Search

Background Host intestinal immune gene signatures and microbial dysregulations expose potential mechanisms in the pathogenesis of inflammatory bowel diseases (IBD). Profiling of mucosa-attached microbiota allows the understanding of locally present microbial communities and their immediate impact on the host. This study aimed to comprehensively examine interactions between host mucosal gene expression and mucosal microbiota in patients with IBD. Methods Intestinal mucosal RNA-sequencing data was combined with mucosal 16S rRNA gene sequencing data from 696 intestinal biopsies derived from 337 patients with IBD (181 with Crohn’s disease [CD] and 156 with ulcerative colitis [UC]) and 16 non-IBD controls (Fig. 1). Mucosal gene expression and bacterial abundances were systematically analyzed in relation to the presence of inflammation, Montreal disease classification, medication use (e.g. TNF-α-antagonists) and dysbiotic status. Pathway-based clustering and network analysis (Sparse-CCA and centrLCC analysis) and individual pairwise gene–taxa associations were investigated to identify host–microbiota interactions in different clinical contexts. Subsequently, the contribution of microbiota to variation in intestinal cell type–enrichment was analyzed. To confirm the key findings, we used publicly available mucosal 16S and RNA-seq datasets for external validation. Results In total, 1,141 inflammation-specific genes and 131 microbial taxa were identified, which were further classified by sparse-CCA into six hubs of molecular pathways associated with specific bacterial groups (FDR Conclusion This study is the largest of its kind demonstrating the diversity and versatility of host-microbe interactions in IBD. Furthermore, it highlights the strong effects of patient traits on these interactions, providing important pathophysiological insights. Overall, we identify multiple host–microbe interactions that may guide microbiota-directed personalized medicine in IBD.

Editorial from Primary hrHPV DNA Testing in Cervical Cancer Screening: How to Manage Screen-Positive Women? A POBASCAM Trial Substudy

Background Protein profiling in patients with inflammatory bowel diseases (IBD) for diagnostic and therapeutic purposes is underexplored. Assessment of interactions between genetics and the plasma proteome could lead to identification of novel disease-associated molecular pathways. In this study, we performed the largest gene-protein association analysis thus far in patients with IBD, taking into account relevant phenotypic covariates and integrating information from multiple biological data layers. Methods Ninety-two (92) inflammation-related proteins were quantified in plasma of 1,028 patients with IBD (567 Crohn’s disease [CD]; 461 ulcerative colitis [UC]) and 148 healthy individuals to assess proteome-phenotype associations. Both whole-exome sequencing (WES) and global screening array (GSA) data of 919 patients with IBD were included to study associations between over 8 million genetic variants and protein levels (protein quantitative trait loci [pQTL]). Cis-pQTLs were defined within ± 1 Mb of the region of each protein-coding gene center, whereas trans-pQTLs were outside of that region. After adjusting for phenotypic covariates, a step-wise conditional analysis was used to identify all independent pQTLs in CD and UC separately, followed by a meta-analysis. Intestinal mucosal RNA sequencing and fecal metagenomic data were used for complementary analyses. Results Thirty-four (34) proteins were differentially abundant between IBD and healthy individuals, of which 24 proteins independent of active inflammation. (Figure 1) Seventy-two (72) proteins were significantly associated to 14 phenotypic factors, including age, sex, medication use, and surgical history. (Figure 2) Fibroblast growth factor-19 (FGF-19) levels were decreased in CD patients with ileal disease or a history of ileocecal resection. Thirteen (13) novel cis-pQTL variants were identified and 10 replicated from previous studies, together affecting 21 different plasma proteins. One trans-pQTL variant of the FUT2 gene (rs602662) and two independent cis-pQTL variants of the CCL25 gene significantly affected plasma C-C motif chemokine ligand 25 (CCL25) levels. (Figure 3) Intestinal gene expression data revealed an overlapping cis-expression (e)QTL-variant (rs3745387) of the CCL25 gene. The FUT2 rs602662 trans-pQTL variant associated significantly with reduced abundances of multiple fecal butyrate-producing bacteria, including the genus Blautia and the species Faecalibacterium prausnitzii. Conclusion This study shows that both genotype and multiple disease phenotypes strongly associate with the plasma proteome in patients with IBD and identifies disease-associated pathways that may help to improve disease management in the future.

Background Patients with IBD show distinct antibody responses, particularly against microbiota. However, a comprehensive overview of the antibody epitope repertoire in IBD is lacking. Here, we characterized serum antibody responses in patients with IBD and population controls using a high-throughput phage-displayed immunoprecipitation sequencing (PhIP-seq) workflow and associated these to disease phenotypes and the faecal microbiome. Methods PhIP-seq was leveraged to characterise antibody responses against 344,000 rationally selected peptide antigens in 497 patients with IBD which were compared with 1,326 individuals from a population-based cohort (Fig. 1A-B). Antibody profiles were linked to 23 IBD-specific clinical features such as disease location and surgical history and to faecal microbiota composition (Fig. 1C). Results Patients with IBD demonstrated distinct antibody epitope repertoires compared with individuals from the general population, with 373 differentially abundant antibody-bound peptides (202 overrepresented, 171 underrepresented) belonging to bacterial flagellins (69), virulence factors (102), other antigens of both commensal and pathogenic bacteria (90) as well as viruses (67) and food proteins (24) (Figure 2). In particular, antibody responses against bacterial flagellins, many of which belong to Lachnospiraceae bacteria (e.g. Roseburia spp.), but also Eubacterium spp. and pathogens (e.g. Legionella, Clostridium, Burkholderia) dominated in patients with Crohn’s disease (CD), and were associated with ileal disease involvement and more complicated disease behaviour (e.g. fibrostenotic disease, surgical history) as well as anti-Saccharomyces cerevisiae antibody positivity. Furthermore, many other antigens were newly identified, e.g. decreased responses to E. coli virulence factors and genome polyproteins of enteroviruses, and increased responses to food antigens (wheat, barley) and autoantigens (particularly collagen type I and VI). Antibody epitope repertoires were able to accurately discriminate CD from population controls (area under the curve [AUC]=0.88, test set evaluation), showing very high discriminative performance (positive and negative predictive value of 72% and 93%, respectively, representing predicted classes in test set) (Fig. 3A-C), which was less accurate for ulcerative colitis (UC) (Fig. 3D-F). Conclusion This study demonstrates the size, diversity and complexity of systemic antibody epitope repertoires in patients with IBD compared to controls, showing that distinct clinical phenotypes of IBD are characterized by unique antibody signatures. PhIP-seq is a powerful tool for identifying systemic immune-based biomarkers and exposing novel immunological targets in immune-mediated inflammatory diseases like IBD.

Background Clinicians face difficulty in positioning biologics and JAK inhibitors in anti-TNF refractory ulcerative colitis (UC) patients. Head-to-head trials comparing the efficacy of vedolizumab and tofacitinib in UC patients are lacking. We aimed to compare the effectiveness and safety of vedolizumab and tofacitinib in anti-TNF experienced UC patients in our prospective, nationwide registry using a propensity score weighted cohort. Methods UC patients who failed anti-TNF treatment (with or without thiopurine) and initiated vedolizumab or tofacitinib treatment subsequently, were identified in the observational prospective Initiative on Crohn and Colitis (ICC) Registry. We selected patients with both clinical (Simple Clinical Colitis Activity Index (SCCAI) >2) and biochemical (C-reactive protein (CRP) >5mg/L or faecal calprotectin (FC) >250 µg/g) or endoscopic disease activity (endoscopic MAYO score ≥ 1) at initiation of therapy. Patients previously treated with vedolizumab or tofacitinib were excluded. Corticosteroid-free clinical remission (SCCAI Results Overall, 83 vedolizumab and 65 tofacitinib treated patients were included (table 1). Propensity score weighted analysis showed that tofacitinib treated patients were more likely to achieve corticosteroid-free clinical remission at week 12, 24 and 52 compared to vedolizumab treated patients (OR: 5.87, 95%CI:3.55–9.70, P Conclusion In tofacitinib treated, anti-TNF experienced, UC patients, we observed that a higher proportion of patients achieved corticosteroid-free remission after 12, 24 and 52 weeks compared to vedolizumab treated patients. In addition, more tofacitinib treated patients achieved biochemical remission at week 12 and 24. There was no statistically significant difference in severe adverse events.

Background Introduction: Neutrophils and neutrophil extracellular traps (NETs) play a significant role in the pathogenesis of ulcerative colitis (UC), a chronic and relapsing inflammatory disease of the colon. Low-density neutrophils (LDNs) are a recently identified subset of neutrophils that are more prone to develop NETs and produce more pro-inflammatory cytokines and calprotectin than neutrophils of normal density. Moreover, LDNs show reduced phagocytotic activity towards bacteria. LDNs are subclassified as mature (CD15+CD14-CD10+) and immature (CD15+CD14-CD10-) based on CD10 expression, of which the immature LDNs are most pro-inflammatory. LDNs have been identified in a number of autoimmune diseases, including systemic lupus erythematosus, psoriasis, antineutrophil cytoplasmic antibody-associated vasculitis, and rheumatoid arthritis, but not yet studied in UC. Objective Examine the existence of LDNs in UC patients and their possible association to disease severity. Methods A total of 13 healthy controls and 20 patients with UC were included. Their clinical activity was evaluated with the Truelove-Witts score. LDNs and subtypes were quantified by flow cytometry in the peripheral blood mononuclear cells (PBMC). Results The relative abundance of LDNs was significantly higher in UC patients compared to healthy controls (1.55±1.14 vs. 0.62±0.36 respectively, P Figure 1 Figure 2 Conclusion LDNs levels are elevated in PBMCs of patients with UC and pro-inflammatory immature LDNs are associated with disease activity.

