HTA challenges for appraising rare disease interventions viewed through the lens of an institutional multidimensional value framework.

INTRODUCTION: Evaluating rare disease interventions poses challenges for HTA agencies, including uncertainties and ethical issues and tensions. INESSS has recently adopted a Statement of Principles and Ethical Foundations which proposes a multidimensional approach to value appraisal as well as five principles to frame the evaluation process. AREAS COVERED: Our aim was to identify and analyze HTA challenges for appraising interventions for rare diseases, using the Statement's approach to value appraisal as an analytical framework, and outline how the Statement's principles can help address these challenges. Challenges, covering a diversity of aspects, were identified by leveraging institutional experience in diverse domains of expertise and consolidated through narrative literature review. Challenges were categorized by value dimension (clinical, populational, economic, organizational, and sociocultural), which allowed to pinpoint how each challenge affects the ability to appraise the value of an intervention. Key ethical tensions across dimensions were also identified. Specific approaches to addressing these challenges - related to knowledge mobilization and integration, deliberation, and recommendation-making - were outlined on the basis of the principles promulgated in the Statement. EXPERT OPINION: A multidimensional approach can be fruitful for analyzing challenges for appraising the value of rare disease interventions and help guide approaches to tackle them.

Artificial Intelligence and Health Technology Assessment: Anticipating a New Level of Complexity.

Artificial intelligence (AI) is seen as a strategic lever to improve access, quality, and efficiency of care and services and to build learning and value-based health systems. Many studies have examined the technical performance of AI within an experimental context. These studies provide limited insights into the issues that its use in a real-world context of care and services raises. To help decision makers address these issues in a systemic and holistic manner, this viewpoint paper relies on the health technology assessment core model to contrast the expectations of the health sector toward the use of AI with the risks that should be mitigated for its responsible deployment. The analysis adopts the perspective of payers (ie, health system organizations and agencies) because of their central role in regulating, financing, and reimbursing novel technologies. This paper suggests that AI-based systems should be seen as a health system transformation lever, rather than a discrete set of technological devices. Their use could bring significant changes and impacts at several levels: technological, clinical, human and cognitive (patient and clinician), professional and organizational, economic, legal, and ethical. The assessment of AI's value proposition should thus go beyond technical performance and cost logic by performing a holistic analysis of its value in a real-world context of care and services. To guide AI development, generate knowledge, and draw lessons that can be translated into action, the right political, regulatory, organizational, clinical, and technological conditions for innovation should be created as a first step.

Utilisation de l'imagerie par résonance magnétique en présence de douleurs musculosquelettiques chez les personnes adultes du Québec: Indications justifiant le recours à l'IRM en présence de douleurs musculosquelettiques / Use of magnetic resonance imaging in the presence of musculoskeletal pain in adults in Quebec: Indications justifying the use of MRI in the presence of musculoskeletal pain

