Reconstructing the molecular life history of gliomas.

At the time of their clinical manifestation, the heterogeneous group of adult and pediatric gliomas carries a wide range of diverse somatic genomic alterations, ranging from somatic single-nucleotide variants to structural chromosomal rearrangements. Somatic abnormalities may have functional consequences, such as a decrease, increase or change in mRNA transcripts, and cells pay a penalty for maintaining them. These abnormalities, therefore, must provide cells with a competitive advantage to become engrained into the glioma genome. Here, we propose a model of gliomagenesis consisting of the following five consecutive phases that glioma cells have traversed prior to clinical manifestation: (I) initial growth; (II) oncogene-induced senescence; (III) stressed growth; (IV) replicative senescence/crisis; (V) immortal growth. We have integrated the findings from a large number of studies in biology and (neuro)oncology and relate somatic alterations and other results discussed in these papers to each of these five phases. Understanding the story that each glioma tells at presentation may ultimately facilitate the design of novel, more effective therapeutic approaches. Acta Neuropathol 2018 May; 135(5):649-670

Antidepressant prescriptions and mental health nurses:An observational study in Dutch general practice from 2011 to 2015

Purpose: The purpose of this study was to investigate developments in antidepressant prescriptions by Dutch general practitioners, alongside the national introduction of mental health nurses. Antidepressant prescriptions are very common in general practice, but are often not in line with recommendations. The recent introduction of mental health nurses may have decreased antidepressant prescriptions, as general practitioners (GPs) have greater potential to offer psychological treatment as a first choice option instead of medication. Material and methods: Anonymised data from the medical records of general practices participating in the NIVEL Primary Care Database in 2011-2015 were analysed in an observational study. We used multilevel logistic regression analyses to determine whether total antidepressant prescriptions and antidepressants prescribed within one week of diagnosing anxiety or depression decreased in the period 2011-2015. We analysed whether changes in antidepressant prescriptions were associated with the employment or consultation of mental health nurses. Results: Antidepressants were prescribed in 30.3% of all anxiety or depression episodes; about half were prescribed within the first week. Antidepressants prescriptions for anxiety or depression increased slightly in the period 2011-2015. The employment of mental health nurses was not associated with a decreased number of prescriptions of antidepressants. Patients who had at least one mental health nurse consultation had fewer immediate prescriptions of antidepressants, but not fewer antidepressants in general. Conclusions: Antidepressant prescriptions are still common in general practice. So far, the introduction of mental health nurses has not decreased antidepressant prescriptions, but it may have a postponing effect

Measuring mental health of the Dutch population: a comparison of the GHQ-12 and the MHI-5

BACKGROUD: The objective is to compare the performance of the MHI-5 and GHQ-12, both measures of general mental health. Therefore, we studied the relationship of the GHQ-12 and MHI-5 with sociodemographic characteristics, self-reported visits to general practice and mental health care, and with diagnoses made by the general practitioner. METHODS: Data were used from the Second Dutch National Survey of General Practice, which was carried out in 104 practices. This study combines data from a representative sample of the Dutch population with data from general practice. RESULTS: The agreement between the GHQ-12 and MHI-5 is only moderate. Both instruments are however similarly associated with demographic characteristics (except age), self-reported health care use, and psychological and social diagnoses in general practice. CONCLUSIONS: The performance of the MHI-5 and GHQ-12 in terms of predicting mental health problems and related help seeking behaviour is similar. An advantage of the MHI-5 is that it has been widely used, not only in surveys of mental health, but also in surveys of general health and quality of life, and it is shorter. A disadvantage of the MHI-5 is that there is no cut-off point. We recommend a study to establish a valid, internationally comparable cut-off point

Group and individual change in cognitive functioning in patients with 1 to 10 brain metastases following Gamma Knife radiosurgery

Aims:  Stereotactic radiosurgery is increasingly used to treat multiple (four or more) brain metastases. Preserving cognitive functions is a highly relevant treatment goal because cognitive deteriorations may negatively affect a patient's quality of life. The aim of this study was to assess cognitive change, at the group and individual level, in patients with 1 to 10 brain metastases up to 9 months after Gamma Knife radiosurgery (GKRS). Materials and methods:  Ninety-two patients with 1 to 10 newly diagnosed brain metastases, expected survival >3 months and Karnofsky Performance Status (KPS) ≥70 and 104 non-cancer controls were included. A neuropsychological test battery was administered before GKRS (n = 92) and at 3 (n = 66), 6 (n = 52) and 9 (n = 41) months after GKRS. The course of test performances, while taking into account practice effects, was analysed using linear mixed models. Pre-GKRS predictors of cognitive trajectories were analysed. To determine proportions of individuals with cognitive changes, reliable change indices, with correction for practice effects, were calculated. Results:  At the group level, immediate memory, working memory and information processing speed significantly improved over 9 months after GKRS. There were no cognitive declines. Neither number nor volume of brain metastases influenced cognitive change over time. At the individual level, proportions of patients with stable, improved or declined performances were comparable with controls, except for information processing speed (more individuals with improvements in patients) and motor dexterity (more improvements and declines in patients). Conclusions:  Cognitive functioning in patients with 1 to 10 brain metastases was preserved, or improved, up to 9 months after GKRS. Neither number nor volume of brain metastases influenced cognitive performance

Unifying Gene Expression Measures from Multiple Platforms Using Factor Analysis

In the Cancer Genome Atlas (TCGA) project, gene expression of the same set of samples is measured multiple times on different microarray platforms. There are two main advantages to combining these measurements. First, we have the opportunity to obtain a more precise and accurate estimate of expression levels than using the individual platforms alone. Second, the combined measure simplifies downstream analysis by eliminating the need to work with three sets of expression measures and to consolidate results from the three platforms

