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With the development of genome sequencing technologies, the amount of data produced has greatly increased in the last two decades. The abundance of digital sequence information (DSI) has provided research opportunities, improved our understanding of the genome, and led to the discovery of new solutions in industry and medicine. It has also posed certain challenges, i.e., how to store and handle such amounts of data. This, coupled with the need for convenience, international cooperation, and the possibility of independent validation, has led to the establishment of numerous databases. Spearheaded with the idea that data obtained with public funds should be available to the public, open access has become the predominant mode of accession. However, the increasing popularity of commercial genetic tests brings back the topic of data misuse, and patient's privacy. At the previous United Nations Biodiversity Conference (COP15, 2022), an issue of the least-developed countries exploiting their natural resources while providing DSI and the most-developed countries benefitting from this was raised. It has been proposed that financial renumeration for the data could help protect biodiversity. With the goal of introducing the topic to those interested in utilizing biological databases, in this publication, we present the history behind the biological databases, their necessity in today's scientific world, and the issues that concern them and their content, while providing scientific and policy context in relation to United Nations Biodiversity Conference (COP16, 21.10-1.11.24).

Ciliates undergo developmentally programmed genome elimination, in which small RNAs direct the removal of transposable elements (TEs) during the development of the somatic nucleus. Twenty-five nucleotide scanRNAs (scnRNAs) are produced from the entire germline genome and transported to the maternal somatic nucleus, where selection of scnRNAs corresponding to germline-specific sequences is thought to take place. Selected scnRNAs then guide the elimination of TEs in the developing somatic nucleus. How germline-specific scnRNAs are selected remains to be determined. Here, we provide important mechanistic insights into the scnRNA selection pathway by identifying a Paramecium homolog of Gtsf1 as essential for the selective degradation of scnRNAs corresponding to retained somatic sequences. Consistently, we also show that Gtsf1 is localized in the maternal somatic nucleus where it associates with the scnRNA-binding protein Ptiwi09. Furthermore, we demonstrate that the scnRNA selection process is critical for genome elimination. We propose that Gtsf1 is required for the coordinated degradation of Ptiwi09-scnRNA complexes that pair with target RNA via the ubiquitin pathway, similarly to the mechanism suggested for microRNA target-directed degradation in metazoans., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Integrin heterodimers containing an Integrin alpha V subunit are essential for development and play critical roles in cell adhesion and signaling. We identified biallelic variants in the gene coding for Integrin alpha V (ITGAV) in three independent families (two patients and four fetuses) that either caused abnormal mRNA and the loss of functional protein or caused mistargeting of the integrin. This led to eye and brain abnormalities, inflammatory bowel disease, immune dysregulation, and other developmental issues. Mechanistically, the reduction of functional Integrin αV resulted in the dysregulation of several pathways including TGF-β-dependent signaling and αVβ3-regulated immune signaling. These effects were confirmed using immunostaining, RNA sequencing, and functional studies in patient-derived cells. The genetic deletion of itgav in zebrafish recapitulated patient phenotypes including retinal and brain defects and the loss of microglia in early development as well as colitis in juvenile zebrafish with reduced SMAD3 expression and transcriptional regulation. Taken together, the ITGAV variants identified in this report caused a previously unknown human disease characterized by brain and developmental defects in the case of complete loss-of-function and atopy, neurodevelopmental defects, and colitis in cases of incomplete loss-of-function., (© 2024 Ghasempour et al.)

Background: This study aims to confirm the associations of air pollution with ulcerative colitis (UC) and Crohn's disease (CD); to explore interactions with genetics and lifestyle; and to characterize potential epigenetic mechanisms., Methods: We identified over 450,000 individuals from the UK Biobank and investigated the relationship between air pollution and incident inflammatory bowel disease (IBD). Cox regression was utilized to calculate hazard ratios (HRs), while also exploring potential interactions with genetics and lifestyle factors. Additionally, we conducted epigenetic Mendelian randomization (MR) analyses to examine the association between air pollution-related DNA methylation and UC. Finally, our findings were validated through genome-wide DNA methylation analysis of UC, as well as co-localization and gene expression analyses., Findings: Higher exposures to NO x (HR = 1.20, 95% CI 1.05-1.38), NO 2 (HR = 1.19, 95% CI = 1.03-1.36), PM 2.5 (HR = 1.19, 95% CI = 1.05-1.36) and combined air pollution score (HR = 1.26, 95% CI = 1.11-1.45) were associated with incident UC but not CD. Interactions with genetic risk score and lifestyle were observed. In MR analysis, we found five and 22 methylated CpG sites related to PM 2.5 and NO 2 exposure to be significantly associated with UC. DNA methylation alterations at CXCR2 and sites within the MHC class III region, were validated in genome-wide DNA methylation analysis, co-localization analysis and analysis of colonic tissue., Interpretation: We report a potential causal association between air pollution and UC, modified by lifestyle and genetic influences. Biological pathways implicated include epigenetic alterations in key genetic loci, including CXCR2 and susceptible loci within MHC class III region., Funding: Xue Li was supported by the Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001) and the National Nature Science Foundation of China (No. 82204019). ET was supported by the CRUK Career Development Fellowship (C31250/A22804) and the Research Foundation Flanders (FWO). JW was supported by Belgium by a PhD Fellowship strategic basic research (SB) grant (1S06023N). JKN was supported by the National Science Center, Poland (No. 2020/39/D/NZ5/02720). The IBD Character was supported by the European Union's Seventh Framework Programme [FP7] grant IBD Character (No. 2858546)., Competing Interests: Declaration of interests JKN reports consulting for Procter & Gamble and grant support from the Biocodex Microbiota Foundation, outside of the submitted work. All the remaining authors declare no potential or actual conflict of interest to the work presented in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: DNA methylation mediates the gene-environment interactions, with implications for health and disease. Studies with sampling at more than one timepoint revealed the considerable variability of the blood methylome, but comprehensive resources on genome-wide methylation stability are still lacking. We aimed to identify methylation sites that remain the most stable across two timepoints in human whole blood. Methods: Publicly available blood DNA methylation data from three cohorts were analysed, which included methylation profiles at two timepoints >1 year apart. The cohorts included pre-/post-pubertal children (Illumina 450k array), the elderly (Illumina 450k array), and middle-aged adults with obesity (Illumina EPIC array). Two metrics were used for the stability assessment: the mean absolute difference (MAD) of beta values between two measurements and the intraclass correlation coefficient (ICC). We searched for probes demonstrating high stability (low MAD and high ICC) across the three cohorts. Data from 51 children, 86 elderly adults, and 120 middle-aged participants were re-analysed. Results: The median interquartile range (IQR) of the maximum (from three datasets) MAD was 2.1% (1.5-2.9%), and the median of the minimum ICC agreement coefficient was 0.053 (-0.077-0.304). The Pearson's correlation coefficient for the ICC vs. maximum MAD was low (r = 0.34, p < 2.2 × 10 -16 ). We found only 239 probes that were highly stable based on both the maximum MAD (<5th percentile, <0.01) and ICC criterion (>95th percentile, >0.74). Conclusions: The whole-blood DNA methylation profile, as measured using microarrays, is dynamic over >1 year, but contains a fraction of stable probes, most of which are related to genomic variation. A resource describing probe stability is made publicly available, with the intention to support biomarker studies and the investigation of early epigenetic programming. The absolute error and correlation are two complementary facets of probe stability that may be considered in further research, especially to determine the stability of probes in health and disease across different tissues and populations.

