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The next generation of Far-infrared and X-ray space observatories will require detector arrays with thousands of transition edge sensor (TES) pixel. It is extremely important to have a tool that is able to characterize all the pixels and that can give a clear picture of the performance of the devices. In particular, we refer to those aspects that can affect the global energy resolution of the array: logarithmic resistance sensitivity with respect to temperature and current (α and β parameters, respectively), uniformity of the TESs and the correct understanding of the detector thermal model. Complex impedance measurement of a TES is the only technique that can give all this information at once, but it has been established only for a single pixel under DC bias. We have developed a complex impedance measurement method for TESs that are AC biased since we are using a MHz frequency domain multiplexing (FDM) system to readout an array. The FDM readout demands for some modifications to the complex-impedance technique and extra considerations, e.g. how to modulate a small fraction of the bias carrier frequencies in order to get a proper excitation current through the TESs and how to perform an accurate demodulation and recombination of the output signals. Also, it requires careful calibration to remove the presence of parasitic impedances in the entire readout system. We perform a complete set of AC impedance measurements for different X-ray TES microcalorimeters based on superconducting TiAu bilayers with or without normal metal Au bar structures. We discuss the statistical analysis of the residual between impedance data and fitting model to determine the proper calorimeter thermal model for our detectors. Extracted parameters are used to improve our understanding of the differences and capabilities among the detectors and additionally the quality of the array. Moreover, we use the results to compare the calculated noise spectra with the measured data.

IntroductionGenetic predisposition to autoimmune encephalitis with antibodies against N-methyl-D-aspartate receptor (NMDAR) is poorly understood. Given the diversity of associated environmental factors (tumors, infections), we hypothesized that human leukocyte antigen (HLA) and killer-cell immunoglobulin-like receptors (KIR), two extremely polymorphic gene complexes key to the immune system, might be relevant for the genetic predisposition to anti-NMDAR encephalitis. Notably, KIR are chiefly expressed by Natural Killer (NK) cells, recognize distinct HLA class I allotypes and play a major role in anti-tumor and anti-infection responses.MethodsWe conducted a Genome Wide Association Study (GWAS) with subsequent control-matching using Principal Component Analysis (PCA) and HLA imputation, in a multi-ethnic cohort of anti-NMDAR encephalitis (n=479); KIR and HLA were further sequenced in a large subsample (n=323). PCA-controlled logistic regression was then conducted for carrier frequencies (HLA and KIR) and copy number variation (KIR). HLA-KIR interaction associations were also modeled. Additionally, single cell sequencing was conducted in peripheral blood mononuclear cells from 16 cases and 16 controls, NK cells were sorted and phenotyped.ResultsAnti-NMDAR encephalitis showed a weak HLA association with DRB1*01:01~DQA1*01:01~DQB1*05:01 (OR=1.57, 1.51, 1.45; respectively), and DRB1*11:01 (OR=1.60); these effects were stronger in European descendants and in patients without an underlying ovarian teratoma. More interestingly, we found increased copy number variation of KIR2DL5B (OR=1.72), principally due to an overrepresentation of KIR2DL5B*00201. Further, we identified two allele associations in framework genes, KIR2DL4*00103 (25.4% vs. 12.5% in controls, OR=1.98) and KIR3DL3*00302 (5.3% vs. 1.3%, OR=4.44). Notably, the ligands of these KIR2DL4 and KIR3DL3, respectively, HLA-G and HHLA2, are known to act as immune checkpoint with immunosuppressive functions. However, we did not find differences in specific KIR-HLA ligand interactions or HLA-G polymorphisms between cases and controls. Similarly, gene expression of CD56dim or CD56bright NK cells did not differ between cases and controls.DiscussionOur observations for the first time suggest that the HLA-KIR axis might be involved in anti-NMDAR encephalitis. While the genetic risk conferred by the identified polymorphisms appears small, a role of this axis in the pathophysiology of this disease appears highly plausible and should be analyzed in future studies.

