Search

The sensitivity of expected annual damage, EAD, is analytically analysed by applying a log-linear relation between return periods and corresponding damages. It is found that the smallest return period for damage should be estimated as precisely as possible, that the percentage uncertainty in the damage estimate is transformed into the same percentage uncertainty in the EAD estimate, and that it is possible to extrapolate beyond the largest return period with corresponding damage assessment. The precision of the estimate of EAD is investigated in detail in the case of only few available data, and it is found that two different methods for numerical integration may result in strongly diverging results. By applying a piecewise log-linear damage function, it is shown that the log-linear model provides a trustworthy estimate of EAD, also in the case of few available data. Finally, the modifications needed in the special case of threshold exceedance data instead of annual maxima data are presented.

For Danish conditions, discrete rain intensity climate factors for a 100-year time horizon are generalized to continuous curves as functions of the return period. Assuming the tails of the distribution functions for T-year events to be approximately exponential, a general formula for projecting current return periods into future return periods is developed. Moreover, the uncertainty of the future T-values due to uncertainty in the climate factor is approximately assessed using first order analysis.

Introduction: The complement system anaphylatoxin C5a is a critical player in inflammation. By binding to complement C5a receptor 1 (C5aR1/CD88), C5a regulates many cellular functions, mainly as a potent pro-inflammatory inducer. We describe the generation and selection of a potent antagonistic C5aR1 mouse monoclonal antibody (mAb). Methods: Initial C5aR1 hybridoma clone selection was performed with a cell-binding study in human whole blood. In-house C5aR1 mAb assessment for C5aR1 inhibition was done via the iLite® C5a assay. C5aR1 mAb specificity was investigated on C5aR1his- and C5aR2his-expressing Flp-In™-CHO cells. Physiological C5aR1 inhibition was assessed via a C5a-driven calcium flux assay and stimulation assay based on isolated polymorphonuclear leukocytes (PMNs) and a whole blood model stimulated with Escherichia coli. Results: The supernatant of hybridoma clones targeting the N-terminal section of C5aR1 displayed efficient binding to C5aR1 in whole blood, which was confirmed for purified mAbs. The C5aR1 mAb 18-41-6 was selected following the assay of in-house C5aR1 mAbs via the iLite® C5a assay. The mAb 18-41-6 was specific for C5aR1. Full-size and/or F(ab’)2 preparations of mAb 18-41-6 were found to efficiently abrogate C5a-induced calcium flux in neutrophils and to significantly reduce the upregulation of the activation markers CD11b (neutrophils, monocytes) and CD66b (neutrophils). Conclusion: Our results demonstrate that mAb 18-41-6 is a valuable tool for investigating the C5a-C5aR1 axis and a potential therapeutic candidate for inflammatory disease treatment.

IntroductionThe complement system is part of innate immunity and is comprised of an intricate network of proteins that are vital for host defense and host homeostasis. A distinct mechanism by which complement defends against invading pathogens is through the membrane attack complex (MAC), a lytic structure that forms on target surfaces. The MAC is made up of several complement components, and one indispensable component of the MAC is C7. The role of C7 in MAC assembly is well documented, however, inherent characteristics of C7 are yet to be investigated.MethodsTo shed light on the molecular characteristics of C7, we examined the properties of serum-purified C7 acquired using polyclonal and novel monoclonal antibodies. The properties of serum‑purified C7 were investigated through a series of proteolytic analyses, encompassing Western blot and mass spectrometry. The nature of C7 protein-protein interactions were further examined by a novel enzyme-linked immunosorbent assay (ELISA), as well as size‑exclusion chromatography. ResultsProtein analyses showcased an association between C7 and clusterin, an inhibitory complement regulator. The distinct association between C7 and clusterin was also demonstrated in serum-purified clusterin. Further assessment revealed that a complex between C7 and clusterin (C7-CLU) was detected. The C7-CLU complex was also identified in healthy serum and plasma donors, highlighting the presence of the complex in circulation. DiscussionClusterin is known to dissociate the MAC structure by binding to polymerized C9, nevertheless, here we show clusterin binding to the native form of a terminal complement protein in vivo. The presented data reveal that C7 exhibits characteristics beyond that of MAC assembly, instigating further investigation of the effector role that the C7-CLU complex plays in the complement cascade.