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.

This work aims to investigate how smoking exerts effect on the development of inflammatory bowel disease (IBD). A prospective cohort study and a Mendelian randomization study are first conducted to evaluate the association between smoking behaviors, smoking-related DNA methylation and the risks of Crohn's disease (CD) and ulcerative colitis (UC). We then perform both genome-wide methylation analysis and co-localization analysis to validate the observed associations. Compared to never smoking, current and previous smoking habits are associated with increased CD (P = 7.09 × 10 -10 ) and UC (P < 2 × 10 -16 ) risk, respectively. DNA methylation alteration at cg17742416 [DNMT3A] is linked to both CD (P = 7.30 × 10 -8 ) and UC (P = 1.04 × 10 -4 ) risk, while cg03599224 [LTA/TNF] is associated with CD risk (P = 1.91 × 10 -6 ), and cg14647125 [AHRR] and cg23916896 [AHRR] are linked to UC risk (P = 0.001 and 0.002, respectively). Our study identifies biological mechanisms and pathways involved in the effects of smoking on the pathogenesis of IBD., (© 2024. The Author(s).)

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-αvβ6 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.

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., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The runt-related transcription factor 3 (RUNX3) regulates the differentiation of monocytes and their response to inflammation. However, the transcriptomic context of RUNX3 expression in blood monocytes remains poorly understood. We aim to learn about RUNX3 from its relationships within transcriptomes of bulk CD14+ cells in adults. This study used immunomagnetically sorted CD14+ cell gene expression microarray data from the Multi-Ethnic Study of Atherosclerosis (MESA, n = 1202, GSE56047) and the Correlated Expression and Disease Association Research (CEDAR, n = 281, E-MTAB-6667) cohorts. The data were preprocessed, subjected to RUNX3 -focused correlation analyses and random forest modeling, followed by the gene ontology analysis. Immunity-focused differential ratio analysis with intermediary inference (DRAIMI) was used to integrate the data with protein-protein interaction network. Correlation analysis of RUNX3 expression revealed the strongest positive association for EVL (r mean = 0.75, p FDR-MESA = 5.37 × 10 -140 , p FDR-CEDAR = 5.52 × 10 -80 ), ARHGAP17 (r mean = 0.74, p FDR-MESA = 1.13 × 10 -169 , p FDR-CEDAR = 9.20 × 10 -59 ), DNMT1 (r mean = 0.74, p FDR-MESA = 1.10 × 10 -169 , p FDR-CEDAR = 1.67 × 10 -58 ), and CLEC16A (r mean = 0.72, p FDR-MESA = 3.51 × 10 -154 , p FDR-CEDAR = 2.27 × 10 -55 ), while the top negative correlates were C2ORF76 (r mean = -0.57, p FDR-MESA = 8.70 × 10 -94 , p FDR-CEDAR = 1.31 × 10 -25 ) and TBC1D7 (r mean = -0.55, p FDR-MESA = 1.36 × 10 -69 , p FDR-CEDAR = 7.81 × 10 -30 ). The RUNX3 -associated transcriptome signature was involved in mRNA metabolism, signal transduction, and the organization of cytoskeleton, chromosomes, and chromatin, which may all accompany mitosis. Transcriptomic context of RUNX3 expression in monocytes hints at its relationship with cell growth, shape maintenance, and aspects of the immune response, including tyrosine kinases.

