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Summary: Background: In industrialized countries, the incidence of inflammatory bowel disease (IBD) appears stabilized. This study examined the incidence and phenotype of IBD in Northern France over a 30-year period. Methods: Including all IBD patients recorded in the EPIMAD population-based registry from 1988 to 2017 in Northern France, we described the incidence and clinical presentation of IBD according to age, sex and time. Findings: A total of 22,879 incident IBD cases were documented (59% (n = 13,445) of Crohn’s disease (CD), 38% (n = 8803) of ulcerative colitis (UC), 3% (n = 631) of IBD unclassified (IBDU)). Over the study period, incidence of IBD, CD and UC was 12.7, 7.2 and 5.1 per 105 person-years, respectively. The incidence of CD increased from 5.1/105 in 1988–1990 to 7.9/105 in 2015–2017 (annual percent change (APC): +1.9%, p

Abstract Autoimmune lymphoproliferative syndrome (ALPS) is a primary disorder of lymphocyte homeostasis, leading to chronic lymphoproliferation, autoimmune cytopenia, and increased risk of lymphoma. The genetic landscape of ALPS includes mutations in FAS, FASLG, and FADD, all associated with apoptosis deficiency, while the role of CASP10 defect in the disease remains debated. In this study, we aimed to assess the impact of CASP10 variants on ALPS pathogenesis. We benefit from thousands of genetic analysis datasets performed in our Institute’s genetic platform to identify individuals carrying CASP10 variants previously suspected to be involved in ALPS outcome: p.C401LfsX15, p.V410I and p.Y446C, both at heterozygous and homozygous state. Clinical and laboratory features of the six included subjects were variable but not consistent with ALPS. Two individuals were healthy. Comprehensive analyses of CASP10 protein expression and FAS-mediated apoptosis were conducted and compared to healthy controls and ALPS patients with FAS mutations. Missense CASP10 variants (p.V410I and p.Y446C), which are common in the general population, did not disrupt CASP10 expression, nor FAS-mediated apoptosis. In contrast, homozygous p.C401LfsX15 CASP10 variant lead to a complete abolished CASP10 expression but had no impact on FAS-mediated apoptosis function. At heterozygous state, this p.C401LfsX15 variant lead to a reduced CASP10 protein levels but remained associated with a normal FAS-mediated apoptosis function. These findings demonstrate that CASPASE 10 is dispensable for FAS-mediated apoptosis. In consequences, CASP10 defect unlikely contribute to ALPS pathogenesis, since they did not result in an impairment of FAS-mediated apoptosis nor in clinical features of ALPS in human. Moreover, the absence of FAS expression up-regulation in subjects with CASP10 variants rule out any compensatory mechanisms possibly involved in the normal apoptosis function observed. In conclusion, this study challenges the notion that CASP10 variants contribute to the development of ALPS.

Objective Data sharing promotes the scientific progress. However, not all data can be shared freely due to privacy issues. This work is intended to foster FAIR sharing of sensitive data exemplary in the biomedical domain, via an integrated computational approach for utilizing and enriching individual datasets by scientists without coding experience. Methods We present an in silico pipeline for openly sharing controlled materials by generating synthetic data. Additionally, it addresses the issue of inexperience to computational methods in a non-IT-affine domain by making use of a cyberinfrastructure that runs and enables sharing of computational notebooks without the need of local software installation. The use of a digital twin based on cancer datasets serves as exemplary use case for making biomedical data openly available. Quantitative and qualitative validation of model output as well as a study on user experience are conducted. Results The metadata approach describes generalizable descriptors for computational models, and outlines how to profit from existing data resources for validating computational models. The use of a virtual lab book cooperatively developed using a cloud-based data management and analysis system functions as showcase enabling easy interaction between users. Qualitative testing revealed a necessity for comprehensive guidelines furthering acceptance by various users. Conclusion The introduced framework presents an integrated approach for data generation and interpolating incomplete data, promoting Open Science through reproducibility of results and methods. The system can be expanded from the biomedical to any other domain while future studies integrating an enhanced graphical user interface could increase interdisciplinary applicability.

