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Novel therapies for multiple myeloma (MM) have improved patient survival, but their high costs strain healthcare budgets. End-of-life phases of treatment are generally the most expensive, however, these high costs may be less justifiable in the context of a less pronounced clinical benefit. To manage drug expenses effectively, detailed information on end-of-life drug administration and costs are crucial. In this retrospective study, we analysed treatment sequences and drug costs from 96 MM patients in the Netherlands who died between January 2017 and July 2019. Patients received up to 16 lines of therapy (median overall survival: 56.5 months), with average lifetime costs of €209 871 (€3111/month; range: €3942–€776 185) for anti-MM drugs. About 85% of patients received anti-MM treatment in the last 3 months before death, incurring costs of €20 761 (range: €70–€50 122; 10% of total). Half of the patients received anti-MM treatment in the last 14 days, mainly fully oral regimens (66%). End-of-life treatment costs are substantial despite limited survival benefits. The use of expensive treatment options is expected to increase costs further. These data serve as a reference point for future cost studies, and further research is needed to identify factors predicting the efficacy and clinical benefit of continuing end-of-life therapy.

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Background: The outcome of non-transplant eligible newly diagnosed multiple myeloma (NDMM) patients is heterogeneous, partly depending on frailty level. The aim of this study was to prospectively investigate the efficacy and safety of Ixazomib-Daratumumab-low-dose dexamethasone (Ixa-Dara-dex) in NDMM intermediate-fit patients. Methods: In this phase II multicenter HOVON-143 study, IMWG Frailty index based intermediate-fit patients, were treated with 9 induction cycles of Ixa-Dara-dex, followed by maintenance with ID for a maximum of 2 years. The primary endpoint was overall response rate on induction treatment. Patients were included from October 2017 until May 2019. Trial Registration Number: NTR6297. Findings: Sixty-five patients were included. Induction therapy resulted in an overall response rate of 71%. Early mortality was 1.5%. At a median follow-up of 41.0 months, median progression-free survival (PFS) was 18.2 months and 3-year overall survival 83%. Discontinuation of therapy occurred in 77% of patients, 49% due to progression, 9% due to toxicity, 8% due to incompliance, 3% due to sudden death and 8% due to other reasons. Dose modifications of ixazomib were required frequently (37% and 53% of patients during induction and maintenance, respectively), mainly due to, often low grade, polyneuropathy. During maintenance 23% of patients received daratumumab alone. Global quality of life (QoL) improved significantly and was clinically relevant, which persisted during maintenance treatment. Interpretation: Ixazomib-Daratumumab-low-dose dexamethasone as first line treatment in intermediate-fit NDMM patients is safe and improves global QoL. However, efficacy was limited, partly explained by ixazomib-induced toxicity, hampering long term tolerability of this 3-drug regimen. This highlights the need for more efficacious and tolerable regimens improving the outcome in vulnerable intermediate-fit patients. Funding: Janssen Pharmaceuticals, Takeda Pharmaceutical Company

Ter gelegenheid van haar 225e verjaardag geeft Rijkswaterstaat Nederland een cadeau: een onderzoeksprogramma als kennisimpuls voor de praktijk van klimaatadaptatie. Deze uitgave toont het programma ‘Kennisimpuls Klimaatadaptatie Rijkswaterstaat’ waarmee Rijkswaterstaat de samenwerking met universiteiten, hbo en mbo intensiveert en onderling integreert, ten dienste van klimaatadaptatie.

The production of type I interferon (IFN) is the hallmark of the innate immune response. Most, if not all, mammalian viruses have a way to circumvent this response. Fundamental knowledge on viral evasion of innate immune responses may facilitate the design of novel antiviral therapies. To investigate how human metapneumovirus (HMPV) interacts with the innate immune response, recombinant viruses lacking G, short hydrophobic (SH), or M2-2 protein expression were assessed for IFN induction in A549 cells. HMPV lacking G or SH protein expression induced similarly low levels of IFN, compared to the wild-type virus, whereas HMPV lacking M2-2 expression induced significantly more IFN than the wild-type virus. However, sequence analysis of the genomes of M2-2 mutant viruses revealed large numbers of mutations throughout the genome. Over 70% of these nucleotide substitutions were A-to-G and T-to-C mutations, consistent with the properties of the adenosine deaminase acting on RNA (ADAR) protein family. Knockdown of ADAR1 by CRISPR interference confirmed the role of ADAR1 in the editing of M2-2 deletion mutant virus genomes. More importantly, Northern blot analyses revealed the presence of defective interfering RNAs (DIs) in M2-2 mutant viruses and not in the wild-type virus or G and SH deletion mutant viruses. DIs are known to be potent inducers of the IFN response. The presence of DIs in M2-2 mutant virus stocks and hypermutated virus genomes interfere with studies on HMPV and the innate immune response and should be addressed in future studies. IMPORTANCE Understanding the interaction between viruses and the innate immune response is one of the barriers to the design of antiviral therapies. Here, we investigated the role of the G, SH, and M2-2 proteins of HMPV as type I IFN antagonists. In contrast to other studies, no IFN-antagonistic functions could be observed for the G and SH proteins. HMPV with a deletion of the M2-2 protein did induce type I IFN production upon infe

