Kinetic characterization of SPR-based biomarker assays enables quality control, calibration free measurements and robust optimization for clinical application.

Biomarker measurements are essential for the early diagnosis of complex diseases. However, many current biomarker assays lack sensitivity and multiplexing capacity, work in a narrow detection range and importantly lack real time quality control opportunities, which hampers clinical translation. In this paper, we demonstrate a toolbox to kinetically characterize a biomarker measurement assay using Surface Plasmon Resonance imaging (SPRi) with ample opportunities for real time quality control by exploiting quantitative descriptions of the various biomolecular interactions. We show an accurate prediction of SPRi measurements at both low and high concentrations of various analytes with deviations <5% between actual measurements and predicted measurement. The biphasic binding sites model was accurate for fitting the experimental curves and enables optimal detection of heterophilic antibodies, cross-reactivity, spotting irregularities and/or other confounders. The toolbox can also be used to create a (simulated) calibration curve, enabling calibration-free measurements with good recovery, it allows for easy assay optimizations, and could help bridge the gap to bring new biomarker assays to the clinic.

Nanoparticle Enhancement Cascade for Sensitive Multiplex Measurements of Biomarkers in Complex Fluids with Surface Plasmon Resonance Imaging.

There is a large unmet need for reliable biomarker measurement systems for clinical application. Such systems should meet challenging requirements for large scale use, including a large dynamic detection range, multiplexing capacity, and both high specificity and sensitivity. More importantly, these requirements need to apply to complex biological samples, which require extensive quality control. In this paper, we present the development of an enhancement detection cascade for surface plasmon resonance imaging (SPRi). The cascade applies an antibody sandwich assay, followed by neutravidin and a gold nanoparticle enhancement for quantitative biomarker measurements in small volumes of complex fluids. We present a feasibility study both in simple buffers and in spiked equine synovial fluid with four cytokines, IL-1ß, IL-6, IFN-γ, and TNF-α. Our enhancement cascade leads to an antibody dependent improvement in sensitivity up to 40 000 times, resulting in a limit of detection as low as 50 fg/mL and a dynamic detection range of more than 7 logs. Additionally, measurements at these low concentrations are highly reliable with intra- and interassay CVs between 2% and 20%. We subsequently showed this assay is suitable for multiplex measurements with good specificity and limited cross-reactivity. Moreover, we demonstrated robust detection of IL-6 and IL-1ß in spiked undiluted equine synovial fluid with small variation compared to buffer controls. In addition, the availability of real time measurements provides extensive quality control opportunities, essential for clinical applications. Therefore, we consider this method is suitable for broad application in SPRi for multiplex biomarker detection in both research and clinical settings.

The Effects of the WNT-Signaling Modulators BIO and PKF118-310 on the Chondrogenic Differentiation of Human Mesenchymal Stem Cells.

