Pholcodine exposure increases the risk of perioperative anaphylaxis to neuromuscular blocking agents: the ALPHO case-control study.

BACKGROUND: Neuromuscular blocking agents (NMBAs) are among the leading cause of perioperative anaphylaxis, and most of these reactions are IgE mediated. Allergic sensitisation induced by environmental exposure to other quaternary ammonium-containing compounds, such as pholcodine, has been suggested. The aim of this study was to assess the relationship between pholcodine exposure and NMBA-related anaphylaxis. METHODS: ALPHO was a multicentre case-control study, comparing pholcodine exposure within a year before anaesthesia between patients with NMBA-related perioperative anaphylaxis (cases) and control patients with uneventful anaesthesia in France. Each case was matched to two controls by age, sex, type of NMBA, geographic area, and season. Pholcodine exposure was assessed by a self-administered questionnaire and pharmaceutical history retrieved from pharmacy records. The diagnostic values of anti-pholcodine and anti-quaternary ammonium specific IgE (sIgE) were also evaluated. RESULTS: Overall, 167 cases were matched with 334 controls. NMBA-related anaphylaxis was significantly associated with pholcodine consumption (odds ratio 4.2; 95% confidence interval 2.3-7.0) and occupational exposure to quaternary ammonium compounds (odds ratio 6.1; 95% confidence interval 2.7-13.6), suggesting that apart from pholcodine, other environmental factors can also lead to sensitisation to NMBAs. Pholcodine and quaternary ammonium sIgEs had a high negative predictive value (99.9%) but a very low positive predictive value (<3%) for identifying NMBA-related reactions. CONCLUSIONS: Patients exposed to pholcodine 12 months before NMBA exposure have a significantly higher risk of an NMBA-related anaphylaxis. The low positive predictive values of pholcodine and quaternary ammonium sIgEs precludes their use to identify a population with a high risk of NMBA-related anaphylaxis. CLINICAL TRIAL REGISTRATION: NCT02250729.

Computed Tomography Bone Imaging: Pushing the Boundaries in Clinical Practice.

Bone microarchitecture has several clinical implications over and above estimating bone strength. Computed tomography (CT) analysis mainly uses high-resolution peripheral quantitative CT and micro-CT, research imaging techniques, most often limited to peripheral skeleton assessment. Ultra-high-resolution (UHR) CT and photon-counting detector CT, two commercially available techniques, provide images that can approach the spatial resolution of the trabeculae, bringing bone microarchitecture analysis into clinical practice and improving depiction of bone vascularization, tumor matrix, and cortical and periosteal bone. This review presents bone microarchitecture anatomy, principles of analysis, reference measurements, and an update on the performance and potential clinical applications of these new CT techniques. We also share our clinical experience and technical considerations using an UHR-CT device.

Oxytocin Controls Chondrogenesis and Correlates with Osteoarthritis.

This study investigated the relationship of oxytocin (OT) to chondrogenesis and osteoarthritis (OA). Human bone marrow and multipotent adipose-derived stem cells were cultured in vitro in the absence or presence of OT and assayed for mRNA transcript expression along with histological and immunohistochemical analyses. To study the effects of OT in OA in vivo, a rat model and a human cohort of 63 men and 19 women with hand OA and healthy controls, respectively, were used. The baseline circulating OT, interleukin-6, leptin, and oestradiol levels were measured, and hand X-ray examinations were performed for each subject. OT induced increased aggrecan, collagen (Col) X, and cartilage oligomeric matrix protein mRNA transcript levels in vitro, and the immunolabelling experiments revealed a normalization of Sox9 and Col II protein expression levels. No histological differences in lesion severity were observed between rat OA groups. In the clinical study, a multivariate analysis adjusted for age, body mass index, and leptin levels revealed a significant association between OA and lower levels of OT (odds ratio = 0.77; p = 0.012). Serum OT levels are reduced in patients with hand OA, and OT showed a stimulatory effect on chondrogenesis. Thus, OT may contribute to the pathophysiology of OA.

[Cutaneous pigmentation related to intravenous iron extravasation: Analysis from the French pharmacovigilance database]. / Pigmentation cutanée liée à l'extravasation de fer injectable. Analyse de la base française de pharmacovigilance de 2000 à 2016.

