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PRSS1 and PRSS2 constitute the only functional copies of a tandemly-arranged five-trypsinogen-gene cluster (i.e., PRSS1, PRSS3P1, PRSS3P2, TRY7 and PRSS2) on chromosome 7q35. Variants in PRSS1 and PRSS2, including missense and copy number variants (CNVs), have been reported to predispose to or protect against chronic pancreatitis (CP). We wondered whether a common trypsinogen pseudogene deletion CNV (that removes two of the three trypsinogen pseudogenes, PRSS3P2 and TRY7) might be associated with CP causation/predisposition.We analyzed the common PRSS3P2 and TRY7 deletion CNV in a total of 1536 CP patients and 3506 controls from France, Germany, India and Japan by means of quantitative fluorescent multiplex polymerase chain reaction.We demonstrated that the deletion CNV variant was associated with a protective effect against CP in the French, German and Japanese cohorts whilst a trend toward the same association was noted in the Indian cohort. Meta-analysis under a dominant model yielded a pooled odds ratio (OR) of 0.68 (95% confidence interval (CI) 0.52-0.89; p = 0.005) whereas an allele-based meta-analysis yielded a pooled OR of 0.84 (95% CI 0.77-0.92; p = 0.0001). This protective effect is explicable by reference to the recent finding that the still functional PRSS3P2/TRY7 pseudogene enhancers upregulate pancreatic PRSS2 expression.The common PRSS3P2 and TRY7 deletion CNV was associated with a reduced risk for CP. This finding provides additional support for the emerging view that dysregulated PRSS2 expression represents a discrete mechanism underlying CP predisposition or protection.

In AECOPD with acidemia, more severe patients— i.e. , nonsurvivors and patients requiring invasive mechanical ventilation—have lower lung mycobiota α-diversity than survivors and patients receiving only noninvasive ventilation, respectively. This study encourages a large multicenter cohort study investigating the role of lung microbiota in severe AECOPD and urges investigation of the role of the fungal kingdom in severe AECOPD.

Background While there seems to be a consensus that a decrease in gut microbiome diversity is related to a decline in health status, the associations between respiratory microbiome diversity and chronic lung disease remain a matter of debate. We provide a systematic review and meta-analysis of studies examining lung microbiota alpha-diversity in patients with asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF) or bronchiectasis (NCFB), in which a control group based on disease status or healthy subjects is provided for comparison. Results We reviewed 351 articles on title and abstract, of which 27 met our inclusion criteria for systematic review. Data from 24 of these studies were used in the meta-analysis. We observed a trend that CF patients have a less diverse respiratory microbiota than healthy individuals. However, substantial heterogeneity was present and detailed using random-effects models, which limits the comparison between studies. Conclusions Knowledge on respiratory microbiota is under construction, and for the moment, it seems that alpha-diversity measurements are not enough documented to fully understand the link between microbiota and health, excepted in CF context which represents the most studied chronic respiratory disease with consistent published data to link alpha-diversity and lung function. Whether differences in respiratory microbiota profiles have an impact on chronic respiratory disease symptoms and/or evolution deserves further exploration.

Advanced glycation end-products (AGE) are the product of non-enzymatic reactions between reduced carbohydrates, peptides, lipids, nucleic acids. AGE accumulate over time, they are considered as the metabolic memory. In certain pathologies such as diabetes mellitus, AGE accumulation is increased and correlated with vascular complications. Patients with chronic intestinal failure dependent on parenteral nutritional have long-term intravenous carbohydrate intakes. The assessment of AGE levels in this population has never been performed. We measured skin AGE levels by auto-fluorescence in 23 adults followed in a tertiary center for chronic intestinal insufficiency and treated with home parenteral nutrition that we compared to the values of the general population. We also analyzed factors associated with elevated AGE. More than half (n=13) had elevated AGE. The presence of elevated AGE was significantly associated with higher parenteral carbohydrate intakes. Patients with elevated AGE had higher intravenous carbohydrate intakes (median 3.3g/kg/day [1.84;3.62]), compared to patients with normal AGE (1.79g/kg/d [1.45;2.26], p=0.03). The presence of chronic renal failure was also associated with elevated AGE. This preliminary study suggests that AGE accumulation is increased in subjects on prolonged parenteral nutrition. Studies with larger numbers will be necessary to confirm this hypothesis and to evaluate the association with cardiovascular events.

