Groeven en graven : nieuw leven voor voormalige zandgroeven in Zuid-Limburg

De milieugroep Regionaal Stort Westelijke Mijnstreek vroeg zich af of de zandgroeves bij Spaubeek en Schinnen niet op een betere en snellere manier ingericht konden worden dan in de planvorming tot nu toe gebeurde. Om deze vraag te beantwoorden is een overzicht gemaakt van de regionale behoeften en gekeken of met een aantal ontwerpen aan die behoeften tegemoet gekomen kan worden. Het blijkt dat een op natuur en licht recreatief medegebruik gerichte inrichting het meest aansluit bij de wensen van bewoners en bestuurder

Measurement of the Neutron Lifetime by Counting Trapped Protons in a Cold Neutron Beam

A measurement of the neutron lifetime $\tau_{n}$ performed by the absolute counting of in-beam neutrons and their decay protons has been completed. Protons confined in a quasi-Penning trap were accelerated onto a silicon detector held at a high potential and counted with nearly unit efficiency. The neutrons were counted by a device with an efficiency inversely proportional to neutron velocity, which cancels the dwell time of the neutron beam in the trap. The result is $\tau_{n} = (886.6\pm1.2{\rm [stat]}\pm3.2{\rm [sys]})$ s, which is the most precise measurement of the lifetime using an in-beam method. The systematic uncertainty is dominated by neutron counting, in particular the mass of the deposit and the $^{6}$Li({\it{n,t}}) cross section. The measurement technique and apparatus, data analysis, and investigation of systematic uncertainties are discussed in detail.Comment: 71 pages, 20 figures, 9 tables; submitted to PR

More frequent, more costly? Health economic modelling aspects of monitoring glaucoma patients in England

BACKGROUND: Chronic open angle glaucoma (COAG) is an age-related eye disease causing irreversible loss of visual field (VF). Health service delivery for COAG is challenging given the large number of diagnosed patients requiring lifelong periodic monitoring by hospital eye services. Yet frequent examination better determines disease worsening and speed of VF loss under treatment. We examine the cost-effectiveness of increasing frequency of VF examinations during follow-up using a health economic model. METHODS: Two different VF monitoring schemes defined as current practice (annual VF testing) and proposed practice (three VF tests per year in the first 2 years after diagnosis) were examined. A purpose written health economic Markov model is used to test the hypothesis that cost effectiveness improves by implementing proposed practice on groups of patients stratified by age and severity of COAG. Further, a new component of the model, estimating costs of visual impairment, was added. Results were derived from a simulated cohort of 10000 patients with quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs) used as main outcome measures. RESULTS: An ICER of £21,392 per QALY was derived for proposed practice improving to a value of £11,382 once savings for prevented visual impairment was added to the model. Proposed practice was more cost-effective in younger patients. Proposed practice for patients with advanced disease at diagnosis generated ICERs > £60,000 per QALY; these cases would likely be on the most intensive treatment pathway making clinical information on speed of VF loss redundant. Sensitivity analysis indicated results to be robust in relation to hypothetical willingness to pay threshold identified by national guidelines, although greatest uncertainty was allied to estimates of implementation and visual impairment costs. CONCLUSION: Increasing VF monitoring at the earliest stages of follow-up for COAG appears to be cost-effective depending on reasonable assumptions about implementation costs. Our health economic model highlights benefits of stratifying patients to more or less monitoring based on age and stage of disease at diagnosis; a prospective study is needed to prove these findings. Further, this works highlights gaps in knowledge about long term costs of visual impairment

High frequency of antidrug antibodies and association of random drug levels with efficacy in certolizumab pegol-treated patients with rheumatoid arthritis: results from the BRAGGSS cohort

