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Inflammatory bowel disease (IBD) is a chronic immune-mediated inflammation of the gastrointestinal tract with a highly heterogeneous presentation. It has a relapsing and remitting clinical course that necessitates lifelong monitoring and treatment. Although the availability of a variety of effective therapeutic options including immunomodulators and biologics (such as TNF, CAM inhibitors) has led to a paradigm shift in the treatment outcomes and clinical management of IBD patients, some patients still either fail to respond or lose their responsiveness to therapy over time. Therefore, according to the recent Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE-II) recommendations, continuous disease monitoring from symptomatic relief to endoscopic healing along with short- and long-term therapeutic responses are critical for providing IBD patients with a tailored therapy algorithm. Moreover, considering the high unmet need for novel therapeutic approaches for IBD patients, various new modulators of cytokine signaling events (for example, JAK/TYK inhibitors), inhibitors of cytokines (for example IL-12/IL-23, IL-22, IL-36, and IL-6 inhibitors), anti-adhesion and migration strategies (for example, β7 integrin, sphingosine 1-phosphate receptors, and stem cells), as well as microbial-based therapeutics to decolonize the bed buds (for example, fecal microbiota transplantation and bacterial inhibitors) are currently being evaluated in different phases of controlled clinical trials. This review aims to offer a comprehensive overview of available treatment options and emerging therapeutic approaches for IBD patients. Furthermore, predictive biomarkers for monitoring the therapeutic response to different IBD therapies are also discussed.

The aim of this study was to utilise corneal confocal microscopy to quantify corneal nerve morphology and establish the presence of sub-clinical small fibre damage and peripheral neuropathy in children with celiac disease. This is a cross-sectional cohort study of twenty children with celiac disease and 20 healthy controls who underwent clinical and laboratory assessments and corneal confocal microscopy. Corneal nerve fiber density (no.mm.sup.2 ), corneal nerve branch density (no.mm.sup.2 ), corneal nerve fiber length (mm.mm.sup.2 ), corneal nerve fiber tortuosity and inferior whorl length (mm.mm.sup.2) were quantified manually. Corneal nerve fiber density (34.7±8.6 vs. 32.9±8.6; P = 0.5), corneal nerve branch density (47.2±24.5 vs. 47.3±20.0; P = 0.1) and corneal nerve fiber length (20.0±5.1 vs. 19.5±4.5; P = 0.8) did not differ between children with celiac disease and healthy controls. Corneal nerve fiber tortuosity (11.4±1.9 vs 13.5±3.0; P = 0.01) was significantly lower and inferior whorl length (20.0±5.5 vs 23.0±3.8; P = 0.06) showed a non-significant reduction in children with celiac disease compared to healthy controls. Inferior whorl length correlated significantly with corneal nerve fiber density (P = 0.005), corneal nerve branch density (P = 0.04), and corneal nerve fiber length (P = 0.002). Corneal confocal microscopy demonstrates minimal evidence of neuropathy in children with celiac disease.

Purpose Although genetic predisposition and exposure to dietary gluten are considered necessary triggers for the development of coeliac disease, alterations in the gut microbial composition may also contribute towards the pathogenesis of coeliac disease. This review aims to provide an overview of the available data on the potential mechanisms through which the gut microbiota plays a role in the causation of coeliac disease and to discuss the potential therapeutic strategies that could diminish the consequences of microbial dysbiosis. Method A search of the literature was performed using the PubMed, Embase, and JSTOR databases; relevant articles were included. Results Recent studies in patients with coeliac disease have reported an increase in the relative amounts of gram negative bacterial genera such as Bacteroides , Prevotella , and Escherichia , and reduced amounts of protective anti-inflammatory bacteria such as Bifidobacteria and Lactobacilli . Dysbiotic microbiota may lead to a dysregulated immune response that may contribute to the pathogenesis of coeliac disease. In infancy, antibiotic use and certain infant feeding practices may lead to alterations in the developing gut microbiota to influence the immune maturation process and predispose to coeliac disease. Conclusion The induction of the intestinal immune system and gluten intolerance may be influenced by the relative abundance of certain microbiota. Factors such as infant feeding practices, diet, antibiotics, and infections, may be involved in the development of coeliac disease due to their influence on gut microbial composition. The efficacy of potential modulators of the gut microbiota such as probiotics, prebiotics, and fecal microbial transplant as adjunctive treatments to gluten-free diet in coeliac disease is unproven and requires further investigation.

