in which the main outcome was a patient-reported outcome but patients were not reported as blinded. Therefore, the outcome assessor  could not be considered as adequately blinded even if the authors mentioned the presence of a blinded data collector who questioned the patients.Only 60% of participants were in agreement with the criterion standard for the item related to intention-to-treat analysis. These results are probably linked to the poor reporting of this issue ,29. BaroThese results are consistent with other studies. Maher et al.  evaluateThe validity of the criterion standard used to assess raters' performance when using the CLEAR NPT could be a limitation. However, this standard was developed by three reviewers, two of whom were involved in the elaboration of the CLEAR NPT. They evaluated all 39 reports independently and according to the user's guide. They discussed all the discrepancies to come to a consensus.Another limitation is related to the rate of participation: 84% of reviewers approached did not participate. The time necessary to participate in this trial could likely explain these results. This may limit the generalisability of the results.Finally, the baseline distribution of reviewers was imbalanced, with more experienced meta-analysts randomised to the control group. The effect of this potential baseline imbalance could dilute the intervention effect.In conclusion, in this study, we attempted to improve the understanding of a quality checklist that evaluates reports of nonpharmacological trials, the CLEAR NPT, with an ICLS. Although this pedagogical tool did not improve participants' performance in using the checklist, our results highlight the lack of consistent understanding of some of the key weapons in the fight against bias. There is an urgent need for specific training to improve the understanding of such quality tools.CONSORT Checklist(48 KB DOC)Click here for additional data file.Trial Protocol(84 KB DOC)Click here for additional data file.Trial Protocol(28 KB DOC)Click here for additional data file.Figure S1(43 KB DOC)Click here for additional data file.Text S1(43 KB DOC)Click here for additional data file.Text S2(82 KB DOC)Click here for additional data file.Text S3(50 KB DOC)Click here for additional data file.Text S4(51 KB DOC)Click here for additional data file.Text S5(102 KB DOC)Click here for additional data file.


Genomic scale projects have compounded the need for rapid and reliable functional annotation methods. Traditional experimental approaches have become outpaced resulting in an ever-increasing proportion of missing annotations. Computational approaches, including those based on sequence, expression, interaction and tertiary structure, have the potential to impact the growing annotation deficit.Despite a recent increase in the number and variety of prediction methods, the computational annotation of protein function remains difficult. This stems from a combination of issues such as the inherent limitations of current tools and databases, the difficulty of assessing the predictive power of different methods and more fundamental problems related to the ambiguity of the definition of function itself.a-là CASP  keep revisiting the problems [it presents]". Function prediction is indeed a challenging endeavor that is further hampered by the lack of a standard assessment framework ,33. It wFor further information and updates on AFP meetings see: