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Anti-Hu encephalitis is a paraneoplastic syndrome in adults. In children, rare cases of anti-Hu encephalitis were reported mostly without underlying tumors and clinical outcome are usually severe. Here, we describe a 4-year-old girl who developed cerebellar syndrome with abnormal behavior. The brain magnetic resonance imaging showed several T2/fluid-attenuated inversion recovery bilateral brain lesions and autoimmune assessment showed positive anti-Hu antibodies. Computed tomography scan revealed ganglioneuroblastoma which was surgically removed 3 months after onset. Aggressive immunotherapy including dexamethasone, rituximab, and intravenous immunoglobulins were used and a marked neurological improvement soon after 9 months of onset was observed with the child being able to go back to school. The short delay between diagnosis and start of aggressive immunotherapy demonstrate the paramount importance of early diagnosis and early specific therapy after onset of symptoms.

Digital health is currently booming, providing major innovations, particularly in terms of changing the practices of the stakeholders in the healthcare system as a whole. It allows our healthcare system to draw on new synergies between independent, hospital and medico-social professionals, as well as on high-performance digital tools for the benefit of all, users, patients and professionals. These tools, or digital solutions, have a strong potential to improve the healthcare system but also a strong potential for economic development. In this respect, the great diversity of existing and future digital solutions, as well as their vast fields of application, are prompting public and private stakeholders in the sector to question their integration into our healthcare system. The resulting challenges concern the identification of the targets they are intended for, the values they embody and, as a result, the methods of funding and evaluation. At a time when the first reimbursement terms for digital solutions are taking shape in the context of the Social Security Financing Bill for 2022, the roundtable wished to propose 8 recommendations to help structure exchanges between the various stakeholders and initiate avenues of work around the integration of digital solutions into the healthcare system. The main orientations are based on the proposal of a common and transparent reflection methodology around the technical scope of these solutions, the values they bring and the funding mechanisms. Other work will be necessary beyond the points addressed by the round table in order to go into greater depth on certain themes such as the adaptation of existing funding methods to the momentum and specificities of digital technology or the development of research work on the evaluation of the value claimed by these digital solutions.

A first episode of acquired demyelinating disorder (ADS) in children is a diagnostic challenge as different diseases can express similar clinical features. Recently, antibodies against myelin oligodendrocyte glycoprotein (MOG) have emerged as a new ADS biomarker, which clearly allow the identification of monophasic and relapsing ADS forms different from MS predominantly in children. Due to the novelty of this antibody there are still challenges and controversies about its pathogenicity and best technique to detect it. In this manuscript we will discuss the recommendations and caveats on MOG antibody assays, role in the pathogenesis, and additionally discuss the usefulness of other potential new biomarkers in MOG-antibody associated disorders (MOGAD).

AIM To describe cognitive abilities through the evaluation of academic difficulties in children with acute demyelinating syndromes (ADS) and myelin oligodendrocyte glycoprotein (MOG) antibodies. METHOD This was an observational, retrospective study of a French paediatric cohort that included children aged 18 years and younger. Clinical, biological, and imaging data were collected and academic outcome was measured. RESULTS Seventy-six children were included in the study with a mean (SD) follow-up of 4 years 7 months (6y 4mo). Median age at disease onset was 9 years 1 months (interquartile range=4y 7mo-13y 11mo; 36 females, 40 males). Thirty-six children relapsed and 20 had academic difficulties at the last follow-up. Academic difficulties, as well as deep grey matter and putaminal lesions (p=0.047 and p=0.006 respectively), were significantly more prevalent in children aged 10 years and younger (p=0.02). Using univariate binary regression analysis, we found that age at disease onset of 10 years and younger (odds ratio [OR] 3.72 [95% confidence interval {CI} 1.19-11.64]; p=0.024), acute disseminated encephalomyelitis at disease onset (OR 52.5 [95% CI 5.97-461.4]; p

International audience; Introduction: Interphasic DNA has a constant three-dimensional conformation, which is particularly striking for spermatic DNA, with distinct chromosomal territories and a constant chromosomal conformation. We hypothesized that this organization is fragile, and that an excess or a lack of chromosomal segments could hinder the genomic structure as a whole.Methods: Five human male chromosomal translocation carriers and five controls were included. Spermatic DNA spatial organization was studied, in both balanced and unbalanced spermatozoa, with two-dimensional fluorescent in situ hybridization (FISH) via analysis of chromosomes not implicated in the cases' translocations, compared to that of normal controls. Two parameters were studied: the distance between the two telomeric ends of chromosome 1, and the area of the chromosomal territories of chromosomes 1 and 17.Results: Sperm FISH analysis of rearrangement carriers revealed changes in the nuclear architecture compared to that of controls. Inter-telomeric distance and chromosomal territories areas were both significantly increased.Discussion: We show that an excess or lack of chromosomal segments can hinder the normal spatial nuclear architecture in sperm. These results show that nuclear architecture is a fragile assembly, and that local chromosomal abnormalities may impact the nucleus as a whole. This suggests a potential avenue for selection of spermatozoa prior to in vitro fertilization, not only in rearrangement carriers but also in the infertile population at large. Furthermore, we suggest that 2D-FISH could possibly be a useful tool in assessing spermatic nuclear organization in a way to evaluate male fertility.

There is increasing knowledge on the role of antibodies against myelin oligodendrocyte glycoprotein (MOG-abs) in acquired demyelinating syndromes and autoimmune encephalitis in children. Better understanding and prediction of outcome is essential to guide treatment protocol decisions. Therefore, this part of the Paediatric European Collaborative Consensus provides an oversight of existing knowledge of clinical outcome assessment in paediatric MOG-ab-associated disorders (MOGAD). The large heterogeneity in disease phenotype, disease course, treatment and follow-up protocols is a major obstacle for reliable prediction of outcome. However, the clinical phenotype of MOGAD appears to be the main determinant of outcome. Patients with a transverse myelitis phenotype in particular are at high risk of accruing neurological disability (motor and autonomic), which is frequently severe. In contrast, having a single episode of optic neuritis any time during disease course is broadly associated with a lower risk of persistent disability. Furthermore, MOG-ab-associated optic neuritis often results in good functional visual recovery, although retinal axonal loss may be severe. The field of cognitive and behavioural outcome and epilepsy following demyelinating episodes has not been extensively explored, but in recent studies acute disseminated encephalomyelitis (-like) phenotype in the young children was associated with cognitive problems and epilepsy in long-term follow-up. In conclusion, main domains of importance in determining clinical outcome in paediatric MOGAD are visual, motor, autonomic and cognitive function. A standardised evaluation of these outcome domains in all children is of importance to allow adequate rehabilitation and follow-up.

Additional file5. Relative risks

Additional file1. Description of patients from the SCAD cohort

Additional file3. Costs for healthcare resource consumption determined in the SCAD–SNDS linkage study.

Additional file4. Input data for the scenario analyses: clinical events

Background Certain telemedicine programmes for heart failure (HF) have been shown to reduce all-cause mortality and heart failure-related hospitalisations, but their cost-effectiveness remains controversial. The SCAD programme is a home-based interactive telemonitoring service for HF, which is one of the largest and longest-running telemonitoring programmes for HF in France. The objective of this cost-utility analysis was to evaluate the cost-effectiveness of the SCAD programme with respect to standard hospital-based care in patients with HF. Methods A Markov model simulating hospitalisations and mortality in patients with HF was constructed to estimate outcomes and costs. The model included six distinct health states (three ‘not hospitalised’ states, two ‘hospitalisation for heart failure’ states, both depending on the number of previous hospitalisations, and one death state). The model lifetime in the base case was 10 years. Model inputs were based on published literature. Outputs (costs and QALYs) were compared between SCAD participants and standard care. Deterministic and probabilistic sensitivity analyses were performed to assess uncertainty in the input parameters of the model. Results The number of quality-adjusted life years (QALYs) was 3.75 in the standard care setting and 4.41 in the SCAD setting. This corresponds to a gain in QALYs provided by the SCAD programme of 0.65 over the 10 years lifetime of the model. The estimated total cost was €30,932 in the standard care setting and €35,177 in the SCAD setting, with an incremental cost of €4245. The incremental cost-effectiveness ratio (ICER) for the SCAD programme over standard care was estimated at €4579/QALY. In the deterministic sensitivity analysis, the variables that had the most impact on the ICER were HF management costs. The likelihood of the SCAD programme being considered cost-effective was 90% at a willingness-to-pay threshold of €11,800. Conclusions Enrolment of patients into the SCAD programme is highly cost-effective. Extension of the programme to other hospitals and more patients would have a limited budget impact but provide important clinical benefits. This finding should also be taken into account in new public health policies aimed at encouraging a shift from inpatient to ambulatory care.

