Rijkswaterstaat:Guardian of the Dutch Delta

Founded in 1798, Rijkswaterstaat, the Dutch government’s agency for infrastructural works, brought flood security, navigable waterways and highways to the Netherlands. It is an iconic institution within Dutch society, best known for its ‘battle against the water’. The Zuiderzee Works (1920–1968) and the Delta Works (1954–1997) brought worldwide acclaim. This chapter tells the story of a humble semi-military organization that developed into a formidable institution of civil engineers with a strong technocratic mission mystique. It also recounts the institutional crisis the agency experienced in the 1970s–1990s when it was too slow to adapt to major sociocultural and political changes. To ride the waves of change, it eventually developed several proactive adaptation strategies and reinvented its mission mystique in managerial terms. Adaptation to climate change now presents another key challenge, for which Rijkswaterstaat will have to develop a new ‘social license to operate’

Sex differences in cardiovascular complications and mortality in hospital patients with covid-19: registry based observational study

Objective To assess whether the risk of cardiovascular complications of covid-19 differ between the sexes and to determine whether any sex differences in risk are reduced in individuals with pre-existing cardiovascular disease. Design Registry based observational study. Setting 74 hospitals across 13 countries (eight European) participating in CAPACITY-COVID (Cardiac complicAtions in Patients With SARS Corona vIrus 2 regisTrY), from March 2020 to May 2021 Participants All adults (aged ≥18 years), predominantly European, admitted to hospital with highly suspected covid-19 disease or covid-19 disease confirmed by positive laboratory test results (n=11 167 patients). Main outcome measures Any cardiovascular complication during admission to hospital. Secondary outcomes were in-hospital mortality and individual cardiovascular complications with ≥20 events for each sex. Logistic regression was used to examine sex differences in the risk of cardiovascular outcomes, overall and grouped by pre-existing cardiovascular disease. Results Of 11 167 adults (median age 68 years, 40% female participants) included, 3423 (36% of whom were female participants) had pre-existing cardiovascular disease. In both sexes, the most common cardiovascular complications were supraventricular tachycardias (4% of female participants, 6% of male participants), pulmonary embolism (3% and 5%), and heart failure (decompensated or de novo) (2% in both sexes). After adjusting for age, ethnic group, pre-existing cardiovascular disease, and risk factors for cardiovascular disease, female individuals were less likely than male individuals to have a cardiovascular complication (odds ratio 0.72, 95% confidence interval 0.64 to 0.80) or die (0.65, 0.59 to 0.72). Differences between the sexes were not modified by pre-existing cardiovascular disease; for the primary outcome, the female-to-male ratio of the odds ratio in those without, compared with those with, pre-existing cardiovascular disease was 0.84 (0.67 to 1.07). Conclusions In patients admitted to hospital for covid-19, female participants were less likely than male participants to have a cardiovascular complication. The differences between the sexes could not be attributed to the lower prevalence of pre-existing cardiovascular disease in female individuals. The reasons for this advantage in female individuals requires further research

The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age-and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to similar to 2.8M SNPs with BMI and WHRadjBMI in four strata (men &lt;= 50y, men &gt; 50y, women &lt;= 50y, women &gt; 50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR&lt; 5%) age-specific effects, of which 11 had larger effects in younger (&lt; 50y) than in older adults (&gt;= 50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may providefurther insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.</p

Bepalen van conversiefactoren om een indicatieve chronische NOAEL uit sub-acute toxiciteitsgegevens af te leiden

