Abstract
Background and Aims
This study aimed to characterize the mucosa-associated microbiota in ileal Crohn’s disease CD patients and in healthy controls in terms of host genotype and inflammation ...status.
Methods
The mucosa-associated microbiotas of intestinal pinch biopsies from 15 ileal CD patients with mild and moderate disease and from 58 healthy controls were analysed based on 16S ribosomal sequencing to determine microbial profile differences between 1 IL23R, NOD2 and ATG16L1 genotypes in healthy subjects, 2 ileal CD patients and control subjects, and 3 inflamed and non-inflamed mucosal tissue in CD patients.
Results
The protective variant of the IL23R gene rs11209026 significantly impacted the microbial composition in the ileum of healthy subjects and was associated with an increased abundance of phylotypes within the family Christensenellaceae as well as increases in diversity and richness. Comparative analysis of healthy and non-inflamed CD microbiome samples indicated a notable decrease in the abundance of Faecalibacterium prausnitzii as well as Shannon diversity and richness. Inflamed and non-inflamed ileal samples of CD subjects had high intra-individual stability and inter-individual variability, but no significant alterations in diversity, richness or taxa were identified. Calprotectin correlated positively with the abundance of Proteobacteria and negatively with diversity in the samples from healthy subjects.
Conclusions
The observation of low diversity and low abundance of beneficial bacteria in healthy control subjects carrying the IL23R rs11209026 wild-type GG genotype indicates that the gut microbiome is influenced by host genetics and is altered prior to disease diagnosis. Faecal calprotectin may be a potential non-invasive screening tool for dysbiosis in subjects without disorders of intestinal inflammation.
We report outcomes and evaluate patient factors and the impact of surgical evolution on outcomes in consecutive ulcerative colitis patients who had restorative proctocolectomy with ileal pouch-anal ...anastomosis (IPAA) at an Australian institution over 26 years.
Data including clinical characteristics, preoperative medical therapy, and surgical outcomes were collected. We divided eligible patients into 3 period arms (period 1, 1990 to 1999; period 2, 2000 to 2009; period 3, 2010 to 2016). Outcomes of interest were IPAA leak and pouch failure.
A total of 212 patients were included. Median follow-up was 50 (interquartile range, 17 to 120) months. Rates of early and late complications were 34.9% and 52.0%, respectively. Early complications included wound infection (9.4%), pelvic sepsis (8.0%), and small bowel obstruction (6.6%) while late complications included small bowel obstruction (18.9%), anal stenosis (16.8%), and pouch fistula (13.3%). Overall, IPAA leak rate was 6.1% and pouch failure rate was 4.8%. Eighty-three patients (42.3%) experienced pouchitis. Over time, we observed an increase in patient exposure to thiopurine (P=0.0025), cyclosporin (P=0.0002), and anti-tumor necrosis factor (P<0.00001) coupled with a shift to laparoscopic technique (P<0.00001), stapled IPAA (P<0.00001), J pouch configuration (P<0.00001), a modified 2-stage procedure (P=0.00012), and a decline in defunctioning ileostomy rate at time of IPAA (P=0.00002). Apart from pouchitis, there was no significant difference in surgical and chronic inflammatory pouch outcomes with time.
Despite greater patient exposure to immunomodulatory and biologic therapy before surgery coupled with a significant change in surgical techniques, surgical and chronic inflammatory pouch outcome rates have remained stable.
Aims
AMG 181 pharmacokinetics/pharmacodynamics (PK/PD), safety, tolerability and effects after single subcutaneous (s.c.) or intravenous (i.v.) administration were evaluated in a randomized, ...double‐blind, placebo‐controlled study.
Methods
Healthy male subjects (n= 68) received a single dose of AMG 181 or placebo at 0.7, 2.1, 7, 21, 70 mg s.c. (or i.v.), 210 mg s.c. (or i.v.), 420 mg i.v. or placebo. Four ulcerative colitis (UC) subjects (n= 4, male : female 2:2) received 210 mg AMG 181 or placebo s.c. (3:1). AMG 181 concentration, anti‐AMG 181‐antibody (ADA), α4β7 receptor occupancy (RO), target cell counts, serum C‐reactive protein, fecal biomarkers and Mayo score were measured. Subjects were followed 3–9 months after dose.
