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Hematopoietic stem cell transplantation is becoming an increasingly important approach to treatment of different malignant and non-malignant disorders. There is thus growing demand for diagnostic assays permitting the surveillance of donor/recipient chimerism posttransplant. Current techniques are heterogeneous, rendering uniform evaluation and comparison of diagnostic results between centers difficult. Leading laboratories from 10 European countries have therefore performed a collaborative study supported by a European grant, the EuroChimerism Concerted Action, with the aim to develop a standardized diagnostic methodology for the detection and monitoring of chimerism in patients undergoing allogeneic stem cell transplantation. Following extensive analysis of a large set of microsatellite/short tandem repeat (STR) loci, the EuroChimerism (EUC) panel comprising 13 STR markers was established with the aim to optimally meet the specific requirements of quantitative chimerism analysis. Based on highly stringent selection criteria, the EUC panel provides multiple informative markers in any transplant setting. The standardized STR-PCR tests permit detection of donor- or recipient-derived cells at a sensitivity ranging between 0.8 and 1.6%. Moreover, the EUC assay facilitates accurate and reproducible quantification of donor and recipient hematopoietic cells. Wide use of the European-harmonized protocol for chimerism analysis presented will provide a basis for optimal diagnostic support and timely treatment decisions.

Background Pain self-management support interventions were effective in controlled clinical trials and meta analyses. However, implementation of these complex interventions may not translate into identical effects. This paper evaluates the implementation of ANtiPain, a cancer pain self-management support intervention in routine clinical practice according to the R each E fficacy- A doption I mplementation M aintenance framework. Methods In this cluster randomized study with a stepped wedge design, N  = 153 adult patients with cancer-related pain were recruited from 01/17 to 05/18 on 17 wards of 3 hospitals in Vienna, Austria. ANtiPain entailed a face-to-face in-hospital session by a trained nurse to prepare discharge according to key strategies, information on pain self-management, and skills building. After discharge, cancer-pain self-management was coached via phone calls. Patient-level data were collected at recruitment, and 2, 4 and 8 weeks after discharge via postal or online questionnaire. Primary outcome was pain interference with daily activities. Secondary outcomes included pain intensity, self-efficacy, and patient satisfaction. Organizational-level data (e.g., on implementation procedures) were collected by study or intervention nurses. The mixed model to analyze patient-level data included a random intercept and a random slope for individual and a random intercept for ward. Results Recruitment was slower than expected and unevenly distributed over wards and hospitals. The face-to-face session was clinically feasible (mean duration = 33 min) as well as the mean amount ( n  = 2) and duration of phone calls (mean = 17 min). Only 16 (46%) of 35 trained nurses performed the intervention on nine wards. To deal with the loss of power, analyses were adapted. Overall effects on pain interference were not significant. However, effects were significant in sub analyses of the nine wards that recruited patients in the intervention period ( p  = .009). Regarding secondary outcomes, the group-by-time effect was significant for self-efficacy ( p  = .033), and patient satisfaction with information on pain-self-management ( p  = .002) and in-hospital pain management ( p  = .018). Conclusions The implementation of ANtiPain improved meaningful patient outcomes on wards that applied the intervention routinely. Our analyses showed that the implementation benefited from being embedded in larger scale projects to improve cancer pain management and that the selection of wards with a high percentage of oncology patients may be crucial. Trial registration ClinicalTrials.gov Identifier: NCT02891785 Date of registration: September 8, 2016.

Atherosclerotic cardiovascular disease causes heart attacks and strokes, which are the leading causes of mortality worldwide 1 . The formation of atherosclerotic plaques is initiated when low-density lipoproteins bind to heparan-sulfate proteoglycans (HSPGs) 2 and become trapped in the subendothelial space of large and medium size arteries, which leads to chronic inflammation and remodelling of the artery wall 2 . A proliferation-inducing ligand (APRIL) is a cytokine that binds to HSPGs 3 , but the physiology of this interaction is largely unknown. Here we show that genetic ablation or antibody-mediated depletion of APRIL aggravates atherosclerosis in mice. Mechanistically, we demonstrate that APRIL confers atheroprotection by binding to heparan sulfate chains of heparan-sulfate proteoglycan 2 (HSPG2), which limits the retention of low-density lipoproteins, accumulation of macrophages and formation of necrotic cores. Indeed, antibody-mediated depletion of APRIL in mice expressing heparan sulfate-deficient HSPG2 had no effect on the development of atherosclerosis. Treatment with a specific anti-APRIL antibody that promotes the binding of APRIL to HSPGs reduced experimental atherosclerosis. Furthermore, the serum levels of a form of human APRIL protein that binds to HSPGs, which we termed non-canonical APRIL (nc-APRIL), are associated independently of traditional risk factors with long-term cardiovascular mortality in patients with atherosclerosis. Our data reveal properties of APRIL that have broad pathophysiological implications for vascular homeostasis. The heparan sulfate proteoglycan-binding cytokine APRIL has a protective role against atherosclerotic disease.

