A method to measure flag performance for the shipping industry

The subject of measuring the performance of registries has been a topic of policy discussions in recent years on the regional level due to the recast of the European Union (EU) port state control (PSC) directive which introduces incentives for flags which perform better. Since the current method used in the EU region entails some shortcomings, it has therefore been the subject of substantial scrutiny. Furthermore, the International Maritime Organization (IMO) developed a set of performance indicators which however lacks the ability to measure compliance as set out in one of its strategic directions towards fostering global compliance. In this article, we develop and test a methodology to measure flag state performance which can be applied to the regional or global level and to other areas of legislative interest (e.g. recognized organizations, Document of Compliance Companies). Our proposed methodology overcomes some of the shortcomings of the present method and presents a more refined, less biased approach of measuring performance. To demonstrate its usefulness, we apply it to a sample of 207,821 observations for a 3 year time frame and compare it to the best know current method in the industry.

A method to measure flag performance for the shipping industry

The subject of measuring the performance of registries has been a topic of policy discussions in recent years on the regional level due to the recast of the European Union (EU) port state control (PSC) directive which introduces incentives for flags which perform better. Since the current method used in the EU region entails some shortcomings, it has therefore been the subject of substantial scrutiny. Furthermore, the International Maritime Organization (IMO) developed a set of performance indicators which however lacks the ability to measure compliance as set out in one of its strategic directions towards fostering global compliance. In this article, we develop and test a methodology to measure flag state performance which can be applied to the regional or global level and to other areas of legislative interest (e.g. recognized organizations, Document of Compliance Companies). Our proposed methodology overcomes some of the shortcomings of the present method and presents a more refined, less biased approach of measuring performance. To demonstrate its usefulness, we apply it to a sample of 207,821 observations for a 3 year time frame and compare it to the best know current method in the industry

Elevated levels of the angiogenic cytokines basic fibroblast growth factor and vascular endothelial growth factor in sera of cancer patients.

The concentration of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) was determined in the serum of 90 untreated and 42 treated metastatic cancer patients, including patients with colorectal, breast, ovarian and renal carcinomas, with an enzyme-linked immunosorbent assay (ELISA). Levels higher than the 95th percentile of the concentrations of a control group, i.e. 7.5 pg ml(-1) for bFGF and 500 pg ml(-1) for VEGF, were identified as 'elevated'. One measurement during follow-up was included into the analysis per patient. For 19 treated patients, consecutive serum samples were analysed. Fifty-seven per cent of all untreated patients had elevated serum levels of one or both angiogenic factors. The fraction of patients with elevated serum levels of bFGF and/or VEGF was similar in the different tumour types. Agreement of bFGF levels and VEGF levels, classified in relation to their respective cut-off values, was present in 67% of all patients. Fifty-eight per cent of the patients with progressive disease during treatment compared with 15% of the patients showing response to treatment (chi-squared test P < 0.05) had elevated bFGF and/or VEGF serum levels. When consecutive serum samples were analysed, two-thirds of the patients showing progressive disease had increasing serum levels of the angiogenic factors compared with less than one-tenth of the patients showing response (chi-squared test P < 0.05). The lack of association between the serum bFGF and VEGF levels and the tumour type may suggest an aspecific host reaction responsible for solid tumour-related angiogenesis. The main determinants of the serum bFGF and VEGF concentration are the progression kinetics of the metastatic carcinomas

Long-Read Sequencing to Unravel Complex Structural Variants of CEP78 Leading to Cone-Rod Dystrophy and Hearing Loss