Background Biological treatment in inflammatory bowel disease (IBD) patients is currently hampered by high non-response rates. To enhance personalized medicine and predict response to biological therapeutics such as vedolizumab, the working mechanism should be elucidated. We aimed to visualize macroscopic and microscopic vedolizumab distribution and detect drug target cells during quantified fluorescence molecular endoscopy (QFME) to improve understanding of the mechanism of action. Methods Vedolizumab-800CW was developed and GMP produced. Forty-three QFME procedures were performed in thirty-seven IBD patients two to four days after intravenous administration of vedolizumab-800CW. Each QFME procedure consisted out of endoscopic assessment of the inflammation status per colonic segment by high-definition white light endoscopy, followed by real-time in vivo assessment of the macro-distribution of fluorescent vedolizumab-800CW signal and quantification by spectroscopy of selected segments. Dose escalation was performed using 0.0 mg, 4.5 mg and 15 mg. Subsequently, two patient cohorts were added that received a dose of 75 mg or 300 mg unlabelled vedolizumab prior to vedolizumab-800CW to assess target saturation. Tissue biopsies were obtained for histopathological assessment, for further ex vivo analysis of the fluorescent signal and for visualization of the microscopic distribution and identification of vedolizumab-800CW target cells by fluorescence microscopy (fig 1). Results Both during in vivo QFME and ex vivo analysis a clear dose- and inflammation severity-dependent increase of the fluorescent drug signal was revealed (fig 2). A significant difference was found between the dose groups for non-inflamed (p=0.0004), mild inflamed (p=0.0397) and severe inflamed (p=0.0056) tissue. In addition, the difference in intrinsic fluorescence between the severe inflamed tissue and non-inflamed tissue was significant within the 15 mg (p Conclusion QFME using vedolizumab-800CW elucidated novel detailed macroscopic and microscopic vedolizumab distribution in the inflamed target organ. In addition, its shows the potential of QFME to better understand local drug distribution, target cell identification and target engagement, which could improve understanding of targeted drugs over standard pharmacokinetic and pharmacodynamic analysis.

Background The number of mucosal neutrophils, as well as the presence of neutrophil extracellular traps (NETs), correlate with disease activity in Ulcerative colitis (UC), an inflammatory bowel disease. Most (~80%) UC patients present atypical Anti-Neutrophil Cytoplasmatic Antibodies (a-ANCAs) to a yet unknown antigen, which shows a different immunofluorescence staining pattern when compared to cytoplasmatic (c-ANCA) and perinuclear (p-ANCA) that target proteinase (PR3) and myeloperoxidase (MPO), respectively. Here, we analyzed whether a-ANCAs specifically bind to NETs. Methods Blood neutrophils were treated to form non-lytic NETs using LPS-treated platelets with and without DNAse and Trypsin. Patient biopsies and in vitro-formed non-lytic NETs were incubated with p-ANCA, c-ANCA and a-ANCA positive patient and ANCA negative control serum and processed for immunofluorescence microscopy. Macrophage-mediated clearance of serum-pretreated NETs was analyzed in real-time using Incucyte microscopy. Results Ethanol-fixed neutrophils displayed c-ANCA, p-ANCA patterns, and a-ANCA web-like staining. Only c- and p-ANCA react to DNAse-treated ethanol-fixed neutrophils (Fig 1). Serum containing a-ANCA’s bound to non-lytic NETs that disappeared upon treatment with DNAse and Trypsin whereas c- and p- ANCA binding did not disappear upon DNAse treatment (Fig 2) indicating that both DNA and proteins are needed for a-ANCAs to bind to non-lytic NETs. In inflamed colonic tissue of UC patients, a-ANCA co-stained with extracellular DNA and neutrophil elastase covering the intestinal epithelium (Fig 3). In vitro, NETs were efficiently cleared by macrophages, which was strongly inhibited after pre-incubating with a-ANCAs (Fig 4). Macrophages exposed to a-ANCA-incubated NETs expressed higher CXCL-8 and IFN-B levels than the NETs exposed to control serum (both p Figure 1 Figure 2 Figure 3 Figure 4 Conclusion a-ANCAs specifically bind to de novo DNA-protein antigens in non-lytic NETs, which prevents efficient macrophage-mediated clearance and induces a pro-inflammatory (M1) phenotype. This inflammatory milieu may contribute to the pathophysiology of UC.

Aims In patients with a history of chronic alcohol abuse, neurocognitive disorders (NCD) are not uncommon. The current study aimed to explore the course of cognitive performance, as measured by the Montreal Cognitive Assessment (MoCA), and everyday cognitive functioning, as measured by the Patient Competency Rating Scale (PCRS), in a large group of patients with alcohol use disorder (AUD) admitted to the Center of Excellence for Korsakov and Alcohol-related Cognitive Impairments. Methods A multiple time-series design was used, in which the MoCA was administered at three time points of assessment, and the PCRS was completed by both the patient and a clinician at two time points, all during clinical treatment. Results A total of 524 patients were included, 71 of whom were diagnosed with AUD only, 284 with AUD and mild NCD (ARCI) and 169 with AUD, major NCD and fulfilling criteria for Korsakoff’s syndrome (KS). Conclusions Cognitive performance improved for all three groups during treatment, sustained abstinence and recovery from AUD. A low memory performance on the MoCA without improvement over time was predictive for KS, while improvement on this domain did not differentiate between AUD and ARCI. Changes in overall cognitive performance and orientation in patients with KS were positively related to changes in everyday cognitive functioning., Short Summary Cognitive performance improves during treatment, sustained abstinence and recovery from AUD. Low memory performance without improvement over time predicted KS, while improvement in memory did not differentiate between AUD and ARCI. Changes in overall cognitive performance and orientation in KS patients were positively related to changes in everyday cognitive functioning.

Contains fulltext : 219365.pdf (Publisher’s version ) (Open Access) Background: The gamma-hydroxybutyric acid (GHB) withdrawal syndrome often has a fulminant course, with a rapid onset and swift progression of severe complications. In clinical practice, two pharmacological regimens are commonly used to counteract withdrawal symptoms during GHB detoxification: tapering with benzodiazepines (BZDs) or tapering with pharmaceutical GHB. In Belgium, standard treatment is tapering with BZDs, while in the Netherlands, pharmaceutical GHB is the preferred treatment method. Though BZDs are cheaper and readily available, case studies suggest GHB tapering results in less severe withdrawal and fewer complications. Objectives: This study aimed to compare two treatments-as-usual in tapering methods on withdrawal, craving and adverse events during detoxification in GHB-dependent patients. Methods: In this multicentre non-randomised indirect comparison of two treatments-as-usual, patients with GHB dependence received BZD tapering (Belgian sample: n = 42) or GHB tapering (Dutch sample: n = 42, matched historical sample). Withdrawal was assessed using the Subjective and Objective Withdrawal Scales, craving was assessed with a Visual Analogue Scale and adverse events were systematically recorded. Differences in withdrawal and craving were analysed using a linear mixed-model analysis, with 'days in admission' and 'detoxification method' as fixed factors. Differences in adverse events were analysed using a Chi-square analysis. Results: Withdrawal decreased over time in both groups. Withdrawal severity was higher in patients receiving BZD tapering (subjective mean = 36.50, standard deviation = 21.08; objective mean = 8.05, standard deviation = 4.68) than in patients receiving pharmaceutical GHB tapering (subjective mean = 15.90; standard deviation = 13.83; objective mean = 3.72; standard deviation = 2.56). No differences in craving were found. Adverse events were more common in the BZD than the GHB group, especially delirium (20 vs 2.5%, respectively). Conclusions: These results support earlier work that BZD tapering might not always sufficiently dampen withdrawal in GHB-dependent patients. However, it needs to be taken into account that both treatments were assessed in separate countries. Based on the current findings, tapering with pharmaceutical GHB could be considered for patients with GHB dependence during detoxification, as it has potentially less severe withdrawal and fewer complications than BZD tapering. 9 p.

Contains fulltext : 203443.pdf (Publisher’s version ) (Open Access) Introduction and Aims: Cognitive impairments in substance use disorder predict treatment outcome and are assumed to differ between substances. They often go undetected, thus the current study focuses on the prevalence of and differences in cognitive functioning across substances by means of a cognitive screen at the early stage of addiction treatment. Design and Methods: The Montreal Cognitive Assessment was administered to outpatients seeking treatment for substance use disorder. Patient characteristics (age, years of regular use, polysubstance use, severity of dependence/abuse, depression, anxiety and stress) were also taken into account. Results: A total of 656 patients were included (n = 391 used alcohol, n = 123 used cannabis, n = 100 used stimulants and n = 26 used opioids). The prevalence of cognitive impairments was 31%. Patients using alcohol had a lower total- and memory domain score than those using cannabis. Patients using opioids scored lower on visuospatial abilities than those using cannabis or stimulants. Younger patients scored higher than older patients. No effect was found for the other investigated characteristics. Discussion and Conclusions: Given the high prevalence of cognitive impairments, standard screening at an early stage of treatment is important to determine the course of treatment and maximise treatment outcome. Caution is needed in interpreting results about opioids due to an underrepresentation of this patient group, and more research is needed on the effect of age on Montreal Cognitive Assessment performance. 8 p.

