Macrophage-Stimulating 1 Polymorphism rs3197999 in Pediatric Patients with Inflammatory Bowel Disease.

Background and Objectives: Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), often necessitates long-term treatment and hospitalizations and also may require surgery. The macrophage-stimulating 1 (MST1) rs3197999 polymorphism is strongly associated with the risk of IBD but its exact clinical correlates remain under investigation. We aimed to characterize the relationships between the MST1 rs3197999 genotype and the clinical characteristics in children and adolescents with IBD within a multi-center cross-sectional study. Materials and Methods: Clinical data included serum C-reactive protein (CRP), albumin, activity indices (PUCAI, PCDAI), anthropometric data, pharmacotherapy details, surgery, and disease severity. Genotyping for rs3197999 was carried out using TaqMan hydrolysis probes. Results: The study included 367 pediatric patients, 197 with Crohn's disease (CD) (40.6% female; a median age of 15.2 years [interquartile range 13.2-17.0]) and 170 with ulcerative colitis (UC) (45.8% female; a median age of 15.1 years [11.6-16.8]). No significant relationships were found between MST1 genotypes and age upon first biologic use, time from diagnosis to biological therapy introduction, PUCAI, PCDAI, or hospitalizations for IBD flares. However, in IBD, the height Z-score at the worst flare was negatively associated with the CC genotype (p = 0.016; CC: -0.4 [-1.2-0.4], CT: -0.1 [-0.7-0.8], TT: 0.0 [-1.2-0.7)]). The TT genotype was associated with higher C-reactive protein upon diagnosis (p = 0.023; CC: 4.3 mg/dL [0.7-21.8], CT 5.3 mg/dL [1.3-17.9], TT 12.2 mg/dL [3.0-32.9]). Conclusions: This study identified links between MST1 rs3197999 and the clinical characteristics of pediatric IBD: height Z-score and CRP. Further studies of the associations between genetics and the course of IBD are still warranted, with a focus on more extensive phenotyping.

Current and emerging biomarkers for ulcerative colitis.

INTRODUCTION: Ulcerative colitis (UC) is a chronic illness requiring lifelong management that could be enhanced by personalizing care using biomarkers. AREAS COVERED: The main biomarker discovery modalities are reviewed, highlighting recent results across the spectrum of applications, including diagnostics (serum anti-αvß6 antibodies achieving an area under the curve [AUC] = 0.99; serum oncostatin M AUC = 0.94), disease activity assessment (fecal calprotectin and serum trefoil factor 3: AUC > 0.90), prognostication of the need for treatment escalation (whole blood transcriptomic panels and CLEC5A/CDH2 ratio: AUC > 0.90), prediction of treatment response, and early identification of patients with subclinical disease. The use of established biomarkers is discussed, along with new evidence regarding autoantibodies, proteins, proteomic panels, transcriptomic signatures, deoxyribonucleic acid methylation patterns, and UC-specific glycomic and metabolic disturbances. EXPERT OPINION: Novel biomarkers will pave the way for optimized UC care. However, validation, simplification, and direct clinical translation of complex models may prove challenging. Currently, few candidates exist to assess key characteristics, such as UC susceptibility, histological disease activity, drug response, and long-term disease behavior. Further research will likely not only reveal new tools to tackle these issues but also contribute to understanding UC pathogenesis mechanisms.

Defining Interactions Between the Genome, Epigenome, and the Environment in Inflammatory Bowel Disease: Progress and Prospects.

Recent advances in our understanding of the pathogenesis of inflammatory bowel disease (IBD) have highlighted the complex interplay between the genome, the epigenome, and the environment. Despite the exciting advances in genomics that have enabled the identification of over 200 susceptibility loci, these only account for a small proportion of the disease variance and the estimated heritability in IBD. It is likely that gene-environment (GxE) interactions contribute to "missing heritability" and these may act through epigenetic mechanisms. Several environmental factors, such as the microbiome, nutrition, and tobacco smoking, induce alterations in the epigenome of children and adults, which may impact disease susceptibility. Other mechanisms for GxE interactions are also directly pertinent in early life. We discuss a model in which environmental factors imprint disease risk in a window of susceptibility during infancy that may contribute to later disease onset, whereas other elements of the exposome act later in life and contribute directly to the pathogenesis and course of the disease. Understanding the mechanisms underlying GxE interactions may provide the basis for new therapeutic targets or preventative strategies for IBD.

