A Magnetic Resonance Imaging Index to Predict Crohn's Disease Postoperative Recurrence: The MONITOR Index.

BACKGROUND & AIMS: We developed and validated a magnetic resonance imaging-based index to predict Crohn's disease (CD) postoperative recurrence (POR). METHODS: Patients with CD who underwent a postoperative evaluation for recurrence (with colonoscopy and MRI no longer than 105 days apart) were included between 2006 and 2016 in University Hospital of Nancy, France. MRI items with good levels of intra-rater and inter-rater agreement (Gwet's coefficient ≥0.5) were selected. The MRI in Crohn's Disease to Predict Postoperative Recurrence (MONITOR) index's performance was assessed in terms of the area under the receiver operating characteristic curve (AUROC) and accuracy, by considering the Rutgeerts score as the gold standard. The MONITOR index was validated with a bootstrap method and an independent cohort. RESULTS: Seventy-three MRI datasets were interpreted by 2 radiologists. Seven items (bowel wall thickness, contrast enhancement, T2 signal increase, diffusion-weighted signal increase, edema, ulcers, and the length of the diseased segment) had a Gwet's coefficient ≥0.5 and were significantly associated with the Rutgeerts score, leading to their inclusion in the MONITOR index. All the items had a weighting of 1, except the "ulcers" item weighting 2.5, reflecting the higher adjusted odds ratio. The AUROC [95% confidence interval] for the prediction of endoscopic POR (Rutgeerts score >i1) was 0.80 [0.70-0.90]. The optimal threshold was a MONITOR index ≥1, giving a sensitivity of 79%, a specificity of 55%, a predictive positive value of 68%, and a predictive negative value of 68%. The bootstrap validation gave an AUROC of 0.85 [0.73-0.97]. In the validation cohort, a MONITOR index ≥1 gave a sensitivity of 87%, a specificity of 75%, a predictive positive value of 84.6%, and a predictive negative value of 75%. CONCLUSIONS: The MONITOR index is an efficient, reliable, easy-to-apply tool that can be used in clinical practice to predict the POR of CD.

IgA vasculitis in patients with inflammatory bowel disease: new insights into the role of TNF-α blockers.

OBJECTIVE: The association of IgA vasculitis (IgAV) and IBD is rarely described, mainly during anti-TNF-α therapy. We aimed to describe the association of IgAV and IBD. METHODS: We retrospectively analysed the association of IgAV and IBD through the implication of the GETAID and FVSG networks. Characteristics of IBD and IgAV were collected using a standardized case report form. RESULTS: Forty-three cases were included. IBD [mainly Crohn's disease (CD) in 58%] preceded IgAV in 38 (88%), with median interval of 9.2 (IQR 5.4-15.4) years. In these 38 patients, at IgAV diagnosis, five (13%) had active IBD and 28 (74%) were treated with anti-TNF-α for a median duration of 31.5 (IQR 19-56) months. Main IgAV manifestations were purpura all patients (100%), joints in 20/35 (57%), renal in 15/35 (43%) and gastrointestinal in 11/35 (31%) involvement. IgAV was treated with glucocorticoids in 25 (66%), colchicine in six (16%), CYC in six (16%) and anti-TNF-α were discontinued in 15/28 (54%). No IgAV relapse occurred when TNF-α blockers were stopped, vs 23% in patients pursuing it. Conversely, five (33%) had IBD flare or complication after anti-TNF-α cessation vs one (8%) in those continuing biologics. Anti-TNF-α were resumed in six (40%), with subsequent IgAV relapse in four (67%). CONCLUSIONS: This large cohort suggests that TNF-α blockers may promote the onset of IgAV in IBD. Discontinuation of anti-TNF-α was associated with vasculitis remission but increased risk of IBD relapses, whereas continuation of anti-TNF-α was associated with IBD remission but vasculitis relapse.

Fructose-1,6-bisphosphatase deficiency causes fatty liver disease and requires long-term hepatic follow-up.

