Engaging student analysis of the practitioner-patient relationship assessed with reflective outcomes.

The representations and beliefs of both patient and practitioner influence the relationship that develops between them. We developed an innovative, interactive teaching tool in two stages (1- interviews with the patient or healthcare practitioner and 2- a session with sharing of the patient's and practitioner's perspective) whose objectives are to recognize the basic characteristics of PPR and identify how it can be influenced by expectations, beliefs and emotions. This pedagogical device was particularly appreciated by the students, as it enabled them to identify the importance of the patient's point of view and to reflect on their future professional identity.

Concordance of judgement: A tool to foster the development of professionalism in dentistry.

INTRODUCTION: Developing professionalism notably involves learning how to make professional judgements in ambiguous situations. The Concordance of Judgement Test (CJT) is a learning tool that was proposed to develop professionalism competencies, but it was never performed in dentistry or used with a synchronous methodology. The present study evaluated the feasibility of the use of CJT in the context of dental education, to foster professionalism and stimulate reflexivity and discussion. MATERIALS AND METHODS: After different steps of optimization, a questionnaire presenting 12 vignettes was submitted to 33 Canadian students. Second, after an additional optimization, a questionnaire of 7 vignettes was submitted to 87 French students. An immediate educational feedback was proposed after each vignette to promote reflexivity and discussions during the experience. RESULTS: The overall experience of the students was reported as good, thanks to the feedback of real-life situations. This promoted reflexivity and stimulated discussion between students and educators regarding professionalism issues. The students considered CJT as a relevant and well-adapted tool, and reported positive feelings regarding the inter-university aspect of the activity. The mean score of the panel members was close to 80/100 and the mean score of the students was 5 to 10 points lower, which is in agreement with docimological performance. CONCLUSION: The results suggested that the use of CJT in a synchronous way was a feasible and relevant tool to motivate the students to improve their professionalism, and to stimulate their reflexivity and discussion. The students reported positive experience with CJT, and we believe that this tool can be integrated in the dental curriculum.

Immune Checkpoint Inhibitor-induced Sicca Syndrome.

The development of sicca in patients treated with immune checkpoint inhibitors (ICIs) is undoubtedly an underestimated complication, but one whose functional consequences and impact on quality of life are significant for patients. This update aims to review the frequency of this complication and different clinical pictures. The authors also propose a diagnostic and therapeutic approach to guide clinicians in daily practice.

[Periodontitis : An underestimated risk of cardiovascular diseases]. / La parodontite : un risque sous-estimé des maladies cardiovasculaires.

Epidemiological studies have identified periodontitis as a contributing factor to cardiovascular risk. Periodontitis is a chronic inflammatory disease that affects the tissues supporting the teeth. Although the nature of the association between periodontitis and cardiovascular disease (CVD) remains to be defined, the low-grade systemic inflammation and chronic bacteremia associated with periodontitis appear to be involved in the development of atherosclerosis and associated cardiovascular pathologies. Periodontal treatment has been shown to improve cardiovascular health parameters. A bidirectional preventive approach, involving the management of both periodontitis and cardiovascular risk factors, could lead to a reduction in morbidity and mortality related to cardiovascular disease.

Title: La parodontite : un risque sous-estimé des maladies cardiovasculaires. Abstract: Les études épidémiologiques identifient la parodontite, maladie inflammatoire chronique des tissus de soutien des dents, comme un facteur contribuant au risque cardiovasculaire. Bien que la nature de l'association entre parodontite et maladies cardio-vasculaires (MCV) reste à définir (causalité ou corrélation), l'inflammation systémique de bas grade et les bactériémies chroniques qui sont associées aux parodontites apparaissent impliquées dans le développement de l'athérosclérose et des maladies cardio-vasculaires associées. Le traitement parodontal semble contribuer à l'amélioration des paramètres de la santé cardiovasculaire. Dès lors, une approche de prévention bidirectionnelle, impliquant à la fois la gestion de la parodontite et des facteurs de risque cardiovasculaire, pourrait permettre une réduction de la morbidité et de la mortalité liées aux MCV.

[Inflammatory diseases of the salivary]. / Pathologies inflammatoires des glandes salivaires.

