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Background: Short-term outcomes of optic neuritis (ON) have been well characterized. Limited data exists on longer-term visual outcomes in patients who present with ON. The large MSBase registry allows for characterization of long-term visual outcomes after ON. Methods: Via the MSBase Registry, data on patients from 41 centers was collected during routine clinical and research visits. Physical and visual disability were measured using the expanded disability status scale (EDSS) and the visual function score (VFS). Inclusion criteria for this analysis included age ≥ 18 years, clinically isolated syndrome (CIS), ON-onset, baseline visit within 6 months of onset, and at least one follow-up visit. Survival analysis was used to evaluate the association of disease-modifying treatment with time to conversion to clinically definite MS or sustained EDSS/VFS progression. Results: Data from 60,933 patients were obtained from the MSBase registry in July 2019. Of these, 1317 patients met inclusion criteria; 935 were treated at some point in disease course, while 382 were never treated. At baseline, mean age was 32.3 ± 8.8 years, 74% were female, median EDSS was 2 (IQR 1–2), and median VFS was 1 (IQR 0–2). Median follow-up time was 5.2 years (IQR 2.4–9.3). Treatment was associated with reduced risk and delayed conversion to clinically definite MS (HR = 0.70, p < 0.001), sustained EDSS progression (HR = 0.46, p < 0.0001) and sustained VFS (HR = 0.41, p < 0.001) progression. Conclusions: In the MSBase cohort, treatment after ON was associated with better visual and neurological outcomes compared to no treatment. These results support early treatment for patients presenting with ON as the first manifestation of MS.

Background This systematic review critically analyzes the current research on micronutrient deficiency in children with inflammatory bowel disease (IBD) and synthesizes these data to provide evidence-based guidelines for nutritional surveillance in this population. Methods We searched 5 databases (Ovid Medline, PubMed, Scopus, CINAHL, and Cochrane Library) for studies evaluating micronutrients in patients with IBD using the following inclusion criteria: 1) original research, 2) published 1996 or later; 3) published in English; 4) human subjects; and 5) containing pediatric data. Studies were reviewed and included based on the strength of research methods. Data on the prevalence of micronutrient deficiencies in pediatric patients with IBD and risk factors for micronutrient deficiency in these patients were extracted from included studies and compared and discussed in preparation of the proposed guidelines and manuscript. Results A total of 39 studies were included in the final review. The data presented in these studies show that iron deficiency and vitamin D deficiency are common in pediatric patients with IBD. Vitamin B12 and folate deficiency are rare. Zinc deficiency, while not common, occurs at a higher rate in patients with Crohn's disease than in healthy controls. There was limited data on vitamins A, E, and C, and selenium, but deficiency of these micronutrients seems rare. Conclusions We recommend annual surveillance of iron and vitamin D in pediatric patients with IBD regardless of disease activity or phenotype. Zinc should be monitored annually in patients with Crohn's disease. There is insufficient evidence to support routine screening for other micronutrient deficiencies.

BACKGROUND. Paneth cell dysfunction has been implicated in a subset of Crohn’s disease (CD) patients. We previously stratified clinical outcomes of CD patients by using Paneth cell phenotypes, which we defined by the intracellular distribution of antimicrobial proteins. Animal studies suggest that Paneth cells shape the intestinal microbiome. However, it is unclear whether Paneth cell phenotypes alter the microbiome complexity in CD subjects. Therefore, we analyzed the correlation of Paneth cell phenotypes with mucosal microbiome composition and ileal RNA expression in pediatric CD and noninflammatory bowel disease (non-IBD) patients. METHODS. Pediatric CD (n = 44) and non-IBD (n = 62) patients aged 4 to 18 were recruited prior to routine endoscopic biopsy. Ileal mucosal samples were analyzed for Paneth cell phenotypes, mucosal microbiome composition, and RNA transcriptome. RESULTS. The prevalence of abnormal Paneth cells was higher in pediatric versus adult CD cohorts. For pediatric CD patients, those with abnormal Paneth cells showed significant changes in their ileal mucosal microbiome, highlighted by reduced protective microbes and enriched proinflammatory microbes. Ileal transcriptome profiles showed reduced transcripts for genes that control oxidative phosphorylation in CD patients with abnormal Paneth cells. These transcriptional changes in turn were correlated with specific microbiome alterations. In non-IBD patients, a subset contained abnormal Paneth cells. However, this subset was not associated with alterations in the microbiome or host transcriptome. CONCLUSION. Paneth cell abnormalities in human subjects are associated with mucosal dysbiosis in the context of CD, and these changes are associated with alterations in oxidative phosphorylation, potentially in a feedback loop. FUNDING. The research was funded by Helmsley Charitable Trust (to T.S. Stappenbeck, R.J. Xavier, and D.P.B. McGovern), Crohn’s and Colitis Foundation of America (to N.H. Salzman, T.S. Stappenbeck, R.J. Xavier, and C. Huttenhower), and Doris Duke Charitable Foundation grant 2014103 (to T.C. Liu).