INTRODUCTION: Intravenous iron infusion may be complicated by extravasation and lead to cutaneous pigmentation. METHODS: We queried the French pharmacovigilance database to assess the spontaneously reported cases over the 2000-2016 period. RESULTS: Fifty-one cases of cutaneous pigmentation related to intravenous iron extravasation were retrieved, none was associated to necrosis. Most of patients were women aged 20 to 49 years old. The pigmentation was mostly a brown coloration, persisting over one month in 19 cases (37.2%) and over 6 months in 9 cases (17.6%). The management of extravasation and pigmentation was heterogeneous and was rarely followed by a decrease of the coloration. CONCLUSION: Cutaneous pigmentation after intravenous iron extravasation can persist over time and create an aesthetic prejudice, particularly in young women. Standardized extravasation and iron-induced pigmentation management procedures appear necessary.

Nicorandil-induced ulcerations: a 10-year observational study of all cases spontaneously reported to the French pharmacovigilance network.

Nicorandil-induced ulcers remain often poorly recognised, with a late diagnosis and an inadequate management. We aimed to provide a clinical overview of the 148 spontaneously reported cases of nicorandil-induced ulcers to the French pharmacovigilance network between 2005 and 2014 and to complete this picture with worldwide published cases over the same period. Spontaneously reported nicorandil-induced ulcers were mainly mucosal (oral and anal) with a previous trauma in 23·0% of patients, revealed by a severe complication in 12·8% of cases. The mean cumulative dose of nicorandil was higher in serious cases. The median delay between the start of nicorandil use and the onset of the ulcer was 23·4 months, and after the ulcer was diagnosed, the median time to incriminate nicorandil was still 3·3 months, being shorter for mucosal ulcerations than for cutaneous ulcerations (5·2 versus 14·0 months, P = 0·001). The anatomic distribution in the 199 published cases differed slightly, but delays were similar. The hypothesis of mechanism becomes more precise, leaving no doubt about the necessity to discontinue the treatment. Practitioners need to be aware that nicorandil-induced ulcers can occur in many locations, possibly multiple and complicated, and should be simply managed by discontinuing treatment with no further reintroduction of nicorandil.

[Acetaminophen: Knowledge, use and overdose risk in urban patients consulting their general practitioner. A prospective, descriptive and transversal study]. / Le paracétamol : connaissance, usage et risque de surdosage en patientèle urbaine de médecine générale. Étude prospective descriptive transversale.

INTRODUCTION: Acetaminophen is the most involved active substance in both unintentional and intentional drug poisoning. However, its availability outside community pharmacies is being debated in France. METHODS: We made, via a self-administered questionnaire, a prospective assessment of knowledge, use and acetaminophen overdose risk in patients consulting their general practitioner, in the Metz Métropole urban area, between May 2015 and February 2016. We estimated the prevalence of potential unintentional overdosage by capture-recapture method. RESULTS: Among 819 responding patients, only 17.9 % had a sufficient knowledge and 20.3 % were at risk for potential unintentional overdose. The risk was higher for patients aged over 55 years or belonging to socioprofessional categories of laborers and inactive. A good knowledge score was a protective factor for overdose risk (P<0.0001). The liver toxicity of acetaminophen was particularly unknown. The prevalence of potential unintentional acetaminophen overdose was estimated at 1 to2 % of the population. CONCLUSION: Proposing acetaminophen outside of pharmacies cannot be recommended in France in such conditions. Information campaigns are needed to limit the risk of unintentional overdose and its consequences on liver toxicity.

[Good use and knowledge of paracetamol (acetaminophen) among self-medicated patients: Prospective study in community pharmacies]. / Étude prospective en pharmacie du bon usage et de la connaissance du paracétamol pris en automédication.