INFLAMMATORY DISEASES OF THE SALIVARY GLANDS. Salivary glands can be affected by inflammatory pathologies. They are most often manifested by the occurrence of swelling of the main salivary glands that can be associated with a dryness. Main inflammatory diseases with salivary gland involvement are Sjögren's disease, IgG4-associated disease and sarcoidosis. These diseases are rare and characterized by systemic involvement. The existence of multiple organ involvement must lead to the diagnosis. The first step in the diagnostic process is to eliminate the much more frequent differential diagnoses, primarily lithiasis and infectious diseases, as well as nutritional causes. In case of suspicion, a biopsy of the minor salivary glands may help to advance the etiological investigation.

glandes salivaires peuvent être le siège de pathologies inflammatoires. Celles-ci se manifestent le plus souvent par la survenue du gonflement des glandes salivaires principales, parfois associé à un syndrome sec. Les principales pathologies inflammatoires avec atteinte des glandes salivaires sont le la maladie de Sjögren, la maladie associée aux IgG4 et la sarcoïdose. Ces maladies sont des pathologies rares avec atteintes systémiques ; l'existence d'atteintes d'organes multiples doit en faire évoquer le diagnostic. La démarche diagnostique élimine dans un premier temps les pathologies lithiasiques et infectieuses, plus fréquentes, ainsi que les causes nutritionnelles. En cas de suspicion, la réalisation d'une biopsie des glandes salivaires accessoires permet d'avancer dans l'enquête étiologique.

Managing the sexualization of the dentist-patient relationship by the patient: Innovative teaching through forum-theatre.

Dental students may be exposed to patients' sexual behavior. We developed a theater-forum session whose aims were to identify when the patient's behavior crosses the line, to collectively develop cover strategies, and to present the reporting system. The strategies pointed out by the group were to ask a pair to be present, set limits on personal life, share discomfort to the patient and report the situation to the staff. Theater-forum is a powerful tool for this learning process.

Management of dental care of patients on immunosuppressive drugs for chronic immune-related inflammatory diseases: a survey of French dentists' practices.

OBJECTIVES: The aim of the study was to provide an overview of the practices of French general dentists (GDs) and specialists (SDs) concerning the management of patients with inflammatory bowel diseases (IBDs), rheumatic inflammatory diseases (IRDs), and vasculitis on biologic disease-modifying antirheumatic drugs (bDMARDs), conventional DMARDs, or immunosuppressants (ISs). MATERIALS AND METHODS: An online national cross-sectional survey with 53 questions was developed by a multidisciplinary team including rheumatologists, gastroenterologists and dentists based on their clinical experience. It was refined following a test with nine dentists in private practice and in hospital before being disseminated to the members of French scientific societies and colleges of dentistry teachers over 3 months. Responses of general dentists versus specialists were compared with respect to their experience in managing patients with IRDs or IBDs, knowledge/training, type of invasive procedure performed, management of medical treatment, perioperative oral-care protocols, and frequency of postoperative complications after invasive dental care procedures. RESULT: In total, 105 practitioners fully completed the survey (participation rate 11.1%). SDs more frequently performed invasive surgical procedures and were more aware of the recommendations of learned societies than GDs. They encountered more post-operative complications for patients on bDMARDs. For both SDs and GDs, most patients were managed without stopping treatment and pre- and postoperative antibiotics were prescribed to more than 75% of patients. When medical treatment was stopped, the decision was made by the prescribing physician. CONCLUSION: Complications were reported more frequently by SDs when highly invasive procedures were performed on patients under active drug therapy. Certain common procedures, such as scaling and root planing, appear to be safe, regardless of treatment management. However, adapted guidelines for the practice of dentistry are needed to standardize the management of patients on bDMARDS, conventional DMARDs, or ISs. CLINICAL RELEVANCE: French dentists perform a wide range of oral procedures on patients on bDMARDS, conventional DMARDs, or ISs under antibiotic coverage and antiseptic mouthwashes. SDs reported more postoperative complications after extensive invasive procedures for patients under active drug therapy, despite their greater knowledge of recommendations on how to manage such patients.

NLRP3 Is Involved in Neutrophil Mobilization in Experimental Periodontitis.