Applying computerized adaptive testing to the four-dimensional symptom questionnaire (4DSQ):A Simulation Study

<strong>Background</strong>: Efficient screening questionnaires are useful in general practice. Computerized adaptive testing (CAT) is a method to improve the efficiency of questionnaires, as only the items that are particularly informative for a certain responder are dynamically selected. Objective: The objective of this study was to test whether CAT could improve the efficiency of the Four-Dimensional Symptom Questionnaire (4DSQ), a frequently used self-report questionnaire designed to assess common psychosocial problems in general practice. <strong>Methods</strong>: A simulation study was conducted using a sample of Dutch patients visiting a general practitioner (GP) with psychological problems (n=379). Responders completed a paper-and-pencil version of the 50-item 4DSQ and a psychometric evaluation was performed to check if the data agreed with item response theory (IRT) assumptions. Next, a CAT simulation was performed for each of the four 4DSQ scales (distress, depression, anxiety, and somatization), based on the given responses as if they had been collected through CAT. The following two stopping rules were applied for the administration of items: (1) stop if measurement precision is below a predefined level, or (2) stop if more than half of the items of the subscale are administered. <strong>Results</strong>: In general, the items of each of the four scales agreed with IRT assumptions. Application of the first stopping rule reduced the length of the questionnaire by 38% (from 50 to 31 items on average). When the second stopping rule was also applied, the total number of items could be reduced by 56% (from 50 to 22 items on average). <strong>Conclusions</strong>: CAT seems useful for improving the efficiency of the 4DSQ by 56% without losing a considerable amount of measurement precision. The CAT version of the 4DSQ may be useful as part of an online assessment to investigate the severity of mental health problems of patients visiting a GP. This simulation study is the first step needed for the development a CAT version of the 4DSQ. A CAT version of the 4DSQ could be of high value for Dutch GPs since increasing numbers of patients with mental health problems are visiting the general practice. In further research, the results of a real-time CAT should be compared with the results of the administration of the full scale. (aut. ref.

Sedentary aging results in structural impairment of the neuromuscular junction and may be attenuated by voluntary endurance exercise

An increasingly prominent change in the aging body is the decrease in muscle mass and strength, a condition known as sarcopenia. This is a major cause for the instability in elderly individuals leading to falls and injuries. One possible cause of sarcopenia is the reduced exercise activity of older individuals. The neuromuscular junction (NMJ) is the connection by which nerves control muscle movement. This study mainly aims to investigates the possibility that alterations in the structures of the neuromuscular junction with ageing might contribute to impaired control and physical maintenance of aging muscle. Changes in the NMJ include the loss of nerve terminal from the postsynaptic membrane leading to denervation and fragmentation of postsynaptic clusters of acetylcholine receptors (AChRs) resulting in tiny islands of receptors. Exercise in ageing animals and humans have shown to have some positive effects on sarcopenic related changes like slowing down the rate of loss in muscle mass and strength. In the neuromuscular junction of old animals and rodents that exercised the age related changes were reported to be less severe and in some cases the NMJ recovered

TumorFusions: an integrative resource for cancer-associated transcript fusions.

Gene fusion represents a class of molecular aberrations in cancer and has been exploited for therapeutic purposes. In this paper we describe TumorFusions, a data portal that catalogues 20 731 gene fusions detected in 9966 well characterized cancer samples and 648 normal specimens from The Cancer Genome Atlas (TCGA). The portal spans 33 cancer types in TCGA. Fusion transcripts were identified via a uniform pipeline, including filtering against a list of 3838 transcript fusions detected in a panel of 648 non-neoplastic samples. Fusions were mapped to somatic DNA rearrangements identified using whole genome sequencing data from 561 cancer samples as a means of validation. We observed that 65% of transcript fusions were associated with a chromosomal alteration, which is annotated in the portal. Other features of the portal include links to SNP array-based copy number levels and mutational patterns, exon and transcript level expressions of the partner genes, and a network-based centrality score for prioritizing functional fusions. Our portal aims to be a broadly applicable and user friendly resource for cancer gene annotation and is publicly available at http://www.tumorfusions.org. Nucleic Acids Res 2018 Jan 4; 46(D1):D1144-D1149

Hospital Mental Health Admissions in Women after Unsuccessful Infertility Treatment and In Vitro Fertilization: An Australian Population-Based Cohort Study

Objective - To examine the association between in vitro fertilization (IVF) and later admission to hospital with a mental health diagnosis in women who remained childless after infertility treatment. Methods - This was a population-based cohort study using linked administrative hospital and registry data. The study population included all women commencing hospital treatment for infertility in Western Australia between the years 1982 and 2002 aged 20–44 years at treatment commencement who did not have a recorded birth by the end of follow-up (15 August 2010) and did not have a hospital mental health admission prior to the first infertility admission (n=6,567). Of these, 2,623 women had IVF and 3,944 did not. We used multivariate Cox regression modeling of mental health admissions and compared women undergoing IVF treatment with women having infertility treatment but not IVF. Results - Over an average of 17 years of follow-up, 411 women in the cohort were admitted to hospital with a mental health diagnosis; 93 who had IVF and 318 who did not. The unadjusted hazard ratio (HR) for a hospital mental health admission comparing women who had IVF with those receiving other infertility treatment was 0.50 (95% confidence interval [CI] 0.40–0.63). After adjustment for age, calendar year and socio-economic status the HR was 0.56 (95% CI 0.44–0.71). Conclusions - IVF treatment is associated with a reduced risk of hospital mental health admissions in women after unsuccessful infertility treatment. This may be explained by the healthy cohort effect