Facial nerve palsy in giant-cell arteritis: case-based review.

Acute peripheral facial nerve palsy is most frequently idiopathic (Bell's palsy) or virally induced, but can also be due to several other conditions. A rare cause is underlying systemic or autoimmune disease. A 79-year-old man presented with peripheral facial nerve palsy, malaise, and fever. Physical examination revealed tenderness of the left temporal artery and reduced pulsatility. 18F-FDG-PET/CT and biopsy of the temporal artery confirmed the diagnosis of giant cell arteritis (GCA). Prompt institution of corticosteroid therapy produced rapid decrease in inflammatory markers and gradual improvement of the facial nerve palsy. We searched the MEDLINE, Embase, and Scopus databases to identify previous reports of peripheral nerve palsy in GCA, other vasculitides, and autoimmune diseases. Facial nerve palsy as the presenting symptom of GCA has very rarely been reported. Although temporal artery biopsy is the gold standard for diagnosis, it may be negative in up to one-third of cases. In doubtful cases, imaging can help establish the diagnosis. Ultrasound, 3 T MRI, and 18F-FDG-PET/CT have all been previously reported to be useful. Peripheral facial nerve palsy may very rarely be the presenting symptom of GCA. Early correct diagnosis is essential for starting appropriate therapy. In patients with atypical features, 18F-FDG-PET/CT may be useful for establishing the diagnosis.

Use of 18F-fluorodeoxyglucose positron emission tomography in the diagnosis of polymyalgia rheumatica-A prospective study of 99 patients.

Objective: Previous studies have shown that the majority of patients with PMR have increased 18F-fluorodeoxyglucose (FDG) uptake around the shoulders, hips and processes of the cervical and lumbar spine on PET. The specificity of these findings for PMR is, however, not known. Methods: We prospectively included 99 consecutive patients with a possible clinical diagnosis of PMR. All patients underwent 18F-FDG-PET scanning before treatment with glucocorticoids was started. The clinical suspicion of PMR was quantified by the treating physician on a scale from 1 to 5. FDG uptake was scored visually in 12 articular regions (scores 0-2) and a total skeletal score was calculated reflecting the FDG uptake in these 12 articular regions. Receiver operating characteristics analysis was performed to determine the optimal clinical and total skeletal score for diagnosing PMR. The gold standard for a diagnosis of PMR was the judgement of an experienced clinician after at least 6 months of follow-up. Results: Sixty-seven patients were diagnosed with PMR while 32 patients got another diagnosis. A clinical score of 4 or more had a sensitivity of 67.2%, specificity of 87.5%, positive predictive value (PPV) of 91.8% and a negative predictive value (NPV) of 56.0% for the diagnosis of PMR. A total skeletal score of 16 or more had a sensitivity, specificity, PPV and NPV of, respectively, 85.1, 87.5, 93.4 and 73.7%. Conclusion: 18F-FDG-PET before starting glucocorticoid therapy improves the diagnostic accuracy compared with a clinical scoring system in patients with clinical suspicion of PMR.

Eschar in a Belgian traveler returning from Central Europe.

BACKGROUND: Tularemia is a zoonotic infection caused by Francisella tularensis, an aerobic, facultative intracellular coccobacillus, encountered especially in the Northern hemisphere. F. tularensis is a pathogen of humans and hundreds of animal species. PATIENTS AND METHODS: A Belgian traveler returning from an adventurous vacation in Central Europe presents fever, flu-like symptoms, a skin ulcer with a necrotic center resembling an eschar on the left thigh and painful left inguinal lymphadenopathy. An enzyme linked immunosorbent assay developed by the National Reference Laboratory for Tularemia, Sciensano, Belgium, detected elevated Ig G antibodies against F. tularensis, while the rest of the serologies were negative. RESULTS: A highly likely case of ulceroglandular tularemia is described and the differential diagnosis is discussed. CONCLUSION: The incidence of tularemia has been increasing throughout Europe in recent years. Physicians should be aware of this disease, its diversity of reservoirs, transmission routes and clinical presentations.

Francisella tularensis subsp. holarctica bacteraemia in an immunocompetent male.

