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The implementation and integration of wastewater-based epidemiology constitutes a valuable addition to existing pathogen surveillance systems, such as clinical surveillance for SARS-CoV-2. In the Netherlands, SARS-CoV-2 variant circulation is monitored by performing whole-genome sequencing on wastewater samples. In this manuscript, we describe the detection of an AY.43 lineage (Delta variant) amid a period of BA.5 (Omicron variant) dominance in wastewater samples from two wastewater treatment plants (WWTPs) during the months of August and September of 2022. Our results describe a temporary emergence, which was absent in samples from other WWTPs, and which coincided with peaks in viral load. We show how these lineage estimates can be traced back to lineage-specific substitution patterns. The absence of this variant from reported clinical data, but high associated viral loads suggest cryptic transmission. Our findings highlight the additional value of wastewater surveillance for generating insights into circulating pathogens.

Background During the COVID-19 pandemic, the spread and diversity of SARS-CoV-2 was monitored non-invasively in more than 99% of Dutch households by a comprehensive wastewater-based epidemiology (WBE) programme which analysed viral RNA in wastewater samples taken at every household wastewater-treatment plant (WWTP) in the Netherlands. In this study, we analyse next-generation sequencing data generated from these wastewater samples for tracking SARS-CoV-2 lineages. We aimed to determine how well patterns of lineage abundances correspond to findings from individual surveillance, including community testing and testing at hospitals, and how WBE can be employed efficiently for future surveillance of SARS-CoV-2. Methods Whole-genome short-read sequencing was performed on 16,631 wastewater samples collected between Apr 9, 2021, and Dec 31, 2023, at 311 WWTPs. Observed lineages were grouped and week-aggregate estimates were compared to estimates from 138,374 individual surveillance sequences generated during the same period. Furthermore, we used resampling to examine the effect of sample size and catchment type on observed lineage dynamics. Results WBE enabled monitoring of SARS-CoV-2 lineages even during periods of reduced circulation in the Dutch population. Wastewater lineage proportions consistently mirrored those of individual surveillance. During periods of low turnover of dominant lineages, nationally representative lineage estimates can be obtained by sequencing only 24 samples per week, whereby population density or total population size of catchment areas would have a negligible effect on country-wide aggregate lineage estimates. Conclusions WBE at household WWTPs is a valuable tool for SARS-CoV-2 surveillance, whereby comparatively little sequence data can be generated to identify lineage dynamics trends in large populations, and which can be scaled up and down in response to emerging lineages of concern. As such, it provides a useful complement to existing surveillance tools, to ensure optimal insight into pathogen diversity and spread.

Background and purpose Virchow-Robin spaces (VRs) are perivascular spaces surrounding the deep perforating brain arteries. VRs dilatation is pathologic, and it could be a manifestation of cerebral small vessel disease. In the present study we assessed the relation between VRs and silent ischemic lesions in a cohort of patients with cerebral small vessel disease. Methods We divided dilated VRs on MRI (1.5 Tesla) into three semi-quantitative categories in 165 first ever lacunar stroke patients. We counted asymptomatic lacunar infarcts and graded white matter lesions, and compared the prevalence of vascular risk factors in different categories of VRs. We also determined independent predictors of silent ischemic lesions. Results VRs at basal ganglia level related to age, hypertension, asymptomatic lacunar infarcts, and white matter lesions. VRs at basal ganglia level predicted silent ischemic lesions (odds ratio 10.58 per higher VRs category; 95 %- confidence interval 3.40 – 32.92). Conclusion Dilated VRs in the basal ganglia relate to the severity of cerebral small vessel disease and might be a manifestation of the same small vessel abnormality that causes silent ischemic lesions. This adds a role for VRs as a potential marker for small vessel disease.

Hepatitis E virus genotype 3 (HEV-3) is a food-borne pathogen causative of hepatitis E infections in humans. In Europe, HEV-3 is mainly transmitted through the consumption of raw or undercooked pork. In order to determine the effectiveness of control measures that can be taken in the industry or by the consumer, it is pivotal to determine the infectivity of HEV present in pork products after thermal food-processing steps. First, we implemented a method for the detection of infectious HEV-3c and HEV-3e in a cell culture medium and in extracts from inoculated pork products. Next, we investigated the effect of the thermal inactivation of HEV by mimicking food-processing steps specific for dried sausage and liver homogenate matrices. After four weeks, HEV-inoculated dried sausage subjected to 21 °C or lower temperatures was still infectious. For the liver homogenate, the highest HEV-3c/e inactivation of the conditions tested was observed at 71 °C for five min or longer. Finally, our method was able to successfully detect and estimate viral loads of infectious HEV in naturally infected pig livers. Our data provide a basis for the future use of the quantitative microbial risk assessment of infectious HEV in pork products that are subjected to thermal food processing steps.