Background Although colorectal cancer (CRC) surveillance is embedded in IBD practice, a subset of patients still develops advanced neoplasia (AN; high-grade dysplasia (HGD) and/or CRC). We aimed to determine the most plausible explanations for AN in IBD patients through assessment of inadequate surveillance. Methods A search of the nationwide histopathology registry of the Netherlands (PALGA) was used to identify IBD patients with AN in seven hospitals. Patients with ulcerative colitis (UC), Crohn’s disease (CD), or IBD-unclassified (IBD-U) from 1 January 1991 until 1 October 2020 were eligible for inclusion. Exclusion criteria comprised familial CRC or AN prior to IBD diagnosis. A root-cause analysis based on the World Endoscopy Organizations’ recommendations was performed to determine inadequate surveillance prior to the first AN, including lack of cecal intubation, insufficient bowel preparation (BBPS Results We included 179 patients with AN (figure 1). Of these, 22 patients (12.3%) were diagnosed with AN before surveillance was indicated. Inadequate surveillance was present in 122 patients (68.2%, n=50 HGD, n=72 CRC), of whom 47 patients (26.3%) did not receive any surveillance colonoscopy before AN diagnosis. A delayed surveillance interval was identified in 44 patients (24.6%), with a median deviation from surveillance recommendations of 19.0 months (IQR 9.5–28.5 months). Furthermore, 56 patients (31.3%) had active inflammation, three had insufficient bowel preparation, and two patients had an incomplete colonoscopy. Younger age at diagnosis (annual OR 0.96, 95% CI 0.94–0.98, p Figure 1. Root-cause analysis flowchart Conclusion The majority of IBD patients with AN in our cohort had prior inadequate surveillance. This observation underlines the importance of adequate surveillance and guideline adherence.

Background Inflammatory bowel disease (IBD) patients are at increased risk of advanced neoplasia (AN) including high grade dysplasia (HGD) and colorectal cancer (CRC). Historically, a (sub)total colectomy was recommended in these patients, but alternatively, endoscopic resection or partial colectomy can be considered as well. We aimed (1) to identify factors associated with AN treatment choice and (2) to assess AN recurrence rates following different treatment modalities. Methods In this retrospective multi-center cohort study we used the Dutch nationwide histopathology registry (PALGA) to identify ulcerative colitis (UC), Crohn’s disease (CD) and IBD-unclassified patients diagnosed with colonic AN between 1991 and 2020 in seven hospitals in the Netherlands. Exclusion criteria were familial CRC or AN prior to IBD diagnosis. Data regarding the first (index) AN, treatment and endoscopic and surgical follow-up were collected. Recurrence was defined as colorectal AN (independent of colonic location) detected after treatment of index AN. Multinomial logistic regression and cox regression analysis were used to assess in respective associations with treatment choice and recurrence free survival. Results We included 189 patients with index AN (n=81 HGD, n=108 CRC) with a median follow up of 27 months (IQR 7–69 months). (Sub)total colectomy was performed in 79 patients (41.8%; n=33 HGD, n=46 CRC), whereas 55 patients (29.1%; n=12 HGD, n=43 CRC) had a partial colectomy. Endoscopic resection was performed in 38 patients (20.1%; n=35 HGD, n=3 CRC), of which EMR/ESD n=12 (6.3%). Seventeen lesions (8.9%; n=1 HGD, n=16 CRC) were not removed, due to comorbidity or metastatic disease. CRC, primary sclerosing cholangitis (PSC), extensive disease and younger age at time of index AN were associated with (sub)total colectomy (Table 1). Twenty-one patients (12.2%) developed recurrence AN (n=12 HGD, n=9 CRC), after a median of 24 months (IQR 14–48; figure 1). Endoscopic resection was associated with recurrence (adjusted hazard ratio 4.0, confidence interval [1.3–12.2], p=0.02), as 14/21 patients (66.7%) with recurrence were initially (for index AN) treated with endoscopic resection. In addition, 3 patients (14.3%) were treated with partial colectomy and 4 (19.0%) with (sub)total colectomy. In 11/21 patients (52.4%) recurrence was treated with surgical resection. Conclusion Factors associated with AN treatment with (sub)total colectomy were CRC, PSC, extensive disease and younger age. After AN treatment, 1 out of 10 IBD patients developed recurrence of AN, mainly after endoscopic resection. This underlines the importance of stringent endoscopic surveillance following treatment of AN, especially after endoscopic resection with residual colon in place.

Background Crohn‘s disease (CD) is a form of inflammatory bowel disease characterized by high infiltration of immune cells into the intestinal tissue, resulting in increased proteolytic mediated extracellular matrix (ECM) remodeling. Disease management has improved with the use of biologics such as vedolizumab (VEDO). However, considering the high rate of primary non-response to VEDO, there is an unmet need for predictive serum biomarkers capable of determining response to treatment prior to its initiation. This study investigated whether biomarkers of neutrophil activity, mucosal damage, and ECM remodeling could serve as non-invasive tools for predicting long-term response to VEDO in patients with CD. Methods Serum biomarkers of human neutrophil elastase (HNE)-derived fragment of calprotectin (CPa9-HNE [serum calprotectin]) and matrix metalloproteinase (MMP)-derived fragments of type I (C1M), III (C3M), IV (C4M), type III collagen formation (PRO-C3), basement membrane turnover (PRO-C4) and T-cell activity (C4G), were measured using protein fingerprint assays in patients with CD (n=32) before VEDO therapy initiation. The ratio C4M/C4G (myeloid/lymphoid mediated degradation) was computed. Long-term response was defined as the continuation of treatment beyond one year after the start of therapy. Baseline biomarker levels were compared between responders and non-responders using Mann-Whitney U-tests, and area under the curve (AUC) values were generated using receiver operating characteristics (ROC) statistics. Biomarker levels were divided into tertiles and chi-square tests were used to investigate the relationship between tertiles and response proportions. Results Biomarkers CPa9-HNE, C1M, C3M, C4M, PRO-C3, C3M/PRO-C3, and C4M/C4G were significantly increased at baseline in non-responders compared with responders (all P Conclusion Baseline levels of serum biomarkers for neutrophil activity (CPa9-HNE [serum calprotectin]) and mucosal damage (C1M, C3M, C4M, C4G, PRO-C4, and PRO-C3) could predict long-term response to VEDO in patients with CD. Therefore, these biomarkers could aid in early decision making concerning treatment with vedolizumab in patients with CD.

Background In patients with Crohn’s disease (CD), postoperative prophylactic medication based on clinical risk stratification is recommended in international guidelines to prevent recurrence after ileocolonic resection (ICR). This study aimed to evaluate the risk of endoscopic recurrence after implementation of a predefined management algorithm after ICR incorporating clinical risk stratification. Methods In this multicenter, prospective clinical cohort study, CD patients (≥16 years) were included who were scheduled for ICR and gave informed consent. Endoscopy-guided treatment (no prophylactic medication directly after ICR) was recommended in patients at low risk (LR) of postoperative recurrence, and prophylactic medication (immunosuppressant/biological) in high risk (HR). HR was defined as ≥1 risk factor: smoking, penetrating disease, re-resection. Clinical and histologic risk factors for endoscopic recurrence (Rutgeerts’ score ≥i2) were assessed using logistic regression models and ROC curves based on predicted probabilities. Results In total 213 CD patients were included (median age 34.5 years, 65.3% women): 93 (43.7%) at LR and 120 (56.3%) at HR (smoking 45 (21.3%); penetrating disease 51 (23.9%); re-resection 51 (23.9%)). Adherence to the proposed management algorithm was 65%; 76/93 (81.7%) in the LR (no prophylaxis) and 61/120 (50.8%) in the HR population (prophylaxis). Endoscopic recurrence in LR patients was 69% without prophylaxis versus 48% with prophylaxis (p=0.070); in HR 78% without prophylaxis versus 55% with prophylaxis (p=0.019). Clinical risk stratification corresponded with an area under the curve (AUC) of 0.64 (95%CI 0.55–0.73) (Figure 1). Clinical factors combined with histology (active inflammation, granulomas, plexitis in resection margins) increased the AUC to 0.69 (95% CI 0.61–0.88) (Figure 1). Conclusion This prophylactic medication algorithm in CD patients based on clinical risk stratification after ICR, results in an absolute risk reduction of endoscopic recurrence of 23% in HR versus 21% increase in LR patients in whom medication is omitted. For this latter population, further refinement of risk stratification is required, and may include histologic assessment.

Background Differentiating absolute iron deficiency from functional iron restriction is challenging in active Inflammatory Bowel Disease (IBD). Hepcidin, the systemic iron regulator, could be the key in the diagnosis and management of absolute iron deficiency. In this study, we assessed hepcidin as a diagnostic iron deficiency marker and we explored the relationship between hepcidin, inflammation, hypoxia, and iron deficiency in patients receiving induction therapy with infliximab (IFX) or vedolizumab (VEDO). Methods 130 patients with IBD, who received induction therapy with IFX or VEDO for active disease, were included in this study. Clinical and biochemical data were extracted from medical records. Serum samples at baseline and week 6 of induction therapy were retrieved from the University Medical Center Groningen (UMCG) biobank and analysed for: hepcidin, inflammation (e.g., interleukins [IL] 6, 10, and Tumour Necrosis Factor-α [TNFα]), oxidative stress (free thiols), and hypoxia (e.g., erythropoietin [EPO], Macrophage Inflammatory Protein-3α [MIP3α]). For comparison, serum samples from 50 age- and gender-matched healthy controls were obtained from pre-donation biobank at the UMCG. Response to therapy was defined by either General Physician’s Assessment at week 14 of induction therapy, normalisation or at least a three-point decrease in clinical scores: Harvey-Bradshaw Index (HBI) for Crohn’s Disease, Simple Clinical Colitis Activity Index (SCCAI) for ulcerative colitis. Results Hepcidin correlated with ferritin and sTfR/log ferritin index [ρ = 0.74 and ρ = -0.79, respectively; P Conclusion Hepcidin reflects iron deficiency in active IBD, but inflammation masks the severity of the deficiency. Induction therapy with either IFX or VEDO modulates hepcidin and iron indices, especially in patients who respond to the therapy.