It is important to determine the effects of immunomodulators on the ability of children to remain on infliximab therapy for Crohn's disease (durability of therapy), given the potential benefits and risks of concomitant therapy-especially with thiopurines in male patients. We investigated how immunomodulatory treatment affects the durability of infliximab therapy.We collected data from the Pediatric Inflammatory Bowel Disease Collaborative Research Group Registry, from January 2002 through August 2014, on 502 children with Crohn's disease who participated in a prospective multicenter study. Data were collected from patients who received at least a 3-dose induction regimen of infliximab, and their concomitant use of immunomodulators: no thiopurine or methotrexate treatment, treatment for 6 months or less during infliximab therapy, or treatment for more than 6 months during infliximab therapy.The probabilities (± standard error) that children remained on infliximab therapy for 1 year, 3 years, and 5 years after the treatment began were 0.84 ± 0.02, 0.69 ± 0.03, and 0.60 ± 0.03, respectively. Age, sex, and disease extent or location did not affect the durability of infliximab therapy. Greater length of concomitant use of immunomodulators was associated with increased time of infliximab therapy. The probability that patients with more than 6 months of immunomodulator use remained on infliximab therapy for 5 years was 0.70 ± 0.04, compared with 0.48 ± 0.08 for patients who did not receive immunomodulators and 0.55 ± 0.06 for patients who received immunomodulators for 6 months or less (P.001). In boys who received immunomodulators for 6 months or more after starting infliximab, the overall durability of infliximab therapy was greater among patients receiving methotrexate than thiopurine (P.01); the probabilities that they remained on infliximab therapy for 5 years were 0.97 ± 0.03 vs 0.58 ± 0.08, respectively.In children with Crohn's disease, concomitant treatment with an immunomodulator for more than 6 months after starting infliximab therapy increases the chances that patients will remain on infliximab. In boys, methotrexate appears to increase the durability of infliximab therapy compared with thiopurine.

Background Multiple Sclerosisismore common inwomenthanmenandfemales have morerelapsesthanmen. Inalargeinternationalcohortwehave evaluatedthe effectofgenderondisabilityaccumulationanddiseaseprogressiontodetermineifmale MSpatientshaveaworse clini-caloutcome thanfemales. Methods Usingthe MSBase Registry, data from15,826MSpatients from 25countrieswasanalysed.Changesin theseverityofMS(EDSS)were comparedbetweensexesusingarepeatedmeasuresanalysisin generalisedlinearmixed models.Kaplan-Meier analysis wasusedto PLOSONE|DOI:10.1371/journal.pone.0122686 June5,2015 1/11OPENACCESSCitation:RibbonsKA,McElduffP,BozC,TrojanoM,IzquierdoG,DuquetteP,etal.(2015)MaleSexIsIndependentlyAssociatedwithFasterDisabilityAccumulationinRelapse-OnsetMSbutNotinPrimaryProgressiveMS.PLoSONE10(6):e0122686.doi:10.1371/journal.pone.0122686AcademicEditor:OrhanAktas,UniversityofDusseldorf,GERMANYReceived:August26,2014Accepted:February26,2015Published:June5,2015Copyright:©2015Ribbonsetal.ThisisanopenaccessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense,whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalauthorandsourcearecredited.DataAvailabilityStatement:Allrelevantdataareavailablefromco-authorsuponrequest.Contactinformationforeachco-authorisinSupportingInformation.Funding:MerckSeronosupportsiMEDwhichisthesoftwareprogramusedbyMSBASEfordataacquisitionateachcollaboratingcentreanddoesnotimpactonthestudiesderivedfromdatacollectedbythisprogram.Thefundershadnoroleinstudydesign,datacollectionandanalysis,decisiontopublish,orpreparationofthemanuscript.