Inactivating variants as well as a missense variant in the centrosomal CEP78 gene have been identified in autosomal recessive cone-rod dystrophy with hearing loss (CRDHL), a rare syndromic inherited retinal disease distinct from Usher syndrome. Apart from this, a complex structural variant (SV) implicating CEP78 has been reported in CRDHL. Here we aimed to expand the genetic architecture of typical CRDHL by the identification of complex SVs of the CEP78 region and characterization of their underlying mechanisms. Approaches used for the identification of the SVs are shallow whole-genome sequencing (sWGS) combined with quantitative polymerase chain reaction (PCR) and long-range PCR, or ExomeDepth analysis on whole-exome sequencing (WES) data. Targeted or whole-genome nanopore long-read sequencing (LRS) was used to delineate breakpoint junctions at the nucleotide level. For all SVs cases, the effect of the SVs on CEP78 expression was assessed using quantitative PCR on patient-derived RNA. Apart from two novel canonical CEP78 splice variants and a frameshifting single-nucleotide variant (SNV), two SVs affecting CEP78 were identified in three unrelated individuals with CRDHL: a heterozygous total gene deletion of 235 kb and a partial gene deletion of 15 kb in a heterozygous and homozygous state, respectively. Assessment of the molecular consequences of the SVs on patient’s materials displayed a loss-of-function effect. Delineation and characterization of the 15-kb deletion using targeted LRS revealed the previously described complex CEP78 SV, suggestive of a recurrent genomic rearrangement. A founder haplotype was demonstrated for the latter SV in cases of Belgian and British origin, respectively. The novel 235-kb deletion was delineated using whole-genome LRS. Breakpoint analysis showed microhomology and pointed to a replication-based underlying mechanism. Moreover, data mining of bulk and single-cell human and mouse transcriptional datasets, together with CEP78 immunostaining on human retina, linked the CEP78 expression domain with its phenotypic manifestations. Overall, this study supports that the CEP78 locus is prone to distinct SVs and that SV analysis should be considered in a genetic workup of CRDHL. Finally, it demonstrated the power of sWGS and both targeted and whole-genome LRS in identifying and characterizing complex SVs in patients with ocular diseases

The merit of high-frequency data in portfolio allocation

This paper addresses the open debate about the usefulness of high-frequency (HF) data in large-scale portfolio allocation. Daily covariances are estimated based on HF data of the S&P 500 universe employing a blocked realized kernel estimator. We propose forecasting covariance matrices using a multi-scale spectral decomposition where volatilities, correlation eigenvalues and eigenvectors evolve on different frequencies. In an extensive out-of-sample forecasting study, we show that the proposed approach yields less risky and more diversified portfolio allocations as prevailing methods employing daily data. These performance gains hold over longer horizons than previous studies have shown

Development of an action programme tackling obesity-related behaviours in adolescents:a participatory system dynamics approach

System dynamics approaches are increasingly addressing the complexity of public health problems such as childhood overweight and obesity. These approaches often use system mapping methods, such as the construction of causal loop diagrams, to gain an understanding of the system of interest. However, there is limited practical guidance on how such a system understanding can inform the development of an action programme that can facilitate systems changes. The Lifestyle Innovations Based on Youth Knowledge and Experience (LIKE) programme combines system dynamics and participatory action research to improve obesity-related behaviours, including diet, physical activity, sleep and sedentary behaviour, in 10–14-year-old adolescents in Amsterdam, the Netherlands. This paper illustrates how we used a previously obtained understanding of the system of obesity-related behaviours in adolescents to develop an action programme to facilitate systems changes. A team of evaluation researchers guided interdisciplinary action-groups throughout the process of identifying mechanisms, applying the Intervention Level Framework to identify leverage points and arriving at action ideas with aligning theories of change. The LIKE action programme consisted of 8 mechanisms, 9 leverage points and 14 action ideas which targeted the system’s structure and function within multiple subsystems. This illustrates the feasibility of developing actions targeting higher system levels within the confines of a research project timeframe when sufficient and dedicated effort in this process is invested. Furthermore, the system dynamics action programme presented in this study contributes towards the development and implementation of public health programmes that aim to facilitate systems changes in practice.</p

Development of an action programme tackling obesity-related behaviours in adolescents:a participatory system dynamics approach