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., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

We evaluated the prevalence of systemic sclerosis (SSc)-related autoantibodies and their clinical significance and compared the sensitivity of two line immunoblot assays on a prospective study group of 96 Polish SSc patients (ACR-EULAR 2013 criteria) whose sera were assessed by indirect immunofluorescence (HEp-2 and monkey liver) and line immunoblot assays: ANA Profile 3 and Systemic Sclerosis Profile by EUROIMMUN (Lübeck, Germany). Organ involvement was evaluated according to the EUSTAR Minimal Essential Data Set. The following autoantibodies’ prevalence was found: Scl-70 (36%), Ro-52 (28%), CENP-B (22%), CENP-A (20%), PM-Scl-75 (20%), PM-Scl-100 (14%), fibrillarin (7%), Th/To (7%), RNA polymerase III 11 kDa (5%), RNA polymerase III 155 kDa (3%), PDGFR (3%), NOR-90 (2%), and Ku (1%). Significant associations between the autoantibodies’ presence and organ involvement were found: ATA (dcSSc > lcSSc, less prevalent muscle weakness), Ro-52 (gangrene, DLCO < 60), CENP-B and A (lcSSc > dcSSc, normal CK), CENP-B (rarer digital ulcers and joint contractures), PM-Scl-100 and 75 (PM/SSc overlap, CK increase, muscle weakness, muscle atrophy), PM-Scl-100 (dcSSc unlikely), PM-Scl-75 (lung fibrosis), fibrillarin (muscle atrophy, proteinuria, conduction blocks, palpitations), Th/To (proteinuria, arthritis, muscle weakness, and rarer esophageal symptoms), RNA Polymerase III 11 kDa (arterial hypertension, renal crisis), RNA polymerase III 155 kDa (renal crisis), and PDGFR (dcSSc, tendon friction rubs). Additionally, the Systemic Sclerosis Profile was significantly more sensitive in detecting SSc-related autoantibodies than ANA Profile 3 (p = 0.002). In conclusion, individual autoantibodies associated with specific characteristics of SSc.

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.

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.

Ulcerative colitis (UC) results from a complex interplay between the environment, gut microbiota, host genetics, and immunity. Runt-related transcription factor 3 (RUNX3) regulates Th1/Th2 balance and, thus, the synthesis of cytokines and inflammation. We aimed to analyze the dependence of RUNX3 promoter 2 ( P2 ) methylation level on: age, sex, body mass index (BMI), C-reactive protein (CRP), serum albumin, disease duration, Pediatric Ulcerative Colitis Activity Index (PUCAI), the Paris classification, and exposure to medications. This multicenter, cross-sectional study recruited hospitalized children with UC. Methylation of RUNX3 P2 was measured with methylation-sensitive restriction enzymes in the whole blood DNA. Sixty-four children were enrolled, with a mean age of 14.5 ± 2.8 years. Half of them were female (51.6%), and the average BMI Z-score was -0.44 ± 1.14. The mean methylation of RUNX3 P2 was 54.1 ± 13.3%. The methylation level of RUNX3 P2 did not correlate with age, sex, nutritional status, CRP, albumin, PUCAI, or the extent of colitis (Paris E1-E4). RUNX3 P2 methylation did not differ between patients recruited within two and a half months of diagnosis and children who had UC for at least a year. Current or past exposure to biologics, immunosuppressants, or steroids was not associated with RUNX3 P2 methylation. Methylation of RUNX3 promoter 2 in whole blood DNA does not seem to be associated with the characteristics of UC in children.

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 Author(s) 2022. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

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 (r CF  = 0.55; r controls  = -0.68; p adj  = 1.60 × 10 -100 ), SRP14 and FAU (r CF  = -0.69; r controls  = 0.48; p adj  = 2.99 × 10 -90 ), SRP14 and GDI2 (r CF  = -0.34; r controls  = 0.60; p adj  = 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.

The Spt4-Spt5 complex is conserved and essential RNA polymerase elongation factor. To investigate the role of the Spt4-Spt5 complex in non-coding transcription during development, we used the unicellular model Paramecium tetraurelia. In this organism harboring both germline and somatic nuclei, massive transcription of the entire germline genome takes place during meiosis. This phenomenon starts a series of events mediated by different classes of non-coding RNAs that control developmentally programmed DNA elimination. We focused our study on Spt4, a small zinc-finger protein encoded in P. tetraurelia by two genes expressed constitutively and two genes expressed during meiosis. SPT4 genes are not essential in vegetative growth, but they are indispensable for sexual reproduction, even though genes from both expression families show functional redundancy. Silencing of the SPT4 genes resulted in the absence of double-stranded ncRNAs and reduced levels of scnRNAs - 25 nt-long sRNAs produced from these double-stranded precursors in the germline nucleus. Moreover, we observed that the presence of a germline-specific Spt4-Spt5m complex is necessary for transfer of the scnRNA-binding PIWI protein between the germline and somatic nucleus. Our study establishes that Spt4, together with Spt5m, is essential for expression of the germline genome and necessary for developmental genome rearrangements., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: We aimed to assess a liposomal fat-soluble vitamin formulation containing vitamin K2 with standard treatment in cystic fibrosis (CF)., Methods: A multi-center randomized controlled trial was carried out in 100 pancreatic-insufficient patients with CF. The liposomal formulation contained vitamin A as retinyl palmitate (2667 IU daily) and beta-carotene (1333 IU), D3 (4000 IU), E (150 IU), K1 (2 mg), and K2 as menaquinone-7 (400 µg). It was compared with the standard vitamin preparations in the closest possible doses (2500 IU, 1428 IU, 4000 IU, 150 IU, 2.14 mg, respectively; no vitamin K2) over 3 months., Results: Forty-two patients finished the trial in the liposomal and 49 in the control group (overall 91 pts: 22.6 ± 7.6 years, 62.6% female, BMI 19.9 ± 2.8 kg/m 2 , FEV1% 70% ± 30%). The main outcome was the change of vitamin status in the serum during the study (liposomal vs. standard): all-trans-retinol (+1.48 ± 95.9 vs. -43.1 ± 121.4 ng/mL, p = 0.054), 25-hydroxyvitamin D3 (+9.7 ± 13.4 vs. +2.0 ± 9.8 ng/mL, p = 0.004), α-tocopherol (+1.5 ± 2.5 vs. -0.2 ± 1.6 µg/mL, p < 0.001), %undercarboxylated osteocalcin (-17.2 ± 24.8% vs. -8.3 ± 18.5%, p = 0.061). The secondary outcome was the vitamin status at the trial end: all-trans-retinol (370.0 ± 116.5 vs. 323.1 ± 100.6 ng/mL, p = 0.045), 25-hydroxyvitamin D3 (43.2 ± 16.6 vs. 32.7 ± 11.5 ng/mL, p < 0.001), α-tocopherol (9.0 ± 3.1 vs. 7.7 ± 3.0 µg/mL, p = 0.037), %undercarboxylated osteocalcin (13.0 ± 11.2% vs. 22.7 ± 22.0%, p = 0.008)., Conclusion: The liposomal fat-soluble vitamin supplement containing vitamin K2 was superior to the standard form in delivering vitamin D3 and E in pancreatic-insufficient patients with CF. The supplement was also more effective in strengthening vitamin K-dependent carboxylation, and could improve vitamin A status.