Mannose-binding lectin-associated serine protease 2 (MASP-2) is the main activator of the lectin complement pathway and has been suggested to be involved in the pathophysiology of coronavirus disease 2019 (COVID-19). To study a possible association between MASP-2 and COVID-19, we aimed at developing a sensitive and reliable MASP-2 ELISA. From an array of novel mouse-monoclonal antibodies using recombinant MASP-2 as antigen, two clones were selected to create a sandwich ELISA. Plasma samples were obtained from 216 healthy controls, 347 convalescent COVID-19 patients, and 147 prospectively followed COVID-19 patients. The assay was specific towards MASP-2 and did not recognize the truncated MASP2 splice variant MAP-2 (MAp19). The limit of quantification was shown to be 0.1 ng/mL. MASP-2 concentration was found to be stable after multiple freeze-thaw cycles. In healthy controls, the mean MASP-2 concentration was 524 ng/mL (95% CI: 496.5–551.6). No significant difference was found in the MASP-2 concentrations between COVID-19 convalescent samples and controls. However, a significant increase was observed in prospectively followed COVID-19 patients (mean: 834 ng/mL [95% CI: 765.3–902.7, p < 0.0001]). In these patients, MASP-2 concentration correlated significantly with the concentrations of the terminal complement complex (ρ = 0.3596, p < 0.0001), with the lectin pathway pattern recognition molecules ficolin-2 (ρ = 0.2906, p = 0.0004) and ficolin-3 (ρ = 0.3952, p < 0.0001) and with C-reactive protein (ρ = 0.3292, p = 0.0002). Overall, we developed a specific quantitative MASP-2 sandwich ELISA. MASP-2 correlated with complement activation and inflammatory markers in COVID-19 patients, underscoring a possible role of MASP-2 in COVID-19 pathophysiology.

The history of Nordic Hydrology/Hydrology Research is described from its initiation in 1970 to its current state in 2021. This includes dramatic changes leading first to an ownership transformation to Nordic Association for Hydrology (NAH) in 1976, and much later, in 2004, to a joint ownership between NAH, British Hydrological Society and IWA Publishing. The development in publication policy during time is covered as well. HIGHLIGHTS Motivation for journal start.; Journal development and management.; Change of journal publisher.; Expansion of journal ownership.; Adoption of open access.;

The paper presents prominent Nordic contributions to stochastic methods in hydrology and water resources during the previous 50 years. The development in methods from analysis of stationary and independent hydrological events to include non-stationarity, risk analysis, big data, operational research and climate change impacts is hereby demonstrated. The paper is divided into four main sections covering flood frequency and drought analyses, assessment of rainfall extremes, stochastic approaches to water resources management and approaches to climate change and adaptation efforts. It is intended as a review paper referring to a rich selection of internationally published papers authored by Nordic hydrologists or hydrologists from abroad working in a Nordic country or in cooperation with Nordic hydrologists. Emerging trends in needs and methodologies are highlighted in the conclusions. HIGHLIGHTS Historical development in use of stochastic methods.; From stationarity to climate change impacts.; From univariate to multivariate problems.; From local to regional problems.;

This study investigates the dynamics of immunological markers after first SARS-CoV-2 vaccination dose in cohort of healthcare professionals in Denmark. Natural infection was associated with higher antibody responses, and IgG decline varied by age, sex, T-cell response, previous infection, and interval between vaccine doses.

