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Abstract Cerebrospinal fluid (CSF) biomarkers reflect brain pathophysiology and are used extensively in translational research as well as in clinical practice for diagnosis of neurological diseases, e.g., Alzheimer’s disease (AD). However, CSF biomarker concentrations may be influenced by non-disease related inter-individual variability. Here we use a data-driven approach to demonstrate the existence of inter-individual variability in mean standardized CSF protein levels. We show that these non-disease related differences cause many commonly reported CSF biomarkers to be highly correlated, thereby producing misleading results if not accounted for. To adjust for this inter-individual variability, we identified and evaluated high-performing reference proteins which improved the diagnostic accuracy of key CSF AD biomarkers. Our reference protein method attenuates the risk for false positive findings, and improves the sensitivity and specificity of CSF biomarkers, with broad implications for both research and clinical practice.

Background Healthcare professionals (HCPs) play an important role in vaccination; those with low confidence in vaccines are less likely to recommend them to their patients and to be vaccinated themselves. The study’s purpose was to adapt and validate long- and short-form versions of the International Professionals’ Vaccine Confidence and Behaviors (I-Pro-VC-Be) questionnaire to measure psychosocial determinants of HCPs’ vaccine confidence and their associations with vaccination behaviors in European countries. Research design and methods After the original French-language Pro-VC-Be was culturally adapted and translated, HCPs involved in vaccination (mainly GPs and pediatricians) across Germany, Finland, France, and Portugal completed a cross-sectional online survey in 2022. A 10-factor multigroup confirmatory factor analysis (MG-CFA) of the long-form (10 factors comprising 34 items) tested for measurement invariance across countries. Modified multiple Poisson regressions tested the criterion validity of both versions. Results 2,748 HCPs participated. The 10-factor structure fit was acceptable to good everywhere. The final MG-CFA model confirmed strong factorial invariance and showed very good fit. The long- and short-form I-Pro-VC-Be had good criterion validity with vaccination behaviors. Conclusion This study validates the I-Pro-VC-Be among HCPs in four European countries; including long- and short-form tools for use in research and public health.

Introduction Physicians play a critical role in encouraging their patients to get vaccinated, in part by responding to patients’ concerns about vaccines. It is, therefore, important to understand what difficulties physicians have in dealing with different concerns they may encounter. The aim of this article was to determine physicians’ perceptions of difficulties in rebutting different antivaccination arguments from patients using data collected as part of a cross-sectional, cross-national questionnaire on physicians’ vaccine attitudes and behaviours.Methods Physicians in 4 European countries (Finland, Germany, France and Portugal, total n=2718) rated 33 different arguments, chosen to represent 11 different psychological motivations underlying vaccine hesitancy, in terms of their perceptions of how difficult each argument would be to rebut.Results Across all countries, physicians perceived arguments based on religious concerns and ‘reactance’ (ie, resistance to perceived curbs of freedom) to be the most difficult to rebut, whereas arguments based on patients’ distorted perception of the risks of disease and vaccines were perceived to be the easiest. There were also between-country differences in the level of perceived difficulty of argument rebuttal. Physicians’ perceived difficulty with rebutting arguments was significantly negatively correlated with their vaccine recommendation behaviours and their preparedness for vaccination discussions.Conclusions Physicians may feel better equipped to counter arguments that can be rebutted with facts and evidence but may struggle to respond when arguments are motivated by psychological dispositions or values.

This Comment piece summarises current challenges regarding routine vaccine uptake in the context of the COVID-19 pandemic and provides recommendations on how to increase uptake. To implement these recommendations, the article points to evidence-based resources that can support health-care workers, policy makers and communicators.

Vaccine hesitancy has become a threat to public health, especially as it is a phenomenon that has also been observed among healthcare professionals. In this study, we analyzed the relationship between endorsement of complementary and alternative medicine (CAM) and vaccination attitudes and behaviors among healthcare professionals, using a cross-sectional sample of physicians with vaccination responsibilities from four European countries: Germany, Finland, Portugal, and France (total N = 2,787). Our results suggest that, in all the participating countries, CAM endorsement is associated with lower frequency of vaccine recommendation, lower self-vaccination rates, and being more open to patients delaying vaccination, with these relationships being mediated by distrust in vaccines. A latent profile analysis revealed that a profile characterized by higher-than-average CAM endorsement and lower-than-average confidence and recommendation of vaccines occurs, to some degree, among 19% of the total sample, although these percentages varied from one country to another: 23.72% in Germany, 17.83% in France, 9.77% in Finland, and 5.86% in Portugal. These results constitute a call to consider health care professionals’ attitudes toward CAM as a factor that could hinder the implementation of immunization campaigns.