The NLRP3 inflammasome is overexpressed in gingiva of periodontitis patients but its role remains unclear. In our study, we use a periodontitis mouse model of ligature, impregnated or not with Porphyromonas gingivalis, in WT or NLRP3 KO mice. After 28 days of induction, ligature alone provoked exacerbated periodontal destruction in KO mice, compared to WT mice, with an increase in activated osteoclasts. No difference was observed at 14 days, suggesting that NLRP3 is involved in regulatory pathways that limit periodontitis. In contrast, in the presence of P. gingivalis, this protective effect of NLRP3 was not observed. Overexpression of NLRP3 in connective tissue of WT mice increased the local production of mature IL-1ß, together with a dramatic mobilization of neutrophils, bipartitely distributed between the site of periodontitis induction and the alveolar bone crest. P. gingivalis enhanced the targeting of NLRP3-positive neutrophils to the alveolar bone crest, suggesting a role for this subpopulation in bone loss. Conversely, in NLRP3 KO mice, mature IL-1ß expression was lower and almost no neutrophils were mobilized. Our study sheds new light on the role of NLRP3 in periodontitis by highlighting the ambiguous role of neutrophils, and P. gingivalis which affects NLRP3 functions.

The influence of non-carious lesions in the surgical treatment of gingival recession: A systematic review & meta-analysis.

BACKGROUND: The presence of a non-carious cervical lesion (NCCL) is a complicating factor for tooth coverage following gingival recession. It is generally associated with disappearance of the enamel-cementum junction, a key landmark, and a surface discrepancy requiring restoration or compensation using a connective tissue graft (CTG). The aim of this systematic review is to study the efficacy of periodontal plastic surgery on recession defects associated with a NCCL, with or without restorative treatment. MATERIALS AND METHODS: RCT assessing the root coverage of teeth with Miller's class I and class II isolated gingival recession with an NCCL published up to April 2020, with at least 10 patients per group and a follow-up longer than 6 months, were included through electronic databases and hand-searched journals. RESULTS: Seven articles were finally included. Treatment systematically consisted of a coronally advanced flap in association with partial or complete restorative treatment ± CTG. Meta-analyses showed that periodontal plastic procedures are less effective in terms of complete root coverage in cases of teeth with an NCCL. Overall Mean Recession Reduction was 2.00 mm (CI: [1.72, 2.28]), and overall mean complete root coverage was 5% (CI: [2,8]). CONCLUSION: The presence of an NCCL is a complicating factor in plastic surgery. The use of CTG without NCCL restoration provides better outcomes except for the reduction of dental hypersensitivity for which the combined treatment (restoration + CTG) is the most effective.

Periodontal and dental health in inflammatory bowel diseases: a systematic review.

Introduction: An increased risk of dental caries and periodontal diseases has been reported for inflammatory bowel disease (IBD) patients and are challenging conditions to manage.Areas covered: The authors searched international databases to find all studies assessing dental/periodontal outcomes in patients with IBD and other immune-mediated inflammatory disease (IMID), as well as the association between IMID medications and dental/periodontal status.Expert opinion: IBD are associated with a higher risk of both periodontitis and caries. Some evidence from rheumatoid arthritis suggests that periodontitis may be associated with a lower response to anti-TNF. There is no reliable evidence that IBD patients may be at greater risk of complications during routine dental care. On the basis of current data, guidelines can be proposed for the dental management focusing on the detection and eradication of infectious foci prior to the implementation of immunosuppressants/biologics and modified dental treatment protocol for invasive dental procedures that includes antibiotic prophylaxis.

Antibiotic Use in Periodontal Therapy among French Dentists and Factors Which Influence Prescribing Practices.

The aim of the present survey is to investigate the use of antibiotics during periodontal therapy among French dentists with a focus on exploring potential differences between various groups of practitioners. A self-administered questionnaire was distributed to different groups of practitioners including members of (i) the French Society of Periodontology and Implantology; (ii) the College of University Teachers in Periodontology and, (iii) private practitioners participating in the French general dental practice-based research network. 272 questionnaires were included in the analysis. Prescription patterns were globally in line with the current recommendations. Systemic antibiotics are most frequently used as a first-line therapy in necrotizing periodontitis (92%) and aggressive periodontitis (53.3% to 66.1%). However, malpractice still exists, including in the management of periodontal abscesses. Antibiotics are prescribed (i) less frequently for periodontal abscesses and (ii) more frequently for generalized aggressive periodontitis by members of the periodontal society and University college (p < 0.05). Amoxicillin (59.9%) and the amoxicillin + metronidazole (59.6%) combination were the most frequently prescribed molecules. Providing a high number of periodontal treatments per week, being more recently graduated, having a post-graduate certificate in periodontology and holding or having held an academic position/hospital practice were all factors associated with a better knowledge of and/or more adequate antibiotic use.