IntroductionCOVID-19 had a major impact on education, resulting in learning losses among students. The Dutch ministry set-up a subsidy for schools to implement catch-up programs in tackling learning losses. In this study, we examine (a) which students participated in the programs, and (b) effectiveness of these programs in remediating learning losses in secondary school students.MethodsSixteen program in eight secondary schools were analyzed using data of 16,675 students (9,784 individual students; 1,336 participating in a catch-up program). Schools implemented three program types: tutoring, homework support, and general skills. Per school, a difference-in-difference design was used, computing two effect sizes: comparing grades of participating and non-participating students; and grades in tutoring-specific subjects to non-tutored subject (specifically for tutoring programs). Effect sizes were combined using meta-analytic regressions in JASP.ResultsAt program onset, students selected for participation had significantly lower overall grades than non-participants, or – for subject-specific tutoring – lower grades specifically in the tutored subject. Tutoring programs significantly increased students’ grades: with higher grades for participants than non-participants, and – for students receiving subject-specific tutoring - higher grades in tutored subjects compared to those in non-tutored subjects. No significant effects were found for homework support and general study skill programs.ConclusionSchools selected students most in need for catch-up programs. Tutoring interventions seemed to remediate part of secondary school students’ learning losses, whereas general skills programs and homework support programs did not. Large between-school heterogeneity was found, implying that program implementation was at least as important as program type and content.

To prevent floods from becoming disasters, social vulnerability must be integrated into flood risk management. This Comment advocates that the welfare of different societal groups should be included by adding recovery capacity, impacts of beyond-design events, and distributional impacts.

The worldwide increase in the incidence of antibiotic resistance of the atypical bacterium Mycoplasma pneumoniae (MP) challenges the treatment of MP infections, especially in children. Therefore, alternative strategies for the treatment of MP infections are warranted. Galacto- and fructo-oligosaccharides (GOS and FOS) are a specific group of complex carbohydrates that were recently shown to possess direct anti-pathogenic properties. In this study, we assessed whether GOS and FOS exert anti-microbial and anti-infective effects against MP and, especially, macrolide-resistant MP (MRMP) in vitro. The MIC values of GOS for MP and MRMP were 4%. In contrast, the MIC values of FOS for both MP and MRMP were 16%. A time-kill kinetic assay showed that FOS possess bacteriostatic properties, while for GOS, a bactericidal effect against MP and MRMP was observed after 24 h at a concentration of 4x MIC. In co-cultures with human alveolar A549 epithelial cells, GOS killed adherent MP and MRMP and also concentration-dependently inhibited their adherence to A549 cells. Further, GOS suppressed (MR)MP-induced IL-6 and IL-8 in A549 cells. None of the aforementioned parameters were affected when FOS were added to these co-cultures. In conclusion, the anti-infective and anti-microbial properties of GOS could provide an alternative treatment against MRMP and MP infections.

This study examined relations of primary school children’s perceived physical competence and sports participation (frequency and type) with social acceptance in the regular classroom and physical education (PE) and whether these relations differed depending on the type of sport children participated in (team vs. individual sports). In total, 182 children (48.9% boys, mean age 9.90 years, SD = 1.23) filled out questions on their perceived physical competence and sports participation and indicated three peers with whom they liked/disliked working in PE and the regular classroom. Multilevel structural equation models in Mplus showed that frequency of sports participation was positively related to social acceptance in the context of PE. Additionally, for children in team sports, the frequency of sports participation was related to their social acceptance in PE, whereas for children in individual sports, perceived physical competence was related to social acceptance in PE. No relations were found in the regular classroom. Relations of perceived physical competence and sports participation with social acceptance seem to depend on the school context and the type of sport involved. In designing PE classrooms, children’s physical competence and sports participation seem essential factors to take into account to provide all children with positive social experiences.

Abstract Flood simulations are important for flood (fatality) risk assessment. This article provides insight into the sensitivity of flood fatality risks to the model resolution of flood simulations and to several uncertain parameters in the loss of life model used. A case study is conducted for river flooding in a polder in the Netherlands (the Bommelerwaard) where the Dutch approach for loss of life estimation is applied. Flood models with resolutions of 100, 25, and 5 m are considered. Results show locally increased mortality rates in higher resolution simulations nearby structures including road embankments, dikes, and culverts. This causes a larger maximum individual risk value (annual probability of death for a person due to flooding) which has consequences for safety standards based on the individual risk criterion. Mortality rate in the breach zone is also affected by representations of buildings as solid objects versus as roughness elements. Furthermore, changes in the loss of life estimation approach via alternative ways of including people's behaviour, building characteristics, and age of the population, have a significant impact on flood fatality risk. Results from this study can be used to support future risk assessments and decision making with respect to safety standards.