Mesenchymal stem cells (MSCs) are multipotent cells, mainly from bone marrow, and an ideal source of cells in bone and cartilage tissue engineering. A study of the chondrogenic differentiation of MSCs is of particular interest for MSCs-based cartilage regeneration. In this study, we aimed to optimize the conditions for the chrondogenic differentiation of MSCs by regulating WNT signaling using the small molecule WNT inhibitor PKF118-310 and activator BIO. Human mesenchymal stem cells (hMSCs) were isolated from bone marrow aspirates and cultured in hMSCs proliferation medium. Pellet culture was subsequently established for three-dimensional chondrogenic differentiation of 5 weeks. WNT signaling was increased by the small molecule glycogen synthase kinase-3 inhibitor 6-bromoindirubin-3-oxim (BIO) and decreased by the WNT inhibitor PKF118-310 (PKF). The effects of BIO and PKF on the chondrogenesis of hMSCs was examined by real-time PCR, histological methods, and ELISA. We found that activation of canonical WNT-signaling by BIO significantly downregulated the expression of cartilage-specific genes SOX9, COL2A1, and ACAN, and matrix metalloproteinase genes MMP1/3/9/13, but increased ADAMTS 4/5. Inhibition of WNT signaling by PKF increased the expression of SOX9, COL2A1, ACAN, and MMP9, but decreased MMP13 and ADAMTS4/5. In addition, a high level of WNT signaling induced the expression of hypertrophic markers COL10A1, ALPL, and RUNX2, the dedifferentiation marker COL1A1, and glycolysis genes GULT1 and PGK1. Deposition of glycosaminoglycan (GAG) and collagen type II in the pellet matrix was significantly lost in the BIO-treated group and increased in the PKF-treated group. The protein level of COL10A1 was also highly induced in the BIO group. Interestingly, BIO decreased the number of apoptotic cells while PKF significantly induced apoptosis during chondrogenesis. The natural WNT antagonist DKK1 and the protein level of MMP1 in the pellet culture medium were decreased after PKF treatment. All of these chondrogenic effects appeared to be mediated through the canonical WNT signaling pathway, since the target gene Axin2 and other WNT members, such as TCF4 and ß-catenin, were upregulated by BIO and downregulated by PKF, respectively, and BIO induced nuclear translocation of ß-catenin while PKF inhibited ß-catenin translocation into the nucleus. We concluded that addition of BIO to a chondrogenic medium of hMSCs resulted in a loss of cartilage formation, while PKF induced chondrogenic differentiation and cartilage matrix deposition and inhibited hypertrophic differentiation. However, BIO promoted cell survival by inhibiting apoptosis while PKF induced cell apoptosis. This result indicates that either an overexpression or overinhibition of WNT signaling to some extent causes harmful effects on chondrogenic differentiation. Cartilage tissue engineering could benefit from the adjustment of the critical level of WNT signaling during chondrogenesis of hMSC.

The Juvenile Sex Offender.

In this article, we investigate whether the life events of marriage, parenthood, and employment were associated with general offending for a Dutch sample of 498 juvenile sex offenders (JSOs). In previous empirical studies, these life events were found to limit adult general offending in the population as well as high-risk samples. A hybrid random effects model is used to investigate within-individual changes of these life events in association with general offending. We also investigated whether the findings differed for child abusers, peer abusers, and group offenders, as they have distinct background profiles. We found that JSOs make limited transitions into the state of marriage, parenthood, and employment, showing overall stagnating participation rates. For the entire sample of JSOs, employment was found to be associated with a decrease in offending. Group offenders benefited most from employment. Marriage and parenthood were not associated with the general offending patterns, whereas for child abusers, parenthood was associated with an increase in offending. We conclude that policies aimed at guidance toward employment, or inclusion into conventional society, may be effective for JSOs.

Toward Worldwide Hepcidin Assay Harmonization: Identification of a Commutable Secondary Reference Material.

BACKGROUND: Absolute plasma hepcidin concentrations measured by various procedures differ substantially, complicating interpretation of results and rendering reference intervals method dependent. We investigated the degree of equivalence achievable by harmonization and the identification of a commutable secondary reference material to accomplish this goal. METHODS: We applied technical procedures to achieve harmonization developed by the Consortium for Harmonization of Clinical Laboratory Results. Eleven plasma hepcidin measurement procedures (5 mass spectrometry based and 6 immunochemical based) quantified native individual plasma samples (n = 32) and native plasma pools (n = 8) to assess analytical performance and current and achievable equivalence. In addition, 8 types of candidate reference materials (3 concentrations each, n = 24) were assessed for their suitability, most notably in terms of commutability, to serve as secondary reference material. RESULTS: Absolute hepcidin values and reproducibility (intrameasurement procedure CVs 2.9%-8.7%) differed substantially between measurement procedures, but all were linear and correlated well. The current equivalence (intermeasurement procedure CV 28.6%) between the methods was mainly attributable to differences in calibration and could thus be improved by harmonization with a common calibrator. Linear regression analysis and standardized residuals showed that a candidate reference material consisting of native lyophilized plasma with cryolyoprotectant was commutable for all measurement procedures. Mathematically simulated harmonization with this calibrator resulted in a maximum achievable equivalence of 7.7%. CONCLUSIONS: The secondary reference material identified in this study has the potential to substantially improve equivalence between hepcidin measurement procedures and contributes to the establishment of a traceability chain that will ultimately allow standardization of hepcidin measurement results.

