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Abstract Background Epidemiological and toxicological studies indicate that increased exposure to air pollutants can lead to neurodegenerative diseases. To further confirm this relationship, we evaluated the association between exposure to ambient air pollutants and corneal nerve measures as a surrogate for neurodegeneration, using corneal confocal microscopy. Methods We used population-based observational cross-sectional data from The Maastricht Study including N = 3635 participants (mean age 59.3 years, 51.6% were women, and 19.9% had type 2 diabetes) living in the Maastricht area. Using the Geoscience and hEalth Cohort COnsortium (GECCO) data we linked the yearly average exposure levels of ambient air pollutants at home address-level [particulate matter with diameters of ≤ 2.5 µm (PM2.5), and ≤ 10.0 µm (PM10), nitrogen dioxide (NO2), and elemental carbon (EC)]. We used linear regression analysis to study the associations between Z-score for ambient air pollutants concentrations (PM2.5, PM10, NO2, and EC) and Z-score for individual corneal nerve measures (corneal nerve bifurcation density, corneal nerve density, corneal nerve length, and fractal dimension). Results After adjustment for potential confounders (age, sex, level of education, glucose metabolism status, corneal confocal microscopy lag time, inclusion year of participants, smoking status, and alcohol consumption), higher Z-scores for PM2.5 and PM10 were associated with lower Z-scores for corneal nerve bifurcation density, nerve density, nerve length, and nerve fractal dimension [stβ (95% CI): PM2.5 -0.10 (-0.14; -0.05), -0.04 (-0.09; 0.01), -0.11 (-0.16; -0.06), -0.20 (-0.24; -0.15); and PM10 -0.08 (-0.13; -0.03), -0.04 (-0.09; 0.01), -0.08 (-0.13; -0.04), -0.17 (-0.21; -0.12)], respectively. No associations were found between NO2 and EC and corneal nerve measures. Conclusions Our population-based study demonstrated that exposure to higher levels of PM2.5 and PM10 are associated with higher levels of corneal neurodegeneration, estimated from lower corneal nerve measures. Our results suggest that air pollution may be a determinant for neurodegeneration assessed in the cornea and may impact the ocular surface health as well.

Reconstruction of historical persons and family ties is the bread and butter of many researchers and genealogists. With the increasing digital availability of historical person records, the scope and depth of person reconstructions speaks to the imagination of researchers and genealogists. Yet, the lack of standardisation in the description of historical person data has hurt the interoperability and sustainability of both small and large databases. Persons in Context, or PiCo, presents a data model for historical person records within the Resource Description Framework (RDF). RDF or Linked Data is specifically designed for clear, unambiguous information exchange between multiple parties over the internet. We show how reuse of existing ontologies and concentric description are the building blocks of a flexible, straightforward, and stringent data model that emphasises provenance.

Background & Aims: Although primary biliary cholangitis (PBC) is considered a rare disorder, accurate determination of its incidence and prevalence remains challenging due to limited comprehensive population-based registries. We aimed to assess the incidence and prevalence of PBC in the Netherlands over time through the nationwide Dutch PBC Cohort Study (DPCS). Methods: DPCS retrospectively included every identifiable patient with PBC in the Netherlands from 1990 onwards in all 71 Dutch hospitals. Incidence and prevalence were assessed between 2008-2018 by Poisson regression between sex and age groups over time. Results: On the 1st of January 2008, there were 1,458 patients with PBC in the Netherlands. Between 2008-2018, 2,187 individuals were newly diagnosed, 46 were transplanted and 468 died. The yearly incidence of PBC in 2008 was 1.38, increasing to 1.74 per 100,000 persons in 2018. When compared to those aged

Abstract A stacked polyphase bridge converter consists of multiple standard, three‐phase two‐level voltage source inverters connected in series to the same dc voltage source. The authors present a decentralised and dynamic dc‐bus reconfiguration strategy for this type of converter. The innovation of the proposed strategy lies in its ability to isolate or reactivate one of the inverters in the series connection online, even in motoring mode, enabling increased fault tolerance and an extended speed range. Both the required hardware alterations and the multi‐agent control strategy are addressed. Its major benefits compared to the state‐of‐the‐art are that only two additional active, unidirectional semiconductor switches are required per inverter, and that the control is based on local computations, local measurements and neighbour‐to‐neighbour communication only. Hence, the scalability and reliability of the hardware are extended towards the control. Simulations and experimental results on a 4 kW modular axial‐flux PMSM prove the feasibility of the concept, and validate that the dc‐bus can be reconfigured in 100 ms, without torque interruption.

In an effort to make pumped hydropower storage (PHS) technology feasible for regions with a flat topography, recent research shows promising results using a contra-rotating reversible pump-turbine at low-head. In this study, the impact of dual variable speed and inlet valve control is analyzed to evaluate the effect of these three degrees of freedom (DOFs) on the system efficiency and operating range. To this end, analytical models are described to assess pump-turbine performance, conduit losses and electromechanical losses. Methodologically, optimal efficiency maps are computed for every combination of the three DOFs to evaluate individual and combined effects on the overall efficiency. Furthermore, three energy storage cycles are analyzed to further study the performance in realistic use-cases. Key conclusions include an increase in round-trip efficiency by combining variable speed ratio and inlet valve control of 5.6% and 2.0% compared with only variable speed ratio control and variable inlet valve control, respectively. Furthermore, it is shown that using only 1 DOF significantly limits the operating range, with the addition of a variable inlet valve granting a higher impact than a variable speed ratio. Combining inlet valve and speed ratio control leads not only to the highest efficiency, but also the largest operating range, with a maximum round-trip efficiency of 67.5% and an energy storage capacity of 58.6 Wh/m2. The results confirm that exploiting both dual variable speed operation and inlet valve control yields the maximum efficiency and operating range, and is thus the preferred topology for contra-rotating reversible pump-turbines in low-head operation.

