Why patients may not exercise their choice when referred for hospital care:An exploratory study based on interviews with patients

Background Various north-western European health-care systems encourage patients to make an active choice of health-care provider. This study explores, qualitatively, patients' hospital selection processes and provides insight into the reasons why patients do or do not make active choices. Methods Semi-structured individual interviews were conducted with 142 patients in two departments of three Dutch hospitals. Interviews were recorded, transcribed and analysed in accordance with the grounded theory approach. Results Three levels of choice activation were identified – passive, semi-active and active. The majority of the patients, however, visited the default hospital without having used quality information or considered alternatives. Various factors relating to patient, provider and health-care system characteristics were identified that influenced patients' level of choice activation. On the whole, the patients interviewed could be classified into five types with regard to how they chose, or ‘ended up at’ a hospital. These types varied from patients who did not have a choice to patients who made an active choice. Conclusions A large variation exists in the way patients choose a hospital. However, most patients tend to visit the default without being concerned about choice. Generally, they do not see any reason to choose another hospital. In addition, barriers exist to making choices. The idea of a patient who actively makes a choice originates from neoclassical microeconomic theory. However, policy makers may try in vain to bring principles originating from this theory into health care. Even so, patients do value the opportunity of attending ‘their’ own hospital

A new subtype of frontotemporal lobar degeneration with FUS pathology

Frontotemporal dementia (FTD) is a clinical syndrome with a heterogeneous molecular basis. The neuropathology associated with most FTD is characterized by abnormal cellular aggregates of either transactive response DNA-binding protein with Mr 43 kDa (TDP-43) or tau protein. However, we recently described a subgroup of FTD patients, representing around 10%, with an unusual clinical phenotype and pathology characterized by frontotemporal lobar degeneration with neuronal inclusions composed of an unidentified ubiquitinated protein (atypical FTLD-U; aFTLD-U). All cases were sporadic and had early-onset FTD with severe progressive behavioural and personality changes in the absence of aphasia or significant motor features. Mutations in the fused in sarcoma (FUS) gene have recently been identified as a cause of familial amyotrophic lateral sclerosis, with these cases reported to have abnormal cellular accumulations of FUS protein. Because of the recognized clinical, genetic and pathological overlap between FTD and amyotrophic lateral sclerosis, we investigated whether FUS might also be the pathological protein in aFTLD-U. In all our aFTLD-U cases (n = 15), FUS immunohistochemistry labelled all the neuronal inclusions and also demonstrated previously unrecognized glial pathology. Immunoblot analysis of protein extracted from post-mortem aFTLD-U brain tissue demonstrated increased levels of insoluble FUS. No mutations in the FUS gene were identified in any of our patients. These findings suggest that FUS is the pathological protein in a significant subgroup of sporadic FTD and reinforce the concept that FTD and amyotrophic lateral sclerosis are closely related condition

De vele dimensies van Europa

Er wordt op verschillende niveaus politiek bedreven: regionaal, nationaal en internationaal, met elk zijn eigen eigenschappen en actoren. Vaak is de nationale politiek bekender bij de Nederlandse burger, terwijl de internationale politiek, met name de Europese politiek, net zo belangrijk is, zo niet belangrijker. Sinds juli 2004 neemt Sophie in ´t Veld namens D66 zitting in het Europees Parlement. We hebben haar gevraagd ons een inzicht te geven in de politiek op Europees niveau

Developments in ROOT I/O and trees

For the last several months the main focus of development in the ROOT I/O package has been code consolidation and performance improvements. Access to remote files is affected both by bandwidth and latency. We introduced a pre-fetch mechanism to minimize the number of transactions between client and server and hence reducing the effect of latency. We will review the implementation and how well it works in different conditions (gain of an order of magnitude for remote file access). We will also review new utilities, including a faster implementation of TTree cloning (gain of an order of magnitude), a generic mechanism for object references, and a new entry list mechanism tuned both for small and large number of selections. In addition to reducing the coupling with the core module and becoming its owns library (libRIO) (as part of the general restructuration of the ROOT libraries), the I/O package has been enhanced in the area of XML and SQL support, thread safety, schema evolution, TTreeFormula, and many other areas. We will also discuss various ways, ROOT will be able to benefit from multi-core architecture to improve I/O performances

