[Modern endoscopy in inflammatory bowel disease].

INTRODUCTION: Endoscopic examinations play a very important role in the diagnosis, progress assessment, and therapy of inflammatory bowel diseases (IBD). This includes not only esophagogastroduodenoscopy, sigmoidoscopy, and ileo-colonoscopy, but also assessment of the small intestine. The work-up of the small intestine is primarily carried out using non-invasive techniques (intestinal ultrasound, magnetic resonance enterography (MRE)). However, if the diagnosis remains unclear, a histological proof is necessary or an endoscopic intervention is required, capsule endoscopy and balloon-assisted enteroscopy are used. Furthermore, endoscopic ultrasound is available to assess perianal fistulizing Crohn's disease, and ERCP (endoscopic retrograde cholangiopancreatography) is used in certain patients with IBD-associated primary sclerosing cholangitis (PSC). Given the high resolution of modern endoscopes and the availability of chromoendoscopy, dysplastic lesions are detected earlier and can often be resected endoscopically. In addition, short strictures/stenoses can be treated using balloon dilatations.

Identification of IL-27 as a novel regulator of major histocompatibility complex class I and class II expression, antigen presentation, and processing in intestinal epithelial cells.

Antigen presentation via major histocompatibility complex (MHC) class I and class II receptors plays a fundamental role in T cell-mediated adaptive immunity. A dysregulation of this fine-tuned recognition might result in the development of autoimmune diseases such as inflammatory bowel diseases that are characterized by chronic relapsing inflammation of the intestinal tract and a damaged intestinal epithelial barrier. While MHCII receptors are usually expressed by professional antigen presenting cells (APC) only, there is increasing evidence that non-immune cells such as intestinal epithelial cells (IEC) might express MHCII upon stimulation with IFN-γ and thus act as non-professional APC. However, little is known about other factors regulating intestinal epithelial MHC expression. Here, we identify IL-27 as an inducer of different MHCI and MHCII receptor subtypes and the invariant chain (CD74/li) in IEC via the STAT1/IRF1/CIITA axis. CIITA, MHCII, and CD74 expression was significantly increased in IEC from Crohn's disease (CD) patients with active disease compared to controls or CD patients in remission. IEC phagocytosed and digested external antigens and apoptotic cells. IL-27 strongly stimulated antigen processing via the immunoproteasome in a IRF1-dependent manner. In co-culture experiments, antigen-primed IEC strongly enhanced lymphocyte proliferation and IL-2 secretion, dependent on direct cell-cell contact. IL-27 pretreatment of IEC significantly increased CD4+ T cell proliferation and reduced IL-2 levels in lymphocytes in coculture. In summary, we identified IL-27 as a novel regulator of IEC antigen processing and presentation via MHCI and MHCII receptors, underscoring the importance of IEC as non-professional APC.

Effectiveness of golimumab in patients with ulcerative colitis: results of a real-life study in Switzerland.

BACKGROUND: Tumor necrosis factor (TNF) inhibitors have improved treatment of ulcerative colitis (UC), but loss of response remains a frequent problem. The anti-TNF agent, golimumab, was approved in Switzerland for the treatment of UC in 2014. This study aims to summarize the experience of golimumab in a real-world setting in Switzerland. METHODS: We analyzed real-world data from 1769 UC patients from the Swiss Inflammatory Bowel Disease Cohort (SIBDC) study and performed a chart review of golimumab-treated patients. We extracted the partial Mayo score at t0 (baseline), t1 (2-16 weeks), t2 (17-35 weeks), and t3 (36-89 weeks). The primary endpoint was clinical response at t1, defined as marked improvement in partial Mayo score and objective parameters. Clinical remission was defined as resolution of symptoms and normalization of objective parameters. RESULTS: Our chart review included 103 UC patients with golimumab treatment (5.8% of all SIBDC UC patients); only 16 (15.5%) were anti-TNF naïve. Sixty-three patients remained on golimumab (61.2%) after 180 days, 51 (44.7%) after 365 days, and 34 (33%) after 630 days after the start of treatment. Upon golimumab treatment, the partial Mayo score decreased from 4 [interquartile range (IQR): 2-6] at t0 to 2 (IQR: 0-4) at t1, 1 (IQR: 0-3.5) at t2, and 1 (IQR: 0-3) at t3 (p < 0.001 for all comparisons with t0). The primary endpoint, clinical response at t1, could be evaluated in 52 patients and was met in 15 individuals (28.8%). Clinical remission at t1 was observed in 8 out of 52 patients (15.4%). Golimumab was generally well tolerated, one patient developed meningitis. The most frequent reasons to stop treatment were primary and secondary non-response. CONCLUSION: Golimumab was used in 5.8% of Swiss UC patients, mainly in biologic-experienced individuals. Golimumab treatment was associated with a sustained reduction of symptoms and clinical response in approximately 30% of patients.[ClinicalTrials.gov identifier: NCT00488631].