In May 2018, Wolvega Equine Hospital (WEH) experienced an EHV-1 outbreak. This outbreak caused significant economic losses and negative publicity for the hospital. How should hospitals prepare themselves for these outbreaks and prevent shedding of the virus on multiple neighboring premises? The hospital transformed most of its activities into mobile practice and the entire infected hospital population was moved to a separate remote location. The hospital was cleaned and disinfected according to the latest recommendations before reopening. Four neighboring professional equine businesses and three privately owned premises were affected by the spread of the virus from the hospital population and initiated quarantine restrictions. Equine hospitals should prepare themselves for EHV-1 outbreaks as the intake of the virus cannot be prevented. A management protocol should include public information protocols, swift client information and quarantine measures that ensure quick containment of the outbreak. Timely reopening of the hospital can be achieved by rehousing the contaminated population. It should also include good regulations with clients and a properly carried out release protocol. Equine sports organizations should establish sufficient vaccination coverage in order to decrease the frequency of EHV-1 outbreaks.

This study aimed to systematically investigate the relation between gross motor skills and aspects of executive functioning (i.e. verbal working memory, visuospatial working memory, response inhibition and interference control) in 8-10 year old children. Additionally, the role of information processing (speed and variability) and lapses of attention in the relation between gross motor skills and executive functions was investigated. Data of 732 Dutch children from grade 3 and 4 were analyzed (50.0% boys, 50.4% grade 3, age = 9.16 ± 0.64 years). Gross motor skills were assessed using three items of the Körper Koordinationstest für Kinder and one item of the Bruininks-Oseretsky test of Motor Proficiency, Second Edition. Executive functions were assessed using the Wechsler Digit Span task (verbal working memory), the Visuospatial Memory task (visuospatial working memory), the Stop Signal task (response inhibition) and a modified version of the Flanker task (interference control). Information processing and lapses of attention were obtained by applying an ex-Gaussian analysis on go trials of the Stop Signal task. Multilevel regression analysis showed that gross motor skills were significantly related to verbal working memory, visuospatial working memory and response inhibition, but not to interference control. Lapses of attention was a significant predictor for all executive functions, whereas processing speed was not. Variability in processing speed was only predictive for visuospatial working memory. After controlling for information processing and lapses of attention, gross motor skills were only significantly related to visuospatial working memory and response inhibition. The results suggest that after controlling for information processing and lapses of attention, gross motor skills are related to aspects of executive functions that are most directly involved in, and share common underlying processes with, gross motor skills.

For comprehensive flood risk management, accurate information on flood hazards is crucial. While in the past an estimate of potential flood consequences in large areas was often sufficient to make decisions on flood protection, there is currently an increasing demand to have detailed hazard maps available to be able to consider other risk-reducing measures as well. Hazard maps are a prerequisite for spatial planning, but can also support emergency management, the design of flood mitigation measures, and the setting of insurance policies. The increase in flood risks due to population growth and economic development in hazardous areas in the past shows that sensible spatial planning is crucial to prevent risks increasing further. Assigning the least hazardous locations for development or adapting developments to the actual hazard requires comprehensive flood hazard maps. Since flood hazard is a multi-dimensional phenomenon, many different maps could be relevant. Having large numbers of maps to take into account does not, however, make planning easier. To support flood risk management planning we therefore introduce a new approach in which all relevant flood hazard parameters can be combined into two comprehensive maps of flood damage hazard and flood fatality hazard.

