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More effective treatment modalities are urgently needed in patients with acute myeloid leukemia (AML) of older age. We hypothesized that adding lenalidomide to intensive standard chemotherapy might improve their outcome. After establishing a safe lenalidomide, dose elderly patients with AML were randomly assigned in this randomized Phase 2 study (n = 222) to receive standard chemotherapy ("3 + 7") with or without lenalidomide at a dose of 20 mg/day 1-21. In the second cycle, patients received cytarabine 1000 mg/m 2 twice daily on days 1-6 with or without lenalidomide (20 mg/day 1-21). The CR/CRi rates in the two arms were not different (69 vs. 66%). Event-free survival (EFS) at 36 months was 19% for the standard arm versus 21% for the lenalidomide arm and overall survival (OS) 35% vs. 30%, respectively. The frequencies and grade of adverse events were not significantly different between the treatment arms. Cardiovascular toxicities were rare and equally distributed between the arms. The results of the present study show that the addition of lenalidomide to standard remission induction chemotherapy does not improve the therapeutic outcome of older AML patients. This trial is registered as number NTR2294 in The NederlandsTrial Register (www.trialregister.nl).

Multiple sclerosis is a chronic inflammatory, demyelinating disease, although it has been suggested that in the progressive late phase, inflammatory lesion activity declines. We recently showed in the Netherlands Brain Bank multiple sclerosis-autopsy cohort considerable ongoing inflammatory lesion activity also at the end stage of the disease, based on microglia/macrophage activity. We have now studied the role of T cells in this ongoing inflammatory lesion activity in chronic multiple sclerosis autopsy cases. We quantified T cells and perivascular T-cell cuffing at a standardized location in the medulla oblongata in 146 multiple sclerosis, 20 neurodegenerative control and 20 non-neurological control brain donors. In addition, we quantified CD3+, CD4+, and CD8+ T cells in 140 subcortical white matter lesions. The location of CD8+ T cells in either the perivascular space or the brain parenchyma was determined using CD8/laminin staining and confocal imaging. Finally, we analysed CD8+ T cells, isolated from fresh autopsy tissues from subcortical multiple sclerosis white matter lesions (n = 8), multiple sclerosis normal-appearing white matter (n = 7), and control white matter (n = 10), by flow cytometry. In normal-appearing white matter, the number of T cells was increased compared to control white matter. In active and mixed active/inactive lesions, the number of T cells was further augmented compared to normal-appearing white matter. Active and mixed active/inactive lesions were enriched for both CD4+ and CD8+ T cells, the latter being more abundant in all lesion types. Perivascular clustering of T cells in the medulla oblongata was only found in cases with a progressive disease course and correlated with a higher percentage of mixed active/inactive lesions and a higher lesion load compared to cases without perivascular clusters in the medulla oblongata. In all white matter samples, CD8+ T cells were located mostly in the perivascular space, whereas in mixed active/inactive lesions, 16.3% of the CD8+ T cells were encountered in the brain parenchyma. CD8+ T cells from mixed active/inactive lesions showed a tissue-resident memory phenotype with expression of CD69, CD103, CD44, CD49a, and PD-1 and absence of S1P1. They upregulated markers for homing (CXCR6), reactivation (Ki-67), and cytotoxicity (GPR56), yet lacked the cytolytic enzyme granzyme B. These data show that in chronic progressive multiple sclerosis cases, inflammatory lesion activity and demyelinated lesion load is associated with an increased number of T cells clustering in the perivascular space. Inflammatory active multiple sclerosis lesions are populated by CD8+ tissue-resident memory T cells, which show signs of reactivation and infiltration of the brain parenchyma., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Cytogenetic risk stratification at diagnosis has long been one of the most useful tools to assess prognosis in acute lymphoblastic leukemia (ALL). To examine the prognostic impact of cytogenetic abnormalities on outcomes after allogeneic hematopoietic cell transplantation, we studied 1731 adults with Philadelphia-negative ALL in complete remission who underwent myeloablative or reduced intensity/non-myeloablative conditioning transplant from unrelated or matched sibling donors reported to the Center for International Blood and Marrow Transplant Research. A total of 632 patients had abnormal conventional metaphase cytogenetics. The leukemia-free survival and overall survival rates at 5 years after transplantation in patients with abnormal cytogenetics were 40% and 42%, respectively, which were similar to those in patients with a normal karyotype. Of the previously established cytogenetic risk classifications, modified Medical Research Council-Eastern Cooperative Oncology Group score was the only independent prognosticator of leukemia-free survival ( P =0.03). In the multivariable analysis, monosomy 7 predicted post-transplant relapse [hazard ratio (HR)=2.11; 95% confidence interval (95% CI): 1.04-4.27] and treatment failure (HR=1.97; 95% CI: 1.20-3.24). Complex karyotype was prognostic for relapse (HR=1.69; 95% CI: 1.06-2.69), whereas t(8;14) predicted treatment failure (HR=2.85; 95% CI: 1.35-6.02) and overall mortality (HR=3.03; 95% CI: 1.44-6.41). This large study suggested a novel transplant-specific cytogenetic scheme with adverse [monosomy 7, complex karyotype, del(7q), t(8;14), t(11;19), del(11q), tetraploidy/near triploidy], intermediate (normal karyotype and all other abnormalities), and favorable (high hyperdiploidy) risks to prognosticate leukemia-free survival ( P =0.02). Although some previously established high-risk Philadelphia-negative cytogenetic abnormalities in ALL can be overcome by transplantation, monosomy 7, complex karyotype, and t(8;14) continue to pose significant risks and yield inferior outcomes., (Copyright© 2020 Ferrata Storti Foundation.)