Iron Deficiency in Inflammatory Bowel Disease Is Associated With Low Levels of Vitamin D Modulating Serum Hepcidin and Intestinal Ceruloplasmin Expression.

INTRODUCTION: Iron deficiency and vitamin D deficiency are common comorbidities in inflammatory bowel disease (IBD). Accumulating evidence indicates that active 1,25-dihydroxyvitamin D (1,25(OH)D) may enhance iron absorption by suppressing hepcidin. We investigated the influence of vitamin D on iron metabolism in patients with IBD and on the expression of genes facilitating intestinal epithelial iron absorption. METHODS: Iron parameters and serum levels of 25-hydroxyvitamin D (25(OH)D), 1,25(OH)D, and hepcidin were measured in 104 adult patients with IBD (67 with Crohn's disease and 37 with ulcerative colitis). Genes involved in iron absorption were tested for induction by 1,25(OH)D in Caco-2 cells, which resemble the small intestinal epithelium. RESULTS: In multiple regression models controlling for age, sex, body mass index, smoking status, disease activity, and C-reactive protein levels, low 25(OH)D levels were associated with iron deficiency in patients with IBD (ß [SE] = -0.064 [0.030], P = 0.029). Vitamin D sufficiency was associated with increased levels of ferritin (ß [SE] = 0.25 [0.11], P = 0.024) and transferrin saturation (ß [SE] = 8.41 [4.07], P = 0.044). Higher 1,25(OH)D:25(OH)D ratios were associated with lower hepcidin levels (ß [SE] = -4.31 [1.67], P = 0.012). Especially in Crohn's disease, increased 1,25(OH)D correlated with higher transferrin saturation (ß [SE] = 0.43 [0.18], P = 0.027). Furthermore, 1,25(OH)D strongly induced the expression of the ferroxidase ceruloplasmin in Caco-2 cells. DISCUSSION: Low vitamin D levels in IBD correlate with iron deficiency. Vitamin D may ameliorate iron deficiency, potentially by downregulating hepcidin and upregulating ceruloplasmin, enhancing intestinal iron absorption.

[Symptoms, diagnostic and therapy of perianal disease in patients with inflammatory bowel diseases]. / Klinik, Diagnostik und Therapie proktologischer Beschwerden bei Patienten mit chronisch entzündlichen Darmerkrankungen.

Symptoms, diagnostic and therapy of perianal disease in patients with inflammatory bowel diseases Abstract. Inflammatory bowel diseases (IBD) frequently affect the perianal region. Due to the great functional importance of the anorectum, this frequently results in a significant burden of disease for the patient. For assessment of perianal IBD symptoms, the clinical history is of great importance. Often, anorectal symptoms are not reported spontaneously by patients, and a respectful direct conversation remains crucial. More than 30 % of patients with Crohn's disease (CD) will develop perianal fistulas. Perianal fistulas can be further characterized by endoscopic ultrasound, MRI, and investigation under anesthesia. These investigations provide complementary information. Fistula therapy is based on symptoms; the short-term goal is improvement of pain and secretion; the long-term goal of treatment remains fistula closure. However, preservation of the anal sphincter is of utmost importance and incontinence needs to be avoided. Antibiotics and/ or seton drainage are the mainstay for acute fistula treatment. The anti-tumor necrosis factor antibody infliximab can improve fistula symptoms, as demonstrated in a randomized controlled study. Surgical fistula closure is only possible in a clinically stable situation without rectal inflammation or other symptoms of active CD. Several surgical strategies exist including 1) fistulotomy, 2) disconnection of the fistula, 3) filling of the fistula tract and 4) fistula ablation. The optimal strategy needs to be decided on an individual basis. Intraoperative application of mesenchymal donor stem cells into the fistula tract and surrounding tissue is possibly the most effective fistula therapy. Due to the significant logistic effort, this therapy is only available in a few selected centers. Currently, stem cell therapy for CD fistulas is limited to patients with no more than two external fistula openings. The therapy of fissures and hemorrhoids in IBD patients is similar to patients without intestinal inflammation; however, due to a high rate of complications, surgery should be avoided whenever possible in CD patients. Incontinence is a frequent problem in IBD patients leading to highly relevant restrictions in daily life. Therapy is directed against intestinal inflammation but also comprises measures for normalization of stool consistency and intestinal motility. However, there are no IBD-specific concepts for the treatment of incontinence. Functional intestinal diseases are frequent in IBD patients and can contribute to urge and incontinence. Some IBD patients might benefit from anorectal physiotherapy. IBD patients have an increased risk for colorectal carcinoma, fistula carcinoma and possibly also anal carcinoma. Therefore, malignancy needs to be excluded at reasonable intervals.