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., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021. Published by Elsevier Ltd.)

Introduction: Smoking is known to affect whole-blood expression and methylation profiles. Although whole-genome methylation studies indicated that effects observed in blood may be driven by changes within leukocyte subtypes, these phenomena have not been explored using expression profiling., Material and Methods: This study reanalyzed data from the Correlated Expression and Disease Association Research (CEDAR) patient cohort recruited by Momozawa et al. (E-MTAB-6667). Data from gene expression profiling of immunomagnetically sorted CD4 + , CD8 + , CD14 + , CD15 + , and CD19 + cells were processed. Differential expression analyses were conducted in each immune cell type, followed by gene ontology analysis and supplementary investigations., Results: Ninety-four differentially expressed genes were found (CD8 + n = 58, CD14 + n = 20, CD4 + n = 14, CD19 + n = 2). Two key smoking-related genes were overexpressed in specific cell types: LRRN3 (CD4 + , CD8 + ) and MMP25 (CD8 + , CD14 + ). In CD4 + cells smoking was associated with reduced expression of the NK cell receptor KLRB1, suggesting CD4 + subpopulation shifts and differences in interferon signaling (reduced IRF1 and IL18RAP in smokers). Key results and their integration with an immune protein-protein interaction network revealed that smoking influences integrins in CD8 + cells (ITGB7, ITGAL, ITGAM, ITGB2). C-type lectin CLEC4A was reduced in CD8 + cells and CLEC10A was increased in CD14 + cells from smokers; moreover, CLEC5A (CD8 + ), CLEC7A (CD8 + ) and CLEC9A (CD19 + ) were related to smoking in supplementary analyses. CD14 + cells from smokers exhibited overexpression of LDLR and the formyl peptide receptor FPR3., Conclusions: Smoking specifically alters vital immune regulation genes in lymphocyte subtypes, especially CD4 + , CD8 + and CD14 + cells., (Copyright © 2022 Termedia.)

Background: Patients with cystic fibrosis (CF) are exposed to overlapping cardiovascular risk factors. We hypothesized that CF is characterized by increased arterial stiffness and greater intima-media thickness (IMT)., Methods: This cross-sectional study assessed the digital volume pulse arterial stiffness index (SI DVP ) using photopletysmography, measured intima-media complex thickness (IMT) at the common carotid artery, and obtained an extended set of clinical and atherosclerosis-related laboratory parameters., Results: Fifty-five patients with moderate-to-severe CF (mean age 26.3±8.6 years, BMI 20.3±3.1 kg/m2, FEV1 62±26%) and 51 healthy controls (25.1±4.4 years, BMI 21.7±3.0 kg/m2) entered the study. SI DVP was greater in pancreatic insufficient (PI), but not pancreatic sufficient (PS) CF patients compared with control (7.3±1.8 m/s vs 6.0±1.2 m/s; p=7.1 × 10 -5 ). IMT was increased in PS (but not PI) participants relative to control (552±69 µm vs 456±95 µm, p=0.0011). SI DVP was also greater in PI than in PS patients (7.3±1.8 m/s vs 6.3±1.7 m/s, p=0.0232) and IMT was higher in PS compared with PI (552±69 µm vs 453±82 µm, p=0.0002). SI DVP independently associated with age, PI, the lack of liver cirrhosis, and with Pseudomonas aeruginosa colonization. PS was the only independent correlate of IMT in CF., Conclusions: PI patients are at risk of developing general arterial stiffness. PS may relate to carotid IMT thickening, which underscores the need for further study that could lead to reconsideration of dietary guidance in PS CF., Competing Interests: Declaration of Competing Interest JKN reports personal fees from Norsa Pharma within an EU-funded project and non-financial support from Nutricia, outside the submitted work. SDC reports personal fees from Norsa Pharma within an EU-funded project, outside the submitted work. JW reports personal fees and non-financial support from Biocodex, BGP Products, Chiesi, Hipp, Humana, Mead Johnson Nutrition, Merck Sharp & Dohme, Nestle, Norsa Pharma, Nutricia, Roche, Sequoia Pharmaceuticals, and Vitis Pharma, outside the submitted work, and also grants, personal fees and non-financial support from Nutricia Research Foundation Poland, also outside the submitted work., (Copyright © 2021. Published by Elsevier B.V.)

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 β-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/m 2 [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).