Analysis of Systemic Epigenetic Alterations in Inflammatory Bowel Disease: Defining Geographical, Genetic and Immune-Inflammatory influences on the Circulating Methylome.

BACKGROUND: Epigenetic alterations may provide valuable insights into gene-environment interactions in the pathogenesis of inflammatory bowel disease [IBD]. METHODS: Genome-wide methylation was measured from peripheral blood using the Illumina 450k platform in a case-control study in an inception cohort (295 controls, 154 Crohn's disease [CD], 161 ulcerative colitis [UC], 28 IBD unclassified [IBD-U)] with covariates of age, sex and cell counts, deconvoluted by the Houseman method. Genotyping was performed using Illumina HumanOmniExpressExome-8 BeadChips and gene expression using the Ion AmpliSeq Human Gene Expression Core Panel. Treatment escalation was characterized by the need for biological agents or surgery after initial disease remission. RESULTS: A total of 137 differentially methylated positions [DMPs] were identified in IBD, including VMP1/MIR21 [p = 9.11 × 10-15] and RPS6KA2 [6.43 × 10-13], with consistency seen across Scandinavia and the UK. Dysregulated loci demonstrate strong genetic influence, notably VMP1 [p = 1.53 × 10-15]. Age acceleration is seen in IBD [coefficient 0.94, p < 2.2 × 10-16]. Several immuno-active genes demonstrated highly significant correlations between methylation and gene expression in IBD, in particular OSM: IBD r = -0.32, p = 3.64 × 10-7 vs non-IBD r = -0.14, p = 0.77]. Multi-omic integration of the methylome, genome and transcriptome also implicated specific pathways that associate with immune activation, response and regulation at disease inception. At follow-up, a signature of three DMPs [TAP1, TESPA1, RPTOR] were associated with treatment escalation to biological agents or surgery (hazard ratio of 5.19 [CI: 2.14-12.56], logrank p = 9.70 × 10-4). CONCLUSION: These data demonstrate consistent epigenetic alterations at diagnosis in European patients with IBD, providing insights into the pathogenetic importance and translational potential of epigenetic mapping in complex disease.

Unexpected Actors in Inflammatory Bowel Disease Revealed by Machine Learning from Whole-Blood Transcriptomic Data.

Although big data from transcriptomic analyses have helped transform our understanding of inflammatory bowel disease (IBD), they remain underexploited. We hypothesized that the application of machine learning using lasso regression to transcriptomic data from IBD patients and controls can help identify previously overlooked genes. Transcriptomic data provided by Ostrowski et al. (ENA PRJEB28822) were subjected to a two-stage process of feature selection to discriminate between IBD and controls. First, a principal component analysis was used for dimensionality reduction. Second, the least absolute shrinkage and selection operator (lasso) regression was employed to identify genes potentially involved in the pathobiology of IBD. The study included data from 294 participants: 100 with ulcerative colitis (48 adults and 52 children), 99 with Crohn's disease (45 adults and 54 children), and 95 controls (46 adults and 49 children). IBD patients presented a wide range of disease severity. Lasso regression preceded by principal component analysis successfully selected interesting features in the IBD transcriptomic data and yielded 12 models. The models achieved high discriminatory value (range of the area under the receiver operating characteristic curve 0.61-0.95) and identified over 100 genes as potentially associated with IBD. PURA, GALNT14, and FCGR1A were the most consistently selected, highlighting the role of the cell cycle, glycosylation, and immunoglobulin binding. Several known IBD-related genes were among the results. The results included genes involved in the TGF-beta pathway, expressed in NK cells, and they were enriched in ontology terms related to immunity. Future IBD research should emphasize the TGF-beta pathway, immunoglobulins, NK cells, and the role of glycosylation.