Liver disease, occurring during pediatric or adult age, is often of undetermined cause. Some cases are probably related to undiagnosed inherited metabolic disorders. Hepatic disorders associated with fructose-1,6-bisphosphatase deficiency, a gluconeogenesis defect, are not reported in the literature. These symptoms are mainly described during acute crises, and many reports do not mention them because hypoglycemia and hyperlactatemia are more frequently in the forefront. Herein, the liver manifestations of 18 patients affected with fructose-1,6-bisphosphatase deficiency are described and the corresponding literature is reviewed. Interestingly, all 18 patients had liver abnormalities either during follow-up (hepatomegaly [n = 8/18], elevation of transaminases [n = 6/15], bright liver [n = 7/11]) or during acute crises (hepatomegaly [n = 10/17], elevation of transaminases [n = 13/16], acute liver failure [n = 6/14], bright liver [n = 4/14]). Initial reports described cases of liver steatosis, when liver biopsy was necessary to confirm the diagnosis by an enzymatic study. There is no clear pathophysiological basis for this fatty liver disease but we postulate that endoplasmic reticulum stress and de novo lipogenesis activation could be key factors, as observed in FBP1 knockout mice. Liver steatosis may expose patients to severe long-term liver complications. As hypoglycemia becomes less frequent with age, most adult patients are no longer monitored by hepatologist. Signs of fructose-1,6-bisphosphatase deficiency may be subtle and can be missed in childhood. We suggest that fructose-1,6-bisphosphatase deficiency should be considered as an etiology of hepatic steatosis, and a liver monitoring protocol should be set up for these patients, during lifelong follow-up.

Low Levels of Fecal Calprotectin 3 Months After Surgery Predict Subsequent Endoscopic Postoperative Remission in Crohn's Disease.

BACKGROUND/AIMS: In Crohn's disease (CD) few data are available on the usefulness of monitoring fecal calprotectin (FC) in the early postoperative setting. We assessed prospectively the accuracy of FC measured 3 months after surgery to predict the risk of endoscopic postoperative recurrence (POR) within 1 year after resection. METHODS: In 55 consecutive CD patients who had undergone ileocolonic resection samples were collected 3 months after surgery for measuring serum CRP and FC. Endoscopic POR was assessed by ileocolonoscopy within 6-12 months (median 7 months). Receiver operating characteristic (ROC) curves were generated to assess accuracy of the markers, to determine the best threshold and to calculate sensitivity, specificity, positive and negative predictive values. RESULTS: In contrast with median CRP levels, median FC concentrations measured 3 months after surgery were significantly higher in patients who later experienced endoscopic POR (Rutgeerts ≥ i2) compared with those who stayed in endoscopic remission within the following 6-12 months (205 µg/g IQR [106-721] vs. 103 µg/g IQR [60-219], p = 0.008). Area under the ROC curve for FC was 0.71. The best cutoff value of FC to identify patients in subsequent endoscopic remission 3 months after surgery was 65 µg/g (96% sensitivity, 31% specificity, 50% positive and 91% negative predictive values). In multivariate analysis, FC < 65 µg/g at 3 months was the only factor associated with subsequent endoscopic remission. CONCLUSION: FC measured 3 months after surgery below 65 µg/g is an accurate marker to identify CD patients who will later stay in endoscopic remission within 1 year after resection.

Severe infantile isolated exocrine pancreatic insufficiency caused by the complete functional loss of the SPINK1 gene.

Exocrine pancreatic insufficiency (EPI) is rare in children, with most if not all cases occurring as part of syndromic conditions such as cystic fibrosis and Shwachman-Diamond syndrome. Here we report two cases, both presenting with severe EPI around 5 months of age. Characterized by diffuse pancreatic lipomatosis, they otherwise exhibited no remarkable deficiencies in other organs. Novel non-identical homozygous variants (a deletion removing the entire SPINK1 gene and an insertion of a full-length inverted Alu element into the 3'-untranslated region of the SPINK1 gene) resulting in the complete functional loss of the SPINK1 gene (encoding pancreatic secretory trypsin inhibitor) were identified in each patient. Having correlated our findings with current knowledge of SPINK1's role in exocrine pancreas pathophysiology, we propose that complete and partial functional losses of the SPINK1 gene are associated with quite distinct phenotypes, the former causing a new pediatric disease entity of severe infantile isolated EPI.

Neurocognitive profiles in MSUD school-age patients.

