Inteelt onder Sallandse korhoenders : de genetische gevolgen van een kleine populatieomvang

Recent werd Alterra gevraagd om de resultaten van onderzoek dat de afgelopen jaren door verschillende instituten is uitgevoerd te bundelen en te integreren om een antwoord te krijgen op de vraag of het korhoen duurzaam voor Nederland behouden kan worden en op welke manier behoud mogelijk is (Jansman et al. 2014). Het voorliggende rapport is een aanvulling op dit basisrapport, waarin dieper wordt ingegaan op de effecten die de sterke afname in populatieomvang heeft gehad op het verloop van genetische processen van de korhoenpopulatie, en de gevolgen die dit kan hebben voor de algehele vitaliteit van de populatie, en diens reproductievermogen in het bijzonder. In dit onderzoek is duidelijk geworden dat de Nederlandse korhoenpopulatie al in 2010 genetisch zeer sterk was verarmd. In 2013, toen slechts zeven individuen overgebleven waren, bleek de variatie nog verder teruggelopen, ook op genen die van belang zijn voor een goed functionerend immuunsystee

Rationale and design of the RESOLVE trial: lanreotide as a volume reducing treatment for polycystic livers in patients with autosomal dominant polycystic kidney disease

Contains fulltext : 109282.pdf (publisher's version ) (Open Access)BACKGROUND: A large proportion of patients with autosomal dominant polycystic kidney disease (ADPKD) suffers from polycystic liver disease. Symptoms arise when liver volume increases. The somatostatin analogue lanreotide has proven to reduce liver volume in patients with polycystic liver disease. However, this study also included patients with isolated polycystic liver disease (PCLD). The RESOLVE trial aims to assess the efficacy of lanreotide treatment in ADPKD patients with symptomatic polycystic livers. In this study we present the design of the RESOLVE trial. METHODS/DESIGN: This open-label clinical trial evaluates the effect of 6 months of lanreotide in ADPKD patients with symptomatic polycystic livers. Primary outcome is change in liver volume determined by computerised tomography-volumetry. Secondary outcomes are changes in total kidney volume, kidney intermediate volume and renal function. Furthermore, urinary (NGAL, alpha1-microglobulin, KIM-1, H-FABP, MCP-1) and serum (fibroblast growth factor 23) biomarkers associated with ADPKD disease severity are assessed to investigate whether these biomarkers predict treatment responses to lanreotide. Moreover, safety and tolerability of the drug in ADPKD patients will be assessed. DISCUSSION: We anticipate that lanreotide is an effective therapeutic option for ADPKD patients with symptomatic polycystic livers and that this trial aids in the identification of patient related factors that predict treatment response. TRIAL REGISTRATION NUMBER: Clinical trials.gov NCT01354405

Conceptual comparison of constructs as first step in data harmonization: Parental sensitivity, child temperament, and social support as illustrations

This article presents a strategy for the initial step of data harmonization in Individual Participant Data syntheses, i.e., making decisions as to which measures operationalize the constructs of interest - and which do not. This step is vital in the process of data harmonization, because a study can only be as good as its measures. If the construct validity of the measures is in question, study results are questionable as well. Our proposed strategy for data harmonization consists of three steps. First, a unitary construct is defined based on the existing literature, preferably on the theoretical framework surrounding the construct. Second, the various instruments used to measure the construct are evaluated as operationalizations of this construct, and retained or excluded based on this evaluation. Third, the scores of the included measures are recoded on the same metric. We illustrate the use of this method with three example constructs focal to the Collaboration on Attachment Transmission Synthesis (CATS) study: parental sensitivity, child temperament, and social support. This process description may aid researchers in their data pooling studies, filling a gap in the literature on the first step of data harmonization. • Data harmonization in studies using combined datasets is of vital importance for the validity of the study results. • We have developed and illustrated a strategy on how to define a unitary construct and evaluate whether instruments are operationalizations of this construct as the initial step in the harmonization process. • This strategy is a transferable and reproducible method to apply to the data harmonization process

Therapeutic implications of improved molecular diagnostics for rare CNS-embryonal tumor entities: results of an international, retrospective study

