Functional diversity of NLRP3 gain-of-function mutants associated with CAPS autoinflammation.

NLRP3-associated autoinflammatory disease is a heterogenous group of monogenic conditions caused by NLRP3 gain-of-function mutations. The poor functional characterization of most NLRP3 variants hinders diagnosis despite efficient anti-IL-1 treatments. Additionally, while NLRP3 is controlled by priming and activation signals, gain-of-functions have only been investigated in response to priming. Here, we characterize 34 NLRP3 variants in vitro, evaluating their activity upon induction, priming, and/or activation signals, and their sensitivity to four inhibitors. We highlight the functional diversity of the gain-of-function mutants and describe four groups based on the signals governing their activation, correlating partly with the symptom severity. We identify a new group of NLRP3 mutants responding to the activation signal without priming, associated with frequent misdiagnoses. Our results identify key NLRP3 residues controlling inflammasome activity and sensitivity to inhibitors, and antagonistic mechanisms with broader efficacy for therapeutic strategies. They provide new insights into NLRP3 activation, an explanatory mechanism for NLRP3-AID heterogeneity, and original tools for NLRP3-AID diagnosis and drug development.

DeepMPTB: a vaginal microbiome-based deep neural network as artificial intelligence strategy for efficient preterm birth prediction.

In recent decades, preterm birth (PTB) has become a significant research focus in the healthcare field, as it is a leading cause of neonatal mortality worldwide. Using five independent study cohorts including 1290 vaginal samples from 561 pregnant women who delivered at term (n = 1029) or prematurely (n = 261), we analysed vaginal metagenomics data for precise microbiome structure characterization. Then, a deep neural network (DNN) was trained to predict term birth (TB) and PTB with an accuracy of 84.10% and an area under the receiver operating characteristic curve (AUROC) of 0.875 ± 0.11. During a benchmarking process, we demonstrated that our DL model outperformed seven currently used machine learning algorithms. Finally, our results indicate that overall diversity of the vaginal microbiota should be taken in account to predict PTB and not specific species. This artificial-intelligence based strategy should be highly helpful for clinicians in predicting preterm birth risk, allowing personalized assistance to address various health issues. DeepMPTB is open source and free for academic use. It is licensed under a GNU Affero General Public License 3.0 and is available at https://deepmptb.streamlit.app/ . Source code is available at https://github.com/oschakoory/DeepMPTB and can be easily installed using Docker ( https://www.docker.com/ ).

Anthracycline-induced cardiotoxicity on regional myocardial work and left ventricular mechanical dispersion in adolescents and young adults in post-lymphoma remission.

BACKGROUND: Myocardial work (MW) is a new echocardiographic tool with a high sensitivity to detect early and subtle alterations of myocardial function. We aimed to evaluate the late effects of anthracyclines by assessing the global and segmental MW and intraventricular mechanical dispersion from speckle tracking echocardiography in childhood lymphoma survivors (CLS). METHODS: Thirty-one young adults including CLS and age-matched healthy controls were enrolled. All underwent echocardiography including an evaluation of left ventricular (LV) morphology and regional function. We assessed LV longitudinal (differentiating sub-endocardial and sub-epicardial layers), circumferential strains and twist, global and regional MW index (MWI). LV mechanical dispersion was assessed from the time dispersion of LV longitudinal strain, from myocardial wasted work (MWW) and myocardial work efficiency (MWE). RESULTS: The longitudinal strains both at the level of the sub-endocardium and sub-epicardium were reduced in CLS compared to controls. The global MWI was also decreased (1668 ± 266 vs 1870 ± 264%.mmHg in CLS patients and controls, respectively, p < 0.05), especially on the apical segments. An increase of LV intraventricular mechanical dispersion was observed in CLS. MWW and MWE remained unchanged compared to controls. CONCLUSION: Our results strongly support that cardiac remodeling is observed in CLS, characterized by a decrease in MW and an increase in LV mechanical dispersion. The apex is specifically altered, but its clinical significance remains uncertain. MW as a complement to strain seems interesting in cancer survivors to detect myocardial dysfunction at early stage and adapt their follow-up.