Tularemia is a rare zoonotic disease caused by the two predominant subspecies of Francisella tularensis, namely subspecies tularensis and subspecies holarctica. The latter is less virulent than the former, is endemic in Europe, and usually has a mild disease course, although respiratory involvement and bacteraemia can occur. Tularemia in Belgium is rare, but the incidence seems to be increasing. It therefore seems prudent to raise awareness among clinicians for this potentially severe disease. We report the first case of pneumonic tularemia with bacteraemia from Belgium, and want to recommend including Francisella tularensis in the differential diagnosis of pneumonia when an unfavorable evolution is seen with standard treatment.

Imported diseases in travellers presenting to the emergency department after a stay in a malaria-endemic country: a retrospective observational study.

BACKGROUND: We aimed to investigate the aetiology and outcomes of illnesses in patients presenting to an emergency department after travelling to a malaria-endemic country, in order to raise awareness of both tropical and cosmopolitan diseases. METHODS: A retrospective chart review was performed for all patients who underwent blood smear testing for malaria at the Emergency Department of the University Hospitals Leuven from 2017 to 2020. Patient characteristics, results of laboratory and radiological examinations, diagnoses, disease course and outcome were collected and analysed. RESULTS: A total of 253 patients were included in the study. The majority of ill travellers returned from Sub-Saharan Africa (68.4%) and Southeast Asia (19.4%). Their diagnoses fell into three major syndrome categories: systemic febrile illness (30.8%), inflammatory syndrome of unknown origin (23.3%) and acute diarrhoea (18.2%). Malaria (15.8%) was the most common specific diagnosis in patients with systemic febrile illness, followed by influenza (5.1%), rickettsiosis (3.2%), dengue (1.6%), enteric fever (0.8%), chikungunya (0.8%) and leptospirosis (0.8%). The presence of hyperbilirubinemia and thrombocytopenia increased the probability of malaria, with a likelihood ratio of 4.01 and 6.03, respectively. Seven patients (2.8%) were treated in the intensive care unit, and none died. CONCLUSION: Systemic febrile illness, inflammatory syndrome of unknown origin and acute diarrhoea were the three major syndromic categories in returning travellers presenting to our emergency department after a stay in a malaria-endemic country. Malaria was the most common specific diagnosis in patients with systemic febrile illness. None of the patients died.

Three ulcerative colitis susceptibility loci are associated with primary sclerosing cholangitis and indicate a role for IL2, REL, and CARD9.

UNLABELLED: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by inflammation and fibrosis of the bile ducts. Both environmental and genetic factors contribute to its pathogenesis. To further clarify its genetic background, we investigated susceptibility loci recently identified for ulcerative colitis (UC) in a large cohort of 1,186 PSC patients and 1,748 controls. Single nucleotide polymorphisms (SNPs) tagging 13 UC susceptibility loci were initially genotyped in 854 PSC patients and 1,491 controls from Benelux (331 cases, 735 controls), Germany (265 cases, 368 controls), and Scandinavia (258 cases, 388 controls). Subsequently, a joint analysis was performed with an independent second Scandinavian cohort (332 cases, 257 controls). SNPs at chromosomes 2p16 (P-value 4.12 × 10(-4) ), 4q27 (P-value 4.10 × 10(-5) ), and 9q34 (P-value 8.41 × 10(-4) ) were associated with PSC in the joint analysis after correcting for multiple testing. In PSC patients without inflammatory bowel disease (IBD), SNPs at 4q27 and 9q34 were nominally associated (P < 0.05). We applied additional in silico analyses to identify likely candidate genes at PSC susceptibility loci. To identify nonrandom, evidence-based links we used GRAIL (Gene Relationships Across Implicated Loci) analysis showing interconnectivity between genes in six out of in total nine PSC-associated regions. Expression quantitative trait analysis from 1,469 Dutch and UK individuals demonstrated that five out of nine SNPs had an effect on cis-gene expression. These analyses prioritized IL2, CARD9, and REL as novel candidates. CONCLUSION: We have identified three UC susceptibility loci to be associated with PSC, harboring the putative candidate genes REL, IL2, and CARD9. These results add to the scarce knowledge on the genetic background of PSC and imply an important role for both innate and adaptive immunological factors.

Malignancies and mortality in 200 patients with primary sclerosering cholangitis: a long-term single-centre study.