Background Fatigue is a common and clinically challenging symptom in patients with inflammatory bowel diseases (IBD). While fatigue occurs most often in patients with active disease, up to 50% of patients with quiescent disease still report significant fatigue of unknown aetiology. Here, we aimed to investigate whether fatigue in patients with quiescent IBD is reflected by circulating inflammatory proteins, that in turn might reflect ongoing subclinical inflammation. Methods Ninety-two (92) different inflammation-related proteins were measured in plasma of 350 patients with quiescent IBD (188 Crohn’s disease [CD]; 162 ulcerative colitis [UC]). Quiescent IBD was defined as clinical (Harvey-Bradshaw Index [HBI] Results None of the analysed plasma proteins were differentially abundant between mildly (1st quartile, Q1) or severely (4th quartile, Q4) fatigued patients under a false discovery rate of 10%. Considering nominal significance (P Conclusion Fatigue in patients with IBD is not clearly reflected by distinct circulating inflammatory protein signatures, which suggests that subclinical immune activation as defined by the studied panel of inflammatory proteins could not be detected. Reduced shedding of the LIF-R protein could be related to fatigue in IBD through modification of the oncostatin-M (OSM) signaling pathway, or through induction of pro-inflammatory phenotypes of T-cells, macrophages, or neural cells. Future studies are warranted to investigate other proteomic or metabolic markers that may accurately reflect fatigue in quiescent IBD, which might represent alternative pathophysiological pathways.

Background Crohn’s disease (CD) and ulcerative colitis (UC) are characterized by intestinal inflammation and increased extracellular matrix (ECM) remodeling, which are key pathophysiological mechanisms in patients with IBD and highly related to mucosal damage. Alterations in intestinal ECM turnover as well as macrophage and neutrophil activity may be reflected by secreted products that are released into the systemic circulation. In this study, we aimed to investigate associations between serum biomarkers of neutrophil activity (serum calprotectin) and collagen degradation (mucosal damage), and disease activity in patients with IBD. Methods Serological biomarkers of collagen formation (PRO-C3, PRO-C4, PRO-C6), matrix metalloproteinase (MMP)-mediated collagen degradation (C1M, C3M, C4M, C4G, C6Ma3) and intestinal inflammation (VICM [macrophage activity], human neutrophil elastase-derived fragment of calprotectin (CPa9-HNE [serum calprotectin, neutrophil activity]) were measured using Protein FingerPrint assay (PFA) technology in 100 patients with IBD (CD: n=44; UC: n=56). Biochemical disease activity was assessed using C-reactive protein (CRP) levels and available faecal calprotectin (FCal) levels. Endoscopic disease activity was determined using the Simple Endoscopic Score for CD (SES-CD) and Mayo endoscopic subscore for UC. Results C1M strongly associated with elevated CRP levels (defined as >5mg/L, P Conclusion C1M and CPa9-HNE levels associate with biochemical (CRP, FCal) and endoscopic disease activity in patients IBD, where C1M demonstrated higher accuracy in UC and CPa9-HNE appeared to be more useful in CD in this cohort. Therefore, C1M and CPa9-HNE could serve as surrogate biomarkers for the assessment of disease activity in patients with UC and CD, respectively. Our results should be validated in additional prospective, larger patient cohorts to corroborate these findings.

Background Inflammatory bowel disease (IBD) is characterized by a disturbed gut microbiota composition. Patients with IBD have elevated levels of mucosal and serum levels of IgG-antibodies directed against bacterial antigens, including flagellins. In this study, we aimed to determine to which faecal bacteria the humoral immune response is directed to in patients with IBD. Methods Faecal and serum samples were collected from patients with IBD (n=55) and age- and sex-matched healthy controls (n=55). Faecal samples were incubated with autologous serum and IgG-coated fractions were isolated by magnetic-activated cell sorting (MACS) and the coating efficiency was assessed by flow cytometry. Bacterial composition of both untreated and IgG-sorted fecal samples was determined by 16S rRNA-gene Illumina sequencing. Results Serum IgG responses were primarily directed to typical small intestinal bacterial genera, including Streptococcus, Lactobacillus, Lactococcus, Enterococcus, Veillonella and Enterobacteriaceae, as well as against specific Lachnospiraceae bacteria, including Coprococcus and Dorea (all P Conclusion The IgG immune response is specifically targeted at typical small intestinal bacterial genera, whereas responses against commensal, rather colonic-type microbiota are lower in patients with IBD. These findings may be indicative of a strong immunological exposure to small intestinal bacteria in concordance with relative immune tolerance against commensal bacteria.

Background Subcutaneous (SC) formulation of vedolizumab (VDZ) is available for Crohn’s disease (CD) and ulcerative colitis (UC). We assessed the efficacy, safety, and pharmacokinetic (PK) profiles of patients with inflammatory bowel diseases (IBD) who switched from intravenous (IV) to SC VDZ treatment in two prospective, real world cohorts. Methods The primary cohort is an ongoing open-label, real life, prospective single centre cohort study. As a validation cohort, we used the Initiative on Crohn and Colitis (ICC) registry, a prospective, observational, nationwide registry including patients switching from IV to SC VDZ. In both cohorts, patients receiving IV VDZ maintenance for >4 months were offered to switch treatment to SC VDZ, 108 mg every 2 weeks. In the primary cohort, assessment of clinical, biochemical and PK parameters took place at baseline, at approximately 10 weeks following the switch and at the physician’s discretion thereafter. In the ICC cohort, follow up visits were at week 12 and 24. The primary endpoint was the proportion of patients discontinuing SC VDZ at week 24. Results In total, 78 (50 CD (64%) and 28 UC (36%)) and 54 patients (29 CD (54%) and 25 UC (46%)) were included in the primary and ICC cohort respectively (table 1). During follow up, 8 (10.3%) of the primary cohort and 6 (11.1%) patients of the ICC cohort stopped VDZ SC during follow-up time till week 24, after a median treatment duration of 18 (IQR=5–19) and 10 (IQR=7–15) weeks, respectively. Treatment withdrawal was most often caused by adverse events (AE), in total for 8 out of 132 patients (6%) (table 2). Four patients had loss of response to SC VDZ. Three of these patients had biochemical disease activity at initiation of SC therapy. Reported AEs included headache and injection related reactions. The median VDZ concentration increased from 11 ug/mL (IQR=9.4–20) to 28 ug/mL (IQR=24.3–31.2, p Conclusion The present abstract reports real world experience of switching IV to SC VDZ maintenance treatment in IBD patients in two observational Dutch cohorts. VDZ concentrations were significantly higher after the switch to SC VDZ. A switch from IV to SC VDZ appears to be effective and safe. However, a proportion of patients switched back to IV VDZ due to injection related AEs.

Background Host intestinal immune gene signatures and microbial dysregulations expose potential mechanisms in the pathogenesis of inflammatory bowel diseases (IBD). Profiling of mucosa-attached microbiota allows the understanding of locally present microbial communities and their immediate impact on the host. This study evaluated interactions between host mucosal gene expression and intestinal mucosa-attached microbiota in IBD. Methods Intestinal mucosal bulk RNA-sequencing data was combined with mucosal 16S rRNA gene sequencing data from 696 intestinal biopsies derived from 337 patients with IBD (181 with Crohn’s disease [CD] and 156 with ulcerative colitis [UC]) and 16 non-IBD controls. Hierarchical all-against-all associations testing (HAllA) was used to assess factors affecting host gene expressions and microbiota. Mucosal cell enrichments were predicted by deconvolution. Linear mixed interaction models were used to investigate host-microbiota interactions, adjusting for age, sex, BMI and batch effects. Variation explanation analysis was performed by Lasso regression. Results In total, 15,934 intestinal genes and 113 microbial taxa were identified and included in subsequent analyses. Host intestinal gene expressions were characterized by tissue- and inflammation-specificity, whereas intraindividual variability of the mucosal microbiota dominated over disease location and inflammation effects. We observed forty associations between the mucosal expression of genes and the abundance of specific microbes independent of dysbiosis (FDR Conclusion Interactions between host intestinal gene expressions and mucosa-attached microbiota are disrupted in patients with IBD. Furthermore, mucosal microbiota are highly personalized and potentially contribute to intestinal cell type alterations. Our study unravels key immune-mediated molecular pathways and relevant bacteria in intestinal tissue, which may guide drug development and precision medicine in IBD.