Pathways of sleep disturbances in juvenile idiopathic arthritis and recommendations for clinical management approaches: A critical review.

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease affecting young people. It has a profound impact on their physical, mental and social lives, leading to long-term disability. With the growing awareness of the importance of sleep in all areas of functioning in young people, an emerging literature has drawn attention to the role of sleep in the pathogenesis of JIA. Sleep disturbances in children and adolescents with JIA arise from a wide range of symptoms and pathways, leading to a vicious cycle that exacerbates subclinical inflammation, symptoms and disease progression. Putative factors contributing to sleep disturbances include chronic inflammation, JIA-associated sleep disorders, JIA symptoms (e.g. pain), psychological comorbidities and potential circadian disruption, which may be exacerbated by the transition to adolescence. Here, we review these pathways and advocate key strategies and alternatives for sleep management in young people with JIA in clinical settings. We identify gaps in knowledge and suggest future directions to improve our understanding of JIA sleep disorders, including clinical trials investigating potential strategies to improve sleep health in this young population.

Left atrial remodeling in adolescents with obesity evaluated by speckle-tracking echocardiography.

BACKGROUND AND AIMS: In adolescents with obesity, a left atrial (LA) enlargement has been reported. However, data regarding its function and its stiffness are missing. The aim of this study was to describe LA morphology and function, using speckle-tracking echocardiography (STE) and to explore their potential determinants in adolescents with obesity. METHODS: Twenty-eight adolescent women with obesity (13.2 ± 1.4 yr) with an illness duration of 130 ± 27 months and 33 controls (14.1 ± 2.0 yr) underwent a resting echocardiography including an analysis of left ventricular (LV) and LA morphologies and strains. A fasting venous blood sample was performed to biochemical determinations including inflammation markers. RESULTS: LA volume and stiffness index were increased in adolescents with obesity compared to controls. LA reservoir, conduit and booster pump functions were not different between groups. By stepwise forward multivariate regression analyses, systolic blood pressures, cardiac output and sedimentation rate were the independent determinants of LA volume (p < 0.0001, ß-coefficient = 0.460) whereas only the body mass index was an independent determinant of LA stiffness (p = 0.003, ß-coefficient = 0.413). CONCLUSION: In adolescents with obesity, we observed a specific LA remodeling, including higher volume and lower stiffness, which could constitute early signs of an altered LV diastolic function.

[Calprotectin levels in meconium measured with an automated immunoassay (Liaison® XL)]. / Valeurs de référence de la calprotectine méconiale (immuno-dosage Liaison® XL).

A threshold of 50 µg fecal calprotectin per g stool sample (µg/g) is commonly used to diagnose chronic inflammatory bowel disease in adult patients and children over 4 years of age. In younger children, fecal calprotectin values are physiologically increased. For the first time, the objective of our study was to establish reference ranges in newborns for the measurement of meconium calprotectin with an automated assay (Liaison® XL, DiaSorin). A prospective study was conducted in 2022 in the Maternity Unit of the Clermont-Ferrand University Hospital, with the inclusion of full-term newborns without intestinal involvement. The quantitative automated Liaison® XL calprotectin assay was assessed on a panel of meconium samples. In our cohort of 132 term neonates, calprotectin values ranged from 21 to 855 µg/g of meconium (2,5th to 97.5th percentile) and the median value was 194 µg/g. In our cohort, only sex-related differences were observed for calprotectin values. No significant differences were found for the other factors studied (maternal or neonatal). Because of inter-individual variability, a sequential measurement of newborn calprotectin from meconium should be considered.

Survey of adolescents' needs and parents' views on sexual health in juvenile idiopathic arthritis.