Contrast-enhanced ultrasound can guide the therapeutic strategy by improving the detection of colorectal liver metastases.

BACKGROUND & AIMS: CT may miss up to 30% of cases of colorectal liver metastases (CRLMs). We assessed the impact of contrast-enhanced ultrasound (CEUS) on the detection of CRLMs and on changes to the therapeutic strategy; additionally, we assessed the accuracy of CEUS in differentiating unclear focal liver lesions (FLLs) compared to staging-CT. METHODS: We prospectively analyzed all patients with newly diagnosed and histologically confirmed colorectal cancer (CRC) at our tertiary gastroenterological center between December 2015 and May 2019. CEUS was performed in a total of 296 patients without CRLMs after staging-CT using the contrast agent (SonoVue®). Standard of reference was obtained by MRI or histology to diagnose CRLMs missed by CT. Benign FLLs were confirmed by MRI or follow-up CT (mean follow-up interval: 18 months). RESULTS: Eight additional CRLMs were detected by CEUS (overall 2.7%; sensitivity 88.9%, specificity 99.0%, positive predictive value 100%, negative predictive value 99.6%). All patients with CRLMs detected only by CEUS were in tumor stage T3/T4 (4.0% additionally detected CRLMs). The number needed to screen to detect 1 additional CRLM by CEUS was 37 in all patients and 24.5 in T3/T4-patients. When results were reviewed by a board-certified radiologist and oncologist, the therapeutic strategy changed in 6 of these 8 patients. Among the 62 patients (20.9%) with unclear FLLs after staging-CT, CEUS determined the dignity (malignant vs. benign) of 98.4% of the FLLs. CONCLUSION: Overall, CEUS detected 2.7% additional CRLMs (including 4.0% in tumor stage T3/T4) with a significant impact on the oncological therapeutic strategy for 75% of these patients. Patients with tumor stage T3/T4 would particularly benefit from CEUS. We propose CEUS as the first imaging modality for CT-detected lesions of unknown dignity. LAY SUMMARY: In patients with newly diagnosed colorectal cancer, contrast-enhanced ultrasound (CEUS) detected additional liver metastases after computed tomography (CT). In the majority of these patients, the oncological therapy was changed after obtaining the CEUS results. After staging-CT, 21% of hepatic lesions remained unclear. In these cases, CEUS was accurate to either reveal or exclude liver metastasis in nearly all patients and could reduce costs (e.g., number of MRI scans).

TNF-Alpha Blockers in Inflammatory Bowel Diseases: Practical Recommendations and a User's Guide: An Update.

BACKGROUND: Anti-tumour necrosis factor-alpha (anti-TNF) antagonists have been the mainstay in the treatment of inflammatory bowel diseases (IBDs) for over 20 years. SUMMARY: This review article aimed to provide an update on recent advances in TNF antagonist therapy for IBDs. Key Messages: Their position in the treatment algorithm has evolved to "rapid step-up therapy" or "top-down therapy" according to disease severity and patients' characteristics. Limitations of anti-TNF antagonists include loss of response in up to 30-50% of patients with or without the development of antibodies. Therapeutic drug monitoring should provide a tailored, personalized approach to this scenario. Recently, biosimilar agents have been approved for IBDs and are considered equivalent in efficacy to the originator.