BACKGROUND: The outcome of primary sclerosing cholangitis (PSC) has improved by liver transplantation (LT), but patients often develop malignancies. We analysed morbidity and mortality patterns to define strategies to prevent complications. METHODS: Two hundred consecutive patients diagnosed before October 2005 were studied. RESULTS: Malignancies developed in 40 (20%) and led to death in 28 patients (45.9% of the 61 mortalities). Cholangiocarcinoma (CCa) developed in 13 patients, and was detected shortly after the diagnosis of PSC in 31%. Colorectal carcinomas were documented in 10 and dysplastic adenomas in four patients; eight had ulcerative colitis, two Crohn's colitis, one unclassified inflammatory bowel disease (IBDu), three had no IBD. Five died of colorectal cancer. Three carcinomas and two adenomas were localized in the caecum or ascending colon, but most (n=10) in the recto-sigmoidal region. Hepatocellular carcinoma developed in three patients with advanced fibrosis/cirrhosis, and pancreatic cancer in five. LT has been carried out in 42 patients, 6.1 years (median, 0.5-25) after the diagnosis of PSC. Mortality was due to hepatic complications in 13 patients. Within 5 years of the diagnosis, deaths were because of malignancy in 12 patients and to hepatobiliary decompensation in only three, whereas 18 had been transplanted. CONCLUSIONS: Since the use of transplantation, malignancies are the major cause of death. CCa has to be searched for in any new symptomatic patient. Colorectal malignancy occurs frequently. Colonoscopy at the diagnosis of PSC is obligatory and should be repeated at 1-2 years interval in the patients with IBD and every 5 years in those without IBD.

Subclinical giant cell arteritis in new onset polymyalgia rheumatica A systematic review and meta-analysis of individual patient data.

OBJECTIVES: To determine the prevalence and predictors of subclinical giant cell arteritis (GCA) in patients with newly diagnosed polymyalgia rheumatica (PMR). METHODS: PubMed, Embase, and Web of Science Core Collection were systematically searched (date of last search July 14, 2021) for any published information on any consecutively recruited cohort reporting the prevalence of GCA in steroid-naïve patients with PMR without cranial or ischemic symptoms. We combined prevalences across populations in a random-effect meta-analysis. Potential predictors of subclinical GCA were identified by mixed-effect logistic regression using individual patient data (IPD) from cohorts screened with PET/(CT). RESULTS: We included 13 cohorts with 566 patients from studies published between 1965 to 2020. Subclinical GCA was diagnosed by temporal artery biopsy in three studies, ultrasound in three studies, and PET/(CT) in seven studies. The pooled prevalence of subclinical GCA across all studies was 23% (95% CI 14%-36%, I2=84%) for any screening method and 29% in the studies using PET/(CT) (95% CI 13%-53%, I2=85%) (n=266 patients). For seven cohorts we obtained IPD for 243 patients screened with PET/(CT). Inflammatory back pain (OR 2.73, 1.32-5.64), absence of lower limb pain (OR 2.35, 1.05-5.26), female sex (OR 2.31, 1.17-4.58), temperature >37° (OR 1.83, 0.90-3.71), weight loss (OR 1.83, 0.96-3.51), thrombocyte count (OR 1.51, 1.05-2.18), and haemoglobin level (OR 0.80, 0.64-1.00) were most strongly associated with subclinical GCA in the univariable analysis but not C-reactive protein (OR 1.00, 1.00-1.01) or erythrocyte sedimentation rate (OR 1.01, 1.00-1.02). A prediction model calculated from these variables had an area under the curve of 0.66 (95% CI 0.55-0.75). CONCLUSION: More than a quarter of patients with PMR may have subclinical GCA. The prediction model from the most extensive IPD set has only modest diagnostic accuracy. Hence, a paradigm shift in the assessment of PMR patients in favour of implementing imaging studies should be discussed.

Genome-wide association analysis in primary sclerosing cholangitis.