Differential correlation network analysis of rectal transcriptomes reveals cystic fibrosis-related disturbance.

Background: Intestinal pathology in cystic fibrosis (CF) remains mechanistically underexplored. Aim: We hypothesized that differential correlation network analysis of expression data would reveal hub genes of CF-related disturbance in the large bowel. Materials & methods: Transcriptomes of 29 rectal tissue samples were accessed at ArrayExpress (E-GEOD-15568 by Stanke et al.). Results: We identified 279 transcript pairs differentially correlating in CF and controls, including: ESRRA and RPL18 (rCF = 0.55; rcontrols = -0.68; padj = 1.60 × 10-100), SRP14 and FAU (rCF = -0.69; rcontrols = 0.48; padj = 2.99 × 10-90), SRP14 and GDI2 (rCF = -0.34; rcontrols = 0.60; padj = 1.05 × 10-78). The genes related to membrane protein targeting (q = 8.34 × 10-14) and one cluster was clearly linked to male infertility. Conclusion:FAU, SRP14 and GDI2 may be involved in a compensatory protein trafficking mechanism in CF rectum, highlighting their potential therapeutic value.

Characterisation of the Circulating Transcriptomic Landscape in Inflammatory Bowel Disease Provides Evidence for Dysregulation of Multiple Transcription Factors Including NFE2, SPI1, CEBPB, and IRF2.

AIM: To assess the pathobiological and translational importance of whole-blood transcriptomic analysis in inflammatory bowel disease [IBD]. METHODS: We analysed whole-blood expression profiles from paired-end sequencing in a discovery cohort of 590 Europeans recruited across six countries in the IBD Character initiative (newly diagnosed patients with Crohn's disease [CD; n = 156], ulcerative colitis [UC; n = 167], and controls [n = 267]), exploring differential expression [DESeq2], co-expression networks [WGCNA], and transcription factor involvement [EPEE, ChEA, DoRothEA]. Findings were validated by analysis of an independent replication cohort [99 CD, 100 UC, 95 controls]. In the discovery cohort, we also defined baseline expression correlates of future treatment escalation using cross-validated elastic-net and random forest modelling, along with a pragmatic ratio detection procedure. RESULTS: Disease-specific transcriptomes were defined in IBD [8697 transcripts], CD [7152], and UC [8521], with the most highly significant changes in single genes, including CD177 (log2-fold change [LFC] = 4.63, p = 4.05 × 10-118), MCEMP1 [LFC = 2.45, p = 7.37 × 10-109], and S100A12 [LFC = 2.31, p = 2.15 × 10-93]. Significantly over-represented pathways included IL-1 [p = 1.58 × 10-11], IL-4, and IL-13 [p = 8.96 × 10-9]. Highly concordant results were obtained using multiple regulatory activity inference tools applied to the discovery and replication cohorts. These analyses demonstrated central roles in IBD for the transcription factors NFE2, SPI1 [PU.1], CEBPB, and IRF2, all regulators of cytokine signalling, based on a consistent signal across cohorts and transcription factor ranking methods. A number of simple transcriptome-based models were associated with the need for treatment escalation, including the binary CLEC5A/CDH2 expression ratio in UC (hazard ratio = 23.4, 95% confidence interval [CI] 5.3-102.0). CONCLUSIONS: Transcriptomic analysis has allowed for a detailed characterisation of IBD pathobiology, with important potential translational implications.

The Relationship between Eosinophil Density in the Colonic Mucosa and Eosinophil Blood Count in Children: A Cross-Sectional Study.

