Prolonged use of nomegestrol acetate and risk of intracranial meningioma: a population-based cohort study.

Background: Nomegestrol acetate (NOMAC) is a synthetic potent progestogen. This study aimed to assess the risk of intracranial meningioma associated with the prolonged use of NOMAC. Methods: Observational cohort study using SNDS data (France). Women included had ≥ one dispensing of NOMAC between 2007 and 2017 (no dispensing in 2006). Exposure was defined as a cumulative dose >150 mg NOMAC within six months after first dispensing. A control group of women (cumulative dose ≤150 mg) was assembled. The outcome was surgery (resection or decompression) or radiotherapy for one or more intracranial meningioma(s). Poisson models assessed the relative risk (RR) of meningioma. Findings: In total, 1,060,779 women were included in the cohort (535,115 in the exposed group and 525,664 in the control group). The incidence of meningioma in the two groups was 19.3 and 7.0 per 100,000 person-years, respectively (age-adjusted RRa = 2.9 [2.4-3.7]). The RRa for a cumulative dose of more than 6 g NOMAC was 12.0 [9.9-16.0]. In the event of treatment discontinuation for at least one year, the risk of meningioma was identical to that in the control group (RRa = 1.0 [0.8-1.3]). The location of meningiomas in the anterior and middle part of the skull base was more frequent with exposure to NOMAC. Interpretation: We observed a strong dose-dependent association between prolonged use of NOMAC and the risk of intracranial meningiomas. These results are comparable to those obtained for cyproterone acetate, although the magnitude of the risk is lower. It is now recommended to stop using NOMAC if a meningioma is diagnosed. Funding: The French National Health Insurance Fund (Cnam) and the French National Agency for Medicines and Health Products Safety (ANSM) via the Health Product Epidemiology Scientific Interest Group EPI-PHARE.

Are current clinical studies on artificial intelligence-based medical devices comprehensive enough to support a full health technology assessment? A systematic review.

INTRODUCTION: Artificial Intelligence-based Medical Devices (AI-based MDs) are experiencing exponential growth in healthcare. This study aimed to investigate whether current studies assessing AI contain the information required for health technology assessment (HTA) by HTA bodies. METHODS: We conducted a systematic literature review based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses methodology to extract articles published between 2016 and 2021 related to the assessment of AI-based MDs. Data extraction focused on study characteristics, technology, algorithms, comparators, and results. AI quality assessment and HTA scores were calculated to evaluate whether the items present in the included studies were concordant with the HTA requirements. We performed a linear regression for the HTA and AI scores with the explanatory variables of the impact factor, publication date, and medical specialty. We conducted a univariate analysis of the HTA score and a multivariate analysis of the AI score with an alpha risk of 5 %. RESULTS: Of 5578 retrieved records, 56 were included. The mean AI quality assessment score was 67 %; 32 % of articles had an AI quality score ≥ 70 %, 50 % had a score between 50 % and 70 %, and 18 % had a score under 50 %. The highest quality scores were observed for the study design (82 %) and optimisation (69 %) categories, whereas the scores were lowest in the clinical practice category (23 %). The mean HTA score was 52 % for all seven domains. 100 % of the studies assessed clinical effectiveness, whereas only 9 % evaluated safety, and 20 % evaluated economic issues. There was a statistically significant relationship between the impact factor and the HTA and AI scores (both p = 0.046). DISCUSSION: Clinical studies on AI-based MDs have limitations and often lack adapted, robust, and complete evidence. High-quality datasets are also required because the output data can only be trusted if the inputs are reliable. The existing assessment frameworks are not specifically designed to assess AI-based MDs. From the perspective of regulatory authorities, we suggest that these frameworks should be adapted to assess the interpretability, explainability, cybersecurity, and safety of ongoing updates. From the perspective of HTA agencies, we highlight that transparency, professional and patient acceptance, ethical issues, and organizational changes are required for the implementation of these devices. Economic assessments of AI should rely on a robust methodology (business impact or health economic models) to provide decision-makers with more reliable evidence. CONCLUSION: Currently, AI studies are insufficient to cover HTA prerequisites. HTA processes also need to be adapted because they do not consider the important specificities of AI-based MDs. Specific HTA workflows and accurate assessment tools should be designed to standardise evaluations, generate reliable evidence, and create confidence.

Prescribing Patterns of Codeine and Alternative Medicines in Children in Europe.