Wind power has emerged as a clean alternative to traditional power production, with a significant increase in its installed capacity observed over the past decade. In numerous regions, wind power producers are now afforded the opportunity to participate in day-ahead energy and reserve markets. In this context, the wind turbines can provide ancillary services such as frequency containment reserve (FCR). However, the provision of ancillary services is known to affect the physical loading on a wind turbine. This loading on different parts of the wind turbine can possibly result in sub-optimal performance leading to a reduced net power output or even a faster degradation of the wind turbine. On the other hand, no or low participation of a wind turbine in ancillary services market will lead to a lesser revenue on a long term. Moreover, low participation of wind turbines in the ancillary market will eventually limit the amount of wind power, since the ancillary services are needed to stabilise the grid and must then be provided by other energy sources. Addressing this challenge requires a holistic method to gauge both load and revenue for wind power producers (WPP), thus enabling them to make informed decisions. This study firstly presents a method of calculating major loads on the wind turbine. Then, a load-aware optimisation method of wind power scheduling in the joint day-ahead energy and reserve market (JERM) is proposed that provides WPPs, an ability to strike a balance between revenue and the physical loading of wind turbine.

Dealing with social rejection is challenging, especially during childhood when behavioral and neural responses to social rejection are still developing. In the current longitudinal study, we used a Bayesian multilevel growth curve model to describe individual differences in the development of behavioral and neural responses to social rejection in a large sample (n > 500). We found a peak in aggression following negative feedback (compared to neutral feedback) during late childhood, as well as individual differences during this developmental phase, possibly suggesting a sensitive window for dealing with social rejection across late childhood. Moreover, we found evidence for individual differences in the linear development of neural responses to social rejection in our three brain regions of interest: The anterior insula, the medial prefrontal cortex, and the dorsolateral prefrontal cortex. In addition to providing insights in the individual trajectories of dealing with social rejection during childhood, this study also makes a meaningful methodological contribution: Our statistical analysis strategy (and can be found in this study’s online supplementary materials at https://jeroendmulder.github.io/social-emotion-regulation/) can be used as an example on how to take into account the many complexities of developmental neuroimaging datasets, while still enabling researchers to answer interesting questions about individual-level relationships.

Abstract The pan‐European power grid is experiencing an increasing penetration of Variable Renewable Energy (VRE). The fluctuating and non‐dispatchable nature of VRE hinders them in providing the Ancillary Service (AS) needed for the reliability and stability of the grid. Therefore, Energy Storage Systems (ESS) are needed along the VRE. Among the different ESS, a particularly viable and reliable option is Pumped Hydro Storage (PHS), given its cost‐effective implementation and considerable lifespan, in comparison to other technologies. Traditional PHS plants with Francis turbines operate at a high head difference. However, not all regions have the necessary topology to make these plants cost‐effective and efficient. Therefore, the ALPHEUS project will introduce low‐head PHS for regions with a relatively flat topography. In this paper, a grid‐forming controlled converter coupled with low‐head PHS that can contribute to the grid stability is introduced, emphasising its ability to provide different AS, especially frequency control, through the provision of fast Frequency Containment Reserve (fFCR) as well as synthetic system inertia. This paper is an extended version of the paper “The Contribution of Low‐head Pumped Hydro Storage to a successful Energy Transition”, which was presented at the 19th Wind Integration Workshop 2020.

Summary: Background: Mycoplasma pneumoniae is a common cause of community-acquired pneumonia in school-aged children and can be preceded by asymptomatic carriage. However, its role in recurrent respiratory tract infections is unclear. We studied the prevalence of M.pneumoniae carriage in children with recurrent respiratory infections and identified associated factors. Methods: We tested M.pneumoniae carriage by qPCR in children with recurrent infections and their healthy family members in a cross-sectional study. Serum and mucosal total and M.pneumoniae-specific antibody levels were measured by ELISA and nasopharyngeal microbiota composition was characterized by 16S-rRNA sequencing. Findings: Prevalence of M.pneumoniae carriage was higher in children with recurrent infections (68%) than their family members without infections (47% in siblings and 27% in parents). M.pneumoniae carriage among family members appeared to be associated with transmission within the household, likely originating from the affected child. In logistic regression corrected for age and multiple comparisons, IgA (OR 0.16 [0.06–0.37]) and total IgG deficiency (OR 0.15 [0.02–0.74]) were less prevalent in M.pneumoniae carriers (n = 78) compared to non-carriers (n = 36). In multivariable analysis, the nasopharyngeal microbiota of M.pneumoniae carriers had lower alpha diversity (OR 0.27 [0.09–0.67]) and a higher abundance of Haemophilus influenzae (OR 45.01 [2.74–1608.11]) compared to non-carriers. Interpretation: M.pneumoniae carriage is highly prevalent in children with recurrent infections and carriers have a less diverse microbiota with an overrepresentation of disease-associated microbiota members compared to non-carriers. Given the high prevalence of M.pneumoniae carriage and the strong association with H. influenzae, we recommend appropriate antibiotic coverage of M.pneumoniae and H. influenzae in case of suspected pneumonia in children with recurrent respiratory tract infections or their family members. Funding: Wilhelmina Children’s Hospital Research Fund, ‘Christine Bader Stichting Irene KinderZiekenhuis’, Sophia Scientific Research Foundation, ESPID Fellowship funded by Seqirus, Hypatia Fellowship funded by Radboudumc and The Netherlands Organisation for Health Research and Development (ZonMW VENI grant to LM Verhagen).

The pathogen Pseudomonas aeruginosa uses a synthase-dependent secretion system for production of the exopolysaccharide alginate, which is associated with lung infection severity. Here, Gheorghita et al. determine the crystal structure of one of the secretion system components (the AlgKX complex) and show that it binds alginate oligosaccharides and is required for polymer production and biofilm attachment.