The ERASMUS program is one of the most popular student exchange projects, particularly among the students of Central and Eastern European countries. However, limited research is available with regard to its influence on the professional and personal development of its participants. The study aimed at investigating the experiences and impact of the ERASMUS program on different domains of the personal and professional life of medical students. A questionnaire containing closed and open-ended questions was distributed among 269 former participants of the ERASMUS program from the Poznan University of Medical Sciences to collect qualitative and quantitative data regarding the topic. The response rate was 41%. Mastering professional foreign language skills was the most frequently reported benefit of ERASMUS (94%), followed by a change of approach towards learning by exposure to innovative teaching techniques, character, professionalism and cultural competency development, impact on the migration decisions of the students, as well as the opportunity to compare healthcare and educational systems across countries. Additionally, 57% of respondents stated that ERASMUS impacted their career plans, and few indicated that it had affected their specialty choice. Approximately 28% of respondents have worked abroad in healthcare or research since graduating. Participation in the ERASMUS program proved to be a unique opportunity for professional and personal development.

Objective: Physical activity plays an important role in maintaining mental and physical health. This study assessed the effect of physical activity monitoring awareness on the physical activity level and subjective self-assessment of physical activity in middle-aged subjects with normal cognitive function (NCF) and mild cognitive impairment (MCI)., Patients and Methods: Thirty-five subjects aged 50-65 years with NCF and MCI were randomised into two experimental groups, each taking part in two one-week intervention periods. Subjects in group A were not aware that their physical activity was monitored in the first week (phase I) and were aware of the monitoring in the second week (phase II), whereas it was the opposite order for group B. Physical activity was assessed using the ActiGraph GT9X accelerometer and International Physical Activity Questionnaire (IPAQ)., Results: A total of 32 subjects (MCI: n = 12, NCF: n = 20) completed both intervention periods, with MCI subjects having significantly lower objectively assessed physical activity than NCF participants. Moreover, subjectively assessed physical activity in the MCI group was significantly higher when the participants were unaware of physical activity monitoring. A significant phase-group interaction was found in total (MET-min/d: p = 0.0072; min/d: p = 0.0194) and moderate (MET-min/d: p = 0.0015; min/d: p = 0.0020) physical activity as well as energy expenditure (p = 0.0366) assessed by the IPAQ and in the percentage of sedentary behaviour (p = 0.0330) and the average number of steps (p = 0.0342) assessed by ActiGraph., Conclusions: The awareness of physical activity assessment might decrease the ability to subjectively assess physical activity in subjects with MCI.

The human leukocyte antigen (HLA) allele group HLA-DQA1*05 predisposes to ulcerative colitis (UC) and is associated with the development of antibodies against infliximab in patients with inflammatory bowel disease (IBD). Therefore, we hypothesized that the presence of HLA-DQA1*05 correlates with characteristics of pediatric IBD. Within a multi-center cohort in Poland, the phenotype at diagnosis and worst flare was established and HLA-DQA1*05 status was assessed enabling genotype-phenotype analyses. HLA-DQA1*05 was present in 221 (55.1%) out of 401 children with IBD (UC n = 188, Crohn's disease n = 213). In UC, the presence of HLA-DQA1*05 was moderately associated with a large extent of colonic inflammation at diagnosis (E4 55% more frequent in HLA-DQA1*05-positive patients, p = 0.012). PUCAI at diagnosis ( p = 0.078) and the time from UC diagnosis to the first administration of biologic treatment ( p = 0.054) did not differ depending on HLA-DQA1*05 status. The number of days of hospitalization for exacerbation was analyzed in 98 patients for whom sufficient follow-up was available and did not differ depending on HLA-DQA1*05 carriership ( p = 0.066). HLA-DQA1*05 carriers with CD were less likely to present with both stenosing and penetrating disease (B2B3, p = 0.048) and to have active disease proximal to the ligament of Treitz (L4a) at the worst flare ( p = 0.046). Future research focusing on explaining and preventing anti-TNF immunogenicity should take into account that ADA may develop not only as an isolated reaction to anti-TNF exposure but also as a consequence of intrinsic differences in the early course of UC.

Automated bowel sound (BS) analysis methods were already well developed by the early 2000s. Accuracy of ~90% had been achieved by several teams using various analytical approaches. Clinical research on BS had revealed their high potential in the non-invasive investigation of irritable bowel syndrome to study gastrointestinal motility and in a surgical setting. This article proposes a novel methodology for the analysis of BS using hybrid convolutional and recursive neural networks. It is one of the first methods of using deep learning to be widely explored. We have developed an experimental pipeline and evaluated our results with a new dataset collected using a device with a dedicated contact microphone. Data have been collected at night-time, which is the most interesting period from a neurogastroenterological point of view. Previous works had ignored this period and instead kept brief records only during the day. Our algorithm can detect bowel sounds with an accuracy >93%. Moreover, we have achieved a very high specificity (>97%), crucial in diagnosis. The results have been checked with a medical professional, and they successfully support clinical diagnosis. We have developed a client-server system allowing medical practitioners to upload the recordings from their patients and have them analyzed online. This system is available online. Although BS research is technologically mature, it still lacks a uniform methodology, an international forum for discussion, and an open platform for data exchange, and therefore it is not commonly used. Our server could provide a starting point for establishing a common framework in BS research.

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 Foxp3 neg 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., (© 2021. The Author(s).)

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., Competing Interests: JN reports personal fees from Norsa Pharma, a grant from Biocodex Microbiota Foundation, and non-financial support from Nutricia outside the submitted work. JW reports personal fees and non-financial support from Biocodex, BGP Products, Chiesi, Hipp, Humana, Mead Johnson Nutrition, Merck Sharp & Dohme, Nestle, Norsa Pharma, Nutricia, Roche, Sequoia Pharmaceuticals, and Vitis Pharma, outside the submitted work, and also grants, personal fees and non-financial support from Nutricia Research Foundation Poland, also outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wielińska-Wiśniewska, Nowak, Da̧browski, Szydłowska, Szczepanik, Cichocka, Krzyżanowska-Jankowska and Walkowiak.)