INTRODUCTION: La douleur d'origine musculosquelettique (DMS) est un problème de santé très commun qui englobe une vaste gamme d'affections touchant les os, les ligaments, les tendons, les muscles et les articulations. Ces douleurs parfois importantes peuvent restreindre le fonctionnement physique et porter significativement atteinte à la qualité de vie. Les causes des DMS sont multiples. L'imagerie médicale est souvent utilisée parmi les différents examens médicaux pour investiguer la cause de ces douleurs. L'imagerie par résonance magnétique (IRM) est indiquée et constitue l'instrument de choix dans plusieurs situations cliniques lors de DMS. On attribue à cet outil diagnostique de plus en plus d'indications cliniques validées par des données probantes. De plus, l'IRM remplace parfois des interventions plus effractives et plus coûteuses. Toutefois, au regard des constats découlant de diverses publications scientifiques, il existe actuellement une controverse quant à une possible surutilisation de l'IRM lors du diagnostic et du suivi des patients souffrant de DMS. La situation québécoise en la matière n'est pas connue. C'est dans ce contexte que le ministère de la Santé et des Services sociaux (MSSS) a mandaté l'Institut national d'excellence en santé et en services sociaux (INESSS) pour qu'il documente cette problématique et formule des recommandations afin d'optimiser l'utilisation de l'IRM dans les cas de DMS. Pour éclairer les décideurs et les cliniciens sur cette question, l'INESSS publie un avis en trois volets: i. Un portrait de l'utilisation globale de l'IRM, au Québec, et une analyse comparative avec les provinces canadiennes et autres pays ou territoires similaires; ii. Une synthèse des lignes directrices relatives aux demandes d'IRM lors de DMS; iii. Une revue des stratégies et outils pour favoriser une utilisation optimale de l'IRM. MÉTHODE: Chaque volet utilise une méthode qui lui est propre pour repérer et analyser les données probantes et contextuelles. Ces analyses et revues (systématiques ou narratives) sont réalisées selon les normes de pratique édictées. Les méthodologies respectives à chacun des volets sont décrites en détail dans les documents associés. Des représentants des parties prenantes (Comité de suivi) et des experts (Comité consultatif) ont accompagné l'INESSS à différentes étapes de la production scientifique. L'équipe de projet de l'INESSS, accompagnée par le Comité consultatif, a élaboré les recommandations qui ont été ensuite soumises pour avis au Comité de suivi. Puis, le rapport préliminaire des résultats a été envoyé en révision scientifique externe. RÉSULTATS: Pour identifier les recommandations basées sur les données probantes scientifiques, les chercheurs ont réalisé une revue des guides de « bon usage ¼ en imagerie. Les critères de sélection étaient les suivants : documents publiés entre 2010 et 2016; de production originale; qui reposent sur une analyse systématisée de la littérature; qui incluent dans le processus un groupe interdisciplinaire de professionnels; et qui formulent les recommandations lors de consensus formels d'experts ou lors de conférences de consensus. Cinq guides provenant respectivement des États-Unis, de la France, du Royaume-Uni, de l'Australie et du Canada ont servi d'assise à l'analyse comparative des recommandations. Afin de s'assurer que les recommandations étaient en adéquation avec la littérature la plus récente, l'INESSS a effectué une recherche exhaustive des revues systématiques et des guides de pratique clinique. Les chercheurs ont repéré 53 documents pertinents. Ils ont ciblé les indications cliniques propres à la lombalgie, à la cervicalgie, à la gonalgie et à la douleur à l'épaule qui conjointement, représentent près des trois quarts du volume des IRM réalisées dans le cadre des DMS. Globalement, les recommandations en rapport à l'IRM étaient somme toute homogènes. Il fait consensus que les indications cliniques relatives à une IRM se basent sur une évaluation clinique bien menée. Les anomalies à l'IRM sont très fréquentes chez les sujets asymptomatiques et toute attribution de causalité doit forcément être faite après corrélation avec les signes et les symptômes cliniques. Les recommandations élaborées dans le cadre de ces travaux sont le reflet de recommandations consensuelles provenant de guides internationaux. Les quelques discordances présentes ont été résolues à l'aide de la revue complémentaire de la littérature et de la consultation d'experts. Les recommandations cliniques détaillées se retrouvent dans le document associé au volet 2. Un total de 37 situations cliniques sont couvertes. CONCLUSION: Le portrait de l'utilisation de l'IRM pour les DMS, au Québec, confirme une utilisation en croissance de l'imagerie par résonance magnétique. La comparaison avec d'autres régions ou pays montre que l'utilisation québécoise n'est pas l'une des plus élevées et qu'il y a probablement place à un gain de productivité pour certaines des installations existantes. Par contre, aucune donnée ne peut servir à se prononcer sur la pertinence des examens. Les indications cliniques sont en grande majorité consensuelles entre les guides de bon usage internationaux. Les experts québécois sont en congruence avec celles-ci et des outils cliniques sont proposés. Des stratégies organisationnelles pour optimiser la pertinence de l'IRM, la plus prometteuse est l'ordonnance électronique, accompagnée du soutien à la décision clinique. Les équipes interdisciplinaires spécialisées en DMS constituent une piste d'intérêt dont l'évaluation est à approfondir. Les stratégies financières et de gouverne ont été mises en œuvre dans d'autres pays ou régions, mais leurs répercussions sont variables quant à l'efficience de l'IRM dans les DMS. Dans les stratégies auprès des professionnels, l'utilisation de l'audit-rétroaction n'a pas eu d'effet statistiquement significatif pour optimiser la pertinence de l'imagerie dans les DMS, mais les initiatives d'amélioration de la qualité qui y ont recours sont prometteuses. L'efficacité des stratégies auprès des patients est à surveiller dans la littérature et dans les expériences en cours au Québec. Puisque le contexte de mise en œuvre a une importance majeure dans l'efficacité des stratégies et des outils, il est suggéré de recourir à une approche graduelle qui comprend un suivi des résultats pour le Québec. Des indicateurs de suivi de la pertinence existent, mais la faisabilité d'en implanter dans la province dépend des systèmes d'information. De tels indicateurs devront être élaborés pour le Québec, de pair avec les outils cliniques informatisés. RECOMMANDATIONS: Plusieurs pistes d'optimisation de la pertinence de l'IRM, la force de leur preuve et leurs limites ont été soulevées dans le présent avis. L'opinion des experts du Comité consultatif et des parties prenantes du Comité de suivi sur les données disponibles et le contexte québécois a été prise en compte et permet à l'INESSS de recommander que: 1) le MSSS: -conçoive un formulaire standardisé de prescription de l'IRM (intégrant les indications pertinentes) relatif aux douleurs musculosquelettiques pour les médecins référents; -pilote et évalue des systèmes d'ordonnance électronique avec soutien à la décision clinique pour l'imagerie (les systèmes pilotés doivent idéalement permettre l'exploitation des données colligées); -explore l'évaluation de la pertinence et de la faisabilité d'implanter, au Québec, des équipes interdisciplinaires spécialisées en DMS dans un continuum de soins relatifs aux douleurs musculosquelettiques. 2) les CISSS / CIUSSS: -se dotent de moyens pour soutenir des activités d'amélioration de la qualité avec audit-rétroaction aux milieux cliniques sur la pertinence de l'IRM dans les cas de DMS. 3) les fédérations médicales (FMOQ, FMSQ) et les programmes universitaires: -mettent sur pied des activités novatrices et des outils de formation et de maintien des compétences en douleurs musculosquelettiques dans un contexte de pertinence des interventions.(AU)