BACKGROUND: Only few data are available on treatment-associated behavior of distinct rare CNS-embryonal tumor entities previously treated as "CNS-primitive neuroectodermal tumors" (CNS-PNET). Respective data on specific entities, including CNS neuroblastoma, FOXR2 activated (CNS NB-FOXR2), and embryonal tumor with multi-layered rosettes (ETMR) are needed for development of differentiated treatment strategies. METHODS: Within this retrospective, international study, tumor samples of clinically well-annotated patients with the original diagnosis of CNS-PNET were analyzed using DNA methylation arrays (n=307). Additional cases (n=66) with DNA methylation pattern of CNS NB-FOXR2 were included irrespective of initial histological diagnosis. Pooled clinical data (n=292) were descriptively analyzed. RESULTS: DNA methylation profiling of "CNS-PNET" classified 58(19%) cases as ETMR, 57(19%) as HGG, 36(12%) as CNS NB-FOXR2, and 89(29%) cases were classified into 18 other entities. Sixty-seven (22%) cases did not show DNA methylation patterns similar to established CNS tumor reference classes. Best treatment results were achieved for CNS NB-FOXR2 patients (5-year PFS: 63%±7%, OS: 85%±5%, n=63), with 35/42 progression-free survivors after upfront craniospinal irradiation (CSI) and chemotherapy. The worst outcome was seen for ETMR and HGG patients with 5-year PFS of 18%±6% and 22%±7%, and 5-year OS of 24%±6% and 25%±7%, respectively. CONCLUSION: The historically reported poor outcome of CNS-PNET patients becomes highly variable when tumors are molecularly classified based on DNA methylation profiling. Patients with CNS NB-FOXR2 responded well to current treatments and a standard-risk-CSI based regimen may be prospectively evaluated. The poor outcome of ETMR across applied treatment strategies substantiates the necessity for evaluation of novel treatments

Initial Results of Secukinumab Drug Survival in Patients with Psoriasis:A Multicentre Daily Practice Cohort Study

Interleukin 17-antagonist secukinumab demonstrated high efficacy for treatment of psoriasis in randomized controlled trials (RCTs). However, performance in daily practice may differ from trials. Drug survival is a comprehensive outcome covering effectiveness and safety, suitable for analyses of daily practice. The aim of this study was to evaluate drug survival of secukinumab in a daily practice psoriasis cohort. Data were collected from 13 hospitals. Drug survival was analysed using Kaplan-Meier survival curves, split for reason of discontinuation. In total, 196 patients were included (83% biologic experienced). Overall, 12 and 18 months drug survival of secukinumab was 76% and 67%, respectively, and was mostly determined by ineffectiveness. There was a trend towards shorter drug survival in women and in biologic experienced patients. Thirteen percent of patients experienced at least 1 episode of fungal infection. This is one of the first studies of drug survival of secukinumab in patients with psoriasis treated in daily practic

Is autoimmunity the Achilles' heel of cancer immunotherapy?

The emergence of immuno-oncology as the first broadly successful strategy for metastatic cancer will require clinicians to integrate this new pillar of medicine with chemotherapy, radiation, and targeted small-molecule compounds. Of equal importance is gaining an understanding of the limitations and toxicities of immunotherapy. Immunotherapy was initially perceived to be a relatively less toxic approach to cancer treatment than other available therapies-and surely it is, when compared to those. However, as the use of immunotherapy becomes more common, especially as first- and second-line treatments, immunotoxicity and autoimmunity are emerging as the Achilles' heel of immunotherapy. In this Perspective, we discuss evidence that the occurrence of immunotoxicity bodes well for the patient, and describe mechanisms that might be related to the induction of autoimmunity. We then explore approaches to limit immunotoxicity, and discuss the future directions of research and reporting that are needed to diminish it

Herkomst en migratie van Nederlandse edelherten en wilde zwijnen : een basiskaart van de genetische patronen in Nederland en omgeving

De laatste jaren worden in toenemende mate incidentele waarnemingen van edelherten en wilde zwijnen buiten de toegewezen leefgebieden gedaan. De vraag is vervolgens of dit om natuurlijke immigratie vanuit (niet-omrasterde) leefgebieden in binnen- of buitenland gaat en waar ze dan vandaan zijn gekomen, of dat het een ontsnapt of losgelaten dier betreft. Om deze vraag in de toekomst in voorkomende gevallen effectief te kunnen beantwoorden, stelde Alterra in opdracht van BIJ12 – Faunafonds en Vereniging Het Edelhert een landelijke genetische referentiedatabase op van de zwijnen- en edelhertenpopulaties in Nederland en nabijgelegen populaties in België en Duitsland. In dit rapport worden de mogelijkheden van deze databases voor herkomstbepalingen nader onderzocht. Tevens geeft dit onderzoek, op basis van de verkregen databases, een overzicht van de genetische vitaliteit van de Nederlandse populaties van beide soorten met betrekking tot diversiteit, inteeltrisico’s en uitwisselingsmogelijkheden