Group B Streptococcus (Streptococcus agalactiae or GBS) is the leading infectious cause of neonatal mortality, causing roughly 150,000 infant deaths and stillbirths annually across the globe. Approximately 20% of pregnant women are asymptomatically colonized by GBS, which is a major risk factor for severe fetal and neonatal infections as well as preterm birth, low birth weight, and neurodevelopmental abnormalities. Current clinical interventions for GBS infection are limited to antibiotics, and no vaccine is available. We previously described VAX-A1 as a highly effective conjugate vaccine against group A Streptococcus that is formulated with three antigens, SpyAD, streptolysin O, and C5a peptidase (ScpA). ScpA is a surface-expressed, well-characterized GAS virulence factor that shares nearly identical sequences with the lesser studied GBS homolog ScpB. Here, we show that GBS C5a peptidase ScpB cleaves human complement factor C5a and contributes to disease severity in the murine models of pneumonia and sepsis. Furthermore, antibodies elicited by GAS C5a peptidase bind to GBS in an ScpB-dependent manner, and VAX-A1 immunization protects mice against lethal GBS heterologous challenge. These findings support the contribution of ScpB to GBS virulence and underscore the importance of choosing vaccine antigens; a universal GAS vaccine such as VAX-A1 whose formulation includes GAS C5a peptidase may have additional benefits through some measure of cross-protection against GBS infections.

Abstract The participation of wind farms in providing ancillary services is an asset for the power system and one way to maintain a strong grid with the increasing penetration of renewable energy sources. Research has shown this to be feasible for wind farms by using efficient prediction and sophisticated control systems. In some parts of the world, strict grid codes are already being implemented that require wind farms to provide ancillary services. Moreover, the primary reserve market in Europe is moving towards shorter procurement periods, providing wind farms an opportunity to more efficiently optimise their resources based on short term forecasts. It can however be challenging for the wind farms to efficiently participate in grid frequency support services, especially for primary reserve services. The reason behind this is the requirement of quick activation and deactivation of power reserve margin for services such as Frequency Containment Reserve (FCR) and Fast Frequency Response (FFR). A full activation of the contracted reserve is required within seconds of a grid frequency dip. A sudden change in wind turbine dynamics is expected to have an impact on the wake behind the wind turbine. The wake effect within a wind farm is taken into thorough consideration in its design process. The effect on the wake due to the wind turbines participating in fast response ancillary services however, remains unexplored. This is a matter of greater concern for wind farms with a high capacity density. To this end, the main contribution of this article is to observe the effect of ancillary service based control system on the wake effect of a wind turbine. Additionally, the capability of developed wind turbines controllers to follow primary reserve services are also tested. FFR and FCR services are tested for a range of frequency designs, these include both synthetic and actual grid frequencies. The synthetic frequency profiles are designed to replicate both fast and slow frequency variations in order to analyse the impact on wake behaviour. The simulations are performed for low and high wind speed including constant as well as turbulent winds.

Abstract Adjuvants play a determinant role in cancer vaccination by optimally activating APCs and shaping the T cell response. Bacterial-derived lipid A is one of the most potent immune-stimulators known, and is recognized via Toll-like receptor 4 (TLR4). In this study, we explore the use of the synthetic, non-toxic, lipid A analog CRX-527 as an adjuvant for peptide cancer vaccines. This well-defined adjuvant was covalently conjugated to antigenic peptides as a strategy to improve vaccine efficacy. We show that coupling of this TLR4 agonist to peptide antigens improves vaccine uptake by dendritic cells (DCs), maturation of DCs and T cell activation in vitro, and stimulates DC migration and functional T cell priming in vivo. This translates into enhanced tumor protection upon prophylactic and therapeutic vaccination via intradermal injection against B16-OVA melanoma and HPV-related TC1 tumors. These results highlight the potential of CRX-527 as an adjuvant for molecularly defined cancer vaccines, and support the design of adjuvant-peptide conjugates as a strategy to optimize vaccine formulation.

Abstract Background Active patient involvement in treatment decisions is seen as a feature of patient‐centred care that will ultimately lead to better healthcare services and patient outcomes. Although many factors have been identified that influence patient involvement in treatment decisions, little is known about the different views that patients have on which factors are most important. Objective This study explores the views of patients with a chronic condition on factors influencing their involvement in treatment decisions. Design Q‐methodology was used to study the views of patients. Respondents were asked to rank a set of 42 statements from the least important to the most important for active patient involvement in treatment decision‐making. The set of 42 statements was developed based on a literature search and a pilot in which two external researchers, 15 patients and four healthcare professionals participated. A total of 136 patients with one of three major chronic conditions were included: diabetes types 1 and 2, respiratory disease (i.e., chronic obstructive pulmonary disease and asthma) and cancer (i.e., breast cancer and prostate cancer). Data were collected in a face‐to‐face interview setting in the Netherlands. Results Four distinct views on the factors influencing active patient involvement were identified among patients with a chronic condition. (1) Enabled involvement: the extent to which patients are facilitated and empowered to participate will lead to patient involvement. (2) Relationship‐driven involvement: the relationship between patients and healthcare professionals drives patient involvement. (3) Disease impact‐driven involvement: the severity of disease drives patient involvement. (4) Cognition‐driven involvement: knowledge and information drive patient involvement. Discussion and Conclusion From the patients' perspective, this study shows that there is no one‐size‐fits‐all approach to involving patients more actively in their healthcare journey. Strategies aiming to enhance active patient involvement among patients with a chronic condition should consider this diversity in perspectives among these patients. Patient Contribution Patients are the respondents as this study researches their perspective on factors influencing patient involvement. In addition, patients were involved in pilot‐testing the statement set.

Abstract Haemophilus influenzae is an opportunistic pathogen adapted to the human respiratory tract. Non-typeable H. influenzae are highly heterogeneous, but few studies have analysed the genomic variability of capsulated strains. This study aims to examine the genetic diversity of 37 serotype f isolates from the Netherlands, Portugal, and Spain, and to compare all capsulated genomes available on public databases. Serotype f isolates belonged to CC124 and shared few single nucleotide polymorphisms (SNPs) (n = 10,999), but a high core genome (> 80%). Three main clades were identified by the presence of 75, 60 and 41 exclusive genes for each clade, respectively. Multi-locus sequence type analysis of all capsulated genomes revealed a reduced number of clonal complexes associated with each serotype. Pangenome analysis showed a large pool of genes (n = 6360), many of which were accessory genome (n = 5323). Phylogenetic analysis revealed that serotypes a, b, and f had greater diversity. The total number of SNPs in serotype f was significantly lower than in serotypes a, b, and e (p