International audience; INTRODUCTION: In recent years, the number of patients managed by poison control centres (PCCs) has increased without a proportional increase in the number of physicians. To improve efficiency without neglecting patient follow-up, some PCCs have begun using text messages. We evaluated the difference in response rates between text messaging and traditional telephone follow-up. MATERIALS AND METHODS: This retrospective, monocentric, non-randomised cohort study was conducted using data from calls made by the New Aquitaine PCC between February 27, 2019, and March 31, 2019. Patients were contacted up to three times by a phone call or short message service (SMS). RESULTS: For the analysis, 823 patients were included. At the end of follow-up, the response rates were similar in the phone call and SMS group (94 vs. 94%; p = 0.76) with median [interquartile range] response times of 0 min [0; 27 min] and 29 min [6; 120 min], respectively. The response rates did not differ in subgroups stratified according to sex, self-poisoning vs. relative response, age class, and solicitation during working hours vs. outside of working hours (all p > 0.5). Moreover, health practitioners required 2.4-fold more time to call than to send text messages (p

Objective This multicentric study aimed to evaluate the quality of life (QOL) in children with Hirschsprung's disease (HD). Methods HD patients aged from 6 to 18 years and followed-up in 2 French pediatric surgery centers were included in this study. QOL was assessed using the HAQL questionnaires according to age (6-11 and 12-18), filled by patients and their parents (proxy reports) and correlated with initial disease characteristics, nutritional status, and functional score of Krickenbeck. Results Sixty-three patients were included. The acquisition of satisfactory voluntary bowel movements was found in only 50% of the 6 to 11 years old and 68% of the teenagers. Seventy percentage of the children and 55% of teenagers had soiling issues. The overall HAQLproxy6--11 score was 528/700; best scores were found for "fecal continence" (94/100), "social functioning" (94/100), and "urinary continence" (92/100) whereas the worst scores were for "general well-being" (64/100) and "diurnal fecal continence" (58/100). The overall HAQLproxy12--16 score was 607/700; best scores were for "urinary continence" (96/100) and "social functioning" (93/100). In a multivariate analysis, soiling was the only factor significantly associated with low QOL (P = 0.03). Conclusions Soiling remains frequent in children operated on for HD and negatively affects their QOL. Assessment and treatment of soiling should be the priority for medical teams in the follow-up of these children.

International audience; Several predictive models have been proposed to understand the microbial risk factors associated with cystic fibrosis (CF) progression. Very few have integrated fungal airways colonisation, which is increasingly recognized as a key player regarding CF progression. To assess the association between the percent predicted forced expiratory volume in 1 s (ppFEV1) change and the fungi or bacteria identified in the sputum, 299 CF patients from the “MucoFong” project were included and followed-up with over two years. The relationship between the microorganisms identified in the sputum and ppFEV1 course of patients was longitudinally analysed. An adjusted linear mixed model analysis was performed to evaluate the effect of a transient or chronic bacterial and/or fungal colonisation at inclusion on the ppFEV1 change over a two-year period. Pseudomonas aeruginosa, Achromobacter xylosoxidans, Stenotrophomonas maltophilia, and Candida albicans were associated with a significant ppFEV1 decrease. No significant association was found with other fungal colonisations. In addition, the ppFEV1 outcome in our model was 11.26% lower in patients presenting with a transient colonisation with non-pneumoniae Streptococcus species compared to other patients. These results confirm recently published data and provide new insights into bacterial and fungal colonisation as key factors for the assessment of lung function decline in CF patients.