Introduction: A stronger evidence level is needed to confirm the benefits and limits of laparoscopic hemihepatectomies., Methods: Laparoscopic and open hemihepatectomies from nine European referral centers were compared after propensity score matching (right and left hemihepatectomies separately, and benign and malignant diseases sub-analyses)., Results: Five hundred and forty-five laparoscopic hemihepatectomies were compared with 545 open. Laparoscopy was associated with reduced blood loss (P < 0.001), postoperative stay (P < 0.001) and minor morbidity (P = 0.002), supported by a lower Comprehensive Complication Index (CCI) (P = 0.035). Laparoscopic right hemihepatectomies were associated with lower ascites (P = 0.016), bile leak (P = 0.001) and wound infections (P = 0.009). Laparoscopic left hemihepatectomies exhibited a lower incidence of bile leak and cardiovascular complications (P = 0.024; P = 0.041), lower minor and major morbidity (P = 0.003; P = 0.044) and reduced CCI (P = 0.002). Laparoscopic major hepatectomies (LMH) for benign disease were associated with lower blood loss (P = 0.001) and bile leaks (P = 0.037) and shorter total stay (P < 0.001). LMH for malignancy were associated with lower blood loss (P < 0.001) and minor morbidity (P = 0.027) supported by a lower CCI (P = 0.021) and shorter stay (P < 0.001)., Conclusion: This multicenter study confirms some associated advantages of laparoscopic left and right hemihepatectomies in malignant and benign conditions highlighting the need for realistic expectations of the minimally invasive approach based on the resected hemiliver and the patients treated., (© 2019 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Minimally invasive surgery (MIS) is quickly becoming mainstream in hepato-pancreato-biliary surgery because of presumed advantages. Surgery for perihilar cholangiocarcinoma (PHC) is highly demanding which may hamper the feasibility and safety of MIS in this setting. This study aimed to systematically review the existing literature on MIS for PHC. A systematic literature review was performed according to the PRISMA statement. The PubMed and EMBASE databases were searched and all studies describing MIS in patients with PHC were included. Data extraction and risk of bias were assessed by two independent researchers. Overall, 21 studies reporting on a total of 142 MIS procedures for PHC were included. These included 82 laparoscopic, 59 robot-assisted and 1 hybrid procedure(s). Risk of bias was deemed substantial. Pooled conversion rate was 7/142 (4.9%), pooled morbidity 30/126 (23.8%), and pooled mortality rate 4/126 (3.2%). The only comparative study, comparing 10 robot-assisted procedures to 32 open procedures, reported a significant increased operative time and higher morbidity rate with MIS. The available evidence on MIS for PHC is limited and generally of poor quality. This systematic review shows that the implementation of MIS for patients with PHC is still in its infancy.

Use of ustekinumab in Crohn's disease was approved in 2016, and consequently data regarding its real-world safety are still limited. We here present a 29-year-old woman with severe therapy-refractory Crohn's disease, who developed an anaplastic large cell T cell lymphoma during treatment with ustekinumab., (Copyright © 2019 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Full-body motion capture typically requires sensors/markers to be placed on each rigid body segment, which results in long setup times and is obtrusive. The number of sensors/markers can be reduced using deep learning or offline methods. However, this requires large training datasets and/or sufficient computational resources. Therefore, we investigate the following research question: "What is the performance of a shallow approach, compared to a deep learning one, for estimating time coherent full-body poses using only five inertial sensors?". We propose to incorporate past/future inertial sensor information into a stacked input vector, which is fed to a shallow neural network for estimating full-body poses. Shallow and deep learning approaches are compared using the same input vector configurations. Additionally, the inclusion of acceleration input is evaluated. The results show that a shallow learning approach can estimate full-body poses with a similar accuracy (~6 cm) to that of a deep learning approach (~7 cm). However, the jerk errors are smaller using the deep learning approach, which can be the effect of explicit recurrent modelling. Furthermore, it is shown that the delay using a shallow learning approach (72 ms) is smaller than that of a deep learning approach (117 ms).

Background: Repeat liver resection is often the best treatment option for patients with recurrent colorectal liver metastases (CRLM). Repeat resections can be complex, however, owing to adhesions and altered liver anatomy. It remains uncertain whether the advantages of a laparoscopic approach are upheld in this setting. The aim of this retrospective, propensity score-matched study was to compare the short-term outcome of laparoscopic (LRLR) and open (ORLR) repeat liver resection., Methods: A multicentre retrospective propensity score-matched study was performed including all patients who underwent LRLRs and ORLRs for CRLM performed in nine high-volume centres from seven European countries between 2000 and 2016. Patients were matched based on propensity scores in a 1 : 1 ratio. Propensity scores were calculated based on 12 preoperative variables, including the approach to, and extent of, the previous liver resection. Operative outcomes were compared using paired tests., Results: Overall, 425 repeat liver resections were included. Of 271 LRLRs, 105 were matched with an ORLR. Baseline characteristics were comparable after matching. LRLR was associated with a shorter duration of operation (median 200 (i.q.r. 123-273) versus 256 (199-320) min; P < 0·001), less intraoperative blood loss (200 (50-450) versus 300 (100-600) ml; P = 0·077) and a shorter postoperative hospital stay (5 (3-8) versus 6 (5-8) days; P = 0·028). Postoperative morbidity and mortality rates were similar after LRLR and ORLR., Conclusion: LRLR for CRLM is feasible in selected patients and may offer advantages over an open approach., (© 2019 BJS Society Ltd Published by John Wiley & Sons Ltd.)

Here we report the transcriptional profile of human microglia, isolated from normal-appearing grey matter (GM) and white matter (WM) of multiple sclerosis (MS) and non-neurological control donors, to find possible early changes related to MS pathology. Microglia show a clear region-specific profile, indicated by higher expression of type-I interferon genes in GM and higher expression of NF-κB pathway genes in WM. Transcriptional changes in MS microglia also differ between GM and WM. MS WM microglia show increased lipid metabolism gene expression, which relates to MS pathology since active MS lesion-derived microglial nuclei show similar altered gene expression. Microglia from MS GM show increased expression of genes associated with glycolysis and iron homeostasis, possibly reflecting microglia reacting to iron depositions. Except for ADGRG1/GPR56, expression of homeostatic genes, such as P2RY12 and TMEM119, is unaltered in normal-appearing MS tissue, demonstrating overall preservation of microglia homeostatic functions in the initiation phase of MS.