Activation of the complement system is mediated by the interaction between pathogens and pattern recognition molecules (PRMs); mannose-binding lectin (MBL), ficolins, and collectin-10/-11 from the lectin pathway and C1q from the classical pathway. Lectin pathway activation specifically depends on proteases named MBL-associated serine proteases (MASPs) that are found in complexes with PRMs. In this study, we hypothesize that MASPs can recognize selected pathogens independently of PRMs. Using different clinical strains of opportunistic fungi, we have observed that MASPs directly recognize certain fungal pathogens in a way that can facilitate complement activation. Among these were Aspergillus fumigatus – a dangerous pathogen, especially for immunocompromised patients. In flow cytometry and fluorescence microscopy, we found that MASP-1 and -3 bound to all A. fumigatus growth stages (conidia, germ tubes, and hyphae), whereas rMASP-2 and the nonproteolytic rMAP-1 did not. Bound rMASPs could recruit rMBL and rficolin-3 to A. fumigatus conidia in a nonclassical manner and activate complement via rMASP-2. In experiments using recombinant and purified components, rMASP-1 increased the neutrophilic phagocytosis of conidia. In serum where known complement activation pathways were blocked, phagocytosis could be mediated by rMASP-3. We have encountered an unknown pathway for complement activation and found that MASP-1 and MASP-3 have dual functions as enzymes and as PRMs.

Abstract Background Numerous studies emphasize the positive effects of physical activity on health and well-being in cancer patients. The effects of physical activity on the working lives of cancer patients have received less attention. The aim of the present study was to examine the association between physical activity and work status in employees with cancer, and the mediating role of return to work self-efficacy (RTWSE) in this association. Methods Data from questionnaires (physical activity, RTWSE, performance status, sociodemographic), patient records, and Danish national registries (work status, education) were collected for 217 employees initiating chemotherapy for cancer. The associations of physical activity at baseline with work status at baseline and at twelve months follow-up, respectively, were estimated with logistic regression. The mediating role of RTWSE was investigated using the Sobel Goodmann test. Results Employees with moderate (> 30 min/day) or high (> 150 min/day) levels of current daily activity at baseline had significantly increased odds for working at baseline (OR = 2.83, 95%CI = 0.73–10.96 and OR = 6.13, 95%CI = 1.68–22.40, respectively) and at twelve months (OR = 3.90, 95%CI = 1.19–12.77 and OR = 3.43, 95%CI = 1.12–10.51, respectively), compared to sedentary employees. Likewise, employees, physically active in their leisure time (light or vigorous psychical activity) for 2–4 h/week or > 4 h/week of light activity at baseline, had increased odds for working at twelve months (OR range = 1.20 (95%CI = 0.40–3.61)–5.39(95%CI = 0.78–37.32)), compared to sedentary employees. RTWSE was not found to mediate the observed associations. Conclusions Physical activity appears positively associated with work status in employees undergoing treatment for cancer in the twelve months period after initiating chemotherapy.

August Colding was one of the three pioneers who in the mid-1800s almost simultaneously and independently formulated the first law of thermodynamics, the two others being Robert Mayer and James Joule. This first, significant achievement was followed by a sequence of other ground-breaking discoveries within a broad range of disciplines: magnetism, steam power, gas production, hydraulics, soil physics, hydrology, heating and ventilation, meteorology, and oceanography. Moreover, he made a significant contribution to the understanding of the spread of cholera. In hydrology, he used evaporation experiments to obtain water balances. Independently, he formulated Darcy's law and was the first to calculate the water table between drainpipes and the piezometric surface in confined aquifers. His main occupation, however, was chief engineer in Copenhagen, where he modernized the city by introducing groundwater-based water supply and building a waterworks delivering pressured, clean water into houses, a gasworks and gas-based street lighting, and a citywide sewage system. Colding has not been as recognized internationally as he might deserve, probably because most of his publications were written in Danish. Even in Denmark, he seems today almost forgotten. This paper highlights his most important scientific contributions, in particular his achievements in hydrology, hydraulics, meteorology, and oceanography.