BACKGROUND: Although the advent of new therapeutics for juvenile idiopathic arthritis (JIA) patients has considerably lessened the impact of the disease and reduced its sequelae, the outcomes of JIA remain important in their lives. Disease repercussions and side effects of treatments may affect sexual health and cause psychological distress. This aim of the study was to determine the expectations of adolescent JIA patients and the perceptions of their parents regarding knowledge and communication with healthcare providers (HCPs) in the field of sexual health (SH). METHODS: In France, from September 2021 to April 2022, a survey was conducted, using anonymous self-administered questionnaires, among JIA patients (adults (aged 18-45 years) to provide insights from their recollection of their adolescence) and their parents in nine rheumatology centers and three patient associations. RESULTS: The responses to the 76 patient questionnaires and 43 parent questionnaires that were collected were analyzed. Half of the patients thought JIA impacted their romantic relationships, but the results were less clear-cut for their sexual activity; and 58.7% of the patients said they would be comfortable discussing the subject with HCPs, but only 26.3% had done so, mainly regarding biomedical issues. The patients and their parents thought that ideally, the topic should be addressed in an individual patient education session at the hospital (51.3% and 34.9%, respectively), in a regular consultation (47.4% and 53.5%), or in a dedicated consultation requested by the adolescent without the adolescent's parents being informed (38.2% and 20.9%). Most of the respondents thought HCPs should be proactive in SH (77.6% of the patients and 69.8% of their parents). More patients than parents said the following digital information tools must be used: videos (29.0% vs. 9.3%, p = 0.0127) and smartphone applications (25.0% vs. 9.3%, p = 0.0372). CONCLUSION: HCPs should consider addressing the unmet need for SH discussions during their patient encounters. To meet this need, we propose concrete actions in line with the wishes of patients and parents. CLINICAL TRIAL REGISTRATION NUMBER: NCT04791189.

Summer diarrhea in children: a monocentric French epidemiological observational study.

Pediatric diarrhea is a major public health problem worldwide. In France, continuous surveillance shows a winter epidemic peak and a more modest summer recrudescence. Few studies describe the infectious agents responsible for pediatric summer diarrhea in France. The objectives were to estimate the prevalence of infectious diarrhea and describe the pathogens responsible for summer diarrhea in children; and to describe common factors that can be used as guidance on the etiology of these diarrheas. A cross-sectional, single-center, epidemiological observational study was conducted in the pediatric emergency department of a French hospital between June and September in 2019 and 2020. Multiplex gastrointestinal pathogen panels were used for diagnostics. A multiple correspondence analysis was used to determine profiles of patients. A total of 95 children were included, of whom 82.1% (78/95) were under five years old. The prevalence of infectious summer diarrhea was 81.1% (77/95, 95%CI 71.7-88.4%). A total of 126 infectious agents were detected (50.0% bacteria, 38.1% viruses, 11.9% parasites). The main enteric pathogens were enteropathogen Escherichia coli (24/126), rotavirus (17/126) and Salmonella (16/126). A co-detection was found in 51.9% (40/77) of cases. Four patient profiles, considering the severity and the pathogen involved, were highlighted.

Impact of BMI z-score on left ventricular mechanics in adolescent girls.

