Impact of 2018 EU Risk Minimisation Measures and Revised Pregnancy Prevention Programme on Utilisation and Prescribing Trends of Medicinal Products Containing Valproate: An Interrupted Time Series Study

Introduction: Due to established teratogenicity of valproates, the EU risk minimisation measures (RMMs) with a pregnancy prevention programme (PPP) for valproate were updated in March 2018. Objectives: To investigate the effectiveness of the 2018 EU RMMs on valproate utilisation in five European countries/regions. Methods: A multi-database, times series study of females of childbearing potential (12–55 years) was conducted using electronic medical records from five countries/regions (01.01.2010–31.12.2020): Denmark, Tuscany (Italy), Spain, the Netherlands, and the UK. Clinical and demographic information from each database was transformed to the ConcePTION Common Data Model, quality checks were conducted and a distributed analysis was performed using common scripts. Incident and prevalent use of valproate, proportion of discontinuers and switchers to alternative medicine, frequency of contraception coverage during valproate use, and occurrence of pregnancies during valproate exposure were estimated per month. Interrupted time series analyses were conducted to estimate the level or trend change in the outcome measures. Results: We included 69,533 valproate users from 9,699,371 females of childbearing potential from the five participating centres. A significant decline in prevalent use of valproates was observed in Tuscany, Italy (mean difference post-intervention −7.7%), Spain (−11.3%), and UK (−5.9%) and a non-significant decline in the Netherlands (−3.3%), but no decline in incident use after the 2018 RMMs compared to the period before. The monthly proportion of compliant valproate prescriptions/dispensings with a contraceptive coverage was low (<25%), with an increase after the 2018 RMMs only in the Netherlands (mean difference post-intervention 12%). There was no significant increase in switching rates from valproates to alternative medicine after the 2018 intervention in any of the countries/regions. We observed a substantial number of concurrent pregnancies during valproate exposure, but with a declining rate after the 2018 RMMs in Tuscany, Italy (0.70 per 1000 valproate users pre- and 0.27 post-intervention), Spain (0.48 and 0.13), the Netherlands (0.34 and 0.00), and an increasing rate in UK (1.13 and 5.07). Conclusion: There was a small impact of the 2018 RMMs on valproate use in the studied European countries/regions. The substantial number of concurrent pregnancies with valproate exposure warrants a careful monitoring of implementation of the existing PPP for valproate in clinical practice in Europe, to see if there is any need for additional measures in the future

Evaluation of focal cartilage lesions of the knee using MRI T2 mapping and delayed Gadolinium Enhanced MRI of Cartilage (dGEMRIC)

Background Assessment of degenerative changes of the cartilage is important in knee cartilage repair surgery. Magnetic Resonance Imaging (MRI) T2 mapping and delayed Gadolinium Enhanced MRI of Cartilage (dGEMRIC) are able to detect early degenerative changes. The hypothesis of the study was that cartilage surrounding a focal cartilage lesion in the knee does not possess degenerative changes. Methods Twenty-eight consecutive patients included in a randomized controlled trial on cartilage repair were evaluated using MRI T2 mapping and dGEMRIC before cartilage treatment was initiated. Inclusion was based on disabling knee problems (Lysholm score of ≤ 75) due to an arthroscopically verified focal femoral condyle cartilage lesion. Furthermore, no major malalignments or knee ligament injuries were accepted. Mean patient age was 33 ± 9.6 years, and the mean duration of knee symptoms was 49 ± 60 months. The MRI T2 mapping and the dGEMRIC measurements were performed at three standardized regions of interest (ROIs) at the medial and lateral femoral condyle, avoiding the cartilage lesion Results The MRI T2 mapping of the cartilage did not demonstrate significant differences between condyles with or without cartilage lesions. The dGEMRIC results did not show significantly lower values of the affected condyle compared with the opposite condyle and the contra-lateral knee in any of the ROIs. The intraclass correlation coefficient (ICC) of the dGEMRIC readings was 0.882. Conclusion The MRI T2 mapping and the dGEMRIC confirmed the arthroscopic findings that normal articular cartilage surrounded the cartilage lesion, reflecting normal variation in articular cartilage quality. Study identifier NCT00885729 , registered April 17 2009