Eosinophils are found in the mucosa of the healthy gastrointestinal tract, but they also often accompany gastrointestinal diseases. We hypothesized that a positive correlation exists between blood eosinophil count and colonic eosinophil mucosal density in children. Electronic health records regarding 181 colonoscopies, performed with biopsy in the years 2019-2022, were screened for information on blood and colonic eosinophil count, age, sex, diagnoses, weight, height, white blood cell (WBC) count, serum C-reactive protein (CRP), and total IgE concentration. The median age (IQR) of the 107 included children (109 colonoscopies) was 12.4 years (8.1-15.5); 32 presented with blood eosinophilia (29.3%). The median eosinophil density/high-power field in the colonic mucosa was 22.5 (9-31). We found a weak correlation between colonic mucosal eosinophil density and blood eosinophil count (r = 0.295, 95% CI 0.108-0.462, p = 0.0018). This association was more pronounced in patients with elevated CRP (r = 0.529, 95% CI 0.167-0.766, p = 0.0054) and older than 12.4 years (r = 0.448, 95% CI 0.197-0.644, p = 0.00068). Peripheral blood eosinophilia might hint at increased mucosal colonic eosinophil density, especially in older children and in the presence of systemic inflammation. However, it seems unlikely that blood and colonic eosinophilia are strongly linked in younger children. Studies in adults are warranted.

Serum bile acids in cystic fibrosis patients - glycodeoxycholic acid as a potential marker of liver disease.

BACKGROUND: Cystic fibrosis (CF) and CF-related liver disease can lead to disturbances in bile acid metabolism. AIM: This study determined serum bile acid concentrations in CF to define their usefulness in liver disease assessment. METHODS: Primary, secondary and conjugated bile acid levels were measured in three CF groups (25 patients each) exhibiting: liver cirrhosis, other liver disease, no liver disease, and in 25 healthy subjects (HS). RESULTS: Bile acid levels were higher in CF patients than in HS, except for glycodeoxycholic acid (GDCA). However, bile acid concentrations did not differ between patients with cirrhosis and other liver involvement. GDCA and deoxycholic acid (DCA) differentiated CF patients with non-cirrhotic liver disease from those without liver disease (GDCA-AUC: 0.924, 95%CI 0.822-1.000, p<0.001; DCA-AUC: 0.867, 95%CI: 0.731-1.000, p<0.001). Principal component analysis revealed that in CF liver disease was related to GDCA, GGTP activity, severe genotype and pancreatic insufficiency. CONCLUSIONS: A CF-specific bile acid profile was defined and shown to relate to liver disease. GDCA differentiates patients with non-cirrhotic liver involvement from those with no detectable liver disease. Hence, GDCA is a candidate for validation as a biomarker of non-cirrhotic progression of liver disease in CF.

Fat-Soluble Vitamin Supplementation Using Liposomes, Cyclodextrins, or Medium-Chain Triglycerides in Cystic Fibrosis: A Randomized Controlled Trial.

Fat-soluble vitamin deficiency remains a challenge in cystic fibrosis (CF), chronic pancreatitis, and biliary atresia. Liposomes and cyclodextrins can enhance their bioavailability, thus this multi-center randomized placebo-controlled trial compared three-month supplementation of fat-soluble vitamins in the form of liposomes or cyclodextrins to medium-chain triglycerides (MCT) in pancreatic-insufficient CF patients. The daily doses were as follows: 2000 IU of retinyl palmitate, 4000 IU of vitamin D3, 200 IU of RRR-α-tocopherol, and 200 µg of vitamin K2 as menaquinone-7, with vitamin E given in soybean oil instead of liposomes. All participants received 4 mg of ß-carotene and 1.07 mg of vitamin K1 to ensure compliance with the guidelines. The primary outcome was the change from the baseline of all-trans-retinol and 25-hydroxyvitamin D3 concentrations and the percentage of undercarboxylated osteocalcin. Out of 75 randomized patients (n = 28 liposomes, n = 22 cyclodextrins, and n = 25 MCT), 67 completed the trial (89%; n = 26 liposomes, n = 18 cyclodextrins, and n = 23 MCT) and had a median age of 22 years (IQR 19-28), body mass index of 20.6 kg/m2 [18.4-22.0], and forced expiratory volume in 1 s of 65% (44-84%). The liposomal formulation of vitamin A was associated with the improved evolution of serum all-trans-retinol compared to the control (median +1.7 ng/mL (IQR -44.3-86.1) vs. -38.8 ng/mL (-71.2-6.8), p = 0.028). Cyclodextrins enhanced the bioavailability of vitamin D3 (+9.0 ng/mL (1.0-17.0) vs. +3.0 ng/mL (-4.0-7.0), p = 0.012) and vitamin E (+4.34 µg/mL (0.33-6.52) vs. -0.34 µg/mL (-1.71-2.15), p = 0.010). Liposomes may augment the bioavailability of vitamin A and cyclodextrins may strengthen the supplementation of vitamins D3 and E relative to MCT in pancreatic-insufficient CF but further studies are required to assess liposomal vitamin E (German Clinical Trial Register number DRKS00014295, funded from EU and Norsa Pharma).