The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to constitute a serious public health threat worldwide. Protective antibody-mediated viral neutralization in response to SARS-CoV-2 infection has been firmly characterized. Where the effects of the antibody response are generally considered to be beneficial, an important biological question regarding potential negative outcomes of a SARS-CoV-2 antibody response has yet to be answered. We determined the distribution of IgG subclasses and complement activation levels in plasma from convalescent individuals using in-house developed ELISAs. The IgG response towards SARS-CoV-2 receptor-binding domain (RBD) after natural infection appeared to be mainly driven by IgG1 and IgG3 subclasses, which are the main ligands for C1q mediated classical complement pathway activation. The deposition of the complement components C4b, C3bc, and TCC as a consequence of SARS-CoV-2 specific antibodies were depending primarily on the SARS-CoV-2 RBD and significantly correlated with both IgG levels and disease severity, indicating that individuals with high levels of IgG and/or severe disease, might have a more prominent complement activation during viral infection. Finally, freshly isolated monocytes and a monocyte cell line (THP-1) were used to address the cellular mediated inflammatory response as a consequence of Fc-gamma receptor engagement by SARS-CoV-2 specific antibodies. Monocytic Fc gamma receptor charging resulted in a significant rise in the secretion of the pro-inflammatory cytokine TNF-α. Our results indicate that SARS-CoV-2 antibodies might drive significant inflammatory responses through the classical complement pathway and via cellular immune-complex activation that could have negative consequences during COVID-19 disease. We found that increased classical complement activation was highly associated to COVID-19 disease severity. The combination of antibody-mediated complement activation and subsequent cellular priming could constitute a significant risk of exacerbating COVID-19 severity.

The alpha/B.1.1.7 SARS-CoV-2 lineage emerged in autumn 2020 in the United Kingdom and transmitted rapidly until winter 2021 when it was responsible for most new COVID-19 cases in many European countries. The incidence domination was likely due to a fitness advantage that could be driven by the receptor-binding domain (RBD) residue change (N501Y), which also emerged independently in other variants of concern such as the beta/B.1.351 and gamma/P.1 strains. Here, we present a functional characterization of the alpha/B.1.1.7 variant and show an eightfold affinity increase towards human angiotensin-converting enzyme-2 (ACE-2). In accordance with this, transgenic hACE2 mice showed a faster disease progression and severity after infection with a low dose of B.1.1.7, compared to an early 2020 SARS-CoV-2 isolate. When challenged with sera from convalescent individuals or anti-RBD monoclonal antibodies, the N501Y variant showed a minor, but significant elevated evasion potential of ACE-2/RBD antibody neutralization. The data suggest that the single asparagine to tyrosine substitution remarkable rise in affinity may be responsible for the higher transmission rate and severity of the B.1.1.7 variant.

Abstract Background The national guideline for sore throat, endorsed by the Danish Society of General Medicine, recommends the use of the modified Centor score and streptococcal rapid antigen detection test to guide diagnosis and treatment of sore throat. The aim was to investigate Danish general practitioners (GPs) routine management of sore throat patients with a focus on the modalities used and adherence to the guideline. Methods A cross-sectional study. GPs in the Central Denmark Region answered an online questionnaire in October 2017. The main outcome measure was modalities used in the management of sore throat patients. Results In total, 266 of 500 (53%) GPs answered the survey. Ten percent of participants were adherent or almost adherent to the guideline, while 82% of GPs added one or more extra modalities (general clinical assessment (67%), biochemical parameters (48%), and throat swabs for bacterial culture (18%)) to differentiate viral and bacterial etiology. Sixty-five percent of participants used the Centor Score or modified Centor Score, 96% of GPs used a streptococcal rapid antigen detection test, and all GPs chose narrow-spectrum penicillin as the first-line antibiotic. The most common reasons for non-adherence to the guideline were greater confidence in the clinical assessment (39%), time pressure (33%), and difficulty recalling the guideline (19%). Conclusion Danish GPs rarely adhere to the recommended sore throat management guideline, but use various combinations of different modalities in the assessment of bacterial infection. This practice may increase antibiotic prescription rates.

After describing the hydrological cycle and defining hydrology in the introduction, the early historical development of hydrology is briefly presented in the second section. Then the incorporation of hydrology within the IUGG and the subsequent development of the association are described chronologically. This description is organized into five sections corresponding to five different periods, focused on the scientific and organizational development of the association during each period. Finally, in the conclusions, the present state of the association is discussed together with an outlook for the future.