INTRODUCTION: Musculoskeletal pain (MSP) is a very common health problem that encompasses a vast array of conditions that affect the bones, ligaments, tendons, muscles and joints. It is sometimes severe and can limit physical functioning and significantly impair quality of life. There are many causes of MSP. Medical imaging is one of the different medical examinations for investigating the cause of such pain, and it is often used for this purpose. Magnetic resonance imaging (MRI) is indicated and is the instrument of choice in several clinical situations involving MSP. This diagnostic tool is being granted an increasing number of evidence-based clinical indications. Furthermore, MRI is sometimes used in place of more invasive and more expensive procedures. However, based on observations from various scientific publications, there is currently some debate over the possible overuse of MRI in the diagnosis and follow-up of patients with MSP. The situation in Québec in this regard is not known. It was in this context that the Ministère de la Santé et des Services sociaux (MSSS) asked the Institut national d'excellence en santé et en services sociaux (INESSS) to document this problem and to make recommendations for optimizing the use of MRI in cases of MSP. To enlighten decision-makers and clinicians about this matter, INESSS is publishing an evaluation in three parts: i. A description of the overall use of MRI in and a comparative analysis with the Canadian provinces and other, similar territories or countries; ii. A summary of the guidelines for ordering an MRI for MSP; iii. A review of the strategies and tools to promote the optimal use of MRI. METHOD: Each part uses its own methodology to identify and analyze the evidence and contextual data. These analyses and reviews (systematic and narrative) were carried out in accordance with the prescribed standards of practice. The respective methodologies for the different parts are described in detail in the related documents. Stakeholder representatives (Monitoring Committee) and experts (Advisory Committee) supported INESSS at different stages of its scientific production. Supported by the Advisory Committee, INESSS's project team developed recommendations, which were then submitted to the Monitoring Committee for its opinion. Subsequently, the preliminary report was sent for external scientific review. RESULTS: A review of systematic reviews and health technology assessment (HTA) reports was conducted to identify effective tools and strategies to promote appropriate imaging. The information was supplemented by a brief review of the grey literature from comparable jurisdictions to identify initiatives of interest. Among the organizational strategies evaluated, computerized physician order entry (CPOE) shows a moderate level of evidence in the imaging literature. It can be effective in influencing. the appropriateness and volume of imaging orders, especially when certain implementation conditions are present: CPOE in an integrated-care system, CPOE with integrated clinical decision support, and audit and feedback in the implementation of these tools. Clinical decision support tools, such as appropriateness criteria reminders on a standardized order form, are promising. The implementation strategy depends, among other things, on the clinical setting (hospital or ambulatory) and its level of computerization. Another organizational strategy identified is the creation of interdisciplinary MSP teams to support primary care physicians. Their role is to triage cases requiring a consultation or specialized examinations, to quickly perform a clinical evaluation of the patient's musculoskeletal system, to facilitate access to effective treatments, and to improve efficiency (including access to advanced imaging). The United Kingdom has built on these teams in its health -care system. They include health professionals with advanced training in MSP (physiotherapists, occupational therapists, primary care physicians with an interest in MSP, and others). These teams have been presented in the literature as a promising avenue for accessing timely and appropriate care and, indirectly, for appropriate imaging, and this strategy should be explored in greater depth. Financial and governance strategies are mainly illustrated by initiatives in Australia, Ontario and the United States. Financial strategies in the United States and Ontario have been implemented to limit coverage for certain examinations or the fees paid for them. Ontario uses a multifaceted intervention for low back pain that combines the aspect of differentiated remuneration, training for professionals and access to interdisciplinary teams. The impact of this project is being assessed. In the United States, the legal framework and the accreditation of imaging clinics are used to guide referral practice ethics. The objective of the Australian initiative in the area of governance was three-fold: an increase in private imaging resources accredited for coverage by the public plan, a reevaluation of fees to prevent an incentive effect, and more stringent requirements with regard to examination appropriateness and to quality and safety criteria. During the midpoint evaluation, the initiatives aimed at improving imaging order appropriateness proved more difficult to implement than expected and had not yielded the desired efficiency gains, while at the same time, there had been a large increase in the number of examinations due to the opening up of coverage in private-sector imaging. Implementation strategies aimed at health professionals, such as audit and feedback and educational materials as isolated interventions, have not been shown to be statistically effective in the case of imaging, but they could have a clinically significant impact in multifaceted interventions. Medical education initiatives aimed at equipping physicians to field patient requests have not been found to have an impact on imaging utilization, but initiatives for training physicians to view differently the role of imaging in evaluating a patient are underway and should be followed. In the studies consulted, implementation strategies aimed at patients (media campaign) have not been shown to have a meaningful effect on behaviours in the medium term. Strategies aimed at better informing patients and including them in the approach to ensure appropriateness should be explored. In the diagnostic area of interest here, the literature supports the implementation of tailored strategies in health-care facilities, and there are several promising avenues: reminders, CPOE and interdisciplinary MSP teams. CONCLUSION: The overview of the use of MRI in MSP in Québec confirms that its use is growing. A comparison with other jurisdictions shows that this use is not one of the highest and that there is probably room for increased productivity at certain existing facilities. However, there are no data for commenting on the appropriateness of these examinations. For the vast majority of the clinical indications, there is a consensus among the international appropriate use guidelines. Experts in Québec are in agreement with these indications, and clinical tools have been proposed. Of the organizational strategies for optimizing MRI appropriateness, the most promising one is CPOE with clinical decision support. Interdisciplinary MSP teams are an avenue of interest that warrants further evaluation. Financial and governance strategies have been put in place in other jurisdictions, but their impact on the efficiency of MRI in MSP varies. In implementation strategies targeting health professionals, the use of audit and feedback has not had a statistically significant impact on optimizing imaging appropriateness in MSP, but quality improvement initiatives that use audit and feedback are promising. The effectiveness of implementation strategies targeting patients should be monitored in the literature and in the ongoing initiatives in Québec. Since the implementation context is of great importance for the effectiveness of strategies and tools, a gradual implementation approach with results monitoring is recommended for the strategies proposed for Québec. Indicators for monitoring appropriateness do exist, but the feasibility of implementing them in Québec depends on the information systems. These indicators should be developed for Québec, together with CPOE. RECOMMENDATIONS: Several ways to optimize MRI appropriateness were raised during the discussion. In light of the available data and the Québec context, INESSS recommends: 1) That the MSSS: -Create a standardized MRI order form (with the relevant indications) for musculoskeletal pain for referring physicians; -Pilot and evaluate CPOE with clinical decision support for imaging (ideally, these systems should permit the use of collected data); -Explore the assessment of the appropriateness and feasibility of setting up interdisciplinary MSP teams in a continuum of MSP care. 2) That CISSSs and CIUSSSs: -Institute the means to support quality improvement activities with audit and feedback in their clinical facilities on the appropriateness of MRI in MSP. 3) That the medical federations (the FMOQ and FMSQ) and university programs: -Set up innovative activities and training and maintenance-of-compet ence tools for musculoskeletal pain in a context of intervention appropriateness.(AU)

Utilisation de l'imagerie par résonance magnétique en présence de douleurs musculosquelettiques chez les personnes adultes du Québec: Stratégies et outils favorisant une utilisation optimale de l'IRM / Use of magnetic resonance imaging in the presence of musculoskeletal pain in adults in Quebec: Strategies and tools for optimal use of MRI

INTRODUCTION: La douleur d'origine musculosquelettique (DMS) est un problème de santé très commun qui englobe une vaste gamme d'affections touchant les os, les ligaments, les tendons, les muscles et les articulations. Ces douleurs parfois importantes peuvent restreindre le fonctionnement physique et porter significativement atteinte à la qualité de vie. Les causes des DMS sont multiples. L'imagerie médicale est souvent utilisée parmi les différents examens médicaux pour investiguer la cause de ces douleurs. L'imagerie par résonance magnétique (IRM) est indiquée et constitue l'instrument de choix dans plusieurs situations cliniques lors de DMS. On attribue à cet outil diagnostique de plus en plus d'indications cliniques validées par des données probantes. De plus, l'IRM remplace parfois des interventions plus effractives et plus coûteuses. Toutefois, au regard des constats découlant de diverses publications scientifiques, il existe actuellement une controverse quant à une possible surutilisation de l'IRM lors du diagnostic et du suivi des patients souffrant de DMS. La situation québécoise en