OSCEGame: A serious game for OSCE training.

BACKGROUND: Objective Structured Clinical Examinations (OSCEs) are amongst the most anxiety-provoking competency assessment methods. An online serious game (OSCEGame) was developed and implemented within the OSCE curriculum. This study aimed to evaluate the usefulness of this serious game on preparedness and reducing OSCE-related stress. METHODS: A serious game was designed to help dental students train for OSCEs. Two game courses (4 stations each) were designed according to year of undergraduate training (4th and 5th year), based on 6 pre-existing multi-competency OSCE stations. The OSCEGame was available online on a learning platform 4 to 6 weeks before the summative OSCEs. Game use was evaluated by analysing connection data. Preparedness, stress and time management skills were assessed using a questionnaire following the summative OCSEs. The results of 4th -year students (OSCE naive population) were compared to those of 5th -year students to assess usefulness and benefits of such preparation method. RESULTS: In total, 97% and 60% of the students in 4th year and 5th year, respectively, used the game. The game was seen as an essential preparation tool to reduce anxiety (for 60% of all students) and increase time management skills (65% of all students). However, significant differences were observed between 4th- and 5th -year students (anxiety reduction: 65% vs. 22%, p < 0.001; time management skills: 59% vs. 41%, p < 0.05) suggesting that it is most useful for OSCE naive students. CONCLUSION: This serious game is a useful time efficient online tool, for OSCE preparation, especially in OSCE naive students.

Disease activity and patient reported outcome measures in Sjögren's - what are the best tools to evaluate?

In primary SS (pSS), clinical features in SS can be divided into two facets: the patient perceived manifestations such as dryness, pain and fatigue, and the systemic manifestations. In the past decades, with efforts made by an international collaboration, consensual clinical indexes were developed for assessing both facets: one patient reported outcome, the EULAR SS Patients Reported Index (ESSPRI), and one activity index for systemic manifestations, the EULAR SS Disease Activity Index (ESSDAI). In addition, objective measures were developed to quantify the importance and consequence of ocular and oral dryness, few being specific of pSS. Work is ongoing to develop indexes combining all these approaches. Recent changes in the assessment of pSS patients, and the emergence of new targeted therapies, have put a greater emphasis on the design of clinical trials in pSS, and led for the first time to a positive randomized clinical trial.

Inflammatory Potential of Four Different Phases of Calcium Pyrophosphate Relies on NF-κB Activation and MAPK Pathways.

Background: Calcium pyrophosphate (CPP) microcrystal deposition is associated with wide clinical phenotypes, including acute and chronic arthritis, that are interleukin 1ß (IL-1ß)-driven. Two CPP microcrystals, namely monoclinic and triclinic CPP dihydrates (m- and t-CPPD), have been identified in human tissues in different proportions according to clinical features. m-CPP tetrahydrate beta (m-CPPTß) and amorphous CPP (a-CPP) phases are considered as m- and t-CPPD crystal precursors in vitro. Objectives: We aimed to decipher the inflammatory properties of the three crystalline phases and one amorphous CPP phase and the intracellular pathways involved. Methods: The four synthesized CPP phases and monosodium urate crystals (MSU, as a control) were used in vitro to stimulate the human monocytic leukemia THP-1 cell line or bone marrow-derived macrophages (BMDM) isolated from WT or NLRP3 KO mice. The gene expression of pro- and anti-inflammatory cytokines was evaluated by quantitative PCR; IL-1ß, IL-6 and IL-8 production by ELISA; and mitogen-activated protein kinase (MAPK) activation by immunoblot analysis. NF-κB activation was determined in THP-1 cells containing a reporter plasmid. In vivo, the inflammatory potential of CPP phases was assessed with the murine air pouch model via cell analysis and production of IL-1ß and CXCL1 in the exudate. The role of NF-κB was determined by a pharmacological approach, both in vivo and in vitro. Results:In vitro, IL-1ß production induced by m- and t-CPPD and m-CPPTß crystals was NLRP3 inflammasome dependent. m-CPPD crystals were the most inflammatory by inducing a faster and higher production and gene expression of IL-1ß, IL-6, and IL-8 than t-CPPD, m-CPPTß and MSU crystals. The a-CPP phase did not show an inflammatory property. Accordingly, m-CPPD crystals led to stronger activation of NF-κB, p38, extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK) MAPKs. Inhibition of NF-κB completely abrogated IL-1ß and IL-8 synthesis and secretion induced by all CPP crystals. Also, inhibition of JNK and ERK1/2 MAPKs decreased both IL-1ß secretion and NF-κB activation induced by CPP crystals. In vivo, IL-1ß and CXCL1 production and neutrophil infiltration induced by m-CPPD crystals were greatly decreased by NF-κB inhibitor treatment. Conclusion: Our results suggest that the inflammatory potential of different CPP crystals relies on their ability to activate the MAPK-dependent NF-κB pathway. Studies are ongoing to investigate the underlying mechanisms.