Second international round robin for the quantification of serum non-transferrin-bound iron and labile plasma iron in patients with iron-overload disorders.

Non-transferrin-bound iron and its labile (redox active) plasma iron component are thought to be potentially toxic forms of iron originally identified in the serum of patients with iron overload. We compared ten worldwide leading assays (6 for non-transferrin-bound iron and 4 for labile plasma iron) as part of an international inter-laboratory study. Serum samples from 60 patients with four different iron-overload disorders in various treatment phases were coded and sent in duplicate for analysis to five different laboratories worldwide. Some laboratories provided multiple assays. Overall, highest assay levels were observed for patients with untreated hereditary hemochromatosis and ß-thalassemia intermedia, patients with transfusion-dependent myelodysplastic syndromes and patients with transfusion-dependent and chelated ß-thalassemia major. Absolute levels differed considerably between assays and were lower for labile plasma iron than for non-transferrin-bound iron. Four assays also reported negative values. Assays were reproducible with high between-sample and low within-sample variation. Assays correlated and correlations were highest within the group of non-transferrin-bound iron assays and within that of labile plasma iron assays. Increased transferrin saturation, but not ferritin, was a good indicator of the presence of forms of circulating non-transferrin-bound iron. The possibility of using non-transferrin-bound iron and labile plasma iron measures as clinical indicators of overt iron overload and/or of treatment efficacy would largely depend on the rigorous validation and standardization of assays.

Influence of paternal age on ongoing pregnancy rate at eight weeks' gestation in assisted reproduction.

A retrospective cohort study was performed with the followings aims: to evaluate the influence of paternal age on best embryo quality available for embryo transfer on the third day; biochemical pregnancy rate; miscarriage rate and ongoing pregnancy rate at 8 weeks' gestational age, after IVF or intracytoplasmic sperm injection (ICSI) treatment, respectively, including treatment with non-ejaculated spermatozoa. In total, 7051 first IVF/ICSI cycles in Radboud university medical center, between 1 January 2001 and 1 June 2013 were included in this study. A statistical model was used to analyse the effect of paternal age and maternal age. No statistically significant differences between the paternal age groups were found with respect to the probability of an ongoing pregnancy after the first cycle (35-44 years: odds ratio [OR] = 0.97 [95% confidence interval [CI]: 0.86 to 1.10] and ≥45 years: OR = 1.01 [95% CI: 0.82 to 1.26]), respectively, compared with <35 years of age (control). Similar results were found with respect to paternal age and the availability of a top quality embryo for transfer, biochemical pregnancy and miscarriage. However, live birth was not taken into account. In conclusion, paternal age did not affect ongoing pregnancy rates in first IVF/ICSI cycles.

Prediction model for recurrence probabilities after intravesical chemotherapy in patients with intermediate-risk non-muscle-invasive bladder cancer, including external validation.

PURPOSE: To develop a model to predict recurrence for patients with intermediate-risk (IR) non-muscle-invasive bladder cancer (NMIBC) treated with intravesical chemotherapy which can be challenging because of the heterogeneous characteristics of these patients. METHODS: Data from three Dutch trials were combined. Patients treated with intravesical chemotherapy with characteristics according to the IR definition of the EAU guideline 2013 were included. Uni- and multivariable Cox regression with selection methods were used to identify predictors of recurrence at 1, 2, and 5 years. An easy-readable table for recurrence probabilities was developed. An external validation was done using data from Spanish patients. RESULTS: A total of 724 patients were available for analyses, of which 305 were primary patients. Recurrences occurred in 413 patients (57%). History of recurrences, history of intravesical treatment, grade 2, multiple tumors, and adjuvant treatment with epirubicin were relevant predictors for recurrence-free survival with hazard ratios of 1.48, 1.38, 1.22, 1.56, and 1.27, respectively. A table for recurrence probabilities was developed using these five predictors. Based on the probability of recurrence, three risk groups were identified. Patients in each of the separate risk groups should be scheduled for less or more aggressive treatment. The model showed sufficient discrimination and good predictive accuracy. External validation showed good validity. CONCLUSION: In our model, we identified five relevant predictors for recurrence-free survival in IR-NMIBC patients treated with intravesical chemotherapy. These recurrence predictors allow the urologists to stratify patients in risk groups for recurrence that could help in deciding for an individualized treatment approach.

