Jacob Broder Brodersen

Polymorphisms in the Inflammatory Pathway Genes TLR2, TLR4, TLR9, LY96, NFKBIA, NFKB1, TNFA, TNFRSF1A, IL6R, IL10, IL23R, PTPN22, and PPARG Are Associated with Susceptibility of Inflammatory Bowel Disease in a Danish Cohort

Background The inflammatory bowel diseases (IBD), Crohns disease (CD) and ulcerative colitis (UC), result from the combined effects of susceptibility genes and environmental factors. Polymorphisms in genes regulating inflammation may explain part of the genetic heritage. Methods Using a candidate gene approach, 39 mainly functional single nucleotide polymorphisms (SNPs) in 26 genes regulating inflammation were assessed in a clinical homogeneous group of severely diseased patients consisting of 624 patients with CD, 411 patients with UC and 795 controls. The results were analysed using logistic regression. Results Sixteen polymorphisms in 13 genes involved in regulation of inflammation were associated with risk of CD and/or UC (p≤0.05). The polymorphisms TLR2 (rs1816702), NFKB1 (rs28362491), TNFRSF1A (rs4149570), IL6R (rs4537545), IL23R (rs11209026) and PTPN22 (rs2476601) were associated with risk of CD and the polymorphisms TLR2 (rs1816702), TLR4 (rs1554973 and rs12377632), TLR9 (rs352139), LY96 (rs11465996), NFKBIA (rs696), TNFA (rs1800629), TNFRSF1A (rs4149570), IL10 (rs3024505), IL23R (rs11209026), PTPN22 (rs2476601) and PPARG (rs1801282) were associated with risk of UC. When including all patients (IBD) the polymorphisms TLR2 (rs4696480 and rs1816702), TLR4 (rs1554973 and rs12377632), TLR9 (rs187084), TNFRSF1A (rs4149570), IL6R (rs4537545), IL10 (rs3024505), IL23R (rs11209026) and PTPN22 (rs2476601) were associated with risk. After Bonferroni correction for multiple testing, both the homozygous and the heterozygous variant genotypes of IL23R G>A(rs11209026) (ORCD,adj: 0.38, 95% CI: 0.21–0.67, p = 0.03; ORIBD,adj 0.43, 95% CI: 0.28–0.67, p = 0.007) and PTPN22 1858 G>A(rs2476601) (ORCD,unadj 0.54, 95% CI: 0.41–0.72, p = 7*10−4; ORIBD,unadj: 0.61, 95% CI: 0.48–0.77, p = 0.001) were associated with reduced risk of CD. Conclusion The biological effects of the studied polymorphisms suggest that genetically determined high inflammatory response was associated with increased risk of CD. The many SNPs found in TLRs suggest that the host microbial composition or environmental factors in the gut are involved in risk of IBD in genetically susceptible individuals.

Associations between functional polymorphisms in the NFκB signaling pathway and response to anti-TNF treatment in Danish patients with inflammatory bowel disease

Antitumor necrosis factor-α (TNF-α) is used for treatment of severe cases of inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC). However, one-third of the patients do not respond to the treatment. Genetic markers may predict individual response to anti-TNF therapy. Using a candidate gene approach, 39 mainly functional single nucleotide polymorphisms (SNPs) in 26 genes regulating inflammation were assessed in 738 prior anti-TNF-naive Danish patients with IBD. The results were analyzed using logistic regression (crude and adjusted for age, gender and smoking status). Nineteen functional polymorphisms that alter the NFκB-mediated inflammatory response (TLR2 (rs3804099, rs11938228, rs1816702, rs4696480), TLR4 (rs5030728, rs1554973), TLR9 (rs187084, rs352139), LY96 (MD-2) (rs11465996), CD14 (rs2569190), MAP3K14 (NIK) (rs7222094)), TNF-α signaling (TNFA (TNF-α) (rs361525), TNFRSF1A (TNFR1) (rs4149570), TNFAIP3(A20) (rs6927172)) and other cytokines regulated by NFκB (IL1B (rs4848306), IL1RN (rs4251961), IL6 (rs10499563), IL17A (rs2275913), IFNG (rs2430561)) were associated with response to anti-TNF therapy among patients with CD, UC or both CD and UC (P⩽0.05). In conclusion, the results suggest that polymorphisms in genes involved in activating NFκB through the Toll-like receptor (TLR) pathways, genes regulating TNF-α signaling and cytokines regulated by NFκB are important predictors for the response to anti-TNF therapy among patients with IBD. Genetically strong TNF-mediated inflammatory response was associated with beneficial response. In addition, the cytokines IL-1β, IL-6 and IFN-γ may be potential targets for treating patients with IBD who do not respond to anti-TNF therapy. These findings should be examined in independent cohorts before these results are applied in a clinical setting.

Polymorphisms in the Toll-Like Receptor and the IL-23/IL-17 Pathways Were Associated with Susceptibility to Inflammatory Bowel Disease in a Danish Cohort.