Resume Dans un contexte de perpetuelle evolution des traitements, l’acces a l’innovation therapeutique est un enjeu majeur pour les patients et pour les differents acteurs impliques dans les procedures de mise a disposition des produits de sante. Les revolutions en matiere de medecine genomique et personnalisee, d’intelligence artificielle et de biotechnologies vont transformer la medecine de demain et l’organisation de notre systeme de sante. Il est ainsi fondamental que la France se prepare a ces mutations et accompagne le developpement de ses entreprises dans ces nouveaux domaines. Le recent Conseil strategique des industries de sante lance par Matignon permet de proposer un arsenal reglementaire propice a l’implementation et la diffusion des innovations therapeutiques. Dans le present atelier, nous declinons un certain nombre de propositions, notre approche se veut pragmatique avec un souci permanent d’acces securise des patients aux medicaments et de simplification des procedures reglementaires. Ceci a ete realise grâce a la participation a cette table ronde de la plupart des acteurs impliques (industriels, Agence nationale de securite du medicament et des produits de sante [ANSM], Haute Autorite de sante [HAS], Institut national du cancer [INCa], Les entreprises du medicament [LEEM], Hopitaux, observatoire du medicament, des dispositifs medicaux et de l’innovation therapeutique…). Les principales propositions tendent a favoriser l’implementation d’essais cliniques sur notre territoire en particulier les phases precoces, un acces plus large aux innovations en favorisant les « early access programs », et en mettant en place des autorisations temporaires d’utilisation pour les extensions d’indication de medicaments deja disponibles qui permettent de prescrire un medicament meme si ce dernier a une autorisation de mise sur le marche (AMM) dans une autre indication. De plus, nous proposons un remboursement dont le maintien serait conditionne par la levee des incertitudes initiales, permettant ainsi une mise a disposition sur la base de donnees preliminaires et prometteuses dans les maladies graves ou le besoin medical n’est pas couvert. Ce mecanisme impliquera une reevaluation a la lumiere de donnees consolidees issues des essais cliniques et/ou de donnees de vie reelle. Enfin, pour mener au mieux ces evaluations, en vue de l’acces ou de la prise en charge, nous proposons la mise en place de conventions de partenariat agences sanitaires/hopitaux afin de favoriser l’emergence d’experts de terrains, l’idee etant de privilegier une expertise ascendante au plus proche des besoins ressentis des patients et de la vie reelle.

In a context of perpetual evolution of treatments, access to therapeutic innovation is a major challenge for patients and the various players involved in the procedures of access to medicines. The revolutions in genomic and personalized medicine, artificial intelligence and biotechnology will transform the medicine of tomorrow and the organization of our health system. It is therefore fundamental that France prepares for these changes and supports the development of its companies in these new areas. The recent "Conseil stratégique des industries de santé" launched by Matignon makes it possible to propose a regulatory arsenal conducive to the implementation and diffusion of therapeutic innovations. In this workshop, we present a number of proposals, our approach having remained pragmatic with a permanent concern to be effective in the short term for the patients and to simplify the procedures as much as possible. This was achieved thanks to the participation in this workshop of most of the players involved (industrial companies, "Agence nationale de sécurité du médicament et des produits de santé", "Haute Autorité de santé", "Institut national du cancer", "Les entreprises du médicament", hospitals, "Observatoire du médicament, des dispositifs médicaux et de l'innovation thérapeutique"…). The main proposals tend to favor the implementation of clinical trials on our territory, especially the early phases, a wider access to innovations by favoring early access programs and setting up a process called "autorisation temporaire d'utilisation d'extension" (ATUext) that make it possible to prescribe a medicinal product even if the latter has a marketing authorisation in another indication. In addition, we propose a conditional reimbursement that will be available based on preliminary data but will require re-evaluation based on consolidated data from clinical trials and/or real-life data. Finally, in order to better carry out these assessments, with a view to access or care, we propose the establishment of partnership agreements with health agencies/hospitals in order to encourage the emergence of field experts, in order to prioritize an ascending expertise closer to patients' needs and to real life.

Objectives To estimate the number of patients with severe spondyloarthritis (SpA) in France, describe their comorbidities and document and value their healthcare resource consumption. Methods Data were retrieved from an insurance claims database covering a 1/97 random sample of the French population. All patients benefiting from full insurance coverage (“ALD”) for severe SpA in 2012 (including cases with structural damage and/or frequent flares) were identified, together with a control group frequency-matched by age and gender. Severe comorbidities were documented through ALD categories. Healthcare resource consumption was documented and valued from the payer's perspective. Rates of comorbidities and costs were compared in SpA patients versus controls using non-parametric testing. Results Overall, 827 patients with ALD status for severe SpA were identified (control group: n = 2.481), corresponding to a prevalence rate of 0.18% [0.17–0.19] for SpA with ALD in the general population. Severe comorbidities more frequent in patients with SpA than in controls included inflammatory bowel disorders (odds ratio: 15.0 [6.2–36.2]), hypertension (2.5 [1.6–3.9]), atrial fibrillation (4.3 [1.9–9.6]) and major depressive disorder (2.1 [1.3–3.6]). Mean per capita annual direct healthcare expenditure was 3.6 [3.2–4.1]-fold higher in SpA patients (€6,122 [€5,838–€6,406]) than in controls (€1,682 [€1,566–€1,798]). Extrapolating to all patients in France, total healthcare cost attributable to severe SpA patients was €391 [€355–€426] million, with medication accounting for 53.8% of this cost. Conclusions The burden of severe SpA in France is substantial, due to the high prevalence, high direct costs and associated comorbidities.