International audience; Objectives: Digestive perianastomotic ulcerations (DPAU) resembling Crohn disease lesions are long-term complications of intestinal resections, occurring in children and young adults. They are known to be uncommon, severe and difficult to treat.Methods: In the absence of recommendations, we performed a large European survey among the members of the ESPGHAN working group on inflammatory bowel disease (IBD) in order to collect the experience of expert pediatric gastroenterologists on DPAU.Results: Fifty-one patients (29 boys and 22 girls) were identified from 19 centers in 8 countries. Most patients were followed after necrotizing enterocolitis (n = 20) or Hirschsprung disease (n = 11). The anastomosis was performed at a median age (interquartile range) of 6 [1–23] months, and first symptoms occurred 39 [22–106] months after surgery. Anemia was the most prevalent symptom followed by diarrhea, abdominal pain, bloating, and failure to thrive. Hypoalbuminemia, elevated CRP, and fecal calprotectin were common. Deep ulcerations were found in 59% of patients usually proximally to the anastomosis (68%). During a median follow-up of 40 [19–67] months, treatments reported to be the most effective included exclusive enteral nutrition (31/35, 88%), redo anastomosis (18/22, 82%), and alternate antibiotic treatment (37/64, 58%).Conclusions: Unfortunately, persistence of symptoms, failure to thrive, and abnormal laboratory tests at last follow-up in most of patients show the burden of DPAU lacking optimal therapy and incomplete understanding of the pathophysiology.

In cystic fibrosis (CF), cystic fibrosis transmembrane regulator (CFTR) dysfunction leads to digestive disorders that promote intestinal inflammation and dysbiosis enhancing gastrointestinal symptoms. In pancreatic insufficiency CF patients, both intestinal inflammation and dysbiosis, are associated with an increase in the fecal calprotectin (FC) level. However, associations between the FC level, gastrointestinal symptoms, and quality of life (QoL) remain poorly studied. We aimed to assess such associations in pancreatic insufficiency CF children. The FC level was measured in pancreatic insufficiency CF children&rsquo, s stool samples. Children and their parents completed two questionnaires: The Gastrointestinal Symptoms Scales 3.0-PedsQLTM and the Quality of Life Pediatric Inventory 4.0-PedsQLTM. Lower scores indicated worse symptomatology or QoL. Thirty-seven CF children were included. A FC level above 250 &micro, g/g was associated with worse gastrointestinal symptoms and QoL scores. The FC level was inversely correlated with several gastrointestinal scores assessed by children (i.e., Total, &ldquo, Heart Burn Reflux&rdquo, &ldquo, Nausea and Vomiting&rdquo, and &ldquo, Gas and Bloating&rdquo, ). Several QoL scores were correlated with gastrointestinal scores. The FC level was weakly associated with clinical parameters. Some gastrointestinal and QoL scores were related to disease severity associated parameters. In CF, the FC level, biomarker previously related to intestinal inflammation and dysbiosis, was associated with worse digestive symptoms and QoL scores.

OBJECTIVES Crohn disease (CD) can affect patient's quality of life (QOL) with physical, social, and psychological impacts. This study aimed to investigate the QOL of children with CD and its relationship with patient and disease characteristics. METHODS Children ages from 10 to 17 years with diagnosed CD for more than 6 months were eligible to this cross-sectional study conducted in 35 French pediatric centers. QOL was assessed by the IMPACT-III questionnaire. Patient and disease characteristics were collected. RESULTS A total of 218 children (42% of girls) were included at a median age of 14 years (interquartile range [IQR]: 13--16). Median duration of CD was 3.2 years (IQR: 1.7-5.1) and 63% of children were in clinical remission assessed by wPCDAI. Total IMPACT-III score was 62.8 (±11.0). The lowest score was in "emotional functioning" subdomain (mean: 42.8 ± 11.2). Clinical remission was the main independent factor associated with QOL of children with CD (5.74 points higher compared with those "with active disease", 95% confidence interval [CI] 2.77--8.70, P