Development of a uniform, very aggressive disease phenotype in all homozygous carriers of the NOD2 mutation p.Leu1007fsX1008 with Crohn's disease and active smoking status resulting in ileal stenosis requiring surgery.

BACKGROUND: NOD2 variants are the strongest genetic predictors for susceptibility to Crohn's disease (CD). However, the clinical value of NOD2 on an individual patient level remains controversial. We aimed to define the predictive power of the major NOD2 mutations regarding complicated CD in a large single center cohort. METHODS: 1076 CD patients were prospectively genotyped for the three common CD-associated NOD2 mutations rs2066844, rs2066845, and rs2066847, followed by detailed genotype-phenotype analyses. RESULTS: Overall, 434 CD patients (40.3%) carried at least one of the three main NOD2 mutations. A significantly higher minor allele frequency (15.6%) of the NOD2 frameshift mutation p.Leu1007fsX1008 (rs2066847) was seen in patients with aggressive disease compared to 8.2% in patients with mild disease (p = 2.6 x 10-5). Moreover, a total of 54 CD patients (5.0%) were homozygous for this NOD2 frameshift mutation. 100% of these patients had ileal disease compared to 82% of NOD2 wild-type carriers (p<0.0001). In homozygous carriers of the NOD2 frameshift mutation, 87% presented with ileal stenosis, 68.5% had fistulas, and 72.2% required CD-related surgery despite immunosuppressive therapy in 87% of these patients. All homozygous carriers of the 1007fs mutation who were active smokers had ileal stenosis and required CD-related surgery. CONCLUSION: Homozygosity for Leu1007fsX1008 is an excellent biomarker for predicting complicated CD on an individual patient level. Active smoking and homozygosity for this mutation is associated with a 100% risk for developing ileal stenosis requiring CD-related surgery. In these patients, smoking cessation and early initiation of immunosuppressive strategies may be beneficial.

Emerging Treatment Options in Inflammatory Bowel Disease: Janus Kinases, Stem Cells, and More.

BACKGROUND: Treatment of inflammatory bowel diseases (IBD) has tremendously improved during the last 20 years; however, a substantial fraction of patients does not respond to available therapies or lose response, and new strategies are needed. SUMMARY: Two pharmacological principles have been successfully used for IBD treatment: inhibition of cellular signaling and interference with leukocyte trafficking. Besides tumor necrosis factor, interleukin (IL)-23 is a promising drug target, and antibodies for the combined inhibition of IL-23 and IL-12 (ustekinumab and briakinumab) or selective IL-23 inhibition (brazikumab, risankizumab, and mirikizumab) seem to be effective in Crohn's disease (CD) with emerging evidence also for ulcerative colitis (UC). Janus kinase (JAK) mediates intracellular signaling of a large number of cytokines. Tofacitinib is the first JAK inhibitor approved for UC, and the JAK inhibitors filgotinib and upadacitinib showed potential in CD. Leukocyte trafficking can be inhibited by interference with lymphocyte integrin-α4ß7 or endothelial MadCAM-1. The α4ß7 integrin inhibitor vedolizumab is an established treatment in IBD, and long-term data of pivotal studies are now available. Additional molecules with therapeutic potential are α4ß7-specific abrilumab, ß7-specific etrolizumab, and the α4-specific small molecule AJM300. PF-00547659, an antibody against endothelial MadCAM-1, also showed therapeutic potential in UC. Modulation of sphingosine-1-phosphate receptor (S1PR) activity is necessary for the egress of lymphocytes into the circulation, and S1PR modulation results in lymphocyte trapping in lymphatic organs. Ozanimod, an S1PR1 and S1PR5 inhibitor, has been successfully tested in initial studies in UC. Mesenchymal stem cell therapy has been approved for the treatment of complex, active CD fistula, and mesenchymal stem cell therapy might be a paradigm shift for this condition. Autologous stem cell transplantation (ASCT) has been successfully used in CD case series; however, in a randomized trial, a highly stringent endpoint was not met. However, considering positive effects in secondary endpoints, ASCT might be a future treatment of last resort in severe, refractory CD cases, provided that safer protocols can be provided. Key messages: New IBD treatments are successful for a significant fraction of patients. However, new strategies for patient selection, treatment combinations, and/or additional therapies must be developed to serve the need of all IBD patients.