BACKGROUND: Antipsychotic medication is effective for symptomatic treatment in schizophrenia-spectrum disorders. After symptom remission, continuation of antipsychotic treatment is associated with lower relapse rates and lower symptom severity compared to dose reduction/discontinuation. Therefore, most guidelines recommend continuation of treatment with antipsychotic medication for at least 1 year. Recently, however, these guidelines have been questioned as one study has shown that more patients achieved long-term functional remission in an early discontinuation condition-a finding that was not replicated in another recently published long-term study. METHODS/DESIGN: The HAMLETT (Handling Antipsychotic Medication Long-term Evaluation of Targeted Treatment) study is a multicenter pragmatic single-blind randomized controlled trial in two parallel conditions (1:1) investigating the effects of continuation versus dose-reduction/discontinuation of antipsychotic medication after remission of a first episode of psychosis (FEP) on personal and social functioning, psychotic symptom severity, and health-related quality of life. In total 512 participants will be included, aged between 16 and 60 years, in symptomatic remission from a FEP for 3-6 months, and for whom psychosis was not associated with severe or life-threatening self-harm or violence. Recruitment will take place at 24 Dutch sites. Patients are randomized (1:1) to: continuation of antipsychotic medication until at least 1 year after remission (original dose allowing a maximum reduction of 25%, or another antipsychotic drug in similar dose range); or gradual dose reduction till eventual discontinuation of antipsychotics according to a tapering schedule. If signs of relapse occur in this arm, medication dose can be increased again. Measurements are conducted at baseline, at 3, and 6 months post-baseline, and yearly during a follow-up period of 4 years. DISCUSSION: The HAMLETT study will offer evidence to guide patien

Effective sexually transmitted infection (STI) control requires opportunities for appropriate testing, counselling and treatment. In the Netherlands, people may attend general practitioners (GPs) and sexual health centres (SHCs; also known as STI clinics) for STI consultations. We assessed the contribution of GPs and SHCs to STI consultations in five Dutch regions with different urbanization levels, using data of urogenital Chlamydia trachomatis (CT) testing. Data (2011-2016) were retrieved from laboratories, aggregated by gender and age group (15-24 and 25-64 years). Results show that test rates and GP contribution varied widely between regions. GP contribution decreased over time in Amsterdam (60-48%), Twente (79-61%), Maastricht (60-50%) and Northeast-Netherlands (82-77%), but not in Rotterdam (65-67%). Decreases resulted from increases in SHC test rates and slight decreases in GP test rates. GPs performed more tests for women and those aged 25-64 years compared to SHCs (relative risks ranging from 1.49 to 4.76 and 1.58 to 7.43, respectively). The average yearly urogenital CT positivity rate was 9.2% at GPs and 10.7% at SHCs. Overall, GPs accounted for most STI consultations, yet SHC contribution increased. Continued focus on good quality STI care at GPs is essential, as increasing demands for care can not be entirely covered by SHCs.

The pathology of progressive multiple sclerosis (MS) is poorly understood. We have previously assessed DNA methylation in the CD4+ T cells of relapsing-remitting (RR) MS patients compared to healthy controls and identified differentially methylated regions (DMRs) in HLA-DRB1 and RNF39. This study aimed to investigate the DNA methylation profiles of the CD4+ T cells of progressive MS patients. DNA methylation was measured in two separate case/control cohorts using the Illumina 450K/EPIC arrays and data was analysed with the Chip Analysis Methylation Pipeline (ChAMP). Single nucleotide polymorphisms (SNPs) were assessed using the Illumina Human OmniExpress24 arrays and analysed using PLINK. Expression was assessed using the Illumina HT12 array and analysed in R using a combination of Limma and Illuminaio. We identified three DMRs at HTR2A, SLC17A9 and HDAC4 that were consistent across both cohorts. The DMR at HTR2A is located within the bounds of a haplotype block; however, the DMR remained significant after accounting for SNPs in the region. No expression changes were detected in any DMRs. HTR2A is differentially methylated in progressive MS independent of genotype. This differential methylation is not evident in RRMS, making it a potential biomarker of progressive disease.