Objective: To compare the learning curves of the self-taught "pioneers" of laparoscopic liver surgery (LLS) with those of the trained "early adopters" in terms of short- and medium-term patient outcomes to establish if the learning curve can be reduced with specific training., Summary of Background Data: It is expected that a wider adoption of a laparoscopic approach to liver surgery will be seen in the next few years. Current guidelines stress the need for an incremental, stepwise progression through the learning curve in order to minimize harm to patients. Previous studies have examined the learning curve in Stage 2 of the IDEAL paradigm of surgical innovation; however, LLS is now in stage 3 with specific training being provided to surgeons., Methods: Using risk-adjusted cumulative sum analysis, the learning curves and short- and medium-term outcomes of 4 "pioneering" surgeons from stage 2 were compared with 4 "early adapting" surgeons from stage 3 who had received specific training for LLS., Results: After 46 procedures, the short- and medium-term outcomes of the "early adopters" were comparable to those achieved by the "pioneers" following 150 procedures in similar cases., Conclusions: With specific training, "early adapting" laparoscopic liver surgeons are able to overcome the learning curve for minor and major liver resections faster than the "pioneers" who were self-taught in LLS. The findings of this study are applicable to all surgical specialties and highlight the importance of specific training in the safe expansion of novel surgical practice.

Thus far, the association between residual vein occlusion and immediate compression therapy and postthrombotic syndrome is undetermined. Therefore, we investigated whether compression therapy immediately after diagnosis of deep vein thrombosis affects the occurrence of residual vein obstruction (RVO), and whether the presence of RVO is associated with postthrombotic syndrome and recurrent venous thromboembolism. In a prespecified substudy within the IDEAL (individualized duration of elastic compression therapy against long-term duration of therapy for prevention of postthrombotic syndrome) deep vein thrombosis (DVT) study, 592 adult patients from 10 academic and nonacademic centers across The Netherlands, with objectively confirmed proximal DVT of the leg, received no compression or acute compression within 24 hours of diagnosis of DVT with either multilayer bandaging or compression hosiery (pressure, 35 mm Hg). Presence of RVO and recurrent venous thromboembolism was confirmed with compression ultrasonography and incidence of postthrombotic syndrome as a Villalta score of at least 5 at 6 and 24 months. The average time from diagnosis until assessment of RVO was 5.3 (standard deviation, 1.9) months. A significantly lower percentage of patients who did receive compression therapy immediately after DVT had RVO (46.3% vs 66.7%; odds ratio, 0.46; 95% confidence interval, 0.27-0.80; P = .005). Postthrombotic syndrome was less prevalent in patients without RVO (46.0% vs 54.0%; odds ratio, 0.65; 95% confidence interval, 0.46-0.92; P = .013). Recurrent venous thrombosis showed no significant association with RVO. Immediate compression should therefore be offered to all patients with acute DVT of the leg, irrespective of severity of complaints. This study was registered at ClinicalTrials.gov (NCT01429714) and the Dutch Trial registry in November 2010 (NTR2597)., (© 2018 by The American Society of Hematology.)

Background: The IDEAL DVT study showed that it was safe to shorten the duration of elastic compression therapy on an individualised basis after deep vein thrombosis for prevention of post-thrombotic syndrome. In this study, we assessed the cost-effectiveness of this strategy., Methods: IDEAL DVT was a multicentre, randomised, non-inferiority trial that included patients with acute proximal deep vein thrombosis of the leg. After 6 months of elastic compression therapy, patients were randomly assigned (1:1) to the standard 2 years of elastic stocking compression therapy or shortened duration of compression therapy based on the patient's Villalta score. For our cost-effectiveness analysis, we assessed quality-adjusted life-years (QALYs), measured with the three-level version of EQ-5D (EQ-5D-3L; Dutch and UK tariff) and the 36-item Short Form Health Survey (SF-36), and costs in € (health-care and societal perspective) according to the intention-to-treat approach. Data were collected at 3, 6, 12, and 24 months after diagnosis of thrombosis. We calculated incremental net monetary benefit using a QALY threshold of €30 000, and obtained bootstrapped means and 95% CIs. IDEAL DVT is registered with ClinicalTrials.gov, number NCT01429714., Findings: Between March 22, 2011, and July 1, 2015, 865 patients were enrolled in IDEAL DVT. 437 were assigned to individualised duration of elastic compression therapy and 428 to standard duration of elastic compression therapy. Nine patients were eventually excluded because of recurrent venous thromboembolism within 6 months after the first event. From a societal perspective, for every QALY lost measured with the EQ-5D Dutch tariff, cost savings were €305·992 (incremental net monetary benefit €3205, 95% CI 502-5741), and for every QALY lost based on the Short-Form Six-Dimension (SF-6D) utility score (derived from SF-36), cost savings were €6030·941 (€3540, 95% CI 1174-5953). Using the UK tariff for EQ-5D, the individualised strategy was more effective and less costly (€4071, 1452-6647). The probability that the individualised strategy was cost-effective was 99% at a threshold of €30 000 per QALY (EQ-5D Dutch tariff)., Interpretation: Individually shortened duration of elastic compression therapy was cost-effective compared with standard duration elastic compression therapy. Use of an individualised approach to elastic stocking compression therapy for the prevention of post-thrombotic syndrome after deep vein thrombosis could lead to substantial costs savings without loss in health-related quality of life., Funding: Netherlands Organisation for Health Research and Development., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Essentials The value of compression therapy in acute phase of deep vein thrombosis is still unclear. Patients with deep vein thrombosis received acute compression hosiery, bandaging, or none. Acute compression reduces irreversible skin signs related to post thrombotic syndrome. Compression hosiery may be the preferred choice for the acute phase SUMMARY: Background The effectiveness of compression therapy in the acute phase of deep vein thrombosis (DVT) is not yet determined. Objectives To investigate the impact of compression therapy in the acute phase of DVT on determinants of the Villalta score, health-related quality of life (HRQOL), and costs. Patients/Methods Eight hundred and sixty-five patients with proximal DVT (substudy of the IDEAL DVT study) received, immediately after DVT diagnosis, either no compression, multilayer bandaging, or hosiery. In the acute phase and 3 months after diagnosis, HRQOL was determined by use of the EQ-5D, SF6D, and VEINES-QoL intrinsic method (VEINES-QoL int ). At 3 months, signs and symptoms were assessed for the total and separate items of the Villalta score, and healthcare costs were calculated. Results The compression groups had lower overall objective Villalta scores than the no-compression group (1.47 [standard deviation (SD) 1.570] and 1.59 [SD 1.64] versus 2.21 [SD 2.15]). The differences were mainly attributable to irreversible skin signs (induration, hyperpigmentation, and venectasia) and pain on calf compression. Subjective and total Villalta scores were similar across groups. Differences in HRQOL were only observed at 1 month; HRQOL was better for hosiery (EQ-5D 0.86 [SD 0.18]; VEINES-QoL int  0.66 [SD 0.18]) than for multilayer compression bandaging (EQ-5D 0.81 [SD 0.23; VEINES-QoL int  0.62 [SD 0.19]). Mean healthcare costs per patient were €417.08 (€354.10 to €489.30) for bandaging, €114.25 (€92.50 to €198.43) for hosiery, and €105.86 (€34.63 to €199.30) for no compression. Conclusions Initial compression reduces irreversible skin signs, edema, and pain on calf compression. Multilayer bandaging is slightly more effective than hosiery, but has substantially higher costs, without a gain in HRQOL. From a patient and economic perspective, compression hosiery would be preferred when initial compression is applied., Trial Registration: IDEAL DVT study ClinicalTrials.gov number, NCT01429714., (© 2018 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.)