An assessment on the unsteady flow distortion generated by an S-duct intake

Closer integration between the fuselage and the propulsion system is expected for futureaircraft toreducefuel consumption, emissions, weight and drag. The use of embedded or partially embedded propulsion systems may require the use of complex intakes. However, thiscanresult in unsteady flow distortion which can adversely affect the propulsion system efficiency and stability. This works assesses the characteristics of the unsteady flow with a view to the potential flow distortion presented to the compression system.Particle image velocimetry is used to measure the flow distortion generated by an S-shaped intake.The time-resolved tracking of the idealized relative incidence angle revealed that most frequent distortion events exhibited90°exposure sector and upto±5°meanrelativeincidence. The imposition of a thicker boundary at the S-duct inlet increased the probability of distortion events that are characterized by a longer exposure sector and higher relative incidence angles.Because of these characteristics, thedistortion caused by the S-duct intake could induce instabilities that are detrimental for the propulsion system performances and stability. Overall, this work proposes a new method to assess thepossible relativeincidence angle on the compressor rotor taking into account the intake flow unsteadiness

Cerebellar c9RAN proteins associate with clinical and neuropathological characteristics of C9ORF72 repeat expansion carriers.

Clinical and neuropathological characteristics associated with G4C2 repeat expansions in chromosome 9 open reading frame 72 (C9ORF72), the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, are highly variable. To gain insight on the molecular basis for the heterogeneity among C9ORF72 mutation carriers, we evaluated associations between features of disease and levels of two abundantly expressed "c9RAN proteins" produced by repeat-associated non-ATG (RAN) translation of the expanded repeat. For these studies, we took a departure from traditional immunohistochemical approaches and instead employed immunoassays to quantitatively measure poly(GP) and poly(GA) levels in cerebellum, frontal cortex, motor cortex, and/or hippocampus from 55 C9ORF72 mutation carriers [12 patients with ALS, 24 with frontotemporal lobar degeneration (FTLD) and 19 with FTLD with motor neuron disease (FTLD-MND)]. We additionally investigated associations between levels of poly(GP) or poly(GA) and cognitive impairment in 15 C9ORF72 ALS patients for whom neuropsychological data were available. Among the neuroanatomical regions investigated, poly(GP) levels were highest in the cerebellum. In this same region, associations between poly(GP) and both neuropathological and clinical features were detected. Specifically, cerebellar poly(GP) levels were significantly lower in patients with ALS compared to patients with FTLD or FTLD-MND. Furthermore, cerebellar poly(GP) associated with cognitive score in our cohort of 15 patients. In the cerebellum, poly(GA) levels similarly trended lower in the ALS subgroup compared to FTLD or FTLD-MND subgroups, but no association between cerebellar poly(GA) and cognitive score was detected. Both cerebellar poly(GP) and poly(GA) associated with C9ORF72 variant 3 mRNA expression, but not variant 1 expression, repeat size, disease onset, or survival after onset. Overall, these data indicate that cerebellar abnormalities, as evidenced by poly(GP) accumulation, associate with neuropathological and clinical phenotypes, in particular cognitive impairment, of C9ORF72 mutation carriers

DLK-1/p38 MAP Kinase Signaling Controls Cilium Length by Regulating RAB-5 Mediated Endocytosis in Caenorhabditis elegans