Abstract It has been increasingly recognized that there is a subset of patients with refractory systemic JIA, who have failed all available medications and may benefit from HSCT. The increasing experience with HSCT in SJIA, suggests that despite the complicated post-HSCT course, short-term, the transplanted patients either achieved SJIA remission or reduced burden of disease. Longer follow-up, however, is needed to better define the long-term outcomes. The discussion at the NextGen 2022 conference was focused on the optimal timing for the procedure, the need for a good control of inflammatory SJIA activity prior to HSCT, and the role of the reduced intensity conditioning regimens as there was a remote concern that such regimens might increase the risk of SJIA relapse after the transplantation. There was unanimous agreement about the importance of long-term registries to address these questions.

For decades, the Catholic monastic tradition has been defined by demographic decline and the closure of monasteries. And yet, new religious groups have emerged that have cultivated their own take on the monastic tradition, while old monasteries have become treasured heritage objects. In recent years, these new religious groups have started to acquire and inhabit old monasteries. It follows that simultaneous re-religionization and heritagization is taking place at these locations. This combination presents a unique opportunity to scrutinize an unexplored entanglement of religion and heritage. Although re-religionization might seem to conflict with the cultural heritage narrative surrounding these monasteries, this article presents Klooster Nieuw Sion—a new Dutch religious initiative—as a case study, indicating that these developments do not only coexist or oppose each other but are also mutually reinforcing. Drawing on our fieldwork, we explore how heritagization can offer new spiritual opportunities for religious actors within these revitalized monastic spaces.

Abstract This paper explores the institutional mainstreaming of nature-based solutions (NBS) to advance a process-based understanding about how to strategically develop the governance capacities needed for systemic, localised and inclusive NBS. To this end, it reports how policy officers in ten European cities have started to mainstream NBS by interacting with and changing incumbent governance arrangements when experimenting with novel governance processes and mechanisms to plan, deliver and steward NBS. Based on these activities of the policy officers, the analysis identifies three strategies, associated stepping stones and changes in governance conditions, to mainstream NBS in governance capacities: institutionalising (a) a systems’ approach to link NBS to policies, regulations, and departments across goals and sectors, (b) inclusive collaborations for localised and inclusive interventions, and (c) reflexivity and learning about how NBS interact with the (institutional, ecological, social, etc.) contexts and create impacts. The strategies illustrate institutional entrepreneurship in interacting with incumbent governance contexts, and how starting from NBS as a type of systemic innovation can promote broader shifts in urban governance arrangements.

Mainstreaming nature-based solutions in cities has grown in scale and magnitude in recent times but is still considered to be the main challenge for transitioning our cities and their communities to be more climate resilient and liveable: environmentally, economically, and socially. Furthermore, taking nature-based solutions to the next level, and scaling them out to all urban contexts to achieve a greater impact, is proving to be slow and often conflicts with other transitioning initiatives such as energy generation, mobility and transport initiatives, and infilling to combat sprawl. So, the task is neither easy nor straightforward; there are many barriers to this novel transition, especially when it comes to collaborative approaches to implementing nature-based solutions with diverse urban communities and within city authorities themselves. This paper reports on a new process that is systematically co-produced and captured as a framework for planning nature-based solutions that emerged during the Connecting Nature project. The Connecting Nature Framework is a three-stage, iterative process that involves seven key activity areas for mainstreaming nature-based solutions: technical solutions, governance, financing and business models, nature-based enterprises, co-production, reflexive monitoring, and impact assessment. The tested and applied framework is designed to address and overcome barriers to the implementation of nature-based solutions in cities via a co-created, iterative, and reflective approach. The planning process guided by the proposed framework has already yielded promising results with some of the cities of the project, though further usage and its adoption by other cities is needed to explore its potential in different contexts especially in the Global South. The paper concludes with suggestions on how this may be realised.

Within the FAIR Data Austria project, supported by the Federal Ministry for Education, Science, and Research (BMBWF), a national strategy has been established to advance the creation of tailored Data Stewardship solutions for the Austrian context. The strategy, formalized as a toolbox, delineates various Data Steward models, corresponding competencies, and accessible training resources. Despite the crucial role of Data Stewardship in supporting data-driven scientific research, Austrian universities encounter challenges in its implementation. Issues include lack of consensus on the skills, roles, and responsibilities of Data Stewards, coupled with insufficient funding for these positions. This article explores these challenges and emphasizes the importance of addressing them to promote effective Data Stewardship within the Austrian academic landscape.