Objectives: To evaluate (i) the association between random certolizumab drug levels, antidrug antibodies (ADAbs) and treatment response in patients with rheumatoid arthritis (RA); (ii) longitudinal factors associated with ADAbs and certolizumab drug levels. Methods: This prospective cohort included 115 patients with RA treated with certolizumab. Serum samples were collected at 3, 6 and 12 months following treatment initiation. Drug levels and ADAbs were measured using ELISA and radioimmunoassay, respectively, at 3, 6 and 12 months. Disease Activity Score in 28 joints (DAS28) were measured at each visit and 12 months European League Against Rheumatism (EULAR) response was calculated. Patient self-reported adherence was collected longitudinally. Ordinal logistic regression and generalised estimating equation were used to test the association: (i) between drug levels, from serum sampled and treatment response; (ii) between ADAbs and drug levels; (iii) patient-centred factors and drug levels. Results: ADAbs were detected in 37% (42/112 patients by 12 months). The presence of ADAbs were significantly associated with lower drug levels over 12 months (β=−0.037, 95% CI −0.055 to 0.018, p<0.0001) but not independently with 12 months EULAR response (β=0.0013 (95% CI −0.0032 to 0.00061), p=0.18). Drug level was associated with 12 months EULAR response (β=0.032 (95% CI 0.0011 to 0.063), p=0.042). In the multivariate model, ADAb level and adherence were significantly associated with drug concentrations. Conclusions: This is the first study to demonstrate that higher certolizumab drug levels are associated with better 12 months EULAR response. ADAbs in certolizumab-treated patients with RA were detected at higher levels than previous studies and help determine the aetiology of a low drug level

Work disability and state benefit claims in early rheumatoid arthritis: the ERAN cohort

Objective. RA is an important cause of work disability. This study aimed to identify predictive factors for work disability and state benefit claims in a cohort with early RA. Methods. The Early RA Network (ERAN) inception cohort recruited from 22 centres. At baseline, and during each annual visit, participants (n = 1235) reported employment status and benefits claims and how both were influenced by RA. Survival analysis derived adjusted hazard ratios (aHRs) and 95% CIs to predict associations between baseline factors and time until loss of employment due to RA or a state benefits claim due to RA. Results. At baseline, 47% of participants were employed and 17% reported claiming benefits due to RA. During follow-up, loss of employment due to RA was reported by 10% (49/475) of the participants and 20% (179/905) began to claim benefits. Independent predictors of earlier work disability were bodily pain (aHR 2.45, 95% CI 1.47, 4.08, P = 0.001) and low vitality (aHR 1.84, 95% CI 1.18, 2.85, P = 0.007). Disability (aHR 1.28, 95% CI 1.02, 1.61, P = 0.033), DAS28 (aHR 1.48, 95% CI 1.05, 2.09, P = 0.026) and extra-articular disease (aHR 1.77, 95% CI 1.17, 2.70, P = 0.007) predicted earlier benefits claims. Conclusion. Work disability and benefits claims due to RA were predicted by different baseline factors. Pain and low vitality predicted work disability. Baseline disability, extra-articular disease manifestations and disease activity predicted new benefits claims due to RA. Future research on interventions targeting these factors could investigate job retention and financial independence

What do We Know About Entrepreneurial Finance and its Relationship with Growth?

This article explores what we do (and do not) know about entrepreneurial finance and its relationship with growth. Broadly, there is a need for research to go beyond traditional supply side/market failure issues to better understand the role of entrepreneurial cognition, objectives, ownership types and firm life-cycle stages in financing/investment decisions. We show that little is known about the pivotal relationship between access to external finance and growth due to limitations in current approaches to testing financial constraints. Instead, we propose that the relationship between funding gaps and business performance as a direct and nuanced approach to identifying financial constraints in different entrepreneurial finance markets requires scrutiny. There is also a necessity for research to disentangle cognitive from financial constraints and to better understand the role of financiers in enabling growth. In particular, there is a need to explore the relationship between non-bank sources of finance and growth, shorn of inherent survival and selection bias. We outline an agenda for future research to address gaps in our understanding

Serum IL-33, a new marker predicting response to rituximab in rheumatoid arthritis