Climate change is projected to cause alterations in northern coastal systems, including humification and intensified nutrient loads, which can lead to ecosystem imbalances and establishment of new bacterial species. Several potential pathogens, such as different species of Legionella, hide in the environment between infections, some by living inside protozoan host cells. Knowledge about the occurrence of Legionella in natural waters is missing, which disable risk assessments of exposure. We performed a study of the species diversity of Legionella in the northern Baltic Sea (Gulf of Bothnia) during early summer to map their occurrence and to identify possible environmental drivers. We detected Legionella and potential protozoan hosts along gradients of the Gulf of Bothnia. We also for the first time present third generation full-length 16S rRNA amplicon sequencing (Nanopore) to resolve environmental species classification of Legionella, with a method suitable to study all bacteria. Our data show that full length 16S rRNA sequences is sufficient to resolve Legionella while the standard short Illumina sequences did not capture the entire diversity. For accurate species classification of Legionella, harmonization between the Nanopore classification methods is still needed and the bias toward the well-studied Legionella pneumophila need to be resolved. Different Legionella species occurred both in the Bothnian Sea and in the Bothnian Bay and their abundance were linked to humic substances and low salinity. The relative abundance of Legionella was higher in the humic-rich northern waters of the Bothnian Bay. The link between Legionella species and humic substances may be indirect via promotion of the heterotrophic microbial food web, allowing Legionella species and similar bacteria to establish. Humic substances are rich in iron, which has been shown crucial for growth of Legionella species and other pathogens. Considering climate change projections in this regional area, with increased humification and freshwater inflow, this bacterial niche containing potential pathogens might become more widespread in the future Baltic Sea. This study demonstrates the significance of DNA sequencing to monitor public health relevant bacteria like Legionella species in the environment. Including sequencing of bacteria and protozoa in the environmental monitoring programs could be used to identify ecosystem imbalances, which enable appropriate responses to emerging diseases.

Francisella tularensis, the bacterium that causes the zoonosis tularemia, and its genetic near neighbor species, can be difficult or impossible to cultivate from complex samples. Thus, there is a lack of genomic information for these species that has, among other things, limited the development of robust detection assays for F. tularensis that are both specific and sensitive. The objective of this study was to develop and validate approaches to capture, enrich, sequence, and analyze Francisella DNA present in DNA extracts generated from complex samples. RNA capture probes were designed based upon the known pan genome of F. tularensis and other diverse species in the family Francisellaceae. Probes that targeted genomic regions also present in non-Francisellaceae species were excluded, and probes specific to particular Francisella species or phylogenetic clades were identified. The capture-enrichment system was then applied to diverse, complex DNA extracts containing low-level Francisella DNA, including human clinical tularemia samples, environmental samples (i.e., animal tissue and air filters), and whole ticks/tick cell lines, which was followed by sequencing of the enriched samples. Analysis of the resulting data facilitated rigorous and unambiguous confirmation of the detection of F. tularensis or other Francisella species in complex samples, identification of mixtures of different Francisella species in the same sample, analysis of gene content (e.g., known virulence and antimicrobial resistance loci), and high-resolution whole genome-based genotyping. The benefits of this capture-enrichment system include: even very low target DNA can be amplified; it is culture-independent, reducing exposure for research and/or clinical personnel and allowing genomic information to be obtained from samples that do not yield isolates; and the resulting comprehensive data not only provide robust means to confirm the presence of a target species in a sample, but also can provide data useful for source attribution, which is important from a genomic epidemiology perspective.

Metaphern des Archipelischen werden oft verwendet, um das Schreiben der deutsch-japanischen Autorin Yoko Tawada zu charakterisieren, wobei die vielen tatsächlich in ihren Texten vorkommenden Insel-Darstellungen weitgehend unbeachtet bleiben. Ausgehend von John Gillis’ Feststellung, „Western culture not only thinks about islands, but thinks with them“ (2004:1), untersucht der vorliegende Beitrag Formen und poetologische Funktionen des Insularen und des Archipelischen in zwei Texten aus Tawadas Sprachpolizei und Spielpolyglotte (2007). Beide Texte, „Ma und Mu“ und „U.S. + S.R. Eine Sauna in Fernosteuropa“, bedienen sich der Insel als Raum und Denkfigur, um häufig mit (abgelegenen) Inseln verbundene Vorstellungen von Originalität und kultureller ‚Reinheit‘ herauszufordern und an ihrer Stelle die archipelischen Interrelationen und die Bedeutung des verbindenden, die Insel mitformenden Wassers zu akzentuieren.