Background: Adolescent weight disorders ranging from anorexia nervosa (AN) to obesity (OB) can impact the heart by causing opposite alterations in its morphology, suggesting a direct impact of body mass index (BMI) on the heart. Cardiac function is relatively preserved as assessed by standard echocardiography. However, few studies have used 2D speckle-tracking echocardiography (2D-STE), which can detect subtle alterations of left ventricular (LV) function by evaluating deformations. This study aimed to assess the link between the BMI z-score of adolescent girls and myocardial function. Methods: Ninety-one adolescent girls comprising 26 AN patients (age 14.6 ± 1.9 years), 28 OB patients (age 13.2 ± 1.4 years), and 37 controls (age 14.0 ± 2.0 years) underwent 2D-STE to assess LV morphology and myocardial global and regional deformations. Results: The BMI z-score of our population ranged from -4.6 to 5.2. LV morphological remodeling was significantly and positively correlated with the BMI z-score (R2 = 0.456, p < 0.0001 for LV mass). Global longitudinal strain (LS) and regional LS recorded at the mid and apical levels were significantly correlated with the BMI z-score (R2 = 0.196, p = 0.0001 and R2 = 0.274, p < 0.0001, respectively, for apical and medial LS). Circumferential strains and twisting mechanics were not correlated with the BMI z-score. Fibrinogen and systolic blood pressure were the main variables explaining the alteration of LS. Conclusion: We observed that the BMI z-score had an impact on LV mechanics, especially on medial and apical LS. Neither circumferential nor twisting mechanics were altered by the BMI z-score in adolescent girls.

Individual and environmental determinants associated with longer times to access pediatric rheumatology centers for patients with juvenile idiopathic arthritis, a JIR cohort study.

BACKGROUND: Despite guidelines, poor access to appropriate care for juvenile idiopathic arthritis (JIA) patients remains a global issue. Prompt referral to a pediatric rheumatology (PR) center and effective care is known to be critical for changing the natural history of the disease and improving long-term prognosis. This project assesses socio-economic factors of delayed referral to a pediatric rheumatologist (PRst) for JIA patients in France and Switzerland within the Juvenile Inflammatory Rheumatism (JIR) Cohort. METHODS: All patients diagnosed with JIA, presenting at one center of the JIRcohort in France or Switzerland with additional data on referral pathway were included. Patient characteristics at first visit to the PR center, dates of visits to healthcare providers during referral, and parent characteristics were extracted from the JIRcohort database. RESULTS: Two hundred fifty children were included. The overall median time to first PR assessment was 2.4 months [1.3; 6.9] and ranged widely across the JIA subtypes, from 1.4 months [0.6; 3.8] for children with systemic juvenile idiopathic arthritis (sJIA) to 5.3 months [2.0; 19.1] for children with enthesitis-related arthritis (ERA). A diagnosis of ERA and an appointment with an orthopedist during the referral pathway were significantly associated with a longer time before the first PR visit (hazard ratio HR 0.50 [95% CI: 0.29; 0.84]) and HR 0.68 [95% CI: 0.49; 0.93], respectively) in multivariable analysis. Having a mother with a post-graduate educational attainment level was tendentially associated with a shorter time before the first PR visit, (HR 1.32 [95% CI: 0.99; 1.78]). CONCLUSIONS: Time to first PRst visit was most often short compared to other studies and close to the British recommendations. However, this time remained too long for many patients. We observed no social inequities in access to a PRst, but we show the need to improve effective pathway and access to a PR center for JIA patients.

Physical activity as a promising alternative for young people with juvenile idiopathic arthritis: Towards an evidence-based prescription.

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in young people. Although biologics now enable most children and adolescents with JIA to enjoy clinical remission, patients present lower physical activity and spend more time in sedentary behavior than their healthy counterparts. This impairment probably results from a physical deconditioning spiral initiated by joint pain, sustained by apprehension on the part of both the child and the child's parents, and entrenched by lowered physical capacities. This in turn may exacerbate disease activity and lead to unfavorable health outcomes including increased risks of metabolic and mental comorbidities. Over the past few decades, there has been growing interest in the health benefits of increased overall physical activity as well as exercise interventions in young people with JIA. However, we are still far from evidence-based physical activity and / or exercise prescription for this population. In this review, we give an overview of the available data supporting physical activity and / or exercise as a behavioral, non-pharmacological alternative to attenuate inflammation while also improving metabolism, disease symptoms, poor sleep, synchronization of circadian rhythms, mental health, and quality of life in JIA. Finally, we discuss clinical implications, identify gaps in knowledge, and outline a future research agenda.