International Paediatric Mitochondrial Disease Scale.

OBJECTIVE: There is an urgent need for reliable and universally applicable outcome measures for children with mitochondrial diseases. In this study, we aimed to adapt the currently available Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) to the International Paediatric Mitochondrial Disease Scale (IPMDS) during a Delphi-based process with input from international collaborators, patients and caretakers, as well as a pilot reliability study in eight patients. Subsequently, we aimed to test the feasibility, construct validity and reliability of the IPMDS in a multicentre study. METHODS: A clinically, biochemically and genetically heterogeneous group of 17 patients (age 1.6-16 years) from five different expert centres from four different continents were evaluated in this study. RESULTS: The feasibility of the IPMDS was good, as indicated by a low number of missing items (4 %) and the positive evaluation of patients, parents and users. Principal component analysis of our small sample identified three factors, which explained 57.9 % of the variance. Good construct validity was found using hypothesis testing. The overall interrater reliability was good [median intraclass correlation coefficient for agreement between raters (ICCagreement) 0.85; range 0.23-0.99). CONCLUSION: In conclusion, we suggest using the IPMDS for assessing natural history in children with mitochondrial diseases. These data should be used to further explore construct validity of the IPMDS and to set age limits. In parallel, responsiveness and the minimal clinically important difference should be studied to facilitate sample size calculations in future clinical trials.

Why might regional vaccinology networks fail? The case of the Dutch-Nordic Consortium.

We analyzed an attempt to develop and clinically test a pneumococcal conjugate vaccine for the developing world, undertaken by public health institutions from the Netherlands, Sweden, Denmark, Norway and Finland: the Dutch Nordic Consortium (DNC), between 1990 and 2000. Our review shows that the premature termination of the project was due less to technological and scientific challenges and more to managerial challenges and institutional policies. Various impeding events, financial and managerial challenges gradually soured the initially enthusiastic collaborative spirit until near the end the consortium struggled to complete the minimum objectives of the project. By the end of 1998, a tetravalent prototype vaccine had been made that proved safe and immunogenic in Phase 1 trials in adults and toddlers in Finland. The planned next step, to test the vaccine in Asia in infants, did not meet approval by the local authorities in Vietnam nor later in the Philippines and the project eventually stopped.The Dutch DNC member, the National Institute of Public Health and the Environment (RIVM) learned important lessons, which subsequently were applied in a following vaccine technology transfer project, resulting in the availability at affordable prices for the developing world of a conjugate vaccine against Haemophilus influenzae type b. We conclude that vaccine development in the public domain with technology transfer as its ultimate aim requires major front-end funding, committed leadership at the highest institutional level sustained for many years and a competent recipient-manufacturer, which needs to be involved at a very early stage of the development.At the national level, RIVM's policy to consolidate its national manufacturing task through securing a key global health position in support of a network of public vaccine manufacturers proved insufficiently supported by the relevant ministries of the Dutch government. Difficulties to keep up with high costs, high-risk innovative vaccine development and production in a public sector setting led to the gradual loss of production tasks and to the 2009 Government decision to privatize the vaccine production tasks of the Institute.

Risk Factors for Symptoms of Depression and Anxiety One Year Poststroke: A Longitudinal Study.