BACKGROUND Methotrexate (MTX) use as an alternative to thiopurines in the treatment of Crohn's disease (CD) in children is increasing. This study was undertaken to assess safety and efficacy of MTX in children with CD. METHODS Patients treated with MTX with a minimum of 1-year follow-up were identified in the Pediatric IBD Collaborative Research Group Registry, a prospective inception cohort study started in 2002. The clinical efficacy and safety of MTX were analyzed retrospectively. RESULTS Two hundred ninety patients treated with MTX were identified. One hundred seventy-two patients received at least 3 months of MTX without thiopurine or biologicals and had ≥1 year of follow-up. Eighty-one of 172 patients (47%) received MTX as first immunomodulator (IMM), of which 22 (27%) achieved ≥12 months of sustained clinical remission without surgery, thiopurine, biologicals, or corticosteroids. Those receiving MTX as second IMM achieved similar remission rate (35%, P = not significant). Fourteen percent received MTX as first IMM in 2002 and 60% in 2010 (P = 0.005). Disease location did not affect outcomes. MTX doses were equivalent in both groups. Fifteen percent of patients developed an alanine aminotransferase >60 international units/liter and 12% developed a white blood cell

Inflammatory bowel disease-associated liver diseases (IBD-LDs) include autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC), and an overlap syndrome. Prospective unbiased multicenter data regarding the frequency of IBD-LD in patients with pediatric inflammatory bowel disease (IBD) are lacking. We examined early alanine aminotransferase (ALT) and γ-glutamyl transpeptidase (GGT) elevations in children diagnosed as having IBD and assessed the likelihood of IBD-LD.Data collected from the prospective observational Pediatric Inflammatory Bowel Disease Collaborative Research Group Registry enrolling children of age16 years within 30 days of diagnosis. AIH, PSC, and overlap syndrome were diagnosed using local institutional criteria.A total of 1569 subjects had liver enzymes available. Of the total, 757 had both ALT and GGT, 800 had ALT only (no GGT), and 12 had GGT only (no ALT). Overall, 29 of 1569 patients (1.8%) had IBD-LD. IBD-LD was diagnosed in 1 of 661 (0.15%) of patients with both ALT and GGT ≤ 50 IU/L compared with 21 of 42 (50%) of patients with both ALT and GGT 50 (odds ratio 660, P 0.0001). Of the 29 patients with IBD-LD, 21 had PSC, 2 had AIH, and 6 had overlap syndrome. IBD-LD was more common in patients with ulcerative colitis and IBD-unclassified (indeterminate colitis) than in those with Crohn disease (4% vs 0.8%, respectively, P 0.001).Elevation of both ALT and GGT within 90 days after the diagnosis of IBD is associated with a markedly increased likelihood of IBD-LD. Both ALT and GGT levels should be measured in all of the pediatric patients newly diagnosed as having IBD.

To identify and develop novel targeted therapies for complex diseases such as Crohn's disease (CD), functional subtypes rooted in pathogenesis must be defined. One candidate method to subtype CD is to define the small intestinal Paneth cell phenotypes based on the intracellular distribution of antimicrobial proteins. We have previously shown that in CD patients, Paneth cell phenotype correlates with the patients' genotype, distinct gene expression signature, presence of granuloma (pathologic hallmark), and time to recurrence after surgery. However, the mechanism by which abnormal Paneth cells contribute to pathogenesis and sub-classify disease in the context of host-microbial interaction is unclear. We analyzed Paneth cell phenotype and its correlation with mucosal microbiome and transcriptome in a cohort of pediatric CD and non-inflammatory bowel disease (IBD) patients.We first retrospectively analyzed Paneth cell phenotypes using archived resection specimens from adult (n = 531) and pediatric (n = 73) CD patients. We next analyzed a prospectively recruited pediatric cohort, including CD (n = 44) and non-IBD (n = 62) patients aged 4 to 18. These patients were recruited at the time of routine endoscopy. Ileal mucosal biopsy samples were collected and analyzed for Paneth cell phenotype (lysozyme/defensin 5 immunofluorescence), mucosal microbiome (16S rRNA sequencing), and transcriptome (RNA-sequencing). Paneth cell phenotype was determined by the percentage of normal Paneth cells in each sample. Type I Paneth cell phenotype was defined as