Functional integration between semiconductors and ferromagnets was demonstrated with the spin-valve transistor. A ferromagnetic multilayer was sandwiched between two device-quality silicon substrates by means of vacuum bonding. The emitter Schottky barrier injected hot electrons into the spin-valve base. The collector Schottky barrier accepts only ballistic electrons, which makes the collector current very sensitive to magnetic fields. Room temperature operation was accomplished by preparing Si-Pt-Co-Cu-Co-Si devices. The vacuum bonding technique allows the realization of many ideas for vertical transport devices and forms a permanent link that is useful in demanding adhesion applications.

Climate change, and especially the associated acceleration of sea-level rise, forms a serious threat to the Wadden Sea. The Wadden Sea contains the world’s largest coherent intertidal flat area and it is known that these flats can drown when the rate of sea-level rise exceeds a critical limit. As a result, the intertidal flats would then be permanently inundated, seriously affecting the ecological functioning of the system. The determination of this critical limit and the modelling of the transient process of how a tidal basin responds to accelerated sea-level rise is of critical importance. In this contribution we revisit the modelling of the response of the Wadden Sea tidal basins to sea-level rise using a basin scale morphological model (aggregated scale morphological interaction between tidal basin and adjacent coast, ASMITA). Analysis using this aggregated scale model shows that the critical rate of sea-level rise is not merely influenced by the morphological equilibrium and the morphological time scale, but also depends on the grain size distribution of sediment in the tidal inlet system. As sea-level rises, there is a lag in the morphological response, which means that the basin will be deeper than the systems morphological equilibrium. However, so long as the rate of sea-level rise is constant and below a critical limit, this offset becomes constant and a dynamic equilibrium is established. This equilibrium deviation as well as the time needed to achieve the dynamic equilibrium increase non-linearly with increasing rates of sea-level rise. As a result, the response of a tidal basin to relatively fast sea-level rise is similar, no matter if the sea-level rise rate is just below, equal or above the critical limit. A tidal basin will experience a long process of ‘drowning’ when sea-level rise rate exceeds about 80% of the critical limit. The insights from the present study can be used to improve morphodynamic modelling of tidal basin response to accelerating sea-level rise and are useful for sustainable management of tidal inlet systems.

Background: The high incidence of post-stroke depression has been claimed to reflect a specific, stroke related pathogenesis in which lesion location plays an important role. To substantiate this claim, post-stroke depression should occur more often than depression after another acute, life threatening, disabling disease that does not involve cerebrovascular damage. Objectives: To compare the cumulative one year incidence of depression after stroke and after myocardial infarction, taking into consideration differences in age, sex, and the level of handicap. Methods: In a longitudinal design, 190 first ever stroke patients and 200 first ever myocardial infarction patients were followed up for one year. Depression self rating scales were used as a screening instrument to detect patients with depressive symptoms. Major and minor depression was assessed at one, three, six, nine, and 12 months after stroke or myocardial infarction according to DSM-IV criteria, using the structured clinical interview from DSM-IV. The severity of depressive symptoms was measured with the Hamilton depression rating scale. Level of disability and handicap was rated with the Rankin handicap scale. Results: The cumulative one year incidence of major and minor depression was 37.8% in stroke patients and 25% in patients with myocardial infarction (hazard ratio 1.6; p = 0.06). This difference disappeared after controlling for sex, age, and level of handicap. In addition, no differences were found in the severity of depressive symptoms or in the time of onset of the depressive episode after stroke or myocardial infarction. Conclusions: Depression occurs equally often during the first year after stroke and after myocardial infarction when non-specific factors such as sex, age, and level of handicap are taken into account. Thus the relatively high incidence of post-stroke depression seems not to reflect a specific pathogenic mechanism. Further research is needed to investigate whether vascular factors play a common role in the development of depression after stroke and myocardial infarction.