Abstract Background Nasopharyngeal colonisation with clinically relevant bacterial pathogens is a risk factor for severe infections, such as pneumonia and bacteraemia. In this study, we investigated the determinants of nasopharyngeal carriage in febrile patients in rural Burkina Faso. Methods From March 2016 to June 2017, we recruited 924 paediatric and adult patients presenting with fever, hypothermia or suspicion of severe infection to the Centre Medical avec Antenne Chirurgicale Saint Camille de Nanoro, Burkina Faso. We recorded a broad range of clinical data, collected nasopharyngeal swabs and tested them for the presence of Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus and Klebsiella pneumoniae by quantitative polymerase chain reaction. Using logistic regression, we investigated the determinants of carriage and aimed to find correlations with clinical outcome. Results Nasopharyngeal colonisation with S. pneumoniae, H. influenzae and M. catarrhalis was highly prevalent and strongly dependent on age and season. Females were less likely to be colonised with S. pneumoniae (OR 0.71, p = 0.022, 95% CI 0.53–0.95) and M. catarrhalis (OR 0.73, p = 0.044, 95% CI 0.54–0.99) than males. Colonisation rates were highest in the age groups

Abstract Introduction We investigated the impact of the Corona Virus Disease 2019 (COVID-19) pandemic and the resulting lockdown on reperfusion treatments and door-to-treatment times during the first surge in Dutch comprehensive stroke centers. Furthermore, we studied the association between COVID-19-status and treatment times. Methods We included all patients receiving reperfusion treatment in 17 Dutch stroke centers from May 11th, 2017, until May 11th, 2020. We collected baseline characteristics, National Institutes of Health Stroke Scale (NIHSS) at admission, onset-to-door time (ODT), door-to-needle time (DNT), door-to-groin time (DGT) and COVID-19-status at admission. Parameters during the lockdown (March 15th, 2020 until May 11th, 2020) were compared with those in the same period in 2019, and between groups stratified by COVID-19-status. We used nationwide data and extrapolated our findings to the increasing trend of EVT numbers since May 2017. Results A decline of 14% was seen in reperfusion treatments during lockdown, with a decline in both IVT and EVT delivery. DGT increased by 12 min (50 to 62 min, p-value of

ABSTRACT The nasopharyngeal commensal Streptococcus pneumoniae can become invasive and cause metastatic infection. This requires the pneumococcus to have the ability to adapt, grow, and reside in diverse host environments. Therefore, we studied whether the likelihood of severe disease manifestations was related to pneumococcal growth kinetics. For 383 S. pneumoniae blood isolates and 25 experimental mutants, we observed highly reproducible growth curves in nutrient-rich medium. The derived growth features were lag time, maximum growth rate, maximum density, and stationary-phase time before lysis. First, the pathogenicity of each growth feature was probed by comparing isolates from patients with and without marked preexisting comorbidity. Then, growth features were related to the propensity of causing severe manifestations of invasive pneumococcal disease (IPD). A high maximum bacterial density was the most pronounced pathogenic growth feature, which was also an independent predictor of 30-day mortality (P = 0.03). Serotypes with an epidemiologically higher propensity for causing meningitis displayed a relatively high maximum density (P

Abstract Background Patients who have been successfully treated for an aneurysmal subarachnoid hemorrhage (aSAH) often retain multiple health complaints, including mood disorders, cognitive complaints, fatigue, and problems with social participation. These problems are not always fully addressed during hospital visits or in current outcome measures, such as the modified Rankin score and the Glasgow Outcome Scale. Here, we present the development of the “Questionnaire for the Screening of Symptoms in aneurysmal Subarachnoid Hemorrhage” (SOS-SAH), which screens for the self-reported symptoms of patients with mild disabilities. Methods During the development of the SOS-SAH we adhered to the PROM-cycle framework for the selection and implementation of patient-reported outcome measures (PROMs). The SOS-SAH was developed in an iterative process informed by a literature study. Patients and healthcare professionals were involved in the development process through participating in a working group, interviews, and a cognitive validation study. Results and conclusions Relevant patient-reported outcomes (PROs) were identified for patients with aSAH. The SOS-SAH was developed primarily using domains and items from existing PROMs and, if necessary, by developing new items. The SOS-SAH consists of 40 items and covers 14 domains: cognitive abilities, hypersensitivity to stimuli, anxiety, depression, fatigue, social roles, personality change, language, vision, taste, smell, hearing, headache, and sexual function. It also includes a proxy measurement for use by family members to assess cognitive functioning and personality change.

The components of an operational wind turbine are continuously impacted by both static and dynamic loads. Regular inspections and maintenance are required to keep these components healthy. The main bearing of a wind turbine is one such component that experiences heavy loading forces during operation. These forces depend on various parameters such as wind speed, operating regime and control actions. When a wind turbine provides frequency containment reserve (FCR) to support the grid frequency, the forces acting upon the main bearing are also expected to exhibit more dynamic variations. These forces have a direct impact on the lifetime of the main bearing. With an increasing trend of wind turbines participating in the frequency ancillary services market, an analysis of these dynamic forces becomes necessary. To this end, this paper assesses the effect of FCR-based control on the main bearing lifetime of the wind turbine. Firstly, a control algorithm is implemented such that the output power of the wind turbine is regulated as a function of grid frequency and the amount of FCR. Simulations are performed for a range of FCR to study the changing behaviour of dynamical forces acting on the main bearing with respect to the amount of FCR provided. Then, based on the outputs from these simulations and using 2 years of LiDAR wind data, the lifetime of the main bearing of the wind turbine is calculated and compared for each of the cases. Finally, based on the results obtained from this study, the impact of FCR provision on the main bearing lifetime is quantified and recommendations are made, that could be taken into account in the operation strategy of a wind farm.

The Neisseria meningitidis serogroup A capsular polysaccharide (MenA CPS) is a component of commercial vaccines, but is unstable. Here, the authors generate glycomimetic oligomers that demonstrate higher stability than their natural counterparts and induce protective antibodies in mice.

Dioxolenium ion intermediates formed from remote positions are hypothesized to direct stereoselective glycosylations. Herein we combine infrared ion spectroscopy, DFT calculations and synthetic work to characterize and study these dioxolenium ions and their role in stereoselective glycosylation reactions.