Acetaminophen (paracetamol), the highest over-the-counter (OTC) selling drug in France, is also the first cause of acute hepatic failure. We aimed to assess the good use and the knowledge of acetaminophen in a setting of urban self-medicated patients. We conducted a prospective observational study in randomly selected community pharmacies of Metz (France) agglomeration. Patients coming to buy OTC acetaminophen for themselves or their family had to answer to an anonymous autoquestionnaire. Responses were individually and concomitantly analyzed through 3 scores: good use, knowledge and overdosage. Twenty-four community pharmacies participated and 302 patients were interviewed by mean of a dedicated questionnaire. Most of patients (84.4%) could be considered as "good users" and independent factors of good use were (i) a good knowledge of acetaminophen (OR=5.3; P<0.0001) and more surprisingly; (ii) the fact of having no children (parentality: OR=0.1; P=0.006). Responses corresponding to involuntary overdosage were mostly due to a too short interval between drug intakes (3hours). Only 30.8% of patients were aware of liver toxicity of acetaminophen and only 40.7% knew the risk of the association with alcohol. Both good use and knowledge were significantly higher in patients looking for information from their pharmacist, physician and package leaflet. Patients should definitely be better informed about acetaminophen to warrant a better safety of its consumption. Pharmacists and physicians have to remind patients the risk factors of unintentional overdose and liver toxicity. Package leaflets have also to be more informative.

PLGA-Based Nanoparticles: a Safe and Suitable Delivery Platform for Osteoarticular Pathologies.

PURPOSE: Despite the promising applications of PLGA based particles, studies examining the fate and consequences of these particles after intra-articular administration in the joint are scanty. This study was carried out to evaluate the neutrality of the unloaded delivery system on different articular cell types. To facilitate tracking, we have thus developed a fluorescent core of particles, combined to a hyaluronate shell for cell recognition. METHODS: Fluorescence pictures were taken at time intervals to assess the internalization and the corresponding inflammatory response was monitored by RT-qPCR and biochemical measurements. After NPs pre-treatment, mesenchymal stem cells (MSCs) were cultured into chondrogenic, adipogenic or osteogenic differentiation media, to investigate if NPs exposure interferes with differentiation ability. Finally, intra-articular injections were performed in healthy rat knees and joint's structure analysed by histological studies. RESULTS: Particles were detected in cytoplasm 8 h after exposure. Internalization led to a slight and reversible increase of inflammatory markers, but lower than in inflammatory conditions. We have confirmed particles exposure minimal neutrality on MSCs pluripotency. Histological exams of joint after intra-articular injections do not demonstrate any side effects of NPs. CONCLUSIONS: Our findings suggest that such a delivery platform is well tolerated locally and could be used to deliver active molecules to the joint.

Profile of adverse drug reactions reported via the Continuum+ platform: Results from three-year regional follow-up.

In 2017, the Continuum+ platform was launched to provide a monitoring solution to home-based cancer care patients: AKO@dom monitoring. This platform also offers the follow-up of adverse drug reactions (ADRs) via direct notification to regional centers of pharmacovigilance (RCPVs). According to previous studies, the AKO@dom monitoring has successfully maintained treatment at the maximum effective dosage, managing ADRs and patient satisfaction. However, on the pharmacovigilance side, opinions are more divided. Due to the launch of the AKO@dom-PICTO experimentation in December 2021, in which our RCPV takes part, and to provide more data on pharmacovigilance, we decided to conduct a descriptive analysis of cases reported to our RCPV via the Continuum+ platform between 2019 and 2022. During these three years, we analyzed 1070 events, corresponding to 37 patients. Patients were primarily women (74.8%) aged around seventy with breast cancer. The most used drugs were tyrosine kinase inhibitors: palbociclib (29.7%), axitinib (16.2%), and cabozantinib (13.2%). Patients had an average of 8 ADRs, including one serious and/or unexpected ADR. Although the Continuum+ platform makes it possible to considerably limit under-reporting in pharmacovigilance, it has shortcomings. The lack of medical elements and context in notifications is a massive problem for analyzing pharmacovigilance reports. Improved access to the platform's medical information for RCPVs and pharmacovigilance training for healthcare professionals would make Continuum+ a helpful tool in pharmacovigilance.

In vivo depiction of cortical bone vascularization with ultra-high resolution-CT and deep learning algorithm reconstruction using osteoid osteoma as a model.