OBJECTIVE: To estimate the relative contribution of psychological factors next to sociodemographic and premorbid/stroke-related factors to the risk of developing symptoms of depression and anxiety after stroke. DESIGN: Multicenter, longitudinal cohort study. SETTING: Patients after stroke from 6 general hospitals. PARTICIPANTS: Patients (N=331) were included at stroke onset and followed up 2 and 12 months after stroke. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Sociodemographic and premorbid/stroke-related information was recorded during hospital admission, whereas psychological characteristics were determined with postal questionnaires 2 months poststroke. Symptoms of depression and anxiety were assessed with the Hospital Anxiety and Depression Scale (HADS) 2 and 12 months poststroke. Multivariable logistic analysis was performed to analyze the influence of sociodemographic, premorbid/stroke-related, and psychological characteristics on depressive symptoms (depression subscale of HADS >7) and symptoms of anxiety (anxiety subscale of HADS >7) 1 year after stroke. RESULTS: Early depression, stroke severity, posterior cerebral artery stroke, and neuroticism independently explained the variance of depressive symptoms 1 year poststroke (discriminative power, 83%; adjusted R(2) value, 36%). Neuroticism and early anxiety independently explained the variance of symptoms of anxiety 1 year poststroke (discriminative power, 88%; adjusted R(2) value, 44%). Based on these predictive models, nomograms were constructed to visually reflect the individual contribution of each risk factor to the development of long-term mood disorders after stroke. CONCLUSIONS: Psychological characteristics are important risk factors for poststroke symptoms of depression and anxiety.

Clinically applied procedures for human ovarian tissue cryopreservation result in different levels of efficacy and efficiency.

PURPOSE: Different protocols are being used worldwide for the cryopreservation of human ovarian tissue for fertility preservation purposes. The efficiency and efficacy of the majority of these protocols has not been extensively evaluated, possibly resulting in sub-optimally cryopreserved ovarian tissue. To address the impact of this issue, we assessed the effects of two clinically successful human ovarian tissue slow-freezing cryopreservation procedures on the quality of the cryopreserved tissue. METHODS: To differentiate between cryopreservation (C) versus thawing (T) related effects, four combinations of these two (A and B) very different cryopreservation/thawing protocols (ACAT, ACBT, BCAT, BCBT) were studied. Before and after cryopreservation and thawing, the percentage of living and morphologically normal follicles, as well as the overall tissue viability, was assessed. RESULTS: Our experiments revealed that the choice of the cryopreservation protocol noticeably affected the overall tissue viability and percentage of living follicles, with a higher viability after protocol BC when compared to AC. No statistically significant differences in tissue viability were observed between the two thawing protocols, but thawing protocol BT required considerably more human effort and materials than thawing protocol AT. Tissue morphology was best retained using the BCAT combination. CONCLUSION: Our results indicate that extensive and systematical evaluation of clinically used protocols is warranted.

Work stress and satisfaction in relation to personality profiles in a sample of Dutch anaesthesiologists: A questionnaire survey.

BACKGROUND: Working in anaesthesia is stressful, but also satisfying. Work-related stress can have a negative impact on mental health, whereas work-related satisfaction protects against these harmful effects. OBJECTIVE(S): How work stress and satisfaction are experienced may be related to personality. Our aim was to study the relationship between personality and perception of work in a sample of Dutch anaesthesiologists. DESIGN: Questionnaire survey. SETTING: Data were collected in the Netherlands from July 2012 until December 2012. PARTICIPANTS: We sent electronic questionnaires to all 1955 practising resident and consultant members of the Dutch Anaesthesia Society. Of those, 655 (33.5%) were returned and could be used for analysis. MAIN OUTCOME MEASURES: The questionnaires assessed general work-related stress and satisfaction and anaesthesia-specific stress. A factor analysis was performed on the stress and satisfaction questionnaires. Personality traits were assessed using the Big Five Inventory. To identify personality profiles, a cluster analysis was performed on the Big Five Inventory. Scores of the extracted factors contributing to job stress and satisfaction were compared between the profiles we identified. RESULTS: Our analysis extracted six factors concerning general job stress. Of those, the emotionally difficult caseload contributed the most to job stress. The analysis also extracted four factors concerning general job satisfaction. Good relationships with patients and their families and being appreciated by colleagues contributed the most to satisfaction. The cluster analysis resulted in two distinct personality profiles: a distressed profile (n = 215) and a resilient profile (n = 440). General and anaesthesia-specific job stress was significantly higher and job satisfaction was significantly lower in the distressed profile, compared with the resilient profile. Experience of the emotionally difficult caseload did not differ between the two profiles CONCLUSION: Personality profiles were found to be related to anaesthesiologists' experience of work-related stress and satisfaction. One-third of the anaesthesiologists in our sample were categorised as distressed and are at risk of developing work-related mental health problems.