The exopolysaccharide galactosaminogalactan (GAG) is an important virulence factor of the fungal pathogen Aspergillus fumigatus. Here, the authors study an A. fumigatus enzyme that deacetylates GAG in a metal-dependent manner and constitutes a founding member of a new carbohydrate esterase family.

Abstract Background A high variety of team interventions aims to improve team performance outcomes. In 2008, we conducted a systematic review to provide an overview of the scientific studies focused on these interventions. However, over the past decade, the literature on team interventions has rapidly evolved. An updated overview is therefore required, and it will focus on all possible team interventions without restrictions to a type of intervention, setting, or research design. Objectives To review the literature from the past decade on interventions with the goal of improving team effectiveness within healthcare organizations and identify the “evidence base” levels of the research. Methods Seven major databases were systematically searched for relevant articles published between 2008 and July 2018. Of the original search yield of 6025 studies, 297 studies met the inclusion criteria according to three independent authors and were subsequently included for analysis. The Grading of Recommendations, Assessment, Development, and Evaluation Scale was used to assess the level of empirical evidence. Results Three types of interventions were distinguished: (1) Training, which is sub-divided into training that is based on predefined principles (i.e. CRM: crew resource management and TeamSTEPPS: Team Strategies and Tools to Enhance Performance and Patient Safety), on a specific method (i.e. simulation), or on general team training. (2) Tools covers tools that structure (i.e. SBAR: Situation, Background, Assessment, and Recommendation, (de)briefing checklists, and rounds), facilitate (through communication technology), or trigger (through monitoring and feedback) teamwork. (3) Organizational (re)design is about (re)designing structures to stimulate team processes and team functioning. (4) A programme is a combination of the previous types. The majority of studies evaluated a training focused on the (acute) hospital care setting. Most of the evaluated interventions focused on improving non-technical skills and provided evidence of improvements. Conclusion Over the last decade, the number of studies on team interventions has increased exponentially. At the same time, research tends to focus on certain interventions, settings, and/or outcomes. Principle-based training (i.e. CRM and TeamSTEPPS) and simulation-based training seem to provide the greatest opportunities for reaching the improvement goals in team functioning.

Pseudomonas aeruginosa, a pathogenic Gram-negative bacterium for which currently antibiotic resistance is posing a significant problem and for which no vaccines are available, protects itself by the formation of a biofilm. The Pel polysaccharide, a cationic polymer composed of cis-linked galactosamine (GalN), N-acetyl galactosamine (GalNAc), glucosamine (GlcN) and N-acetyl glucosamine (GlcNAc) monosaccharides, is an important constituent of the biofilm. Well-defined Pel oligosaccharides will be valuable tools to probe the biosynthesis machinery of this polysaccharide and may serve as diagnostic tools or be used as components of glycoconjugate vaccines. We here, report on the development of synthetic chemistry to access well-defined Pel-oligosaccharides. The chemistry hinges on the use of di-tert-butylsilylidene protected GalN and GlcN building blocks, which allow for completely cis-selective glycosylation reactions. We show the applicability of the chemistry by the assembly of a matrix of 3 × 6 Pel heptasaccharides, which has been generated from a single set of suitably protected Pel heptasaccharides, in which a single glucosamine residue is incorporated and positioned at different places along the Pel oligo-galactosamine chain.

Human-adapted bacterial pathogens have evolved specific mechanisms to colonize their host niche. Phase variation is a contingency strategy to allow adaptation to changing conditions, as phase-variable bacterial loci rapidly and reversibly switch their expression.

Abstract Background Patients with X-linked agammaglobulinemia (XLA) are protected against invasive bacterial infections due to IgG replacement therapy, but are still at higher risk for mucosal infections of the gut and respiratory tract. This might be explained by to the lack of IgA and IgM, as these antibodies are especially important for protection against invading bacterial pathogens on the mucosal surface. Methods In an attempt to eliminate a chronic norovirus infection in a patient with X-linked agammaglobulinemia, fresh frozen plasma (FFP) was given two times a week for 3 weeks. At each visit, pre- and post-FFP infusion serum and saliva was collected to determine IgG-, IgA- and IgM-concentrations and serum half-life was calculated. Functionality of the immunoglobulins pre- and post-FFP infusion in both serum and saliva was tested by measuring complement activation, agglutination and killing of non-typeable Haemophilus influenzae (NTHi). Results Administration of FFP failed to eradicate the chronic norovirus infection. Serum IgA and IgM half-life was 4.2 ± 0.3 and 3.8 ± 0.3 days, respectively. The presence of serum IgM was associated with increased complement binding and complement-mediated killing of NTHi. IgA in saliva was detectable post-FFP and was associated with increased agglutination of NTHi. IgM in saliva was not detectable. Conclusions We conclude that FFP treatment, although ineffective in clearing a chronic norovirus infection in this single patient, might be beneficial to prevent or eliminate bacterial infections in XLA patients by increasing IgM dependent complement-mediated killing in serum and IgA dependent bacterial agglutination on the mucosal surface.

Scientific research can be categorized into: a) descriptive research, with the main goal to summarize characteristics of a group (or person); b) predictive research, with the main goal to forecast future outcomes that can be used for screening, selection, or monitoring; and c) explanatory research, with the main goal to understand the underlying causal mechanism, which can then be used to develop interventions. Since each goal requires different research methods in terms of design, operationalization, model building and evaluation, it should form an important basis for decisions on how to set up and execute a study. To determine the extent to which developmental research is motivated by each goal and how this aligns with the research designs that are used, we evaluated 100 publications from the Consortium on Individual Development (CID). This analysis shows that the match between research goal and research design is not always optimal. We discuss alternative techniques, which are not yet part of the developmental scientist’s standard toolbox, but that may help bridge some of the lurking gaps that developmental scientists encounter between their research design and their research goal. These include unsupervised and supervised machine learning, directed acyclical graphs, Mendelian randomization, and target trials.