Het afkoppelen van regenwater is een onderwerp dat momenteel veel gemeenten in Nederland bezig houdt. Eén van de opties is om regenwater te laten infiltreren in het openbaar groen middels wadi’s: een verdieping in het landschap, meestal ingezaaid met gras. Die invulling van een wadi voegt echter niet veel toe aan de biodiversiteit of de belevingswaarde van het openbaar groen. Maar hoe moet het dan wel? Drie deeltijdstudenten Tuin- en Landschapsinrichting deden er afstudeeronderzoek naar.

De ondergrondse wateropslag heeft voordelen voor de waterkwaliteit van het oppervlaktewater en het ondergronds opgeslagen water. Door het opvangen en opslaan van drainagewater worden de nutriënt fluxen naar het oppervlaktewater vermindert. Deze nutriënten verdwijnen ondergronds, waar de nutriënten afgebroken of vastgelegd worden. Literatuuronderzoek toont kansen voor de afbraak van ziektekiemen, verantwoordelijk voor bijvoorbeeld bruinrot en stengelnatrot, tijdens ondergrondse opslag.

Dit rapport ‘Eigen watervoorziening - Gewasbeschermingsmiddelen’ is onderdeel van de serie rapporten van het project Spaarwater I. Binnen dit project is in 2015 een verkennend onderzoek gedaan naar het voorkomen van gewasbestrijdingsmiddelen op de pilot locatie in Breezand. Op deze pilot locatie wordt drainwater afgevangen en ondergronds in een aquifer opgeslagen. In de zomerperiode wordt dit hergebruikt als irrigatiewater. Het drainwater en het water uit de ondergrondse opslag is gedurende 2015 verschillende malen bemonsterd en geanalyseerd op een 29 gewasbeschermingsmiddelen. De concentraties bleken relatief laag te zijn. Het bleek dat 7 stoffen de normen voor oppervlaktewater en of grondwater overschreden. Twee stoffen doen dat in ruime mate, namelijk: pirimifos-methyl en carbendazim. De concentraties van geanalyseerde stoffen, toegepast in 2015, vertonen een piek na april, maar in november zijn deze al sterk verlaagd of niet meer meetbaar. Vanwege dit patroon wordt aanbevolen om alleen na november drainwater in te nemen voor de opslag. De stoffen, die in 2014 of eerder zijn toegepast, vertonen daarentegen geen seizoenmatig verloop maar een min of meer stabiele lage achtergrondconcentratie. Er is geen duidelijk relatie tussen de concentraties van de stoffen en bekende sorptiecoëfficiënten en afbraaksnelheden. Deze parameters zijn echter bepaald voor anaerobe milieus, maar kunnen in het anaerobe grondwatermilieu van het perceel en aquifer andere waarden hebben. Afbraakprocessen kunnen daar mogelijk sneller of langzamer verlopen. De aanbeveling wordt gedaan om te onderzoeken of de dosering van bepaalde risicovolle stoffen kan worden verlaagd of dat bepaalde stoffen kunnen worden vervangen. Ook wordt nader onderzoek aanbevolen naar chemische filtratie van het afgevangen drainwater. Een groot deel van de gewasbeschermingsmiddelen kan tijdens percolatie door goed doorlatende filters van organisch materiaal (stro, pitten, harde schillen) worden geadsorbeerd. Toepassing

Als gevolg van de zandsuppletie en het ontstaan van de nieuwe duinen voor de Hondsbossche en Pettemer Zeewering is het mogelijk dat de zoute kwel onder de dijk afneemt en het bovenste grondwater en het water in de sloten verzoeten. Deze verzoeting heeft gevolgen voor de flora en de fauna van dit zout tot brakwatergebied. Het doel van de referentiemeting is het huidige watersysteem in beeld te brengen en een voorstel te doen voorde monitoring voorafgaand (nulmeting) en na aanleg.Om de verwachte verzoeting in de Lei- en Hargerpolder als gevolg van de kustversterking zo veel mogelijk te voorkomen en de huidige zoute condities te behouden is onderzoek uitgevoerd naar mogelijke mitigerende maatregelen. Dit heeft geleid tot de keuze voor een maatregel die financierbaar is en ook recht doet aan de randvoorwaarden van water- en natuurbeheerders.