Acute generalized exanthematous pustulosis: European expert consensus for diagnosis and management.

Acute generalized exanthematous pustulosis (AGEP) is a rare, usually drug-induced, acute pustular rash. Despite the lack of strong data supporting the effectiveness of topical or systemic corticosteroids in this drug reaction, they are widely used. More generally, there is no consensus on the diagnostic modalities and the management of patients with AGEP. We aimed to provide European expert recommendations for the diagnosis and management or patients with AGEP. Members of the ToxiTEN group of the European Reference Network (ERN)-skin, all dermatologists and/or allergologists with expertise in drug reactions, elaborated these recommendations based on their own experience and on a review of the literature. Recommendations were separated into the following categories: professionals involved, assessment of the diagnosis of AGEP, management of the patient and allergological work-up after the acute phase. Consensus was obtained among experts for the list of professionals involved for the diagnosis and management of AGEP, including the minimum diagnostic work-up, the setting of management, the treatments, the modalities and the timing of allergological work-up and follow-up. European experts in drug allergies propose herein consensus on the diagnosis and management of patients with AGEP. A multidisciplinary approach is warranted, including dermatologists, allergologists and pharmacovigilance services.

Childhood epidermal necrolysis and erythema multiforme major: a multicentre French cohort study of 62 patients.

INTRODUCTION: The distinction between epidermal necrolysis [EN; including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and overlap syndrome] and erythema multiforme major (EMM) in children is confusing. We aimed to better describe and compare these entities. MATERIALS AND METHODS: This French retrospective multicentre study included children ≤18 years old referred for EN or EMM between 1 January 2008 and 1 March 2019. According to pictures, children were reclassified into TEN/overlap, SJS or EMM/unclassified (SJS/EMM) groups and compared for epidemiological and clinical data, triggers, histology and follow-up. RESULTS: We included 62 children [43 boys, median age 10 years (range 3-18)]: 16 with TEN/overlap, 11 SJS and 35 EMM. The main aetiologies were drugs in EN and infections (especially Mycoplasma pneumoniae) in EMM (P < 0.001), but 35% of cases remained idiopathic (TEN/overlap, 47%; SJS, 24%; EMM, 34%). The typical target lesions predominated in EMM (P < 0.001), the trunk was more often affected in EN (P < 0.001), and the body surface area involved was more extensive in EN (P < 0.001). Mucosal involvement did not differ between the groups. Two patients with idiopathic TEN died. Histology of EMM and EN showed similar features. The recurrence rate was 42% with EMM, 7% with TEN/overlap and 0 with SJS (P < 0.001). Sequelae occurred in 75% of EN but involved 55% of EMM. CONCLUSION: Clinical features of EN and EMM appeared well demarcated, with few overlapping cases. Idiopathic forms were frequent, especially for EN, meaning that a wide and thorough infectious screening, repeated if needed, is indicated for all paediatric cases of EN/EMM without any trigger drug. We propose a comprehensive panel of investigations which could be a standard work-up in such situation. Sequelae affected both EN and EMM.

Live-imaging of revertant and therapeutically restored dystrophin in the DmdEGFP-mdx mouse model for Duchenne muscular dystrophy.

BACKGROUND: Dmdmdx , harbouring the c.2983C>T nonsense mutation in Dmd exon 23, is a mouse model for Duchenne muscular dystrophy (DMD), frequently used to test therapies aimed at dystrophin restoration. Current translational research is methodologically hampered by the lack of a reporter mouse model, which would allow direct visualization of dystrophin expression as well as longitudinal in vivo studies. METHODS: We generated a DmdEGFP-mdx reporter allele carrying in cis the mdx-23 mutation and a C-terminal EGFP-tag. This mouse model allows direct visualization of spontaneously and therapeutically restored dystrophin-EGFP fusion protein either after natural fibre reversion, or for example, after splice modulation using tricyclo-DNA to skip Dmd exon 23, or after gene editing using AAV-encoded CRISPR/Cas9 for Dmd exon 23 excision. RESULTS: Intravital microscopy in anaesthetized mice allowed live-imaging of sarcolemmal dystrophin-EGFP fusion protein of revertant fibres as well as following therapeutic restoration. Dystrophin-EGFP-fluorescence persisted ex vivo, allowing live-imaging of revertant and therapeutically restored dystrophin in isolated fibres ex vivo. Expression of the shorter dystrophin-EGFP isoforms Dp71 in the brain, Dp260 in the retina, and Dp116 in the peripheral nerve remained unabated by the mdx-23 mutation. CONCLUSION: Intravital imaging of DmdEGFP-mdx muscle permits novel experimental approaches such as the study of revertant and therapeutically restored dystrophin in vivo and ex vivo.