A Rare Case of a Traumatic Posterior Hip Dislocation in a 3-Year-Old Boy: A Case Report and Review of the Literature.

We present a rare case of neglected hip dislocation in a 3-year-old boy. Hip dislocations in childhood represent less than 6% of all injuries. The boy presented to the ED with ongoing hip pain after his leg got stuck in a carousel. The physical and radiologic examination revealed a posterior right hip dislocation. The closed reduction failed, so open reduction during surgery was performed. The postoperative protocol included 3 days of immobilization with early mobilization and pain-adapted weight bearing. No signs of femoral head malperfusion occurred 2 months after the injury. The patient did not complain of any limitations such as weight bearing problems or loss of range of motion. In comparison to adults, there are several specialties such as the fact that minor trauma can lead to hip dislocations due to the laxity of the ligaments, and due to the limited direct anamnestic options, neglected hip dislocations can occur. The treatment should focus on immediate proper reduction. The main complications after traumatic hip dislocation are avascular necrosis of the femoral head, redislocation, and early osteoarthritis.

Expression of AXL receptor tyrosine kinase relates to monocyte dysfunction and severity of cirrhosis.

Infectious complications in patients with cirrhosis frequently initiate episodes of decompensation and substantially contribute to the high mortality. Mechanisms of the underlying immuneparesis remain underexplored. TAM receptors (TYRO3/AXL/MERTK) are important inhibitors of innate immune responses. To understand the pathophysiology of immuneparesis in cirrhosis, we detailed TAM receptor expression in relation to monocyte function and disease severity prior to the onset of acute decompensation. TNF-α/IL-6 responses to lipopolysaccharide were attenuated in monocytes from patients with cirrhosis (n = 96) compared with controls (n = 27) and decreased in parallel with disease severity. Concurrently, an AXL-expressing (AXL+) monocyte population expanded. AXL+ cells (CD14+CD16highHLA-DRhigh) were characterised by attenuated TNF-α/IL-6 responses and T cell activation but enhanced efferocytosis and preserved phagocytosis of Escherichia coli Their expansion correlated with disease severity, complications, infection, and 1-yr mortality. AXL+ monocytes were generated in response to microbial products and efferocytosis in vitro. AXL kinase inhibition and down-regulation reversed attenuated monocyte inflammatory responses in cirrhosis ex vivo. AXL may thus serve as prognostic marker and deserves evaluation as immunotherapeutic target in cirrhosis.

Contrast-enhanced ultrasound (CEUS) has excellent diagnostic accuracy in differentiating focal liver lesions: results from a Swiss tertiary gastroenterological centre.

INTRODUCTION: Focal liver lesions (FLLs) are common on conventional ultrasound. Contrast-enhanced ultrasound (CEUS) is highly accurate for differentiating between benign and malignant FLLs, with an accuracy comparable to that of contrast-enhanced CT and contrast-enhanced MRI. Notably, there is no evidence supporting the routine use of CEUS for evaluating benign and malignant FLLs in Switzerland. In this study, we assessed the use of CEUS in a clinical routine setting in a tertiary Swiss gastroenterology centre. METHODS: We analysed all CEUS investigations performed on new or unclear FLLs in our department between November 2011 and March 2013. In all patients, the CEUS results (benign versus malignant FLLs) were compared with CT or MRI findings. To avoid interobserver variation, CEUS was performed by a single experienced gastroenterologist using one ultrasound device (Acuson Sequoia 512®, Siemens, Erlangen, Germany). All patients were examined using the intravenous application of 1.5–2 ml Sonovue®. An FLL with arterial enhancement with wash-out in any vascular phase was defined as a malignant FLL. Malignant FLLs were confirmed by histology. RESULTS: The study included 112 patients. None of them experienced side effects after injection of Sonovue®. The final diagnoses included malignant FLLs (n = 37) and benign FLLs (n = 75) that ranged in size from 7 to 120 mm. The biopsy-proven malignant FLLs (n = 37) included hepatocellular carcinoma, metastatic cancers, peripheral cholangiocarcinoma and primary B-cell lymphoma. CEUS correctly identified 36 out of 37 malignant FLLs, showing a sensitivity of 96–97.2% and a negative predictive value (NPV) of 94.1–98.5%. In contrast, CT/MRI did not identify three metastatic cancers, one HCC, one peripheral cholangiocarcinoma and one primary lymphoma in the liver as malignant FLLs, resulting in a sensitivity of 80.6–80.9% and an NPV of 78.9–89.8%. All these malignant FLLs were correctly classified by CEUS. CONCLUSIONS: In daily clinical practice, CEUS is a fast imaging tool which uses a renal-independent contrast agent and shows excellent accuracy for differentiating between malignant and benign FLLs in about five minutes. The use of CEUS helps to avoid false negative results from CT/MRI and improves sensitivity. CEUS should be the first diagnostic step for investigating new or unclear FLLs.