Background. Recent works have suggested a possible link between IL-33 and B-cell biology. We aimed to study in different cohorts and with an accurate ELISA assay the possible association between serum IL-33 detection and response to rituximab (RTX) in rheumatoid arthritis (RA) patients. Method. Serum IL-33, rheumatoid factor (RF), anti-citrullinated cyclic peptide antibodies (anti-CCP), high serum IgG level were assessed in 111 RA patients receiving a first course of 2 grams RTX (cohort 1) in an observational study and in 74 RA patients treated with the same schedule in routine care (cohort 2). Uni and multivariate analyzes identified factors associated with a European League Against Rheumatism response at 24 weeks. Results. At week 24, 84/111 (76%) and 54/74 (73%) patients reached EULAR response in the cohorts 1 and 2, respectively. Serum IL-33 was detectable in only 33,5% of the patients. In the combined cohorts, presence of RF or anti-CCP (OR 3.27, 95%CI [1.13-9.46]; p=0.03), high serum IgG (OR 2.32, 95%CI [1.01-5.33]; p=0.048) and detectable serum IL-33 (OR 2.40, 95%CI [1.01-5.72]; p=0.047) were all associated with RTX response in multivariate analysis. Combination of these 3 factors increased the likelihood to response to RTX. When serum IL-33 detection was added to seropositivity and serum IgG level, 100% of the patients with the 3 risk factors (corresponding to 9% of the population) responded to RTX (OR versus patients with none of the 3 risk factors = 29.61; 95% CI [1.30-674.79] p=0.034) Conclusion. Detectable serum IL-33 may predict clinical response to RTX, independently of and synergistically with autoantibodies and serum IgG level

Consensus on circulatory shock and hemodynamic monitoring. Task force of the European Society of Intensive Care Medicine.

OBJECTIVE: Circulatory shock is a life-threatening syndrome resulting in multiorgan failure and a high mortality rate. The aim of this consensus is to provide support to the bedside clinician regarding the diagnosis, management and monitoring of shock. METHODS: The European Society of Intensive Care Medicine invited 12 experts to form a Task Force to update a previous consensus (Antonelli et al.: Intensive Care Med 33:575-590, 2007). The same five questions addressed in the earlier consensus were used as the outline for the literature search and review, with the aim of the Task Force to produce statements based on the available literature and evidence. These questions were: (1) What are the epidemiologic and pathophysiologic features of shock in the intensive care unit ? (2) Should we monitor preload and fluid responsiveness in shock ? (3) How and when should we monitor stroke volume or cardiac output in shock ? (4) What markers of the regional and microcirculation can be monitored, and how can cellular function be assessed in shock ? (5) What is the evidence for using hemodynamic monitoring to direct therapy in shock ? Four types of statements were used: definition, recommendation, best practice and statement of fact. RESULTS: Forty-four statements were made. The main new statements include: (1) statements on individualizing blood pressure targets; (2) statements on the assessment and prediction of fluid responsiveness; (3) statements on the use of echocardiography and hemodynamic monitoring. CONCLUSIONS: This consensus provides 44 statements that can be used at the bedside to diagnose, treat and monitor patients with shock

Genome-Wide Association Study and Gene Expression Analysis Identifies CD84 as a Predictor of Response to Etanercept Therapy in Rheumatoid Arthritis