Background SCAD is a 3-month telemonitoring program for HF patients, associated with therapeutic education, proposed after an acute HF episode. SCAD is based on an interactive algorithm allowing to generate educative messages and alarms based on patients' responses registered on a digital tablet. It is funded by the French Health Insurance through a pilot program: ETAPES (470€/patient). Purpose To describe the profile of patients using SCAD & assess the medico-economic impact of the SCAD system. Methods Multicenter retrospective cohort study using SCAD data matched with French Health Insurance data. All patients telemonitored by SCAD in 7 centers have been included, since 01/01/2010 to 12/31/2016. Only direct costs were considered, estimated from a societal perspective limited to reimbursements. Analyses were performed to assess the difference in healthcare consumptions and costs between the year before and the year after inclusion in the SCAD program. Patients who died in the 12 months after SCAD initiation were excluded. Results 627 patients benefited from SCAD program between 01/01/2010 and 12/31/2016 and were retrieved in French Health Insurance data through probabilistic matching. Out of the 627 patients, 99 died in the 12 months after SCAD initiation. Analyses were performed on 528 patients.72.2% were male, mean age was 66.0 years old and mean BMI 28.2. HFrEF represented 51.9% of patients, HFmrEF 25.9% and HFpEF 22.2%. 58.0% were in NYHA class 2 at baseline, 29.2% in class 3, 8.5% in class 1 and 4.3% in class 4. Mean Charlson Comorbidity Index score was 2.6 at baseline. Patients reported their level of fatigue (10 representing significant fatigue) and morale (10 = good morale) at baseline: mean fatigue=4.0/10 & mean morale=7.4/10. Medico economic results are presented in table 1 and show an important & significant decrease of hospitalizations costs and some transfer of cost toward ambulatory care. Conclusion On the year following remote monitoring, total health expenditure has been reduced by 18% on average (mean=3 210€/patient) and 42% in median (5 500€/patient) vs 12 months before. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): This analysis has been funded through an institutional grant from Amgen

Imaging plays a crucial role in differentiating the spectrum of paediatric acquired demyelinating syndromes (ADS), which apart from myelin oligodendrocyte glycoprotein antibody associated disorders (MOGAD) includes paediatric multiple sclerosis (MS), aquaporin-4 antibody neuromyelitis optica spectrum disorders (NMOSD) and unclassified patients with both monophasic and relapsing ADS. In contrast to the imaging characteristics of children with MS, children with MOGAD present with diverse imaging patterns which correlate with the main demyelinating phenotypes as well as age at presentation. In this review we describe the common neuroradiological features of children with MOGAD such as acute disseminated encephalomyelitis, optic neuritis, transverse myelitis, AQP4 negative NMOSD. In addition, we report newly recognized presentations also associated with MOG-ab such as the ‘leukodystophy-like’ phenotype and autoimmune encephalitis with predominant involvement of cortical and deep grey matter structures. We further delineate the features, which may help to distinguish MOGAD from other ADS and discuss the future role of MR-imaging in regards to treatment decisions and prognosis in children with MOGAD. Finally, we propose an MRI protocol for routine examination and discuss new imaging techniques, which may help to better understand the neurobiology of MOGAD.

