Summary
Background
Crohn's disease recurs in the majority of patients after intestinal resection.
Aim
To compare the relative efficacy of thiopurines and anti‐TNF therapy in patients at high risk of ...disease recurrence.
Methods
As part of a larger study comparing post‐operative management strategies, patients at high risk of recurrence (smoker, perforating disease, ≥2nd operation) were treated after resection of all macroscopic disease with 3 months metronidazole together with either azathioprine 2 mg/kg/day or mercaptopurine 1.5 mg/kg/day. Thiopurine‐intolerant patients received adalimumab induction then 40 mg fortnightly. Patients underwent colonoscopy at 6 months with endoscopic recurrence assessed blind to treatment.
Results
A total of 101 patients 50% male; median (IQR) age 36 (25–46) years were included. There were no differences in disease history between thiopurine‐ and adalimumab‐treated patients. Fifteen patients withdrew prior to 6 months, five due to symptom recurrence (of whom four were colonoscoped). Endoscopic recurrence (Rutgeerts score i2–i4) occurred in 33 of 73 (45%) thiopurine vs. 6 of 28 (21%) adalimumab‐treated patients intention‐to‐treat (ITT); P = 0.028 or 24 of 62 (39%) vs. 3 of 24 (13%) respectively per‐protocol analysis (PPA); P = 0.020. Complete mucosal endoscopic normality (Rutgeerts i0) occurred in 17/73 (23%) vs. 15/28 (54%) (ITT; P = 0.003) and in 27% vs. 63% (PPA; P = 0.002). The most advanced disease (Rutgeerts i3 and i4) occurred in 8% vs. 4% (thiopurine vs. adalimumab).
Conclusions
In Crohn's disease patients at high risk of post‐operative recurrence adalimumab is superior to thiopurines in preventing early disease recurrence.
Summary
Background
Therapeutic drug monitoring (TDM) in inflammatory bowel disease (IBD) patients receiving anti‐tumour necrosis factor (TNF) agents can help optimise outcomes. Consensus statements ...based on current evidence will help the development of treatment guidelines.
Aim
To develop evidence‐based consensus statements for TDM‐guided anti‐TNF therapy in IBD.
Methods
A committee of 25 Australian and international experts was assembled. The initial draft statements were produced following a systematic literature search. A modified Delphi technique was used with 3 iterations. Statements were modified according to anonymous voting and feedback at each iteration. Statements with 80% agreement without or with minor reservation were accepted.
Results
22/24 statements met criteria for consensus. For anti‐TNF agents, TDM should be performed upon treatment failure, following successful induction, when contemplating a drug holiday and periodically in clinical remission only when results would change management. To achieve clinical remission in luminal IBD, infliximab and adalimumab trough concentrations in the range of 3‐8 and 5‐12 μg/mL, respectively, were deemed appropriate. The range may differ for different disease phenotypes or treatment endpoints—such as fistulising disease or to achieve mucosal healing. In treatment failure, TDM may identify mechanisms to guide subsequent decision‐making. In stable clinical response, TDM‐guided dosing may avoid future relapse. Data indicate drug‐tolerant anti‐drug antibody assays do not offer an advantage over drug‐sensitive assays. Further data are required prior to recommending TDM for non‐anti‐TNF biological agents.
Conclusion
Consensus statements support the role of TDM in optimising anti‐TNF agents to treat IBD, especially in situations of treatment failure.
Given that cardiovascular safety liabilities remain a major cause of drug attrition during preclinical and clinical development, adverse drug reactions, and post‐approval withdrawal of medicines, the ...Medical Research Council Centre for Drug Safety Science hosted a workshop to discuss current challenges in determining, understanding and addressing ‘Cardiovascular Toxicity of Medicines’. This article summarizes the key discussions from the workshop that aimed to address three major questions: (i) what are the key cardiovascular safety liabilities in drug discovery, drug development and clinical practice? (ii) how good are preclinical and clinical strategies for detecting cardiovascular liabilities? and (iii) do we have a mechanistic understanding of these liabilities? It was concluded that in order to understand, address and ultimately reduce cardiovascular safety liabilities of new therapeutic agents there is an urgent need to:
•
Fully characterize the incidence, prevalence and impact of drug‐induced cardiovascular issues at all stages of the drug development process.
•
Ascertain the predictive value of existing non‐clinical models and assays towards the clinical outcome.
•
Understand the mechanistic basis of cardiovascular liabilities; by addressing areas where it is currently not possible to predict clinical outcome based on preclinical safety data.
