Assessing quality and reducing batch variety in Golden Honeydew Melons : GreenCHAINge Fruit & Vegetables WP2

The general objective in GreenCHAINge Fruit & Vegetables Work package 2 (GreenCHAINge) is to obtain high quality and uniform melons and papaya’s on the shelf. This report focuses on the melons, being one of the exotic products for the breeding company East West Seed and the wholesaler Frankort & Koning. To obtain high quality and uniform melons on the shelf in supermarkets, it is essential to: - Store melons at optimal conditions; - Harvest melons at an optimal maturity stage

From Good to Better: New Dutch Guidelines for Economic Evaluations in Healthcare

Many countries have national guidelines for performing economic evaluations in healthcare.1 These guidelines should ensure the comparability and quality of such evaluations, which should facilitate making well informed policy decisions regarding reimbursement of interventions. Given the developments in both the methodology and policy context of economic evaluation of healthcare interventions, these guidelines require periodical revision. Recently, the Dutch National Health Care Institute issued new guidance for economic evaluations in healthcare [1]. The new guidelines update and replace three separately published previous guidelines: those for pharmacoeconomic evaluation (latest version 2006), outcomes research (latest version 2008) as well as the Dutch costing manual (latest version 2010). In this editorial, we highlight the distinguishing features of the new Dutch guidelines. Moreover, we highlight which developments, in our opinion, are desirable in coming updates, but are still in development or controversial

Distributional consequences of including survivor costs in economic evaluations

Medical interventions that increase life expectancy of patients result in additional consumption of non‐medical goods and services in ‘added life years’. This paper focuses on the distributional consequences across socio‐economic groups of including these costs in cost effectiveness analysis. In that context, it also highlights the role of remaining quality of life and household economies of scale. Data from a Dutch household spending survey was used to estimate non‐medical consumption and household size by age and educational attainment. Estimates of non‐medical consumption and household size were combined with life tables to estimate what the impact of including non‐medical survivor costs would be on the incremental cost effectiveness ratio (ICER) of preventing a death at a certain age. Results show that including non‐medical survivor costs increases estimated ICERs most strongly when interventions are targeted at the higher educated. Adjusting for household size (lower educated people less often live additional life years in multi‐person households) and quality of life (lower educated people on average spend added life years in poorer health) mitigates this difference. Ignoring costs of non‐medical consumption in economic evaluations implicitly favors interventions targeted at the higher educated and thus potentially amplifies socio‐economic inequalities in health

Understanding central nervous system efficacy of antimicrobials

The requirements for antimicrobial treatment to reach the central nervous system (CNS) are of maximal importance, for two major reasons: (i) the brain is an immuno-privileged site, with virtually no leukocytes in the brain parenchyma or cerebrospinal fluid (CSF) at baseline; (ii) the blood–brain barrier (BBB) drastically reduces the diffusion of antimicrobials into the CNS [1]. Treatment of CNS infections has been a major area of research since the discovery of the first antimicrobials. Treatment regimens recommended for encephalitis [2, 3], meningitis [4], and brain abscess [5], have to comply with the pharmacokinetic (PK), and pharmacodynamic (PD) characteristics of available antibacterial, antiviral, antifungal, and antiparasitic agents [6]. Due to the numerous constraints created by the BBB, therapeutic options are quite limited, so that current practices for treatment of CNS infections are remarkably similar worldwide, with much less heterogeneity than for other major infectious diseases (e.g. pneumonia, abdominal, or skin and skin structure infections). This paper summarizes the main parameters that must be taken into account to ensure efficacy of antimicrobial agents in the CNS, with an emphasis on antibacterial drugs

Genetic Variation in the β2-Adrenocepter Gene Is Associated with Susceptibility to Bacterial Meningitis in Adults