Background: Most people experience low back pain (LBP) at least once in their life and for some patients this evolves into a chronic condition. One way to prevent acute LBP from transiting into chronic LBP, is to ensure that patients receive the right interventions at the right moment. We started research in the design of a clinical decision support system (CDSS) to support patients with LBP in their self-referral to primary care. For this, we explored the possibilities of using supervised machine learning. We compared the performances of the three classification models - i.e. 1. decision tree, 2. random forest, and 3. boosted tree - to get insight in which model performs best and whether it is already acceptable to use this model in real practice., Methods: The three models were generated by means of supervised machine learning with 70% of a training dataset (1288 cases with 65% GP, 33% physio, 2% self-care cases). The cases in the training dataset were fictive cases on low back pain collected during a vignette study with primary healthcare professionals. We also wanted to know the performance of the models on real-life low back pain cases that were not used to train the models. Therefore we also collected real-life cases on low back pain as test dataset. These cases were collected with the help of patients and healthcare professionals in primary care. For each model, the performance was measured during model validation - with 30% of the training dataset -as well as during model testing - with the test dataset containing real-life cases. The total observed accuracy as well as the kappa, and the sensitivity, specificity, and precision were used as performance measures to compare the models., Results: For the training dataset, the total observed accuracies of the decision tree, the random forest and boosted tree model were 70%, 69%, and 72% respectively. For the test dataset, the total observed accuracies were 71%, 53%, and 71% respectively. The boosted tree appeared to be the best for predicting a referral advice with a fair accuracy (Kappa between 0.2 and 0.4). Next to this, the measured evaluation measures show that all models provided a referral advice better than just a random guess. This means that all models learned some implicit knowledge of the provided referral advices in the training dataset., Conclusions: The study showed promising results on the possibility of using machine learning in the design of our CDSS. The boosted tree model performed best on the classification of low back pain cases, but still has to be improved. Therefore, new cases have to be collected, especially cases that are classified as self-care cases. This to be sure that also the self-care advice can be predicted well by the model., (Copyright © 2017 Elsevier B.V. All rights reserved.)

In multiple sclerosis (MS), activated microglia and infiltrating macrophages phagocytose myelin focally in (chronic) active lesions. These demyelinating sites expand in time, but at some point turn inactive into a sclerotic scar. To identify molecular mechanisms underlying lesion activity and halt, we analyzed genome-wide gene expression in rim and peri-lesional regions of chronic active and inactive MS lesions, as well as in control tissue. Gene clustering revealed patterns of gene expression specifically associated with MS and with the presumed, subsequent stages of lesion development. Next to genes involved in immune functions, we found regulation of novel genes in and around the rim of chronic active lesions, such as NPY, KANK4, NCAN, TKTL1 , and ANO4 . Of note, the presence of many foamy macrophages in active rims was accompanied by a congruent upregulation of genes related to lipid binding, such as MSR1, CD68, CXCL16 , and OLR1 , and lipid uptake, such as CHIT1, GPNMB , and CCL18 . Except CCL18 , these genes were already upregulated in regions around active MS lesions, showing that such lesions are indeed expanding. In vitro downregulation of the scavenger receptors MSR1 and CXCL16 reduced myelin uptake. In conclusion, this study provides the gene expression profile of different aspects of MS pathology and indicates that early demyelination, mediated by scavenger receptors, is already present in regions around active MS lesions. Genes involved in early demyelination events in regions surrounding chronic active MS lesions might be promising therapeutic targets to stop lesion expansion.