OBJECTIVES: The aim of this study was to perform a cross-cultural adaptation of the return-to-work self-efficacy (RTWSE-19) scale into Danish and test the reliability, validity and responsiveness of the final version. METHODS: The adaptation process followed standard guidelines and the pretest was performed on 40 sickness absence beneficiaries. Tests of reliability, validity and responsiveness of the final version was performed on 782 participants of whom 440 (56%) responded. For the sub- and global scales, internal consistency was evaluated by Cronbach’s alpha and reproducibility using paired t-test and intraclass correlation coefficient (ICC), respectively Responsiveness was evaluated by paired t-test and the association between RTWSE-19 and job status at ten weeks was tested in a logistic regression model, adjusted for gender, age and baseline job status. RESULTS: The face validity and reliability of the Danish version of the RTWSE-19 questionnaire were satisfactory. The internal consistency (alpha) for the three subscales ranged from 0.93 to 0.97. A test-retest showed no difference as well as high ICC between scale scores at baseline and one week later. The content validity of the final version was confirmed. High baseline RTWSE-19 level was associated with being at work after ten weeks odds ratio (OR) 3.24, 95% confidence interval (95% CI) 1.48–7.07. CONCLUSIONS: The RTWSE-19 cross-cultural translation to Danish was performed satisfactorily. A modified final version was produced, and the test of the instrument’s reliability and validity showed that the psychometric properties of the questionnaire were partly confirmed. The instrument may be useful in rehabilitation practice to guide further assessment, goal setting and RTW decision-making.

Overexploitation of groundwater reserves is a major environmental problem around the world. In many river basins, groundwater and surface water are used conjunctively and joint optimization strategies are required. A hydroeconomic modeling approach is used to find cost-optimal sustainable surface water and groundwater allocation strategies for a river basin, given an arbitrary initial groundwater level in the aquifer. A simplified management problem with conjunctive use of scarce surface water and groundwater under inflow and recharge uncertainty is presented. Because of head-dependent groundwater pumping costs the optimization problem is nonlinear and non-convex, and a genetic algorithm is used to solve the one-step-ahead subproblems with the objective of minimizing the sum of immediate and expected future costs. A real-world application in the water-scarce Ziya River basin in northern China is used to demonstrate the model capabilities. Persistent overdraft from the groundwater aquifers on the North China Plain has caused declining groundwater levels. The model maps the marginal cost of water in different scenarios, and the minimum cost of ending groundwater overdraft in the basin is estimated to be CNY 5.58 billion yr−1. The study shows that it is cost-effective to slowly recover the groundwater aquifer to a level close to the surface, while gradually lowering the groundwater value to the equilibrium at CNY 2.15 m−3. The model can be used to guide decision-makers to economic efficient long-term sustainable management of groundwater and surface water resources.

Enteroaggregative Escherichia coli (EAEC) causes acute and persistent diarrhea worldwide. Still, the involvement of host factors in EAEC infections is unresolved. Binding of recognition molecules from the lectin pathway of complement to EAEC strains have been observed, but the importance is not known. Our aim was to uncover the involvement of these molecules in innate complement dependent immune protection toward EAEC. Binding of mannose-binding lectin, ficolin-1, -2, and -3 to four prototypic EAEC strains, and ficolin-2 binding to 56 clinical EAEC isolates were screened by a consumption-based ELISA method. Flow cytometry was used to determine deposition of C4b, C3b, and the bactericidal C5b-9 membrane attack complex (MAC) on the bacteria in combination with different complement inhibitors. In addition, the direct serum bactericidal effect was assessed. Screening of the prototypic EAEC strains revealed that ficolin-2 was the major binder among the lectin pathway recognition molecules. However, among the clinical EAEC isolates only a restricted number (n = 5) of the isolates bound ficolin-2. Using the ficolin-2 binding isolate C322-17 as a model, we found that incubation with normal human serum led to deposition of C4b, C3b, and to MAC formation. No inhibition of complement deposition was observed when a C1q inhibitor was added, while partial inhibition was observed when ficolin-2 or factor D inhibitors were used separately. Combining the inhibitors against ficolin-2 and factor D led to virtually complete inhibition of complement deposition and protection against direct bacterial killing. These results demonstrate that ficolin-2 may play an important role in innate immune protection against EAEC when an appropriate ligand is exposed, but many EAEC strains evade lectin pathway recognition and may, therefore, circumvent this strategy of innate host immune protection.