Objective To evaluate the presentation, therapeutic management, and long-term outcome of children with very early-onset (VEO) (≤5 years of age) inflammatory bowel disease (IBD). Study design Data were obtained from an inception cohort of 1928 children with IBD enrolled in a prospective observational registry at multiple centers in North America. Results One hundred twelve children were ≤5 years of age with no child enrolled at P = .04), and 11- to 16-year-olds (22.3%, P P = .01). Five years postdiagnosis, there was no difference in disease activity among the 3 groups. However, compared with the oldest group, a greater proportion of 1- to 5-year-olds with CD were receiving corticosteroids ( P P P P Conclusions Children with VEO-CD are more likely to have mild disease at diagnosis and present with a colonic phenotype with change to an ileocolonic phenotype noted at 6-10 years of age. Five years after diagnosis, children with VEO-CD and VEO-UC are more likely to have been administered corticosteroids and immunomodulators despite similar disease activity in all age groups. This may suggest development of a more aggressive disease phenotype over time.

Inhalant misuse is the intentional inhalation of volatile substances in order to obtain euphoric, disinhibiting, and exciting effects. Solvents, glues, adhesives, paints, varnishes, paint removers, dry cleaning agents, spray paints, nail polish removers, typewriter correction fluids, and aerosol propellants are common sources of volatile substance abuse. In recent years the abuse of inhalant substances, not only among those who abuse other drugs but also in teenagers and younger children, has been reported. We reviewed retrospectively the cases of inhalant misuse reported to the Spanish Poison Control Center.Human intoxications from abuse of inhalant substances registered by our service from 1991 to 2000 were studied. Data analyzed were relative to age, gender, signs and symptoms, drug dependence antecedents, and severity of symptoms of the patients. The type of product and composition were also investigated.During the study period 109 cases of patients aged from 8 to 50 years were collected. A percentage of 36.6% was less or equal to 20 years old. Seventy percent corresponded to males. Of the patients, 11% presented dependence antecedents to other abuse drugs and 72.5% were symptomatic. In the symptomatic exposures clinical features affected the following systems: CNS (62.8%), gastrointestinal (8.1%), cardiovascular (8.1%), respiratory (2.9%), peripheral nervous system (1.1%), renal (1.1%), haematological (1.1%), hepatic (1.7%), and other (13.1%). The commercial products more frequently inhaled were solvents (34.9%) and glues/adhesives (22.9%). We noted the use of medicines with ethyl chloride-local anaesthetic (8.3%), three cases with aerosol bronchodilator (with fluorocarbons as propellants), and one case of xylazine inhalation. The composition most often involved was aromatic hydrocarbons (46.9%), halogenated hydrocarbons (16.5%), aliphatic hydrocarbons (11.4%), ketones (10.1%), local anaesthetic (ethyl chloride) (8.4%), ethers (2.5%), nitrous oxides (2.5%), and aliphatic nitrites (1.7%). The calls received were 59.6% from health care units and 22% from general public. Only 14% of cases were at home and 48% had moderate to severe clinical effects. Acute intoxications occurred in 82% of cases.Inhalation of volatile substance as abuse drugs has been detected in different age groups, including very young people. Although the principal source was industrial products, the use of drugs such as local anaesthetics and aerosol broncodilators was also detected. Based on epidemiological studies in the Spanish population (essentially adolescents and childhood) together with the ability of a Poison Center to detect sentinel-events, the community and authorities should develop strategies to prevent these exposures and the later use of other substances of abuse. In fact, recently a Law on Drug Dependences and Other Addictive Alterations has been approved in Madrid in order to take precautionary measures.