Background The links between microbial environmental exposures and asthma are well documented, but no study has combined deep-sequencing results from pulmonary and indoor microbiomes of asthmatic patients with spirometry, clinical and endotype parameters. Objective The goal of this study was to investigate the links between indoor microbial exposures and pulmonary microbial communities and to document the role of microbial exposures on inflammatory and clinical outcomes of patients with severe asthma (SA). Methods Fifty-five SA patients from the national COBRA cohort were enrolled for analyzing their indoor microbial flora through the use of electrostatic dust collectors (EDCs). Among these patients, 22 were able to produce sputa during stable or pulmonary exacerbation periods and had complete pairs of EDC and sputum samples, both collected and analysed. We used amplicon targeted metagenomics to compare microbial communities from EDC and sputum samples of patients according to type 2 (T2)-asthma endotypes. Results Compared to patients with T2-low SA, patients with T2-high SA exhibited an increase in bacterial alpha-diversity and a decrease in fungal alpha-diversity of their indoor microbial floras, the latter being significantly correlated with FeNO levels. The beta-diversity of the EDC mycobiome significantly clustered according to T2 endotypes. Moreover, the proportion of fungal taxa in common between sputum and EDC samples was significantly higher when patients exhibited acute exacerbation. Conclusion These results illustrated, for the first time, a potential association between the indoor mycobiome and clinical features of SA patients, which should renew interest in deciphering the interactions between indoor environment, fungi, and host in asthma., Graphical abstract, Capsule summary. This study is the first to date that investigates both the endogenous and the exogenous mycobiomes and microbiomes of asthmatic patients and reveals associations between indoor microbial communities, exacerbation, and T2 of severe asthma.

BACKGROUND Malnutrition is often underdiagnosed in hospitalised children, although it is associated with postoperative complications, longer hospital lengths of stay and increased healthcare-related costs. OBJECTIVE We aimed to estimate the frequency of, and identify factors associated with, malnutrition in children undergoing anaesthesia. DESIGN Cross-sectional observational study. SETTING Paediatric anaesthesia department at the University Children's Hospital, Bordeaux, France. PARTICIPANTS A total of 985 patients aged less than 18 years. MAIN OUTCOME MEASURES Anthropometric measurements, American Society of Anesthesiologists physical status classification score and the Pediatric Nutritional Risk Score (PNRS) recorded at the pre-anaesthesia evaluation. RESULTS When assessed as a Waterlow index less than 80%, malnutrition was present in 7.6% children. This increased to 8.1% of children assessed by clinical signs and to 11% of children when defined by a BMI less than the third percentile. In a univariate analysis, children with a BMI less than the third percentile were more often born prematurely (22.4 vs 10.4%; P = 0.0008), were small for gestational age at birth (18.4 vs 4.5%; P

Cystic fibrosis (CF) is a systemic genetic disease that leads to pulmonary and digestive disorders. In the majority of CF patients, the intestine is the site of chronic inflammation and microbiota disturbances. The link between gut inflammation and microbiota dysbiosis is still poorly understood. The main objective of this study was to assess gut microbiota composition in CF children depending on their intestinal inflammation. We collected fecal samples from 20 children with CF. Fecal calprotectin levels were measured and fecal microbiota was analyzed by 16S rRNA sequencing. We observed intestinal inflammation was associated with microbiota disturbances characterized mainly by increased abundances of Staphylococcus, Streptococcus, and Veillonella dispar, along with decreased abundances of Bacteroides, Bifidobacterium adolescentis, and Faecalibacterium prausnitzii. Those changes exhibited similarities with that of Crohn&rsquo, s disease (CD), as evidenced by the elevated CD Microbial-Dysbiosis index that we applied for the first time in CF. Furthermore, the significant over-representation of Streptococcus in children with intestinal inflammation appears to be specific to CF and raises the issue of gut&ndash, lung axis involvement. Taken together, our results provide new arguments to link gut microbiota and intestinal inflammation in CF and suggest the key role of the gut&ndash, lung axis in the CF evolution.

International audience; In recent years, the gut microbiota has been considered as a full-fledged actor of the gut-brain axis, making it possible to take a new step in understanding the pathophysiology of both neurological and psychiatric diseases. However, most of the studies have been devoted to gut bacterial microbiota, forgetting the non-negligible fungal flora. In this review, we expose how the role of the fungal component in the microbiota-gut-brain axis is legitimate, through its interactions with both the host, especially with the immune system, and the gut bacteria. We also discuss published data that already attest to a role of the mycobiome in the microbiota-gut-brain axis, and the impact of fungi on clinical and therapeutic research.