The migratory behavior of wild birds contributes to the geographical spread of ticks and their microorganisms. In this study, we aimed to investigate the dispersal and co-occurrence of Francisella and spotted fever group Rickettsia (SFGR) in ticks infesting birds migrating northward in the African-Western Palaearctic region (AWPR). Birds were trapped with mist nests across the Mediterranean basin during the 2014 and 2015 spring migration. In total, 575 ticks were collected from 244 birds. We screened the ticks for the species Francisella tularensis, the genus Francisella, and SFGR by microfluidic real-time PCR. Confirmatory analyses and metagenomic sequencing were performed on tick samples that putatively tested positive for F. tularensis during initial screenings. Hyalomma rufipes was the most common tick species and had a high prevalence of Francisella, including co-occurrence of Francisella and SFGR. Metagenomic analysis of total DNA extracted from two H. rufipes confirmed the presence of Francisella, Rickettsia, and Midichloria. Average nucleotide identity and phylogenetic inference indicated the highest identity of the metagenome-assembled genomes to a Francisella-like endosymbiont (FLE), Rickettsia aeschlimannii, and Midichloria mitochondrii. The results of this study suggest that (i) FLE- and SFGR-containing ticks are dispersed by northbound migratory birds in the AWPR, (ii) H. rufipes likely is not involved in transmission of F. tularensis in the AWPR, and (iii) a dual endosymbiosis of FLEs and Midichloria may support some of the nutritional requirements of H. rufipes.

Many contemporary autobiographical texts that depict a transcultural self prominently feature waterscapes in the foreground. The present study focuses on how rivers are functionalized in two autobiographical accounts: the essayistic Flodernas bok (The book of rivers, 2012) by the Swedish poet and essayist Nina Burton, and the autofictional novel Am Fluß (2014) by Esther Kinsky. Both combine the literary representation of travels along rivers with an exploration of European cultural history, but also the history of the self.Using Schmitz-Emans’s (2008) concept of ‘water writing’ for studying ‘riverlike’ writing modes and discussing the findings against the backdrop of research on the cultural significance of water, this article demonstrates how both texts challenge the presumed linearity of rivers by focusing on how they are embedded in a global circuit of waters. It shows that a river’s ability to transgress national borders makes ‘river writing’ attractive for autobiographical enterprises. Finally, both texts emphasize the relationship between man and water as well as that between man and the environment through water. This relatedness of humans and landscape through the fluid element indicates that the self is not sovereign, stable and hovering above its environment, but rather an embedded entity, interwoven in complex fluid networks of interaction.

Abstract Background Human monoclonal antibody ustekinumab is a novel Crohn’s disease (CD) treatment blocking pro-inflammatory cytokines interleukin-12 and 23. The study’s objective was to assess cost-effectiveness of ustekinumab in moderate to severely active CD in Sweden. Methods A cost-effectiveness model with an induction phase decision-tree structure and a maintenance phase Markov cohort structure was constructed. CD was represented by five health-states: remission, mild, moderate-severe, surgery and death. Ustekinumab was compared to adalimumab in patients who had failed conventional care, some of which had tried TNF-alpha-inhibitor(s) without experiencing treatment failure or side effects (“conventional care failure population”) and to vedolizumab in patients previously failing TNF-alpha-inhibitor treatment. Discontinuation probabilities, utilities and ustekinumab induction efficacy were sourced from phase-III trials. Maintenance and comparator efficacy came from network-meta and treatment-sequence analyses. Resource use and unit costs were derived from literature and validated by clinical experts. The analysis had a societal perspective, a life-time time-horizon, and 2-year treatment duration. The results robustness was tested in univariate and probabilistic sensitivity analyses. Cost-effectiveness was estimated using quality-adjusted life-years (QALYs). Results Ustekinumab dominated adalimumab in conventional care failure population (costs: − €6984, QALYs: + 0.232). In TNF-alpha-inhibitor failure population ustekinumab accrued 0.133 more QALYs than vedolizumab, yielding a €30,282 incremental cost-effectiveness ratio. Results were sensitive to decreasing the time horizon and increased treatment duration. At Swedish reference willingness-to-pay of €63,000 (SEK 600,000), ustekinumab had 94% probability of being cost-effective versus adalimumab, and 72% versus vedolizumab. Conclusions Results indicate ustekinumab dominates adalimumab in conventional care failure population, and is cost-effective versus vedolizumab in TNF-alpha-inhibitor failure population.