Periodontal reconstruction by heparan sulfate mimetic-based matrix therapy in Porphyromonas gingivalis-infected mice.

BACKGROUND: Periodontitis is a set of chronic inflammatory diseases affecting the supporting structures of the teeth, during which a persistent release of lytic enzymes and inflammatory mediators causes a self-perpetuating vicious cycle of tissue destruction and repair. A matrix-based therapy using a heparan sulfate (HS) analogue called ReGeneraTing Agent (RGTA) replaces destroyed HS by binding to available heparin-binding sites of structural molecules, leading to restoration of tissue homeostasis in several inflammatory tissue injuries, including a hamster periodontitis model. METHODS: The ability of RGTA to restore the periodontium was tested in a model of Porphyromonas gingivalis-infected Balb/cByJ mice. After 12 weeks of disease induction, mice were treated weekly with saline or RGTA (1.5 mg/kg) for 8 weeks. Data were analyzed by histomorphometry. RESULTS: RGTA treatment restored macroscopic bone loss. This was related to (1) a significant reduction in gingival inflammation assessed by a decrease in infiltrated connective tissue, particularly in cells expressing interleukin 1ß, an inflammatory mediator selected as a marker of inflammation; (2) a normalization of bone resorption parameters, i.e. number, activation and activity of osteoclasts, and number of preosteoclasts; (3) a powerful bone formation reaction. The Sharpey's fibers of the periodontal ligament recovered their alkaline phosphatase coating. This was obtained while P. gingivalis infection was maintained throughout the treatment period. CONCLUSIONS: RGTA treatment was able to control the chronic inflammation characteristic of periodontitis and blocked destruction of periodontal structures. It ensured tissue regeneration with recovery of the periodontium's anatomy.

NAMPT expression in osteoblasts controls osteoclast recruitment in alveolar bone remodeling.

In bone remodeling, osteoclasts are recruited via increased production of RANKL (receptor activator of nuclear factor-κB ligand) and migrate to the bone surface, aided by matrix metalloproteinases (MMPs). NAMPT (nicotinamide phosphoribosyl transferase), which catalyzes the rate-limiting step in the NAD+ salvage pathway, increases during in vitro osteogenic differentiation and inhibits RANKL-induced osteoclast differentiation. Alveolar bone loss, due to disturbance of the remodeling process, is a major feature of periodontitis. Thus, we investigated the role of NAMPT in a synchronized alveolar bone remodeling rat model. NAMPT expression increased in osteogenic cells during the remodeling activation phase, in parallel with RANKL and MMP-2 expression. Inhibition of NAMPT activity, by systemic delivery of its selective inhibitor FK866, decreased the recruitment of osteoclasts, but not their activity. In vitro, NAMPT mRNA, and protein expression also increased during osteoblast differentiation in primary calvarial osteoblast cultures. Recombinant NAMPT and NMN, its direct metabolite, dose-dependently increased bone marker expression, including that of sialoprotein (BSP) and osteocalcin (OC), whereas their expression was inhibited by FK866 treatment. Recombinant NAMPT did not regulate MMP-2, -9, MMP-13, or RANKL/OPG mRNA expression in osteoblasts. Our data suggest that de novo NAMPT synthesis in osteoblasts controls cell differentiation through osteoclast recruitment during the activation of bone remodeling.