Maple syrup urine disease (MSUD), an inborn error of amino acids catabolism is characterized by accumulation of branched chain amino acids (BCAAs) leucine, isoleucine, valine and their corresponding alpha-ketoacids. Impact on the cognitive development has been reported historically, with developmental delays of varying degree. Currently, earlier diagnosis and improved management allow a better neurodevelopment, without requirement of special education. However, specific impairments can be observed, and so far, results of detailed neurocognitive assessments are not available. The aim of this study was to analyse neurocognitive profiles of French MSUD patients. This was a multicentre retrospective study on MSUD patients who underwent neurocognitive evaluation at primary school age. Twenty-one patients with classical neonatal onset MSUD were included. The patients' mean age at the time of evaluation was 8.7 years. The mean intellectual quotient (IQ) score was in the normal range (95.1 ± 12.6). In a subset of eight patients, a consistent developmental pattern of higher verbal than performance IQ was observed (mean of the difference 25.7 ± 8.7, p < 0.0001). No correlation could be established between this pattern and long-term metabolic balance (BCAA blood levels), or severity of acute metabolic imbalances, or leucine blood levels at diagnosis and time to toxin removal procedure. These data show that some MSUD patients may exhibit an abnormal neurocognitive profile with higher verbal than performance abilities. This might suggest an executive dysfunction disorder that would need to be further investigated by specialized testing. This pattern is important to detect in MSUD, as appropriate neuropsychological treatment strategies should be proposed.

Real-life effectiveness of allogeneic expanded adipose-derived mesenchymal stem cell therapy for perianal fistulizing refractory Crohn's disease.

BACKGROUND: Real life data about the long-term efficacy of darvadstrocel for treating perianal fistulas in Crohn's disease (CD) remain scarce. AIM: To report the effectiveness and safety of darvadstrocel therapy to close perianal fistula in a real-life cohort of CD patients. METHODS: All patients with CD suffering complex draining perianal fistulas who consecutively underwent administration of a single local injection of darvadstrocel at two centres were followed up and evaluated. The primary endpoint was clinical remission (closure of all external openings with no discharge at pressure) at week 24. Combined remission (defined as clinically plus MRI-assessed fistula closure) were also assessed at week 24 and 52. RESULTS: A total of 36 CD patients (19 Male, mean age 38.5 years) were included with a median follow up of 16 months. Clinical remission was achieved in 17 out of 36 patients (47.2 %) and combined remission in 15 out of 36 patients (41.6 %) at week 24. At week 52, clinical and combined remission was achieved in 17 out of 36 patients (47.2 %) and in 15 out of 33 evaluable patients (45.4 %), respectively. CONCLUSION: In this real-world setting, a successful response to darvadstrocel therapy based on clinical remission was reported in around half of the patients and combined remission including radiological assessment in more than 4 out of 10 patients.

Physical Activity and IBD: State of Art and Knowledge, Patients and Healthcare Professionals Points of View, A French Multicenter Cross Sectional Study.

BACKGROUND: Several studies have reported low levels of physical activity (PA) in patients with inflammatory bowel diseases (IBD), possibly related to a lack of information and support, despite the many recognized benefits such as cardiovascular prevention or quality of life (QoL) improvement. METHODS: The purpose of our study was to identify challenges faced by patients and to evaluate IBD impact on PA and QoL by using the International Physical Activity Questionnaire short form and the 32-item Inflammatory Bowel Disease Questionnaire (IBDQ-32) questionnaire, respectively. We also assessed the expectations and knowledge of patients and healthcare professionals using the MICI-Active questionnaire that we developed. RESULTS: We included 298 IBD patients in 4 French hospitals, with a mean age of 38 years. We found a decrease in training frequency since IBD diagnosis, regardless of age, gender, symptom intensity, or type of disease. Moreover, there was an increase in low intensity activities like walking and a decrease in competitions and sports club registrations. Intensity of symptoms has a negative impact on QoL, as evidenced by the worsening of IBDQ score. Conversely, a higher PA intensity was correlated with a higher IBDQ score, regardless of symptoms intensity. The main barrier to PA was fatigue (56%), and the main fear was diarrhea (42%). Furthermore, 75% of patients did not feel sufficiently informed, and 61% were interested in coaching. A total of 112 healthcare professionals were interviewed, 62.5% said they had already discussed of PA with their patients, but 98% felt that they lacked knowledge. CONCLUSIONS: Inflammatory bowel disease constraints and symptoms have a strong impact on PA. Work needs to be done to better train practitioners to improve IBD patient management, who have much to gain from better PA.