Recently, the biased β2-adrenoceptor/β-arrestin pathway was shown to play a pivotal role in crossing of the blood brain barrier by Neisseria meningitidis. We hypothesized that genetic variation in the β2-adrenoceptor gene (ADRB2) may influence susceptibility to bacterial meningitis. In a prospective genetic association study we genotyped 542 patients with CSF culture proven community acquired bacterial meningitis and 376 matched controls for 2 functional single nucleotide polymorphisms in the β2-adrenoceptor gene (ADRB2). Furthermore, we analyzed if the use of non-selective beta-blockers, which bind to the β2-adrenoceptor, influenced the risk of bacterial meningitis. We identified a functional polymorphism in ADRB2 (rs1042714) to be associated with an increased risk for bacterial meningitis (Odds ratio [OR] 1.35, 95% confidence interval [CI] 1.04–1.76; p = 0.026). The association remained significant after correction for age and was more prominent in patients with pneumococcal meningitis (OR 1.52, 95% CI 1.12–2.07; p = 0.007). For meningococcal meningitis the difference in genotype frequencies between patients and controls was similar to that in pneumococcal meningitis, but this was not statistically significant (OR 1.43, 95% CI 0.60–3.38; p = 0.72). Patients with bacterial meningitis had a lower frequency of non-selective beta-blockers use compared to the age matched population (0.9% vs. 1.8%), although this did not reach statistical significance (OR 1.96 [95% CI 0.88–4.39]; p = 0.09). In conclusion, we identified an association between a genetic variant in the β2-adrenoceptor and increased susceptibility to bacterial meningitis. The potential benefit of pharmacological treatment targeting the β2-adrenoceptor to prevent bacterial meningitis in the general population or patients with bacteraemia should be further studied in both experimental studies and observational cohorts

Effectiveness of Seizure Dogs for People With Severe Refractory Epilepsy:Results From the EPISODE Study

BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate whether people living with severe medically refractory epilepsy (PSRE) benefit from a seizure dog. METHODS: An individual-level stepped-wedge randomized controlled trial was conducted. The study was conducted in the Netherlands among adults with daily to weekly seizures. All participants were included simultaneously (on June 1, 2019) while receiving usual care. Then, during the 36-month follow-up, they received a seizure dog in a randomized sequence. Participants kept a seizure diary and completed 3-monthly surveys. Seizure frequency was the primary outcome. Secondary outcomes included seizure-free days, seizure severity, health-related quality of life (HRQoL), and well-being. Data were analyzed using generalized linear mixed modeling (GLMM). The models assumed a delayed intervention effect, starting when the seizure dog reached an advanced stage of training. Effects were calculated as changes per 28-day period with the intervention. RESULTS: Data were collected from 25 participants, of whom 20 crossed over to the intervention condition. The median follow-up was 19 months with usual care and 12 months with the intervention. On average, participants experienced 115 (SD 164) seizures per 28-day period in the usual care condition and 73 (SD 131) seizures in the intervention condition. Seven participants achieved a reduction of 50% or more at the end of follow-up. GLMM indicated a 3.1% decrease in seizure frequency for each consecutive 28-day period with the intervention (0.969, 95% CI 0.960-0.977). Furthermore, an increase in the number of seizure-free days was observed (1.012, 95% CI 1.009, 1.015), but no effect on seizure severity measured with the NHS3. Generic HRQoL scores improved, as reflected in the decrease in EQ-5D-5L utility decrement (0.975, 95% CI 0.954-0.997). Smaller improvements were observed on overall self-rated HRQoL, epilepsy-specific HRQoL, and well-being, measured with the EQ VAS, QOLIE-31-P, and ICECAP-A, respectively. DISCUSSION: Seizure dogs reduce seizure frequency, increase the number of seizure-free days, and improve the quality of life of PSRE. The magnitude of the effect on generic HRQoL indicates that seizure dogs benefit PSRE beyond the impact on seizure frequency alone. Early discontinuation of seizure dog partnerships suggests that this intervention is not suitable for all PSRE and requires further study. TRIAL REGISTRATION INFORMATION: This study was registered in the Dutch Trial Register (NL6682) on November 28, 2017. Participants were enrolled on June 1, 2019. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that seizure dogs are associated with a decrease in seizure frequency in adult patients with medically refractory epilepsy.</p

Second-Generation Everolimus-Eluting Stents Versus First-Generation Sirolimus-Eluting Stents in Acute Myocardial Infarction 1-Year Results of the Randomized XAMI (XienceV Stent vs. Cypher Stent in Primary PCI for Acute Myocardial Infarction) Trial