Background Vedolizumab is a monoclonal antibody which blocks integrin α4β7 inhibiting trafficking of T-lymphocytes into the gut. Unfortunately, up to 60% of vedolizumab patients experience non-response. The mechanism of action of vedolizumab is not elucidated, predictors of response are unknown and data for local drug distribution in the gut are lacking. In this clinical trial, we investigated the feasibility of assessing local distribution of fluorescently labelled vedolizumab in the gut mucosa of inflammatory bowel diseases (IBD) patients to finally enable prediction of therapy response in individual patients. Methods Vedolizumab (Entyvio, Takeda Pharma) was labelled to IRDye 800CW under cGMP conditions to yield clinical grade vedolizumab-800CW. In this dose-escalation trial, vedolizumab naïve IBD patients and IBD patients treated with vedolizumab for at least 14 weeks were included. Patients received an intravenous dose of fluorescently labelled vedolizumab of either 0 mg, 4.5 mg, 15 mg or 15 mg + 75 mg unlabelled vedolizumab 3 days prior colonoscopy. In vivo fluorescence imaging was assessed by fibre-based wide-field fluorescence molecular endoscopy (FME) and quantified by spectroscopy in healthy, mildly inflamed and severely inflamed tissue. All assessed tissue was biopsied for ex vivo examination of the fluorescent signal, fluorescence microscopy and spectroscopy. Results Up to submission 34 patients completed tracer injection and FME. An interim analysis was performed after 20 patients (5 in each dose group), which showed in severely inflamed tissue an 8 fold higher fluorescent signal in the 15 mg dose group (0.049 Q*μfa,x [mm-1]) compared to the control group (0.006 μfa,x [mm-1]) (p0.99), suggesting that the drug target was still not saturated. The optimal dosage group of 15 mg was expanded up to 18 IBD patients, amongst them 6 IBD patients after 14 weeks of treatment regimen. Fluorescence microscopy showed clustering of fluorescent signals especially in inflamed mucosa. Additional experiments to detect vedolizumab target cells are ongoing. Conclusion In vivo visualization of fluorescent vedolizumab revealed a clear dose-dependent correlation between mucosal drug concentrations and the severity of mucosal inflammation. Fluorescence molecular endoscopy is a promising novel tool to get insight in drug distribution in IBD, detect target cells, assess target engagement and possibly predict therapy response in individual patients.

Background Vedolizumab has shown efficacy, safety and tolerability as treatment for patients with inflammatory bowel disease (IBD). However, vedolizumab induction therapy only shows clinical response and remission in roughly 55% and 30% of IBD patients, respectively. Vedolizumab binds and blocks migration of T-lymphocytes and eosinophils. In this study, we aimed to explore the predictive value of mucosal eosinophils and serum eotaxin-1, an eosinophil chemoattractant, regarding response to vedolizumab induction therapy. Methods 84 IBD patients treated within the University Medical Center Groningen (UMCG) (37 Crohn’s disease [CD], 47 ulcerative colitis [UC]) were included. In a subset of 24 IBD patients (9 CD, 15 UC) histopathological data were analyzed for eosinophil counts in high power fields (hpf) in non-inflamed colon ascendens tissue prior to vedolizumab treatment. In another subset of 64 IBD patients, (28 CD, 36 UC) baseline serum eotaxin-1 was quantified prior to vedolizumab treatment. Clinical response or remission was defined as a decrease of the Harvey Bradshaw Index (HBI) for CD or Simple Clinical Colitis Activity Index (SCCAI) for UC together with physician’s global assessment (PGA). Serum eotaxin-1 was externally assessed as a biomarker for response to vedolizumab induction therapy in 100 IBD patients derived from the GEMINI 1 & 2 trials. Results Baseline eosinophil mucosal count was significantly higher in vedolizumab induction therapy responders, compared to primary non responders (69[34–138] vs. 24[18–28] eosinophils/hpf respectively, P 30 eosinophils/hpf with a sensitivity of 90.9% and specificity of 92.3% (Youden’s index 0.83). Results derived from the GEMINI I & II cohorts did not show any associations between eotaxin-1 levels and therapy response. Conclusion Mucosal eosinophil abundance in non-inflamed colon ascendens biopsies can predict vedolizumab induction therapy response in IBD patients. More studies are warranted to confirm these preliminary results and further investigate the additional value of eotaxin-1 regarding predicting vedolizumab therapy response.

Contains fulltext : 228501.pdf (Publisher’s version ) (Open Access) In the past decades, monitoring programs have been developed for healthcare professionals with substance use disorders. We aimed to explore estimates of abstinence and work retention rates after participation in such monitoring programs. A literature search was performed using PubMed, Embase, PsycINFO, and CINAHL. Twenty-nine observational studies reporting on success rates (abstinence and work retention) of monitoring for healthcare professionals with a substance use disorder were included in the meta-analysis. Quality-effects models calculated pooled success rates and corresponding 95%-Confidence Intervals (CI), with subgroup analyses on monitoring elements and patient characteristics. Pooled success rates were 72% for abstinence (95%-CI = 63-80%) and 77% for work retention (95%-CI = 61-90%). Heterogeneity across studies was partly explained by the starting moment of monitoring, showing higher abstinence rates for studies that started monitoring after treatment completion (79%; 95%-CI = 72-85%) compared to studies that started monitoring with treatment initiation (61%; 95%-CI = 50-72%). About three-quarters of healthcare professionals with substance use disorders participating in monitoring programs are abstinent during follow-up and working at the end of the follow-up period. Due to selection and publication bias, no firm conclusions can be drawn about the effectiveness of monitoring for healthcare professionals with SUD. 31 p.

Contains fulltext : 236708.pdf (Publisher’s version ) (Open Access) Background: Over the past decades gamma-hydroxybutyrate (GHB) has emerged as a popular drug with high potential of (ab)use due to its euphoric and relaxing effects. An overview of different populations using GHB is urgently needed, since this would enable development of adequate prevention and treatment policies to diminish the risks associated with GHB use. We systematically reviewed literature on different GHB using populations, comparing demographic characteristics, GHB use patterns, psychosocial aspects and psychiatric comorbidity. Methods: We conducted a systematic review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines using Rayyan software. Original studies published from January 1997 up to October 2019 on GHB use were included. Out of 80 full-text articles, 60 articles of 51 unique studies were included. Most studies included people using GHB 1) presenting at emergency departments (n = 22), 2) recruited from the general population (n = 11), or 3) presenting at addiction care (n = 8). Results: Three main sub-populations of people using GHB are described in the literature: people using GHB recreationally without adverse effects; people using GHB recreationally with adverse effects, and people with dependence on GHB. These groups show considerable overlap in gender, age range, and comorbid substance use, as well as amount of GHB use per occasion. Differences are related to frequency and function of GHB use, the number of comas experienced, as well as work status, and psychiatric comorbidity. Conclusion: Policy interventions should aim at preventing the transition from recreational substance use to GHB use, as most users are experienced recreational substance users prior to starting GHB use. When people use GHB regularly, interventions should aim at reducing the level of GHB use and preventing GHB use-related harm. Longitudinal studies and population-based probability sampling are required for more insight in the dynamics of GHB use in different sub-populations, and the transition from one group to the other, ultimately leading to dependence on GHB. 8 p.

Background Both vedolizumab and ustekinumab can be considered for the treatment of Crohn’s disease (CD) when anti-TNF treatment fails. However, head-to-head trials are currently not available or planned in the near future. The aim of this study was to compare vedolizumab and ustekinumab in CD patients using a quasi-experimental study design in a prospective registry specifically developed for comparative studies. Methods CD patients who failed anti-TNF treatment and started vedolizumab or ustekinumab in standard care as second-line biological and naïve to the latter two therapies, were identified in the observational prospective ICC Registry. Corticosteroid-free clinical remission (Harvey Bradshaw Index ≤4), biochemical remission (C-reactive protein ≤5 mg/l and faecal calprotectin ≤250 µg/g), combined corticosteroid-free clinical and biochemical remission, and safety outcomes were compared after 52 weeks of treatment. To adjust for confounding and selection bias, we used multiple logistic regression (correcting for current smoker, disease duration, complicated disease (stricturing or penetrating behaviour), prior CD-related surgery, number of prior anti-TNF treatments, HBI at baseline and biochemical disease at baseline) and propensity score matching (variables include the same variables as logistic regression analysis with addition of disease location and behaviour, corticosteroid and immunosuppressant use at baseline). Results In total, 128 vedolizumab- and 85 ustekinumab-treated patients fulfilled the inclusion criteria. By using propensity score matching, 69 vedolizumab-treated patients were matched with 69 ustekinumab-treated patients. After adjusting for confounders, ustekinumab-treated patients were more likely to achieve corticosteroid-free clinical remission (OR: 2.56, 95% CI: 1.35–4.87, p = 0.004), biochemical remission (OR: 2.22, 95% CI: 1.04–4.74, p = 0.040), and combined corticosteroid-free clinical and biochemical remission (OR: 2.58, 95% CI: 1.15–5.78, p = 0.022), while safety outcomes (infections: OR: 1.26, 95% CI: 0.63–2.54, p = 0.517; adverse events: OR: 1.33, 95% CI: 0.62–2.81, p = 0.464; hospitalisations: OR: 0.67, 95% CI: 0.32–1.39, p = 0.282) were comparable between the two groups. The propensity score matched cohort showed comparable results. Conclusion In this prospective, comparative analysis ustekinumab was associated with higher effectiveness outcomes of ustekinumab when compared with vedolizumab. Safety outcomes were comparable after 52 weeks of treatment in CD patients who have failed anti-TNF treatment.