We showed a strong impact of IBD on physical activity (PA) and quality of life, assessed by questionnaire in 298 IBD patients. In addition, we identified the main barriers to PA and interviewed health professionals about their knowledge about it.

Anti-hemagglutinin monomeric nanobody provides prophylactic immunity against H1 subtype influenza A viruses.

Influenza viruses constitute a major threat to human health globally. The viral surface glycoprotein hemagglutinin (HA) is the immunodominant antigen, contains the site for binding to the cellular receptor (RBS), and it is the major target of neutralizing antibody responses post-infection. We developed llama-derived single chain antibody fragments (VHHs) specific for type A influenza virus. Four VHHs were identified and further characterized. VHH D81 bound residues in the proximity of the C-terminal region of HA1 of H1 and H5 subtypes, and showed weak neutralizing activity, whereas VHH B33 bound residues in the proximity of the N-terminal region of the HA's stem domain (HA2) of H1, H5, and H9 subtypes, and showed no neutralizing activity. Of most relevance, VHHs E13 and G41 recognized highly conserved conformational epitopes on the H1 HA's globular domain (HA1) and showed high virus neutralizing activity (ranging between 0.94 to 0.01µM), when tested against several human H1N1 isolates. Additionally, E13 displayed abrogated virus replication of a panel of H1N1 strains spanning over 80 years of antigenic drift and isolated from human, avian, and swine origin. Interestingly, E13 conferred protection in vivo at a dose as low as 0.05 mg/kg. Mice treated with E13 intranasally resulted in undetectable virus challenge loads in the lungs at day 4 post-challenge. The transfer of sterilizing pan-H1 immunity, by a dose in the range of micrograms given intranasally, is of major significance for a monomeric VHH and supports the further development of E13 as an immunotherapeutic agent for the mitigation of influenza infections.

Use of imaging modalities for decision-making in inflammatory bowel disease.

Cross-sectional magnetic resonance enterography (MRE) and intestinal ultrasonography (IUS) provide valuable and noninvasive information to accurately assess disease activity, severity, and extent; detect complications; and monitor the response to treatment, as well as predict the postoperative recurrence of Crohn's disease and a negative disease course. Therefore, both imaging modalities are emerging as pivotal diagnostic tools to achieve the emerging therapeutic target of transmural healing associated with better disease outcomes. Despite its numerous potential advantages over endoscopy and even MRE and its good availability, IUS is still widely underused to monitor and manage inflammatory bowel disease (IBD) patients and help in making clinical decisions in routine practice. This situation is clearly due to the absence of validated, reliable, and responsive indices, as well as the lack of trained gastroenterologists and radiologists, as IUS is a component of radiologist expertise in several countries but not yet integrated into the training program of gastroenterologists. However, there is an increasing body of evidence in the literature that IUS and MRE are both becoming essential imaging resources to help clinicians in making reliable decisions. Here, we discuss the up-to-date evidence about the usefulness and performance of cross-sectional imaging, focusing on the ability of bowel US and MRE to aid clinical decision-making for the optimal management and monitoring of IBD.

Drug-Induced sleep endoscopy in children: NAVOTEL scoring system development.