The aim of the study was to obtain basic data on individual biological variation, the required number of specimens to define the homeostatic setpoint (the aspired value of a variable adjusted to the individuals homeostasis) and critical differences of selected chemistry parameters in budgerigars (Melopsittacus undulatus). Blood from 99 healthy budgerigars was sampled 12 times at four-week intervals. Aspartate aminotransferase (ast), calcium, creatine kinase (ck), glutamate dehydrogenase (gldh), glucose, lactate dehydrogenase (ldh), total protein and uric acid were investigated. The indices of individuality obtained in the present study were relatively low (total protein 0·93, ast 1·02, gldh 1·04, ck 1·12, ldh 1·24, uric acid 1·26, glucose 1·39, calcium 1·61) and suggest that population-based reference limits might be useful. Comparison of data showed that the application of intraindividual reference values identified much greater variation in the reference values than using conventional population-based reference limits. Otherwise, the moderate to low degrees of individuality may allow the use of reference values of one individual as a standard for another individual of the same species. The critical differences that define the change needed between two serial results to indicate a biological change was highest in gldh with 120 per cent or 1·7 U/l. In calcium, a change of 30·5 per cent or 0·5 mmol/l would be significant. In the other parameters critical differences varied between 38 per cent in glucose, up to 93 per cent in uric acid.

Background Long-term outcomes of lung transplantation are severely affected by comorbidities and development of chronic rejection. Among the comorbidities, kidney insufficiency is one of the most frequent and it is mainly caused by the cumulative effect of calcineurin inhibitors (CNIs). Currently, the most used immunosuppression protocols worldwide include induction therapy and a triple-drug maintenance immunosuppression, with one calcineurin inhibitor, one anti-proliferative drug, and steroids. Our center has pioneered the use of alemtuzumab as induction therapy, showing promising results in terms of short- and long-term outcomes. The use of alemtuzumab followed by a low-dose double drug maintenance immunosuppression, in fact, led to better kidney function along with excellent results in terms of acute rejection, chronic lung allograft dysfunction, and survival (Benazzo et al., PLoS One 14(1):e0210443, 2019). The hypothesis driving the proposed clinical trial is that de novo introduction of low-dose everolimus early after transplantation could further improve kidney function via a further reduction of tacrolimus. Based on evidences from kidney transplantation, moreover, alemtuzumab induction therapy followed by a low-dose everolimus and low-dose tacrolimus may have a permissive action on regulatory immune cells thus stimulating allograft acceptance. Methods A randomized prospective clinical trial has been set up to answer the research hypothesis. One hundred ten patients will be randomized in two groups. Treatment group will receive the new maintenance immunosuppression protocol based on low-dose tacrolimus and low-dose everolimus and the control group will receive our standard immunosuppression protocol. Both groups will receive alemtuzumab induction therapy. The primary endpoint of the study is to analyze the effect of the new low-dose immunosuppression protocol on kidney function in terms of eGFR change. The study will have a duration of 24 months from the time of randomization. Immunomodulatory status of the patients will be assessed with flow cytometry and gene expression analysis. Discussion For the first time in the field of lung transplantation, this trial proposes the combined use of significantly reduced tacrolimus and everolimus after alemtuzumab induction. The new protocol may have a twofold advantage: (1) further reduction of nephrotoxic tacrolimus and (2) permissive influence on regulatory cells development with further reduction of rejection episodes. Trial registration EUDRACT Nr 2018-001680-24. Registered on 15 May 2018