Voor de normstelling van chemische stoffen, bijvoorbeeld voor het vaststellen van een Aanvaarde Dagelijkse Inname (ADI) of Toelaatbare Dagelijkse Inname (TDI), zijn gegevens over de chronische toxiciteit noodzakelijk. Vaak zijn echter slechts acute en sub-acute toxiciteitsgegevens beschikbaar. Om met de beperkte toxiciteitsgegevens toch een chronische No-observed-adverse-effect-level (NOAELchronisch ) te schatten, is een pragmatische methode ontwikkeld. Conversiefactoren werden bepaald door de distributie van de ratio's tussen (sub)-acute en chronische toxiciteitsgegevens van een groot aantal stoffen te evalueren. De 95% betrouwbaarheidsbovengrens van het 95ste percentiel van de ratio-verdeling definieren we als de conversiefactor om een NOAELchronisch te schatten (indicatieve NOAELchronisch). Op deze manier is rekening gehouden met de variatie in distributie (95ste percentiel) en met de schattingsfout (95% betrouwbaarheidsbovengrens). De NOAELsub-acuut van oraal gedoseerde stoffen correleerde beter met de NOAELchronisch dan de LD50. Voor de afleiding van de indicatieve NOAELchronisch verdient daarom de NOAELsub-acuut de voorkeur. Op basis van 57 NOAELsub-acuut/NOAELchronisch ratio's werd de conversiefactor voor de NOAELsub-acuut bepaald op 92. Voor de LD50 (n = 244) werd een conversiefactor van 1.7x10.000 afgeleid. Multiple regressie-analyse liet zien dat het combineren van een LD50 met een NOAELsub-acuut de schatting van de NOAELchronisch nauwelijks verbetert, ten opzichte van de schatting op basis van de NOAELsub-acuut als enige variabele. Gezien de slechte correlatie van de LD50 met de NOAELchronisch en de zeer beperkte meerwaarde van de LD50 bij een bekende NOAELsub-acuut, zou het vereist stellen van acute studies nader beschouwd moeten worden. Analyse van de inhalatoire data resulteerde in een conversiefactor van 8.8x10.000 en 6.8x10.000 voor respectievelijk een LC50 en een NOAELsub-acuut. Deze hoge factoren zijn gedeeltelijk te wijten aan het beperkte aantal stoffen waarvoor ratio's konden worden berekend. Evaluatie van de ratio NOAELsemi-chronisch/NOAELchronisch gaf een conversiefactor van 46 aan voor de oraal toegediende stoffen. Dit betekent dat de defaultwaarde van 10 eerder verhoogd zou moeten worden dan verlaagd, zoals soms gesuggereerd wordt. De conversiefactor voor de extrapolatie van LOAEL naar NOAEL werd op 12 geschat en ligt wel nabij de huidige defaultwaarde van 10.For the setting of Health-Based-Acceptable-Exposure-Levels (HBAELs), such as Acceptable Daily Intake (ADI) or Tolerable Daily Intake (TDI), chronic toxicity data of chemical substances are required. However, the available data sets often contain acute and sub-acute toxicity data only. To estimate a chronic No-observed-adverse-effect-level (NOAELchronic) from these limited data, a pragmatic method was developed. Conversion factors were assessed by evaluating the distributions of ratios between (sub-)acute and chronic toxicity data for a large number of compounds. We defined the upper limit of the 95% confidence interval of the 95th percentile of the relevant ratio distribution as a conversion factor to estimate a NOAELchronic (i.e. indicative NOAELchronic). In this way both the variation in the distribution (95th percentile) and the estimation error (upper limit of the 95% confidence interval) were taken into account. For orally dosed compounds, the NOAELsub-acute correlated better to the NOAEL chronic than the LD50. Therefore, we recommend to derive an indicative NOAELchronic from a NOAELsub-acute. Based on 57 ratios of NOAELsub-acute to NOAEL chronic, we assessed for the NOAELsub-acute a conversion factor of 92. For the LD50 (n = 244), the conversion factor was 1.7x10.000. Multiple regression analysis showed that the combination of an LD50 and NOAELsub-acute hardly improved the estimation of NOAEL chronic, compared to a model having only a NOAELsub-acute available. In view of the poor correlation of the LD50 with the NOAELchronic and the low surplus value of the LD50 when a NOAELsub-acute is available, the requisite of acute studies should be reconsidered. Analysis of the inhalatory data resulted in conversion factors of 8.8x10.000 and 6.8x10.000 for an LC50 and a NOAELsub-acute, respectively. These large factors are partly due to the small number of substances for which ratios could be calculated. The evaluation of the ratio of the NOAELsemichronic to NOAELchronic for orally dosed compounds, resulted in a conversion factor of 46. This indicates, that the default uncertainty factor of 10 for this extrapolation should be increased rather than decreased, as has been proposed by others. For the extrapolation of LOAEL to NOAEL the conversion factor was estimated 12, which is close to the current default value of 10.DGM/SV

Association of transcriptomic signatures of inflammatory response with viral control after dendritic cell-based therapeutic vaccination in hiv-1 infected individuals

Systems vaccinology has seldomly been used in therapeutic HIV-1 vaccine research. Our aim was to identify early gene ‘signatures’ that predicted virus load control after analytical therapy interruption (ATI) in participants of a dendritic cell-based HIV-1 vaccine trial (DCV2). mRNA and miRNA were extracted from frozen post-vaccination PBMC samples; gene expression was determined by microarray method. In gene set enrichment analysis, responders showed an up-regulation of 14 gene sets (TNF-alpha/NFkB pathway, inflammatory response, the complement system, Il6 and Il2 JAK-STAT signaling, among others) and a down-regulation of 7 gene sets (such as E2F targets or interferon alpha response). The expression of genes regulated by three (miR-223-3p, miR-1183 and miR-8063) of the 9 differentially expressed miRNAs was significantly down-regulated in responders. The deregulation of certain gene sets related to inflammatory processes seems fundamental for viral control, and certain miRNAs may be important in fine-tuning these processes.</p