OBJECTIVES: Pediatric drug-induced sleep endoscopy (DISE) lacks a universal and easy-to-use scoring system. The velum, oropharynx, tongue, epiglottis (VOTE) scoring system is widely used but needs to be completed in pediatrics. The main objective of this study was to investigate the distribution of obstructive sites in DISE and to propose an appropriate pediatric scoring system. The secondary objective was to evaluate the changes in surgical management induced by the proposed scoring system. METHODS: A single-center prospective 5-year study was conducted from March 2016 to December 2021, including 99 children with a mean age of 7.2 years (±3.7), with pathological preoperative sleep recordings and undergoing DISE. The distribution of all upper airway obstructive sites was studied. RESULTS: Adenoids (A) were the most frequent obstructive site (63% of patients), and the nasal cavities (N) and the larynx (L) were other frequent obstructive sites. These sites are not explored by the VOTE scoring system, leading to the creation of the nose, adenoids, velum, oropharynx, tongue, epiglottis, larynx (NAVOTEL) scoring system. NAVOTEL was significantly correlated with the severity of obstructive sleep apnea-hypopnea syndrome (OSAS) (ρ = 0.2; p = 0.04) and highlighted obstructive sites in 6/9 patients with VOTE = 0. Of these patients, 4 had a complete obstructive site, and 3 had a multisite obstruction. VOTE indicated 8 additional surgical actions; NAVOTEL indicated 50 other actions compared to clinical examination. The NAVOTEL scoring system was exhaustive regarding surgical indications for OSAS. CONCLUSIONS: The NAVOTEL scoring system is exhaustive in pediatric DISE and correlated to OSAS severity. It should be preferred in pediatric DISE.

Case Report: Longitudinal follow-up and testicular sperm extraction in a patient with a pathogenic NR5A1 (SF-1) frameshift variant: p.(Phe70Serfs*5).

Background: Steroidogenic factor 1 (SF-1), encoded by the nuclear receptor subfamily 5 group A member 1 (NR5A1) gene, is a transcriptional factor crucial for adrenal and gonadal organogenesis. Pathogenic variants of NR5A1 are responsible for a wide spectrum of phenotypes with autosomal dominant inheritance including disorders of sex development and oligospermia-azoospermia in 46,XY adults. Preservation of fertility remains challenging in these patients. Objective: The aim was to offer fertility preservation at the end of puberty in an NR5A1 mutated patient. Case report: The patient was born of non-consanguineous parents, with a disorder of sex development, a small genital bud, perineal hypospadias, and gonads in the left labioscrotal fold and the right inguinal region. Neither uterus nor vagina was detected. The karyotype was 46,XY. Anti-Müllerian hormone (AMH) and testosterone levels were low, indicating testicular dysgenesis. The child was raised as a boy. At 9 years old, he presented with precocious puberty treated by triptorelin. At puberty, follicle-stimulating hormone (FSH), luteinising hormone (LH), and testosterone levels increased, whereas AMH, inhibin B, and testicular volume were low, suggesting an impaired Sertoli cell function and a partially preserved Leydig cell function. A genetic study performed at almost 15 years old identified the new frameshift variant NM_004959.5: c.207del p.(Phe70Serfs*5) at a heterozygous state. He was thus addressed for fertility preservation. No sperm cells could be retrieved from three semen collections between the ages of 16 years 4 months and 16 years 10 months. A conventional bilateral testicular biopsy and testicular sperm extraction were performed at 17 years 10 months of age, but no sperm cells were found. Histological analysis revealed an aspect of mosaicism with seminiferous tubules that were either atrophic, with Sertoli cells only, or presenting an arrest of spermatogenesis at the spermatocyte stage. Conclusion: We report a case with a new NR5A1 variant. The fertility preservation protocol proposed at the end of puberty did not allow any sperm retrieval for future parenthood.

Changes in the clinical management of 5α-reductase type 2 and 17ß-hydroxysteroid dehydrogenase type 3 deficiencies in France.

Objectives: To examine the changes in diagnostic practices and clinical management of patients with 5α-reductase type 2 (SRD5A2) or 17ß-hydroxysteroid dehydrogenase type 3 (HSD17B3) deficiency since molecular diagnoses became available. Methods: Clinical, laboratory, and therapeutic data were retrieved from the medical records of 52 patients with a molecular diagnosis of SRD5A2 (n = 31) or HSD17B3 (n = 21) deficiency. Temporal trends regarding age at assessment and initial sex assignment over 1994-2020 were qualitatively analyzed. Age at molecular diagnosis was compared between two subgroups of patients according to their year of birth. Results: Fifty-eight percent (n = 30) patients were diagnosed during the perinatal period, 33% (n = 17) during infancy, and 9% (n = 5) during adolescence or adulthood. Over the studied period, the patients' age at initial assessment and diagnosis frankly decreased. The median (range) age at diagnostic confirmation was 10.5 (0-53.2) years for patients born before 2007 and 0.4 (0-9.3) years for those born in 2007 or later (P = 0.029). Genetic testing identified 27 different variants for the SRD5A2 gene (30% novel, n = 8) and 18 for the HSD17B3 gene (44% novel, n = 8). Before 2002, most patients were initially assigned as females (95%, n = 19), but this proportion dropped for those born later (44%, n = 14; P < 0.001). The influence of initial genital appearance on these decisions seemingly decreased in the most recent years. Therapeutic interventions differed according to the sex of rearing. Ten percent (n = 2) patients requested female-to-male reassignment during adulthood. Conclusion: This study showed, over the past two decades, a clear trend toward earlier diagnosis and assignment of affected newborns as males.