In electronic health (eHealth) research, limited insight has been obtained on process outcomes or how the use of technology has contributed to the users' ability to have a healthier life, improved well-being, or activate new attitudes in their daily tasks. As a result, eHealth is often perceived as a black box. To open this black box of eHealth, methodologies must extend beyond the classic effect evaluations. The analyses of log data (anonymous records of real-time actions performed by each user) can provide continuous and objective insights into the actual usage of the technology. However, the possibilities of log data in eHealth research have not been exploited to their fullest extent. The aim of this paper is to describe how log data can be used to improve the evaluation and understand the use of eHealth technology with a broader approach than only descriptive statistics. This paper serves as a starting point for using log data analysis in eHealth research. Here, we describe what log data is and provide an overview of research questions to evaluate the system, the context, the users of a technology, as well as the underpinning theoretical constructs. We also explain the requirements for log data, the starting points for the data preparation, and methods for data collection. Finally, we describe methods for data analysis and draw a conclusion regarding the importance of the results for both scientific and practical applications. The analysis of log data can be of great value for opening the black box of eHealth. A deliberate log data analysis can give new insights into how the usage of the technology contributes to found effects and can thereby help to improve the persuasiveness and effectiveness of eHealth technology and the underpinning behavioral models., (©Floor Sieverink, Saskia Kelders, Mannes Poel, Lisette van Gemert-Pijnen. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 07.08.2017.)

Background: Haemovigilance is the process of surveillance of blood transfusion procedures including unexpected hazards and reactions during the transfusion pathway in both donors and recipients. The haemovigilance team aims to increase blood transfusion safety and to decrease both morbidity and mortality in donors and recipients. The team collects data about transfusion reactions and incidents, instructs the involved health workers and assures the tracing of blood components. The haemovigilance team at the University Hospitals Leuven has played a pioneering role in the development of haemovigilance in Belgium Although the literature about safety and quality improvements by haemovigilance systems is abundant, there are no published data available measuring their financial impact in a hospital. Therefore, we studied the costs and returns of the haemovigilance team at the University Hospitals Leuven., Material and Methods: This study has a descriptive explorative design. Research of the current costs and returns of the haemovigilance team were based upon data from the Medical Administration of the hospital. Data were analyzed descriptively., Results: The haemovigilance team of the University Hospitals Leuven is financially viable: the direct costs are covered by the annual financial support of the National Public Health Service. The indirect returns come from two important tasks of the haemovigilance team itself: correction of the electronic registration of administered blood component and improvement of the return of conform preserved blood components to the blood bank., Discussion: Besides safety and quality improvement, which are obviously their main goals, the haemovigilance team also implies a financial benefit for the hospital., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Microglia are key players in the central nervous system in health and disease. Much pioneering research on microglia function has been carried out in vivo with the use of genetic animal models. However, to fully understand the role of microglia in neurological and psychiatric disorders, it is crucial to study primary human microglia from brain donors. We have developed a rapid procedure for the isolation of pure human microglia from autopsy tissue using density gradient centrifugation followed by CD11b-specific cell selection. The protocol can be completed in 4 h, with an average yield of 450,000 and 145,000 viable cells per gram of white and grey matter tissue respectively. This method allows for the immediate phenotyping of microglia in relation to brain donor clinical variables, and shows the microglia population to be distinguishable from autologous choroid plexus macrophages. This protocol has been applied to samples from over 100 brain donors from the Netherlands Brain Bank, providing a robust dataset to analyze the effects of age, post-mortem delay, brain acidity, and neurological diagnosis on microglia yield and phenotype. Our data show that cerebrospinal fluid pH is positively correlated to microglial cell yield, but donor age and post-mortem delay do not negatively affect viable microglia yield. Analysis of CD45 and CD11b expression showed that changes in microglia phenotype can be attributed to a neurological diagnosis, and are not influenced by variation in ante- and post-mortem parameters. Cryogenic storage of primary microglia was shown to be possible, albeit with variable levels of recovery and effects on phenotype and RNA quality. Microglial gene expression substantially changed due to culture, including the loss of the microglia-specific markers, showing the importance of immediate microglia phenotyping. We conclude that primary microglia can be isolated effectively and rapidly from human post-mortem brain tissue, allowing for the study of the microglial population in light of the neuropathological status of the donor.

Elderly patients with diffuse large B-cell lymphoma (DLBCL) are frequently not treated with standard immunochemotherapy, and this influences survival negatively. The purpose of this study was to gain more insight into treatment decision-making by hematologists. Case vignettes concerning patients with DLBCL were presented to hematologists in the Netherlands. Patient characteristics (age, comorbidity) differed per case. Respondents were asked in each case if they would treat the patient with curative intent by means of full-dose chemotherapy or chemotherapy with dose reduction or if they would not treat the patient with curative intent. The vast majority of respondents would treat an elderly patient diagnosed with DLBCL without a relevant medical history with full-dose chemotherapy irrespective of age. In the presence of comorbidity, lack of social support, cognitive disorders, and untreated depression dose reductions in advance are frequently applied or patients are not treated with curative intent. This is most pronounced for patients aged older than 80 years. Respondents working in a university hospital more frequently refrain form full-dose chemotherapy with curative intent compared to respondents working in tertiary medical teaching hospitals or general hospitals. Patients without a relevant medical history are generally treated with curative intent irrespective of age. Cognitive disorders, comorbidity, and depression reduce the change of being treated with curative intent. This is most prominent in the eldest patient category.