INTRODUCTION: Concerns over serious respiratory depression in children led to two European Union (EU) referral procedures (in 2013 and 2015) to review the benefit-risk balance of codeine in this population when used for pain relief, cough or cold. Consequently, codeine should no longer be used in children aged < 12 years and restrictions were introduced for treatment in children ≥ 12 years. OBJECTIVE: This multinational collaborative study aimed to assess the effectiveness of these risk minimisation measures by evaluating changes in prescribing of codeine and alternative treatments. METHOD: Children under 12 and 12-18 years old were followed between 2010 and 2017 to analyse quarterly trends in prescribing of codeine and alternative treatments in electronic health records from France, Germany, Norway, Spain and the United Kingdom using interrupted time series analysis. RESULTS: Overall prescribing of codeine in children decreased in all five countries, reaching near zero prevalence in children under 12 years of age. This was accompanied by an increase in use of other opioid analgesics in France (from 0.15 to 0.56 prevalence per 100 person-years immediately after the first referral), Norway (from 0.0006 to 0.0013 at the end of the study), the United Kingdom (from 0.018 to 0.05 at the end of the study), and an increase in non-opioid analgesics in Norway (from 0.045 to 0.075 at the end of the study) after the referral on pain relief indication. The referral on cough/cold indication led to a decrease in use of opioid and non-opioid antitussives in children aged < 12 years in France (from 10 to 7 and 20 to 16, respectively) and had no impact in other countries. Overall prescribing trends for codeine and alternatives were similar across both age groups within each country. CONCLUSION: The decrease in use of codeine shows that healthcare professionals followed the adopted measures and switched prescribing practices for pain management in children aged < 18 years towards opioid or non-opioid analgesics depending on national clinical and reimbursement settings. Whist the magnitude of the first referral on pain differed between countries, the second referral on cough/cold had only a minimal impact on the use of codeine and antitussives.

Use of high dose cyproterone acetate and risk of intracranial meningioma in women: cohort study.

OBJECTIVE: To assess the risk of meningioma associated with use of high dose cyproterone acetate, a progestogen indicated for clinical hyperandrogenism. DESIGN: Observational cohort study. SETTING: Data from SNDS, the French administrative healthcare database, between 2007 and 2015. PARTICIPANTS: 253 777 girls and women aged 7-70 years living in France who started cyproterone acetate between 2007 and 2014. Participants had at least one reimbursement for high dose cyproterone acetate and no history of meningioma or benign brain tumour, or long term disease status. Participants were considered to be exposed when they had received a cumulative dose of at least 3 g during the first six months (139 222 participants) and very slightly exposed (control group) when they had received a cumulative dose of less than 3 g (114 555 participants). 10 876 transgender participants (male to female) were included in an additional analysis. MAIN OUTCOME MEASURE: Surgery (resection or decompression) or radiotherapy for one or more intracranial meningiomas. RESULTS: Overall, 69 meningiomas in the exposed group (during 289 544 person years of follow-up) and 20 meningiomas in the control group (during 439 949 person years of follow-up) were treated by surgery or radiotherapy. The incidence of meningioma in the two groups was 23.8 and 4.5 per 100 000 person years, respectively (crude relative risk 5.2, 95% confidence interval 3.2 to 8.6; adjusted hazard ratio 6.6, 95% confidence interval 4.0 to 11.1). The adjusted hazard ratio for a cumulative dose of cyproterone acetate of more than 60 g was 21.7 (10.8 to 43.5). After discontinuation of cyproterone acetate for one year, the risk of meningioma in the exposed group was 1.8-fold higher (1.0 to 3.2) than in the control group. In a complementary analysis, 463 women with meningioma were observed among 123 997 already using cyproterone acetate in 2006 (risk of 383 per 100 000 person years in the group with the highest exposure in terms of cumulative dose). Meningiomas located in the anterior skull base and middle skull base, particularly the medial third of the middle skull base, involving the spheno-orbital region, appeared to be specific to cyproterone acetate. An additional analysis of transgender participants showed a high risk of meningioma (three per 14 460 person years; 20.7 per 100 000 person years). CONCLUSIONS: A strong dose-effect relation was observed between use of cyproterone acetate and risk of intracranial meningiomas. A noticeable reduction in risk was observed after discontinuation of treatment.

Autologous adipose-derived stromal vascular fraction in patients with systemic sclerosis: 12-month follow-up.

OBJECTIVE: Impaired hand function greatly contributes to disability and reduced quality of life in SSc patients. Autologous adipose-derived stromal vascular fraction (ADSVF) is recognized as an easily accessible source of regenerative cells. We reported positive 6-month safety and efficacy results from an open-label clinical trial assessing s.c. injection of autologous ADSVF into the fingers in SSc patients. The objective of this report is to describe the effects at 12 months. METHODS: Twelve females, mean age 54.5 years (s.d. 10.3), were assessed 1 year after ADSVF injection. Patients were eligible if they had a Cochin Hand Function Scale score >20/90. ADSVF was obtained from lipoaspirate using an automated processing system and subsequently injected into the s.c. tissue of each finger in contact with neurovascular pedicles in a one-time procedure. Endpoints were changes in hand disability and skin fibrosis, vascular manifestations, pain and quality of life at the 12 month follow-up. During the visit, patients estimated the benefit of the procedure with a specific self-completed questionnaire. RESULTS: A significant decrease from baseline of 51.3% (P < 0.001) for Cochin Hand Function Scale score, 63.2% (P < 0.001) for RP severity and 46.8% (P = 0.001) for quality of life (Scleroderma Health Assessment Questionnaire) was observed. A significant improvement of finger oedema, skin sclerosis, motion and strength of the hands and of the vascular suppression score was also noted. The reduction in hand pain approached statistical significance (P = 0.052). The questionnaire revealed a benefit in daily activities, housework and social activities. CONCLUSION: ADSVF injection is a promising therapy and appears to have benefits that extend for at least 1 year.