•
Provide scientists in all disciplines with additional skills to enable them to better integrate preclinical and clinical data and to better understand the biological and clinical significance of observed changes.
•
Develop more appropriate, highly relevant and predictive tools and assays to identify and wherever feasible to eliminate cardiovascular safety liabilities from molecules and wherever appropriate to develop clinically relevant and reliable safety biomarkers.
We report the first measurement of coherent elastic neutrino-nucleus scattering (CEvNS) on argon using a liquid argon detector at the Oak Ridge National Laboratory Spallation Neutron Source. Two ...independent analyses prefer CEvNS over the background-only null hypothesis with greater than 3σ significance. The measured cross section, averaged over the incident neutrino flux, is (2.2±0.7)×10^{-39} cm^{2}-consistent with the standard model prediction. The neutron-number dependence of this result, together with that from our previous measurement on CsI, confirms the existence of the CEvNS process and provides improved constraints on nonstandard neutrino interactions.
Background. Cytomegalovirus (CMV) is a leading cause of congenital illness and disability, including hearing loss and mental retardation. However, there are no nationwide estimates of CMV ...seroprevalence among pregnant women or the overall population of the United States. Methods. To determine CMV prevalence in a representative sample of the US population, we tested serum samples for CMV-specific immunoglobulin G from participants aged ⩾6 years (n = 21,639) in the third National Health and Nutrition Examination Survey (1988–1994). Results. The prevalence of CMV infection was 58.9% in individuals ⩾6 years old. CMV seroprevalence increased gradually with age, from 36.3% in 6–11-year-olds to 90.8% in those aged ⩾80 years. CMV seroprevalence differed by race and/or ethnicity as follows: 51.2% in non-Hispanic white persons, 75.8% in non-Hispanic black persons, and 81.7% in Mexican Americans. Racial and/or ethnic differences in CMV seroprevalence persisted when controlling for household income level, education, marital status, area of residence, census region, family size, country of birth, and type of medical insurance. Among women, racial and/or ethnic differences were especially significant; between ages 10–14 years and 20–24 years, seroprevalence increased 38% for non-Hispanic black persons, 7% for non-Hispanic white persons, and <1% for Mexican Americans. Conclusions. On the basis of these results, we estimate that each year in the United States ∼340,000 non-Hispanic white persons, 130,000 non-Hispanic black persons, and 50,000 Mexican American women of childbearing age experience a primary CMV infection. Given the number of women at risk and the significance of congenital disease, development of programs for the prevention of CMV infection, such as vaccination or education, is of considerable public health importance.
Summary
Background
Acute severe ulcerative colitis (ASUC) is a potentially life‐threatening complication of ulcerative colitis.
Aim
To develop consensus statements based on a systematic review of the ...literature of the management of ASUC to improve patient outcome.
Methods
Following a literature review, the Delphi method was used to develop the consensus statements. A steering committee, based in Australia, generated the statements of interest. Three rounds of anonymous voting were carried out to achieve the final results. Acceptance of statements was pre‐determined by ≥80% votes in ‘complete agreement’ or ‘agreement with minor reservation’.
Results
Key recommendations include that patients with ASUC should be: hospitalised, undergo unprepared flexible sigmoidoscopy to assess severity and to exclude cytomegalovirus colitis, and be provided with venous thromboembolism prophylaxis and intravenous hydrocortisone 100 mg three or four times daily with close monitoring by a multidisciplinary team. Rescue therapy such as infliximab or ciclosporin should be started if insufficient response by day 3, and colectomy considered if no response to 7 days of rescue therapy or earlier if deterioration. With such an approach, it is expected that colectomy rate during admission will be below 30% and mortality less than 1% in specialist centres.
Conclusion
These evidenced‐based consensus statements on acute severe ulcerative colitis, developed by a multidisciplinary group, provide up‐to‐date best practice recommendations that improve and harmonise management as well as provide auditable quality assessments.