BACKGROUND & AIMS: We aimed to characterize the genetic susceptibility to primary sclerosing cholangitis (PSC) by means of a genome-wide association analysis of single nucleotide polymorphism (SNP) markers. METHODS: A total of 443,816 SNPs on the Affymetrix SNP Array 5.0 (Affymetrix, Santa Clara, CA) were genotyped in 285 Norwegian PSC patients and 298 healthy controls. Associations detected in this discovery panel were re-examined in independent case-control panels from Scandinavia (137 PSC cases and 368 controls), Belgium/The Netherlands (229 PSC cases and 735 controls), and Germany (400 cases and 1832 controls). RESULTS: The strongest associations were detected near HLA-B at chromosome 6p21 (rs3099844: odds ratio [OR], 4.8; 95% confidence interval [CI], 3.6-6.5; P = 2.6 x 10(-26); and rs2844559: OR, 4.7; 95% CI, 3.5-6.4; P = 4.2 x 10(-26) in the discovery panel). Outside the HLA complex, rs9524260 at chromosome 13q31 showed significant associations in 3 of 4 study panels. Lentiviral silencing of glypican 6, encoded at this locus, led to the up-regulation of proinflammatory markers in a cholangiocyte cell line. Of 15 established ulcerative colitis susceptibility loci, significant replication was obtained at chromosomes 2q35 and 3p21 (rs12612347: OR, 1.26; 95% CI, 1.06-1.50; and rs3197999: OR, 1.22; 95% CI, 1.02-1.47, respectively), with circumstantial evidence supporting the G-protein-coupled bile acid receptor 1 and macrophage-stimulating 1, respectively, as the likely disease genes. CONCLUSIONS: Strong HLA associations and a subset of genes involved in bile homeostasis and other inflammatory conditions constitute key components of the genetic architecture of PSC.

Cocaine-induced midline destruction.

In patients presenting with nasal septum perforation, the differential diagnosis between ANCA-associated vasculitis and cocaine-induced midline destruction (CIMD) can be challenging. We describe the case of a 28-year old man who presented with a nasal septum perforation. He admitted the use of cocaine and showed no other symptoms of systemic inflammation. Perinuclear anti-neutrophilic cytoplasmatic antibodies (p-ANCAs) came back positive, as did anti-proteinase 3-antibodies. Further testing revealed antibodies to human neutrophil elastase (HNE), typically found in CIMD but rarely in ANCA-associated vasculitis. The combination of an atypical ANCA-pattern and the detection of HNE-antibodies led to the diagnosis of CIMD. In conclusion, HNE antibodies can be used to distinguish between CIMD and ANCA-associated vasculitis.

The impact of childhood 13-valent pneumococcal conjugate vaccination on overall invasive pneumococcal disease, including the oldest old.

Objectives: Our aim was to compare serotype distribution in invasive pneumococcal disease (IPD) in the Belgian population before and after introduction of the 13-valent conjugte vaccine (PCV13) in the national childhood vaccination schedule.Methods: Serotyping was performed on 12,534 pleural fluid and bacteraemic Streptococcus pneumoniae isolates sent to the National Reference Centre. We compared the distribution of serotypes (ST)/serogroups (SG) between the periods before (2007-2010) and after (2012-2015) the introduction of PCV13, in children and adults of different age groups, including older individuals (65-84 and ≥85 years).Results: The introduction of PCV13 in the childhood immunization program resulted in a reduction of 16% of all IPD-isolates. The prevalence of PCV13-SG decreased in all age groups: from 81% to 53% (p < 0.0001) in children <18 years, and from 69% to 53% (p < 0.0001) in individuals aged 18-64. This effect was also observed in age groups 65-84 (64% to 50%, p < 0.0001) and ≥85 years (63% to 47%; p < 0.0001). The proportion of IPD cases caused by non-PCV13 SG increased from 31% to 49% between the two periods, indicating replacement with non-vaccine SG. The coverage rate for the 23-valent polysaccharide vaccine (PPV23) in all age groups remains as high as 89% for the total group.Conclusion: After introduction of PCV13, a reduction of PCV13-serotypes occurred in IPD in all age groups. This supports the rationale to combine the effect of PCV13 with the broader coverage of PPV23 as a vaccination strategy for adults.

Bilateral Mondor's disease in chikungunya virus infection.

Chikungunya virus (CHIKV) is an arthropod-borne virus that is transmitted by Aedes mosquitoes, and its main features are high fever and (debilitating) arthritis. Infection with CHIKV, as well as other viruses, has been associated with hypercoagulable states and may be linked with the development of venous thrombosis. In fact, the development of deep venous thrombosis has been described in CHIKV infection. We present a case of superficial thrombophlebitis of the thoracic wall, known as Mondor's disease, associated with CHIKV infection. To our knowledge, this probable association has never been described before.

Granulomatosis with polyangiitis with breast involvement mimicking metastatic cancer: Case report and literature review.

Granulomatosis with polyangiitis (GPA) is a systemic inflammatory disease, characterized by the presence of necrotizing vasculitis of small and medium-sized vessels, granulomatous inflammation and anti-neutrophil cytoplasmic antibodies (ANCAs). The diagnosis can be challenging due to the variable clinical presentation and possible involvement of virtually all organ systems. A correct diagnosis is indispensable for a timely start of medical treatment and to avoid unnecessary surgery. Therefore, cooperation with and the input of the pathologist is crucial. We report a case of a woman presenting with suspected metastatic cancer. The diagnosis of GPA was made mainly based on breast biopsy, and the patient was treated accordingly, with full recovery. This report provides a case description and a brief review of the literature.