Encephalitis and poor neuronal death-mediated control of herpes simplex virus in human inherited RIPK3 deficiency.

Inborn errors of TLR3-dependent type I IFN immunity in cortical neurons underlie forebrain herpes simplex virus-1 (HSV-1) encephalitis (HSE) due to uncontrolled viral growth and subsequent cell death. We report an otherwise healthy patient with HSE who was compound heterozygous for nonsense (R422*) and frameshift (P493fs9*) RIPK3 variants. Receptor-interacting protein kinase 3 (RIPK3) is a ubiquitous cytoplasmic kinase regulating cell death outcomes, including apoptosis and necroptosis. In vitro, the R422* and P493fs9* RIPK3 proteins impaired cellular apoptosis and necroptosis upon TLR3, TLR4, or TNFR1 stimulation and ZBP1/DAI-mediated necroptotic cell death after HSV-1 infection. The patient's fibroblasts displayed no detectable RIPK3 expression. After TNFR1 or TLR3 stimulation, the patient's cells did not undergo apoptosis or necroptosis. After HSV-1 infection, the cells supported excessive viral growth despite normal induction of antiviral IFN-ß and IFN-stimulated genes (ISGs). This phenotype was, nevertheless, rescued by application of exogenous type I IFN. The patient's human pluripotent stem cell (hPSC)-derived cortical neurons displayed impaired cell death and enhanced viral growth after HSV-1 infection, as did isogenic RIPK3-knockout hPSC-derived cortical neurons. Inherited RIPK3 deficiency therefore confers a predisposition to HSE by impairing the cell death-dependent control of HSV-1 in cortical neurons but not their production of or response to type I IFNs.

Comparison of short- and long-term effectiveness between ustekinumab and vedolizumab in patients with Crohn's disease refractory to anti-tumour necrosis factor therapy.

BACKGROUND: The best option between vedolizumab and ustekinumab after anti-tumour necrosis factor (TNF) failure remains unclear in Crohn's disease. AIMS: To compare the short- and long-term effectiveness of vedolizumab and ustekinumab in Crohn's disease patients with prior anti-TNF exposure. METHODS: All Crohn's disease patients treated with ustekinumab or vedolizumab after exposure to at least one anti-TNF agent were included from two referral centres. Primary endpoint was corticosteroid-free clinical remission defined as Crohn's disease activity index <150 at week 54. Deep remission (corticosteroid-free clinical remission and faecal calprotectin <100 µg/g) was assessed at week 14. Propensity-matched analyses were applied to make the two groups comparable. RESULTS: Overall, 312 patients (ustekinumab = 224 and vedolizumab = 88) were included. After propensity score analysis, ustekinumab was more effective to achieve corticosteroid-free clinical remission at week 54 (49.3% vs 41.2%, P = 0.04) and deep remission at Week 14 (25.9% vs 3.8%, P = 0.02) than vedolizumab. The rate of primary nonresponders (6.7% vs 14.8%, P = 0.034) and the long-term risk of drug discontinuation due to therapeutic failure (HR = 1.53 [1.04-2.07], P = 0.029) were lower in patients treated with ustekinumab compared with vedolizumab. Predictors of ustekinumab failure were complicated phenotype (odds ratio [OR] = 2.35 [1.31-4.22]; P = 0.004) and anti-TNF primary non-response (OR = 2.55 [1.27-5.12]; P = 0.008). We did not find any predictor of corticosteroid-free clinical remission in patients treated with vedolizumab. Vedolizumab was less effective than ustekinumab in patients >35 years old (OR = 0.41 [0.19-0.87]), with noncomplicated phenotype (OR=0.42 [0.18-0.96]), no prior bowel resection (OR = 0.49 [0.24-0.96]), and no steroids at baseline (OR=0.47 [0.23-0.97]). CONCLUSION: Ustekinumab was more effective to achieve early and long-term effectiveness than vedolizumab in Crohn's disease patients who previously failed response to anti-TNF agents.