Long-term evolving profile of childhood autoimmune blistering diseases: Retrospective study on 38 children.

BACKGROUND: Autoimmune bullous dermatoses (AIBDs) in children are uncommon, and their long-term evolution remains unknown. OBJECTIVE: The aim of this retrospective study was to characterize the long-term prognosis of AIBDs that started during childhood. METHODS: We conducted a monocentric retrospective study, in the French dermatology centre, by including all children affected by AIBDs. The long-term outcome was obtained through a phone call questionnaire. RESULTS: Sixty-three patients were included from January 1993 to December 2015, 34 female and 29 males: 27 Linear immunoglobulin A disease (LAD), 12 bullous pemphigoid (BP), 12 pemphigus, 8 herpetiform dermatitis (DH) and 4 epidermolysis bullosa aquisita (EBA). The mean age was 4.7 years old. Twenty-five patients were lost during the follow-up. For the 38 remaining patients, the mean follow-up duration for all pathologies was 6.6 years. Twenty-nine of them had at least one relapse. Late relapses were observed in two cases of DH and six cases of pemphigus (7-34 months). The mean treatment duration was 30.6 months with variability according to the AIBDs. Topical corticosteroids were used alone, effectively, for seven patients and in association with other treatment in 19 patients in complete remission. Complete remission was noted in 34/38 children with a follow-up of 4.4 years (0.08-19.5). The mean duration to complete remission was 30.5 months (6-114 months). Late nasal synechiae were reported in one EBA only. There was no significant associated comorbidity, but an association with a primary immune deficiency (PID) was observed in two cases. CONCLUSION: Childhood AIBDs appear to be of good overall prognosis but a long-term follow-up is mandatory, as relapses can be late, except for BP. The use of topical corticosteroids is frequently effective alone or in association. The association with PID leads to think about the possibility of a possible underlying dysimmunity in the child.

Blood and nasal epigenetics correlate with allergic rhinitis symptom development in the environmental exposure unit.

BACKGROUND: Epigenetic alterations may represent new therapeutic targets and/or biomarkers of allergic rhinitis (AR). Our aim was to examine genome-wide epigenetic changes induced by controlled pollen exposure in the environmental exposure unit (EEU). METHODS: 38 AR sufferers and eight nonallergic controls were exposed to grass pollen for 3 hours on two consecutive days. We interrogated DNA methylation at baseline and 3 hours in peripheral blood mononuclear cells (PBMCs) using the Infinium Methylation 450K array. We corrected for demographics, cell composition, and multiple testing (Benjamini-Hochberg) and verified hits using bisulfite PCR pyrosequencing and qPCR. To extend these findings to a clinically relevant tissue, we investigated DNA methylation and gene expression of mucin 4 (MUC4), in nasal brushings from a separate validation cohort exposed to birch pollen. RESULTS: In PBMCs of allergic rhinitis participants, 42 sites showed significant DNA methylation changes of 2% or greater. DNA methylation changes in tryptase gamma 1 (TPSG1), schlafen 12 (SLFN12), and MUC4 in response to exposure were validated by pyrosequencing. SLFN12 DNA methylation significantly correlated with symptoms (P < 0.05), and baseline DNA methylation pattern was found to be predictive of symptom severity upon grass allergen exposure (P = 0.029). Changes in MUC4 DNA methylation in nasal brushings in the validation cohort correlated with drop in peak nasal inspiratory flow (Spearman's r = 0.314, P = 0.034), and MUC4 gene expression was significantly increased (P < 0.0001). CONCLUSION: This study revealed novel and rapid epigenetic changes upon exposure in a controlled allergen challenge facility, and identified baseline epigenetic status as a predictor of symptom severity.