Over the past few years, increasing interest in the role of autoantibodies against myelin oligodendrocyte glycoprotein (MOG-abs) as a new candidate biomarker in demyelinating central nervous system diseases has arisen. MOG-abs have now consistently been identified in a variety of demyelinating syndromes, with a predominance in paediatric patients. The clinical spectrum of these MOG-ab-associated disorders (MOGAD) is still expanding and differs between paediatric and adult patients. This first part of the Paediatric European Collaborative Consensus emphasises the diversity in clinical phenotypes associated with MOG-abs in paediatric patients and discusses these associated clinical phenotypes in detail. Typical MOGAD presentations consist of demyelinating syndromes, including acute disseminated encephalomyelitis (ADEM) in younger, and optic neuritis (ON) and/or transverse myelitis (TM) in older children. A proportion of patients experience a relapsing disease course, presenting as ADEM followed by one or multiple episode(s) of ON (ADEM-ON), multiphasic disseminated encephalomyelitis (MDEM), relapsing ON (RON) or relapsing neuromyelitis optica spectrum disorders (NMOSD)-like syndromes. More recently, the disease spectrum has been expanded with clinical and radiological phenotypes including encephalitis-like, leukodystrophy-like, and other non-classifiable presentations. This review concludes with recommendations following expert consensus on serologic testing for MOG-abs in paediatric patients, the presence of which has consequences for long-term monitoring, relapse risk, treatments, and for counselling of patient and families. Furthermore, we propose a clinical classification of paediatric MOGAD with clinical definitions and key features. These are operational and need to be tested, however essential for future paediatric MOGAD studies.

Purpose:Human chorionic gonadotropin stimulates fetal testosterone production and contributes to normal development of male genitalia. Using population based data we hypothesized that differences in maternal free beta human chorionic gonadotropin may be associated with hypospadias.Materials and Methods:Data were obtained from the Paris Registry of Congenital Malformations (REMAPAR) (2011 to 2016). The initial study population included 3,172 pregnant women who gave birth to a singleton live born male infant with a congenital malformation. After exclusion of cases with unknown beta human chorionic gonadotropin and those with chromosomal or genetic abnormalities, the study population included 194 boys with isolated hypospadias and 1,075 controls. For cases with operative notes (125) we obtained data on type (proximal/distal) of hypospadias. Using quantile regression we compared median values of multiple of median beta human chorionic gonadotropin measured for first trimester Down syndrome screening (10th to 13th gestational weeks) for overall as well as by type of hypospadias vs controls. We also considered possible effects of placental dysfunction (maternal age, intrauterine growth retardation and preterm births) as potential confounding factors.Results:Overall the median beta human chorionic gonadotropin multiple of median was comparable for women who had an infant with hypospadias vs controls (0.99 vs 0.95, p=0.3). However, proximal hypospadias was associated with a statistically significant higher median multiple of median than distal hypospadias or unspecified (1.49 vs 0.92 vs 1.05, p=0.02). The estimates were comparable after adjustment for placental dysfunction.Conclusions:Our findings support the hypothesis that an alteration in maternal beta human chorionic gonadotropin levels is associated with hypospadias. However, this association appears to be limited to proximal hypospadias.

A first episode of acquired demyelinating disorder (ADS) in children is a diagnostic challenge as different diseases can express similar clinical features. Recently, antibodies against myelin oligodendrocyte glycoprotein (MOG) have emerged as a new ADS biomarker, which clearly allow the identification of monophasic and relapsing ADS forms different from MS predominantly in children. Due to the novelty of this antibody there are still challenges and controversies about its pathogenicity and best technique to detect it. In this manuscript we will discuss the recommendations and caveats on MOG antibody assays, role in the pathogenesis, and additionally discuss the usefulness of other potential new biomarkers in MOG-antibody associated disorders (MOGAD).

In recent years, the understanding about the different clinical phenotypes, diagnostic and prognostic factors of myelin oligodendrocyte glycoprotein-antibody-associated disorders (MOGAD) has significantly increased. However, there is still lack of evidence-based treatment protocols for acute attacks and children with a relapsing course of the disease. Currently used acute and maintenance treatment regimens are derived from other demyelinating central nervous system diseases and are mostly centre-specific. Therefore, this part of the Paediatric European Collaborative Consensus attempts to provide recommendations for acute and maintenance therapy based on clinical experience and evidence available from mainly retrospective studies. In the acute attack, intravenous methylprednisolone (IVMP) leads to a favourable outcome in the majority of patients and can be followed by tapering of oral steroids up to a maximum of three months to maintain the benefit of acute treatment by suppressing disease activity. Intravenous immunoglobulins (IVIG) and plasmapheresis constitute second-line therapies in case of insufficient response to IVMP. After a first relapse, maintenance treatment should be started in order to prevent further relapses and the possibility of permanent sequelae. Four first-line therapies consisting of rituximab (RTX), azathioprine, mycophenolate mofetil or monthly IVIG have been identified by the consensus group. In case of further relapses despite maintenance treatment, the consensus group recommends treatment escalation with RTX or IVIG, followed by combining those two, and ultimately adding maintenance oral steroids. Many open questions remain which need to be addressed in further international prospective evaluation of MOGAD treatment. This international collaboration is essential to expand the state of current knowledge.