Safety, tolerability and potential efficacy of injection of autologous adipose-derived stromal vascular fraction in the fingers of patients with systemic sclerosis: an open-label phase I trial.

BACKGROUND: In patients with systemic sclerosis (scleroderma, SSc), impaired hand function greatly contributes to disability and reduced quality of life, and is insufficiently relieved by currently available therapies. Adipose tissue-derived stromal vascular fraction (SVF) is increasingly recognised as an easily accessible source of regenerative cells with therapeutic potential in ischaemic or autoimmune diseases. We aimed to measure for the first time the safety, tolerability and potential efficacy of autologous SVF cells local injections in patients with SSc with hand disability. METHODS: We did an open-label, single arm, at one study site with 6-month follow-up among 12 female SSc patients with Cochin Hand Function Scale score >20/90. Autologous SVF was obtained from lipoaspirates, using an automated processing system, and subsequently injected into the subcutaneous tissue of each finger in contact with neurovascular pedicles. Primary outcome was the number and the severity of adverse events related to SVF-based therapy. Secondary endpoints were changes in hand disability and fibrosis, vascular manifestations, pain and quality of life from baseline to 2 and 6 months after cell therapy. FINDINGS: All enrolled patients had surgery, and there were no dropouts or patients lost to follow-up. No severe adverse events occurred during the procedure and follow-up. Four minor adverse events were reported and resolved spontaneously. A significant improvement in hand disability and pain, Raynaud's phenomenon, finger oedema and quality of life was observed. INTERPRETATION: This study outlines the safety of the autologous SVF cells injection in the hands of patients with SSc. Preliminary assessments at 6 months suggest potential efficacy needing confirmation in a randomised placebo-controlled trial on a larger population. FUNDING: GFRS (Groupe Francophone de Recherche sur la Sclérodermie). CLINICAL TRIALS NUMBER: NCT01813279.

New fat-derived products for treating skin-induced lesions of scleroderma in nude mice.

INTRODUCTION: Scleroderma is characterized by cutaneous manifestations that mainly affect the hands, arms and face. As of today, there is no treatment for fibrotic skin lesions of scleroderma. Previously we generated and validated a model of scleroderma-like skin sclerosis in nude mice, appropriate to inject human derived products. We showed that the subcutaneous injection of micro-fat (MF), purified and injected using small caliber cannulas, have anti-fibrotic and pro-angiogenic effects and appears more suitable for the treatment of skin lesions of scleroderma compared to the gold standard (Coleman's technique or macro-fat). Here we compared the long-term efficacy of micro-fat "enriched" with other therapeutic products including the stromal vascular fraction (SVF) of fat and platelet-rich plasma (PRP) from blood in our murine model of scleroderma. METHODS: We used 72 nude mice in this study. We formed six experimental groups: Macro-fat, MF, SVF, PRP, MF + SVF, MF + PRP. This project has three phases: i) Induction of skin sclerosis by daily subcutaneous injections of bleomycin (BLM) for 4 weeks in nude mice; ii) Purification and injection of the different cell therapy products; iii) Histological analyses done 8 weeks post-injections. RESULTS: MF + SVF and MF + PRP significantly reversed dermal and epidermal sclerosis (P <0.01). Macro-fat, SVF, PRP only corrected the dermal sclerosis (P <0.05). Epidermal sclerosis was reduced in treatments containing MF (P <0.01). MF was more stable. Products containing the SVF were associated with a significant increase of the local vascularization (P <0.01). CONCLUSIONS: All tested substances were effective in treating skin-induced lesions of scleroderma with different levels of fibrosis and vascular improvement; MF derived products are more stable and SVF demonstrated better pro-angiogenic effects. The observed efficacy of this combination of products in the animal model provides a rationale for potential clinical applications to treat human disease.

Palladium-catalyzed Saegusa-Ito oxidation: synthesis of α,ß-unsaturated carbonyl compounds from trimethylsilyl enol ethers.

Palladium-catalyzed Saegusa-Ito oxidation of trimethylsilyl enol ethers is possible using Oxone as a stoichiometric oxidant and sodium hydrogen phosphate as a buffer. Cyclic and acyclic enones as well as α,ß-unsaturated aldehydes are obtained in good to excellent yields.