[Fear of childbirth among nulliparous women: Relations with pain during delivery, post-traumatic stress symptoms, and postpartum depressive symptoms]. / La peur de l'accouchement chez des nullipares: lien avec la douleur lors de l'accouchement, les symptômes de stress post-traumatique et les symptômes dépressifs post-partum.

OBJECTIVE: Fear of childbirth is common in women who are pregnant with their first child and is associated with important consequences such as abortions and miscarriages. Twenty percent of nulliparous women seem to exhibit a mild or moderate fear, while 6% present an excessive and irrational fear known as tocophobia. Tocophobia is suggested to be associated with many negative consequences such as postpartum depression (PPD) and Post-traumatic stress (PTS). However, there is little empirical evidence to support these relationships. Recently, Fairbrother and Woody (2007) did not observe a link between the fear of childbirth and symptoms of PPD and PTS in nulliparous women. Some results, near the significance level, could be explained by a lack of statistical power. The present study focused on the link between the fear of childbirth and the process of delivery, the perception of pain, PPD and PTS. More specifically, it aimed to test three hypotheses: (i) fear of childbirth will be linked to the process of delivery, especially regarding the perception of pain, the use of anaesthesia and the use of Caesarean section; (ii) a high level of fear of childbirth will be associated with more negative postpartum consequences (namely PPD/PTS symptoms); (iii) the process of delivery and pain will also be related to post-delivery symptoms. Mediation effects were tested. METHOD: Data from a longitudinal study were used to meet the hypotheses. A total of 176 nulliparous pregnant women responded to questionnaires at two time measurements (during pregnancy and at 5weeks postpartum). RESULTS: Fear of childbirth is related to the perception of pain at birth among women delivering vaginally, in the absence of anaesthesia. It is also linked to symptoms of PPD and PTS, regardless of whether or not anaesthesia was used. Fear of childbirth also appears to be strongly associated to symptoms of PTS in women who have experienced an unplanned caesarean section. Thus, symptoms of postpartum PTS could play a mediating role in the link between fear of childbirth and PPD. CONCLUSIONS: These results support the relevance of taking into account the fear of childbirth and perception of pain in connection with symptoms of PTS and PPD in nulliparous women. The unplanned caesarean section (including emergency caesarean) also appears to be important in the study of the relationship between fear and symptoms of PTS. Fear of childbirth could render the experience of childbearing more negative and predispose to PTS and PPD. Enabling psychological vulnerabilities could also be an interesting avenue for understanding these links. Limitations are discussed.

[Lightning strike and lesions outside the brain: Clinical cases and a review of the literature]. / Les atteintes extra-cérébrales de la foudre : vignettes cliniques et revue de la littérature.

INTRODUCTION: Every year, 240,000 people are struck by lightning worldwide, causing injuries leading to significant handicaps. Most of the symptoms involve brain lesions; neuromuscular sequelae and myelopathy are less common. OBSERVATIONS: We describe five cases of patients struck by lightning with various clinical presentations. The first patient presented painful paresthesias in both upper limbs that disappeared 18 months later; the injury was a plexopathy. The second patient developed proximal weakness in the upper-left limb due to a myopathy. Two patients presented with various motor weaknesses in the lower limbs due to motor neuron disease and myelopathy. The last patient had a transient tetraplegy, which resolved in 5minutes; the diagnosis was keraunoparalysis. DISCUSSION: Lightning injuries can have many consequences depending on the different mechanisms involved. The clinical presentation is often due to a very focal lesion without any secondary extension. Motor neuron disease probably results from post-traumatic myelopathy. We discuss the ALS-electrocution association, frequently described in the literature. CONCLUSION: Various peripheral nerve and spinal cord lesions can be seen in lightning strike victims involving myelopathy, motor neuron, muscle and plexus. Clinical syndromes are often atypical but outcome is often favorable.

Asymmetric bi-layer PFSA membranes as model systems for the study of water management in the PEMFC.