Inflammation is a part of the initial process leading to atherosclerosis and cholesterol crystals (CC), found in atherosclerotic plaques, which are known to induce complement activation. The pentraxins C-reactive protein (CRP), long pentraxin 3 (PTX3), and serum amyloid P component (SAP) are serum proteins associated with increased risk of cardiovascular events and these proteins have been shown to interact with the complement system. Whether the pentraxins binds to CC and mediate downstream complement-dependent inflammatory processes remains unknown. Binding of CRP, PTX3, and SAP to CC was investigated in vitro by flow cytometry and fluorescence microscopy. CRP, PTX3, and SAP bound to CC in a concentration-dependent manner. CRP and PTX3 interacted with the complement pattern recognition molecule C1q on CC by increasing the binding of both purified C1q and C1q in plasma. However, CRP was the strongest mediator of C1q binding and also the pentraxin that most potently elevated C1q-mediated complement activation. In a phagocytic assay using whole blood, we confirmed that phagocytosis of CC is complement dependent and initiated by C1q-mediated activation. The pathophysiological relevance of the in vitro observations was examined in vivo in human atherosclerotic plaques. CRP, PTX3, and SAP were all found in atherosclerotic plaques and were located mainly in the cholesterol-rich necrotic core, but co-localization with the terminal C5b-9 complement complex was only found for CRP. In conclusion, this study identifies CRP as a strong C1q recruiter and complement facilitator on CC, which may be highly relevant for the development of atherosclerosis.

The complement system is a crucial defensive network that protects the host against invading pathogens. It is part of the innate immune system and can be initiated via three pathways: the lectin, classical and alternative activation pathway. Overall the network compiles a group of recognition molecules that bind specific patterns on microbial surfaces, a group of associated proteases that initiates the complement cascade, and a group of proteins that interact in proteolytic complexes or the terminal pore-forming complex. In addition, various regulatory proteins are important for controlling the level of activity. The result is a pro-inflammatory response meant to combat foreign microbes. Microbial elimination is, however, not a straight forward procedure; pathogens have adapted to their environment by evolving a collection of evasion mechanisms that circumvent the human complement system. Complement evasion strategies features different ways of exploiting human complement proteins and moreover features different pathogen-derived proteins that interfere with the normal processes. Accumulated, these mechanisms target all three complement activation pathways as well as the final common part of the cascade. This review will cover the currently known lectin pathway evasion mechanisms and give examples of pathogens that operate these to increase their chance of invasion, survival and dissemination.

Aspergillus fumigatus infections are associated with a high mortality rate for immunocompromised patients. The complement system is considered to be important in protection against this fungus, yet the course of activation is unclear. The aim of this study was to unravel the role of the classical, lectin and alternative pathways under both immunocompetent and immunocompromised conditions to provide a relevant dual-perspective on the response against A. fumigatus.Conidia (spores) from a clinical isolate of A. fumigatus were combined with various human serum types (including serum deficient of various complement components and serum from umbilical cord blood). We also combined this with inhibitors against C1q, mannose-binding lectin (MBL) and ficolin-2 before complement activation products and phagocytosis were detected by flow cytometry.Our results showed that alternative pathway amplified complement on A. fumigatus, but required classical and/or lectin pathway for initiation. In normal human serum this initiation came primarily from the classical pathway. However, with a dysfunctional classical pathway (C1q-deficient serum), lectin pathway activated complement and mediated opsonophagocytosis through MBL. To model the antibody-decline in a compromised immune system, we used serum from normal umbilical cords and found MBL to be the key complement initiator. In another set of experiments serum from patients with different kinds of immunoglobulin insufficiencies showed that the MBL lectin pathway contribution was highest in the samples with the lowest IgG/IgM binding.In conclusion, lectin pathway appears to be the primary route of complement activation in the absence of anti-A. fumigatus antibodies, whereas in a balanced immune state classical pathway is the main activator. This suggests a crucial role for the lectin pathway in innate immune protection against A. fumigatus in immunocompromised patients.