Predicting therapy response to mycophenolic acid using UGT1A9 genotyping: towards personalized medicine in atopic dermatitis

Atopic dermatitis (AD) is a very common chronic inflammatory skin disease requiring long-term treatment. Mycophenolic acid (MPA) is used off-label in treatment of patients with severe AD failing Cyclosporin A (CsA) treatment, however clinical efficacy is observed in only half of the AD patients. In blood, MPA levels are known to have a large interindividual variability. Low MPA exposure and increased enzyme activity correlates with the presence of UGT1A9 polymorphisms. In this retrospective study, 65 adult AD patients treated with MPA were classified as responder or non-responder to MPA treatment. UGT1A9 polymorphisms were determined using PCR. A significantly higher number of UGT1A9 polymorphisms was found in the group that did not respond to MPA treatment. Of the patients that carried a UGT1A9 polymorphism, 85.7% were non-responsive to MPA treatment. This implies that non-responsiveness in AD patients is more likely to occur in carriers of a UGT1A9 polymorphism. In a binary logistic regression analysis the odds ratio (OR) was 8.65 (95% confidence interval: 0.93–80.17). Our results show that UGT1A9 polymorphisms can be used to identify patients with non-responsiveness to MPA. Patients with UGT1A9 polymorphisms might benefit from higher MPA dosage

Prevalence and clinical significance of lumbosacral transitional vertebra (LSTV) in a young back pain population with suspected axial spondyloarthritis: results of the SPondyloArthritis Caught Early (SPACE) cohort

Imaging- and therapeutic targets in neoplastic and musculoskeletal inflammatory diseas

Outcomes in octogenarians and the effect of comorbidities after intact abdominal aortic aneurysm repair in the Netherlands: a nationwide cohort study

Objective: Age is an independent risk factor for mortality after both elective open surgical repair (OSR) and endovascular aneurysm repair (EVAR). As a result of an ageing population, and the less invasive nature of EVAR, the number of patients over 80 years (octogenarians) being treated is increasing. The mortality and morbidity following aneurysm surgery are increased for octogenarians. However, the mortality for octogenarians who have either low or high peri-operative risks remains unclear. The aim of this study was to provide peri-operative outcomes of octogenarians vs. non-octogenarians after OSR and EVAR for intact aneurysms, including separate subanalyses for elective and urgent intact repair, based on a nationwide cohort. Furthermore, the influence of comorbidities on peri-operative mortality was examined.Methods: All patients registered in the Dutch Surgical Aneurysm Audit (DSAA) undergoing intact AAA repair between 2013 and 2018, were included. Patient characteristics and peri-operative outcomes (peri-operative mortality, and major complications) of octogenarians vs. non-octogenarians for both OSR and EVAR were compared using descriptive statistics. Multivariable logistic regression analyses were used to examine whether age and the presence of cardiac, pulmonary, or renal comorbidities were associated with mortality.Results: This study included 12 054 EVAR patients (3 015 octogenarians), and 3 815 OSR patients (425 octogenarians). Octogenarians in both the EVAR and OSR treatment groups were more often female and had more comorbidities. In both treatment groups, octogenarians had significantly higher mortality rates following intact repair as well as higher major complication rates. Mortality rates of octogenarians were 1.9% after EVAR and 11.8% after OSR. Age >= 80 and presence of cardiac, pulmonary, and renal comorbidities were associated with mortality after EVAR and OSR.Conclusion: Because of the high peri-operative mortality rates of octogenarians, awareness of the presence of comorbidities is essential in the decision making process before offering aneurysm repair to this cohort, especially when OSR is considered.Development and application of statistical models for medical scientific researc

TNF signalling drives expansion of bone marrow CD4+ T cells responsible for HSC exhaustion in experimental visceral leishmaniasis

Visceral leishmaniasis is associated with significant changes in hematological function but the mechanisms underlying these changes are largely unknown. In contrast to naïve mice, where most long-term hematopoietic stem cells (LT-HSCs; LSK CD150+ CD34- CD48- cells) in bone marrow (BM) are quiescent, we found that during Leishmania donovani infection most LT-HSCs had entered cell cycle. Loss of quiescence correlated with a reduced self-renewal capacity and functional exhaustion, as measured by serial transfer. Quiescent LT-HSCs were maintained in infected RAG2 KO mice, but lost following adoptive transfer of IFNγ-sufficient but not IFNγ-deficient CD4+ T cells. Using mixed BM chimeras, we established that IFNγ and TNF signalling pathways converge at the level of CD4+ T cells. Critically, intrinsic TNF signalling is required for the expansion and/or differentiation of pathogenic IFNγ+CD4+ T cells that promote the irreversible loss of BM function. These finding provide new insights into the pathogenic potential of CD4+ T cells that target hematopoietic function in leishmaniasis and perhaps other infectious diseases where TNF expression and BM dysfunction also occur simultaneously

Autoantibodies against type I IFNs in patients with life-threatening COVID-19

Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-w (IFN-w) (13 patients), against the 13 types of IFN-a (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men

Comparison of outcome and characteristics between 6343 COVID-19 patients and 2256 other community-acquired viral pneumonia patients admitted to Dutch ICUs

Purpose: Describe the differences in characteristics and outcomes between COVID-19 and other viral pneumonia patients admitted to Dutch ICUs. Materials and methods: Data from the National-Intensive-Care-Evaluation-registry of COVID-19 patients admitted between February 15th and January 1th 2021 and other viral pneumonia patients admitted between January 1st 2017 and January 1st 2020 were used. Patients' characteristics, the unadjusted, and adjusted in-hospital mortality were compared. Results: 6343 COVID-19 and 2256 other viral pneumonia patients from 79 ICUs were included. The COVID-19 patients included more male (71.3 vs 49.8%), had a higher Body-Mass-Index (28.1 vs 25.5), less comorbidities (42.2 vs 72.7%), and a prolonged hospital length of stay (19 vs 9 days). The COVID-19 patients had a significantly higher crude in-hospital mortality rate (Odds ratio (OR) = 1.80), after adjustment for patient characteristics and ICU occupancy rate the OR was respectively 3.62 and 3.58. Conclusion: Higher mortality among COVID-19 patients could not be explained by patient characteristics and higher ICU occupancy rates, indicating that COVID-19 is more severe compared to other viral pneumonia. Our findings confirm earlier warnings of a high need of ICU capacity and high mortality rates among relatively healthy COVID-19 patients as this may lead to a higher mental workload for the staff. (c) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/)