From optimal to practical safety standards for dike-ring areas

After the flood disaster in 1953 in the southwestern part of the Netherlands, Van Dantzig tried to solve the economic decision problem concerning the optimal height of dikes. His solution has a fixed probability of flooding after each investment (Econometrica, 1956). However, when there is economic growth, not the probability of flooding but the expected yearly loss by flooding is the key variable in the real optimal safety strategy. Under some conditions, it is optimal to keep this expected loss within a constant interval. Therefore, when the potential damage increases by economic growth, the flooding probability has to decline in the course of time in order to keep the expected loss between the fixed boundaries. The purpose of the paper is to show the implications of the optimal solution in case there are differences between costs and benefits among dike-ring areas. Further, the paper focuses on the translation of the theoretical results into new legal standards that can work well in practice. Cost benefit analysis, optimal height of dikes, optimal safety standards.

Towards targeted therapies for phospholamban cardiomyopathy:data from a new preclinical model

In this PhD thesis, we investigated the cardiomyopathy that results from the p.Arg14del (R14del) mutation of the phospholamban (PLN) gene. This is a common genetic deviation, especially in the Netherlands, and mutation carriers have an increased risk of developing heart failure. Little is known about how this mutation leads to cardiomyopathy, and there is no effective cure other than heart transplantation. Therefore, we aimed to generate a novel mouse model to study the disease pathophysiology and screen therapeutic options. First, we validated that PLN-R14del mice develop heart failure with similar disease characteristics as has been observed in human patients. We examined the molecular changes that underlie the disease in great detail and in association with disease progression. We concluded that aggregation of PLN protein in the cardiomyocytes of PLN-R14del mutant mice was (one of) the first hallmark(s) of the disease, and therefore may play a causal role. Finally, we tested several therapeutic therapies in this new mouse model. Standard heart failure medication did not improve the disease, and therefore we tested experimental treatments that are not (yet) commercially available. Reducing the amount of PLN and PLN aggregation in the heart using a gene therapy approach was found to be successful. Further research is required to establish whether (chronic) use of this treatment is also safe and effective in human patients, but these first results are very promising

Optimal safety standards for dike-ring areas

After the flood disaster in 1953 in the southwestern part of the Netherlands, Van Dantzig tried to solve the economic-decision problem concerning the optimal height of dikes. His formula with a fixed exceedance probability after each investment (Econometrica, 1956) is still in use today in cost benefit analysis of flood-protection measures. However, his solution is both incomplete and wrong. In the context of economic growth, not the exceedance probability but the expected yearly loss by flooding is the key variable in the real optimal safety strategy. Under some conditions, it is optimal to keep this expected loss within a constant interval. Therefore, when the potential damage increases by economic growth, the flooding probability has to decline in the course of time in order to keep the expected loss between the fixed boundaries. The paper gives the formulas for the optimal boundaries for a more complicated problem which is more in line with engineering experience. One condition is that the rate of return at the moment of investment (FYRR) has to be zero (or positive). Then the net present value (NPV) of a safety investment will be very positive or even infinite. Therefore, in case of economic growth the well known NPV criterion in cost benefit analysis of a single project is not a sufficient criterion for investing. An application of the model with the original figures for the dike ring Central Holland has been added as well as a recent application for dike ring areas along the river Rhine.

Immune regulation in IgA nephropathy

IgA nephropathy (IgAN) is the most common form of glomerulonephritis worldwide. The hallmark of the disease is depositions of polymeric IgA1 in the mesangium of the glomeuli. These depositions will lead to inflammation in the kidneys and eventually to deterioration of renal function. The pathogenesis of IgAN is not clear, but it is generally accepted that disturbances in the immune system of IgAN patients are responsible for this disease. In the current thesis we have investigated the immune response of IgAN patients in comparison with control persons. We have shown that IgAN patients have a hampered primary IgA immune response upon mucosal vaccination with a neoantigen, whereas a systemic vaccination with a neoantigen resulted in a similar immune response in both groups. We hypothesized that dendritic cells (DC), as professional antigen presenting cells could have an impaired function , or that less DC are present in the nasal mucosa. We were able to show that the number of DC present in the nasal mucosa of IgAN patients was not reduced as compared with controls. Using an in vitro model we studied the function of DC in the primary immune response and showed that DC of IgAN patients induced less IgA production in na_ve B cells than DC of control persons. Furthermore we studied the size distribution of the antigen specific IgA molecules in IgAN patients. In summary we showed that patients with IgAN have an impaired IgA production upon mucosal vaccination with a neoantigen and that at least part of this IgA hypo response is due to an impaired capacity of DC to induce IgA production, whereas the number of mucosal DC in IgAN patients is not reduced.Groene Hart Ziekenhuis, Gouda Fresenius Medical Care, Baxter Renal Division, Amgen B.V., Novartis Pharma B.V., Shire NederlandUBL - phd migration 201