Influence of Perinatal Factors on Blood Tryptase and Fecal Calprotectin Levels in Newborns.

BACKGROUND: Blood tryptase and fecal calprotectin levels may serve as biomarkers of necrotizing enterocolitis. However, their interpretation may be hindered by the little-known effects of perinatal factors. The aim of this study was to compare the tryptase and calprotectin levels in newborns according to their term, trophicity, and sex. METHOD: One hundred and fifty-seven premature newborns and 157 full-term newborns were included. Blood tryptase and fecal calprotectin were assayed. RESULTS: Blood tryptase levels were higher in premature than in full-term newborns (6.4 vs. 5.2 µg/L; p < 0.001). In situations of antenatal use of corticosteroids (p = 0.007) and non-exclusive use of human milk (p = 0.02), these levels were also higher. However, in multiple linear regression analyses, only prematurity significantly influenced tryptase levels. Fecal calprotectin levels were extremely wide-ranging and were much higher in female than in male newborns (300.5 vs. 110.5 µg/g; p < 0.001). CONCLUSIONS: The differences in tryptase levels according to term could be linked to early aggression of the still-immature digestive wall in premature newborns, in particular, by enteral feeding started early. The unexpected influence of sex on fecal calprotectin levels remains unexplained.

Pediatric ANCA vasculitis: clinical presentation, treatment, and outcomes in a French retrospective study.

BACKGROUND: Pediatric ANCA vasculitis is a rare group of diseases with a scarcity of data in children. Annual incidence appeared to increase in the last several years, placing higher interest in the clinical and therapeutical outcomes of the disorder. Also, the growing use of rituximab questions the latest outcomes in these diseases. We therefore conducted a retrospective study to better understand the current characteristics, management, and the latest outcomes of the disorder. METHODS: We conducted a 9-year retrospective study of 46 children in 14 different centers across France to describe their clinical and laboratory presentations, therapeutic regimens, and kidney outcome. RESULTS: P-ANCA appeared to be a potential marker for higher relapse risk. Compared to adults, we found that ear-nose-throat presentations were frequent (45.7%) and more severe. Despite an evolution in the treatment management, kidney outcome remained poor with a substantial proportion of chronic kidney disease (54.8% at 1 year). Mortality stays low with 3 patients (6.5%) deceased at the end of our study. CONCLUSION: Clinical presentation was as previously described and time to diagnosis remains long. P-ANCA is a statistically significant marker for increased relapse risk. We observed a modification in the treatment regimens over the past several years with a growing use of rituximab and a decreasing use of cyclophosphamide. Despite these changes, kidney outcome remains poor and prospective studies should be conducted to assess the most appropriate therapeutic modality for each patient. A higher resolution version of the Graphical abstract is available as Supplementary information.

Isocaloric Diets with Different Protein-Carbohydrate Ratios: The Effect on Sleep, Melatonin Secretion and Subsequent Nutritional Response in Healthy Young Men.

This study aimed to determine the short-term effect of two isocaloric diets differing in the ratio of protein−carbohydrate on melatonin levels, sleep, and subsequent dietary intake and physical activity in healthy young men. Twenty-four healthy men took part in a crossover design including two sessions of three days on isocaloric diets whether high-protein, low-carbohydrate (HPLC) or low-protein, high-carbohydrate (LPHC) followed by 24-h free living assessments. Sleep was measured by ambulatory polysomnography pre-post-intervention. Melatonin levels were assessed on the third night of each session on eight-point salivary sampling. Physical activity was monitored by accelerometry. On day 4, participants reported their 24-h ad-libitum dietary intake. LPHC resulted in better sleep quality and increased secretion of melatonin compared to HPLC. A significant difference was noted in sleep efficiency (p < 0.05) between the two sessions. This was mainly explained by a difference in sleep onset latency (p < 0.01) which was decreased during LPHC (PRE: 15.8 ± 7.8 min, POST: 11.4 ± 4.5 min, p < 0.001). Differences were also noted in sleep staging including time spent on REM (p < 0.05) and N1 (p < 0.05). More importantly, REM latency (PRE: 97.2 ± 19.9 min, POST 112.0 ± 20.7 min, p < 0.001) and cortical arousals (PRE: 7.2 ± 3.9 event/h, POST 8.5 ± 3.3 event/h) increased in response to HPLC diet but not LPHC. On day 4, 24-h ad-libitum energy intake was higher following HPLC compared to LPHC (+64 kcal, p < 0.05) and explained by increased snacking behavior (p < 0.01) especially from carbohydrates (p < 0.05). Increased carbohydrates intake was associated with increased cortical arousals.