Reliability of Capillary Complete Blood Count in Children With Acute Gastroenteritis.

Background: To assess the reliability of complete blood count (CBC) in the capillary blood of children with acute gastroenteritis (AGE), with a focus on leukocytes. Methods: This was a retrospective cross-sectional study. Complete blood count was compared between the capillary and venous blood in children admitted to a pediatric gastroenterology department with primary diagnosis of AGE (ICD-10 A09, A08.0, A08.2). Capillary blood was obtained in the emergency room and venous blood was sampled in the ward shortly thereafter during peripheral intravenous line placement. Results: One hundred and forty children were included. The mean (±SD) age and weight of patients were 3.0 ± 2.9 years and 16 ± 9 kg; 26% had leukocytosis. The mean difference between obtaining results of capillary and venous blood tests was 2 ± 1 h. Area under the receiver operating characteristic curve (AUC) for the identification of leukocytosis using the capillary blood was 0.98 (95% CI 0.96-1.0). The sensitivity and specificity were 86 and 98%, respectively (accuracy 95%). The positive and negative predictive values were 94 and 95%, respectively. The intraclass correlation coefficient revealed high concordance between capillary and venous CBC measurements (leukocyte count 0.94, hemoglobin 0.88, erythrocyte count 0.77, hematocrit 0.79, platelet count 0.90). Matched pairs comparisons revealed marginally higher erythrocytes (difference of medians: 0.2 T/L), hemoglobin (0.3 g/dL), hematocrit (1.0%), and platelets (9 G/L) in the capillary blood. Conclusion: Capillary CBC is useful in detecting leukocytosis in children with AGE.

Expression profiling of ileal mucosa in asthma reveals upregulation of innate immunity and genes characteristic of Paneth and goblet cells.

BACKGROUND: The expression profiles of the intestinal mucosa have not been comprehensively investigated in asthma. We aimed to explore this in the Correlated Expression and Disease Association Research (CEDAR) patient cohort. METHODS: Differential expression analysis of ileal, transverse colon, and rectal biopsies were supplemented by a comparison of transcriptomes from platelets and leukocytes subsets, including CD4+, CD8+, CD14+, CD15+, and CD19+ cells. Asthma patients (n = 15) and controls (n = 15) had similar age (p = 0.967), body mass index (p = 0.870), similar numbers of females (80%) and smoking rates (13.3%). RESULTS: Significant differential expression was found in the ileum alone, and not in any other cell/tissue types. More genes were found to be overexpressed (1,150) than under-expressed (380). The most overexpressed genes included Fc Fragment of IgG Binding Protein (FCGBP, logFC = 3.01, pFDR = 0.015), Mucin 2 (MUC2, logFC = 2.78, pFDR = 0.015), and Alpha 1B Defensin (DEFA1B, logFC = 2.73, pFDR = 0.024). Gene ontology implicated the immune system, including interleukins 4 and 13, as well as antimicrobial peptides in this overexpression. There was concordance of gene over- (STAT1, XBP1) and underexpression (NELF, RARA) in asthma and Crohn's disease ileum when our results were compared to another dataset (p = 3.66 × 10-7). CONCLUSION: Ileal mucosa in asthma exhibits a specific transcriptomic profile, which includes the overexpression of innate immune genes, mostly characteristic of Paneth and goblet cells, in addition to other changes that may resemble Crohn's disease.