PURPOSE: The purpose of this study was to evaluate the ability to depict in vivo bone vascularization using ultra-high-resolution (UHR) computed tomography (CT) with deep learning reconstruction (DLR) and hybrid iterative reconstruction algorithm, compared to simulated conventional CT, using osteoid osteoma as a model. MATERIALS AND METHODS: Patients with histopathologically proven cortical osteoid osteoma who underwent UHR-CT between October 2019 and October 2022 were retrospectively included. Images were acquired with a 1024 × 1024 matrix and reconstructed with DLR and hybrid iterative reconstruction algorithm. To simulate conventional CT, images with a 512 × 512 matrix were also reconstructed. Two radiologists (R1, R2) independently evaluated the number of blood vessels entering the nidus and crossing the bone cortex, as well as vessel identification and image quality with a 5-point scale. Standard deviation (SD) of attenuation in the adjacent muscle and that of air were used as image noise and recorded. RESULTS: Thirteen patients with 13 osteoid osteomas were included. There were 11 men and two women with a mean age of 21.8 ± 9.1 (SD) years. For both readers, UHR-CT with DLR depicted more nidus vessels (11.5 ± 4.3 [SD] (R1) and 11.9 ± 4.6 [SD] (R2)) and cortical vessels (4 ± 3.8 [SD] and 4.3 ± 4.1 [SD], respectively) than UHR-CT with hybrid iterative reconstruction (10.5 ± 4.3 [SD] and 10.4 ± 4.6 [SD], and 4.1 ± 3.8 [SD] and 4.3 ± 3.8 [SD], respectively) and simulated conventional CT (5.3 ± 2.2 [SD] and 6.4 ± 2.5 [SD], 2 ± 1.2 [SD] and 2.4 ± 1.6 [SD], respectively) (P < 0.05). UHR-CT with DLR provided less image noise than simulated conventional CT and UHR-CT with hybrid iterative reconstruction (P < 0.05). UHR-CT with DLR received the greatest score and simulated conventional CT the lowest score for vessel identification and image quality. CONCLUSION: UHR-CT with DLR shows less noise than UHR-CT with hybrid iterative reconstruction and significantly improves cortical bone vascularization depiction compared to simulated conventional CT.

Adverse drug reaction profile of third-generation smallpox vaccines used in France during the 2022 monkeypox epidemic.

Due to the start of the monkeypox epidemic in 2022, we retrospectively analyzed the adverse drug reactions (ADRs) reported in France after monkeypox vaccinations with the third-generation smallpox vaccine. Ninety-eight cases, representing 172 ADRs, were reported. ADRs were mostly expected reactogenicity reactions occurring within days after the first dose of vaccine and having a quick favorable outcome. Unexpected facial palsy and vaccination failure are discussed.

Drug-induced radiation recall reactions and non-anticancer drugs: A descriptive analysis from VigiBase®.

Radiation recall reactions are inflammatory reactions confined to previously irradiated tissues, often of drug-induced etiology, particularly with anticancer therapies. Other drugs, in particular COVID-19 vaccines, may also be involved. To describe radiation recall reactions under non-anticancer drugs more precisely, we extracted the cases of radiation recall reactions associated with non-anticancer drugs from WHO pharmacovigilance database VigiBase®. We performed two analyses from this extraction: a global analysis and an analysis focusing on vaccination-related issues. We extracted 120 cases corresponding to 269 drugs, of which 130 were non-anticancer (22 vaccines). Among the non-anticancer drugs, tozinameran was the most reported treatment (4.46% of cases), followed by levofloxacin (2.97%) and folinic acid (2.60%), dexamethasone (2.23), and ChAdOx1 nCoV-19 vaccine and prednisone (1.86% each). Among vaccines, tozinameran (54.55% of cases) was the most reported, followed by ChAdOx1 nCoV-19 (22.73%), HPV and inactivated influenza vaccine (9.09% each), and elasomeran (4.55%). Our study first describes the occurrence of radiation recall reactions during non-anticancer treatment. It also highlights a potential safety signal with COVID-19 vaccines.

Non-medical use of baclofen: A case series and review of the literature.