As custom arrays are cheaper than generic GWAS arrays, larger sample size is achievable for gene discovery. Custom arrays can tag more variants through denser genotyping of SNPs at associated loci, ...but at the cost of losing genome-wide coverage. Balancing this trade-off is important for maximizing experimental designs. We quantified both the gain in captured SNP-heritability at known candidate regions and the loss due to imperfect genome-wide coverage for inflammatory bowel disease using immunochip (iChip) and imputed GWAS data on 61,251 and 38.550 samples, respectively. For Crohn's disease (CD), the iChip and GWAS data explained 19 and 26% of variation in liability, respectively, and SNPs in the densely genotyped iChip regions explained 13% of the SNP-heritability for both the iChip and GWAS data. For ulcerative colitis (UC), the iChip and GWAS data explained 15 and 19% of variation in liability, respectively, and the dense iChip regions explained 10 and 9% of the SNP-heritability in the iChip and the GWAS data. From bivariate analyses, estimates of the genetic correlation in risk between CD and UC were 0.75 (SE 0.017) and 0.62 (SE 0.042) for the iChip and GWAS data, respectively. We also quantified the SNP-heritability of genomic regions that did or did not contain the previous 163 GWAS hits for CD and UC, and SNP-heritability of the overlapping loci between the densely genotyped iChip regions and the 163 GWAS hits. For both diseases, over different genomic partitioning, the densely genotyped regions on the iChip tagged at least as much variation in liability as in the corresponding regions in the GWAS data, however a certain amount of tagged SNP-heritability in the GWAS data was lost using the iChip due to the low coverage at unselected regions. These results imply that custom arrays with a GWAS backbone will facilitate more gene discovery, both at associated and novel loci.
With excellent energy resolution and ultralow-level radiogenic backgrounds, the high-purity germanium detectors in the Majorana Demonstrator enable searches for several classes of exotic dark matter ...(DM) models. In this work, we report new experimental limits on keV-scale sterile neutrino DM via the transition magnetic moment from conversion to active neutrinos ν_{s}→ν_{a}. We report new limits on fermionic dark matter absorption (χ+A→ν+A) and sub-GeV DM-nucleus 3→2 scattering (χ+χ+A→ϕ+A), and new exclusion limits for bosonic dark matter (axionlike particles and dark photons). These searches utilize the (1-100)-keV low-energy region of a 37.5-kg y exposure collected by the Demonstrator between May 2016 and November 2019 using a set of ^{76}Ge-enriched detectors whose surface exposure time was carefully controlled, resulting in extremely low levels of cosmogenic activation.
The COHERENT experiment is well poised to test sub-GeV dark matter models using detectors sensitive to coherent elastic neutrino-nucleus scattering (CEvNS) in the π+ decay-at-rest (π-DAR) neutrino ...beam produced by the Spallation Neutron Source. We show a planned 750-kg single-phase liquid argon scintillation detector would place leading limits on scalar light dark matter models for dark matter particles produced through vector and leptophobic portals in the absence of other effects beyond the standard model. The characteristic timing profile of a π-DAR beam allows a unique opportunity for constraining systematic uncertainties on the standard model background using a time window where dark matter signal is not expected, enhancing expected sensitivity. Additionally, we discuss future prospects which show that an on-axis CEvNS detector would probe the thermal abundance for a scalar dark matter candidate for all couplings α′ ≤ 1 for 15 MeV dark matter with just 1.0 tonne-yr of exposure with increased exposure testing a wider range of dark matter masses and spins.
Crohn's disease and ulcerative colitis are lifelong diseases seen predominantly in the developed countries of the world. Whereas ulcerative colitis is a chronic inflammatory condition causing diffuse ...and continuous mucosal inflammation of the colon, Crohn's disease is a heterogeneous entity comprised of several different phenotypes, but can affect the entire gastrointestinal tract. A change in diagnosis from Crohn's disease to ulcerative colitis during the first year of illness occurs in about 10 % - 15 % of cases. Inflammatory bowel disease (IBD) restricted to the colon that cannot be characterized as either ulcerative colitis or Crohn's disease is termed IBD-unclassified (IBDU). The advent of capsule and both single- and double-balloon-assisted enteroscopy is revolutionizing small-bowel imaging and has major implications for diagnosis, classification, therapeutic decision making and outcomes in the management of IBD. The role of these investigations in the diagnosis and management of IBD, however, is unclear. This document sets out the current Consensus reached by a group of international experts in the fields of endoscopy and IBD at a meeting held in Brussels, 12-13th December 2008, organised jointly by the European Crohn's and Colitis Organisation (ECCO) and the Organisation Mondiale d'Endoscopie Digestive (OMED). The Consensus is grouped into seven sections: definitions and diagnosis; suspected Crohn's disease; established Crohn's disease; IBDU; ulcerative colitis (including ileal pouch-anal anastomosis IPAA); paediatric practice; and complications and unresolved questions. Consensus guideline statements are followed by comments on the evidence and opinion. Statements are intended to be read in context with qualifying comments and not read in isolation.
PDF