Despite technological progress, we lack a consensus on the method of conducting automated bowel sound (BS) analysis and, consequently, BS tools have not become available to doctors. We aimed to briefly review the literature on BS recording and analysis, with an emphasis on the broad range of analytical approaches. Scientific journals and conference materials were researched with a specific set of terms (Scopus, MEDLINE, IEEE) to find reports on BS. The research articles identified were analyzed in the context of main research directions at a number of centers globally. Automated BS analysis methods were already well developed by the early 2000s. Accuracy of 90% and higher had been achieved with various analytical approaches, including wavelet transformations, multi-layer perceptrons, independent component analysis and autoregressive-moving-average models. Clinical research on BS has exposed their important potential in the non-invasive diagnosis of irritable bowel syndrome, in surgery, and for the investigation of gastrointestinal motility. The most recent advances are linked to the application of artificial intelligence and the development of dedicated BS devices. BS research is technologically mature, but lacks uniform methodology, an international forum for discussion and an open platform for data exchange. A common ground is needed as a starting point. The next key development will be the release of freely available benchmark datasets with labels confirmed by human experts.

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., (© 2021. The Author(s).)

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-β/IL-2Rβ, GATA/CBF-β, 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., (© 2021 The Scandinavian Foundation for Immunology.)

(1) Background: Lactose digestion depends on persistence genotypes (including rs4988235), the frequency of which exhibits broad geographical variability. However, little is known about the relationship between lactase ( LCT ) genotypes and intestinal expression of LCT . We aimed to investigate ileal expression of LCT depending on main genetic polymorphisms (rs4988235, rs3754689, rs3739022), age, sex, smoking status, body mass index (BMI), and the expression of other genes; (2) Methods: phenotype, array-based genotype, and ileal mucosal biopsy expression data were obtained from the CEDAR study; (3) Results: analyses included 196 healthy Europeans (53.6% women) aged 53.0 ± 13.6 years with a mean BMI of 25.6 ± 4.2 kg/m 2 , of whom 17.4% were smoking. Ileal LCT expression was mostly independent of age, sex, BMI, or smoking. Rs4988235 homozygous minor allele (GG) associated with lower LCT expression (vs. AG p = 2.2 × 10 -6 , vs. AA p = 1.1 × 10 -7 ). Homozygous major allele of rs3754689 (GG) was related to higher LCT expression (vs. AG p = 1.7 × 10 -5 , vs. AA p = 0.0074). Rs3754689 genotype did not modify LCT expression (GG vs. AG p = 0.051) in rs4988235-heterozygous subgroup. Interestingly, CD14 , which is a marker of monocytes and macrophages, was the strongest negative transcriptomic correlate of LCT expression (r = -0.57, p FDR = 1.1 × 10 -14 ); (4) Conclusions: both rs4988235 and rs3754689 associated with ileal LCT expression, which did not seem related to age, sex, smoking, or BMI. The inverse correlation between LCT and CD14 expression in the ileum is striking and requires further investigation.

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.

We hypothezied that telomere length is considerably altered in cystic fibrosis (CF) patients compared to healthy subjects (HS), and that leukocyte telomere length variation reflects the severity of CF. Relative telomere length (RTL) was assessed by qPCR in 70 children aged 5-10 (34 CF; 36 HS) and 114 adults aged 18-45 (53 CF; 61 HS). Telomere length was similar in CF and HS (median (interquartile range): 0.799 (0.686-0.950) vs. 0.831 (0.707-0.986); p = 0.5283) both in children and adults. In adults, women had longer telomeres than men (0.805 (0.715-0.931) vs. 0.703 (0.574-0.790); p = 0.0002). Patients treated with inhaled corticosteroids had a shorter RTL compared to those without steroid therapy (0.765 (0.664-0.910) vs. 0.943 (0.813-1.191); p = 0.0007) and this finding remained significant after adjusting for gender, age, BMI, and child/adult status ( p = 0.0003). Shorter telomeres were independently associated with the presence of comorbidities (0.763 (0.643-0.905) vs. 0.950 (0.783-1.130); p = 0.0006) and antibiotic treatment at the moment of blood sampling (0.762 (0.648-0.908) vs. 0.832 (0.748-1.129); p = 0.0172). RTL correlated with number of multiple-day hospitalizations (rho = -0.251; p = 0.0239), as well as number of hospitalization days (rho = -0.279; p = 0.0113). Leukocyte RTL in children and adults with CF was not shorter than in healthy controls, and did not seem to have any potential as a predictor of CF survival. However, it inversely associated with the investigated clinical characteristics.

Twitter has considerable capacity for health education and proves to be an efficient and accessible communication tool in the coronavirus disease-19 (COVID-19) pandemic. Although many stakeholders saturate Twitter with COVID-19-related information, it remains unknown who disseminates information most efficaciously. COVID-19-related tweets were obtained from Twitter accounts of health agencies, governmental authorities, universities, scientific journals, medical associations, and celebrities. Posts' impact was measured with the nominal and relative (%followers) number of likes and retweets. A sentiment analysis was conducted.We have identified 17,331 COVID-19-related tweets posted by 338 accounts in >4 months since the virus began to spread. The largest number of likes was received by tweets of celebrities (median nominal, relative likes; 14,918, 0.036 percent), politicians (259, 0.174 percent), and health agencies (231, 0.007 percent). Most retweeted messages were also posted by celebrities (2,366, 0.005 percent), health agencies (130, 0.004 percent), and politicians (55, 0.041 percent). Retweets and likes peaked in March 2020, and the overall sentiment of the tweets was growing steadily. Whereas celebrities and politicians posted positive messages, the scientific and health authorities often employed a negative vocabulary. The posts with positive sentiment gained more likes and relative likes than nonpositive. During the pandemic, the tweets of celebrities and politicians related to COVID-19 outperform those coming from health and scientific institutions. Active engagement of Twitter influencers may help key messages go viral.