Open data provide the scientific community and other stakeholders with unrestricted access to data. Open data serve as a foundation for reproducing research findings, while also facilitating collaboration and enabling novel discoveries. However, open data practices are still not commonly applied. To contribute to the implementation of open data strategy in academia in Austria and beyond, a collection of local strategies from regional universities and higher education institutions in the Austrian provinces of Styria and Carinthia was compiled through workshop-based discussions between participants from research support service units at research-performing organizations. The collection was further organized into categories based on application time scenarios, target groups, and involved parties, as well as corresponding thematic focus. A strategic guide consisting of various measures has been developed to encourage the adoption of open data practices from an organizational standpoint. Designed for adaptability, it aims to be applicable and modifiable by all interested research and higher education institutions, regardless of their priorities and resources. Our guideline aids research organizations in crafting a tailored strategy to enhance their data dissemination practices, thereby increasing their research visibility and impact.

Enhanced resolution of 7 T magnetic resonance imaging (MRI) scanners has considerably advanced our knowledge of structure and function in human and animal brains. Post-industrialized countries are particularly prone to an ever-increasing number of ageing individuals and ageing-associated neurodegenerative diseases. Neurodegenerative diseases are associated with volume loss in the affected brain. MRI diagnoses and monitoring of subtle volume changes in the ageing/diseased brains have the potential to become standard diagnostic tools. Even with the superior resolution of 7 T MRI scanners, the microstructural changes comprising cell types, cell numbers, and cellular processes, are still undetectable. Knowledge of origin, nature, and progression for microstructural changes are necessary to understand pathogenetic stages in the relentless neurodegenerative diseases, as well as to develop therapeutic tools that delay or stop neurodegenerative processes at their earliest stage. We illustrate the gap in resolution by comparing the identical regions of the post-mortem in situ 7 T MR images (virtual autopsy or virtopsy) with the histological observations in serial sections through the same brain. We also described the protocols and limitations associated with these comparisons, as well as the necessity of supercomputers and data management for "Big data". Analysis of neuron and/or glial number by using a body of mathematical tools and guidelines (stereology) is time-consuming, cumbersome, and still restricted to trained human investigators. Development of tools based on machine learning (ML) and artificial intelligence (AI) could considerably accelerate studies on localization, onset, and progression of neuron loss. Finally, these observations could disentangle the mechanisms of volume loss into stages of reversible atrophy and/or irreversible fatal cell death. This AI- and ML-based cooperation between virtopsy and histology could bridge the present gap between virtual reality and neuropathology. It could also culminate in the creation of an imaging-associated comprehensive database. This database would include genetic, clinical, epidemiological, and technical aspects that could help to alleviate or even stop the adverse effects of neurodegenerative diseases on affected individuals, their families, and society.

Abstract Introduction The epidemiology and clinical presentation of systemic juvenile idiopathic arthritis (sJIA) in the Afro-Caribbean population is not well described. Methods Retrospective study conducted between January 2000 and January 2022 in the French Overseas Departments of America. Clinical data were obtained from multiple sources: computerized hospital archives, registries of referring pediatricians, and the French National Registry for rare diseases. The disease studied was sJIA defined according to international criteria. Results Twenty-five patients were identified. Mean age at diagnosis was 7.5 years (range: 1.2—14.9 years) and mean duration of follow-up was 5.2 years (range: 0.5—16 years). All patients had joint involvement at diagnosis with 68% presenting inflammatory arthritis and 32% inflammatory joint pain. Sixteen percent had coronary involvement at onset. More than half (52%) suffered from macrophage activation syndrome (MAS) during childhood (32% at onset). The mean number of flares in childhood was 2 (Range: 1—5). Sixty-eight percent of patients had disease control during childhood without biotherapy. The most frequent second line treatment was anakinra (7/8). There was no difference in clinical or biological severity according to gender. The median duration of treatment during childhood was 5 months (range: 2—144) and 72% had a cumulative treatment duration of less than one year. Conclusion These patients of Afro-Caribbean origin suffering from sJIA showed some specificities, such as a higher rate of MAS and coronary involvement at onset. The incidence per year was stable over a 20-year period. Overall outcomes during childhood were similar to western countries.