The objectives of this study were to compare health-related quality of life (HRQOL) between multiple myeloma (MM) patients aged ≤65 and >65 years and to compare this with a normative population. Factors associated with HRQOL were identified. The population-based Eindhoven Cancer Registry was used to select MM patients diagnosed from 1999 to 2010. Patients (n = 289) were invited to complete the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and Quality of Life Questionnaire Multiple Myeloma Module 20 (QLQ-MY20), and 212 patients responded (73 %). Data from the normative population (n = 568) were used for comparison. MM patients >65 years scored better on emotional functioning (p < 0.05) and financial problems (p < 0.01) compared to patients ≤65 years. Patients ≤65 years reported better body image and future perspective (p < 0.01). Compared to the normative population, patients ≤65 years scored worse on all EORTC QLQ-C30 functioning scales and on global health/QOL, fatigue, pain, dyspnea, appetite loss, and financial problems (p < 0.01). Patients >65 years scored worse on social, physical, and role functioning and on global health/QOL, fatigue, pain, and dyspnea (p < 0.01). Younger patients had worse HRQOL compared to the normative population than elderly patients. Patients with comorbidities reported lower QOL. The longer the time since diagnosis, the better the physical functioning. No major differences in HRQOL were found between younger and older MM patients. Compared to that of the normative population, HRQOL in younger patients was worse than that in older patients. The number of comorbidities and time since diagnosis were associated with HRQOL. MM patients reported that a high symptom burden and therapy should, besides prolonging survival, be aimed at improving HRQOL.

The objective of this study was to compare health-related quality of life (HRQOL) between diffuse large B cell lymphoma (DLBCL) survivors of different age categories (18-59/60-75/76-85 years) and to compare their HRQOL with an age- and sex-matched normative population. The population-based Eindhoven Cancer Registry was used to select all patients diagnosed with DLBCL from 1999 to 2010. Patients (n = 363) were invited to complete the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) questionnaire, and 307 survivors responded (85 %). Data from an age- and sex-matched normative population (n = 596) were used for comparison. DLBCL survivors aged 18-59 years scored better on physical functioning, quality of life, appetite loss and constipation than survivors of 76-85 years old (all p < 0.05). Financial problems more often occurred in survivors aged 18-59 years compared to survivors of 76-85 years old (p < 0.01). Compared to the normative population, DLBCL survivors aged 18-59 years showed worse scores on cognitive and social functioning and on dyspnea and financial problems (p < 0.01, large- and medium-size effects). In survivors of the other age categories, only differences with trivial or small-size effects were found. Although younger DLBCL survivors have better HRQOL than older survivors, the differences found between younger survivors and normative population were the largest. This suggests that having DLBCL has a greater impact on younger than older survivors and that the worse HRQOL observed in older DLBCL survivors in comparison with younger survivors is caused mostly by age itself and not by the disease.

Background: Elderly patients with non-Hodgkin's lymphoma (NHL) are often not treated with standard immunochemotherapy and this might have a negative impact on their survival. Little is known about the determinants that play a role in treatment decision-making of clinicians regarding elderly patients with NHL. The objective of this study was to gain more insight into these determinants., Methods: A survey was conducted amongst haematologists in the Netherlands. The survey contained questions about comorbidity, polypharmacy, social setting, nutritional status, depression, mild cognitive impairment, dementia, activities of daily living (ADL) and instrumental activities of daily living (IADL) in relation to treatment decisions in elderly NHL patients., Results: Of all comorbidities, respondents designated cognitive disorders and cardiovascular comorbidity as the most important factors when assessing whether an older patient with NHL is eligible for curative treatment. Also in decreasing degree of importance ADL, IADL and depressive disorder are frequently included in treatment decision-making. Almost half of the respondents feel that treatment of the elderly person is complicated as a result of a lack of scientific evidence., Conclusion: Haematologists are aware of coexisting problems in elderly patients and they frequently take comorbidities, cognitive disorders and functional status into consideration in treatment decision-making. Future studies are needed to determine the exact role that these factors should play in the treatment of elderly patients. Furthermore, haematologists feel that treatment of the elderly is complicated and there is a lack of scientific evidence, and therefore older adults should be better represented in clinical trials.

Automatic sleep staging on an online basis has recently emerged as a research topic motivated by fundamental sleep research. The aim of this paper is to find optimal signal processing methods and machine learning algorithms to achieve online sleep staging on the basis of a single EEG signal. The classification performance obtained using six different EEG signals and various signal processing feature sets is compared using the kappa statistic which has very recently become popular in sleep staging research. A variable duration of the EEG segment (or epoch) to decide on the sleep stage is also analyzed. Spectral-domain, time-domain, linear, and nonlinear features are compared in terms of performance and two types of machine learning approaches (random forests and support vector machines) are assessed. We have determined that frontal EEG signals, with spectral linear features, epoch durations between 18 and 30 seconds, and a random forest classifier lead to optimal classification performance while ensuring real-time online operation.

Visual attention is used to selectively filter relevant information depending on current task demands and goals. Visual attention is called object-based attention when it is directed to coherent forms or objects in the visual field. This study used real-time functional magnetic resonance imaging for moment-to-moment decoding of attention to spatially overlapped objects belonging to two different object categories. First, a whole-brain classifier was trained on pictures of faces and places. Subjects then saw transparently overlapped pictures of a face and a place, and attended to only one of them while ignoring the other. The category of the attended object, face or place, was decoded on a scan-by-scan basis using the previously trained decoder. The decoder performed at 77.6% accuracy indicating that despite competing bottom-up sensory input, object-based visual attention biased neural patterns towards that of the attended object. Furthermore, a comparison between different classification approaches indicated that the representation of faces and places is distributed rather than focal. This implies that real-time decoding of object-based attention requires a multivariate decoding approach that can detect these distributed patterns of cortical activity., (© 2013 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Brain–computer interfaces (BCI) provide a valuable new input modality within human–computer interaction systems. However, like other body-based inputs such as gesture or gaze based systems, the system recognition of input commands is still far from perfect. This raises important questions, such as what level of control should such an interface be able to provide. What is the relationship between actual and perceived control? And in the case of applications for entertainment in which fun is an important part of user experience, should we even aim for the highest level of control, or is the optimum elsewhere? In this paper, we evaluate whether we can modulate the amount of control and if a game can be fun with less than perfect control. In the experiment users (n = 158) played a simple game in which a hamster has to be guided to the exit of a maze. The amount of control the user has over the hamster is varied. The variation of control through confusion matrices makes it possible to simulate the experience of using a BCI, while using the traditional keyboard for input. After each session the user completed a short questionnaire on user experience and perceived control. Analysis of the data showed that the perceived control of the user could largely be explained by the amount of control in the respective session. As expected, user frustration decreases with increasing control. Moreover, the results indicate that the relation between fun and control is not linear. Although at lower levels of control fun does increase with improved control, the level of fun drops just before perfect control is reached (with an optimum around 96%). This poses new insights for developers of games who want to incorporate some form of BCI or other modality with unreliable input in their game: for creating a fun game, unreliable input can be used to create a challenge for the user.