Langerhans cells (LCs) are antigen-presenting cells that reside in the skin. They uniquely express high levels of the C-type lectin receptor Langerin (CD207), which is an attractive target for antigen delivery in immunotherapeutic vaccination strategies against cancer. We here assess a library of 20 synthetic, well-defined mannoside clusters, built up from one, two, and three of six monomannosides, dimannosides, or trimannosides, appended to an oligopeptide backbone, for binding with Langerin using surface plasmon resonance and flow cytometric quantification. It is found that Langerin binding affinity increases with increasing number of mannosides. Hexavalent presentation of the mannosides resulted in binding affinities ranging from 3 to 12 μM. Trivalent presentation of the dimannosides and trimannosides led to Langerin affinity in the same range. The model melanoma gp100 antigenic peptide was subsequently equipped with a hexavalent cluster of the dimannosides and trimannosides as targeting moieties. Surprisingly, although the bifunctional conjugates were taken up in LCs in a Langerin-dependent manner, limited antigen presentation to cytotoxic T cells was observed. These results indicate that targeting glycan moieties on immunotherapeutic vaccines should not only be validated for target binding, but also on the continued effects on biology, such as antigen presentation to both CD8+ and CD4+ T cells.

Background and study aims Delayed bleeding (DB) is the most frequent major adverse event after endoscopic mucosal resection (EMR) of large non-pedunculated colorectal polyps (LNPCPs). Evidence-based guidelines for management of DB are lacking. We aimed to evaluate the clinical presentation, treatment and outcome of patients with DB and to determine factors associated with hemostatic therapy. Patients and methods Patients with DB were identified by analyzing all consecutive EMR procedures for LNPCPs (≥ 2 cm) from one academic center (2012–2017) and seven regional hospitals (2015–2017). DB was defined as any postprocedural bleeding necessitating emergency department presentation, hospitalization or reintervention. Outcome of DB was assessed for three clinical scenarios: continued bleeding (CB), spontaneous resolution without recurrent bleeding during 24 hours observation (SR), and recurrent bleeding (RB). Variables associated with hemostatic therapy were analyzed using logistic regression. Results DB occurred after 42/542 (7.7 %) EMR procedures and re-colonoscopy was performed in 30 patients (72 %). Re-colonoscopy and hemostatic therapy rates were 92 % and 75 % for CB (n = 24), 25 % and 8 % for SR (n = 12), and 83 % and 67 % for RB (n = 6), respectively. Frequent hematochezia (≥ hourly) was the only factor significantly associated with hemostatic therapy (RR 2.23, p = 0.01). Re-bleeding after endoscopic hemostatic therapy occurred in 3/22 (13.6 %) patients. Conclusion Ongoing or recurrent hematochezia is associated with a high rate of hemostatic therapy, warranting re-colonoscopy in these patients. A conservative approach is justified when bleeding spontaneously settles, and without recurrent hematochezia during 24 hours observation patients can be safely discharged without endoscopic re-examination.

Background Learning to predict threatening events enables an organism to engage in protective behavior and prevent harm. Failure to differentiate between cues that truly predict danger and those that do not, however, may lead to indiscriminate fear and avoidance behaviors, which in turn may contribute to disability in people with persistent pain. We aimed to test whether people with persistent neck pain exhibit contingency learning deficits in predicting pain relative to pain-free, gender-and age-matched controls. Method We developed a differential predictive learning task with a neck pain-relevant scenario. During the acquisition phase, images displaying two distinct neck positions were presented and participants were asked to predict whether these neck positions would lead to pain in a fictive patient with persistent neck pain (see fictive patient scenario details in Appendix A). After participants gave their pain-expectancy judgment in the hypothetical scenario, the verbal outcome (PAIN or NO PAIN) was shown on the screen. One image (CS+) was followed by the outcome “PAIN”, while another image (CS−) was followed by the outcome “NO PAIN”. During the generalization phase, novel but related images depicting neck positions along a continuum between the CS+ and CS− images (generalization stimuli; GSs) were introduced to assess the generalization of acquired predictive learning to the novel images; the GSs were always followed by the verbal outcome “NOTES UNREADABLE” to prevent extinction learning. Finally, an extinction phase was included in which all images were followed by “NO PAIN” assessing the persistence of pain-expectancy judgments following disconfirming information. Results Differential pain-expectancy learning was reduced in people with neck pain relative to controls, resulting from patients giving significantly lower pain-expectancy judgments for the CS+, and significantly higher pain-expectancy judgments for the CS−. People with neck pain also demonstrated flatter generalization gradients relative to controls. No differences in extinction were noted. Discussion The results support the hypothesis that people with persistent neck pain exhibit reduced differential pain-expectancy learning and flatter generalization gradients, reflecting deficits in predictive learning. Contrary to our hypothesis, no differences in extinction were found. These findings may be relevant to understanding behavioral aspects of chronic pain.

Hypoxia and inflammation are closely intertwined phenomena. Critically ill patients often suffer from systemic inflammatory conditions and concurrently experience short-lived hypoxia. We evaluated the effects of short-term hypoxia on systemic inflammation, and show that it potently attenuates pro-inflammatory cytokine responses during murine endotoxemia. These effects are independent of hypoxia-inducible factors (HIFs), but involve augmented adenosine levels, in turn resulting in an adenosine 2B receptor-mediated post-transcriptional increase of interleukin (IL)-10 production. We translated our findings to humans using the experimental endotoxemia model, where short-term hypoxia resulted in enhanced plasma concentrations of adenosine, augmentation of endotoxin-induced circulating IL-10 levels, and concurrent attenuation of the pro-inflammatory cytokine response. Again, HIFs were shown not to be involved. Taken together, we demonstrate that short-term hypoxia dampens the systemic pro-inflammatory cytokine response through enhanced purinergic signaling in mice and men. These effects may contribute to outcome and provide leads for immunomodulatory treatment strategies for critically ill patients. Keywords: Adenosine, Adenosine 2B receptor, Cytokines, Hypoxia, Endotoxin

