Mesenchymal stromal cells (MSC) possess immunomodulatory properties and low immunogenicity, both crucial properties for their development into an effective cellular immunotherapy. They have shown ...benefit in clinical trials targeting liver diseases; however the efficacy of MSC therapy will benefit from improvement of the immunomodulatory and immunogenic properties of MSC.
MSC derived from human umbilical cords (ucMSC) were treated for 3 days in vitro with various inflammatory factors, interleukins, vitamins and serum deprivation. Their immunogenicity and immunomodulatory capacity were examined by gene-expression analysis, surface-marker expressions, IDO activity, PGE
secretion and inhibition of T cell proliferation and IFNγ production. Furthermore, their activation of NK cell cytotoxicity was investigated via CD107a expression on NK cells. The immunomodulatory capacity, biodistribution and survival of pre-treated ucMSC were investigated in a CCl
-induced liver disease mouse model. In addition, capacity of pre-treated MSC to ameliorate liver inflammation was examined in an ex vivo liver inflammation co-culture model.
IFN-γ and a multiple cytokine cocktail (MC) consisting of IFN-γ, TGFβ and retinoic acid upregulated the expression of immunomodulatory factor PD-L1 and IDO activity. Subsequently, both treatments enhanced the capacity of ucMSC to inhibit CD4 and CD8 T cell proliferation and IFN-γ production. The susceptibility of ucMSC for NK cell lysis was decreased by IFN-β, TGFβ and MC treatment. In vivo, no immunomodulation was observed by the ucMSC. Four hours after intravenous infusion in mice with CCl
-induced inflammatory liver injury, the majority of ucMSC were trapped in the lungs. Rapid clearance of ucMSC(VitB
), ucMSC(Starv + VitB
) and ucMSC(MC) and altered bio-distribution of ucMSC(TGFβ) compared to untreated ucMSC was observed. In the ex vivo co-culture system with inflammatory liver slices ucMSC(MC) showed significantly enhanced modulatory capacity compared to untreated ucMSC.
The present study demonstrates the responsiveness of ucMSC to in vitro optimisation treatment. The observed improvements in immunomodulatory capacity as well as immunogenicity after MC treatment may improve the efficacy of ucMSC as immunotherapy targeted towards liver inflammation.
This two-wave (16-month lag) Belgian panel study is one of the first to test theory-driven hypotheses on the relations between job resources, work engagement, and actual turnover across time. The ...study focuses on three groups: stayers, workers who have obtained promotions ("promotion makers"), and external job movers. In line with the Job Demands-Resources model, we hypothesized normal cross-lagged effects of job resources on work engagement for stayers. Based on broaden-and-build theory, a reversed causal effect of work engagement on job resources was predicted for the job changers. Additionally, we examined whether the changes in the job change groups matched the refuge hypothesis (that less engaged workers change to jobs providing more resources) or the positive gain hypothesis (that engaged workers get promoted to jobs having even more resources). The results partially supported our hypotheses. We found that low work engagement, low job autonomy, and low departmental resources predicted actual transfer to another company. Furthermore, for stayers we found positive effects of job autonomy on work engagement, but also reversed causal effects. For external movers and promotion makers the expected reversed causal effects of work engagement were found. The across time mean changes support the positive gain hypothesis for promotion makers, and the refuge hypothesis for external movers.