Brain-computer interfaces (BCIs) are known to suffer from spontaneous changes in the brain activity. If changes in the mental state of the user are reflected in the brain signals used for control, the behavior of a BCI is directly influenced by these states. We investigate the influence of a state of loss of control in a variant of Pacman on the performance of BCIs based on motor control. To study the effect a temporal loss of control has on the BCI performance, BCI classifiers were trained on electroencephalography (EEG) recorded during the normal control condition, and the classification performance on segments of EEG from the normal and loss of control condition was compared. Classifiers based on event-related desynchronization unexpectedly performed significantly better during the loss of control condition; for the event-related potential classifiers there was no significant difference in performance.

A brain-computer interface (BCI) enables direct communication from the brain to devices, bypassing the traditional pathway of peripheral nerves and muscles. Traditional approaches to BCIs require the user to train for weeks or even months to learn to control the BCI. In contrast, BCIs based on machine learning only require a calibration session of less than an hour before the system can be used, since the machine adapts to the user's existing brain signals. However, this calibration session has to be repeated before each use of the BCI due to inter-session variability, which makes using a BCI still a time-consuming and an error-prone enterprise. In this work, we present a second-order baselining procedure that reduces these variations, and enables the creation of a BCI that can be applied to new subjects without such a calibration session. The method was validated with a motor-imagery classification task performed by 109 subjects. Results showed that our subject-independent BCI without calibration performs as well as the popular common spatial patterns (CSP)-based BCI that does use a calibration session.

We present a detailed discussion of a recently demonstrated experimental technique capable of measuring the correlation function of a pulsed light source with picosecond time resolution. The measurement involves a streak camera in single photon counting mode, which is modified such that a signal at a fixed repetition rate, and well defined energy, can be monitored after each pulsed laser excitation. The technique provides further insight into the quantum optical properties of pulsed light emission from semiconductor nanostructures, and the dynamics inside a pulse, on the sub-nanosecond time scale.

Background: Globally, cataract is the leading cause of blindness and impaired vision. Cataract surgery is an attractive treatment option but it remains unavailable in sufficient quantity for the vast majority of the world population living in areas without access to specialized health care. Reducing blindness from cataract requires solutions that can be applied outside operating theatres. Cataract is a protein conformational disease characterized by accumulation of light absorbing, fluorescent and scattering protein aggregates. The aim of the study was to investigate whether these compounds were susceptible to photobleaching by a non-invasive procedure and whether this would lead to optical rejuvenation of the lens., Methodology/principal Findings: Nine human donor lenses were treated with an 800 nm infra-red femtosecond pulsed laser in a treatment zone measuring 1x1x0.52 mm. After laser treatment the age-induced yellow discoloration of the lens was markedly reduced and the transmission of light was increased corresponding to an optical rejuvenation of 3 to 7 years., Conclusions/significance: The results demonstrate that the age-induced yellowing of the human lens can be bleached by a non-invasive procedure based on femtosecond laser photolysis. Cataract is a disease associated with old age. At the current technological stage, lens aging is delayed but with a treatment covering the entire lens volume complete optical rejuvenation is expected. Thus, femtosecond photolysis has the potential clinical value of replacing invasive cataract surgery by a non-invasive treatment modality that can be placed in mobile units, thus breaking down many of the barriers impeding access to treatment in remote and poor regions of the world.

Quantum mechanically indistinguishable particles such as photons may show collective behavior. Therefore, an appropriate description of a light field must consider the properties of an assembly of photons instead of independent particles. We have studied multiphoton correlations up to fourth order in the single-mode emission of a semiconductor microcavity in the weak and strong coupling regimes. The counting statistics of single photons were recorded with picosecond time resolution, allowing quantitative measurement of the few-photon bunching inside light pulses. Our results show bunching behavior in the strong coupling case, which vanishes in the weak coupling regime as the cavity starts lasing. In particular, we verify the n factorial prediction for the zero-delay correlation function of n thermal light photons.

Background: An 81-year-old woman was diagnosed with chronic carbon monoxide poisoning. Her symptoms closely resembled those of someone with depression, although some of her symptoms were atypical. Because carbon monoxide is a colourless, odourless gas, the cause of her condition remained unclear for several weeks. If psychiatrists are better informed about the affective and neuropsychological symptoms that frequently accompany carbon monoxide poisoning, they should be able to recognise the symptoms sooner. This in turn should lead to a better outcome for the patient.

Optical and electrical tuning of the propagation time of 170 fs pulses in a quantum dot semiconductor amplifier at room temperature is demonstrated. Both pulse slowdown and advancement is possible and we achieve fractional delays (delay divided with pulse duration) of up to 40%. The results are explained by a simple gain saturation model.

We experimentally demonstrate slow-down of light by a factor of three in a 100 microm long semiconductor waveguide at room temperature and at a record-high frequency of 16.7 GHz. It is shown that the group velocity can be controlled all-optically as well as through an applied bias voltage. A semi-analytical model based on the effect of coherent population oscillations and taking into account propagation effects is derived and is shown to well account for the experimental results. It is shown that the carrier lifetime limits the maximum achievable delay. Based on the general model we analyze fundamental limitations in the application of light slowdown due to coherent population oscillations.