Still’s disease is an inflammatory syndrome linked to the development of further immune dysregulation and hypercytokinaemia termed macrophage activation syndrome. Here the authors implicate the mechanistic target of rapamycin complex 1 in murine models of Still’s disease and macrophage activation syndrome, and provide associations with clinical cases in patients

IntroductionAmong immune cells, activated monocytes play a detrimental role in chronic and viral-induced inflammatory pathologies, particularly in Juvenile Idiopathic Arthritis (JIA), a childhood rheumatoid arthritis (RA) disease. The uncontrolled activation of monocytes and excessive production of inflammatory factors contribute to the damage of bone-cartilage joints. Despite the moderate beneficial effect of current therapies and clinical trials, there is still a need for alternative strategies targeting monocytes to treat RA.MethodsTo explore such an alternative strategy, we investigated the effects of targeting the CXCR4 receptor using the histamine analog clobenpropit (CB). Monocytes were isolated from the blood and synovial fluids of JIA patients to assess CB's impact on their production of key inflammatory cytokines. Additionally, we administered daily intraperitoneal CB treatment to arthritic mice to evaluate its effects on circulating inflammatory cytokine levels, immune cell infiltrates, joints erosion, and bone resorption, as indicators of disease progression.ResultsOur findings demonstrated that CXCR4 targeting with CB significantly inhibited the spontaneous and induced-production of key inflammatory cytokines by monocytes isolated from JIA patients. Furthermore, CB treatment in a mouse model of collagen-induce arthritis resulted in a significant decrease in circulating inflammatory cytokine levels, immune cell infiltrates, joints erosion, and bone resorption, leading to a reduction in disease progression.DiscussionIn conclusion, targeting CXCR4 with the small amino compound CB shows promise as a therapeutic option for chronic and viral-induced inflammatory diseases, including RA. CB effectively regulated inflammatory cytokine production of monocytes, presenting a potential targeted approach with potential advantages over current therapies. These results warrant further research and clinical trials to explore the full therapeutic potential of targeting CXCR4 with CB-like molecules in the management of various inflammatory diseases.

For decades, the Catholic monastic tradition has been defined by demographic decline and the closure of monasteries. And yet, new religious groups have emerged that have cultivated their own take on the monastic tradition, while old monasteries have become treasured heritage objects. In recent years, these new religious groups have started to acquire and inhabit old monasteries. It follows that simultaneous re-religionization and heritagization is taking place at these locations. This combination presents a unique opportunity to scrutinize an unexplored entanglement of religion and heritage. Although re-religionization might seem to conflict with the cultural heritage narrative surrounding these monasteries, this article presents Klooster Nieuw Sion—a new Dutch religious initiative—as a case study, indicating that these developments do not only coexist or oppose each other but are also mutually reinforcing. Drawing on our fieldwork, we explore how heritagization can offer new spiritual opportunities for religious actors within these revitalized monastic spaces. [ABSTRACT FROM AUTHOR]

Abstract Background Childhood Polyarteritis nodosa (PAN) is a systemic vasculitis with necrotizing inflammation of medium- and small-sized arteries. Disease evolution may be severe and refractory to standard treatment including prednisone, azathioprine and cyclophosphamide. Case presentation We present the case of a young girl with severe PAN resulting in progressive ischemia and necrosis of fingers and toes. Biological work-up revealed increased acute phase reactants and interleukin-6 levels. She was only partially controlled despite high-dose corticosteroids and cyclophosphamide infusions, and eventually achieved rapid improvement and sustained remission on tocilizumab. Further, we review the current evidence of the interleukin-6-inhibitor tocilizumab for the treatment of PAN. Conclusion Tocilizumab may be an efficient therapeutic option in a subset of treatment-refractory children with PAN.