Celiac disease (CeD) is a common small bowel enteropathy characterized by an altered adaptive immune system and increased mucosal antigen presenting cells. This study aims to establish if quantification of corneal Langerhans cells (LCs) using corneal confocal microscopy (CCM) could act as a surrogate marker for antigen presenting cell status and hence disease activity in children with CeD. Twenty children with stable CeD and 20 age-matched controls underwent CCM and quantification of central corneal total, mature and immature LC density. There was no difference in age (11.78 ± 1.7 vs. 12.83 ± 1.91; P  = 0.077) or height (1.38 ± 0.14 vs. 1.44 ± 0.13; P  = 0.125). BMI (18.81 ± 3.90 vs. 22.26 ± 5.47; P  = 0.031) and 25 OHD levels (43.50 ± 13.36 vs. 59.77 ± 22.45; P  = 0.014) were significantly lower in children with CeD compared to controls. The total (33.33(16.67–59.37) vs. 51.56(30.21–85.42); P  = 0.343), immature (33.33(16.67–52.08) vs. 44.79(29.17–82.29); P  = 0.752) and mature (1.56(0–5) vs. 1.56(1.04–8.33); P  = 0.752) LC density did not differ between the CeD and control groups. However, immature (r = 0.535, P  = 0.015), mature (r = 0.464, P  = 0.039), and total (r = 0.548, P  = 0.012) LC density correlated with age. Immature (r = 0.602, P  = 0.038) and total (r = 0.637, P  = 0.026) LC density also correlated with tissue transglutaminase antibody (Anti-TtG) levels assessed in 12/20 subjects with CeD. There was no difference in corneal LC density between children with CeD and controls. However, the correlation between corneal LC density and anti-TtG levels suggests a relationship with disease activity in CeD and requires further study.

ImportanceChildren with neurodevelopmental disorders have a higher prevalence of sleep disturbances. Currently there is variation in the use of melatonin; hence, an up-to-date systematic review is indicated to summarise the current available evidence.ObjectiveTo determine the efficacy and safety of melatonin as therapy for sleep problems in children with neurodevelopmental disorders.Data sources and study selectionsPubMed, Embase, the Cumulative Index to Nursing and Allied Health Literature and the Cochrane Central Register of Controlled Trials were searched from inception up to January 2018. Two reviewers performed data assessment and extraction. We assessed randomised controlled trials that compared melatonin with placebo or other intervention for the management of sleep disorders in children (<18 years) with neurodevelopmental disorders.Data extraction and synthesisWe identified 3262 citations and included 13 studies in this meta-analysis.Main outcomesMain outcomes included total sleep time, sleep onset latency, frequency of nocturnal awakenings and adverse events.ResultsThirteen randomised controlled trials (n=682) met the inclusion criteria. A meta-analysis of nine studies (n=541) showed that melatonin significantly improved total sleep time compared with placebo (mean difference (MD)=48.26 min, 95% CI 36.78 to 59.73, I2=31%). In 11 studies (n=581), sleep onset latency improved significantly with melatonin use (MD=−28.97, 95% CI −39.78 to −18.17). No difference was noted in the frequency of nocturnal awakenings (MD=−0.49, 95% CI −1.71 to 0.73). No medication-related serious adverse event was reported.ConclusionMelatonin appeared safe and effective in improving sleep in the studied children. The overall quality of the evidence is limited due to heterogeneity and inconsistency. Further research is needed.