Current understanding of fibrosis in genetic cardiomyopathies

Myocardial fibrosis is the excessive deposition of extracellular matrix proteins, including collagens, in the heart. In cardiomyopathies, the formation of interstitial fibrosis and/or replacement fibrosis is almost always part of the pathological cardiac remodeling process. Different forms of cardiomyopathies show particular patterns of myocardial fibrosis that can be considered as distinctive hallmarks. Although formation of fibrosis is initially aimed to be a reparative mechanism, in the long term, on-going and excessive myocardial fibrosis may lead to arrhythmias and stiffening of the heart wall and subsequently to diastolic dysfunction. Ultimately, adverse remodeling with progressive myocardial fibrosis can lead to heart failure. Not surprisingly, the presence of fibrosis in cardiomyopathies, even when subtle, has consistently been associated with complications and adverse outcomes. In the last decade, non-invasive in vivo techniques for visualization of myocardial fibrosis have emerged, and have been increasingly used in research and in the clinic. In this review, we will describe the epidemiology, distribution, and role of myocardial fibrosis in genetic cardiomyopathies, including hypertrophic, dilated, arrhythmogenic, and non-compaction cardiomyopathy, and a few specific forms of genetic cardiomyopathies

Time-saving opportunities in knee osteoarthritis: T2 mapping and structural imaging of the knee using a single 5-min MRI scan.

OBJECTIVES: To assess the discriminative power of a 5-min quantitative double-echo steady-state (qDESS) sequence for simultaneous T2 measurements of cartilage and meniscus, and structural knee osteoarthritis (OA) assessment, in a clinical OA population, using radiographic knee OA as reference standard. METHODS: Fifty-three subjects were included and divided over three groups based on radiographic and clinical knee OA: 20 subjects with no OA (Kellgren-Lawrence grade (KLG) 0), 18 with mild OA (KLG2), and 15 with moderate OA (KLG3). All patients underwent a 5-min qDESS scan. We measured T2 relaxation times in four cartilage and four meniscus regions of interest (ROIs) and performed structural OA evaluation with the MRI Osteoarthritis Knee Score (MOAKS) using qDESS with multiplanar reformatting. Between-group differences in T2 values and MOAKS were calculated using ANOVA. Correlations of the reference standard (i.e., radiographic knee OA) with T2 and MOAKS were assessed with correlation analyses for ordinal variables. RESULTS: In cartilage, mean T2 values were 36.1 ± SD 4.3, 40.6 ± 5.9, and 47.1 ± 4.3 ms for no, mild, and moderate OA, respectively (p < 0.001). In menisci, mean T2 values were 15 ± 3.6, 17.5 ± 3.8, and 20.6 ± 4.7 ms for no, mild, and moderate OA, respectively (p < 0.001). Statistically significant correlations were found between radiographic OA and T2 and between radiographic OA and MOAKS in all ROIs (p < 0.05). CONCLUSION: Quantitative T2 and structural assessment of cartilage and meniscus, using a single 5-min qDESS scan, can distinguish between different grades of radiographic OA, demonstrating the potential of qDESS as an efficient tool for OA imaging. KEY POINTS: • Quantitative T 2values of cartilage and meniscus as well as structural assessment of the knee with a single 5-min quantitative double-echo steady-state (qDESS) scan can distinguish between different grades of knee osteoarthritis (OA). • Quantitative and structural qDESS-based measurements correlate significantly with the reference standard, radiographic degree of OA, for all cartilage and meniscus regions. • By providing quantitative measurements and diagnostic image quality in one rapid MRI scan, qDESS has great potential for application in large-scale clinical trials in knee OA

Managing children with daytime urinary incontinence:a survey of Dutch general practitioners