Anti-tumor necrosis factor alpha (anti-TNF) biologic therapy is a widely used treatment for rheumatoid arthritis (RA). It is unknown why some RA patients fail to respond adequately to anti-TNF therapy, which limits the development of clinical biomarkers to predict response or new drugs to target refractory cases. To understand the biological basis of response to anti-TNF therapy, we conducted a genome-wide association study (GWAS) meta-analysis of more than 2 million common variants in 2,706 RA patients from 13 different collections. Patients were treated with one of three anti-TNF medications: etanercept (n = 733), infliximab (n = 894), or adalimumab (n = 1,071). We identified a SNP (rs6427528) at the 1q23 locus that was associated with change in disease activity score (ΔDAS) in the etanercept subset of patients (P = 8×10-8), but not in the infliximab or adalimumab subsets (P>0.05). The SNP is predicted to disrupt transcription factor binding site motifs in the 3′ UTR of an immune-related gene, CD84, and the allele associated with better response to etanercept was associated with higher CD84 gene expression in peripheral blood mononuclear cells (P = 1×10-11 in 228 non-RA patients and P = 0.004 in 132 RA patients). Consistent with the genetic findings, higher CD84 gene expression correlated with lower cross-sectional DAS (P = 0.02, n = 210) and showed a non-significant trend for better ΔDAS in a subset of RA patients with gene expression data (n = 31, etanercept-treated). A small, multi-ethnic replication showed a non-significant trend towards an association among etanercept-treated RA patients of Portuguese ancestry (n = 139, P = 0.4), but no association among patients of Japanese ancestry (n = 151, P = 0.8). Our study demonstrates that an allele associated with response to etanercept therapy is also associated with CD84 gene expression, and further that CD84 expression correlates with disease activity. These findings support a model in which CD84 genotypes and/or expression may serve as a useful biomarker for response to etanercept treatment in RA patients of European ancestry. © 2013 Cui et al

Boost modalities in cervical cancer: dosimetric comparison between intracavitary BT vs. intracavitary + interstitial BT vs. SBRT.

This study compares the dosimetric plans of three distinct boost modalities in cervical cancer (CC): intracavitary (IC) with tandem/ovoids brachytherapy (BT), IC + interstitial (IS) BT, and Stereotactic-Body-Radiotherapy (SBRT). The aim is to determine the dosimetric impact in terms of target coverage and organ at risk (OAR) doses. 24 consecutive IC + IS BT boost treatment plans were retrospectively identified. For each plan included, two additional plans were created: IC-BT and SBRT. Importantly, no planning target volume (PTV) or planning (organ at) risk volume (PRV) margins were generated, therefore all structures were identical for any boost modality. Two different normalizations were performed: (1) Normalization to the target: prescription of 7.1 Gy to the D90% (defined as the minimum dose covering 90%) of the high-risk clinical target volume (HR-CTV); (2) Normalization to the OARs. HR-CTV coverage and OARs sparing were compared. The equivalent doses in 2 Gy fractions (EQD2) of EBRT and BT for CTV-HR and OARs were calculated using the linear-quadratic model with α/β of 10 (EQD2 &lt;sub&gt;10&lt;/sub&gt; ) and 3 (EQD2 &lt;sub&gt;3&lt;/sub&gt; ), respectively RESULTS: A total of 72 plans were investigated. In the first normalization, the mean EQD2 &lt;sub&gt;3-&lt;/sub&gt; D2cc (defined as the minimal dose of the 2 cc) of OAR was significantly higher in the IC-BT plans, and the bladder D2cc hard constraint could not be reached. IC + IS BT leads to a 1 Gy mean absolute decrease of bladder EQD2 &lt;sub&gt;3&lt;/sub&gt; -D2cc (relative dose: -19%), allowing to reach the hard constraint. SBRT (without PTV) delivers the lowest EQD2 &lt;sub&gt;3&lt;/sub&gt; -D2cc to the OAR. In the second normalization, IC-BT provides a significantly lower dose to the EQD2 &lt;sub&gt;10&lt;/sub&gt; -D90% (6.62 Gy) and cannot achieve the coverage goal. SBRT (without PTV) yields the highest dose to the D90% of HR-CTV and a significantly lower EQD2 &lt;sub&gt;10&lt;/sub&gt; -D50% and D30%. The key dosimetric benefit of BT over SBRT without PTV is a significantly higher D50% and D30% in the HR-CTV, which increases the local and conformal dose to the target. IC + IS BT vs. IC-BT provides significantly better target coverage and a lower dose to the OARs, making it the preferred boost modality in CC