BACKGROUND: Palmitic-acid esterified to the sn-1,3 positions of the glycerol backbone (alpha, alpha'-palmitate), the predominant palmitate conformation in regular infant formula fat, is poorly absorbed and might cause abdominal discomfort. In contrast, palmitic-acid esterified to the sn-2 position (beta-palmitate), the main palmitate conformation in human milk fat, is well absorbed. The aim of the present study was to examine the influence of high alpha, alpha'-palmitate fat (HAPF) diet and high beta-palmitate fat (HBPF) diet on colitis development in Muc2 deficient (Muc2(-/-)) mice, a well-described animal model for spontaneous enterocolitis due to the lack of a protective mucus layer. METHODS: Muc2(-/-) mice received AIN-93G reference diet, HAPF diet or HBPF diet for 5 weeks after weaning. Clinical symptoms, intestinal morphology and inflammation in the distal colon were analyzed. RESULTS: Both HBPF diet and AIN-93G diet limited the extent of intestinal erosions and morphological damage in Muc2(-/-) mice compared with HAPF diet. In addition, the immunosuppressive regulatory T (Treg) cell response as demonstrated by the up-regulation of Foxp3, Tgfb1 and Ebi3 gene expression levels was enhanced by HBPF diet compared with AIN-93G and HAPF diets. HBPF diet also increased the gene expression of Pparg and enzymatic antioxidants (Sod1, Sod3 and Gpx1), genes all reported to be involved in promoting an immunosuppressive Treg cell response and to protect against colitis. CONCLUSIONS: This study shows for the first time that HBPF diet limits the intestinal mucosal damage and controls the inflammatory response in Muc2(-/-) mice by inducing an immunosuppressive Treg cell response.

BACKGROUND: Mucin Muc2 is the structural component of the intestinal mucus layer. Absence of Muc2 leads to loss of this layer allowing direct bacterial-epithelial interactions. We hypothesized that absence of the mucus layer leads to increased expression of innate defense peptides. Specifically, we aimed to study the consequence of Muc2 deficiency (Muc2(-/-)) on the expression of regenerating islet-derived protein 3 beta (Reg3β), regenerating islet-derived protein 3 gamma (Reg3γ), and angiogenin-4 (Ang4) in the intestine shortly before and after weaning. METHODS: Intestinal tissues of Muc2(-/-) and wild-type (WT) mice were collected at postnatal day 14 (P14, i.e. pre-weaning) and P28 (i.e. post-weaning). Reg3β, Reg3γ, and Ang4 expression was studied by quantitative real-time PCR, Western-blot, in situ hybridization, and immunohistochemistry. RESULTS: Reg3β and Reg3γ were expressed by diverging epithelial cell types; namely enterocytes, Paneth cells, and goblet cells. Additionally, Ang4 expression was confined to Paneth cells and goblet cells. Expression of Reg3β, Reg3γ, and Ang4 differed between WT and Muc2(-/-) mice before and after weaning. Interestingly, absence of Muc2 strongly increased Reg3β and Reg3γ expression in the small intestine and colon. Finally, morphological signs of colitis were only observed in the distal colon of Muc2(-/-) mice at P28, where and when expression levels of Reg3β, Reg3γ, and Ang4 were the lowest. CONCLUSIONS: Expression of Reg3 proteins and Ang4 by goblet cells point to an important role for goblet cells in innate defense. Absence of Muc2 results in up-regulation of Reg3β and Reg3γ expression, suggesting altered bacterial-epithelial signaling and an innate defense response in Muc2(-/-) mice. The inverse correlation between colitis development and Reg3β, Reg3γ, and Ang4 expression levels might point toward a role for these innate defense peptides in regulating intestinal inflammation.

Abstract Sea level rise (SLR) will affect water levels and increase flood risk in river deltas. To adapt river deltas to SLR, various strategies can be followed. Many urbanised river deltas already have flood protection in place. Continuing a protection strategy under an increasing SLR, would mean higher embankments along the coast and rivers and possibly closing off the river mouths from the sea. However, closing of rivers will hamper the river flow. How to adapt river deltas and enabling rivers to discharge into the sea is a challenging question. This paper assesses impacts of SLR on flood risks in the Rhine‐Meuse Delta in the Netherlands in case the current protection strategy is continued and explores two alternative protection strategies: (1) a closed system with pumps and discharge sluices and (2) an open system in which rivers are diverted to less densely populated areas. The second alternative results in a more flexible river delta, which can accommodate larger SLR. The paper shows that a systems approach and using quantitative assessments of the implications of strategies is possible. This is needed to further assess the adaptation options, so we can anticipate and adapt when needed and avoid regret of decisions.