INTRODUCTION: La douleur d'origine musculosquelettique (DMS) est un problème de santé très commun qui englobe une vaste gamme d'affections touchant les os, les ligaments, les tendons, les muscles et les articulations. Ces douleurs parfois importantes peuvent restreindre le fonctionnement physique et porter significativement atteinte à la qualité de vie. Les causes des DMS sont multiples. L'imagerie médicale est souvent utilisée parmi les différents examens médicaux pour investiguer la cause de ces douleurs. L'imagerie par résonance magnétique (IRM) est indiquée et constitue l'instrument de choix dans plusieurs situations cliniques lors de DMS. On attribue à cet outil diagnostique de plus en plus d'indications cliniques validées par des données probantes. De plus, l'IRM remplace parfois des interventions plus effractives et plus coûteuses. Toutefois, au regard des constats découlant de diverses publications scientifiques, il existe actuellement une controverse quant à une possible surutilisation de l'IRM lors du diagnostic et du suivi des patients souffrant de DMS. La situation québécoise en la matière n'est pas connue. C'est dans ce contexte que le ministère de la Santé et des Services sociaux (MSSS) a mandaté l'Institut national d'excellence en santé et en services sociaux (INESSS) pour qu'il documente cette problématique et formule des recommandations afin d'optimiser l'utilisation de l'IRM dans les cas de DMS. Pour éclairer les décideurs et les cliniciens sur cette question, l'INESSS publie un avis en trois volets: i. Un portrait de l'utilisation globale de l'IRM, au Québec, et une analyse comparative avec les provinces canadiennes et autres pays ou territoires similaires; ii. Une synthèse des lignes directrices relatives aux demandes d'IRM lors de DMS; iii. Une revue des stratégies et outils pour favoriser une utilisation optimale de l'IRM. MÉTHODE: Chaque volet utilise une méthode qui lui est propre pour repérer et analyser les données probantes et contextuelles. Ces analyses et revues (systématiques ou narratives) sont réalisées selon les normes de pratique édictées. Les méthodologies respectives à chacun des volets sont décrites en détail dans les documents associés. Des représentants des parties prenantes (Comité de suivi) et des experts (Comité consultatif) ont accompagné l'INESSS à différentes étapes de la production scientifique. L'équipe de projet de l'INESSS, accompagnée par le Comité consultatif, a élaboré les recommandations qui ont été ensuite soumises pour avis au Comité de suivi. Puis, le rapport préliminaire des résultats a été envoyé en révision scientifique externe. RESULTS: A review of systematic reviews and health technology assessment (HTA) reports was conducted to identify effective tools and strategies to promote appropriate imaging. The information was supplemented by a brief review of the grey literature from comparable jurisdictions to identify initiatives of interest. Among the organizational strategies evaluated, computerized physician order entry (CPOE) shows a moderate level of evidence in the imaging literature. It can be effective in influencing the appropriateness and volume of imaging orders, especially when certain implementation conditions are present: CPOE in an integrated-care system, CPOE with integrated clinical decision support, and audit and feedback in the implementation of these tools. Clinical decision support tools, such as appropriateness criteria reminders on a standardized order form, are promising. The implementation strategy depends, among other things, on the clinical setting (hospital or ambulatory) and its level of computerization. Another organizational strategy identified is the creation of interdisciplinary MSP teams to support primary care physicians. Their role is to triage cases requiring a consultation or specialized examinations, to quickly perform a clinical evaluation of the patient's musculoskeletal system, to facilitate access to effective treatments, and to improve efficiency (including access to advanced imaging). The United Kingdom has built on these teams in its health -care system. They include health professionals with advanced training in MSP (physiotherapists, occupational therapists, primary care physicians with an interest in MSP, and others). These teams have been presented in the literature as a promising avenue for accessing timely and appropriate care and, indirectly, for appropriate imaging, and this strategy should be explored in greater depth. Financial and governance strategies are mainly illustrated by initiatives in Australia, Ontario and the United States. Financial strategies in the United States and Ontario have been implemented to limit coverage for certain examinations or the fees paid for them. Ontario uses a multifaceted intervention for low back pain that combines the aspect of differentiated remuneration, training for professionals and access to interdisciplinary teams. The impact of this project is being assessed. In the United States, the legal framework and the accreditation of imaging clinics are used to guide referral practice ethics. The objective of the Australian initiative in the area of governance was three-fold: an increase in private imaging resources accredited for coverage by the public plan, a reevaluation of fees to prevent an incentive effect, and more stringent requirements with regard to examination appropriateness and to quality and safety criteria. During the midpoint evaluation, the initiatives aimed at improving imaging order appropriateness proved more difficult to implement than expected and had not yielded the desired efficiency gains, while at the same time, there had been a large increase in the number of examinations due to the opening up of coverage in private-sector imaging. Implementation strategies aimed at health professionals, such as audit and feedback and educational materials as isolated interventions, have not been shown to be statistically effective in the case of imaging, but they could have a clinically significant impact in multifaceted interventions. Medical education initiatives aimed at equipping physicians to field patient requests have not been found to have an impact on imaging utilization, but initiatives for training physicians to view differently the role of imaging in evaluating a patient are underway and should be followed. In the studies consulted, implementation strategies aimed at patients (media campaign) have not been shown to have a meaningful effect on behaviours in the medium term. Strategies aimed at better informing patients and including them in the approach to ensure appropriateness should be explored. In the diagnostic area of interest here, the literature supports the implementation of tailored strategies in health-care facilities, and there are several promising avenues: reminders, CPOE and interdisciplinary MSP teams. CONCLUSION: The overview of the use of MRI in MSP in Québec confirms that its use is growing. A comparison with other jurisdictions shows that this use is not one of the highest and that there is probably room for increased productivity at certain existing facilities. However, there are no data for commenting on the appropriateness of these examinations. For the vast majority of the clinical indications, there is a consensus among the international appropriate use guidelines. Experts in Québec are in agreement with these indications, and clinical tools have been proposed. Of the organizational strategies for optimizing MRI appropriateness, the most promising one is CPOE with clinical decision support. Interdisciplinary MSP teams are an avenue of interest that warrants further evaluation. Financial and governance strategies have been put in place in other jurisdictions, but their impact on the efficiency of MRI in MSP varies. In implementation strategies targeting health professionals, the use of audit and feedback has not had a statistically significant impact on optimizing imaging appropriateness in MSP, but quality improvement initiatives that use audit and feedback are promising. The effectiveness of implementation strategies targeting patients should be monitored in the literature and in the ongoing initiatives in Québec. Since the implementation context is of great importance for the effectiveness of strategies and tools, a gradual implementation approach with results monitoring is recommended for the strategies proposed for Québec. Indicators for monitoring appropriateness do exist, but the feasibility of implementing them in Québec depends on the information systems. These indicators should be developed for Québec, together with CPOE. RECOMMENDATIONS: Several ways to optimize MRI appropriateness were raised during the discussion. In light of the available data and the Québec context, INESSS recommends: -That the MSSS: -Create a standardized MRI order form (with the relevant indications) for musculoskeletal pain for referring physicians; -Pilot and evaluate CPOE with clinical decision support for imaging (ideally, these systems should permit the use of collected data); -Explore the assessment of the appropriateness and feasibility of setting up interdisciplinary MSP teams in a continuum of MSP care. 1) That CISSSs and CIUSSSs: -Institute the means to support quality improvement activities with audit and feedback in their clinical facilities on the appropriateness of MRI in MSP. 2) That the medical federations (the FMOQ and FMSQ) and university programs: -Set up innovative activities and training and maintenance-of-compet ence tools for musculoskeletal pain in a context of intervention appropriateness.(AU)