Cilia are sensory organelles present on almost all vertebrate cells. Cilium length is constant, but varies between cell types, indicating that cilium length is regulated. How this is achieved is unclear, but protein transport in cilia (intraflagellar transport, IFT) plays an important role. Several studies indicate that cilium length and function can be modulated by environmental cues. As a model, we study a C. elegans mutant that carries a dominant active G protein α subunit (gpa-3QL), resulting in altered IFT and short cilia. In a screen for suppressors of the gpa-3QL short cilium phenotype, we identified uev-3, which encodes an E2 ubiquitin-conjugating enzyme variant that acts in a MAP kinase pathway. Mutation of two other components of this pathway, dual leucine zipper-bearing MAPKKK DLK-1 and p38 MAPK PMK-3, also suppress the gpa-3QL short cilium phenotype. However, this suppression seems not to be caused by changes in IFT. The DLK-1/p38 pathway regulates several processes, including microtubule stability and endocytosis. We found that reducing endocytosis by mutating rabx-5 or rme-6, RAB-5 GEFs, or the clathrin heavy chain, suppresses gpa-3QL. In addition, gpa-3QL animals showed reduced levels of two GFP-tagged proteins involved in endocytosis, RAB-5 and DPY-23, whereas pmk-3 mutant animals showed accumulation of GFP-tagged RAB-5. Together our results reveal a new role for the DLK-1/p38 MAPK pathway in control of cilium length by regulating RAB-5 mediated endocytosis

Temporal course of cognitive and behavioural changes in motor neuron diseases

Background Cognitive and behavioural dysfunction may occur in people with motor neuron disease (MND), with some studies suggesting an association with the C9ORF72 repeat expansion. Their onset and progression, however, is poorly understood. We explored how cognition and behaviour change over time, and whether demographic, clinical and genetic factors impact these changes. Methods Participants with MND were recruited through the Phenotype-Genotype-Biomarker study. Every 3–6 months, the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) was used to assess amyotrophic lateral sclerosis (ALS) specific (executive functioning, verbal fluency, language) and ALS non-specific (memory, visuospatial) functions. Informants reported on behaviour symptoms via semi-structured interview. Results Participants with neuropsychological data at ≥3 visits were included (n=237, mean age=59, 60% male), of which 18 (8%) were C9ORF72 positive. Baseline cognitive impairment was apparent in 18 (8%), typically in ALS specific domains, and associated with lower education, but not C9ORF72 status. Cognition, on average, remained stable over time, with two exceptions: (1) C9ORF72 carriers declined in all ECAS domains, (2) 8%–9% of participants with baseline cognitive impairment further declined, primarily in the ALS non-specific domain, which was associated with less education. Behavioural symptoms were uncommon. Conclusions In this study, cognitive dysfunction was less common than previously reported and remained stable over time for most. However, cognition declines longitudinally in a small subset, which is not entirely related to C9ORF72 status. Our findings raise questions about the timing of cognitive impairment in MND, and whether it arises during early clinically manifest disease or even prior to motor manifestations

Optical Imaging

Optical Coherence Tomography (OCT)We describe the fundamental concept of optical coherence tomography (OCT) and discuss the two main working principles time domain OCT and frequency domain OCT. Then, we review extended functionalities including spectrally and polarization-resolved OCT as well as Doppler-OCT and show concepts for contrast enhancement. Based on these fundamentals, we demonstrate the potential of OCT for small animal imaging on the basis of exemplary studies on retinal imaging and lung imaging.Optoacoustic ImagingThis chapter deals with the fascinating topic of optoacoustic imaging, a recent powerful addition to the arsenal of in vivo functional and molecular small animal imaging. Due to its hybrid nature, involving optical excitation and ultrasonic detection, optoacoustics overcomes the imaging depth limitations of optical microscopy related to light scattering in living tissues while further benefiting from the compelling advantages of optical contrast. To this end, optoacoustic imaging has been shown capable of delivering multiple types of imaging contrast (structural, functional, kinetic, molecular) within a single imaging modality. It can further deliver images with high spatiotemporal resolution that rivals performance of other well-established whole-body imaging modalities. As such, optoacoustics can play a vital role in biomedical research, from early disease detection and monitoring of dynamic phenomena noninvasively to accelerating drug discovery.Optical ProbesThis chapter is devoted to the properties and application of fluorescence dyes as probes for optical imaging. A variety of agents have been described to date, including nontargeting dyes, vascular agents, targeted conjugates, activatable dyes, and sensing probes. The major classes encompass polymethine dyes and xanthenes dyes, both of which are commercially available in broad variations. Addressing the purpose of optical animal imaging, the most relevant parameters to apply such probes are discussed, thereby supporting the reader in choosing reasonable imaging probes and in preparing bioconjugates for his studies