Endoscopic Treatment of Early Barrett's Adenocarcinoma and Dysplasia: Focus on Submucosal Cancer.

BACKGROUND/AIMS: Eradication of early Barrett's neoplasia by endoscopic resection and radiofrequency ablation is safe and effective. In T1b adenocarcinoma, standard of care remains controversial. We investigated the therapeutic outcome between high-grade dysplasia (HGD)/mucosal adenocarcinoma and submucosal adenocarcinoma in Barrett's patients. We hypothesised similar outcome in low-risk (LR) T1b compared to T1a/HGD. METHODS: Patients with endoscopically treated Barrett's esophagus were included in a Swiss tertiary center cohort study. Primary outcome parameter was complete eradication of early neoplasia. Secondary outcome parameters were recurrence-free survival and safety of endoscopic treatment. RESULTS: Forty-eight patients (1 female) with median Barrett's length C4M6 and mean age of 66 years were included. Complete endoscopic eradication of HGD/T1a was achieved in 33 out of 35 and in 11 out of 13 T1b adenocarcinoma. During a median follow-up of 41 (interquartile range 28-63) months no systemic recurrence was observed in endoscopically treated HGD/T1a and LR -T1b and one in a high-risk T1b adenocarcinoma after surgery. Local recurrences were amenable to surgical or endoscopic re-treatment. No lymphnode metastasis was detected in initial staging with esophageal endosonography/positron emission tomography-CT. CONCLUSION: Comparable endoscopic eradication and recurrence rate were observed in HGD/T1a and LR T1b adenocarcinoma. Carefully selected LR T1b cancer may receive endoscopic treatment in an expert center without any negative impact on recurrence.

Functional Toll-Like Receptor (TLR)2 polymorphisms in the susceptibility to inflammatory bowel disease.

BACKGROUND: The recent genome-wide association studies (GWAS) in inflammatory bowel disease (IBD) suggest significant genetic overlap with complex mycobacterial diseases like tuberculosis or leprosy. TLR variants have previously been linked to susceptibility for mycobacterial diseases. Here we investigated the contribution to IBD risk of two TLR2 polymorphisms, the low-prevalence variant Arg753Gln and the GTn microsatellite repeat polymorphism in intron 2. We studied association with disease, possible correlations with phenotype and gene-gene interactions. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a large study in 843 patients with Crohn's disease, 426 patients with ulcerative colitis and 805 healthy, unrelated controls, all of European origin. Overall, the frequency for carriers of shorter GTn repeats in intron 2 of the TLR2 gene, which have previously been associated with low TLR2 expression and high IL-10 production, was slightly elevated in Crohn's disease and ulcerative colitis compared to healthy controls (16.0% resp. 16.7% vs. 12.8%). The highest frequency of short GTn carriers was noted among IBD patients on anti TNF-alpha therapy. However, none of these differences was significant in the multivariate analysis. The Arg753Gln polymorphism showed no association with any clinical subtype of IBD, including extensive colitis, for which such an association was previously described. We found no association with specific phenotypic disease subgroups. Also, epistasis analysis revealed no significant interactions between the two TLR2 variants and confirmed IBD susceptibility genes. CONCLUSIONS: The two functional relevant polymorphisms in TLR2, the GTn microsatellite repeat polymorphism in intron 2 and the Arg753Gln variant do not seem to play a role in the susceptibility to Crohn's disease or ulcerative colitis.

A Pleiotropic Missense Variant in SLC39A8 Is Associated With Crohn's Disease and Human Gut Microbiome Composition.