Utilisation de l'imagerie par résonance magnétique en présence de douleurs musculosquelettiques chez les personnes adultes du Québec: Portrait de l'utilisation de l'IRM dans le réseau public québécois / Use of magnetic resonance imaging in the presence of musculoskeletal pain in adults in Quebec: A portrait of the use of MRI in the Québec public network

INTRODUCTION: La douleur d'origine musculosquelettique (DMS) est un problème de santé très commun qui englobe une vaste gamme d'affections touchant les os, les ligaments, les tendons, les muscles et les articulations. Ces douleurs parfois importantes peuvent restreindre le fonctionnement physique et porter significativement atteinte à la qualité de vie. Les causes des DMS sont multiples. L'imagerie médicale est souvent utilisée parmi les différents examens médicaux pour investiguer la cause de ces douleurs. L'imagerie par résonance magnétique (IRM) est indiquée et constitue l'instrument de choix dans plusieurs situations cliniques lors de DMS. On attribue à cet outil diagnostique de plus en plus d'indications cliniques validées par des données probantes. De plus, l'IRM remplace parfois des interventions plus effractives et plus coûteuses. Toutefois, au regard des constats découlant de diverses publications scientifiques, il existe actuellement une controverse quant à une possible surutilisation de l'IRM lors du diagnostic et du suivi des patients souffrant de DMS. La situation québécoise en la matière n'est pas connue. C'est dans ce contexte que le ministère de la Santé et des Services sociaux (MSSS) a mandaté l'Institut national d'excellence en santé et en services sociaux (INESSS) pour qu'il documente cette problématique et formule des recommandations afin d'optimiser l'utilisation de l'IRM dans les cas de DMS. Pour éclairer les décideurs et les cliniciens sur cette question, l'INESSS publie un avis en trois volets: i. Un portrait de l'utilisation globale de l'IRM, au Québec, et une analyse comparative avec les provinces canadiennes et autres pays ou territoires similaires; ii. Une synthèse des lignes directrices relatives aux demandes d'IRM lors de DMS; iii. Une revue des stratégies et outils pour favoriser une utilisation optimale de l'IRM. MÉTHODE: Chaque volet utilise une méthode qui lui est propre pour repérer et analyser les données probantes et contextuelles. Ces analyses et revues (systématiques ou narratives) sont réalisées selon les normes de pratique édictées. Les méthodologies respectives à chacun des volets sont décrites en détail dans les documents associés. Des représentants des parties prenantes (Comité de suivi) et des experts (Comité consultatif) ont accompagné l'INESSS à différentes étapes de la production scientifique. L'équipe de projet de l'INESSS, accompagnée par le Comité consultatif, a élaboré les recommandations qui ont été ensuite soumises pour avis au Comité de suivi. Puis, le rapport préliminaire des résultats a été envoyé en révision scientifique externe. RÉSULTATS: Les informations recueillies reposent en grande partie sur l'analyse de données clinico-administratives, notamment celles colligées dans les banques de données de la Régie de l'assurance maladie du Québec (RAMQ), de l'Institut canadien d'information sur la santé (ICIS) et de l'Organisation de coopération et de développement économiques (OCDE). Une recherche non systématisée de la littérature scientifique et grise a complété l'information. Plusieurs paramètres ont été analysés tels que le nombre d'examens réalisés, la croissance de la demande, le champ de pratique des médecins référents, les caractéristiques des usagers, le nombre d'appareils, l'utilisation des appareils, les ressources humaines et les temps d'attente. Les constats clés sont les suivants: -Le nombre d'examens d'IRM réalisés au Québec a virtuellement triplé au cours de la dernière décennie; -Les douleurs musculosquelettiques sont à l'origine d'une proportion importante des examens d'IRM réalisés au Québec. Près de la moitié des examens ciblent le rachis ou les extrémités; -On observe une variation régionale, au Québec, dans le recours à l'IRM, selon la région sociosanitaire de résidence des usagers. Les multiples facteurs confondants ne permettent toutefois pas de cibler une cause précise. La population, les conditions d'accès, les facteurs socio-économiques, de même que des différences dans l'organisation des services et la pratique sont autant de facteurs pouvant influer sur l'utilisation; -La comparaison du taux d'examens d'IRM par habitant, au Québec, montre que le taux de la province est légèrement inférieur à la moyenne canadienne. Il est plus de deux fois plus faible que celui d'autres pays tels que les États-Unis, le Japon, l'Allemagne et la France. La littérature ne documente pas de taux optimal; -Les données suggèrent qu'il est probable que l'efficience dans l'utilisation des appareils d'IRM puisse être améliorée dans certains établissements, au Québec; -Les données disponibles ne permettent pas de déterminer la proportion d'examens d'IRM non pertinents réalisés au Québec. CONCLUSION: Le portrait de l'utilisation de l'IRM pour les DMS, au Québec, confirme une utilisation en croissance de l'imagerie par résonance magnétique. La comparaison avec d'autres régions ou pays montre que l'utilisation québécoise n'est pas l'une des plus élevées et qu'il y a probablement place à un gain de productivité pour certaines des installations existantes. Par contre, aucune donnée ne peut servir à se prononcer sur la pertinence des examens. Les indications cliniques sont en grande majorité consensuelles entre les guides de bon usage internationaux. Les experts québécois sont en congruence avec celles-ci et des outils cliniques sont proposés. Des stratégies organisationnelles pour optimiser la pertinence de l'IRM, la plus prometteuse est l'ordonnance électronique, accompagnée du soutien à la décision clinique. Les équipes interdisciplinaires spécialisées en DMS constituent une piste d'intérêt dont l'évaluation est à approfondir. Les stratégies financières et de gouverne ont été mises en œuvre dans d'autres pays ou régions, mais leurs répercussions sont variables quant à l'efficience de l'IRM dans les DMS. Dans les stratégies auprès des professionnels, l'utilisation de l'audit-rétroaction n'a pas eu d'effet statistiquement significatif pour optimiser la pertinence de l'imagerie dans les DMS, mais les initiatives d'amélioration de la qualité qui y ont recours sont prometteuses. L'efficacité des stratégies auprès des patients est à surveiller dans la littérature et dans les expériences en cours au Québec. Puisque le contexte de mise en œuvre a une importance majeure dans l'efficacité des stratégies et des outils, il est suggéré de recourir à une approche graduelle qui comprend un suivi des résultats pour le Québec. Des indicateurs de suivi de la pertinence existent, mais la faisabilité d'en implanter dans la province dépend des systèmes d'information. De tels indicateurs devront être élaborés pour le Québec, de pair avec les outils cliniques informatisés. RECOMMANDATIONS: Plusieurs pistes d'optimisation de la pertinence de l'IRM, la force de leur preuve et leurs limites ont été soulevées dans le présent avis. L'opinion des experts du Comité consultatif et des parties prenantes du Comité de suivi sur les données disponibles et le contexte québécois a été prise en compte et permet à l'INESSS de recommander que: 1) le MSSS: -conçoive un formulaire standardisé de prescription de l'IRM (intégrant les indications pertinentes) relatif aux douleurs musculosquelettiques pour les médecins référents; -pilote et évalue des systèmes d'ordonnance électronique avec soutien à la décision clinique pour l'imagerie (les systèmes pilotés doivent idéalement permettre l'exploitation des données colligées); -explore l'évaluation de la pertinence et de la faisabilité d'implanter, au Québec, des équipes interdisciplinaires spécialisées en DMS dans un continuum de soins relatifs aux douleurs musculosquelettiques. 2) les CISSS / CIUSSS: -se dotent de moyens pour soutenir des activités d'amélioration de la qualité avec audit-rétroaction aux milieux cliniques sur la pertinence de l'IRM dans les cas de DMS. 3) les fédérations médicales (FMOQ, FMSQ) et les programmes universitaires: -mettent sur pied des activités novatrices et des outils de formation et de maintien des compétences en douleurs musculosquelettiques dans un contexte de pertinence des interventions.(AU)