Psychological distress, burnout and personality traits in Dutch anaesthesiologists: A survey.

BACKGROUND: The practice of anaesthesia comes with stress. If the demands of a stressful job exceed the resources of an individual, that person may develop burnout. Burnout poses a threat to the mental and physical health of the anaesthesiologist and therefore also to patient safety. OBJECTIVES: Individual differences in stress appraisal (perceived demands) are an important factor in the risk of developing burnout. To explore this possible relationship, we assessed the prevalence of psychological distress and burnout in the Dutch anaesthesiologist population and investigated the influence of personality traits. DESIGN: Survey study. SETTING: Data were collected in the Netherlands from July 2012 until December 2012. PARTICIPANTS: We sent electronic surveys to all 1955 practising resident and consultant members of the Dutch Anaesthesia Society. Of these, 655 (33.5%) were returned and could be used for analysis. MAIN OUTCOME MEASURES: Psychological distress, burnout and general personality traits were assessed using validated Dutch versions of the General Health Questionnaire (cut-off point ≥2), the Maslach Burnout Inventory and the Big Five Inventory. Sociodemographic variables and personality traits were entered into regression models as predictors for burnout and psychological distress. RESULTS: Respectively, psychological distress and burnout were prevalent in 39.4 and 18% of all respondents. The prevalence of burnout was significantly different in resident and consultant anaesthesiologists: 11.3% vs. 19.8% (χ 5.4; P < 0.02). The most important personality trait influencing psychological distress and burnout was neuroticism: adjusted odds ratio 6.22 (95% confidence interval 4.35 to 8.90) and 6.40 (95% confidence interval 3.98 to 10.3), respectively. CONCLUSION: The results of this study show that psychological distress and burnout have a high prevalence in residents and consultant anaesthesiologists and that both are strongly related to personality traits, especially the trait of neuroticism. This suggests that strategies to address the problem of burnout would do well to focus on competence in coping skills and staying resilient. Personality traits could be taken into consideration during the selection of residents. In future longitudinal studies the question of how personal and situational factors interact in the development of burnout should be addressed.

Subcutaneous Stimulation as ADD-ON Therapy to Spinal Cord Stimulation Is Effective in Treating Low Back Pain in Patients With Failed Back Surgery Syndrome: A Multicenter Randomized Controlled Trial.

OBJECTIVE: Suppression of back pain with traditional spinal cord stimulation (SCS) in failed back surgery syndrome patients is often insufficient. The objective of this study was to investigate the efficacy of subcutaneous stimulation (SubQ) as ADD-ON therapy to SCS in treating back pain in failed back surgery syndrome patients. MATERIALS AND METHODS: Patients with a minimal pain score of 50 on a 100 mm visual analog scale for both leg and back pain were eligible. If pain reduction after trial SCS was ≥50% for the leg but <50% for the back, patients received additional SubQ leads and were randomized in a 1:1 ratio in a study arm with subcutaneous leads switched on (SubQ ADD-ON) and an arm with subcutaneous leads switched off (Control). The primary outcome was the percentage of the patients, at three months since implantation, with ≥50% reduction of back pain. RESULTS: A total of 97 patients were treated with SCS for leg and back pain. Of these, 52 patients were randomized and allocated to the Control group (n = 24) or to the SubQ ADD-ON group (n = 28). The percentage of patients with ≥50% reduction of back pain was significantly higher in the SubQ ADD-ON group (42.9%) compared to the Control group (4.2%). Mean visual analog scale for back pain, at three months, was a statistically significant 28.1 mm lower in the SubQ ADD-ON group compared to the Control group. CONCLUSION: Subcutaneous stimulation as an ADD-ON therapy to SCS is effective in treating back pain in failed back surgery syndrome patients where SCS is only effective for pain in the leg.