Pro-Resolving Factors Released by Macrophages After Efferocytosis Promote Mucosal Wound Healing in Inflammatory Bowel Disease.

Nonresolving inflammation is a critical driver of several chronic inflammatory diseases, including inflammatory bowel diseases (IBD). This unresolved inflammation may result from the persistence of an initiating stimulus or from the alteration of the resolution phase of inflammation. Elimination of apoptotic cells by macrophages (a process called efferocytosis) is a critical step in the resolution phase of inflammation. Efferocytosis participates in macrophage reprogramming and favors the release of numerous pro-resolving factors. These pro-resolving factors exert therapeutic effects in experimental autoimmune arthritis. Here, we propose to evaluate the efficacy of pro-resolving factors produced by macrophages after efferocytosis, a secretome called SuperMApo, in two IBD models, namely dextran sodium sulfate (DSS)-induced and T cell transfer-induced colitis. Reintroducing these pro-resolving factors was sufficient to decrease clinical, endoscopic and histological colitis scores in ongoing naive T cell-transfer-induced colitis and in DSS-induced colitis. Mouse primary fibroblasts isolated from the colon demonstrated enhanced healing properties in the presence of SuperMApo, as attested by their increased migratory, proliferative and contractive properties. This was confirmed by the use of human fibroblasts isolated from patients with IBD. Exposure of an intestinal epithelial cell (IEC) line to these pro-resolving factors increased their proliferative properties and IEC acquired the capacity to capture apoptotic cells. The improvement of wound healing properties induced by SuperMApo was confirmed in vivo in a biopsy forceps-wound colonic mucosa model. Further in vivo analysis in naive T cell transfer-induced colitis model demonstrated an improvement of intestinal barrier permeability after administration of SuperMApo, an intestinal cell proliferation and an increase of α-SMA expression by fibroblasts, as well as a reduction of the transcript coding for fibronectin (Fn1). Finally, we identified TGF-ß, IGF-I and VEGF among SuperMApo as necessary to favor mucosal healing and confirmed their role both in vitro (using neutralizing antibodies) and in vivo by depleting these factors from efferocytic macrophage secretome using antibody-coated microbeads. These growth factors only explained some of the beneficial effects induced by factors released by efferocytic macrophages. Overall, the administration of pro-resolving factors released by efferocytic macrophages limits intestinal inflammation and enhance tissue repair, which represents an innovative treatment of IBD.

Reference values for the external genitalia of full-term and pre-term female neonates.

BACKGROUND AND OBJECTIVES: Identifying virilisation of the genitalia in female newborns early during the neonatal period is important to diagnose pathologies. However, there is no clear threshold for clitoromegaly or for the anogenital ratio. The objective of this study was to define reference values for the external genitalia of full-term and pre-term female neonates. DESIGN: This was a prospective study of all females born in the study centre between May 2014 and July 2016. Clitoral length and anogenital ratio were measured in 619 newborns with a gestational age of 24+2 to 41+3 weeks during their first 3 days of life. Associations between the values at day 3 and gestational age, birth weight and other newborn characteristics were examined by linear regression. RESULTS: The mean clitoral length at day 3 of life was 3.69±1.53 mm (n=551; 95th percentile, 6.5 mm; maximum, 8 mm), and the mean anogenital ratio was 0.42±0.09 (95th percentile, 0.58). There was no significant variation with gestational age or birth weight, and no significant difference between the results at day 0 and day 3. CONCLUSION: These results suggest that clitoromegaly can be defined as a clitoral length >6.5 mm. Values ≥8 mm should prompt further investigations. An anogenital ratio >0.6 should be considered a sign of virilisation. Since clitoral size does not vary with gestational age or birth weight, clitoromegaly should not be attributed to prematurity.