Abstract Background There is limited real-world data on the economic burden of patients with autosomal dominant polycystic kidney disease (ADPKD). The objective of this study was to estimate the annual direct and indirect costs of patients with ADPKD by severity of the disease: chronic kidney disease (CKD) stages 1–3; CKD stages 4–5; transplant recipients; and maintenance dialysis patients. Methods A retrospective study of ADPKD patients was undertaken April–December 2014 in Denmark, Finland, Norway and Sweden. Data on medical resource utilisation were extracted from medical charts and patients were asked to complete a self-administered questionnaire. Results A total of 266 patients were contacted, 243 (91%) of whom provided consent to participate in the study. Results showed that the economic burden of ADPKD was substantial at all levels of the disease. Lost wages due to reduced productivity were large in absolute terms across all disease strata. Mean total annual costs were highest in dialysis patients, driven by maintenance dialysis care, while the use of immunosuppressants was the main cost component for transplant care. Costs were twice as high in patients with CKD stages 4–5 compared to CKD stages 1–3. Conclusions Costs associated with ADPKD are significant and the progression of the disease is associated with an increased frequency and intensity of medical resource utilisation. Interventions that can slow the progression of the disease have the potential to lead to substantial reductions in costs for the treatment of ADPKD.

A milder climate has during the last decade contributed to an increased density and spreading of ixodid ticks, thus enhancing their role as emerging vectors for pathogenic microorganisms in northern Europe. It remains unclear if they contribute to the occurrence of infections caused by the bacteria Bartonella spp., Francisella tularensis subspecies holarctica and the parasite Toxoplasma gondii in Sweden and on the Åland islands, Finland. In this study, we want to improve understanding of the tick-borne transmission of these pathogens. Volunteers were recruited at primary healthcare centers. Ticks and blood samples were acquired from participants recruited in 2008 and 2009. Health questionnaires were completed, and medical records were acquired where applicable. Feeding time was estimated and screening of pathogens in the ticks was performed through real-time PCR. Ticks (n = 1849) were of mixed developmental stages: 76 larvae, 1295 nymphs, 426 adults and 52 undetermined. All analyzed ticks were considered negative for these pathogens since the CT-values were all below the detection limit for Bartonella spp. (1663 ticks), Francisella spp. (1849 ticks) and Toxoplasma gondii (1813 ticks). We assume that infections with these pathogens are caused by other transmission pathways within these regions of Sweden and the Åland islands, Finland.

In recent years, an increasing diversity of species has been recognized within the family Francisellaceae. Unfortunately, novel isolates are sometimes misnamed in initial publications or multiple sources propose different nomenclature for genetically highly similar isolates. Thus, unstructured and occasionally incorrect information can lead to confusion in the scientific community. Historically, detection of Francisella tularensis in environmental samples has been challenging due to the considerable and unknown genetic diversity within the family, which can result in false positive results. We have assembled a comprehensive collection of genome sequences representing most known Francisellaceae species/strains and restructured them according to a taxonomy that is based on phylogenetic structure. From this structured dataset, we identified a small number of genomic regions unique to F. tularensis that are putatively suitable for specific detection of this pathogen in environmental samples. We designed and validated specific PCR assays based on these genetic regions that can be used for the detection of F. tularensis in environmental samples, such as water and air filters.

Summer outbreaks of tularemia that occurred from 1995 through 2005 in 2 locations in Sweden affected 441 persons. We performed an epidemiologic investigation of these outbreaks using a novel strategy, involving high-resolution genotyping of Francisella tularensis isolates obtained from 136 patients (using 18 genetic markers developed from 6 F. tularensis genome sequences) and interviews with the patients. Strong spatial associations were found between F. tularensis subpopulations and the places of disease transmission; infection by some subpopulations occurred within areas as small as 2 km2, indicating unidentified environmental point sources of tularemia. In both locations, disease clusters were associated with recreational areas beside water, and genetic subpopulations were present throughout the tularemia season and persisted over years. High-resolution genotyping in combination with patients’ statements about geographic places of disease transmission provided valuable indications of likely sources of infection and the causal genotypes during these tularemia outbreaks.