Efficacy of strength and aerobic exercise on patient-reported outcomes and structural changes in patients with knee osteoarthritis: study protocol for a randomized controlled trial

Open Access Highly Accessed Study protocol Efficacy of strength and aerobic exercise on patient-reported outcomes and structural changes in patients with knee osteoarthritis: study protocol for a randomized controlled trial Britt Elin Øiestad1*, Nina Østerås2, Richard Frobell3, Margreth Grotle4, Helga Brøgger5 and May Arna Risberg16 * Corresponding author: Britt E Øiestad [email protected] Author Affiliations 1 Norwegian Research Center for Active Rehabilitation (NAR), Department of Orthopedics, Oslo University Hospital, Kirkeveien 166, 0407 Oslo, Norway 2 National Resource Center for Rehabilitation in Rheumatology, Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway 3 Department of Orthopaedics, Lund University Hospital, Lund, Sweden 4 Oslo University College, Oslo, Norway 5 Department of Radiology, Oslo University Hospital Ullevaal, Oslo, Norway 6 Department of Sport Medicine, Norwegian School of Sport Sciences, Oslo, Norway For all author emails, please log on. BMC Musculoskeletal Disorders 2013, 14:266 doi:10.1186/1471-2474-14-266 The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1471-2474/14/266 Received: 29 July 2013 Accepted: 11 September 2013 Published: 12 September 2013 © 2013 Øiestad et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background Despite an extensive literature on treatment interventions for patients with knee osteoarthritis, studies comparing the efficacy of different exercise interventions and living the life as usual on quality of life, cartilage quality and cost-effectiveness are lacking. The aim of the present study is to compare the efficacy of two different exercise programs compared to a control group in individuals with established radiographic and symptomatic knee osteoarthritis on self-reported knee-related quality of life, knee pain, physical function, and cartilage quality. Methods/Design A three-armed randomized controlled trial involving two exercise interventions and a control group of individuals doing as they usually do is described. The patients will have mild to moderate radiographic osteoarthritis according to the Kellgren and Lawrence classification (grade 2–3), and fulfill the American College of Rheumatology clinical criteria, be aged between 45 and 65 years, and have no other serious physical or mental illnesses. The patients will be randomly allocated to a strength exercise group; a cycling group, or a control group. The primary outcome is the Knee injury and Osteoarthritis Outcome Score knee-related quality of life subscale. Secondary outcomes include all five Knee Injury and Osteoarthritis Outcome Score subscales, morphological evaluation of cartilage including focal thickness, subchondral bone marrow edema, proteoglycan content and collagen degradation (measured using magnetic resonance imaging clinical sequences, T2 mapping and T1ρ), specific serum biomarkers, isokinetic muscle strength, maximal oxygen uptake, quality of life (EuroQol 5D), and self-efficacy (Arthritis Self-Efficacy Scale). A sample size calculation on the primary outcome showed that 207 individuals, 69 in each group, is needed to detect a clinically relevant difference of 10 points with 80% power and a significance level of 5%. Assessments will be conducted at baseline, 14 weeks, 1 year and 2 years post-randomization. The interventions will be a 14 weeks exercise program. Discussion Although exercise therapy has been found to be effective in knee osteoarthritis, the knowledge of the underlying mechanisms for why exercise works is lacking. This study will contribute with knowledge on the efficacy of strength exercise versus cycling on patient-reported outcomes, cartilage quality and cost-effectiveness. Trial registration Clinicaltrial.gov Identifier: NCT01682980

Efficacy of strength and aerobic exercise on patient-reported outcomes and structural changes in patients with knee osteoarthritis: study protocol for a randomized controlled trial