Duplication of the IL2RA locus causes excessive IL-2 signaling and may predispose to very early onset colitis.

Single genetic mutations predispose to very early onset inflammatory bowel disease (VEO-IBD). Here, we identify a de novo duplication of the 10p15.1 chromosomal region, including the IL2RA locus, in a 2-year-old girl with treatment-resistant pancolitis that was brought into remission by colectomy. Strikingly, after colectomy while the patient was in clinical remission and without medication, the peripheral blood CD4:CD8 ratio was constitutively high and CD25 expression was increased on circulating effector memory, Foxp3+, and Foxp3neg CD4+ T cells compared to healthy controls. This high CD25 expression increased IL-2 signaling, potentiating CD4+ T-cell-derived IFNγ secretion after T-cell receptor (TCR) stimulation. Restoring CD25 expression using the JAK1/3-inhibitor tofacitinib controlled TCR-induced IFNγ secretion in vitro. As diseased colonic tissue, but not the unaffected duodenum, contained mainly CD4+ T cells with a prominent IFNγ-signature, we hypothesize that local microbial stimulation may have initiated colonic disease. Overall, we identify that duplication of the IL2RA locus can associate with VEO-IBD and suggest that increased IL-2 signaling predisposes to colonic intestinal inflammation.

Volumetric Optical Imaging and Quantitative Analysis of Age-Related Changes in Anterior Human Vitreous.

Purpose: The purpose of this study was to characterize age-related changes in anterior human vitreous with 3-D swept source optical coherence tomography (SS-OCT) and evaluate associations with axial length (AL) and contrast sensitivity function (CSF). Methods: There were 49 phakic eyes in 49 patients (40.0 ± 19.3 years) had 3-D volumetric scanning of the lens and retrolental vitreous with SS-OCT at 1050 nm. OCT-derived indices of vitreous optical density (VOD), vitreous opacification ratio (VOR), and lens optical density (LOD) were correlated with AL and double-pass assessment of retinal point spread function (Objective Scatter Index [OSI]). CSF was measured using an adaptive-optics visual simulator (area under log-log contrast sensitivity function [AULCSF]). Results: Vitreous SS-OCT detected gel vitreous, liquefied lacunae, Berger's space, retrolental laminae, and fibrous opacifications. VOD, VOR, and LOD showed high reproducibility (intraclass correlation coefficients 0.968, 0.975, and 0.998, respectively). VOD was highly correlated with VOR (Pearson's R = 0.96, P < 0.000001). VOD, VOR, and LOD correlated with age (R = 0.48, 0.58, and 0.85, P < 0.001 for each). VOR and LOD correlated with OSI (R = 0.36, P = 0.0094, and R = 0.36, P = 0.0096, respectively). VOR correlated negatively with AULCSF (R = -0.53, P < 0.00009), which was related to OSI. Myopic eyes had higher OSI than nonmyopic eyes (P = 0.0121), consistent with correlation between OSI and AL (R = 0.37, P = 0.0091). Multivariable regression confirmed these findings. Conclusions: SS-OCT visualized microstructural features of anterior human vitreous, where opacification is associated with increased light scattering and CSF degradation. SS-OCT enables high-resolution optical evaluation of vitreous opacities.

Waiting in the wings: RUNX3 reveals hidden depths of immune regulation with potential implications for inflammatory bowel disease.