System dynamics approaches are increasingly addressing the complexity of public health problems such as childhood overweight and obesity. These approaches often use system mapping methods, such as the construction of causal loop diagrams, to gain an understanding of the system of interest. However, there is limited practical guidance on how such a system understanding can inform the development of an action programme that can facilitate systems changes. The Lifestyle Innovations Based on Youth Knowledge and Experience (LIKE) programme combines system dynamics and participatory action research to improve obesity-related behaviours, including diet, physical activity, sleep and sedentary behaviour, in 10–14-year-old adolescents in Amsterdam, the Netherlands. This paper illustrates how we used a previously obtained understanding of the system of obesity-related behaviours in adolescents to develop an action programme to facilitate systems changes. A team of evaluation researchers guided interdisciplinary action-groups throughout the process of identifying mechanisms, applying the Intervention Level Framework to identify leverage points and arriving at action ideas with aligning theories of change. The LIKE action programme consisted of 8 mechanisms, 9 leverage points and 14 action ideas which targeted the system’s structure and function within multiple subsystems. This illustrates the feasibility of developing actions targeting higher system levels within the confines of a research project timeframe when sufficient and dedicated effort in this process is invested. Furthermore, the system dynamics action programme presented in this study contributes towards the development and implementation of public health programmes that aim to facilitate systems changes in practice.</p

Linkage and association studies identify a novel locus for Alzheimer disease at 7q36 in a Dutch population-based sample

We obtained conclusive linkage of Alzheimer disease (AD) with a candidate region of 19.7 cM at 7q36 in an extended multiplex family, family 1270, ascertained in a population-based study of early-onset AD in the northern Netherlands. Single-nucleotide polymorphism and haplotype association analyses of a Dutch patient-control sample further supported the linkage at 7q36. In addition, we identified a shared haplotype at 7q36 between family 1270 and three of six multiplex AD-affected families from the same geographical region, which is indicative of a founder effect and defines a priority region of 9.3 cM. Mutation analysis of coding exons of 29 candidate genes identified one linked synonymous mutation, g.38030G-->C in exon 10, that affected codon 626 of the PAX transactivation domain interacting protein gene (PAXIP1). It remains to be determined whether PAXIP1 has a functional role in the expression of AD in family 1270 or whether another mutation at this locus explains the observed linkage and sharing. Together, our linkage data from the informative family 1270 and the association data in the population-based early-onset AD patient-control sample strongly support the identification of a novel AD locus at 7q36 and re-emphasize the genetic heterogeneity of AD

Loss of DPP6 in neurodegenerative dementia : a genetic player in the dysfunction of neuronal excitability

Emerging evidence suggested a converging mechanism in neurodegenerative brain diseases (NBD) involving early neuronal network dysfunctions and alterations in the homeostasis of neuronal firing as culprits of neurodegeneration. In this study, we used paired-end short-read and direct long-read whole genome sequencing to investigate an unresolved autosomal dominant dementia family significantly linked to 7q36. We identified and validated a chromosomal inversion of ca. 4Mb, segregating on the disease haplotype and disrupting the coding sequence of dipeptidyl-peptidase 6 gene (DPP6). DPP6 resequencing identified significantly more rare variants-nonsense, frame-shift, and missense-in early-onset Alzheimer's disease (EOAD, p value = 0.03, OR = 2.21 95% CI 1.05-4.82) and frontotemporal dementia (FTD, p = 0.006, OR = 2.59, 95% CI 1.28-5.49) patient cohorts. DPP6 is a type II transmembrane protein with a highly structured extracellular domain and is mainly expressed in brain, where it binds to the potassium channel K(v)4.2 enhancing its expression, regulating its gating properties and controlling the dendritic excitability of hippocampal neurons. Using in vitro modeling, we showed that the missense variants found in patients destabilize DPP6 and reduce its membrane expression (p < 0.001 and p < 0.0001) leading to a loss of protein. Reduced DPP6 and/or K(v)4.2 expression was also detected in brain tissue of missense variant carriers. Loss of DPP6 is known to cause neuronal hyperexcitability and behavioral alterations in Dpp6-KO mice. Taken together, the results of our genomic, genetic, expression and modeling analyses, provided direct evidence supporting the involvement of DPP6 loss in dementia. We propose that loss of function variants have a higher penetrance and disease impact, whereas the missense variants have a variable risk contribution to disease that can vary from high to low penetrance. Our findings of DPP6, as novel gene in dementia, strengthen the involvement of neuronal hyperexcitability and alteration in the homeostasis of neuronal firing as a disease mechanism to further investigate