Background The modified Rutgeerts score (mRS) differentiates i2 into lesions confined to the anastomosis (i2a) vs. ileal lesions (i2b), and is considered appropriate to assess postoperative recurrence in Crohn’s disease (CD) patients. This study aimed to assess the predictive value of mRS at index endoscopy after primary ileocolic resection for the risk of re-resection and severe endoscopic inflammation after long-term follow-up. In addition, we aimed to predict the association of i2a and i2b for both outcomes. Methods Data of CD patients who underwent a ICR, between 2000 – 2019, were retrospectively collected from a national, multicenter database. Patients were eligible for inclusion if ≥1 postoperative endoscopy assessed with the mRS was available. Primary outcome was re-resection per mRS (i0-i4) at index (i.e. first postoperative) endoscopy. Secondary outcome was severe endoscopic inflammation (defined as i3-i4) for a subset of patients (mRS i0-i2b). Rates for both outcomes were compared in subgroups (i0-i1, i2a-i2b, i3-i4) by Kaplan-Meier analyses. Multivariable analysis was conducted to identify risk factors for both outcomes. Results In total, 638 patients were included. Index endoscopy was performed at median 8.5 months (IQR: 5.9 – 22.8) after ICR(Table 1), with a mRS of i0(30.4%), i1(17.7%), i2a(15.8%), i2b(19.6%), i3(9.6%) and i4(6.9%). After a mean follow up of 6.5 years (SD: 4.7), re-resection rate (Figure 1) was 7.2% for patients with a mRS of i0, 6.2%(i1), 14.9%(i2a), 18.4%(i2b), 22.9%(i3) and 47.7%(i4). Re-resection rates in the subgroups were significantly higher in the group with a mRS i2a-i2b (16.8%) vs. i0-i1 (6.8%) (log-rank test, p Conclusion After primary ICR, the ascending order of the mRS corresponds with an increasing long-term risk of re-resection. In multivariable analysis, anastomotic lesions (i2a) are not significantly associated with the risk of re-resection and progression to severe endoscopic inflammation, in contrast to i2b lesions. The influence of therapeutic decisions on these associations requires further investigation.

Background Patients with Inflammatory Bowel Disease (IBD) frequently use immunomodulating treatment, which may render them at increased risk of attenuated immunogenicity after vaccination. Immunosuppressive drugs, such as TNF-α-antagonists, have shown an attenuating effect on serological response after SARS-CoV-2 infection. Here we assessed the effects of different types of immunosuppressive medications on the serological response after vaccination against SARS-CoV-2 in patients with IBD. Methods This was a prospective observational cohort study in patients with IBD of whom IgG antibody titers were measured after 2–10 weeks after full vaccination against SARS-CoV-2. Patient demographics, clinical characteristics as well as a previous history of SARS-Cov-2 infection, type of vaccine (mRNA or vector), and medication use were recorded at time of sampling. The primary study outcome was the anti-SARS-CoV-2 spike (S) antibody concentrations, measured using chemiluminescence microparticle immunoassay (CMIA) after full vaccination. Results 312 IBD patients were included (172 Crohn’s disease [CD] and 140 ulcerative colitis [UC]). Seroconversion (defined as titer of >50 AU/ml) was achieved in 98,3% of patients. Antibody concentrations were significantly lower in patients treated with TNF-α-antagonists vs. non-users of TNF-α-antagonists (geometric mean [95% confidence interval]: 2204 [1655–2935] vs. 5002 [4089–6116] AU/ml, P50 years) (-54%, P Conclusion TNF-α-antagonist use is strongly associated with an attenuated serological response after vaccination, independent of the type of vaccination (mRNA/vector), the time interval between vaccination and sampling, prior SARS-CoV-2 infection and patient age. Patients treated with systemic steroids who received mRNA vaccines demonstrated lower anti-SARS-CoV-2 antibody titers compared with patients who were steroid-free at time of serology.

Background Iron deficiency (ID) and anaemia in Inflammatory Bowel Disease (IBD) are associated with reduced quality of life, worse disease outcomes, and an increase in healthcare costs. In the European guidelines, anaemia is listed as one of the treatment goals. The data on the prevalence of anaemia and ID are inconsistent. Therefore, we evaluated the prevalence of ID, anaemia, and potential risk factors in a large Dutch outpatient population. Methods Between January and November 2021, consecutive adult outpatients with IBD, who did not have significant comorbidities associated with anaemia, were included in this study across 16 general, teaching, and academic hospitals within the Netherlands. Besides demographic and clinical data, relevant biochemical parameters such as haemoglobin (Hb), Mean Corpuscular Volume (MCV), iron indices, and inflammatory markers (e.g., C-reactive protein (CRP) and faecal calprotectin (FCP)) were extracted from medical records. Active IBD was defined by either CRP >5mg/L or FCP >150mg/g. ID was defined by ferritin Results In total, 2197 patients (1271 CD, 849 UC, and 77 IBDU) were included in the study. The overall prevalence of anaemia, iron-deficiency anaemia (IDA), and ID was: 18.0%, 12.2%, and 43.4%, respectively. The prevalence of all three conditions did not differ between the CD and UC groups (P>0.05). Severe anaemia (Hb Conclusion One in five ambulatory IBD patients presents with anaemia that is primarily caused by ID. Inflammation increases the risk of ID and anaemia regardless of IBD type or disease location. High ID prevalence suggests the need for screening and treatment optimisation.

IntroductionAn important aspect of depression relapse prevention programs is identifying personalized warning signals (PWS). These PWS are typically defined as depressive symptoms. Yet, no study has investigated to what extend PWS fit within the diagnostic classification framework, and how this compares to a more transdiagnostic, integrative approach towards depression.ObjectivesTo examine how well PWS reflect depressive symptoms, describe the remaining PWS, and examine how well PWS can be assigned to domains of an existing transdiagnostic and integrative framework, the positive health concept.Methods162 PWS of 66 individuals with a history of depression were labeled as one or more symptoms of depression or to a residual category. The same process was repeated for labeling the domains of the positive health model. Labeling was done by three independent reviewers (inter-rater percent agreement: symptoms: 0.83 & positive health domains: 0.73). Disagreements were resolved by discussion.ResultsThe three most commonly reported depressive symptoms were insomnia/hypersomnia, anhedonia and fatigue/loss of energy. However, sixty-five percent of the PWS were not depressive symptoms, but other symptoms (e.g. irritability, rumination) or aspects of functioning (e.g. withdrawing, managing time). The positive health domains captured all the PWS. However, 44% of PWS were labeled as multiple positive health domains, whereas labeling as symptoms of depression resulted in almost no such overlap.ConclusionsA more transdiagnostic and integrative approach seems necessary to capture PWS. Depending on one’s purpose, one may consider expanding the definition with other symptoms and aspects of functioning, or using the positive health concept.

Contains fulltext : 237001.pdf (Publisher’s version ) (Open Access) (1) Background: Virtual reality (VR) has been investigated in a variety of psychiatric disorders, including addictive disorders (ADs); (2) Objective: This systematic review evaluates the current evidence of immersive VR (using head-mounted displays) in the clinical assessment and treatment of ADs; (3) Method: PubMed and PsycINFO were queried for publications up to November 2020; (4) Results: We screened 4519 titles, 114 abstracts and 85 full-texts, and analyzed 36 articles regarding the clinical assessment (i.e., diagnostic and prognostic value; n = 19) and treatment (i.e., interventions; n = 17) of ADs. Though most VR assessment studies (n = 15/19) showed associations between VR-induced cue-reactivity and clinical parameters, only two studies specified diagnostic value. VR treatment studies based on exposure therapy showed no or negative effects. However, other VR interventions like embodied and aversive learning paradigms demonstrated positive findings. The overall study quality was rather poor; (5) Conclusion: Though VR in ADs provides ecologically valid environments to induce cue-reactivity and provide new treatment paradigms, the added clinical value in assessment and therapy remains to be elucidated before VR can be applied in clinical care. Therefore, future work should investigate VR efficacy in randomized clinical trials using well-defined clinical endpoints. 26 p.

Intensive care (IC)-afdelingen hebben regelmatig te maken met patienten bij wie op een zeker moment de behandeling medisch zinloos of onwenselijk wordt geacht. 1) Jaarlijks worden er ongeveer 85 duizend patienten op een IC in Nederland opgenomen. Ongeveer 8 procent van deze patienten overlijdt tijdens de opname op de IC. 2) Bij ongeveer 85 procent van hen wordt de behandeling gestaakt of wordt er geen nieuwe levensreddende behandeling gestart. 3) Vanwege de vergrijzing, de complexiteit van IC-patienten en de toename van ernstig zieke patienten wordt verwacht dat dit aantal nog verder zal stijgen. 4)

Background There is little information about how healthcare professionals feel about providing palliative care for patients with a substance use disorder (SUD). Therefore, this study aims to explore: 1) the problems and needs experienced by healthcare professionals, volunteers and experts-by-experience (HCP/VE) during their work with patients with SUD in a palliative care trajectory and; 2) to make suggestions for improvements using the quality of care model by Donabedian (Structure, Process, Outcome). Methods A qualitative study was conducted, consisting of six focus group interviews which consisted of HCP/VE working with patients with SUD in a palliative care phase. At the end of the focus group interviews, participants structured and summarized their experiences within a Strengths, Weaknesses, Opportunities and Threats (SWOT) framework. Interview transcripts (other than the SWOT) were analysed by the researchers following procedures from the Grounded Theory Approach (‘Grounded Theory Lite’). SWOT-findings were not subjected to in-depth analysis. Results HCP/VE stated that within the Structure of care, care networks are fragmented and HCP/VE often lack knowledge about patients’ multiplicity of problems and the time to unravel these. Communication with this patient group appears limited. The actual care-giving Process requires HCP/VE a lot of creativity and time spent seeking for cooperation with other caregivers and appropriate care settings. The latter is often hindered by stigma. Since no formalized knowledge is available, care-delivery is often exclusively experience-based. Pain-medication is often ineffective due to active substance use. Finally, several Outcomes were brought forward: Firstly, a palliative care phase is often identified only at a late stage. Secondly, education and a (mobile) team of expertise are desired. Thirdly, care for the caregivers themselves is often de-prioritized. Conclusions Better integration and collaboration between the different professionals with extensive experience in addiction, palliative and general curative care is imperative to assure good palliative care for patients with SUD. Currently, the resources for this care appear to be insufficient. Development of an educational program and social mapping may be the first steps in improving palliative care for patients with severe SUD.