Genome-wide associations of human gut microbiome variation and implications for causal inference analyses.

Recent population-based1-4 and clinical studies5 have identified a range of factors associated with human gut microbiome variation. Murine quantitative trait loci6, human twin studies7 and microbiome genome-wide association studies1,3,8-12 have provided evidence for genetic contributions to microbiome composition. Despite this, there is still poor overlap in genetic association across human studies. Using appropriate taxon-specific models, along with support from independent cohorts, we show an association between human host genotype and gut microbiome variation. We also suggest that interpretation of applied analyses using genetic associations is complicated by the probable overlap between genetic contributions and heritable components of host environment. Using faecal 16S ribosomal RNA gene sequences and host genotype data from the Flemish Gut Flora Project (n = 2,223) and two German cohorts (FoCus, n = 950; PopGen, n = 717), we identify genetic associations involving multiple microbial traits. Two of these associations achieved a study-level threshold of P = 1.57 × 10-10; an association between Ruminococcus and rs150018970 near RAPGEF1 on chromosome 9, and between Coprococcus and rs561177583 within LINC01787 on chromosome 1. Exploratory analyses were undertaken using 11 other genome-wide associations with strong evidence for association (P < 2.5 × 10-8) and a previously reported signal of association between rs4988235 (MCM6/LCT) and Bifidobacterium. Across these 14 single-nucleotide polymorphisms there was evidence of signal overlap with other genome-wide association studies, including those for age at menarche and cardiometabolic traits. Mendelian randomization analysis was able to estimate associations between microbial traits and disease (including Bifidobacterium and body composition); however, in the absence of clear microbiome-driven effects, caution is needed in interpretation. Overall, this work marks a growing catalogue of genetic associations that will provide insight into the contribution of host genotype to gut microbiome. Despite this, the uncertain origin of association signals will likely complicate future work looking to dissect function or use associations for causal inference analysis.

Prediction models for diagnosis and prognosis of covid-19: systematic review and critical appraisal

OBJECTIVE: To review and appraise the validity and usefulness of published and preprint reports of prediction models for diagnosing coronavirus disease 2019 (covid-19) in patients with suspected infection, for prognosis of patients with covid-19, and for detecting people in the general population at increased risk of covid-19 infection or being admitted to hospital with the disease. DESIGN: Living systematic review and critical appraisal by the COVID-PRECISE (Precise Risk Estimation to optimise covid-19 Care for Infected or Suspected patients in diverse sEttings) group. DATA SOURCES: PubMed and Embase through Ovid, up to 1 July 2020, supplemented with arXiv, medRxiv, and bioRxiv up to 5 May 2020. STUDY SELECTION: Studies that developed or validated a multivariable covid-19 related prediction model. DATA EXTRACTION: At least two authors independently extracted data using the CHARMS (critical appraisal and data extraction for systematic reviews of prediction modelling studies) checklist; risk of bias was assessed using PROBAST (prediction model risk of bias assessment tool). RESULTS: 37 421 titles were screened, and 169 studies describing 232 prediction models were included. The review identified seven models for identifying people at risk in the general population; 118 diagnostic models for detecting covid-19 (75 were based on medical imaging, 10 to diagnose disease severity); and 107 prognostic models for predicting mortality risk, progression to severe disease, intensive care unit admission, ventilation, intubation, or length of hospital stay. The most frequent types of predictors included in the covid-19 prediction models are vital signs, age, comorbidities, and image features. Flu-like symptoms are frequently predictive in diagnostic models, while sex, C reactive protein, and lymphocyte counts are frequent prognostic factors. Reported C index estimates from the strongest form of validation available per model ranged from 0.71 to 0.99 in prediction models for the general population, from 0.65 to more than 0.99 in diagnostic models, and from 0.54 to 0.99 in prognostic models. All models were rated at high or unclear risk of bias, mostly because of non-representative selection of control patients, exclusion of patients who had not experienced the event of interest by the end of the study, high risk of model overfitting, and unclear reporting. Many models did not include a description of the target population (n=27, 12%) or care setting (n=75, 32%), and only 11 (5%) were externally validated by a calibration plot. The Jehi diagnostic model and the 4C mortality score were identified as promising models. CONCLUSION: Prediction models for covid-19 are quickly entering the academic literature to support medical decision making at a time when they are urgently needed. This review indicates that almost all pubished prediction models are poorly reported, and at high risk of bias such that their reported predictive performance is probably optimistic. However, we have identified two (one diagnostic and one prognostic) promising models that should soon be validated in multiple cohorts, preferably through collaborative efforts and data sharing to also allow an investigation of the stability and heterogeneity in their performance across populations and settings. Details on all reviewed models are publicly available at https://www.covprecise.org/. Methodological guidance as provided in this paper should be followed because unreliable predictions could cause more harm than benefit in guiding clinical decisions. Finally, prediction model authors should adhere to the TRIPOD (transparent reporting of a multivariable prediction model for individual prognosis or diagnosis) reporting guideline. SYSTEMATIC REVIEW REGISTRATION: Protocol https://osf.io/ehc47/, registration https://osf.io/wy245. READERS' NOTE: This article is a living systematic review that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication. This version is update 3 of the original article published on 7 April 2020 (BMJ 2020;369:m1328). Previous updates can be found as data supplements (https://www.bmj.com/content/369/bmj.m1328/related#datasupp). When citing this paper please consider adding the update number and date of access for clarity.