ObjectivesThe goal of this study was to compare the efficacy and safety of second-generation everolimus-eluting stents (EES) with first-generation sirolimus-eluting stents (SES) in primary percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI).BackgroundDrug-eluting stents (DES) in AMI are still feared for possible late and very late stent thrombosis (ST). Newer-generation DES, with more hemocompatible polymers and improved healing, may show promise regarding increased efficacy of DES with improved safety. However, no randomized trials in AMI are available.MethodsA total of 625 patients with AMI were randomized (2:1) to receive EES or SES in the XAMI (XienceV Stent vs Cypher Stent in Primary PCI for Acute Myocardial Infarction) trial. Primary endpoint was major adverse cardiac events (MACE) at 1 year consisting of cardiac death, nonfatal AMI, or any target vessel revascularization. The study was powered for noninferiority of EES. Secondary endpoints comprised ST rates and MACE rate up to 3 years.ResultsThe MACE rate was 4.0% for EES and 7.7% for SES; the absolute difference was −3.7% (95% confidence interval: −8.28 to −0.03; p = 0.048) and relative risk was 0.52 (95% confidence interval: 0.27 to 1.00). One-year cardiac mortality was low at 1.5% for EES versus 2.7% for SES (p = 0.36), and 1-year incidence of definite and/or probable ST was 1.2% for EES versus 2.7% for SES (p = 0.21).ConclusionsIn this all-comer, randomized, multicenter AMI trial, second-generation EES was noninferior to SES, and superiority for MACE was suggested. ST rate in EES at 1-year was low, but long-term follow-up and larger studies will have to show whether very late ST rates will also be improved in newer DES. (XienceV Stent vs Cypher Stent in Primary PCI for Acute Myocardial Infarction [XAMI]; NTR1123

V-akt murine thymoma viral oncogene homolog 3 (AKT3) contributes to poor disease outcome in humans and mice with pneumococcal meningitis

Pneumococcal meningitis is the most common and severe form of bacterial meningitis. Fatality rates are substantial, and long-term sequelae develop in about half of survivors. Here, we have performed a prospective nationwide genetic association study using the Human Exome BeadChip and identified gene variants in encoding dynactin 4 (DCTN4), retinoic acid early transcript 1E (RAET1E), and V-akt murine thymoma viral oncogene homolog 3 (AKT3) to be associated with unfavourable outcome in patients with pneumococcal meningitis. No clinical replication cohort is available, so we validated the role of one of these targets, AKT3, in a pneumococcal meningitis mouse model. Akt3 deficient mice had worse survival and increased histopathology scores for parenchymal damage (infiltration) and vascular infiltration (large meningeal artery inflammation) but similar bacterial loads, cytokine responses, compared to wild-type mice. We found no differences in cerebrospinal fluid cytokine levels between patients with risk or non-risk alleles. Patients with the risk genotype (rs10157763, AA) presented with low scores on the Glasgow Coma Scale and high rate of epileptic seizures. Thus, our results show that AKT3 influences outcome of pneumococcal meningiti

Infection of zebrafish embryos with live fluorescent Streptococcus pneumoniae as a real-time pneumococcal meningitis model

Background: Streptococcus pneumoniae is one of the most important causes of bacterial meningitis, an infection where unfavourable outcome is driven by bacterial and host-derived toxins. In this study, we developed and characterized a pneumococcal meningitis model in zebrafish embryos that allows for real-time investigation of early host-microbe interaction. Methods: Zebrafish embryos were infected in the caudal vein or hindbrain ventricle with green fluorescent wild-type S. pneumoniae D39 or a pneumolysin-deficient mutant. The kdrl:mCherry transgenic zebrafish line was used to visualize the blood vessels, whereas phagocytic cells were visualized by staining with far red anti-L-plastin or in mpx:GFP/mpeg1:mCherry zebrafish, that have green fluorescent neutrophils and red fluorescent macrophages. Imaging was performed by fluorescence confocal and time-lapse microscopy. Results: After infection by caudal vein, we saw focal clogging of the pneumococci in the blood vessels and migration of bacteria through the blood-brain barrier into the subarachnoid space and brain tissue. Infection with pneumolysin-deficient S. pneumoniae in the hindbrain ventricle showed attenuated growth and migration through the brain as compared to the wild-type strain. Time-lapse and confocal imaging revealed that the initial innate immune response to S. pneumoniae in the subarachnoid space mainly consisted of neutrophils and that pneumolysin-mediated cytolytic activity caused a marked reduction of phagocytes. Conclusions: This new meningitis model permits detailed analysis and visualization of host-microbe interaction in pneumococcal meningitis in real time and is a very promising tool to further our insights in the pathogenesis of pneumococcal meningitis