Aim: The aim of this study was to investigate the prognostic accuracy of different subtypes of mild cognitive impairment (MCI): amnestic MCI, multiple domain MCI, and single non-memory domain MCI, for the development of Alzheimer’s dementia (AD) and vascular dementia (VaD). Patients: Nondemented patients from a memory clinic cohort (n = 118), and a stroke cohort (n = 80, older than 55 years and with a cognitive impairment). Results: ‘Multiple domain MCI’ had the highest sensitivity for both AD (80.8%) and VaD (100%), and ‘amnestic MCI’ had the highest specificity (85.9% for AD, 100% for VaD). The positive predictive value was low for all subtypes (0.0–32.7%), whereas the negative predictive value was high (72.8–100%). Discussion: The subtype ‘multiple domain MCI’ has high sensitivity in identifying people at risk for developing AD or VaD. The predictive accuracy of the MCI subtypes was similar for both AD and VaD.

Abstract Objective: To investigate the effectiveness of aspirin and coumarin in preventing thromboembolism in patients with non-rheumatic atrial fibrillation in general practice. Design: Randomised controlled trial. Participants: 729 patients aged ≥60 years with atrial fibrillation, recruited in general practice, who had no established indication for coumarin. Mean age was 75 years and mean follow up 2.7 years. Setting: Primary care in the Netherlands. Interventions: Patients eligible for standard intensity coumarin (international normalised ratio 2.5-3.5) were randomly assigned to standard anticoagulation, very low intensity coumarin (international normalised ratio 1.1-1.6), or aspirin (150 mg/day) (stratum 1). Patients ineligible for standard anticoagulation were randomly assigned to low anticoagulation or aspirin (stratum 2). Main outcome measures: Stroke, systemic embolism, major haemorrhage, and vascular death. Results: 108 primary events occurred (annual event rate 5.5%), including 13 major haemorrhages (0.7% a year). The hazard ratio was 0.91 (0.61 to 1.36) for low anticoagulation versus aspirin and 0.78 (0.34 to 1.81) for standard anticoagulation versus aspirin. Non-vascular death was less common in the low anticoagulation group than in the aspirin group (0.41, 0.20 to 0.82). There was no significant difference between the treatment groups in bleeding incidence. High systolic and low diastolic blood pressure and age were independent prognostic factors. Conclusion: In a general practice population (without established indications for coumarin) neither low nor standard intensity anticoagulation is better than aspirin in preventing primary outcome events. Aspirin may therefore be the first choice in patients with atrial fibrillation in general practice. Key messages Studies have shown that patients with non-rheumatic atrial fibrillation may benefit from anticoagulation This study in a general practice population found no benefit of standard or low dose anticoagulation on risk of stroke, systemic embolism, major haemorrhage, or vascular death when compared with aspirin Hypertension and age were prognostic factors for event occurrence Aspirin is the treatment of choice for preventing thromboembolism in primary care patients at low risk

Aims To determine whether mitral annular calcification and aortic valve calcification, with or without stenosis, are expressions of atherosclerotic disease. Methods The incidence of atherosclerotic risk factors was analysed in patients with mitral annular calcification and aortic valve calcification and in control patients from a prospective echocardiographic database of 8160 consecutive patients; 657 patients (8%) were identified with mitral annular calcification and 815 (9%) with a calcified aortic valve, of whom 515 (6.3%) had stenosis with a minimal aortic valve gradient of 16 mm Hg. In these patients, cardiac and vascular risk factors were compared with 568 control patients using multiple logistic regression analysis. Results Age (odds ratio (OR) varying from 5.78 to 104, depending on age class), female sex (OR 1.75), hypertension (OR 2.38), diabetes mellitus (OR 2.85), and hypercholesterolaemia (OR 2.95) were strongly and significantly associated with aortic valve calcification without stenosis, as were age (OR varying from 8.82 to 67, depending on age class), female sex (OR 2.22), hypertension (OR 2.72), diabetes mellitus (OR 2.49), and hypercholesterolaemia (OR 2.86) with mitral annular calcification. Age (OR varying from 1.11 to 7.7), hypertension (OR 1.91), and hypercholesterolaemia (OR 2.55) were strongly and significantly associated with stenotic aortic valve calcification. Conclusions Mitral annular calcification and stenotic or non-stenotic aortic valve calcification have a high incidence of atherosclerotic risk factors, suggesting they should be considered as manifestations of generalised atherosclerosis.