Aims/Introduction Corneal confocal microscopy is a rapid, non‐invasive ophthalmic technique to identify subclinical neuropathy. The aim of this study was to quantify corneal nerve morphology in children with type 1 diabetes mellitus compared with age‐matched healthy controls using corneal confocal microscopy. Materials and Methods A total of 20 participants with type 1 diabetes mellitus (age 14 ± 2 years, diabetes duration 4.08 ± 2.91 years, glycated hemoglobin 9.3 ± 2.1%) without retinopathy or microalbuminuria and 20 healthy controls were recruited from outpatient clinics. Corneal confocal microscopy was undertaken, and corneal nerve fiber density (n/mm2), corneal nerve branch density (n/mm2), corneal nerve fiber length (mm/mm2), corneal nerve fiber tortuosity and inferior whorl length (mm/mm2) were quantified manually. Results Corneal nerve fiber density (22.73 ± 8.84 vs 32.92 ± 8.59; P < 0.001), corneal nerve branch density (26.19 ± 14.64 vs 47.34 ± 20.01; P < 0.001), corneal nerve fiber length (13.26 ± 4.06 vs 19.52 ± 4.54; P < 0.001) and inferior whorl length (15.50 ± 5.48 vs 23.42 ± 3.94; P < 0.0001) were significantly lower, whereas corneal nerve fiber tortuosity (14.88 ± 5.28 vs 13.52 ± 3.01; P = 0.323) did not differ between children with type 1 diabetes mellitus and controls. Glycated hemoglobin correlated with corneal nerve fiber tortuosity (P < 0.006) and aspartate aminotransferase correlated with corneal nerve fiber density (P = 0.039), corneal nerve branch density (P = 0.003) and corneal nerve fiber length (P = 0.037). Conclusion Corneal confocal microscopy identifies significant subclinical corneal nerve loss, especially in the inferior whorl of children with type 1 diabetes mellitus without retinopathy or microalbuminuria. This is the first study showing significant corneal nerve loss in the central cornea and inferior whorl, indicative of early subclinical neuropathy in children with type 1 diabetes mellitus without microalbuminuria or retinopathy.

Vitamin D inadequacy appears to be on the rise globally, and it has been linked to an increased risk of osteoporosis, as well as metabolic, cardiovascular, and autoimmune diseases. Vitamin D concentrations are partially determined by genetic factors. Specific single nucleotide polymorphisms (SNPs) in genes involved in vitamin D transport, metabolism, or binding have been found to be associated with its serum concentration, and these SNPs differ among ethnicities. Vitamin D has also been suggested to be a regulator of the gut microbiota and vitamin D deficiency as the possible cause of gut microbial dysbiosis and inflammation. This pilot study aims to fill the gap in our understanding of the prevalence, cause, and implications of vitamin D inadequacy in a pediatric population residing in Qatar. Blood and fecal samples were collected from healthy subjects aged 4–14 years. Blood was used to measure serum metabolite of vitamin D, 25-hydroxycholecalciferol 25(OH)D. To evaluate the composition of the gut microbiota, fecal samples were subjected to 16S rRNA gene sequencing. High levels of vitamin D deficiency/insufficiency were observed in our cohort with 97% of the subjects falling into the inadequate category (with serum 25(OH)D < 75 nmol/L). The CT genotype in rs12512631, an SNP in the GC gene, was associated with low serum levels of vitamin D (ANOVA, p = 0.0356) and was abundant in deficient compared to non-deficient subjects. Overall gut microbial community structure was significantly different between the deficient (D) and non-deficient (ND) groups (Bray Curtis dissimilarity p = 0.049), with deficient subjects also displaying reduced gut microbial diversity. Significant differences were observed among the two major gut phyla, Firmicutes (F) and Bacteroidetes (B), where deficient subjects displayed a higher B/F ratio (p = 0.0097) compared to ND. Vitamin D deficient children also demonstrated gut enterotypes dominated by the genus Prevotella as opposed to Bacteroides. Our findings suggest that pediatric vitamin D inadequacy significantly impacts the gut microbiota. We also highlight the importance of considering host genetics and baseline gut microbiome composition in interpreting the clinical outcomes related to vitamin D deficiency as well as designing better personalized strategies for therapeutic interventions.