Introduction: Administration of butyrate enemas might improve the health status of patients with inflammatory bowel disease (IBD). However, the results seem equivocal. Therefore, this systematic review aimed to assess the effect of sodium butyrate enemas on disease activity index (DAI), endoscopic scores, as well as histological and inflammatory parameters in IBD patients., Methods: The PubMed, Scopus, Web of Science, and Cochrane databases were searched. Randomised controlled trials published in English that assessed the effect of butyrate enemas on DAI, clinical symptoms, inflammatory markers, as well as histological and endoscopic scores in patients with Crohn's disease (CD) and ulcerative colitis (UC) were included in the analysis., Results: Eight studies involving 227 UC patients were included in this analysis. Only one study reported significant differences in DAI between groups. Besides, butyrate treatment groups did not differ significantly from controls concerning the effect on endoscopic and histological scores. Moreover, butyrate enemas exerted a significant effect on few inflammatory parameters measured in colonic mucosal biopsies., Conclusion: The current evidence is limited and does not support the application of butyrate enemas in UC. There are no reliable data regarding the efficacy of butyrate enemas in CD. The systematic review protocol was registered in the PROSPERO database (CRD42020163654)., (© 2020 S. Karger AG, Basel.)

Background: MicroRNAs [miRNAs] are cell-specific small non-coding RNAs that can regulate gene expression and have been implicated in inflammatory bowel disease [IBD] pathogenesis. Here we define the cell-specific miRNA profiles and investigate its biomarker potential in IBD., Methods: In a two-stage prospective multi-centre case control study, next generation sequencing was performed on a discovery cohort of immunomagnetically separated leukocytes from 32 patients (nine Crohn's disease [CD], 14 ulcerative colitis [UC], eight healthy controls) and differentially expressed signals were validated in whole blood in 294 patients [97 UC, 98 CD, 98 non-IBD, 1 IBDU] using quantitative PCR. Correlations were analysed with phenotype, including need for early treatment escalation as a marker of progressive disease using Cox proportional hazards., Results: In stage 1, each leukocyte subset [CD4+ and CD8+ T-cells and CD14+ monocytes] was analysed in IBD and controls. Three specific miRNAs differentiated IBD from controls in CD4+ T-cells, including miR-1307-3p [p = 0.01], miR-3615 [p = 0.02] and miR-4792 [p = 0.01]. In the extension cohort, in stage 2, miR-1307-3p was able to predict disease progression in IBD (hazard ratio [HR] 1.98, interquartile range [IQR]: 1.20-3.27; logrank p = 1.80 × 10-3), in particular CD [HR 2.81; IQR: 1.11-3.53, p = 6.50 × 10-4]. Using blood-based multimarker miRNA models, the estimated chance of escalation in CD was 83% if two or more criteria were met and 90% for UC if three or more criteria are met., Interpretation: We have identified and validated unique CD4+ T-cell miRNAs that are differentially regulated in IBD. These miRNAs may be able to predict treatment escalation and have the potential for clinical translation; further prospective evaluation is now indicated., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Competing Interests: Competing interests: JKN: Received personal fees from Norsa Pharma and non-financial support from Nutricia. LK: Received personal fees from Nutricia, Vitaflo, Recordati and non-financial support from Nutricia and Recordati. AB-P: Received personal fees from Nutricia, Sanofi and Vitaflo. JW: Received personal fees and non-financial support from Biocodex, BGP Products, Chiesi, Hipp, Humana, Mead Johnson Nutrition, Merck Sharp & Dohme, Nestle, Norsa Pharma, Nutricia, Roche, Sequoia Pharmaceuticals, and Vitis Pharma, as well as research grants, personal fees and non-financial support from Nutricia Research Foundation Poland, outside the submitted work. All other authors report no disclosures.