BACKGROUND & AIMS: Genome-wide association studies have identified 200 inflammatory bowel disease (IBD) loci, but the genetic architecture of Crohn's disease (CD) and ulcerative colitis remain incompletely defined. Here, we aimed to identify novel associations between IBD and functional genetic variants using the Illumina ExomeChip (San Diego, CA). METHODS: Genotyping was performed in 10,523 IBD cases and 5726 non-IBD controls. There were 91,713 functional single-nucleotide polymorphism loci in coding regions analyzed. A novel identified association was replicated further in 2 independent cohorts. We further examined the association of the identified single-nucleotide polymorphism with microbiota from 338 mucosal lavage samples in the Mucosal Luminal Interface cohort measured using 16S sequencing. RESULTS: We identified an association between CD and a missense variant encoding alanine or threonine at position 391 in the zinc transporter solute carrier family 39, member 8 protein (SLC39A8 alanine 391 threonine, rs13107325) and replicated the association with CD in 2 replication cohorts (combined meta-analysis P = 5.55 × 10(-13)). This variant has been associated previously with distinct phenotypes including obesity, lipid levels, blood pressure, and schizophrenia. We subsequently determined that the CD risk allele was associated with altered colonic mucosal microbiome composition in both healthy controls (P = .009) and CD cases (P = .0009). Moreover, microbes depleted in healthy carriers strongly overlap with those reduced in CD patients (P = 9.24 × 10(-16)) and overweight individuals (P = 6.73 × 10(-16)). CONCLUSIONS: Our results suggest that an SLC39A8-dependent shift in the gut microbiome could explain its pleiotropic effects on multiple complex diseases including CD.

Impact of intraprosthetic drilling on the strength of the femoral stem in periprosthetic fractures: A finite element investigation.

Treatment of periprosthetic femur fractures after total hip arthroplasty remains a major challenge in orthopedic surgery. Recently, a novel surgical technique using intraprosthetic screw fixation has been suggested. The purpose of this study was to evaluate the influence of drilling the femoral hip stem on integrity and strength of the implant. The hypothesis was that intraprosthetic drilling and screw fixation would not cause the load limit of the prosthesis to be exceeded and that deformation would remain within the elastic limit. A sawbone model with a conventional straight hip stem was used and a Vancouver C periprosthetic fracture was created. The fracture was fixed with a nine-hole less invasive stabilization system plate with two screws drilled and inserted through the femoral hip stem. Three different finite element models were created using ANSYS software. The models increased in complexity including joint forces and stress risers from three different dimensions. A variation of drilling positions was analyzed. Due to the complexity of the physiological conditions in the human femur, the most complex finite element model provided the most realistic results. Overall, significant changes in the stresses to the prosthesis caused by the drilling procedure were observed. While the stresses at the site of the bore hole decreased, the load increased in the surrounding stem material. This effect is more pronounced and further the holes were apart, and it was found that increasing the number of holes could counteract this. The maximum load was still found to be in the area of the prosthesis neck. No stresses above the load limit of titanium alloy were detected. All deformations of the prosthesis stem remained in the elastic range. These results may indicate a potential role for intraprosthetic screw fixation in the future treatment of periprosthetic femur fractures.

Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study.

BACKGROUND: Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohn's disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases. METHODS: This study included patients from 49 centres in 16 countries in Europe, North America, and Australasia. We applied the Montreal classification system of inflammatory bowel disease subphenotypes to 34,819 patients (19,713 with Crohn's disease, 14,683 with ulcerative colitis) genotyped on the Immunochip array. We tested for genotype-phenotype associations across 156,154 genetic variants. We generated genetic risk scores by combining information from all known inflammatory bowel disease associations to summarise the total load of genetic risk for a particular phenotype. We used these risk scores to test the hypothesis that colonic Crohn's disease, ileal Crohn's disease, and ulcerative colitis are all genetically distinct from each other, and to attempt to identify patients with a mismatch between clinical diagnosis and genetic risk profile. FINDINGS: After quality control, the primary analysis included 29,838 patients (16,902 with Crohn's disease, 12,597 with ulcerative colitis). Three loci (NOD2, MHC, and MST1 3p21) were associated with subphenotypes of inflammatory bowel disease, mainly disease location (essentially fixed over time; median follow-up of 10·5 years). Little or no genetic association with disease behaviour (which changed dramatically over time) remained after conditioning on disease location and age at onset. The genetic risk score representing all known risk alleles for inflammatory bowel disease showed strong association with disease subphenotype (p=1·65 × 10(-78)), even after exclusion of NOD2, MHC, and 3p21 (p=9·23 × 10(-18)). Predictive models based on the genetic risk score strongly distinguished colonic from ileal Crohn's disease. Our genetic risk score could also identify a small number of patients with discrepant genetic risk profiles who were significantly more likely to have a revised diagnosis after follow-up (p=6·8 × 10(-4)). INTERPRETATION: Our data support a continuum of disorders within inflammatory bowel disease, much better explained by three groups (ileal Crohn's disease, colonic Crohn's disease, and ulcerative colitis) than by Crohn's disease and ulcerative colitis as currently defined. Disease location is an intrinsic aspect of a patient's disease, in part genetically determined, and the major driver to changes in disease behaviour over time. FUNDING: International Inflammatory Bowel Disease Genetics Consortium members funding sources (see Acknowledgments for full list).