New bi-layer PFSA membranes made of Nafion® NRE212 and Aquivion™ E79-05s with different equivalent weights are prepared with the aim of managing water repartition in the PEMFC. The membrane water transport properties, i.e. back-diffusion and electroosmosis, as well as the electrochemical performances, are compared to those of state-of-art materials. The actual water content (the inner water concentration profile across the membrane thickness) is measured under operation in the fuel cell by in situ Raman microspectroscopy. The orientation of the equivalent weight gradient with respect to the water external gradient and to the proton flow direction affects the membrane water content, the water transport ability and, thus, the fuel cell performances. Higher power outputs, related to lower ohmic losses, are observed when the membrane is assembled with the lower equivalent weight layer (Aquivion™) at the anode side. This orientation, corresponding to enhanced water transport by back-flow while electroosmosis remains unaffected, results in the higher hydration of the membrane and of the anode active layer during operation. Also, polarization data suggest a different water repartition in the fuel cell along the on-plane direction. Even if the interest in multi-layer PFSA membranes as perspective electrolytes for PEMFCs is not definitively attested, these materials appear to be excellent model systems to establish relationships between the membrane transport properties, the water distribution in the fuel cell and the electrochemical performances. Thanks to the micrometric resolution, in situ Raman microspectroscopy proves to be a unique tool to measure the actual hydration of the membrane at the surface swept by the hydrated feed gases during operation, so that it can be used as a local probe of the water concentration evolution along the gas distribution channels according to changing working conditions.

Prevalence and sport-related predictors of disturbed eating attitudes and behaviors: Moderating effects of sex and age.

Very few studies examined the prevalence and sport-related predictors of disturbed eating attitudes and behaviors (DEABs) among adolescents involved in sport practice, and their results are mixed and inconclusive. These inconsistencies are most likely due to their methodological heterogeneity and to the fact that none of these studies took into consideration the potentially relevant characteristics of the sport practice context. This study attempts to answer this limitation among French adolescents not involved or involved in various sports contexts defined based on their organization, leanness-centration, and competitive level. Participants were 335 adolescents involved in sport practice, and 435 adolescents not involved in any form of regular sport practice. The DEABs were measured using the Eating Attitudes Test-26. Global results do not showed any significant association between the status of the participants and DEAB. However, these results drastically changed when we considered the potential moderating role of sex and age on these relations. Indeed, sports involvement in general, and involvement in leanness and competitive sports were found to exert sex- and age-differentiated effects on the risks of presenting clinically significant levels of DEAB. This study suggests the importance of monitoring, preventive, and early intervention mechanisms within the context of practice, particularly for adolescent girls.

Ptosis secondary to orbital metastasis undetected by magnetic resonance imaging: A case report.

We report a patient with isolated ptosis secondary to orbital metastasis but no evidence of a neoplastic process on magnetic resonance imaging (MRI). A 69-year-old male was referred to our hospital with ptosis of the right upper eyelid and secondary frontalis muscle overaction on the left side for six months. The palpebral fissure was 3mm on the right and 16mm on the left, and levator function was 6mm and 19mm respectively. Three years previously, he had undergone surgical resection of the left lower lobe of the lung due to a T1 N0 M0 adenocarcinoma, and no recurrence had since been observed. An MRI was performed to rule out ptosis secondary to metastasis. Thyroid dysfunction and myasthenia were also ruled out. The ptosis was attributed to an isolated microvascular third nerve palsy. A standard external levator advancement was performed. Six months after the surgery, the patient presented with intense pain, minimal ptosis, edema and diplopia. A new MRI revealed an orbital metastasis measuring 2.4×1.0×1.6cm in the superior orbit, exerting mass effect on the superior rectus and the levator palpebrae superioris muscle. A positron emission tomography scan revealed a recurrence of the lung cancer with multiple bony metastases. The patient underwent chemotherapy consisting of the taxol-carboplatin protocol. Our report highlights the importance of a high index of suspicion of a neoplastic etiology in patients with mild symptoms and a history of cancer even if imaging does not initially reveal a mass or infiltration.

Chapitre 2. L'autonomisation des comités nationaux d'éthique de la recherche en Afrique : perspective historique et enjeux actuels.