Results
Following s.c. dosing, AMG 181 was absorbed with a median tmax ranging between 2–10 days and a bioavailability between 82% and 99%. Cmax and AUC increased dose‐proportionally and approximately dose‐proportionally, respectively, within the 70–210 mg s.c. and 70–420 mg i.v. ranges. The linear β‐phase t1/2 was 31 (range 20–48) days. Target‐mediated disposition occurred at serum AMG 181 concentrations of less than 1 μg ml−1. The PD effect on α4β7 RO showed an EC50 of 0.01 μg ml−1. Lymphocytes, eosinophils, CD4+ T cells and subset counts were unchanged. AMG 181‐treated UC subjects were in remission with mucosal healing at weeks 6, 12 and/or 28. The placebo‐treated UC subject experienced colitis flare at week 6. No ADA or AMG 181 treatment‐related serious adverse events were observed.
Conclusions
AMG 181 has PK/PD, safety, and effect profiles suitable for further testing in subjects with inflammatory bowel diseases.
Gastroenterology Departments at hospitals within Australia receive thousands of General Practitioner (GP)-referral letters for gastrointestinal investigations every month. Many of these requests are ...for colonoscopy. This study aims to evaluate the performance of the current symptoms-based triage system compared to a novel risk score using objective markers.
Patients with lower abdominal symptoms referred by their GPs and triaged by a Gastroenterology consultant to a colonoscopy consent clinic were recruited into the study. A risk assessment tool (RAT) was developed using objective data (clinical, demographic, pathology (stool test, FIT), standard blood tests and colonoscopy outcome). Colonoscopy and histology results were scored and then stratified as either significant bowel disease (SBD) or non-significant bowel disease (non-SBD).
Of the 467 patients in our study, 45.1% were male, the mean age was 54.3 ± 13.8 years and mean BMI was 27.8 ± 6.2. Overall, 26% had SBD compared to 74% with non-SBD (42% of the cohort had a normal colonoscopy). Increasing severity of referral symptoms was related to a higher triage category, (rectal bleeding, P = 2.86*10
; diarrhoea, P = 0.026; abdominal pain, P = 5.67*10
). However, there was no significant difference in the prevalence of rectal bleeding (P = 0.991) or diarrhoea (P = 0.843) for SBD. Abdominal pain significantly reduced the risk of SBD (P = 0.0344, OR = 0.52, CI = 0.27-0.95). Conversely, the RAT had a very high specificity of 98% with PPV and NPV of SBD prediction, 74% and 77%, respectively. The RAT provided an odds ratio (OR) of 9.0, 95%CI 4.29-18.75, p = 2.32*10
), higher than the FIT test (OR = 5.3, 95%CI 2.44-11.69, p = 4.88*10
), blood score (OR = 2.8, 95%CI 1.72- 4.38, p = 1.47*10
) or age (OR = 2.5, 95%CI 1.61-4.00, 5.12*10
) independently. Notably, the ORs of these individual objective measures were higher than the current practice of symptoms-based triaging (OR = 1.4, 95%CI 0.88-2.11, p = 0.153).
It is critical that individuals with high risk of having SBD are triaged to the appropriate category with the shortest wait time. Here we provide evidence that a combination of blood markers, demographic markers and the FIT test have a higher diagnostic accuracy for SBD than FIT alone.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Retrospective studies observe an increased risk of keratinocyte carcinomas (KCs) in patients with inflammatory bowel disease (IBD) on thiopurine (TP) medication. The role of traditional ...risk factors such as skin type and sun protection behavior has not been studied in this population. This study aimed to examine traditional KC risk factors and thiopurine use on skin cancer development in an IBD cohort.
Methods
Consecutive IBD patients were recruited from four specialist centers in Australia and New Zealand, each with varying UV exposure indices. Data pertaining to race, skin color, freckling and sun protection behavior, dose of TP therapy, and skin cancer development were elicited through a self-reported questionnaire.
Results
A total of 691 IBD patients were included with 62 reporting KC development. Thiopurine usage was similar among patients who developed skin cancer compared with those who did not (92% vs. 89%,
p
= 0.3). There was no statistically significant association between KC development and TP dose or 6-thioguanine nucleotide levels. In multivariate modeling, four factors were independently and significantly associated with KC: age over 61 years old versus less than 30 years old (OR 6.76; 95% CI 2.38–19.18), residing in Brisbane versus Christchurch (OR 3.3; 95% CI 1.6–6.8), never staying in the shade versus staying in the shade ≥ 50% of the time (OR 3.8; 95% CI 1.4–10.5), and having a skin type that never tanned versus other skin types (OR 6.9; 95% CI 2.9–16.0).