Objectives: The Internet has become the main source of health-related information including nutrition. The aim of this study was to rank the most popular diets among Google users globally and regionally in addition to secular and seasonal trends in the years 2004 to 2019., Methods: We used Google Trends (GT) to identify and analyze course over time and regional interest of 47 topics related to diets. We analyzed secular trends using the Seasonal Mann-Kendall test and seasonal variation using time-series decomposition. The topic "Mediterranean diet" (MedD) was used as a benchmark. We calculated the interest of all topics in proportion to the relative search volume (RSV) of MedD., Results: Globally, Google users were particularly interested in veganism (19.54 times higher than MedD), vegetarianism (15.09 times higher than MedD), and gluten-free diet (11.11 times higher than MedD). Veganism was the most frequently searched diet type in 23 countries followed by vegetarianism (14), ketogenic diet (7), and low-carbohydrate diet (7). Whereas an increase of RSV over time was observed for 23 diets, a decrease was noted for 20. The most dynamic increase was found for FODMAP (6.12 RSV/year), gluten-free diet (5.95 RSV/year), and raw veganism (5.72 RSV/year). Sharp declines concerned negative-calorie food (-4.34 RSV/year), macrobiotic diet (-3.89 RSV/year), and cabbage soup diet (-3.50 RSV/year). The interest in most diets falls in December but peaks in January., Conclusion: Veganism, vegetarianism, and gluten-free diet attract the largest public interest globally. Both secular trends and seasonal variation shape the ever-changing landscape of diet popularity. GT holds promise as a valuable tool in local and international nutrition research., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Microwave heating of foods may alter their content. Yet, parents commonly heat infant formula in the microwave oven. The study aimed at understanding whether microwave heating of formula changes its fatty acid (FA) composition. Portions of infant formula were prepared and divided in three parts: control (sampled twice: at the start and after 30 minutes), microwave (sampled twice: after reaching 37°C and 50°C), and water bath (sampled twice: after reaching 37°C and 50°C). In thus obtained samples, a total profile of 25 FA was assessed using gas chromatography-mass spectrometry. Overall, fourteen portions were prepared, which were sampled 84 times yielding 2075 individual total FA level measurements. Few differences were identified between the microwave, control, and water bath groups. Microwave warming to 37°C was associated with increases of C12 (median increased by +0.40%, p = 0.0063), C14 (+0.05%, p = 0.0091), and C4 content (+6.90%, p = 0.0131). Microwaving up to 50°C slightly decreased C16:1trans (-5.00%, p = 0.0463) and C18:2trans1 (-5.13%, p = 0.0231). A paired comparison of pooled control and microwaved samples revealed increases in C12 (+0.18%, p = 0.0490) as well as a loss of C18:2trans1 (also -5.13%, p = 0.0073) and C18:2trans3 (-5.56%, p = 0.0042) after microwave treatment. C18:2trans1 (-2.63%, p = 0.0132) and C18:3trans1 (-2.26%, p = 0.0434) were lower in microwaved samples compared with the water bath. A slightly lower C18:2 content was found in the water bath samples than in the control groups (-0.11%, p = 0.0430). None of these differences would remain significant after a correction for multiple comparisons. Microwave heating of infant formula to 37°C or 50°C might marginally alter its total FA profile. Further studies are required to determine whether it alters the rate of free radical formation., Competing Interests: The authors have read the journal's policy and have the following competing interests: JKN reports part-time employment at Norsa Pharma within an EU-funded project and national conference travel support from Nutricia, both outside the submitted work. JW received travel grants/honoraria from Biocodex, BGP Products, Chiesi, Hipp, Humana, Mead Johnson Nutrition, Merck Sharp & Dohme, Nestle, Norsa Pharma, Nutricia, Roche, Sequoia Pharmaceuticals, and Vitis Pharma, as well as research grants, personal fees and non-financial support from Nutricia Research Foundation Poland, outside the submitted work. SDC reports conference travel support from Nestle and Nutricia, outside the submitted work. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare.

The current rapid spread of the novel coronavirus (SARS-CoV-2) causing coronavirus disease 2019 (COVID-19) 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 six in vitro studies reporting on the influence of lithium on coronaviral infections. We propose mechanistic investigation of the influence of lithium - alone and with chloroquine - on the SARS-CoV-2 infection., Competing Interests: Competing interests: JKN reports personal fees from Norsa Pharma and non-financial support from Nutricia outside the submitted work. JW reports personal fees and non-financial support from Biocodex, BGP Products, Chiesi, Hipp, Humana, Mead Johnson Nutrition, Merck Sharp & Dohme, Nestle, Norsa Pharma, Nutricia, Roche, Sequoia Pharmaceuticals, and Vitis Pharma, outside the submitted work, and also grants, personal fees and non-financial support from Nutricia Research Foundation Poland, also outside the submitted work., (Copyright: © 2020 Nowak JK and Walkowiak J.)

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)., Competing Interests: Competing interests: JKN reports personal fees from Norsa Pharma and non-financial support from Nutricia outside the submitted work. JW reports personal fees and non-financial support from Biocodex, BGP Products, Chiesi, Hipp, Humana, Mead Johnson Nutrition, Merck Sharp & Dohme, Nestle, Norsa Pharma, Nutricia, Roche, Sequoia Pharmaceuticals, and Vitis Pharma, outside the submitted work, and also grants, personal fees and non-financial support from Nutricia Research Foundation Poland, also outside the submitted work., (Copyright: © 2020 Nowak JK and Walkowiak J.)

Background: The interest in cystic fibrosis (CF) dyslipidaemia as a potential risk factor for cardiovascular disease is increasing with patients' survival. This study aimed to investigate CF dyslipidaemia, its clinical correlates and links to oxidized low-density lipoprotein (oxLDL), adiponectin, and apolipoprotein E (APOE)., Methods: This cross-sectional study assessed clinical characteristics of CF, as well as the serum lipid profile, oxLDL, adiponectin, and APOE., Results: In total, 108 CF subjects were enrolled in this study, with a median age of 22 years, BMI of 20.5 kg/m 2 , FEV1% of 61%, of which 81% were pancreatic insufficient (PI). Healthy subjects (HS; n = 51) were in similar age. Hypocholesterolaemia occurred in 31% of CF subjects and in no HS. Hypertriglyceridaemia concerned 21% of patients (HS: 8%, p = .04), and low HDL-C 45% (HS: 6%, p < .0001). At least one of these three CF dyslipidaemia disturbances was present in 62% of CF subjects, but there were no significant differences in oxLDL, oxLDL/LDL-C ratio, adiponectin, and APOE between CF and HS groups. PI was independently associated with low total cholesterol, LDL-C, and non-high density lipoprotein cholesterol, with age and sex also modifying lipid levels. In CF (n = 42), triglycerides did not correlate with serum tumour necrosis factor α (TNF-α)., Conclusions: CF dyslipidaemia is highly prevalent and heterogenous. The lipid profile weakly associates with the clinical characteristics of CF as well as oxLDL, adiponectin, and APOE. Further research is needed, especially regarding HDL function in CF, the causes of hypertriglyceridaemia, and the value of essential fatty acid supplementation for CF dyslipidaemia., (Copyright © 2019. Published by Elsevier B.V.)