Abstract Background Juvenile idiopathic arthritis (JIA) is the most common pediatric rheumatic disease and the most common systemic disorder associated with uveitis in childhood. Uveitis is more common in JIA patients who are antinuclear antibody (ANA)-positive, have an early-onset disease, and have oligoarticular arthritis. JIA-associated uveitis (JIA-uveitis) is typically anterior, chronic, bilateral, nongranulomatous, and asymptomatic. Visual outcomes in JIA-uveitis have improved with current screening and treatment options; however, many patients fail to respond or do not achieve long-lasting remission. Baricitinib, an oral selective Janus kinase (JAK)1 and 2 inhibitor, may impact key cytokines implicated in the pathogenesis of JIA-uveitis or ANA-positive uveitis, representing a potential novel treatment option for disease management. Methods The multicenter, phase 3 trial will be conducted using an open-label Bayesian design. The study will enroll at least 20 and up to 40 patients aged 2 to

Brain malformations involving the corpus callosum are common in children with developmental disabilities. We identified DCC mutations in four families and five sporadic individuals with isolated agenesis of the corpus callosum (ACC) without intellectual disability. DCC mutations result in variable dominant phenotypes with decreased penetrance, including mirror movements and ACC associated with a favorable developmental prognosis. Possible phenotypic modifiers include the type and location of mutation and the sex of the individual.

Objectives To assess the tolerance and efficacy of targeted therapies prescribed off-label in refractory low-prevalence autoimmune and inflammatory systemic diseases.Methods The TATA registry (TArgeted Therapy in Autoimmune Diseases) is a prospective, observational, national and independent cohort follow-up. The inclusion criteria in the registry are as follows: age >18 years; low-prevalence autoimmune and inflammatory systemic disease treated with off-label drugs started after 1 January 2019.Results Hundred (100) patients (79 women) were enrolled. The median age was 52.5 years (95% CI 49 to 56) and the median disease duration before enrolment was 5 years (3 to 7). The targeted therapies at enrolment were as follows: Janus kinase/signal transducers and activators of transcription inhibitors (44%), anti-interleukin (IL)-6R (22%), anti-IL-12/23, anti-IL-23 and anti-IL-17 (9%), anti-B cell activating factor of the tumour necrosis factor family (5%), abatacept (5%), other targeted treatments (9%) and combination of targeted treatments (6%). 73% of patients were receiving corticosteroid therapy at enrolment (median dose 10 mg/day). The current median follow-up time is 9 months (8 to 10).Safety: 11 serious infections (incidence rate of 14.8/100 patient-years) and 1 cancer (1.3 cancers/100 patient-years) were observed. Two patients died from severe COVID-19 (2.7 deaths/100 patient-years).Efficacy: the targeted treatment was considered effective by the clinician in 56% of patients and allowed, in responders, a median reduction of oral corticosteroids of 15 (9 to 21) mg/day, below 7.5 mg/day in 76% of patients, while 28% discontinued.Conclusion These initial results of the TATA registry confirm the diversity of targeted treatments prescribed off-label in refractory autoimmune diseases and their corticosteroid-sparing effect when effective. Tolerance was acceptable in these refractory patients with a long history of treatment with immunosuppressive drugs.

Abstract Background Surgeries for idiopathic uveitis and juvenile idiopathic arthritis-associated uveitis in children are complex because of the high risk of inflammatory postoperative complications. There is no consensus about treatment adaptation during the perioperative period. The objectives of this study are to report the therapeutic changes made in France and to determine whether maintaining or stopping immunosuppressive therapies is associated with an increased risk of surgical site infection or an increased risk of uveitis or arthritis flare-up. Methods We conducted a retrospective cohort study between January 1, 2006 and December 31, 2018 in six large University Hospitals in France. Inclusion criteria were chronic idiopathic uveitis or chronic uveitis associated with juvenile idiopathic arthritis under immunosuppressive therapies at the time of the surgical procedure, operated before the age of 16. Data on perioperative treatments, inflammatory relapses and post-operative infections were collected. Results A total of 76 surgeries (42% cataract surgeries, 30% glaucoma surgeries and 16% posterior capsule opacification surgeries) were performed on 37 children. Adaptation protocols were different in the six hospitals. Immunosuppressive therapies were discontinued in five cases (7%) before surgery. All the children in the discontinuation group had an inflammatory relapse within 3 months after surgery compared to only 25% in the other group. There were no postoperative infections. Conclusions The results of this study show varying practices between centres. The benefit-risk balance seems to favour maintaining immunosuppressive therapies during surgery. Further studies are needed to determine the optimal perioperative treatments required to limit post-operative inflammatory relapses.