To develop effective and accurate typing of strains of Francisella tularensis, a potent human pathogen and a putative bioterrorist agent, we combined analysis of insertion-deletion (indel) markers with multiple-locus variable-number tandem repeat analysis (MLVA). From 5 representative F. tularensis genome sequences, 38 indel markers with canonical properties, i.e., capable of sorting strains into major genetic groups, were selected. To avoid markers with a propensity for homoplasy, we used only those indels with 2 allelic variants and devoid of substantial sequence repeats. MLVA included sequences with much diversity in copy number of tandem repeats. The combined procedure allowed subspecies division, delineation of clades A.I and A.II of subspecies tularensis, differentiation of Japanese strains from other strains of subspecies holarctica, and high-resolution strain typing. The procedure uses limited amounts of killed bacterial preparations and, because only 1 single analytic method is needed, is time- and cost-effective.

Mutation of the melanocortin-receptor 4 (MC4R) is the most frequent cause of severe obesity in humans. Binding of agouti-related peptide (AgRP) to MC4R involves the co-receptor syndecan-3, a heparan sulfate proteoglycan. The proteoglycan can be structurally modified by the enzyme heparanase. Here we tested the hypothesis that heparanase plays a role in food intake behaviour and energy balance regulation by analysing body weight, body composition and food intake in genetically modified mice that either lack or overexpress heparanase. We also assessed food intake and body weight following acute central intracerebroventricular administration of heparanase; such treatment reduced food intake in wildtype mice, an effect that was abolished in mice lacking MC4R. By contrast, heparanase knockout mice on a high-fat diet showed increased food intake and maturity-onset obesity, with up to a 40% increase in body fat. Mice overexpressing heparanase displayed essentially the opposite phenotypes, with a reduced fat mass. These results implicate heparanase in energy balance control via the central melanocortin system. Our data indicate that heparanase acts as a negative modulator of AgRP signaling at MC4R, through cleavage of heparan sulfate chains presumably linked to syndecan-3.

A robust, rapid and flexible real-time PCR assay for hierarchical genetic typing of clinical and environmental isolates of Francisella is presented. Typing markers were found by multiple genome and gene comparisons, from which 23 canonical single nucleotide polymorphisms (canSNPs) and 11 canonical insertion-deletion mutations (canINDELs) were selected to provide phylogenetic guidelines for classification from genus to isolate level. The specificity of the developed assay, which uses 68 wells of a 96-well real-time PCR format with a detection limit of 100 pg DNA, was assessed using 62 Francisella isolates of diverse genetic and geographical origins. It was then successfully used for typing 14 F. tularensis subsp. holarctica isolates obtained from tularemia patients in Sweden in 2008 and five more genetically diverse Francisella isolates of global origins. When applied to human ulcer specimens for direct pathogen detection the results were incomplete due to scarcity of DNA, but sufficient markers were identified to detect fine-resolution differences among F. tularensis subsp. holarctica isolates causing infection in the patients. In contrast to other real-time PCR assays for Francisella, which are typically designed for specific detection of a species, subspecies, or strain, this type of assay can be easily tailored to provide appropriate phylogenetic and/or geographical resolution to meet the objectives of the analysis.

This article explores the depiction of the sailor and the conflict between bourgeois life and its fluid 'other' in Theodor Storm's novella 'Hans und Heinz Kirch' (1883). The analysis brings together spatial theory, in particular Deleuze and Guattari's understanding of 'smooth' and 'striated' spaces, and reception aesthetics. Next to the 'smooth', fluid border of the ocean, the article identifies other in‐between areas which play a central role in the novella as spheres of negotiating story and identity: the sailor's skin as the border between self and other; and the omissions of language and narration. It argues that the many 'Leerstellen' of the text correspond to the openness of the sea and open up to a 'travelling' reading. Readers are invited to actively explore the open spaces and ambiguities of the text and thus contribute to the production of meaning. Placing Storm's novella in the context of maritime modernity and regarding correspondences between the narrative discourse and the conflict between 'smooth' and 'striated' space, this article offers a new perspective on Storm. [ABSTRACT FROM AUTHOR]