Anti-tumour necrosis factor discontinuation in inflammatory bowel disease patients in remission: study protocol of a prospective, multicentre, randomized clinical trial

Background: Patients with inflammatory bowel disease who achieve remission with anti-tumour necrosis factor (anti-TNF) drugs may have treatment withdrawn due to safety concerns and cost considerations, but there is a lack of prospective, controlled data investigating this strategy. The primary study aim is to compare the rates of clinical remission at 1?year in patients who discontinue anti-TNF treatment versus those who continue treatment. Methods: This is an ongoing, prospective, double-blind, multicentre, randomized, placebo-controlled study in patients with Crohn?s disease or ulcerative colitis who have achieved clinical remission for ?6?months with an anti-TNF treatment and an immunosuppressant. Patients are being randomized 1:1 to discontinue anti-TNF therapy or continue therapy. Randomization stratifies patients by the type of inflammatory bowel disease and drug (infliximab versus adalimumab) at study inclusion. The primary endpoint of the study is sustained clinical remission at 1?year. Other endpoints include endoscopic and radiological activity, patient-reported outcomes (quality of life, work productivity), safety and predictive factors for relapse. The required sample size is 194 patients. In addition to the main analysis (discontinuation versus continuation), subanalyses will include stratification by type of inflammatory bowel disease, phenotype and previous treatment. Biological samples will be obtained to identify factors predictive of relapse after treatment withdrawal. Results: Enrolment began in 2016, and the study is expected to end in 2020. Conclusions: This study will contribute prospective, controlled data on outcomes and predictors of relapse in patients with inflammatory bowel disease after withdrawal of anti-TNF agents following achievement of clinical remission. Clinical trial reference number: EudraCT 2015-001410-1

Defining spatial genetic structure and management units for vulnerable koala (Phascolarctos cinereus) populations in the Sydney region, Australia

Context: Mammal populations around the world are increasingly threatened with population fragmentation because of loss of habitat or barriers to gene flow. The investigation of koala populations in the Sydney region not only provides valuable information about this vulnerable species, but also serves as a model for other species that have suffered major rapid declines in population size, and are now recovering in fragmented habitat. The peri-urban study region allows investigation of the impact of landscape features such as major roads and housing developments on koala gene flow.\ud \ud Aims: Animals originating from four geographic sampling areas around Sydney, New South Wales, Australia, were\ud examined to determine population structure and gene flow and to identify barriers to gene flow and management units.\ud \ud Methods: The present study examined 12 microsatellite loci and used Bayesian assignment methods and genic frequency\ud analysis methods to identify demographically separate populations and barriers to gene flow between those populations.\ud \ud Key results: Three discrete populations were resolved, with all displaying moderate to high levels of genetic\ud differentiation among them (q = 0.141–0.224). The allelic richness and heterozygosity of the Blue Mountains\ud population (A = 6.46, HO = 0.66) is comparable to the highest diversity found in any koala population previously\ud investigated. However, considerably lower genetic diversity was found in the Campbelltown population (A = 3.17,\ud HO = 0.49), which also displayed evidence of a recent population bottleneck (effective population size estimated at 16–21).\ud \ud Conclusions: Animals separated by a military reserve were identified as one population, suggesting that the reserve\ud maintains gene flow within this population. By contrast, strong differentiation of two geographically close populations separated by several potential barriers to gene flow suggested these land-use features pose barriers to gene flow.\ud \ud Implications: Implications of these findings for management of koala populations in the Greater Sydney region are\ud discussed. In particular, the need to carefully consider the future of a military reserve is highlighted, along with possible solutions to allow gene flow across the proposed barrier regions. Because these are demographically separate populations, specific management plans tailored to the needs of each population will need to be formulated