The surgical challenges of disorders of sex development (DSD).

Disorders of Sex Development (DSD) remain a fascinating challenge for the paediatricians, endocrinologists, biologists, psychiatrists, geneticists, radiologists, surgeons and for the whole society. This article aims at highlighting the current controversies and questions met with genital reconstruction in children born with abnormal genitalia. The main current techniques of masculinization and feminization are reviewed with their progress and their problems. The tools of decision used to assign a gender in some newborns with complex DSD are discussed showing that at the dawn of the third millenium, one still does not know why a boy is a boy, and a girl is a girl.

Sarcopenia and visceral obesity assessed by computed tomography are associated with adverse outcomes in patients with Crohn's disease.

BACKGROUND: Altered body composition may impact on the clinical course of Crohn's disease (CD) but is not detected by the simple body mass index (BMI) assessment. AIM: To assess the prevalence of sarcopenia and visceral obesity by a single computed tomography (CT) slice, and its association with adverse events in an adult hospitalized CD cohort. METHODS: 88 CD patients who had abdominal CT scans during hospitalization were retrospectively enrolled. The skeletal muscle index (SMI) at the third lumbar vertebra level was used to assess sarcopenia. Sarcopenia was defined as a SMI <38.5 cm2/m2 in women, <52.4 cm2/m2 in men and visceral obesity as a visceral fat area ≥130 cm2. Clinical malnutrition was defined by a BMI <18.5 kg/m2. Univariate analysis was performed, and predictors for surgery in the follow-up were entered in a stepwise logistic regression model for multivariate analysis. RESULTS: The prevalence of sarcopenia was 58%, malnutrition 21.6%, and visceral obesity 19.3%. Among sarcopenic patients, 49% had a normal BMI, 13.7% were overweight, and 1(2%) was obese. Sarcopenic CD patients had significantly more abscesses (51% vs 16.7%, p = 0.001), hospitalizations (61.2% vs 36.1%, p = 0.022) and digestive surgery (63.3% vs 27.8%, p = 0.001) than non-sarcopenic patients during the follow-up, whereas usual malnutrition assessment was not correlated with disease outcomes. In multivariate analysis, both sarcopenia and visceral obesity were associated with further occurrence of digestive surgery. CONCLUSION: Both sarcopenia and visceral obesity were associated with adverse outcomes in severe CD patients whereas usual nutritional assessment was not.

Preoperative Topical Estrogen Treatment vs Placebo in 244 Children With Midshaft and Posterior Hypospadias.

PURPOSE: Urethral fistula and dehiscence are common after hypospadias surgery. Preoperative androgens have been considered to reduce these complications although this consideration is not evidence-based. Dermatologists have reported the benefits of topical estrogens on skin healing. We investigated whether the preoperative use of topical promestriene could reduce healing complications in hypospadias surgery. Our primary objective was to demonstrate a reduction of healing complications with promestriene vs placebo. Impact on reoperations and other complications, clinical tolerance, bone growth, and biological systemic effects of the treatment were also considered. METHODS: We conducted a prospective, randomized, placebo-controlled, double-blind, parallel group trial between 2011 and 2015 in 4 French centers. One-stage transverse preputial island flap urethroplasty (onlay urethroplasty) was selected for severe hypospadias. Promestriene or placebo was applied on the penis for 2 months prior to surgery. The primary outcome was the presence of postoperative urethral fistula or dehiscence in the first year postsurgery. For safety reasons, hormonal and anatomical screenings were performed. RESULTS: Out of 241 patients who received surgery, 122 patients were randomized to receive placebo, and 119 patients received promestriene. The primary outcome was unavailable for 11 patients. Healing complications were assessed at 16.4% (19/116) in the placebo vs 14.9% (17/114) in the promestriene arm, and the odds ratio adjusted on center was 0.93 (95% confidence interval 0.45-1.94), P = 0.86. CONCLUSIONS AND RELEVANCE: Although we observed an overall lower risk of complications compared to previous publications, postsurgery complications were not different between promestriene and placebo, because of a lack of power of the study or the inefficacy of promestriene.