This paper examines and compares real-time estimates of the trend-cycle component using moving averages constructed with local polynomial regression. It enables the reproduction of Henderson's symmetric and Musgrave's asymmetric filters used in the X-13ARIMA-SEATS seasonal adjustment algorithm. This paper proposes two extensions of local polynomial filters for real-time trend-cycle estimates: first including a timeliness criterion to minimize the phase shift; second with procedure for parametrizing asymmetric filters locally while they are generally parametrized globally, which can be suboptimal around turning points. An empirical comparison, based on simulated and real data, shows that modeling polynomial trends that are too complex introduces more revisions without reducing the phase shift, and that local parametrization reduces the delay in detecting turning points and reduces revisions. The results are reproducible and all the methods can be easily applied using the R package rjd3filters. [ABSTRACT FROM AUTHOR]

Abstract Background Some patients with systemic juvenile idiopathic arthritis (SJIA) and severe, refractory disease achieved remission through intensive immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (HSCT). However, disease relapsed in most cases. More recently selected SJIA patients received allogenic HSCT from a HLA-identical sibling or a HLA matched unrelated donor. While most transplanted patients achieved sustained SJIA remission off-treatment, the procedure-related morbidity was high. Case report A girl presented SJIA with a severe disease course since the age of 15 months. She was refractory to the combination of methotrexate and steroids to anti-interleukin (IL)-1, then anti-IL-6, tumor necrosis factor alpha inhibitors, and thalidomide. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated, as no HLA matched donor was available. The patient received a T replete bone marrow graft at the age of 3.7 years. Conditioning regimen contained Rituximab, Alemtuzumab, Busulfan, and Fludarabine. Cyclophosphamide at D + 3 and + 4 post HSCT was used for graft-versus-host-disease prophylaxis, followed by Cyclosporin A and Mycophenolate Mofetil. Post HSCT complications included severe infections, grade 3 intestinal graft-versus-host-disease, autoimmune thyroiditis, and immune thrombocytopenia. Three years after HSCT, the child is alive and well, notwithstanding persistent hypothyroidy requiring substitution. Immune thrombocytopenia had resolved. Most importantly, SJIA was in complete remission, off immunosuppressive drugs. Conclusion Allogenic HSCT may be a therapeutic option, even with a HLA haplo-identical alternative donor, in patients with inflammatory diseases such as SJIA. Despite increased experience with this treatment, the risk of life-threatening complications restrains its indication to selected patients with severe, refractory disease.

Abstract Background Malignant brain tumor diseases exhibit differences within molecular features depending on the patient’s age. Methods In this work, we use gene mutation data from public resources to explore age specifics about glioma. We use both an explainable clustering as well as classification approach to find and interpret age-based differences in brain tumor diseases. We estimate age clusters and correlate age specific biomarkers. Results Age group classification shows known age specifics but also points out several genes which, so far, have not been associated with glioma classification. Conclusions We highlight mutated genes to be characteristic for certain age groups and suggest novel age-based biomarkers and targets.

The relation between liturgical practice and theological reflection is by no means self-evident, especially in a secularized society. How can academic theology be rooted in liturgical life, and how can liturgical involvement play a vital role in the task of theology to reflect on liturgical tradition and practice? Liturgical theology is an attempt to bridge that gap between practice and reflection. The voice of practitioners as part of theological discourse is an important ingredient for this hermeneutical dialogue. Monastic life offers a space where liturgical and theological life can meet, especially in Benedictine abbeys. There, liturgical experience (theologia prima) is directly linked to theological reflection (theologia secunda), which leads to critical impulses for both, liturgy and theology, inside and outside abbey walls. Today, monastic communities are shrinking, but there is a growing interest in liturgical life among affiliated members of abbeys: the number of Benedictine oblates are growing. What is their view on liturgical experience, reflection and criticism? In this article, I present findings from a qualitative survey among fifty-three Dutch Benedictine oblates. Their answers are analyzed by coding procedures and interpreted theologically. They form an example of liturgical theology as practice-reflection.