INTRODUCTION: Musculoskeletal pain (MSP) is a very common health problem that encompasses a vast array of conditions that affect the bones, ligaments, tendons, muscles and joints. It is sometimes severe and can limit physical functioning and significantly impair quality of life. There are many causes of MSP. Medical imaging is one of the different medical examinations for investigating the cause of such pain, and it is often used for this purpose. Magnetic resonance imaging (MRI) is indicated and is the instrument of choice in several clinical situations involving MSP. This diagnostic tool is being granted an increasing number of evidence-based clinical indications. Furthermore, MRI is sometimes used in place of more invasive and more expensive procedures. However, based on observations from various scientific publications, there is currently some debate over the possible overuse of MRI in the diagnosis and follow-up of patients with MSP. The situation in Québec in this regard is not known. It was in this context that the Ministère de la Santé et des Services sociaux (MSSS) asked the Institut national d'excellence en santé et en services sociaux (INESSS) to document this problem and to make recommendations for optimizing the use of MRI in cases of MSP. To enlighten decision-makers and clinicians about this matter, INESSS is publishing an evaluation in three parts: i. A description of the overall use of MRI in and a comparative analysis with the Canadian provinces and other, similar territories or countries; ii. A summary of the guidelines for ordering an MRI for MSP; iii. A review of the strategies and tools to promote the optimal use of MRI. METHOD: Each part uses its own methodology to identify and analyze the evidence and contextual data. These analyses and reviews (systematic and narrative) were carried out in accordance with the prescribed standards of practice. The respective methodologies for the different parts are described in detail in the related documents. Stakeholder representatives (Monitoring Committee) and experts (Advisory Committee) supported INESSS at different stages of its scientific production. Supported by the Advisory Committee, INESSS's project team developed recommendations, which were then submitted to the Monitoring Committee for its opinion. Subsequently, the preliminary report was sent for external scientific review. RESULTS: The information gathered is largely based on an analysis of clinical/administrative data, notably, those compiled in the databases of the Régie de l'assurance maladie du Québec (RAMQ), the Canadian Institute for Health Information (CIHI) and the Organization for Economic Cooperation and Development (OECD). These data were supplemented by a nonsystematic search of the scientific and grey literature. Several parameters were analyzed, such as the number of examinations performed, the increase in the demand, referring physician specialty, user characteristics, the number of MRI units and their use, human resources and wait times. The key observations are as follows: -The number of MRI examinations performed in Québec has essentially tripled in the past decade; - Musculoskeletal pain accounts for a large proportion of the MRI examinations performed in Québec. Nearly half of them target the spine or the extremities; - The use of MRI in Québec differs according to the users' health and social services region of residence. However, because of the multiple confounding factors, the exact cause cannot be identified. The population, the conditions for access, socioeconomic factors, and differences in service and practice organization are all factors that can influence use; -The comparison of the MRI examination rate per capita in Québec shows that the provincial rate is slightly lower than the Canadian average. It is more than two times lower than that of other countries, such as the United States, Japan, Germany and France. The literature does not mention an optimal rate; -The data suggest that the efficiency of the use of MRI units could probably be improved at certain Québec facilities; -The proportion of inappropriate MRI examinations performed in Québec cannot be determined from the available data. CONCLUSION: The overview of the use of MRI in MSP in Québec confirms that its use is growing. A comparison with other jurisdictions shows that this use is not one of the highest and that there is probably room for increased productivity at certain existing facilities. However, there are no data for commenting on the appropriateness of these examinations. For the vast majority of the clinical indications, there is a consensus among the international appropriate use guidelines. Experts in Québec are in agreement with these indications, and clinical tools have been proposed. Of the organizational strategies for optimizing MRI appropriateness, the most promising one is CPOE with clinical decision support. Interdisciplinary MSP teams are an avenue of interest that warrants further evaluation. Financial and governance strategies have been put in place in other jurisdictions, but their impact on the efficiency of MRI in MSP varies. In implementation strategies targeting health professionals, the use of audit and feedback has not had a statistically significant impact on optimizing imaging appropriateness in MSP, but quality improvement initiatives that use audit and feedback are promising. The effectiveness of implementation strategies targeting patients should be monitored in the literature and in the ongoing initiatives in Québec. Since the implementation context is of great importance for the effectiveness of strategies and tools, a gradual implementation approach with results monitoring is recommended for the strategies proposed for Québec. Indicators for monitoring appropriateness do exist, but the feasibility of implementing them in Québec depends on the information systems. These indicators should be developed for Québec, together with CPOE. RECOMMENDATIONS: Several ways to optimize MRI appropriateness were raised during the discussion. In light of the available data and the Québec context, INESSS recommends: 1) That the MSSS: -Create a standardized MRI order form (with the relevant indications) for musculoskeletal pain for referring physicians; -Pilot and evaluate CPOE with clinical decision support for imaging (ideally, these systems should permit the use of collected data); -Explore the assessment of the appropriateness and feasibility of setting up interdisciplinary MSP teams in a continuum of MSP care. 2) That CISSSs and CIUSSSs: -Institute the means to support quality improvement activities with audit and feedback in their clinical facilities on the appropriateness of MRI in MSP. 3) That the medical federations (the FMOQ and FMSQ) and university programs: -Set up innovative activities and training and maintenance-of-competence tools for musculoskeletal pain in a context of intervention appropriateness.