Triage nurse-initiated X-ray radiography in minor trauma.

BACKGROUND: Overcrowding of paediatric emergency departments (EDs) is a worldwide issue, where improving the quality of care is a priority. The main objective of this study was to determine the effect of triage nurse-initiated X-ray radiography on length of stay in paediatric emergency admissions. METHODS: This retrospective, monocentric, descriptive study was performed in two successive 3-month periods: a pre-protocol ('before') period from 3 February to 3 May 2020 and a protocol ('after') period from 4 May to 2 August 2020, when patients underwent nurse-initiated X-ray radiography. The study involved all patients who were aged ≥3 years, valid, non-hyperalgic, accompanied by their parents and consulting at the paediatric ED for a simple closed distal trauma, involving a single limb segment or joint. RESULTS: A total of 695 patients were included, 298 in the first period and 397 in the second period. The median length of stay in the paediatric ED was significantly shorter during the second period (119 min [80, 165] vs. 80 min [60, 105], P < 0.001), i.e. a median reduction time of 39 min or 33% (effect size = - 0.68, 95% confidence interval [-0.84 to -0.53]). Triage nurse requests were judged 'adequate and sufficient' in 95.2% of cases, with only 2.0% of instances deemed 'unnecessary' by the medical team. In 2.8% of cases, 'another X-ray' was required to support diagnosis. CONCLUSIONS: The application of a triage nurse X-ray protocol significantly reduced the length of stay in a paediatric ED. The quality of patient management remained unchanged, and nurse requests were relevant.

Is an association of acro-osteolysis, bone fragility, and enchondromatosis a newfound disease caused by an amplification of PTHLH? A case report.

BACKGROUND: Acro-osteolysis (AO) refers to resorption of the distal finger and toe phalanges. It displays two patterns: (i) diffuse AO and (ii) transverse or bandlike AO. AO can be a sign of local distress (e.g. of toxic origin), but is very often a sign of a constitutional or systemic acquired disorder. CASE PRESENTATION: A 15-year-old girl was referred to a paediatric rheumatologist for recurrent pain in her fingertips. She presented a particular cross-sectional AO associated with the presence of intraosseous cysts and bone fragility with atypical fractures. Initial laboratory tests and radiological examination did not allow an etiological diagnosis. Genetic studies revealed a 12p11.22-p11.23 microduplication of 900 kb including the PTHLH (parathyroid hormone-like hormone) gene, which encodes for a hormone involved in the regulation of endochondral ossification and differentiation of chondrocytes, via its PTHLH receptor. CONCLUSIONS: To date, 12p11.22-p11.23 duplications have been reported in five families with skeletal abnormalities, and in particular AO and enchondromatosis associated with bone fragility. This new observation, added to the other reported cases, suggests a close relationship between the presence of this microduplication and the skeletal abnormalities found in the patient. We suggest the descriptive name ABES (acro-osteolysis, bone fragility and enchondromatosis syndrome) to designate this disorder.

Corrigendum: Left Ventricular Strains and Myocardial Work in Adolescents With Anorexia Nervosa.

[This corrects the article DOI: 10.3389/fcvm.2022.798774.].