Open Access Highly Accessed Study protocol Efficacy of strength and aerobic exercise on patient-reported outcomes and structural changes in patients with knee osteoarthritis: study protocol for a randomized controlled trial Britt Elin Øiestad1*, Nina Østerås2, Richard Frobell3, Margreth Grotle4, Helga Brøgger5 and May Arna Risberg16 * Corresponding author: Britt E Øiestad [email protected] Author Affiliations 1 Norwegian Research Center for Active Rehabilitation (NAR), Department of Orthopedics, Oslo University Hospital, Kirkeveien 166, 0407 Oslo, Norway 2 National Resource Center for Rehabilitation in Rheumatology, Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway 3 Department of Orthopaedics, Lund University Hospital, Lund, Sweden 4 Oslo University College, Oslo, Norway 5 Department of Radiology, Oslo University Hospital Ullevaal, Oslo, Norway 6 Department of Sport Medicine, Norwegian School of Sport Sciences, Oslo, Norway For all author emails, please log on. BMC Musculoskeletal Disorders 2013, 14:266 doi:10.1186/1471-2474-14-266 The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1471-2474/14/266 Received: 29 July 2013 Accepted: 11 September 2013 Published: 12 September 2013 © 2013 Øiestad et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background Despite an extensive literature on treatment interventions for patients with knee osteoarthritis, studies comparing the efficacy of different exercise interventions and living the life as usual on quality of life, cartilage quality and cost-effectiveness are lacking. The aim of the present study is to compare the efficacy of two different exercise programs compared to a control group in individuals with established radiographic and symptomatic knee osteoarthritis on self-reported knee-related quality of life, knee pain, physical function, and cartilage quality. Methods/Design A three-armed randomized controlled trial involving two exercise interventions and a control group of individuals doing as they usually do is described. The patients will have mild to moderate radiographic osteoarthritis according to the Kellgren and Lawrence classification (grade 2–3), and fulfill the American College of Rheumatology clinical criteria, be aged between 45 and 65 years, and have no other serious physical or mental illnesses. The patients will be randomly allocated to a strength exercise group; a cycling group, or a control group. The primary outcome is the Knee injury and Osteoarthritis Outcome Score knee-related quality of life subscale. Secondary outcomes include all five Knee Injury and Osteoarthritis Outcome Score subscales, morphological evaluation of cartilage including focal thickness, subchondral bone marrow edema, proteoglycan content and collagen degradation (measured using magnetic resonance imaging clinical sequences, T2 mapping and T1ρ), specific serum biomarkers, isokinetic muscle strength, maximal oxygen uptake, quality of life (EuroQol 5D), and self-efficacy (Arthritis Self-Efficacy Scale). A sample size calculation on the primary outcome showed that 207 individuals, 69 in each group, is needed to detect a clinically relevant difference of 10 points with 80% power and a significance level of 5%. Assessments will be conducted at baseline, 14 weeks, 1 year and 2 years post-randomization. The interventions will be a 14 weeks exercise program. Discussion Although exercise therapy has been found to be effective in knee osteoarthritis, the knowledge of the underlying mechanisms for why exercise works is lacking. This study will contribute with knowledge on the efficacy of strength exercise versus cycling on patient-reported outcomes, cartilage quality and cost-effectiveness. Trial registration Clinicaltrial.gov Identifier: NCT01682980

Temporary Bridge Plating vs Primary Arthrodesis of the First Tarsometatarsal Joint in Lisfranc Injuries: Randomized Controlled Trial