Current Concepts for Patellar Dislocation.

CONTEXT: Patellar dislocation usually occurs to the lateral side, leading to ruptures of the Medial Patellofemoral Ligament (MPFL) in about 90% of the cases. Even though several prognostic factors are identified for patellofemoral instability after patellar dislocation so far, the appropriate therapy remains a controversial issue. EVIDENCE ACQUISITION: Authors searched the Medline library for studies on both surgical and conservative treatment for patellar dislocation and patellofemoral instability. Additionally, the reference list of each article was searched for additional studies. RESULTS: A thorough analysis of the anatomical risk factors with a particular focus on patella alta, increased Tibial Tuberosity-Trochlear Groove (TT-TG) distance, trochlear dysplasia as well as torsional abnormalities should be performed early after the first dislocation to allow adequate patient counseling. Summarizing the results of all published randomized clinical trials and comparing surgical and conservative treatment after the first-time patellar dislocation until today indicated no significant evident difference for children, adolescents, and adults. Therefore, nonoperative treatment was indicated after a first-time patellar dislocation in the vast majority of patients. CONCLUSIONS: Surgical treatment for patellar dislocation is indicated primarily in case of relevant concomitant injuries such as osteochondral fractures, and secondarily for recurrent dislocations.

Lipocalin-2 Is a Disease Activity Marker in Inflammatory Bowel Disease Regulated by IL-17A, IL-22, and TNF-α and Modulated by IL23R Genotype Status.

BACKGROUND: Lipocalin-2 (LCN2) is a potent bacteriostatic protein. We aimed to investigate its role as a disease activity marker in patients with inflammatory bowel disease (IBD) and its induction by the Th17 cytokines IL-17A, IL-22, and TNF-α in colonic epithelial cells. Moreover, we analyzed the influence of IBD-associated IL23R alleles on LCN2 serum levels in IBD patients. METHODS: LCN2 serum levels were determined in 131 IBD patients (71 with Crohn's disease [CD], 60 with ulcerative colitis [UC]) and 63 healthy controls. IBD patients were genotyped for 10 IBD-associated IL23R polymorphisms. LCN2 expression after stimulation with IL-17A, IL-22, and TNF-α was measured in human colonic epithelial cell lines. RESULTS: A significant upregulation of serum LCN2 in active IBD (median [IQR], 36.84 [21.17-73.74] ng/mL; P = 0.01) compared with healthy controls (24.22 [17.76-35.25] ng/mL) was confined to active UC (42.21 [28.97-73.74] ng/mL; P = 0.0006). LCN2 proved to be a marker of UC disease activity (area under the curve 0.75, sensitivity 0.83, specificity 0.63; P = 0.0002). IL-17A showed a synergistic effect with IL-22 and TNF-α in inducing colonic epithelial expression of LCN2 and its essential transcription factor IKBZ. In CD, LCN2 concentrations were significantly modulated by IL23R genotype status with homozygous carriers of IBD risk-increasing alleles showing particularly low LCN2 levels. CONCLUSIONS: Serum LCN2 proves to be a biomarker of active UC. Lower LCN2 levels in CD patients carrying IBD risk-increasing IL23R variants may result from a restricted upregulation of LCN2 due to an impaired Th17 immune response.