Abstract Background A recent increase in children admitted with hypotensive shock and fever in the context of the COVID-19 outbreak requires an urgent characterization and assessment of the involvement of SARS-CoV-2 infection. This is a case series performed at 4 academic tertiary care centers in Paris of all the children admitted to the pediatric intensive care unit (PICU) with shock, fever and suspected SARS-CoV-2 infection between April 15th and April 27th, 2020. Results 20 critically ill children admitted for shock had an acute myocarditis (left ventricular ejection fraction, 35% (25–55); troponin, 269 ng/mL (31–4607)), and arterial hypotension with mainly vasoplegic clinical presentation. The first symptoms before PICU admission were intense abdominal pain and fever for 6 days (1–10). All children had highly elevated C-reactive protein (> 94 mg/L) and procalcitonin (> 1.6 ng/mL) without microbial cause. At least one feature of Kawasaki disease was found in all children (fever, n = 20, skin rash, n = 10; conjunctivitis, n = 6; cheilitis, n = 5; adenitis, n = 2), but none had the typical form. SARS-CoV-2 PCR and serology were positive for 10 and 15 children, respectively. One child had both negative SARS-CoV-2 PCR and serology, but had a typical SARS-CoV-2 chest tomography scan. All children but one needed an inotropic/vasoactive drug support (epinephrine, n = 12; milrinone, n = 10; dobutamine, n = 6, norepinephrine, n = 4) and 8 were intubated. All children received intravenous immunoglobulin (2 g per kilogram) with adjuvant corticosteroids (n = 2), IL 1 receptor antagonist (n = 1) or a monoclonal antibody against IL-6 receptor (n = 1). All children survived and were afebrile with a full left ventricular function recovery at PICU discharge. Conclusions Acute myocarditis with intense systemic inflammation and atypical Kawasaki disease is an emerging severe pediatric disease following SARS-CoV-2 infection. Early recognition of this disease is needed and referral to an expert center is recommended. A delayed and inappropriate host immunological response is suspected. While underlying mechanisms remain unclear, further investigations are required to target an optimal treatment.

In response to socioeconomic development, the number of machine learning applications has increased, along with the calls for algorithmic transparency and further sustainability in terms of energy efficient technologies. Modern computer algorithms that process large amounts of information, particularly artificial intelligence methods and their workhorse machine learning, can be used to promote and support sustainability; however, they consume a lot of energy themselves. This work focuses and interconnects two key aspects of artificial intelligence regarding the transparency and sustainability of model development. We identify frameworks for measuring carbon emissions from Python algorithms and evaluate energy consumption during model development. Additionally, we test the impact of explainability on algorithmic energy consumption during model optimization, particularly for applications in health and, to expand the scope and achieve a widespread use, civil engineering and computer vision. Specifically, we present three different models of classification, regression and object-based detection for the scenarios of cancer classification, building energy, and image detection, each integrated with explainable artificial intelligence (XAI) or feature reduction. This work can serve as a guide for selecting a tool to measure and scrutinize algorithmic energy consumption and raise awareness of emission-based model optimization by highlighting the sustainability of XAI.

Vutiglabridin is a clinical-stage synthetic small molecule that is being developed for the treatment of obesity and its target proteins have not been fully identified. Paraoxonase-1 (PON1) is an HDL-associated plasma enzyme that hydrolyzes diverse substrates including oxidized low-density lipoprotein (LDL). Furthermore, PON1 harbors anti-inflammatory and antioxidant capacities and has been implicated as a potential therapeutic target for treating various metabolic diseases. In this study, we performed a non-biased target deconvolution of vutiglabridin using Nematic Protein Organisation Technique (NPOT) and identified PON1 as an interacting protein. We examined this interaction in detail and demonstrate that vutiglabridin binds to PON1 with high affinity and protects PON1 against oxidative damage. Vutiglabridin treatment significantly increased plasma PON1 levels and enzyme activity but not PON1 mRNA in wild-type C57BL/6J mice, suggesting that vutiglabridin modulates PON1 post-transcriptionally. We further investigated the effects of vutiglabridin in obese and hyperlipidemic LDLR−/− mice and found that it significantly increases plasma PON1 levels, while decreasing body weight, total fat mass, and plasma cholesterol levels. Overall, our results demonstrate that PON1 is a direct, interacting target of vutiglabridin, and that the modulation of PON1 by vutiglabridin may provide benefits for the treatment of hyperlipidemia and obesity.