Background: Unstable Lisfranc injuries are best treated with anatomic reduction and stable fixation. There are controversies regarding which type of stabilization is best. In the present study, we compared primary arthrodesis of the first tarsometatarsal (TMT) joint to temporary bridge plating in unstable Lisfranc injuries. Methods: Forty-eight patients with Lisfranc injuries were included and followed for 2 years. Twenty-four patients were randomized to primary arthrodesis (PA) of the medial 3 TMT joints, whereas 24 patients were randomized to temporary bridge plate (BP) over the first TMT joint and primary arthrodesis of the second and third TMT joints. The main outcome parameter was the American Orthopaedic Foot &amp; Ankle Society (AOFAS) midfoot scale and the secondary outcome parameters were the 36-Item Short Form Health Survey (SF-36) and visual analog scale for pain (VAS pain). Computed tomography (CT) scans pre- and postoperatively were obtained. Radiographs were obtained at follow-ups. Pedobarographic examination was performed at the 2-year follow-up. Twenty-two of 24 patients in the PA and 23/24 in the BP group completed the 2-year follow-up. Results: The mean AOFAS midfoot score 2 years postoperatively was 89 (SD 9) in the PA group and 85 (SD 15) in the BP group ( P = .32). There were no significant differences between the groups with regard to SF-36 or VAS pain scores. The alignment of the first metatarsal was better in the BP group than in the PA group measured by the anteroposterior Meary angle ( P = .04). The PA group had a reduced peak pressure under the fifth metatarsal ( P = .047). In the BP group, 11/24 patients had radiologic signs of osteoarthritis in the first TMT joint. Conclusion: Both treatment groups had good outcome scores. The first metatarsal was better aligned in the BP group; however, there was a high incidence of radiographic osteoarthritis in this group. Level of Evidence: Therapeutic level I, prospective randomized controlled study

Outcome after nonoperative treatment of stable Lisfranc injuries. A prospective cohort study

Background The aim of this study was to evaluate the outcome after nondisplaced and stable Lisfranc injuries. Methods 26 patients with injuries to the Lisfranc joint complex detected on CT scans, but without displacement were tested to be stable using a fluoroscopic stress test. The patients were immobilized in a non-weightbearing short leg cast for 6 weeks. The final follow-up was 55 (IQR 53–60) months after injury. Results All the Lisfranc injuries were confirmed to be stable on follow-up weightbearing radiographs at a minimum of 3 months after injury. Median American Foot and Ankle Society (AOFAS) midfoot score at 1-year follow-up was 89 (IQR 84–97) and at final follow-up 100 (IQR 90–100); The AOFAS score continued to improve after 1-year (P=.005). The median visual analog scale (VAS) for pain was 0 (IQR 0–0) at the final follow-up. One patient had radiological signs of osteoarthritis at 1-year follow-up. Conclusion Stable Lisfranc injuries treated nonoperatively had an excellent outcome in this study with a median follow-up of 55 months. The AOFAS score continued to improve after 1 year

Lisfranc injuries: Incidence, mechanisms of injury and predictors of instability

Background In Lisfranc injuries the stability of the tarsometatarsal joints guides the treatment of the injury. Determining the stability, especially in the subtle Lisfranc injuries, can be challenging. The purpose of this study was to identify incidence, mechanisms of injury and predictors for instability in Lisfranc injuries. Methods Eighty-four Lisfranc injuries presenting at Oslo University Hospital between September 2014 and August 2015 were included. The diagnosis was based on radiologically verified injuries to the tarsometatarsal joints. Associations between radiographic findings and stability were examined. Results The incidence of Lisfranc injuries was 14/100,000 person-years, and only 31% were high-energy injuries. The incidence of unstable injuries was 6/100,000 person–years, and these were more common in women than men (P = 0.016). Intraarticular fractures in the two lateral tarsometatarsal joints increased the risk of instability (P = 0.007). The height of the second tarsometatarsal joint was less in the unstable injuries than in the stable injuries (P = 0.036). Conclusion The incidence of Lisfranc injuries in the present study is higher than previously published. The most common mechanism of injury is low-energy trauma. Intraarticular fractures in the two lateral tarsometatarsal joints, female gender and shorter second tarsometatarsal joint height increase the risk of an unstable injury

Additional file 1: of Evaluation of focal cartilage lesions of the knee using MRI T2 mapping and delayed Gadolinium Enhanced MRI of Cartilage (dGEMRIC)

Scanprotocol dGEMRIC. (DOC 28 kb