BACKGROUND: Complex interactions between the environment and the mucosal immune system underlie inflammatory bowel disease (IBD). The involved cytokine signalling pathways are modulated by a number of transcription factors, one of which is runt-related transcription factor 3 (RUNX3). OBJECTIVE: To systematically review the immune roles of RUNX3 in immune regulation, with a focus on the context of IBD. METHODS: Relevant articles and reviews were identified through a Scopus search in April 2020. Information was categorized by immune cell types, analysed and synthesized. IBD transcriptome data sets and FANTOM5 regulatory networks were processed in order to complement the literature review. RESULTS: The available evidence on the immune roles of RUNX3 allowed for its description in twelve cell types: intraepithelial lymphocyte, Th1, Th2, Th17, Treg, double-positive T, cytotoxic T, B, dendritic, innate lymphoid, natural killer and macrophages. In the gut, the activity of RUNX3 is multifaceted and context-dependent: it may promote homeostasis or exacerbated reactions via cytokine signalling and regulation of receptor expression. RUNX3 is mostly engaged in pathways involving ThPOK, T-bet, IFN-γ, TGF-ß/IL-2Rß, GATA/CBF-ß, SMAD/p300 and a number of miRNAs. RUNX3 targets relevant to IBD may include RAG1, OSM and IL-17B. Moreover, in IBD RUNX3 expression correlates positively with GZMM, and negatively with IFNAR1, whereas in controls, it strongly associates with TGFBR3. CONCLUSIONS: Dysregulation of RUNX3, mostly in the form of deficiency, likely contributes to IBD pathogenesis. More clinical research is needed to examine RUNX3 in IBD.

Circulating brain-derived neurotrophic factor, leptin, neuropeptide Y, and their clinical correlates in cystic fibrosis: a cross-sectional study.

INTRODUCTION: Cystic fibrosis (CF) involves chronic inflammation and decreased pulmonary function, which increase caloric demand. Yet, sufficient energy provision is hindered by reduced appetite and fat malabsorption. Brain-derived neurotrophic factor (BDNF), leptin, and neuropeptide Y (NPY) belong to energy balance-regulating factors. We aimed to assess their concentrations in CF patients in order to search for potential clinical correlates. MATERIAL AND METHODS: This was an exploratory, cross-sectional study. Patients' weight and height Z-scores, forced expiratory volume in 1 s (FEV1%), exocrine pancreatic status (fecal elastase-1), genotypes, and other characteristics were assessed. Serum concentrations of BDNF, leptin, NPY, IL-6, and TNF-α were measured using ELISA. RESULTS: The study enrolled 56 patients, of whom 29 (52%) were female and 17 (30%) were younger than 16 years. Median (1st-3rd quartile) mass Z-score was -0.85 (-1.56-(-0.36)); median FEV1 was 70.5% (45.0-89.5); 48 (86%) patients had exocrine pancreatic insufficiency and 8 (14%) diabetes. Overall, median concentrations were: BDNF: 33.91 ng/ml (26.40-40.43), leptin: 12.05 ng/ml (8.93-17.77), NPY: 2.86 ng/ml (1.75-4.42). None of these factors correlated with mass Z-score, FEV1%, IL-6 or TNF-α. Leptin and NPY correlated negatively (ρ = -0.62, p = 3 × 10-7); BDNF/NPY ratio was associated with leptin (ρ = 0.54, p = 2 × 10-5), BDNF/leptin ratio correlated with NPY (ρ = 0.60, p = 1 × 10-6). In a multivariable regression analysis NPY was weakly, but independently, associated with FEV1%, and leptin with age. CONCLUSIONS: BDNF and leptin were not associated with weight Z-score or FEV1%. Serum NPY concentrations seemed to be lower in CF patients with reduced pulmonary function independently of malnutrition and inflammation.

Lithium and coronaviral infections. A scoping review.

The current rapid spread of the novel coronavirus (2019-nCoV) originating from Wuhan, China, calls for a rapid response from the research community. Lithium is widely used to treat bipolar disorder, but has been shown to exhibit antiviral activity. This brief review took a systematic approach to identify five in vitro studies reporting on the influence of lithium on coronaviral infections. We propose that in the case of urgent need, lithium be explored as a potential treatment or prophylaxis for the novel Wuhan coronavirus (2019-nCoV).