Abstract Background Hospitals are confronted with increasing safety demands from a diverse set of stakeholders, including governmental organisations, professional associations, health insurance companies, patient associations and the media. However, little is known about the effects of these institutional and competitive pressures on hospital safety management. Previous research has shown that organisations generally shape their safety management approach along the lines of control- or commitment-based management. Using a heuristic framework, based on the contextually-based human resource theory, we analysed how environmental pressures affect the safety management approach used by hospitals. Methods A qualitative study was conducted into hospital care in the Netherlands. Five hospitals were selected for participation, based on organisational characteristics as well as variation in their reputation for patient safety. We interviewed hospital managers and staff with a central role in safety management. A total of 43 semi-structured interviews were conducted with 48 respondents. The heuristic framework was used as an initial model for analysing the data, though new codes emerged from the data as well. Results In order to ensure safe care delivery, institutional and competitive stakeholders often impose detailed safety requirements, strong forces for compliance and growing demands for accountability. As a consequence, hospitals experience a decrease in the room to manoeuvre. Hence, organisations increasingly choose a control-based management approach to make sure that safety demands are met. In contrast, in case of more abstract safety demands and an organisational culture which favours patient safety, hospitals generally experience more leeway. This often results in a stronger focus on commitment-based management. Conclusions Institutional and competitive conditions as well as strategic choices that hospitals make have resulted in various combinations of control- and commitment-based safety management. A balanced approach is required. A strong focus on control-based management generates extrinsic motivation in employees but may, at the same time, undermine or even diminish intrinsic motivation to work on patient safety. Emphasising commitment-based management may, in contrast, strengthen intrinsic motivation but increases the risk of priorities being set elsewhere. Currently, external pressures frequently lead to the adoption of control-based management. A balanced approach requires a shift towards more trust-based safety demands.

Renewable Energy Sources (RES) have drawn significant attention in the past years to make the transition towards low carbon emissions. On the one hand, the intermittent nature of RES, resulting in variable power generation, hinders their high-level penetration in the power system. On the other hand, RES can aid not only to supply much more eco-friendly energy but also it allows the power system to enhance its stability by ancillary service provision. This article reviews the challenges related to the most intermittent RES utilised in Belgium, that is, wind energy and solar energy. Additionally, wind speed and solar irradiance variations, which are the cause of wind and solar intermittency, are studied. Then, recent techniques to forecast their changes, and approaches to accommodate or mitigate their impacts on the power system, are discussed. Finally, the latest statistics and future situation of RES in the Belgian power system are evaluated.

Abstract Interest in high-sensitivity cardiac troponin I(hs-cTnI) and T(hs-cTnT) has expanded from acute cardiac care to cardiovascular disease(CVD) risk stratification. Whether hs-cTnI and hs-cTnT are interchangeable in the ambulant setting is largely unexplored. Cardiac injury is a mechanism that may underlie the associations between troponin levels and mortality in the general population. In the population-based Maastricht Study, we assessed the correlation and concordance between hs-cTnI and hs-cTnT. Multiple regression analyses were conducted to assess the association of hs-cTnI and hs-cTnT with electrocardiographic (ECG) changes indicative of cardiac abnormalities. In 3016 eligible individuals(mean age,60 ± 8years;50.6%,men) we found a modest correlation between hs-cTnI and hs-cTnT(r = 0.585). After multiple adjustment, the association with ECG changes indicative of cardiac abnormalities was similar for both hs-cTn assays(OR,hs-cTnI:1.72,95%CI:1.40-2.10;OR,hs-cTnT:1.60,95%CI:1.22–2.11). The concordance of dichotomized hs-cTnI and hs-cTnT was κ = 0.397(≥sex-specific 75th percentile). Isolated high levels of hs-cTnI were associated with ECG changes indicative of cardiac abnormalities(OR:1.93,95%CI:1.01–3.68), whereas isolated high levels of hs-cTnT were not(OR:1.07,95%CI:0.49–2.31). In conclusion, there is a moderate correlation and limited concordance between hs-cTnI and hs-cTnT under non-acute conditions. These data suggest that associations of hs-cTnI and hs-cTnT with cardiac injury detected by ECG are driven by different mechanisms. This information may benefit future development of CVD risk stratification algorithms.

Dendritic cells (DCs) are important initiators of adaptive immunity, and they possess a multitude of Pattern Recognition Receptors (PRR) to generate an adequate T cell mediated immunity against invading pathogens. PRR ligands are frequently conjugated to tumor-associated antigens in a vaccination strategy to enhance the immune response toward such antigens. One of these PPRs, DC-SIGN, a member of the C-type lectin receptor (CLR) family, has been extensively targeted with Lewis structures and mannose glycans, often presented in multivalent fashion. We synthesized a library of well-defined mannosides (mono-, di-, and tri-mannosides), based on known “high mannose” structures, that we presented in a systematically increasing number of copies (n = 1, 2, 3, or 6), allowing us to simultaneously study the effect of mannoside configuration and multivalency on DC-SIGN binding via Surface Plasmon Resonance (SPR) and flow cytometry. Hexavalent presentation of the clusters showed the highest binding affinity, with the hexa-α1,2-di-mannoside being the most potent ligand. The four highest binding hexavalent mannoside structures were conjugated to a model melanoma gp100-peptide antigen and further equipped with a Toll-like receptor 7 (TLR7)-agonist as adjuvant for DC maturation, creating a trifunctional vaccine conjugate. Interestingly, DC-SIGN affinity of the mannoside clusters did not directly correlate with antigen presentation enhancing properties and the α1,2-di-mannoside cluster with the highest binding affinity in our library even hampered T cell activation. Overall, this systematic study has demonstrated that multivalent glycan presentation can improve DC-SIGN binding but enhanced binding cannot be directly translated into enhanced antigen presentation and the sole assessment of binding affinity is thus insufficient to determine further functional biological activity. Furthermore, we show that well-defined antigen conjugates combining two different PRR ligands can be generated in a modular fashion to increase the effectiveness of vaccine constructs.

Wind energy is an important renewable source with a stochastic nature. To capture this energy, variable speed generators are installed in wind towers and different maximum power point (MPP) tracking (MPPT) strategies have been developed in literature to maximise the output power. However, in gusty weather, wind turbines fail to track the optimum operating point due to their relatively high inertia. This paper proposes an innovative MPPT strategy to capture the energy of wind gusts. The developed controller consists of a conventional TSR control together with a bidirectional controller, which takes over the control of the rectifier under varying wind condition. The simulation results show an overall efficiency improvement and more stability for the proposed strategy.