Background The inflammatory bowel diseases (IBD), Crohn’s disease (CD) and ulcerative colitis (UC), result from the combined effects of susceptibility genes and environmental factors. Previous studies have shown that polymorphisms in the Toll-like receptor (TLR), the apoptosis, the IL-23/IL-17 and the interferon gamma (IFNG) pathways are associated with risk of both CD and UC. Methods Using a candidate gene approach, 21 functional single nucleotide polymorphisms (SNPs) in 15 genes were assessed in a clinical homogeneous group of severely diseased ethnic Danish patients consisting of 624 patients with CD, 411 patients with UC and 795 controls. The results were analysed using logistic regression. Results The polymorphisms TLR5 (rs5744174) and IL12B (rs6887695) were associated with risk of CD, and TLR1 (rs4833095) and IL18 (rs187238) were associated with risk of both CD and UC (p<0.05). After Bonferroni correction for multiple testing, the homozygous variant genotype of TLR1 743 T>C (rs4833095) was associated with increased risk CD (OR: 3.15, 95% CI: 1.59–6.26, p = 0.02) and CD and UC combined (OR: 2.96, 95% CI: 1.64–5.32, p = 0.005). Conclusion Our results suggest that genetically determined high activity of TLR1 and TLR5 was associated with increased risk of both CD and UC and CD, respectively. This supports that the host microbial composition or environmental factors in the gut are involved in risk of IBD. Furthermore, genetically determined high activity of the IL-23/IL-17 pathway was associated with increased risk of CD and UC. Overall, our results support that genetically determined high inflammatory response was associated with increased risk of both CD and UC.

The Stop-Only-While-Shocking algorithm reduces hands-off time by 17% during cardiopulmonary resuscitation - a simulation study.

Introduction Reducing hands-off time during cardiopulmonary resuscitation (CPR) is believed to increase survival after cardiac arrests because of the sustaining of organ perfusion. The aim of our study was to investigate whether charging the defibrillator before rhythm analyses and shock delivery significantly reduced hands-off time compared with the European Resuscitation Council (ERC) 2010 CPR guideline algorithm in full-scale cardiac arrest scenarios. Methods The study was designed as a full-scale cardiac arrest simulation study including administration of drugs. Participants were randomized into using the Stop-Only-While-Shocking (SOWS) algorithm or the ERC2010 algorithm. In SOWS, chest compressions were only interrupted for a post-charging rhythm analysis and immediate shock delivery. A Resusci Anne HLR-D manikin and a LIFEPACK 20 defibrillator were used. The manikin recorded time and chest compressions. Results Sample size was calculated with an &agr; of 0.05 and 80% power showed that we should test four scenarios with each algorithm. Twenty-nine physicians participated in 11 scenarios. Hands-off time was significantly reduced 17% using the SOWS algorithm compared with ERC2010 [22.1% (SD 2.3) hands-off time vs. 26.6% (SD 4.8); P<0.05]. Conclusion In full-scale cardiac arrest simulations, a minor change consisting of charging the defibrillator before rhythm check reduces hands-off time by 17% compared with ERC2010 guidelines.

Genetically determined high activity of IL-12 and IL-18 in ulcerative colitis and TLR5 in Crohns disease were associated with non-response to anti-TNF therapy

Anti-tumour necrosis factor-α (TNF-α) is used for treatment of severe cases of inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC). However, one-third of the patients do not respond to the treatment. A recent study indicated that genetically determined high activity of pro-inflammatory cytokines, including interleukin-1β (IL-1β), IL-6 and interferon gamma (IFN-γ), are associated with non-response to anti-TNF therapy. Using a candidate gene approach, 21 functional single-nucleotide polymorphisms (SNPs) in 14 genes in the Toll-like receptors, the inflammasome and the IFNG pathways were assessed in 482 and 256 prior anti-TNF naïve Danish patients with CD and UC, respectively. The results were analysed using logistic regression (adjusted for age and gender). Eight functional SNPs were associated with anti-TNF response either among patients with CD (TLR5 (rs5744174) and IFNGR2 (rs8126756)), UC (IL12B (rs3212217), IL18 (rs1946518), IFNGR1 (rs2234711), TBX21 (rs17250932) and JAK2 (rs12343867)) or in the combined cohort of patient with CD and UC (IBD) (NLRP3 (rs10754558), IL12B (rs3212217) and IFNGR1 (rs2234711)) (P<0.05). Only the association with heterozygous genotype of IL12B (rs3212217) (OR: 0.24, 95% CI: 0.11–0.53, P=0.008) among patients with UC withstood Bonferroni correction for multiple testing. In conclusion, Our results suggest that SNPs associated with genetically determined high activity of TLR5 among patients with CD and genetically determined high IL-12 and IL-18 levels among patients with UC were associated with non-response. Further studies will evaluate whether these genes may help stratifying patients according to the expected response to anti-TNF treatment.