Background: In the Netherlands, parents of children with daytime urinary incontinence (UI) first consult general practitioners (GPs). However, GPs need more specific guidelines for daytime UI management, resulting in care and referral decisions being made without clear guidance.Objectives: We aimed to identify Dutch GP considerations when treating and referring a child with daytime UI.Methods: We invited GPs who referred at least one child aged 4–18 years with daytime UI to secondary care. They were asked to complete a questionnaire about the referred child and the management of daytime UI in general.Results: Of 244 distributed questionnaires, 118 (48.4%) were returned by 94 GPs. Most reported taking a history and performing basic diagnostic tests like urine tests (61.0%) and physical examinations (49.2%) before referral. Treatment mostly involved lifestyle advice, with only 17.8% starting medication. Referrals were usually at the explicit wish of the child/parent (44.9%) or because of symptom persistence despite treatment (39.0%). GPs usually referred children to a paediatrician (n = 99, 83.9%), only referring to a urologist in specific situations. Almost half (41.4%) of the GPs did not feel competent to treat children with daytime UI and more than half (55.7%) wanted a clinical practice guideline. In the discussion, we explore the generalisability of our findings to other countries.Conclusion: GPs usually refer children with daytime UI to a paediatrician after a basic diagnostic assessment, usually without offering treatment. Parental or child demand is the primary stimulus for referral.</p

Can we predict the clinical outcome of arthroscopic partial meniscectomy? A systematic review

NHS-Prospero registration number 42016048592 Objective In order to make a more evidence-based selection of patients who would benefit the most from arthroscopic partial meniscectomy (APM), knowledge of prognostic factors is essential. We conducted a systematic review of predictors for the clinical outcome following APM. Design Systematic review Data sources Medline, Embase, Cochrane Central Register, Web of Science, SPORTDiscus, PubMed Publisher, Google Scholar Inclusion criteria Report an association between factor(s) and clinical outcome; validated questionnaire; follow-up >1 year. Exclusion criteria 1 year) are associated with worse clinical outcome following APM. In addition, resecting >50% of meniscal tissue and leaving a non-intact meniscal rim after meniscectomy are intra-articular predictive factors for worse clinical outcome. Moderate evidence was found that sex, onset of symptoms (acute or chronic), tear type or preoperative sport level are not predictors for clinical outcome. Conflicting evidence was found for the prognostic value of age, perioperative chondral damage, body mass index and leg alignment. Summary/conclusion Long duration of symptoms (>1 year), radiological knee osteoarthritis and resecting >50% of meniscus are associated with a worse clinical outcome following APM. These prognostic factors should be considered in clinical decision making for patients with meniscal tears

Development and assessment of a digital X-ray software tool to determine vertebral rotation in adolescent idiopathic scoliosis

BACKGROUND CONTEXT: The amount of vertebral rotation in the axial plane is of key importance in the prognosis and treatment of adolescent idiopathic scoliosis (AIS). Current methods to determine vertebral rotation are either designed for use in analogue plain radiographs and not useful in digital images, or lack measurement precision and are therefore less suitable for the follow-up of rotation in AIS patients.PURPOSE: This study aimed to develop a digital X-ray software tool with high measurement precision to determine vertebral rotation in AIS, and to assess its (concurrent) validity and reliability.STUDY DESIGN/SETTING: In this study a combination of basic science and reliability methodology applied in both laboratory and clinical settings was used.METHODS: Software was developed using the algorithm of the Perdriolle torsion meter for analogue AP plain radiographs of the spine. Software was then assessed for (1) concurrent validity and (2) intra-and interobserver reliability. Plain radiographs of both human cadaver vertebrae and outpatient AIS patients were used. Concurrent validity was measured by two independent observers, both experienced in the assessment of plain radiographs. Reliability-measurements were performed by three independent spine surgeons.RESULTS: Pearson correlation of the software compared with the analogue Perdriolle torsion meter for mid-thoracic vertebrae was 0.98, for low-thoracic vertebrae 0.97 and for lumbar vertebrae 0.97. Measurement exactness of the software was within 5 degrees in 62% of cases and within 10 degrees in 97% of cases. Intraclass correlation coefficient (ICC) for inter-observer reliability was 0.92 (0.91-0.95), ICC for intra-observer reliability was 0.96 (0.94-0.97).CONCLUSIONS: We developed a digital X-ray software tool to determine vertebral rotation in AIS with a substantial concurrent validity and reliability, which may be useful for the follow-up of vertebral rotation in AIS patients. (C) 2015 Elsevier Inc. All rights reserved.</p