Since the 60s, and particularly after various scandals in the 90s, national research ethics committees in Africa have established themselves as key players in the field of international clinical research. Notably based on the principle of double ethical review, their existence has historically been aimed at preventing a form of ethical dumping, a temptation that still exists today on the part of some research promoters. While the international framework of “soft” law has favored their emergence and legitimacy, a legal and regulatory framework of “hard” law is also necessary at local level for each national research ethics committee, to ensure its proper functioning and the optimal fulfillment of its missions. The aim of this article is to analyze the similarities and differences between three national ethics committees in Africa, specifically the CNERS of Guinea, the CNERS of Benin and the CNESVS of Côte d’Ivoire, in terms of status, missions, legal or regulatory ground and, more generally, autonomy. This analysis will enable us, on the one hand, to take account of common logistical difficulties and, on the other, to go beyond differences in legal status and missions to define what enables this type of committee to fully exercise its role(s). Finally, this article proposes to model the various elements that contribute to the autonomy and resilience of a national research ethics committee, around a notion proposed on this occasion: the “circles of autonomy”.

Psychiatric burden in a cohort of adults with Niemann Pick type C disease: from psychotic symptoms to frontal lobe behavioral disorders.

OBJECTIVES: To describe Niemann-Pick type C (NP-C) behavioral symptoms (focusing on psychotic symptoms) and its relation to frontal lobe functioning. METHODS: We retrospectively reviewed medical charts of NP-C-patients followed in the Lysosomal Diseases reference center in Paris Pitié-Salpêtrière. We collected demographic data, psychiatric clinical manifestations, psychometric scales, and extended neuropsychological data including executive and behavioral frontal lobe functions evaluations. RESULTS: Nineteen patients were included in the study with ten of them having experienced at least one acute psychotic episode, being inaugural for six of them. Most of the patients suffered from behavioral (15/17) and cognitive disorders (18/19) (including executive dysfunction (11/12), apathy (13/17), impaired social cognition (11/13) and stereotyped behaviors (5/10). For five patients, quality of life was significantly impaired by these abnormal behaviors. Concerning frontal neuropsychological evaluation, Facial emotion recognition was by far the most performed neuropsychological test (n = 8) and the score was always abnormal. It is noteworthy that psychotic symptoms were often drug resistant (8/9) and that Miglustat was associated with a better control of psychotic symptoms. CONCLUSIONS: We report a high frequency of psychiatric symptoms in NP-C encompassing acute psychotic manifestations, often presenting early in the course of the disease with atypical features. We also report disabling behavioral manifestations related to frontal dysfunction.

Towards a clinical consensus on the management of pregnancy and birth after laparoscopic and open myomectomy: A survey of obstetricians and gynaecologists.

OBJECTIVES: The primary aim was to assess if a clinical consensus regarding the management of pregnancy post myomectomy existed amongst consultant obstetricians and gynaecologists. Secondary objectives were to evaluate factors which influence the clinician's decision making in this group of women. STUDY DESIGN: Electronic survey sent to all consultants working in the North Central and East London deanery, Kent Surrey and Sussex deanery and Imperial NHS Trust to assess opinions on mode of birth post myomectomy, intervals advised to pregnancy post myomectomy, factors influencing the management of delivery in the scarred uterus post myomectomy, opinions on induction of labour and questions relating to operative notes. RESULTS: 209 consultant responses received between 07/03/2022-07/05/2022 (44% response rate); 77% (161/209) practicing obstetricians and gynaecologists, 10% (21/109) pure gynaecologists and 13% (27/209) pure obstetricians. The majority would support a vaginal birth after open myomectomy (75%) and laparoscopic myomectomy (79%). No consensus was found as to the optimal time interval between myomectomy and pregnancy. Higher frequency of performing myomectomy and a greater level of experience were significantly associated with a shorter interval to pregnancy advised. The most important operative factors influencing decision to support trial of labour post myomectomy were breach of uterine cavity; location of fibroids removed and number of incisions on the uterus. 77% believe women should be given a choice regarding mode of delivery post myomectomy in a similar way to previous LSCS. 82.8% would support enrolment of patients into a prospective trial to investigate delivery post myomectomy. CONCLUSIONS: We present a comprehensive survey of clinician opinions on pregnancy post myomectomy demonstrating that the majority of consultant obstetricians and gynaecologists sampled would support vaginal birth post myomectomy; counselling patients in a similar way to VBAC; a standardised myomectomy operation note and enrolment of patients in a future prospective trial. Wide variation in opinion regarding interval to pregnancy post myomectomy has been highlighted. We believe this information will facilitate counselling discussions and empower women with subsequent pregnancies after myomectomy to make an informed decision on mode of birth post myomectomy.