A proposal for a study on treatment selection and lifestyle recommendations in chronic inflammatory diseases: A Danish multidisciplinary collaboration on prognostic factors and personalised medicine

Chronic inflammatory diseases (CIDs), including Crohn’s disease and ulcerative colitis (inflammatory bowel diseases, IBD), rheumatoid arthritis, psoriasis, psoriatic arthritis, spondyloarthritides, hidradenitis suppurativa, and immune-mediated uveitis, are treated with biologics targeting the pro-inflammatory molecule tumour necrosis factor-α (TNF) (i.e., TNF inhibitors). Approximately one-third of the patients do not respond to the treatment. Genetics and lifestyle may affect the treatment results. The aims of this multidisciplinary collaboration are to identify (1) molecular signatures of prognostic value to help tailor treatment decisions to an individual likely to initiate TNF inhibitor therapy, followed by (2) lifestyle factors that support achievement of optimised treatment outcome. This report describes the establishment of a cohort that aims to obtain this information. Clinical data including lifestyle and treatment response and biological specimens (blood, faeces, urine, and, in IBD patients, intestinal biopsies) are sampled prior to and while on TNF inhibitor therapy. Both hypothesis-driven and data-driven analyses will be performed according to pre-specified protocols including pathway analyses resulting from candidate gene expression analyses and global approaches (e.g., metabolomics, metagenomics, proteomics). The final purpose is to improve the lives of patients suffering from CIDs, by providing tools facilitating treatment selection and dietary recommendations likely to improve the clinical outcome.

Capsule endoscopy for the diagnosis and follow up of crohn’s disease: A comprehensive review of current status

Capsule endoscopy (CE) has revolutionized the diagnosis and monitoring of small bowel Crohn’s disease (CD). The procedure is patient friendly and noninvasive, and compared to cross-sectional imaging, CE allows a direct and detailed evaluation of the entire small bowel mucosa with a high sensitivity for the earliest lesions of CD. Today, CE is the leading modality for visualizing the small bowel in suspected CD, and validated activity indices are available for the follow up of patients with established CD. CE of the entire gastrointestinal tract (panenteric CE) was recently introduced as a new diagnostic approach in patients examined for CD, and preliminary results are promising. There are important limitations, involving mainly capsule retention. Furthermore, a diagnostic criterion for CD has never been validated, and lesions detected by CE are not specific for CD. Hence, concern has been raised about a low specificity compared to other diagnostic modalities. Important questions about the optimal bowel preparation, selection of patients for CE and the optimal reading protocol remain to be clarified. The aim of this review is to evaluate the performance of CE for diagnosing CD and assess disease activity in known CD; to compare the diagnostic accuracy of CE to that of cross-sectional imaging; to discuss limitations; and to define the place of CE in the diagnostic algorithm in suspected or known CD.

Respiratory rate - interobserver reliability study

Background Measuring respiratory rate (RR) is one of the most basic clinical observations performed when accessing acutely ill patients. RR is included in most triage systems and risk stratifications tools, but unlike the other vital signs, RR is typically obtained by a manual count by the nursing staff. Considering how often RR is used in clinical practice and contained in triage systems, it is remarkable how few studies on inter-observer/rater agreement have actually been performed. Furthermore, the existing studies are all made with few observers and many patients, and none of them have been performed in an actual acute setting of an emergency department (ED). We therefore aimed to determine the interobserver variability of RR counts, using a larger number of observers on few same patients in the setting of an ED.

Triage of acute medical patients - interobserver Reliability

Background In most emergency departments (ED) around the world, patients are initially assessed using a triage system or risk stratification tools. The result of the scores is an important factor in determining the course of treatment for critically ill patients. Several different systems are used, but most include blood pressure, respiratory rate, pulse, and level of consciousness and the individual systems then have a number of different parameters. Considering the vital role the results of these scores have on the course of treatment, the number of studies on inter-observer reliability is limited. The aim of this study was to measure the inter-observer variability when assessing patients using the Danish Emergency Process Triage (DEPT) (using only vital signs), the Modified Early Warning Score (MEWS), the HOTEL score, the Simple Clinical Score (SCS) and PARIS score.

Inter-Observer Agreement in Measuring Respiratory Rate.

Background Respiratory rate (RR) is an important vital sign which is strongly correlated with in-hospital mortality. At the same time, RR is the most likely vital sign to be omitted when assessing a patient. We believe that one reason for this could be the difficulty in measure the RR, since it is not read off a monitor, but counted manually. Also there is the possibility of assessment bias and the inter-observer reliability becomes important. We therefore set out to investigate how the nursing staff counting the actual number of respirations per minute would agree with the nursing staff using a predefined ordinal scale. Methods For this prospective study, we recorded five videos of a young healthy man breathing approximately 5, 10, 15, 30 and 60 times per minute. The videos were shown in a random order to a suitable sample of the nursing staff. The participants were randomized into two groups; one to count the exact number of breaths per minute, and one to use a predefined ordinal scale. Results Comparing the exact number of breaths per minute, the Intra Class Coefficient (ICC) was 0.99 (95% CI: 0.97–1.00). Comparing the RR using the predefined scale, the overall Kappa Fleiss Coefficient was 0.75. Conclusions The inter-observer agreement was high when comparing the use of the actual number of breaths per minute and substantial when comparing the use of the predefined scale. This is the largest inter-observer study on RR to date. However, further studies on the use of scaled comparisons of RR are needed.