Coordination of early cellular reactions during activation of bone resorption in the rat mandible periosteum: An immunohistochemical study.

The activation step of bone remodeling remains poorly characterized. Activation comprises determination of the site to be remodeled, osteoclast precursor recruitment, their migration to the site of remodeling, and differentiation. These actions involve different compartments and cell types. The aim of this study was to investigate events and cell types involved during activation. We used a bone remodeling model in rats where extractions of the upper jaw molars initiate remodeling of the antagonist lower jaw (mandible) cortex along the periosteum. In this model osteoclastic resorption peaks 4 days after extractions. We previously reported that mast cell activation in the periosteum fibrous compartment is an early event of activation, associated with recruitment of circulating monocyte osteoclast precursors. By using immunohistochemistry, we observed 9 hours after induction a spatially oriented expression of InterCellular Adhesion Molecule-1 in the vessels that was inhibited by antagonists of histamine receptors 1 and 2. It was followed at 12 hours by the recruitment of ED1+ monocytes. In parallel, at 9 hours, Vascular Cellular Adhesion Molecule-1+ fibroblast-like cells scattered in the fibrous compartment of the periosteum between the vessels and the osteogenic compartment increased; these cells may be implicated in osteoclast precursor migration. Receptor Activator of NF KappaB Ligand+ cells increased at 12 hours in the osteogenic compartment and reached a peak at 18 hours. At 24 hours the numbers of osteogenic cells and subjacent osteocytes expressing semaphorin 3a, a repulsive for osteoclast precursors, decreased before returning to baseline at 48 hours. These data show that during activation the two periosteum compartments and several cell types are coordinated to recruit and guide osteoclast precursors towards the bone surface.

Expression and function of visfatin (Nampt), an adipokine-enzyme involved in inflammatory pathways of osteoarthritis.

INTRODUCTION: Visfatin is an adipokine that may be involved in intertissular joint communication in osteoarthritis (OA). With a homodimeric conformation, it exerts nicotinamide phosphoribosyltransferase (Nampt) enzymatic activity, essential for nicotinamide adenine dinucleotide biosynthesis. We examined the tissular origin and conformation of visfatin/Nampt in human OA joints and investigated the role of visfatin/Nampt in chondrocytes and osteoblasts by studying Nampt enzymatic activity. METHODS: Synovium, cartilage and subchondral bone from human OA joints were used for protein extraction or incubated for 24 hours in serum-free media (conditioned media), and synovial fluid was obtained from OA patients. Visfatin/Nampt expression in tissular extracts and conditioned media was evaluated by western blot and enzyme-linked immunosorbent assay (ELISA), respectively. Nampt activity was assessed in OA synovium by colorimetric assay. Primary cultures of murine chondrocytes and osteoblasts were stimulated with visfatin/Nampt and pretreated or not with APO866, a pharmacologic inhibitor of Nampt activity. The effect on cytokines, chemokines, growth factors and hypertrophic markers expression was examined by quantitative reverse transcriptase polymerase chain reaction and/or ELISA. RESULTS: In tissular explants, conditioned media and synovial fluid, visfatin/Nampt was found as a homodimer, corresponding to the enzymatically active conformation. All human OA joint tissues released visfatin/Nampt (synovium: 628 ± 106 ng/g tissue; subchondral bone: 195 ± 26 ng/g tissue; cartilage: 152 ± 46 ng/g tissue), with significantly higher level for synovium (P <0.0005). Nampt activity was identified ex vivo in synovium. In vitro, visfatin/Nampt significantly induced the expression of interleukin 6, keratinocyte chemoattractant and monocyte chemoattractant protein 1 in chondrocytes and osteoblasts. APO866 decreased the mRNA and protein levels of these pro-inflammatory cytokines in the two cell types (up to 94% and 63% inhibition, respectively). Levels of growth factors (vascular endothelial growth factor, transforming growth factor ß) and hypertrophic genes were unchanged with treatment. CONCLUSION: Visfatin/Nampt is released by all human OA tissues in a dimeric enzymatically active conformation and mostly by the synovium, which displays Nampt activity. The Nampt activity of visfatin is involved in chondrocyte and osteoblast activation, so targeting this enzymatic activity to disrupt joint tissue interactions may be novel in OA therapy.