Chimaerism of FACS-sorted leucocyte subsets (CD14+, CD15+, CD3-/56+, CD3+/4+, CD3+/8+, CD19+) was monitored prospectively between days +14 and +100 in 39 children undergoing allogeneic stem cell transplantation with reduced intensity-conditioning regimens. Cell subsets exceeding 1% of nucleated cells were subject to cell sorting. Chimaerism was analysed by dual-colour FISH and/or by short tandem repeat-polymerase chain reaction. The chimaerism pattern on day +28 was evaluated with regard to its correlation with graft rejection. Of 39 patients, nine patients had donor chimaerism (DC) in all subsets. Mixed/recipient chimaerism (MC/RC) was detectable within T cells in 62%, within NK cells in 39% and within monocytes and granulocytes in 38% of the patients. The correlation of secondary graft rejection with the chimaerism pattern on day +28 revealed the strongest association between RC in NK-cells (P<0.0001), followed by T cells (P=0.001), and granulocytes and monocytes (P=0.034). Notably, patients with RC in T cells rejected their graft only if MC or RC was also present in the NK-cell subset. By contrast, none of the children with DC in NK cells experienced a graft rejection. These observations suggest that, in the presence of recipient T-cell chimaerism, the chimaerism status in NK-cells on day +28 might be able to identify patients at high risk for late graft rejection.

Cytomegalovirus (CMV) DNAemia was detected by PCR in 30/125 (24%) consecutive paediatric patients undergoing allogeneic stem cell transplantation. All patients with CMV DNAemia received pre-emptive ganciclovir until two consecutive negative results were obtained. CMV-IgG-positive patients (R+) had a significantly increased risk of DNAemia as compared to CMV-IgG-negative (R-) patients (62% vs 8%) P<0.0001. The incidence of DNAemia was 71% (10/14) in R+ transplanted from seronegative donors (D-) compared to 54% (13/32) in those transplanted from seropositive donors (D+). Of 30 (40%) children with DNAemia, 12 developed CMV disease despite pre-emptive treatment. The overall incidence of disease was 0% (0/59) for R-/D-, 9% (3/23) for R+/D+, 7% (2/29) for R-/D+ and 57% (8/14) for R+/D-. In patients with DNAemia, 4/20 (20%) patients with D+ and 8/10 (80%) with D- became symptomatic. In the multivariate analysis of both groups, patients at risk (R+ and/or D+) and patients with DNAemia, a negative donor serostatus was the only factor associated with a significantly increased incidence of disease. Seven of 9 patients with lethal CMV disease had received CMV-IgG-negative grafts. The data suggest that in CMV seropositive recipients donor CMV seropositivity is associated with a reduced incidence of CMV disease and a favourable outcome following pre-emptive treatment.

Reference ranges for clinical chemistry variables were established for 99 budgerigars sampled monthly for 12 months. The data from the repeated measurements were compiled to obtain the most reliable population-based reference range defined to be relevant for the population of budgerigars over the whole year. Outlying values were excluded by reference to the population-based reference range and to previously determined values from the same individual, following the guidelines of the International Federation of Clinical Chemistry. The exclusion of outliers significantly reduced the calculated reference ranges.

The effects of intravenous fluid therapy on fluid compartments and hemodynamics of the human body remain enigmatic. We therefore tested the efficacy of bioimpedance spectroscopy in a crossover study, where 15 males received 0.5 ml/kg/min ELO-MEL-isoton (osmolarity = 302 mosmol/l) during 60 minutes, or nothing at all. In group “Fluid”, fluid load increased from −0.2 ± 1.0 l extracellular volume at baseline to its maximum of 1.0 ± 0.9 l in minute 70, and remained continuously elevated throughout minute 300. In group “Zero”, fluid load decreased from 0.5 ± 1.1 l at baseline to its minimum of −1.1 ± 1.1 l in minute 300. In group “Fluid”, intracellular volume decreased from 26.8 ± 3.9 l at baseline to its minimum of 26.0 ± 3.9 l in minute 70, and remained continuously decreased throughout minute 300. In group “Zero”, intracellular volume increased from 26.5 ± 3.8 l at baseline to its maximum of 27.1 ± 3.9 l in minute 120, and decreased thereafter. In group “Fluid” compared to “Zero”, systolic blood pressure was significantly higher, from minute 50–90. In conclusion, intravenous fluid therapy caused a clinically meaningful, sustained increase in fluid load, and a decrease in intracellular volume. These data raise interest in studying fluid administration by the gastrointestinal route, perhaps even when managing critical illness.