Genetic risk profiling and prediction of disease course in Crohn's disease patients.

BACKGROUND & AIMS: Clinical presentation at diagnosis and disease course of Crohn's disease (CD) are heterogeneous and variable over time. Early introduction of immunomodulators and/or biologicals might be justified in patients at risk for disease progression, so it is important to identify these patients as soon as possible. We examined the influence of recently discovered CD-associated susceptibility loci on changes in disease behavior and evaluated whether a genetic risk model for disease progression could be generated. METHODS: Complete medical data were available for 875 CD patients (median follow-up time, 14 years; interquartile range, 7-22). Fifty CD-associated polymorphisms were genotyped. Kaplan-Meier survival analyses, multiple logistic regression, and generalized multifactor dimensionality reduction analyses (GMDR) were performed, correcting for follow-up time. RESULTS: Homozygosity for the rs1363670 G-allele in a gene encoding a hypothetical protein near the IL12B gene was independently associated with stricturing disease behavior (odds ratio [OR], 5.48; 95% confidence interval [CI], 1.60-18.83; P = .007) and with shorter time to strictures (P = .01), especially in patients with ileal involvement (P = .0002). Male patients carrying at least one rs12704036 T-allele in a gene desert had the shortest time to non-perianal fistula (P < .0001). The presence of a C-allele at the CDKAL1 single nucleotide polymorphism rs6908425 and the absence of NOD2 variants were independently associated with development of perianal fistula (OR, 8.86; 95% CI, 1.13-69.78; P = .04 and OR, 0.56; 95% CI, 0.38-0.83; P = .004, respectively), particularly when colonic involvement and active smoking were present. CONCLUSIONS: CD-associated polymorphisms play a role in disease progression and might be useful in identifying patients who could benefit from an early top-down treatment approach.

Confirmation of multiple Crohn's disease susceptibility loci in a large Dutch-Belgian cohort.

OBJECTIVES: Inflammatory bowel diseases (IBD)-Crohn's disease (CD) and ulcerative colitis (UC)-are chronic gastrointestinal inflammatory disorders with a complex genetic background. A genome-wide association scan by the Wellcome Trust Case Control Consortium (WTCCC) recently identified several novel susceptibility loci. METHODS: We performed a large replication study in 2,731 Dutch and Belgian IBD patients (1,656 CD and 1,075 UC) and 1,086 controls. In total, 40 single nucleotide polymorphisms (SNPs) that showed moderate or strong association in the WTCCC study, along with SNPs in the previously identified genes IL23R, ATG16L1, and NELL1, were studied. RESULTS: We confirmed the associations with IL23R (rs11209026, P=2.69E-12), ATG16L1 (rs2241880, P=4.82E-07), IRGM (rs4958847, P=2.26E-05), NKX2-3 (rs10883365, P=5.91E-06), 1q24 (rs12035082, P=1.51E-05), 5p13 (rs17234657, P=2.62E-05), and 10q21 (rs10761659, P=8.95E-04). We also identified associations with cyclin Y (CCNY; rs3936503, P=2.09 E-04) and Hect domain and RCC1-like domain 2 (HERC2; rs916977, P=1.12E-04). Pooling our data with the original WTCCC data substantiated these associations. Several SNPs were also moderately associated with UC. Two genetic risk profiles based on the number of risk alleles and based on a weighted score were created. On the basis of these results, we calculated sensitivities, specificities, positive and negative predictive values, and likelihood ratios for CD. CONCLUSIONS: We replicated genetic associations for CD with IL23R, ATG16L1, IRGM, NKX2-3, 1q24, 10q21, 5p13, and PTPN2 and report evidence for associations with HERC2 and CCNY. Pooling our data with the results of the WTCCC strengthened the results, suggesting genuine genetic associations. We show that a genetic risk profile can be constructed that is clinically useful and that can aid in making treatment decisions.