The aim of this study was to investigate whether subtle differences in molecular properties affected polymeric micelle characteristics and their ability to deliver poorly water-soluble drugs into the skin. D-α-tocopherol-polyethylene glycol 1000 was used to prepare micelles containing ascomycin-derived immunosuppressants—sirolimus (SIR), pimecrolimus (PIM) and tacrolimus (TAC)—which have similar structures and physicochemical properties and have dermatological applications. Micelle formulations were prepared by thin-film hydration and extensively characterized. Cutaneous delivery and biodistribution were determined and compared. Sub-10 nm micelles were obtained for the three immunosuppressants with incorporation efficiencies >85%. However, differences were observed for drug loading, stability (at the highest concentration), and their in vitro release kinetics. These were attributed to differences in drug aqueous solubility and lipophilicity. Differences between the cutaneous biodistribution profiles and drug deposition in the different skin compartments pointed to the impact of differences in thermodynamic activity. Therefore, despite their structural similarities, SIR, TAC and PIM did not demonstrate the same behaviour either in the micelles or when applied to the skin. These outcomes indicate that polymeric micelles should be optimized even for closely related drug molecules and support the hypothesis that drugs are released from micelles prior to skin penetration.

Abstract Background Patients with polyarticular-course juvenile idiopathic arthritis (pJIA), receiving disease-modifying anti-rheumatic drugs with immunosuppressive effects, may be at increased risk of vaccine-preventable infections. This substudy assessed protective antibody responses to diphtheria and tetanus vaccination given prior to study enrolment in patients with pJIA. Findings This was a substudy of a 24-month, single-arm, open-label, multicenter, Phase III trial (NCT01844518) of subcutaneous abatacept in children with active pJIA (N = 219). Patients aged 2–5 years, with ≥2 continuous months of weekly weight-tiered (10– 0.1 IU/mL), and safety, were assessed. Overall, 29 patients were analyzed: 19 (65.5%), 1 (3.4%) and 9 (31.0%) patients had > 12, 6–12 and 2–

Abstract Background Chronic musculoskeletal pain (MSP) is frequent in adolescents and has major medical and social consequences. In many cases, when no cause has been clearly established, this pain may be considered to be chronic idiopathic MSP. Our study seeks to identify general criteria for this type of pain through the experience of professionals from tertiary care centers with expertise in pediatric and adolescent chronic MSP. Methods Cross-sectional multicenter qualitative study. Semi-structured interviews of 25 professionals at a rheumatology reference center and in its network for pain management, including diverse specialists and professions. Interpretative Phenomenological Analysis is used to explore the data. Results This approach led us to identify 10 themes organized around three superordinate themes covering different stages of the diagnostic process: 1) the medical pain history up to the consultation at the reference center; 2) the professional’s subjective feelings about the clinical presentation; 3) from the clinical examination to diagnosis and treatment of chronic idiopathic MSP. The main elements guiding this diagnosis do not come from the physical examination but from the medical history and the professionals’ subjective feelings, that is, their clinical judgment. The professionals’ impression of uneasiness and frustration, induced by patients and their parents, is of major importance. Conclusion The principal elements guiding the diagnosis of chronic idiopathic MSP do not come primarily from the physical examination but rather from the pain history and the health professional’s subjective feelings. Our results suggest that the concept of Juvenile Fibromyalgia (JFM) does not appear to cover all situations of chronic idiopathic MSP in adolescence. A constellation of non-organic criteria enables diagnosis of the latter; these criteria should be validated to avoid medical nomadism and multiple investigations and to shorten the interval until patients receive optimal pain management. Clinical trial registration clinicaltrials.gov, NCT03171792, https://clinicaltrials.gov/ct2/show/NCT03171792?term=LACHAL&cntry=FR&city=paris&rank=1