Abstract Background and purpose The Dutch national guideline on heavy menstrual bleeding was updated and published in 2013. It recommended (for the first time) that uterine artery embolization (UAE) should be part of counseling of women with symptomatic fibroids. We aimed to evaluate the implementation of UAE for symptomatic uterine fibroids in the Netherlands and to investigate gynecologists preference and other influential factors. Methods The primary outcome was to examine the UAE/hysterectomy ratio before and after introduction of the 2013 guideline by the use of annual hospital reports. The secondary outcome assessed factors that could influence implementation by means of a questionnaire to gynecologists. Results A total of 29/30 (97%) UAE+ hospitals and 36/52 (69%) UAE- hospitals sent their annual reports. The UAE/hysterectomy percentages in 2012, 2013 and 2014 were 7,0%, 7.0% and 6.9%, respectively. Regarding the questionnaire, the response rates were 88% and 91%, respectively. In both groups we observed a high self-perceived tendency for UAE counseling (90% versus 70%, p = .001). Approximately 50% of gynecologists from UAE- hospitals indicate they have insufficient information about UAE for appropriate counseling and 40% doubts the effectiveness of UAE. Furthermore, in the majority of gynecologists some ‘urban myths’ about the effectiveness and side-effects of UAE seem to persevere. Conclusion Adding UAE as a treatment option to the national guideline did not change the number of performed UAEs for symptomatic fibroids. It might be useful to develop an option grid in order to offer appropriate, independent counseling and encourage shared decision making.

Abstract Background Due to the increase in elderly patients who undergo major abdominal surgery there is a subsequent increase in postoperative complications, prolonged hospital stays, health-care costs and mortality rates. Delirium is a frequent and severe complication in the ‘frail’ elderly patient. Different preoperative approaches have been suggested to decrease incidence of delirium by improving patients’ baseline health. Studies implementing these approaches are often heterogeneous, have a small sample and do not provide high-quality or successful strategies. The aim of this study is to prevent postoperative delirium and other complications by implementing a unique multicomponent and multidisciplinary prehabilitation program. Methods This is a single-center controlled before-and-after study. Patients aged ≥70 years in need of surgery for colorectal cancer or an abdominal aortic aneurysm are considered eligible. Baseline characteristics (such as factors of frailty, physical condition and nutritional state) are collected prospectively. During 5 weeks prior to surgery, patients will follow a prehabilitation program to optimize overall health, which includes home-based exercises, dietary advice and intravenous iron infusion in case of anaemia. In case of frailty, a geriatrician will perform a comprehensive geriatric assessment and provide additional preoperative interventions when deemed necessary. The primary outcome is incidence of delirium. Secondary outcomes are length of hospital stay, complication rate, institutionalization, 30-day, 6- and 12-month mortality, mental health and quality of life. Results will be compared to a retrospective control group, meeting the same inclusion and exclusion criteria, operated on between January 2013 and October 2015. Inclusion of the prehabilitation cohort started in November 2015; data collection is ongoing. Discussion This is the first study to investigate the effect of prehabilitation on postoperative delirium. The aim is to provide evidence, based on a large sample size, for a standardized multicomponent strategy to improve patients’ preoperative physical and nutritional status in order to prevent postoperative delirium and other complications. A multimodal intervention was implemented, combining physical, nutritional, mental and hematinic optimization. This research involves a large cohort, including patients most at risk for postoperative adverse outcomes. Trial registration The protocol is retrospectively registered at the Netherlands National Trial Register (NTR) number: NTR5932. Date of registration: 05-04-2016.

This paper addresses the large differences that are found between damage estimates of different flood damage models. It explains how implicit assumptions in flood damage functions and maximum damages can have large effects on flood damage estimates. This explanation is then used to quantify the uncertainty in the damage estimates with a Monte Carlo analysis. The Monte Carlo analysis uses a damage function library with 272 functions from seven different flood damage models. The paper shows that the resulting uncertainties in estimated damages are in the order of magnitude of a factor of 2 to 5. The uncertainty is typically larger for flood events with small water depths and for smaller flood events. The implications of the uncertainty in damage estimates for flood risk management are illustrated by a case study in which the economic optimal investment strategy for a dike segment in the Netherlands is determined. The case study shows that the uncertainty in flood damage estimates can lead to significant over- or under-investments.