Economic evaluation of occupational therapy in Parkinson's disease: A randomized controlled trial.

BACKGROUND: A large randomized clinical trial (the Occupational Therapy in Parkinson's Disease [OTiP] study) recently demonstrated that home-based occupational therapy improves perceived performance in daily activities of people with Parkinson's disease (PD). The aim of the current study was to evaluate the cost-effectiveness of this intervention. METHODS: We performed an economic evaluation over a 6-month period for both arms of the OTiP study. Participants were 191 community-dwelling PD patients and 180 primary caregivers. The intervention group (n = 124 patients) received 10 weeks of home-based occupational therapy; the control group (n = 67 patients) received usual care (no occupational therapy). Costs were assessed from a societal perspective including healthcare use, absence from work, informal care, and intervention costs. Health utilities were evaluated using EuroQol-5d. We estimated cost differences and cost utility using linear mixed models and presented the net monetary benefit at different values for willingness to pay per quality-adjusted life-year gained. RESULTS: In our primary analysis, we excluded informal care hours because of substantial missing data for this item. The estimated mean total costs for the intervention group compared with controls were €125 lower for patients, €29 lower for caregivers, and €122 higher for patient-caregiver pairs (differences not significant). At a value of €40,000 per quality-adjusted life-year gained (reported threshold for PD), the net monetary benefit of the intervention per patient was €305 (P = 0.74), per caregiver €866 (P = 0.01) and per patient-caregiver pair €845 (P = 0.24). CONCLUSION: In conclusion, occupational therapy did not significantly impact on total costs compared with usual care. Positive cost-effectiveness of the intervention was only significant for caregivers.

Urinary cytokines in patients treated with intravesical mitomycin-C with and without hyperthermia.

OBJECTIVES: To explore whether urinary cytokine and chemokine (CK) levels differed between cold mitomycin-C (cold-MMC)-treated patients and chemohyperthermia (C-HT)-treated patients, to shed light on the possible molecular mechanisms that might explain the superior outcome of C-HT. Furthermore, CK-differences were explored between C-HT responders and C-HT non-responders. METHODS: Twelve NMIBC patients were included. Nine received six-weekly C-HT, and three received four-weekly cold-MMC instillations. Urine was collected on 8-12 time points before and after every treatment. MDC, IL-2, IL-6, IL-8, IP-10, MCP-1 and RANTES were determined by Luminex(®)-analysis. RESULTS: Elevated urinary CK levels were observed in both groups after treatment. In general, CK-peaks were lower in the cold-MMC group in comparison with levels in the C-HT group. Significant higher MCP-1 and IL-6 levels were observed in C-HT-treated patients. Additionally, significant cumulative effects were observed for IP-10 and IL-2. However, IP-10 and IL-2 levels did not significantly differ between treatments. MDC levels after the first week of treatment were significantly higher in the C-HT responders compared with the non-responders. CONCLUSION: MMC treatment leads to elevated urinary CK levels with significantly higher MCP-1 and IL-6 levels in C-HT-treated patients. Increased MDC levels after the first C-HT instillation appear to be related to good clinical outcome and might be of additional value to personalize treatment. Studies involving more patients and longer follow-up are needed to substantiate this observation.

Effectiveness and cost-effectiveness of a self-management group program to improve social participation in patients with neuromuscular disease and chronic fatigue: protocol of the Energetic study.