Contains fulltext : 219394.pdf (Publisher’s version ) (Open Access) Objectives: The Montreal Cognitive Assessment (MoCA) is a cognitive screen, available in three alternate versions. Aims of the current study were to examine the effects of age, education and intelligence on MoCA performance and to determine the alternate-form equivalence and test?retest reliability of the MoCA, in a group of healthy participants. Method: In 210 participants, two MoCA versions and an estimator for premorbid intelligence were administered at two time points. Results: Age, education and estimated premorbid intelligence correlated significantly with the total score (MoCA-TS) and the Memory Index Score (MoCA-MIS). Systematic differences between MoCA version 7.1 and alternate versions 7.2 and 7.3 were only found for the items animal naming, abstract reasoning and sentence repetition. Test-retest reliability of the MoCA-TS was good between 7.1 and 7.2 (ICC: 0.64) and excellent between 7.1 and 7.3 (ICC: 0.82). For the MoCA-MIS, coefficients were poor (ICC: 0.32) to fair (ICC: 0.48), respectively. Conclusion: Adequate norms are needed that take the effects of age, education and intelligence on MoCA performance into account. All three MoCA versions are largely equivalent based on MoCA-TS and the test?retest reliabilities show that this score is suitable to monitor cognitive change over time. Comparisons of the domain-specific scores should be interpreted with caution. Key points: The MoCA total score is a reliable cognitive measure. All three MoCA versions are largely equivalent. Age, education and intelligence are predictors of MoCA performance in healthy participants. Future studies should focus on collecting normative data for age, education and intelligence for use in clinical practice. 8 p.

Current simulations of ultraviolet-visible absorption lineshapes, and dynamics of condensed phase systems, largely adopt a harmonic description to model vibrations. Often, this involves a model of displaced harmonic oscillators that have the same curvature. Although convenient, for many realistic molecular systems this approximation no longer suffices. We elucidate non-standard harmonic, and anharmonic effects, on linear absorption and dynamics using a stochastic Schr\"{o}dinger equation approach to account for the environment. Firstly, a harmonic oscillator model with ground and excited potentials that differ in curvature is utilised. Using this model, it is shown that curvature difference gives rise to an additional sub-structure in the vibronic progression of absorption spectra. This effect is explained, and subsequently quantified, via a derived expression for the Franck-Condon coefficients. Subsequently, anharmonic features in dissipative systems are studied, using a Morse potential, and parameters that correspond to the diatomic molecule $H_{2}$ for differing displacements and environment interaction. Lastly using a model potential, the population dynamics and absorption spectra for the stiff-stilbene photoswitch is presented and features are explained by a combination of curvature difference and anharmonicity in the form of potential energy barriers on the excited potential., Comment: 16 pages, 9 figures

Abstract We numerically study a particle in a box with moving walls. In the case where the walls are oscillating sinusoidally with a small amplitude, we show that states up to the fourth state can be populated with more than 80 percent population, while higher lying states can also be selectively excited. This work introduces a way of controlling quantum systems which does not rely on (dipole) selection rules. Graphical abstract

Background Systematic research into palliative care (PC) for people with substance use disorder (SUD) and multiple problems is scarce. The existing literature shows problems in the organizational structure of this care, e.g., lack of clear care pathways. Furthermore, negative attitudes of healthcare professionals (HCPs) and stigmatization surrounding SUD, and patients’ care-avoidance and non-disclosure of substance use are hindering factors in providing timely and person-centered PC. Furthermore, the experiences and needs of patients and proxies themselves are unknown. Therefore, this study aims to explore which problems and needs patients with SUD and multiple problems, and their proxies, experience in a PC phase. Methods Data-collection of this qualitative study consisted of semi-structured interviews with patients with SUD and multiple problems in a PC phase, and their proxies, about their experiences in PC and their well-being. Interviews were inductively analyzed. Results Nine patients and three proxies were included. Six patients suffered from COPD, one patient from cirrhosis of the liver and two patients from both. Seven patients stayed in a nursing home and two had a room in either a social care service (hostel) or an assisted living home where medical care was provided. Five themes were identified: 1) healthcare delivery (including HCPs behaviour and values); 2) end-of-life (EOL) preferences (mostly concerning only the individual patient and the ‘here-and-the-now’); 3) multidimensional problems; 4) coping (active and passive) and; 5) closed communication. Proxies’ experiences with healthcare differed. Emotionally, they were all burdened by their histories with the patients. Conclusions This study shows that talking about and anticipating on PC with this patient-group appears hard due to patients’ closed and avoiding communication. Furthermore, some of patients’ EOL-preferences and needs, and coping-strategies, seem to differ from the more generally-accepted ideas and practices. Therefore, educating HCPs in communicating with this patient-group, is needed. Electronic supplementary material The online version of this article (10.1186/s12904-019-0443-4) contains supplementary material, which is available to authorized users.

Contains fulltext : 234242.pdf (Publisher’s version ) (Open Access) The gamma-hydroxybutyric acid (GHB) withdrawal syndrome can have a fulminant course, complicated by severe complications such as delirium or seizures. Detoxification by tapering with pharmaceutical GHB is a safe way to manage GHB withdrawal. However, a detailed description of the course of the GHB withdrawal syndrome is currently lacking. This study aimed to (1) describe the course of GHB withdrawal symptoms over time, (2) assess the association between vital signs and withdrawal symptoms, and (3) explore sex differences in GHB withdrawal. In this observational multicenter study, patients with GHB use disorder (n = 285) were tapered off with pharmaceutical GHB. The most reported subjective withdrawal symptoms (SWS) were related to cravings, fatigue, insomnia, sweating and feeling gloomy. The most prevalent objective withdrawal symptoms (OWS) were related to cravings, fatigue, tremors, sweating, and sudden cold/warm feelings. No association between vital signs and SWS/OWS was found. Sex differences were observed in the severity and prevalence of specific withdrawal symptoms. Our results suggest that the GHB withdrawal syndrome under pharmaceutical GHB tapering does not strongly differ from withdrawal syndromes of other sedative drugs. The lack of association between vital signs and other withdrawal symptoms, and the relative stability of vitals over time suggest that vitals are not suitable for withdrawal monitoring. The reported sex differences highlight the importance of a personalized approach in GHB detoxification. 15 p.

Item does not contain fulltext Objectives: Gamma-hydroxybutyric acid (GHB) withdrawal is a complex syndrome which can be potentially life-threatening. Additionally, GHB-dependent patients frequently report co-occurring substance use of other psychoactive drugs. We assessed the add-on effect of co-use on GHB withdrawal symptoms. Methods: We conducted an open-label, pretest-posttest design study with 95 patients selected from 229 inpatients admitted for detoxification, who were divided into GHB only (GO, n = 40), GHB plus sedatives (GSE, n = 38), and GHB plus stimulants (GST, n = 17) groups. GHB withdrawal was evaluated by means of the Subjective Withdrawal Scale. Co-use add-on effects on the severity of withdrawal symptoms were evaluated 2.5 hours after the last illicit GHB self-administration (T1) when withdrawal was expected and 2.5 hours later, after administration of a very low dose of pharmaceutical GHB (T2). Results: The GO group reported high scores of psychomotor retardation symptoms at both T1 and T2, and also high cravings, agitation, and restlessness at T1, and anxiety at T2. The GSE group reported the highest score in psycho-autonomic distress symptoms at both T1 and T2, whereas the GST group reported the highest score in psycho-motor stress factor at T2. There was no significant difference in withdrawal intensity in all symptom clusters between T1 and T2 for both GSE and GO groups. However, after 5 hours, the GST group reported significant decreases in intensity for all symptoms except for psycho-motor stress. At T1, GST and GSE groups reported more muscle twitches than the GO group as a significant add-on effect to the GHB withdrawal. At T2, the GST group experienced more agitation (P = 0.009), restlessness (P = 0.001), and rapid pulse (P = 0.034) than the GO group. Conclusions: Co-use, especially of stimulants, caused an add-on effect on the GHB withdrawal symptoms within the first 5 hours. 7 p.