Socially mediated polyandry: a new benefit of communal nesting in mammals.

In many species, females have evolved behavioral strategies to reduce the risk of infanticide. For instance, polyandry can create paternity confusion that inhibits males from killing offspring they could have sired. Here, the authors propose that females could socially obtain the same benefits by nesting communally. Singly sired litters could be perceived as a large multiply sired litter once pooled together in a single nest. Long-term data from a wild house mouse population showed that monandrous litters (singly sired) were more common in communal than in solitary nests and 85% of them were raised with litters sired by different males hence becoming effectively polyandrous (multiply sired). These socially polyandrous litters had significantly higher offspring survival than genetically or socially monandrous litters and reached a similar survival to that of multiply sired litters raised in solitary or communal nests. Furthermore, the number of sires within nests significantly improved offspring survival whereas the number of mothers did not. These results suggest that the survival benefits associated with communal nesting are driven by polyandry and not communal defense. This socially mediated polyandry was as efficient as multiple paternity in preventing infanticide, and may also occur in other infanticidal and polytocous species where the caring parent exhibits social behavior.

A selfish genetic element influencing longevity correlates with reactive behavioural traits in female house mice (Mus domesticus).

According to theory in life-history and animal personality, individuals with high fitness expectations should be risk-averse, while individuals with low fitness expectations should be more bold. In female house mice, a selfish genetic element, the t haplotype, is associated with increased longevity under natural conditions, representing an appropriate case study to investigate this recent theory empirically. Following theory, females heterozygous for the t haplotype (+/t) are hypothesised to express more reactive personality traits and be more shy, less explorative and less active compared to the shorter-lived homozygous wildtype females (+/+). As males of different haplotype do not differ in survival, no similar pattern is expected. We tested these predictions by quantifying boldness, exploration, activity, and energetic intake in both +/t and +/+ mice. +/t females, unlike +/+ ones, expressed some reactive-like personality traits: +/t females were less active, less prone to form an exploratory routine and tended to ingest less food. Taken together these results suggest that differences in animal personality may contribute to the survival advantage observed in +/t females but fail to provide full empirical support for recent theory.

The role of arginine methylation in the DNA damage response.

Post-translational modifications are well-known modulators of DNA damage signaling and epigenetic gene expression. Protein arginine methylation is a covalent modification that results in the addition of methyl groups to the nitrogen atoms of the arginine side chains and is catalyzed by a family of protein arginine methyltransferases (PRMTs). In the past, arginine methylation was mainly observed on abundant proteins such as RNA-binding proteins and histones, but recent advances have revealed a plethora of arginine methylated proteins implicated in a variety of cellular processes including RNA metabolism, epigenetic regulation and DNA repair pathways. Herein, we discuss these recent advances, focusing on the role of PRMTs in DNA damage signaling and its importance for maintaining genomic stability.

Pairing context determines condition-dependence of song rate in a monogamous passerine bird.

Condition-dependence of male ornaments is thought to provide honest signals on which females can base their sexual choice for genetic quality. Recent studies show that condition-dependence patterns can vary within populations. Although long-term association is thought to promote honest signalling, no study has explored the influence of pairing context on the condition-dependence of male ornaments. In this study, we assessed the influence of natural variation in body condition on song rate in zebra finches (Taeniopygia guttata) in three different situations: during short and long encounters with an unfamiliar female, and within heterosexual mated pairs. We found consistent individual differences in male directed and undirected song rate. Moreover, body condition had a positive effect on song rate in paired males. However, male song rate was not influenced by body condition during short or long encounters with unfamiliar females. Song rate appears to be an unreliable signal of condition to prospective females as even poor-condition birds can cheat and sing at a high rate. By contrast, paired females can reliably use song rate to assess their mate's body condition, and possibly the genetic quality. We propose that species' characteristics, such as mating system, should be systematically taken into account to generate relevant hypotheses about the evolution of condition-dependent male ornaments.

Handling stress does not reflect personality in female zebra finches (Taeniopygia guttata).

Although increasing attention is given to both the causes and consequences of variation in animal personality, the measurement of personality in captive or free-ranging individuals remains an issue. In particular, one important question concerns whether personality should be established from the existence of complex behavioral syndromes (a suite of correlated behavioral traits) or could be more easily deduced from a single variable. In that context, it has recently been suggested that handling stress, measured through breathing rate during handling, could be a good descriptor of personality, at least in passerine birds. The authors experimentally investigated to what extent handling stress was correlated with personality in female zebra finches (Taeniopygia guttata), as assessed from a suite of repeatable behavioral traits, including activity, exploratory behavior, neophobia, and reaction to startle. Although breathing rate was repeatable across individuals, it was not related to any behavioral trait, suggesting that it cannot be used to quickly predict personality, at least in zebra finches. Breathing rate during handling, in addition, was related to morphology, questioning the fact that breathing rate during handling reflects personality irrespective of individual state. The authors suggest that inference on global personality from a reduced number of traits should be performed with caution.