The immunomodulatory capacity of mesenchymal stem or stromal cells (MSC) makes them a promising tool for treatment of immune disease and organ transplantation. The effects of MSC on B cells are ...characterized by an abrogation of plasmablast formation and induction of regulatory B cells (Bregs). It is, however, unknown how MSC interact with B cells under inflammatory conditions. In this study, adipose tissue-derived MSC were pretreated with 50 ng/ml IFN-γ for 96 h (MSC-IFN-γ) to simulate inflammatory conditions. Mature B cells were obtained from spleens by CD43
selection. B cells were co-cultured with MSC and stimulated with anti-IgM, anti-CD40, and IL-2; and after 7 days, B cell proliferation, phenotype, Immunoglobulin-G (IgG), and IL-10 production were analyzed. MSC did not inhibit B cell proliferation but increased the percentage of CD38
CD24
B cells (Bregs) and IL-10 production, while MSC-IFN-γ significantly reduced B cell proliferation and inhibited IgG production by B cells in a more potent fashion but did not induce Bregs or IL-10 production. Both MSC and MSC-IFN-γ required proximity to target cells and being metabolically active to exert their effects. Indoleamine 2,3 dioxygenase expression was highly induced in MSC-IFN-γ and was responsible of the anti-proliferative and Breg reduction since addition of tryptophan (TRP) restored MSC properties. Immunological conditions dictate the effect of MSC on B cell function. Under immunological quiescent conditions, MSC stimulate Breg induction; whereas, under inflammatory conditions, MSC inhibit B cell proliferation and maturation through depletion of TRP. This knowledge is useful for customizing MSC therapy for specific purposes by appropriate pretreatment of MSC.
Case-mix based prospective payment of homecare is being implemented in several countries to work towards more efficient and client-centred homecare. However, existing models can only explain a ...limited part of variance in homecare use, due to their reliance on health- and function-related client data. It is unclear which predictors could improve predictive power of existing case-mix models. The aim of this study was therefore to identify relevant predictors of homecare use by utilizing the expertise of district nurses and health insurers.
We conducted a two-round Delphi-study according to the RAND/UCLA Appropriateness Method. In the first round, participants assessed the relevance of eleven client characteristics that are commonly included in existing case-mix models for predicting homecare use, using a 9-Point Likert scale. Furthermore, participants were also allowed to suggest missing characteristics that they considered relevant. These items were grouped and a selection of the most relevant items was made. In the second round, after an expert panel meeting, participants re-assessed relevance of pre-existing characteristics that were assessed uncertain and of eleven suggested client characteristics. In both rounds, median and inter-quartile ranges were calculated to determine relevance.
Twenty-two participants (16 district nurses and 6 insurers) suggested 53 unique client characteristics (grouped from 142 characteristics initially). In the second round, relevance of the client characteristics was assessed by 12 nurses and 5 health insurers. Of a total of 22 characteristics, 10 client characteristics were assessed as being relevant and 12 as uncertain. None was found irrelevant for predicting homecare use. Most of the client characteristics from the category 'Daily functioning' were assessed as uncertain. Client characteristics in other categories - i.e. 'Physical health status', 'Mental health status and behaviour', 'Health literacy', 'Social environment and network', and 'Other' - were more frequently considered relevant.
According to district nurses and health insurers, homecare use could be predicted better by including other more holistic predictors in case-mix classification, such as on mental functioning and social network. The challenge remains, however, to operationalize the new characteristics and keep stakeholders on board when developing and implementing case-mix classification for homecare prospective payment.
Summary
Background
Tioguanine (or thioguanine) is an alternative drug for IBD patients who fail prior conventional immunomodulating therapy.
Aim
To report effectiveness, safety and therapeutic drug ...monitoring in a cohort of patients with prolonged tioguanine maintenance therapy.
Methods
In this nationwide, multicentre study, medical records of tioguanine‐ using IBD patients were retrospectively reviewed. Response to therapy was defined as clinical effectiveness without (re)initiation of corticosteroids, concurrent biological therapy or surgical intervention. All adverse events that occurred during the follow‐up were listed and graded according to the common terminology criteria (CTC).
Results
Two hundred and seventy‐four patients (female 63%, Crohn's disease in 68%) were included with median treatment duration of 51 months, 1567 patient‐years of follow‐up and median 20 mg/d tioguanine dosage. Tioguanine was tolerated in 79%, clinical effectiveness at 6 months was documented in 66% and sustained clinical effectiveness during 12 months in 51% of patients. Forty‐one per cent of patients developed adverse events: 5% were graded as severe. Adverse events comprised infection requiring hospitalisation in three and skin cancer in eight patients (two melanomas). Asymptomatic nodular regenerative hyperplasia of the liver occurred in two out of 52 patients with liver biopsies (3.8%) and portal hypertension in three whereof one potentially associated with tioguanine (0.4%). Clinical effectiveness was correlated with 6‐thioguanine nucleotide threshold concentrations >682 pmol/8×108 RBC (P < 0.05).