Conclusion
Skin type, age, and sun protection behavior are more important risk factors for KC development than thiopurine medication use in this IBD population.
Compromised skeletal status is a frequent finding in patients with Crohn's disease (CD), leading to increased fracture risk. Low body weight is associated with bone mineral density (BMD) in CD, ...although the relative importance of its components, lean and fat mass, is unclear. Muscle strength is also a predictor of BMD in nondiseased populations; however, its association with bone in CD is unknown. We examined the independent effects of body composition and muscle strength on regional and whole-body BMD in a cohort of CD patients. Sixty men and women, aged 22-72 years, with disease duration of 13 ± 7 years, underwent scanning of the spine, hip, forearm, and whole-body BMD by dual-energy X-ray absorptiometry (DXA). Lean tissue, appendicular muscle mass (AMM), and fat mass were derived by DXA and grip strength by dynamometry. Medical history, medication usage, clinical variables, and nutritional intake were obtained by questionnaire. Prevalence of osteopenia and osteoporosis was 32 and 17%, respectively, with osteopenia more common at the hip and osteoporosis more common at the spine. In multiple regression analyses, AMM was an independent predictor of whole-body and regional BMD whereas lean mass was an independent predictor at the hip. Neither grip strength nor fat mass was independently associated with BMD. Of the components of body composition, muscle mass was strongly associated with regional and whole-body BMD. Preserving or augmenting muscle mass in this population may be a useful strategy to preserve BMD and thereby reduce fracture risk.
Ulcerative colitis UC is a major form of inflammatory bowel disease globally. Phenotypic heterogeneity is defined by several variables including age of onset and disease extent. The genetics of ...disease severity remains poorly understood. To further investigate this, we performed a genome wide association GWA study using an extremes of phenotype strategy.
We conducted GWA analyses in 311 patients with medically refractory UC MRUC, 287 with non-medically refractory UC non-MRUC and 583 controls. Odds ratios ORs were calculated for known risk variants comparing MRUC and non-MRUC, and controls.
MRUC-control analysis had the greatest yield of genome-wide significant single nucleotide polymorphisms SNPs 2018, including lead SNP = rs111838972 OR = 1.82, p = 6.28 × 10-9 near MMEL1 and a locus in the human leukocyte antigen HLA region lead SNP = rs144717024, OR = 12.23, p = 1.7 × 10-19. ORs for the lead SNPs were significantly higher in MRUC compared to non-MRUC p < 9.0 × 10-6. No SNPs reached significance in the non-MRUC-control analysis (top SNP, rs7680780 OR 2.70, p = 5.56 × 10-8). We replicate findings for rs4151651 in the Complement Factor B CFB gene and demonstrate significant changes in CFB gene expression in active UC. Detailed HLA analyses support the strong associations with MHC II genes, particularly HLA-DQA1, HLA-DQB1 and HLA-DRB1 in MRUC.
Our MRUC subgroup replicates multiple known UC risk variants in contrast to non-MRUC and demonstrates significant differences in effect sizes compared to those published. Non-MRUC cases demonstrate lower ORs similar to those published. Additional risk and prognostic loci may be identified by targeted recruitment of individuals with severe disease.
Primary open-angle glaucoma (POAG) is a major cause of irreversible blindness worldwide. We performed a genome-wide association study in an Australian discovery cohort comprising 1,155 cases with ...advanced POAG and 1,992 controls. We investigated the association of the top SNPs from the discovery stage in two Australian replication cohorts (932 cases and 6,862 controls total) and two US replication cohorts (2,616 cases and 2,634 controls total). Meta-analysis of all cohorts identified three loci newly associated with development of POAG. These loci are located upstream of ABCA1 (rs2472493G, odds ratio (OR) = 1.31, P = 2.1 × 10(-19)), within AFAP1 (rs4619890G, OR = 1.20, P = 7.0 × 10(-10)) and within GMDS (rs11969985G, OR = 1.31, P = 7.7 × 10(-10)). Using RT-PCR and immunolabeling, we show that these genes are expressed within human retina, optic nerve and trabecular meshwork and that ABCA1 and AFAP1 are also expressed in retinal ganglion cells.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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