BACKGROUND: Chronic fatigue is present in more than 60% of the patients with a neuromuscular disease and can be their most disabling symptom. In combination with other impairments, fatigue often results in low levels of physical activity and decreased social participation, leading to high societal costs. 'Energetic' is a self-management group program aimed at improving social participation, physical endurance and alleviating fatigue in these patients. The primary aim of this study is to evaluate the effectiveness and cost-effectiveness of the Energetic program. METHODS/DESIGN: A multicentered, assessor-blinded, two-armed randomized controlled trial is conducted with evaluations at inclusion and four, seven and fifteen months later. The study includes patients with a neuromuscular disease and chronic fatigue and, when present, their caregivers. The participants are randomized (ratio 1:1) to either an intervention group, receiving the Energetic program, or a control group, receiving usual care (i.e., no specific intervention). The Energetic program covers four months and includes four modules: 1) individually tailored aerobic exercise training; 2) education about aerobic exercise; 3) self-management training in applying energy conservation strategies; and 4) implementation and relapse prevention in daily life. Two months after cessation of the program a booster session is provided. The primary outcome is the perceived performance score of the Canadian Occupational Performance Measure (COPM). Secondary outcomes include the COPM-satisfaction score, and measures of fatigue, physical endurance, activity engagement, mood, and self-efficacy. Caregiver burden is also evaluated as a secondary outcome. Health-related quality of life and medical and societal costs are assessed to estimate cost-effectiveness of the program. DISCUSSION: The Energetic study is the first randomized controlled trial to evaluate the effectiveness and cost-effectiveness of a combined physical and self-management group training program for improving social participation, physical endurance and alleviating fatigue in patients with neuromuscular diseases. It will generate new insights in (cost-)effective rehabilitation strategies for these incurable conditions. TRIAL REGISTRATION: Clinicaltrials.gov NCT02208687 .

Testing feasibility and reliability of a set of quality indicators to evaluate the organization of palliative care across Europe: a pilot study in 25 countries.

BACKGROUND: A well-organized palliative care service is a prerequisite for offering good palliative care. Reliable and feasible quality indicators are needed to monitor the quality of their organization. AIM: To test feasibility and reliability of a previously developed set of quality indicators in settings and services that provide palliative care across Europe. METHODS: A total of 38 quality indicators, applicable in all types of settings, rated in a RAND Delphi process, and operationalized into 38 yes/no questions, were used. Descriptives statistics, factor and reliability analyses, analysis of variance, and chi-square analyses were used. DESIGN: Cross-sectional online survey. SETTING/PARTICIPANTS: Questionnaires were sent to representatives of 217 palliative care settings in 25 countries. Included settings were hospices, inpatient dedicated palliative care beds, palliative care outpatient clinics, palliative care units, day care centers for palliative care, palliative care home support teams, inpatient palliative care support teams, care homes, and nursing homes. RESULTS: All invited 25 European Association of Palliative Care countries took part. In total, 107 out of 217 participants responded (57%). The quality indicators were reduced to four coherent sub-scales, being "equipment and continuity of care," "structured documentation of essential palliative care elements in the medical record," "training and appraisal of personnel," and "availability of controlled drugs." No significant differences in quality criteria between the different types of settings and services were identified. CONCLUSION: The set of quality indicators appeared to measure four reliable domains that assess the organization of different palliative care settings. It can be used as a starting point for quality improvement activities.

The long-term prognosis of Legg-Calvé-Perthes disease: a historical prospective study with a median follow-up of forty one years.

PURPOSE: The purpose of this study is predicting the clinical and radiological long-term outcome and identifying prognostic factors of Legg-Calvé-Perthes disease (LCPD) in Catterall 2 and 3 hips. METHODS: Sixty hips (59 patients) were diagnosed with LCPD between 1959 to 1974 and were followed prospectively. Forty-two of these 60 hips were classified as Catterall 2 or 3. In 2002, 33 hips (32 patients) with Catterall type 2 or 3 were evaluated clinically and radiographically. In 2010, 27 hips (26 patients) were re-evaluated. RESULTS: In 2002, 15 hips had Catterall 2 type LCPD and 18 hips Catterall 3. Twelve of the 33 hips (36%) had signs of osteoarthritis. In 2010, 14 hips were classified as Catterall 2 and 13 hips as Catterall 3. Catterall 2 hips had a significantly better Harris Hip Score (HHS) (p = 0.001). There were 15 hips (55%) with signs of osteoarthritis. CONCLUSION: The long-term prognosis of LCPD Catterall type 2 and 3 is relatively benign. However, more than 50% of the patients will develop signs of osteoarthritis between the 4th and 5th decades. At the latest follow-up a strong increase in the number of cases with osteoarthritis was seen. Sphericity of the femoral head is an important predicting factor in the development of osteoarthritis.