BACKGROUND: Baclofen is widely used for spastic disorders and, most recently, for addictive disorders. The first signals of baclofen abuse occurred in the last decade. This study aims to assess the motives, diversion sources, and routes of administration associated with the non-medical use of baclofen and examine health problems related to the non-medical use of baclofen. METHODS: Spontaneous reports of baclofen abuse reported to the addictovigilance centre of East France were analysed. A literature search was conducted using PubMed®, Web of Sciences®, and Google Scholar® databases. Both investigations were performed in February 2021 without a time limit. RESULTS: Forty-six cases were analysed (33 from the literature review and 13 from the addictovigilance base). Baclofen's non-medical use mainly affected male subjects with addictive history, but issues of primary abuse in subjects without any substance abuse history were also observed. Euphoria search was the most common reason for misuse. The route of administration included oral, snorting, and sublingual use. Some cases involving illegal sources were also observed. Most patients misusing baclofen presented severe complications, mainly represented by neurological and respiratory disturbances. Physical and psychological dependence on baclofen was observed in three persons. CONCLUSIONS: Although baclofen abuse remains relatively infrequent or (most likely) underestimated, this study helped confirm baclofen's intrinsic abuse potential and make visible the baclofen-abuse-related health visible harms. Careful consideration and benefit-risk analysis should be employed when prescribing baclofen, and emergency departments should be aware of baclofen dangers in abuse situations.

Radiological evolution of progestogen-induced meningioma: A monocentric retrospective study.

Cyproterone acetate (CPA) is known to induce meningioma, and recently, nomegestrol acetate (NMA) and chlormadinone acetate (CMA) were also involved. Progestagen-induced meningioma management starts with progestogen discontinuation and is either interventional (surgery and/or radiotherapy) or conservative (clinical and MRI radiological follow-up). We performed a retrospective volumetric radiological outcomSe study of progestogen-induced meningiomas diagnosed in our hospital. We analysed progestogen-related meningiomas diagnosed until 30 June 2021, with at least one diagnostic and one follow-up MRI results. Meningioma volumes were centrally retrospectively measured using a T1-weighted 3D millimeter sequence with gadolinium injection on a postprocessing console. We analysed 98 meningiomas of 38 females and one transgender (male-to-female), of which 25 (64.1%) had taken CPA, seven (17.9%) NMA, three (7.7%) CMA, and four (10.2%) several progestogens. Eleven patients (24 meningiomas) underwent interventional management, seven patients had meningiomas followed by conservative or interventional management, and 21 patients (51 meningiomas) had only conservative management. Of these 21 patients, 17 had discontinued their progestogen less than 6 months before, of which 14 (82.3%) had decreased or stable meningioma(s) during a 24-month median follow-up (3 to 75) period. Overall, four of the 39 patients experienced meningioma progression (three during conservative treatment and one after surgery), including two patients who had continued NMA or CMA treatment several years after diagnosis. Our study confirms a generally favourable outcome of progestogen-related meningioma after conservative treatment, especially for CPA. It also underlines the need for progestogen discontinuation at meningioma diagnosis.

COVID-19 Vaccination and the Incidence of De Novo or Recurrent Rheumatoid Arthritis: A French and International (VigiBase) Signal Detection Study.

COVID-19 vaccination is critical in frequently immunocompromised patients with rheumatoid arthritis (RA). However, there is a question about the risk of RA flares following vaccination. Our study intended to find out about cases of new RA or flare-ups in people who already had RA that were reported in French and international pharmacovigilance databases after COVID-19 vaccination. We performed a "case-noncase" method in the international pharmacovigilance database VigiBase to identify the risk of RA following COVID-19 vaccination compared with other nonlive vaccines. Using the French Pharmacovigilance Database (FPVD), a descriptive analysis was carried out for RA cases after COVID-19 immunization and a multivariate logistic regression analysis was conducted to compare variables in the new-onset vs. flare-up groups. In 2021, 2,387 cases of RA were reported from 2,817,902 adverse drug reactions associated with COVID-19 vaccines recorded in VigiBase. The reporting odds ratio of RA onset with COVID-19 vaccines compared with the other nonlive vaccines was 0.66 (P < 0.0001). The FPVD reported 161 cases of RA with COVID-19 vaccines, including 77 new-onset RA and 84 cases of RA flare-up. In 88 cases (84.7%), RA occurred after the first dose. The mean time between vaccination and disease onset was 14 ± 21 days, and the delay was significantly shorter in the flare-up group. We do not show a higher risk of RA after COVID-19 vaccination compared with other nonlive vaccines in adults. De novo RA was more likely to happen quickly, be more severe, and have a worse outcome than flares in patients with RA.