Background and Purpose: The goal of this study was to compare the inter-observer variability between CT and MRI for the delineation of pharyngo-laryngeal SCC, parotid glands and spinal cord., Patients and Methods: Twenty pharyngo-laryngeal tumors were delineated by five observers on CT and MRI, using consistent delineation guidelines. Spinal cords and parotid glands were also delineated on CT and MRI by three observers. Mean GTVs and coefficients of variation were calculated for each observer and compared using ANOVA and its derived Pearson intra-class coefficient (R). For GTVs, a mismatch analysis (ratio between intersection and union volumes) was also performed., Results: Regarding oropharyngeal GTVs (n=10), no significant difference was observed between observers either with CT (33.9, 31.1, 32, 34 and 34.7 ml, five observers, P=0.47) or with MRI (30.5, 29.4, 30.1 and 31.5 ml, four observers, P=0.59). CVs (13.6 vs 12.9%), (0.98 vs 0.99) and mismatches (0.43 vs 0.42) between CT and MRI did not significantly differ. Regarding laryngeal-hypopharyngeal GTVs (n=10), no significant difference was observed between observers either on CT (18.1, 20.7, 20.9, 19.3 and 21.9 ml, five observers, P=0.29) or on MRI (19.3, 21.5, 20, 22.1 and 21.8 ml, five observers, P=0.16). CVs (20.2 vs 13.8%), (0.94 vs 0.94) and mismatches (0.31 vs 0.41) were comparable. Regarding OARs, a small but significant difference in mean parotid volume was observed between observers (P<0.001) and between modalities (P<0.001) (CT: 34.8, 29.4, and 26.8 ml; MRI: 30.6, 27.9 and 20.4 ml). Similar results were obtained for mean spinal cord volumes (CT: 10.7, 10.6, and 9.5 ml; MRI: 8.7, 8.5 and 8.2 ml; P=0.05).

Bilingual written language representation was investigated with the masked phonological priming paradigm. Pseudohomophonic and control primes of French target words were used to show that Dutch-French bilinguals exhibit the same pattern of phonological and orthographic priming as native French speakers, which suggests that the same processes underlie first-and second-language processing. It was also found that for bilinguals, but not monolinguals, it is possible to prime a target word of the second language with a homophonic stimulus (either word or nonword) of the first language. This interlingual phonological priming effect was of the same size as the intralingual priming effect. Implications for theories of bilingual written language representation and for the interpretation of the masked phonological priming paradigm are discussed.

Patients with a monoclonal gammopathy without evidence of lymphoproliferative or plasma cell malignancy within a year are still at risk for malignant transformation to multiple myeloma, Waldenström's macroglobulinaemia or non-Hodgkin's lymphoma. In a prospective study performed at the Mayo Clinic, the cumulative incidence of malignant transformation was 29% in 14 years. We conducted a retrospective study to determine the frequency of malignant transformation among 334 unselected out-patients with monoclonal gammopathy of undetermined significance (MGUS) from a community hospital in Southeastern Netherlands. The cumulative incidence of malignant transformation was 11% in 14 years (95% confidence interval 6-17%). The long-term survival of patients with MGUS was slightly lower than that of the average regional population. In a nested case-control study, presence of a kappa light chain was found to be a risk factor for malignant transformation (70% of patients who developed malignant transformation compared to 30% of the control group, P < 0.01). Likewise, an initial high gamma globulin level was also found to be a risk factor (18.7 g/l v 13.7 g/l in the control group, P < 0.01). As neither risk factor has been described before, the significance of these factors for definition of a high-risk group among patients with monoclonal gammopathy remains to be determined.

Thirteen years after its discovery, there is still controversy over the chemical identity of endothelium-derived relaxing factor (EDRF). Although pharmacological and chemical evidence indicates that EDRF is nitric oxide, other candidates, including S-nitrosocysteine, dinitrosyl-iron-cysteine complex, nitroxyl and hydroxylamine, have been proposed to account for the vasorelaxant properties of EDRF. Such diverse compounds should differ in their stability and in reactivity with oxyhaemoglobin and with redox-active nucleophiles such as thiols. Here we use a bioassay to compare the pharmacodynamic profiles of these and other compounds with those of nitric oxide and EDRF. We find that some S-nitrosothiols, dinitrosyl-iron-cysteine complex, sodium nitroxyl and hydroxylamine can be eliminated as candidates as they are more stable than EDRF and less susceptible to inhibition by oxyhaemoglobin. Co-infusion of cysteine revealed major differences between the remaining candidates because it reduced the effect of authentic nitric oxide and EDRF on the bioassay tissues but enhanced the survival of S-nitrosocysteine and S-nitrosocysteamine. Our results further support the evidence that EDRF, the pharmacological entity described by Furchgott and Zawadzki, is nitric oxide.

A woman with myelofibrosis and myeloid metaplasia had a karyotype of 47,X,del(X)(q22),+del(X)(q22) in unstimulated peripheral blood and bone marrow aspirate cultures. The normal X chromosome was late replicating, and the two deleted X chromosomes always replicated early and synchronously. The karyotype from phytohemagglutin-stimulated peripheral blood cultures was uniformly 46,XX. Structurally abnormal X chromosomes are exceedingly rare in myeloproliferative disease. The abnormal karyotype very likely reflects monoclonal proliferation of an abnormal myeloid cell line. The X chromosome inactivation process, which acts upon embryonic somatic cells of all mammals, apparently does not react to postembryonic nondisjunction of the active X chromosome.

The patient presented here was known to have been suffering from diabetes mellitus for 3 yr, when the suspicion arose that we were dealing with a factitious disease. The coincidence of several other factitious illnesses led us to the diagnosis of Munchausen's syndrome, self-inflicted diabetes mellitus being part of this syndrome.