This paper discusses a new method for flood risk assessment in river deltas. Flood risk analysis of river deltas is complex, because both storm surges and river discharges may cause flooding and the effect of upstream breaches on downstream water levels and flood risk must be taken into account. This paper presents a Monte Carlo-based flood risk analysis framework for policy making, which considers both storm surges and river flood waves and includes effects from hydrodynamic interaction on flood risk. It was applied to analyse societal flood fatality risk in the Rhine–Meuse delta.

To make informed flood risk management (FRM) decisions in large protected river systems, flood risk and hazard analyses should include the potential for dike breaching. ‘Load interdependency’ analyses attempt to include the system-wide effects of dike breaching while accounting for the uncertainty of both river loads and dike fragility. The intensive stochastic computation required for these analyses often precludes the use of complex hydraulic models, but simpler models may miss spatial inundation interactions such as flows that ‘cascade’ between compartmentalised regions and overland flows that ‘shortcut’ between river branches. The potential for these interactions in the Netherlands has previously been identified, and so a schematisation of the Dutch floodplain and protection system is here developed for use in a load interdependency analysis. The approach allows for the spatial distribution of hazard to be quantified under various scenarios and return periods. The results demonstrate the importance of including spatial inundation interactions on hazard estimation at three specific locations, and for the system in general. The modelling approach can be used at a local scale to focus flood-risk analysis and management on the relevant causes of inundation, and at a system-wide scale to estimate the overall impact of large-scale measures.

In order to increase the flood resilience of cities (i.e., the ability to cope with flood hazards), it is also crucial to make critical infrastructure functions resilient, since these are essential for urban society. Cities are complex systems with many actors of different disciplines and many interdependent critical infrastructure networks and functions. Common flood risk analysis techniques provide useful information but are not sufficient to obtain a complete overview of the effects of flooding and potential measures to increase flood resilience related to critical infrastructure networks. Therefore, a more comprehensive approach is needed which helps accessing knowledge of actors in a structured way. Fort Lauderdale, Florida, United States has suffered from flood impacts, especially from disruptions in critical infrastructure. This paper shows how shared insight among different sectors and stakeholders into critical infrastructure resilience and potential resilience-enhancing measures was obtained using input from these actors. It also provides a first quantitative indication of resilience, indicated by the potential disruption due to floods and the effect of measures on resilience. The paper contributes to the existing literature on resilience specifically by considering the duration of disruption, the inclusion of critical infrastructure disruption in flood impact analysis, and the step from resilience quantification to measures.

Endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) play important roles in chronic intestinal inflammation. Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency in preterm infants and is characterized by acute intestinal inflammation and necrosis. The objective of the study is to investigate the role of ER stress and the UPR in NEC patients.Ileal tissues from NEC and control patients were obtained during surgical resection and/or at stoma closure. Splicing of XBP1 was detected using PCR, and gene expression was quantified using qPCR and Western blot.Splicing of XBP1 was only detected in a subset of acute NEC (A-NEC) patients, and not in NEC patients who had undergone reanastomosis (R-NEC). The other ER stress and the UPR pathways, PERK and ATF6, were not activated in NEC patients. A-NEC patients showing XBP1 splicing (A-NEC-XBP1s) had increased mucosal expression of GRP78, CHOP, IL6 and IL8. Similar results were obtained by inducing ER stress and the UPR in vitro. A-NEC-XBP1s patients showed altered T cell differentiation indicated by decreased mucosal expression of RORC, IL17A and FOXP3. A-NEC-XBP1s patients additionally showed more severe morphological damage and a worse surgical outcome. Compared with A-NEC patients, R-NEC patients showed lower mucosal IL6 and IL8 expression and higher mucosal FOXP3 expression.XBP1 splicing, ER stress and the UPR in NEC are associated with increased IL6 and IL8 expression levels, altered T cell differentiation and severe epithelial injury.