Increasing Collagen to Bioink Drives Mesenchymal Stromal Cells-Chondrogenesis from Hyaline to Calcified Layers.

The bioextrusion of mesenchymal stromal cells (MSCs) directly seeded in a bioink enables the production of three-dimensional (3D) constructs, promoting their chondrogenic differentiation. Our study aimed to evaluate the effect of different type I collagen concentrations in the bioink on MSCs' chondrogenic differentiation. We printed 3D constructs using an alginate, gelatin, and fibrinogen-based bioink cellularized with MSCs, with four different quantities of type I collagen addition (0.0, 0.5, 1.0, and 5.0 mg per bioink syringe). We assessed the influence of the bioprinting process, the bioink composition, and the growth factor (TGF-ꞵ1) on the MSCs' survival rate. We confirmed the biocompatibility of the process and the bioinks' cytocompatibility. We evaluated the chondrogenic effects of TGF-ꞵ1 and collagen addition on the MSCs' chondrogenic properties through macroscopic observation, shrinking ratio, reverse transcription polymerase chain reaction, glycosaminoglycan synthesis, histology, and type II collagen immunohistochemistry. The bioink containing 0.5 mg of collagen produces the richest hyaline-like extracellular matrix, presenting itself as a promising tool to recreate the superficial layer of hyaline cartilage. The bioink containing 5.0 mg of collagen enhances the synthesis of a calcified matrix, making it a good candidate for mimicking the calcified cartilaginous layer. Type I collagen thus allows the dose-dependent design of specific hyaline cartilage layers.

Alternative for anti-TNF antibodies for arthritis treatment.

Tumor necrosis factor-α (TNF-α), a proinflammatory cytokine, plays a key role in the pathogenesis of many inflammatory diseases, including arthritis. Neutralization of this cytokine by anti-TNF-α antibodies has shown its efficacy in rheumatoid arthritis (RA) and is now widely used. Nevertheless, some patients currently treated with anti-TNF-α remain refractory or become nonresponder to these treatments. In this context, there is a need for new or complementary therapeutic strategies. In this study, we investigated in vitro and in vivo anti-inflammatory potentialities of an anti-TNF-α triplex-forming oligonucleotide (TFO), as judged from effects on two rat arthritis models. The inhibitory activity of this TFO on articular cells (synoviocytes and chondrocytes) was verified and compared to that of small interfering RNA (siRNA) in vitro. The use of the anti-TNF-α TFO as a preventive and local treatment in both acute and chronic arthritis models significantly reduced disease development. Furthermore, the TFO efficiently blocked synovitis and cartilage and bone destruction in the joints. The results presented here provide the first evidence that gene targeting by anti-TNF-α TFO modulates arthritis in vivo, thus providing proof-of-concept that it could be used as therapeutic tool for TNF-α-dependent inflammatory disorders.

Retrospective medical record evaluation: reliability in assessing causation, preventability, and disability of adverse events.

PURPOSE: The purpose of this article is to assess the reliability of an in-depth analysis on causation, preventability, and disability by two separate review teams on five selected adverse events in acute hospitals: pressure ulcer, postoperative pulmonary embolism or deep vein thrombosis, postoperative sepsis, ventilator-associated pneumonia and postoperative wound infection. DESIGN/METHODOLOGY/APPROACH: The analysis uses a retrospective medical record review of 1,515 patient records by two independent teams in eight acute Belgian hospitals for the year 2005. The Mann-Whitney U-test is used to identify significant differences between the two review teams regarding occurrence of adverse events as well as regarding the degree of causation, preventability, and disability of found adverse events. FINDINGS: Team 1 stated a high probability for health care management causation in 95.5 per cent of adverse events in contrast to 38.9 per cent by Team 2. Likewise, high preventability was considered in 83.1 per cent of cases by Team 1 versus 51.7 per cent by Team 2. Significant differences in degree of disability between the two teams were also found for pressure ulcers, postoperative pulmonary embolism or deep vein thrombosis and postoperative wound infection, but not for postoperative sepsis and ventilator-associated pneumonia. ORIGINALITY/VALUE: New insight on the degree of and reasons for the huge differences in adverse event evaluation is provided.