Spondyloarthritis (SpA) pathophysiology remains largely unknown. While the association with genetic factors has been established for decades, the influence of gut microbiota is only an emerging direction of research. Despite the remarkable efficacy of anti-TNF-α treatments, non-responders are frequent and no predictive factors of patient outcome have been identified. Our objective was to investigate the modifications of intestinal microbiota composition in patients suffering from SpA three months after an anti-TNF-α treatment. We performed 16S rDNA sequencing of 38 stool samples from 19 spondyloarthritis patients before and three months after anti-TNF-α treatment onset. SpA activity was assessed at each time using ASDAS and BASDAI scores. Some modifications of the microbiota composition were observed after three months of anti-TNF-α treatment, but no specific taxon was modified, whatever the clinical response. We identified a particular taxonomic node before anti-TNF-α treatment that can predict the clinical response as a biomarker, with a higher proportion of Burkholderiales order in future responder patients. This study suggests a cross-influence between anti-TNF-α treatment and intestinal microbiota. If its results are confirmed on larger groups of patients, it may pave the way to the development of predictive tests suitable for clinical practices.

Objectives Cystic fibrosis-related liver disease (CFLD) can develop silently in early life and approximately 10% of children with cystic fibrosis (CF) become cirrhotic before adulthood. Clinical, biological, and ultrasound criteria used to define CFLD often reveal liver involvement at an advanced stage. The aim of this retrospective study was to assess the progression of liver stiffness measurement (LSM) in pediatric patients with CF. Methods The change of LSM, expressed as kPa/year and %/year, was measured using transient elastography (Fibroscan) in 82 children with CF (median age: 6.8 years, interquartile range [IQR]: 5.8). Mean time interval between the 2 LSM was 3.5 years. Results Median initial liver stiffness was 3.7 kPa (IQR: 1.3), and then progressed by 0.23 kPa/year, that is, 6%/year. The 7 patients who developed CFLD had a higher initial level of alanine aminotransferase (50 [IQR: 15] vs 30 [IQR: 18], P = 0.0001) and presented a more rapid progression of LSM (0.94 vs 0.23 kPa/year, P = 0.02). Conclusions The present study shows that the slope of worsening of liver stiffness is greater in patients who will develop CFLD, suggesting that annual transient elastography may be useful to detect risk of severe liver disease at an earlier stage.

Objectives To describe diffusing capacity for carbon monoxide (DLCO) and its components, that is, membrane diffusing capacity (DmCO) and pulmonary capillary blood volume (Vc) in children with Crohn's disease (CD), and to investigate the correlation between these parameters and disease activity. Working Hypothesis The most common lung function abnormalities are a reduced pulmonary DLCO and small airways disorders which are in many instances, clinically silent. No valid explanations have been proposed regarding the modifications in gas transfer capacity in active CD. Methods DLCO, DmCO, and Vc were measured in 25 CD children by the simultaneous single breath lung diffusing capacity method using nitric oxide (NO) and carbon monoxide (CO) transfer. These parameters were analyzed in relation to the CD disease activity index. Results DLCO (90.7 ± 4.5% vs 128.5 ± 4.7%; P

Background Bronchial remodeling is a key feature of asthma that is already present in preschoolers with wheezing. Moreover, bronchial smooth muscle (BSM) remodeling at preschool age is predictive of asthma at school age. However, the mechanism responsible for BSM remodeling in preschoolers with wheezing remains totally unknown. In contrast, in adult asthma, BSM remodeling has been associated with an increase in BSM cell proliferation related to increased mitochondrial mass and biogenesis triggered by an altered calcium homeostasis. Indeed, BSM cell proliferation was decreased in vitro by the calcium channel blocker gallopamil. Objective Our aim was to investigate the mechanisms involved in BSM cell proliferation in preschoolers with severe wheezing, with special attention to the role of mitochondria and calcium signaling. Methods Bronchial tissue samples obtained from 12 preschool controls without wheezing and 10 preschoolers with severe wheezing were used to measure BSM mass and establish primary BSM cell cultures. BSM cell proliferation was assessed by manual counting and flow cytometry, ATP content was assessed by bioluminescence, mitochondrial respiration was assessed by using either the Seahorse or Oroboros technique, mitochondrial mass and biogenesis were assessed by immunoblotting, and calcium response to carbachol was assessed by confocal microscopy. The effect of gallopamil was also evaluated. Results BSM mass, cell proliferation, ATP content, mitochondrial respiration, mass and biogenesis, and calcium response were all increased in preschoolers with severe wheezing compared with in the controls. Gallopamil significantly decreased BSM mitochondrial biogenesis and mass, as well as cell proliferation. Conclusion Mitochondria are key players in BSM cell proliferation in preschoolers with severe wheezing and could represent a potential target to treat BSM remodeling at an early stage of the disease.