ObjectivesTo summarise the published evidence on the gastrointestinal manifestations of COVID-19 in children and to determine the prevalence of gastrointestinal symptoms.MethodsIn this systematic review and meta-analysis, we searched PubMed, Embase, CINAHL and the WHO’s database of publications on novel coronavirus. We included English language studies that had described original demographic and clinical characteristics of children diagnosed with COVID-19 and reported on the presence or absence of gastrointestinal symptoms. Meta-analysis was conducted using the random-effects model. The pooled prevalence of gastrointestinal symptoms was expressed as proportion and 95% CI.ResultsThe search identified 269 citations. Thirteen studies (nine case series and four case reports) comprising data for 284 patients were included. Overall, we rated four studies as having a low risk of bias, eight studies as moderate and one study as high risk of bias. In a meta-analysis of nine studies, comprising 280 patients, the pooled prevalence of all gastrointestinal symptoms was 22.8% (95% CI 13.1% to 35.2%; I2=54%). Diarrhoea was the most commonly reported gastrointestinal symptom followed by vomiting and abdominal pain.ConclusionsNearly a quarter of children with COVID-19 have gastrointestinal symptoms. It is important for clinicians to be aware of the gastrointestinal manifestation of COVID-19.PROSPERO registration numberCRD42020177569.

Coeliac disease (CD) and Type 1 diabetes mellitus (T1DM) are immune-mediated diseases. Emerging evidence suggests that dysbiosis in the gut microbiome plays a role in the pathogenesis of both diseases and may also be associated with the development of neuropathy. The primary goal in this cross-sectional pilot study was to identify whether there are distinct gut microbiota alterations in children with CD (n = 19), T1DM (n = 18) and both CD and T1DM (n = 9) compared to healthy controls (n = 12). Our second goal was to explore the relationship between neuropathy (corneal nerve fiber damage) and the gut microbiome composition. Microbiota composition was determined by 16S rRNA gene sequencing. Corneal confocal microscopy was used to determine nerve fiber damage. There was a significant difference in the overall microbial diversity between the four groups with healthy controls having a greater microbial diversity as compared to the patients. The abundance of pathogenic proteobacteria Shigella and E. coli were significantly higher in CD patients. Differential abundance analysis showed that several bacterial amplicon sequence variants (ASVs) distinguished CD from T1DM. The tissue transglutaminase antibody correlated significantly with a decrease in gut microbial diversity. Furthermore, the Bacteroidetes phylum, specifically the genus Parabacteroides was significantly correlated with corneal nerve fiber loss in the subjects with neuropathic damage belonging to the diseased groups. We conclude that disease-specific gut microbial features traceable down to the ASV level distinguish children with CD from T1DM and specific gut microbial signatures may be associated with small fiber neuropathy. Further research on the mechanisms linking altered microbial diversity with neuropathy are warranted.

ImportanceProlonged seizures are life-threatening emergencies associated with significant morbidity.ObjectiveTo determine the efficacy and safety of levetiracetam in treating convulsive status epilepticus (CSE) in childhood.Data sources and study selectionsPubMed, Embase, the Cochrane Central Register of Controlled Trials and Cumulative Index to Nursing and Allied Health Literature were searched from inception up to April 2020. Only randomised controlled trials (RCTs) that included children aged 1 month–18 years were assessed. Two reviewers performed data assessment and extraction.Data extraction and synthesisTen studies out of the 20 637 citations identified were included.Main outcomesCessation of seizure activities, time to cessation of seizure activities, need for rapid sequence intubation (RSI), intensive care unit (ICU) admission, recurrence of seizures at 24 hours, adverse events and all-cause mortality.ResultsWe included 10 RCTs (n=1907). There was no significant difference in cessation of seizure activities when levetiracetam was compared with phenytoin (risk ratio (RR)=1.03, 95% CI 0.98 to 1.09), levetiracetam to fosphenytoin (RR=1.16, 95% CI 1.00 to 1.35) or levetiracetam to valproate (RR=1.10, 95% CI 0.94 to 1.27). No differences were found in relation to the timing of cessation of seizures for levetiracetam versus phenytoin (mean difference (MD)=−0.45, 95% CI −1.83 to 0.93), or levetiracetam versus fosphenytoin (MD=−0.70, 95% CI −4.26 to 2.86). There were no significant differences with regard to ICU admissions, adverse events, recurrence of seizure at 24 hours, RSI and all-cause mortality.ConclusionLevetiracetam is comparable to phenytoin, fosphenytoin and valproate as a second line treatment of paediatric CSE.