Requirement for functional DNA polymerase eta in genome-wide repair of UV-induced DNA damage during S phase.

The autosomal recessive disorder Xeroderma pigmentosum-variant (XPV) is characterized (i) at the cellular level by dramatic hypermutability and defective recovery of DNA synthesis following UV exposure, and (ii) clinically by abnormal sunlight sensitivity and remarkable predisposition to skin cancer. These phenotypes are clearly attributable to germline mutations in POLH, encoding DNA polymerase eta (poleta) normally required for accurate translesion DNA synthesis (TLS) past UV-induced cyclobutane pyrimidine dimers. Here we demonstrate that patient-derived XPV-skin fibroblasts exposed to 15J/m(2) of UV also exhibit (in addition to abnormal TLS) a significant defect in global-genomic nucleotide excision repair (GG-NER) exclusively during S phase. This cell cycle-specific GG-NER defect can be complemented by ectopic expression of wild-type poleta, but not of poleta variants deficient in either nuclear relocalization or PCNA interaction. We highlight a previous study from our laboratory demonstrating that UV-exposed, ATR-deficient Seckel syndrome fibroblasts, like XPV fibroblasts, manifest strong attenuation of GG-NER uniquely in S phase populations. We now present further evidence suggesting that deficient S phase repair can be rescued in both XPV- and Seckel syndrome-cells if the formation of blocked replication forks post-UV is either prevented or substantially reduced, i.e., following, respectively, pharmacological inhibition of DNA synthesis prior to UV irradiation, or exposure to a relatively low UV dose (5J/m(2)). Our findings in cultured cells permit speculation that abrogation of GG-NER during S phase might partially contribute (in a synergistic manner with defective, atypically error-prone TLS) to the extreme state of UV-hypermutability leading to accelerated skin cancer development in XPV patients. Moreover, based on the overall data, we postulate that loss of either functional poleta or -ATR engenders abnormal persistence of stalled replication forks at UV-adducted sites in DNA which, in turn, can actively and/or passively trigger GG-NER inhibition.

ATR kinase as master regulator of nucleotide excision repair during S phase of the cell cycle.

Nucleotide excision repair (NER) is a major determinant in cancer development and treatment via its essential role in eliminating highly-genotoxic, helix-distorting DNA adducts that block replication and transcription. Over the years, many elegant studies employing UV as model mutagen have led to a detailed understanding of how the NER pathway itself is coordinated. Nonetheless relatively little is known regarding any precise functions of various preeminent mutagen-responsive signaling cascades lying upstream of NER, notably those mediated by the canonical MAPKs or the PIKK family members ATR and ATM. Here we present a brief overview of NER, mostly in the context of studies on human cells treated with UV, and describe recent results from our laboratory which have significantly elucidated the role of UV-induced signal transduction in this repair pathway.

ATR kinase is required for global genomic nucleotide excision repair exclusively during S phase in human cells.

Global-genomic nucleotide excision repair (GG-NER) is the only pathway available to humans for removal, from the genome overall, of highly genotoxic helix-distorting DNA adducts generated by many environmental mutagens and certain chemotherapeutic agents, e.g., UV-induced 6-4 photoproducts (6-4PPs) and cyclobutane pyrimidine dimers (CPDs). The ataxia telangiectasia and rad-3-related kinase (ATR) is rapidly activated in response to UV-induced replication stress and proceeds to phosphorylate a plethora of downstream effectors that modulate primarily cell cycle checkpoints but also apoptosis and DNA repair. To investigate whether this critical kinase might participate in the regulation of GG-NER, we developed a novel flow cytometry-based DNA repair assay that allows precise evaluation of GG-NER kinetics as a function of cell cycle. Remarkably, inhibition of ATR signaling in primary human lung fibroblasts by treatment with caffeine, or with siRNA specifically targeting ATR, resulted in total inhibition of 6-4PP removal during S phase, whereas cells repaired normally during either G(0)/G(1) or G(2)/M. Similarly striking S-phase-specific defects in GG-NER of both 6-4PPs and CPDs were documented in ATR-deficient Seckel syndrome skin fibroblasts. Finally, among six diverse model human tumor strains investigated, three manifested complete abrogation of 6-4PP repair exclusively in S-phase populations. Our data reveal a highly novel role for ATR in the regulation of GG-NER uniquely during S phase of the cell cycle, and indicate that many human cancers may be characterized by a defect in this regulation.

A sensitive flow cytometry-based nucleotide excision repair assay unexpectedly reveals that mitogen-activated protein kinase signaling does not regulate the removal of UV-induced DNA damage in human cells.

In response to diverse genotoxic stimuli (e.g. UV and cisplatin), the mitogen-activated protein kinases ERK1/2, JNK1/2, and p38alpha/beta become rapidly phosphorylated and in turn activate multiple downstream effectors that modulate apoptosis and/or growth arrest. Furthermore, previous lines of evidence have strongly suggested that ERK1/2 and JNK1/2 participate in global-genomic nucleotide excision repair, a critical antineoplastic pathway that removes helix-distorting DNA adducts induced by a variety of mutagenic agents, including UV. To rigorously evaluate the potential role of mitogen-activated protein kinases in global-genomic nucleotide excision repair, various human cell strains (primary skin fibroblasts, primary lung fibroblasts, and HCT116 colon carcinoma cells) were treated with highly specific chemical inhibitors, which, following UV exposure, (i) abrogated the capacities of ERK1/2, JNK1/2, or p38alpha/beta to phosphorylate specific downstream effectors and (ii) characteristically modulated cellular proliferation, clonogenic survival, and/or apoptosis. A highly sensitive flow cytometry-based nucleotide excision repair assay recently optimized and validated in our laboratory was then employed to directly demonstrate that the kinetics of UV DNA photoadduct repair are highly similar in mock-treated versus mitogen-activated protein kinase inhibitor-treated cells. These data on primary and tumor cells treated with pharmacological inhibitors were fully corroborated by repair studies using (i) short hairpin RNA-mediated knockdown of ERK1/2 or JNK1/2 in human U2OS osteosarcoma cells and (ii) expression of a dominant negative p38alpha mutant in human primary lung fibroblasts. Our results provide solid evidence for the first time, in disaccord with a burgeoning perception, that mitogen-activated protein kinase signaling does not influence the efficiency of human global-genomic nucleotide excision repair.