Conclusions
Long‐term tioguanine therapy for at least 12 months was effective in 51% and well tolerated as a maintenance treatment for IBD in about 70% of patients. Adverse events were common, but mainly mild or moderate. 6‐Thioguanine nucleotide threshold concentration ≥ 700 pmol/8×108 RBC is proposed as target level with higher odds for clinical effectiveness.
Classification is a defining factor for competition in wheelchair sports, but it is a delicate and time-consuming process with often questionable validity. New inertial sensor-based measurement ...methods applied in match play and field tests allow for more precise and objective estimates of the impairment effect on wheelchair-mobility performance. The aim of the present research was to evaluate whether these measures could offer an alternative point of view for classification.
Six standard wheelchair-mobility performance outcomes of different classification groups were measured in match play (n = 29), as well as best possible performance in a field test (n = 47).
In match results, a clear relationship between classification and performance level is shown, with increased performance outcomes in each adjacent higher-classification group. Three outcomes differed significantly between the low- and mid-classified groups, and 1, between the mid- and high-classified groups. In best performance (field test), there was a split between the low- and mid-classified groups (5 out of 6 outcomes differed significantly) but hardly any difference between the mid- and high-classified groups. This observed split was confirmed by cluster analysis, revealing the existence of only 2 performance-based clusters.
The use of inertial sensor technology to obtain objective measures of wheelchair-mobility performance, combined with a standardized field test, produced alternative views for evidence-based classification. The results of this approach provide arguments for a reduced number of classes in wheelchair basketball. Future use of inertial sensors in match play and field testing could enhance evaluation of classification guidelines, as well as individual athlete performance.
Dealing with contaminants in Coulomb excitation of radioactive beams Morrison, L; Hadyńska-Klęk, K; Podolyák, Zs ...
27th International Nuclear Physics Conference, INPC 2019,Glasgow, United Kingdom,2019-07-29 - 2019-08-02,
12/2020, Letnik:
1643, Številka:
1
Journal Article, Conference Proceeding
Recenzirano
Odprti dostop
Data analysis of the Coulomb excitation experiment of the exotic 206Hg nucleus, recently performed at CERN's HIE-ISOLDE facility, needs to account for the contribution to target excitation due to the ...strongly-present beam contaminant 130Xe. In this paper, the contamination subtraction procedure is presented.
Background
Off‐label prescribing is encountered across various fields of medicine and creates alternative treatment options, but is associated with unknown safety risks. The use of off‐label drugs ...for the treatment of patients with inflammatory bowel diseases (IBD) has not been characterised before.
Aim
To assess the proportion and characteristics of off‐label prescribing for IBD in tertiary care centres in the Netherlands.
Methods
A prospective database of IBD patients from all Dutch university hospitals was used to collect data on drug prescriptions for IBD and demographics. Drugs were classified as off‐label if they were unlicensed for Crohn's disease and/or ulcerative colitis by the Medicines Evaluation Board. Uni‐ and multivariable analyses were used to identify patient‐specific characteristics predictive of increased off‐label use.
Results
For the induction and/or maintenance treatment of 4583 IBD patients, 12 651 historical and current drug records were available in the database. Of these, 2374 (19%) were considered off‐label prescriptions. Out of 4583 IBD patients, 1477 (32%) were exposed to off‐label drugs. Commonly prescribed off‐label IBD drugs were mercaptopurine (18%), beclomethasone (12%), thioguanine (4%) and allopurinol (3%). Non‐thiopurine/methotrexate off‐label drugs were prescribed in 243 patients (6%), including biological agents or tofacitinib in 47 IBD patients (1%). Off‐label prescriptions were more common in ulcerative colitis than Crohn's disease (37% vs 29%, P < 0.001). Smokers and patients that received ≥5 drug types during their disease course were more likely to be exposed to off‐label drugs (smoking 33% vs 27% and multiple drug use 66% vs 22%, both P < 0.001).
Conclusion
About one‐fifth of prescriptions for IBD were off‐label and one‐third of IBD patients, especially ulcerative colitis patients, were exposed to off‐label drugs.
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