Introduction: although central venous catheter (CVC) related thrombosis (CRT) is a severe complication of home parenteral nutrition (HPN) in children, the amount and quality of data in this area remain suboptimal. The aims of this study were to assess CRT management in French centers, and to search for characteristics associated with CRT amongst HPN children. Methods: we performed 2 studies. An online cross-sectional survey was distributed electronically to French HPN centers. A monocentric retrospective cohort including all children on HPN in Bordeaux University Hospital Center between 2008 and 2020 was conducted. Results: responses from 27 centers (21 pediatrics) were collected. We found high variability in the majority of pediatric centers answers to the cross-sectional survey, and these answers were often departed from published guidelines and from adult centers answers. Thirty patients and 140 CVC were included in our second study (38,030 CVC-days). Ten CRTs were diagnosed, amongst 23% of patients and 7.8% of tunneled CVC. Per 1000 CVC-days, 1.1 imaging for CRT research was performed, and 19% of them were positive. CVC type (CIP vs Broviac: OR=53.98 [IC95% 1.15 – 2544.57], p=0.04) and the number of CVC per patient (OR=1.61 [IC95% 1.00 – 2.60], p=0.05) were associated with CRT. We found a tendency for infection (OR=0.1 [IC95% 0.01 – 1.02], p=0.05) and S. aureus infection (OR=10.35 [IC95% 0.85 – 125.80], p=0.07) to be associated with CRT. Conclusion: CRT management varies widely amongst pediatric HPN centers. There is a need for collaborative research in this field., Introduction : bien que la thrombose sur cathéter veineux central (CVC) soit une complication grave pour les patients en nutrition parentérale à domicile (NPAD), celle-ci demeure peu étudiée. Les objectifs de cette étude étaient de faire un état des lieux des pratiques et de rechercher des caractéristiques associées aux thromboses sur CVC chez les enfants en NPAD. Méthodes : nous avons mené́ deux études : une analyse nationale des pratiques par auto-questionnaire envoyé́ aux centres de NPAD français, et une étude de cohorte rétrospective mono centrique incluant les enfants suivis en NPAD au CHU de Bordeaux entre 2008 et 2020. Résultats : vingt-sept centres, dont 21 pédiatriques, ont répondu au questionnaire. Les pratiques des centres pédiatriques variaient significativement d’un centre à l’autre, et différaient des recommandations et des pratiques des centres adultes. Trente patients et 140 CVC ont été́ inclus dans notre seconde étude (38030 CVC-jours). Dix épisodes de thrombose ont été́ diagnostiqués, chez 23 % des patients et 7,8 % des CVC tunnellisés. Pour 1000 CVC-jours, 1,1 imagerie pour recherche de thrombose était réalisée, et était positive dans 19 % des cas. Le type de CVC était associé à la thrombose (CIP vs Broviac : OR=53,98 [IC95% 1,15 – 2544,57], p=0,04), ainsi que le nombre de CVC par patient (OR=1,61 [IC95% 1,00 – 2,60], p=0,05). Il existait une tendance pour l’infection (OR=0,1 [IC95% 0,01 – 1,02], p=0,05) et l’infection à S. aureus (OR=10,35 [IC95% 0,85 – 125,80], p=0,07). Conclusion : la prise en charge des thromboses sur CVC chez l’enfant en NPAD reste hétérogène. Des recherches prospectives et multicentriques sont nécessaires.