BACKGROUND & AIMS: Vitamin D deficiency is common in Crohn's disease (CD). High-dose vitamin D had anti-inflammatory effects in preclinical studies and trials of patients with CD. We performed a randomized trial to determine whether high-dose vitamin D prevents postoperative recurrence of CD after ileocolonic resection. METHODS: Patients with CD after ileocolonic resection with ileocolonic anastomosis were assigned randomly to groups given weekly 25,000 IU oral vitamin D (n = 72) or placebo (n = 71) for 26 weeks, at 17 hospitals in The Netherlands and Belgium, from February 2014 through June 2017. Patients were assessed at baseline and at weeks 2, 6, 12, and 26 for laboratory and clinical parameters, and underwent ileocolonoscopy at 26 weeks. The primary end point was endoscopic recurrence (modified Rutgeerts score, ≥i2b, as assessed by blinded readers) at 26 weeks. Secondary end points included clinical recurrence (Crohn's disease activity index, ≥220), quality of life (measured by the 36-Item Short Form Health Survey, Inflammatory Bowel Disease Questionnaire, and EuroQol, a 5-dimension questionnaire), and outcomes associated with the baseline serum concentration of vitamin D. RESULTS: In the vitamin D group, serum levels of 25-hydroxy vitamin D increased from a median of 42 nmol/L at baseline to 81 nmol/L at week 26 (P < .00001), whereas levels did not change significantly in the placebo group and remained unchanged at 43 nmol/L. In the intention-to-treat analysis, the proportion of patients with endoscopic recurrence at 26 weeks did not differ significantly between the vitamin D vs the placebo group (58% vs 66%; P = .37). The cumulative rate of clinical recurrence did not differ significantly between the groups (18.1% in the vitamin D group vs 18.3% in the placebo group; P = .91). Quality of life improved slightly over time in both groups, but did not differ significantly between groups (P = .07). There were few adverse events in either group. CONCLUSIONS: High-dose vitamin D, compared with placebo, did not reduce the incidence of postoperative endoscopic or clinical recurrence of CD in patients who underwent ileocolonic resection with ileocolonic anastomosis. ClinicalTrials.gov no: NCT02010762. ispartof: CLINICAL GASTROENTEROLOGY AND HEPATOLOGY vol:19 issue:8 pages:1573-+ ispartof: location:United States status: published

Item does not contain fulltext 4 p.

Contains fulltext : 213436.pdf (Publisher’s version ) (Open Access) This case report presents the case of a 29 weeks pregnant woman in her late twenties who was seen at the emergency department of a hospital with a seizure of unknown cause. By anamnesis and hetero-anamnesis the use of illicit gamma-hydroxybutyric acid (GHB) was revealed. Examination showed dilated pupils, sweating, tremor, tachycardia and bradyphrenic thinking. Subsequently, the seizure was indicated as a severe illicit GHB withdrawal symptom. Thereafter, treatment had to be decided on in the absence of evidence-based and practiced-based guidelines and treatment options for this specific patient population. Initially diazepam was started, which was later on substituted by sodium oxybate. Despite the critical professional situation the patient gave birth to a healthy daughter after 37 weeks of pregnancy. 4 p.

Contains fulltext : 197451.pdf (Publisher’s version ) (Open Access) Objective: The current study assessed the criterion validity of the Montreal Cognitive Assessment (MoCA) as a short cognitive screen for use in addiction health care. Method: Eighty-two patients were assessed with two parallel versions of the MoCA; at intake (baseline) and directly preceding an extensive neuropsychological assessment (NPA) approximately 8 weeks later (follow-up). Results: Of all included patients, 54.9% were classified as having substance-induced neurocognitive disorder. The most common primary substance of abuse was alcohol (70.7%). The criterion validity was determined predictively and concurrently, and sensitivities of .56 and .67 and specificities of .62 and .73 were found, respectively. Conclusion: While the MoCA is an adequate screen when administered at the same time as the NPA, the predictive validity of administering this cognitive screen at intake is limited. Furthermore, the relation between MoCA domain scores and the performance on their corresponding cognitive domain in the NPA is more reliable when the MoCA is administered at the same time as the NPA. While the MoCA can be used to screen for cognitive impairments in patients in addiction health care, the instrument?s sensitivity is not optimal, which should be taken into account when interpreting results. 8 p.

Background Tofacitinib is a janus kinase 1 and 3 inhibitor approved for the treatment of ulcerative colitis (UC). Real-world evidence is needed to evaluate the effectiveness, usage and safety in daily practice. Methods UC patients in whom tofacitinib was started in 15 hospitals (8 academic, 7 non-academic) participated in the ICC Registry: a Dutch prospective, observational registry. Visits were planned at baseline, Week 12, and 24. Patients with both clinical (Short Clinical Colitis Activity Index (SCCAI) >2) and objective disease activity (endoscopy (Mayo >0), C-reactive protein (CRP) >5 mg/l or faecal calprotectin (FCP) >250 µg/g) were included. In this study, corticosteroid-free clinical remission (SCCAI ≤2), biochemical remission (FCP ≤250 µg/g), combined corticosteroid-free clinical and biochemical remission, predictors of remission, safety outcomes, dose optimisation, and effect on lipids were determined at Week 24. Only patients from centres with routine endoscopic follow-up (regardless of symptoms) were analysed to determine endoscopic remission (Mayo = 0) at Week 12. All analyses were done on an intention-to-treat basis. Results In total, 111 UC patients (95% anti-TNF, 60% vedolizumab, 4% ustekinumab exposed) were followed for a median of 24 weeks (IQR 12–26). All patients had both active clinical and objective disease (SCCAI 8 (IQR 5–11), FCP 1800µg/g (IQR 633–2682)). Corticosteroid-free clinical, biochemical, and combined corticosteroid-free clinical and biochemical remission rate at week 24 was 29%, 25%, and 19%, respectively. Endoscopic remission was achieved in 21% of patients (n = 33) at Week 12. Prior vedolizumab exposure was associated with a lower remission rate at week 24 (OR 0.33, 95% CI 0.11–0.94) in multivariable analysis. In total, 36 patients (88 per 100 patient-years) experienced tofacitinib-related adverse events (most common: cutaneous lesions and headache) of which 6 patients (18 per 100 patient-years) discontinued treatment. No thromboembolic events were reported. We observed 4 cases of herpes zoster re-activation but no severe infections (requiring hospitalisation). During follow-up 14 hospitalisations and 5 (4.5%) colectomies were performed. Cholesterol, HDL, and LDL increased between baseline and week 12 (18% (95% CI 9–26, n = 35), 18% (95% CI 8–28, n = 35) and 27% (95% CI 14–39, n = 35), respectively). At week 24, 33% of patients used 10 mg twice daily. Conclusion Tofacitinib is an effective treatment for UC after anti-TNF and/or vedolizumab failure. We did observe a relatively high rate of adverse events in this refractory UC cohort.

Background The specific palliative care needs and problems of patients with a substance use disorder and multiple problems, and those of their proxies, are under recognized Besides, the organization of palliative care, including the division of health care professionals’ responsibilities, is often unclear. Perspectives of patients and proxies are hardly known. We describe the outline of a study designed to explore how palliative care for patients with a substance use disorder is organized in the Netherlands and to explore problems and needs, as well as possible improvements from the healthcare professionals’, patients’ and proxies’ perspective. The aim of this protocol paper is to provide insights in ways to conduct research with vulnerable research participants and to offer a detailed description of the study design. The broader study aims to gain insight in and formulate recommendations on how to improve palliative care for patients with a substance use disorder. Methods A qualitative study with patients, proxies and healthcare professionals. Semi-structured interviews will be held with 10–15 patients who suffer from a severe substance use disorder. They are in a palliative care trajectory and either diagnosed with a chronic or life-threatening disease or, as a result of addictive behavior, a physical deterioration without the prospect of cure. Semi-structured interviews will also be held with 5–10 proxies. Healthcare professionals, volunteers and/or ‘experts-by-experience’ (n = 24–40) will be participating in semi-structured group interviews. All (group) interviews will be thematically analyzed. Additionally, a strengths, weaknesses, opportunities and threats (SWOT) analysis will be applied to the group interview data with the aim to summarize and concretize the findings. Discussion Everyone has a right to an optimal end-of-life phase of life and a dignified dying process. This study will provide valuable knowledge about palliative care for patients with a substance use disorder and explicitly bring to light the needs and problems of the patients and their proxies and healthcare professionals in a palliative care phase. Electronic supplementary material The online version of this article (10.1186/s12904-018-0351-z) contains supplementary material, which is available to authorized users.

Recently, DNA methylation analysis of FAM19A4 in cervical scrapes has been shown to adequately detect high-grade cervical intraepithelial neoplasia and cervical cancer (≥ CIN3) in high-risk HPV (hrHPV)-positive women. Here, we compared the clinical performance of FAM19A4 methylation analysis to cytology and HPV16/18 genotyping, separately and in combination, for ≥ CIN3 detection in hrHPV-positive women participating in a prospective observational multi-center cohort study. The study population comprised hrHPV-positive women aged 18-66 years, visiting a gynecological outpatient clinic. From these women, cervical scrapes and colposcopy-directed biopsies (for histological confirmation) were obtained. Cervical scrapes were analyzed for FAM19A4 gene promoter methylation, cytology and HPV16/18 genotyping. Methylation analysis was performed by quantitative methylation-specific PCR (qMSP). Sensitivities and specificities for ≥ CIN3 were compared between tests. Stratified analyses were performed for variables that potentially influence marker performance. Of all 508 hrHPV-positive women, the sensitivities for ≥ CIN3 of cytology, FAM19A4 methylation analysis, and cytology combined with HPV16/18 genotyping were 85.6, 75.6 and 92.2%, respectively, with corresponding specificities of 49.8, 71.1 and 29.4%, respectively. Both sensitivity and specificity of FAM19A4 methylation analysis were associated with age (p ≤ 0.001 each). In women ≥ 30 years (n = 287), ≥ CIN3 sensitivity of FAM19A4 methylation analysis was 88.3% (95%CI: 80.2-96.5) which was noninferior to that of cytology [85.5% (95%CI: 76.0-94.0)], at a significantly higher specificity [62.1% (95%CI: 55.8-68.4) compared to 47.6% (95%CI: 41.1-54.1)]. In conclusion, among hrHPV-positive women from an outpatient population aged ≥ 30 years, methylation analysis of FAM19A4 is an attractive marker for the identification of women with ≥ CIN3.