The impact of patients as trainers on registered nurses' patient engagement in primary care clinics: a qualitative study.

BACKGROUND: In Canada, primary care is usually the front door to health care for people with health issues. Among these primary care services are primary care clinics (PCC), where the competencies of registered nurses (RNs) are needed. However, nursing practice in PCCs is variable and sometimes suboptimal from one PCC to another. In 2019, the Quebec Ministry of Health and Social Services deployed a practical guide for RNs practicing in PCCs. This guide was intended to support best professional and interprofessional practices and enhance the quality of services offered according to a physical-social vision of care, interprofessional collaboration and partnership with the patient. The Formation de formateurs en première ligne (F2PL) project team developed a train-the-trainer educational intervention to support RNs in assimilating the content of this guide. This educational intervention is uncommon because it includes patients as trainers (PTs). PTs developed and provided andragogic content about patient's experience to enhance patient engagement. OBJECTIVE: To describe the impacts of the educational intervention provided by the PTs in nurses' patient engagement practices in PCCs. METHODS: A descriptive qualitative approach was used to describe in-depth changes in RNs' practices. Individual interviews were conducted with 10 RNs and 3 PTs to explore the changes in RNs' practice and the barriers and facilitators to adopting this new practice. An inductive and deductive thematic analysis was carried out according to a conceptual model of patient engagement (the Montreal Model), and emerging themes were condensed into propositions. To ensure credibility, a peer review was conducted with the F2PL team, which includes a patient co-leader. RESULTS: The educational intervention provided by PTs has impacted RNs' practice in 3 ways: awareness or reminding of general principles, updating commitment to already known principles and enhancing the development of new professional skills. CONCLUSIONS: PTs could effectively support the RNs' motivation to use patient engagement practices in primary care.

[Undesired side effects of tapentadol in comparison to oxycodone. A meta-analysis of randomized controlled comparative studies]. / Unerwünschte Nebenwirkungen von Tapentadol im Vergleich zu Oxycodon. Eine Metaanalyse randomisierter, kontrollierter Vergleichsstudien.

OBJECTIVE: Tapentadol is a new centrally acting analgesic with a dual mode of action as an agonist of the µ-opioid receptor and as a norepinephrine reuptake inhibitor. The aim of the present study was to evaluate the results from randomized controlled trials investigating the relative amount of adverse effects using tapentadol or oxycodone for the treatment of pain. METHODS: A quantitative systematic review was carried out according to the PRISMA recommendations on randomized controlled trials comparing tapentadol and oxycodone in pain treatment. The incidences of typical adverse side effects of opioid-based analgesic therapy (e.g. nausea, vomiting, obstipation or pruritus) were extracted and the pooled relative risks (RR) with corresponding 95% confidence intervals (CI) were calculated. RESULTS: A total of 9 trials involving 7,948 patients were included and of these 2,810 patients were treated with oxycodone and 5,138 were treated with tapentadol in equivalent analgesic dosages as documented by an equivalent analgesic effect. The risk of typical opioid-based adverse effects, such as nausea (RR 0.61; 95% CI 0.57-0.66), vomiting (RR 0.50, 95% CI: 0.41-0.60), obstipation (RR 0.47, 95%-CI 0.40-0.56), dizziness (RR 0.86, 95% CI 0.78-0.95), somnolence (RR 0.76, 95% CI 0.67-0.86) and pruritus (RR 0.46, 95% CI 0.37-0.58) was reduced when tapentadol was used for analgesic treatment. These adverse effects were investigated in all nine trials. The risk for dryness of the mouth (6 trials, 6,218 patients, RR 1.79, 95% CI 1.40-2.29) and dyspepsia (1 trial, 646 patients, RR 2.75, 95% CI 1.09-6.94) was increased when tapentadol was used instead of oxycodone. There were no significant differences in the relative risk for any other investigated adverse effect such as dysentery, headache or fatigue. CONCLUSION: The results show that using tapentadol significantly reduces the risk of the typical opioid-based adverse effects compared with oxycodone while providing equivalent analgesic treatment.