A Correction to this paper has been published: https://doi.org/10.1038/s41467-020-20120-4

The use of structural equation models for causal inference from panel data is critiqued in the causal inference literature for unnecessarily relying on a large number of parametric assumptions, and alternative methods originating from the potential outcomes framework have been recommended, such as inverse probability weighting (IPW) estimation of marginal structural models (MSMs). To better understand this criticism, we describe three phases of causal research. We explain (differences in) the assumptions that are made throughout these phases for structural equation modeling (SEM) and IPW-MSM approaches using an empirical example. Second, using simulations we compare the finite sample performance of SEM and IPW-MSM for the estimation of time-varying exposure effects on an end-of-study outcome under violations of parametric assumptions. Although increased reliance on parametric assumptions does not always translate to increased bias (even under model misspecification), researchers are still well-advised to acquaint themselves with causal methods from the potential outcomes framework.

With the increasing shares of intermittent renewable sources in the grid, it becomes increasingly essential to quantify the requirements of the power systems flexibility. In this article, an adjusted weight flexibility metric (AWFM) is developed to quantify the available flexibility within individual generators as well as within the overall system. The developed metric is useful for power system operators who require a fast, simple, and offline metric. This provides a more realistic and accurate quantification of the available technical flexibility without performing time-consuming multi-temporal simulations. Another interesting feature is that it can be used to facilitate scenario comparisons. This is achieved by developing a new framework to assure the consistency of the metric and by proposing a new adjusted weighting mechanism based on correlation analysis and analytic hierarchy process (AHP). A new ranking approach based on flexibility was also proposed to increase the share of the renewable energy sources (RESs). The proposed framework was tested on the IEEE RTS-96 test-system. The results demonstrate the consistency of the AWFM. Moreover, the results show that the proposed metric is adaptive as it automatically adjusts the flexibility index with the addition or removal of generators. The new ranking approach proved its ability to increase the wind share from 28% to 37.2% within the test system. The AWFM can be a valuable contribution to the field of flexibility for its ability to provide systematic formulation for the precise analysis and accurate assessment of inherent technical flexibility for a low carbon power system.

The increased penetration of renewable energy sources in the electrical grid raises the need for more power system flexibility. One of the high potential groups to provide such flexibility is the industry. Incentives to do so are provided by variable pricing and remuneration of supplied ancillary services. The operational flexibility of a chlor-alkali electrolysis process shows opportunities in the current energy and ancillary services markets. A co-optimisation of operating the chlor-alkali process under an hourly variable priced electricity sourcing strategy and the delivery of Frequency Containment Reserve (FCR) is the core of this work. A short term price prediction for the Day-Ahead Market (DAM) and FCR market as input for a deterministic optimisation shows good results under standard DAM price patterns, but leaves room for improvement in case of price fluctuations, e.g., as caused by Renewable Energy Sources (RES). A two-stage stochastic optimisation is considered to cope with the uncertainties introduced by the exogenous parameters. An improvement of the stochastic solution over the deterministic Expected Value (EV) solution is shown.

This article investigates the impact of the pitch-to-stall and pitch-to-feather control concepts on horizontal axis wind turbines (HAWTs) with different blade designs. Pitch-to-feather control is widely used to limit the power output of wind turbines in high wind speed conditions. However, stall control has not been taken forward in the industry because of the low predictability of stalled rotor aerodynamics. Despite this drawback, this article investigates the possible advantages of this control concept when compared to pitch-to-feather control with an emphasis on the control performance and its impact on the pitch mechanism and structural loads. In this study, three HAWTs with different blade designs, i.e., untwisted, stall-regulated, and pitch-regulated blades, are investigated. The control system is validated in both uniform and turbulent wind speed. The results show that pitch-to-stall control enhances the constant power control for wind turbines with untwisted and stall-regulated blade designs. Stall control alleviates the fore-aft tower loading and the blades flapwise moment of the wind turbine with stall-regulated blades in uniform winds. However, in turbulent winds, the flapwise moment increases to a certain extent as compared to pitch-to-feather control. Moreover, pitch-to-stall control considerably reduces the summed blade pitch movement, despite that it increases the risk of surface damage in the rolling bearings due to oscillating movements with a small amplitude.

Patients with primary immunoglobulin deficiency have lower immunoglobulin levels or decreased immunoglobulin function, which makes these patients more susceptible to bacterial infection. Most prevalent are the selective IgA deficiencies (~1:3,000), followed by common variable immune deficiency (~1:25,000). Agammaglobulinemia is less common (~1:400,000) and is characterized by very low or no immunoglobulin production resulting in a more severe disease phenotype. Therapy for patients with agammaglobulinemia mainly relies on prophylactic antibiotics and the use of IgG replacement therapy, which successfully reduces the frequency of invasive bacterial infections. Currently used immunoglobulin preparations contain only IgG. As a result, concurrent IgA and IgM deficiency persist in a large proportion of agammaglobulinemia patients. Especially patients with IgM deficiency remain at risk for recurrent infections at mucosal surfaces, which includes the respiratory tract. IgA and IgM have multiple functions in the protection against bacterial infections at the mucosal surface. Because of their multimeric structure, both IgA and IgM are able to agglutinate bacteria efficiently. Agglutination allows for entrapment of bacteria in mucus that increases clearance from the respiratory tract. IgA is also important for blocking bacterial adhesion by interfering with bacterial adhesion receptors. IgM in its place is very well capable of activating complement, therefore, it is thought to be important in complement-mediated protection at the mucosal surface. The purpose of this Mini Review is to highlight the latest advances regarding IgA- and IgM-enriched immunoglobulin replacement therapy. We describe the different IgA- and IgM-enriched IgG formulations, their possible modes of action and potential to protect against respiratory tract infections in patients with primary immunoglobulin deficiencies.

The incidence of severe Haemophilus influenza infections, such as sepsis and meningitis, has declined substantially since the introduction of the H. influenzae serotype b vaccine. However, the H. influenzae type b vaccine fails to protect against nontypeable H. influenzae strains, which have become increasingly frequent causes of invasive disease, especially among children and the elderly. We summarize recent literature supporting the emergence of invasive nontypeable H. influenzae and describe mechanisms that may explain its increasing prevalence over the past 2 decades.