Polymorphisms in innate immunity genes predispose to bacteremia and death in the medical intensive care unit.

OBJECTIVE: Critically ill patients are at risk of sepsis, organ failure, and death. Studying the impact of genetic determinants may improve our understanding of the pathophysiology and allow identification of patients who would benefit from specific treatments. Our aim was to study the influence of single nucleotide polymorphisms in selected genes involved in innate immunity on the development of bacteremia or risk of death in patients admitted to a medical intensive care unit. DESIGN, SETTING, AND PATIENTS: DNA was available from 774 medical intensive care unit patients. We selected 31 single nucleotide polymorphisms in 14 genes involved in host innate immune defense. Serum levels of MASP2 and chemotactic capacity, phagocytosis, and killing capacity of monocytes at admission were quantified. Univariate Kaplan-Meier estimates with log-rank analysis and multivariate logistic regression were performed. Bootstrap resampling technique and ten-fold cross-validation were used to assess replication stability, prognostic importance of the variables, and repeatability of the final regression model. MAIN RESULTS: Patients with at least one NOD2 variant were shown to have a reduced phagocytosis by monocytes (p = 0.03) and a higher risk of bacteremia than wild-type patients (p = 0.02). The NOD2/TLR4 combination was associated with bacteremia using survival analyses (time to bacteremia development, log-rank p < 0.0001), univariate regression (p = 0.0003), and multivariate regression analysis (odds ratio [OR] 4.26, 95% confidence interval [CI] 1.85-9.81; p = 0.0006). Similarly, the same combination was associated with hospital mortality using survival analysis (log-rank p = 0.03), univariate regression (p = 0.02), and multivariate regression analysis (OR 2.27, 95% CI 1.09-4.74; p = 0.03). Also variants in the MASP2 gene were significantly associated with hospital mortality (survival analysis log-rank-p = 0.003; univariate regression p = 0.02; multivariate regression analysis OR 2.35, 95% CI 1.38-3.99; p = 0.002). CONCLUSIONS: Functional polymorphisms in genes involved in innate immunity predispose to severe infections and death, and may become part of a risk model, allowing identification of patients at risk, who could benefit from early introduction of specific preventive or therapeutic interventions.

The Crohn's disease susceptibility gene DLG5 as a member of the CARD interaction network.

Discs large homolog 5 (DLG5), a member of the membrane-associated guanylate kinase (MAGUK) family of scaffolding proteins, has been associated with Crohn's disease (CD), but its role in the pathogenesis of this inflammatory bowel disease is disputed. Here, we used sequence comparisons and phylogenies to analyse the DLG5 gene and its protein product. We identified a 5' exon, which codes for an N-terminal caspase recruitment domain (CARD) and experimentally confirmed its expression in colonic tissue. DLG5 shares this new domain with nucleotide-binding oligomerisation domain containing 2 (NOD2); the first CD susceptibility factor identified in genetic studies. An extensive phylogenetic analysis redefines the family organisation of the MAGUK proteins: DLG5 is closely related to CARD10, CARD11 and CARD14, CARD-containing proteins which initiate pro-inflammatory NFkappaB signalling, but not to DLG1-4, previously considered the closest related proteins. Therefore, we suggest renaming DLG5 to correctly annotate the gene in its phylogenetic and functional context. Our study provides evidence that the scaffolding protein DLG5 belongs to the CARD protein family. Thus, DLG5 likely acts in the regulation of NFkB activation or caspase activation as part of host defence mechanisms. As there is substantial crosstalk between CARD-mediated pathways, both CD susceptibility genes, NOD2 and DLG5, may interact functionally to contribute to CD risk.