Education, employment, and income among people living with cystic fibrosis across three decades - A matched cohort study using Danish health registries.

BACKGROUND: Past and ongoing advancements in cystic fibrosis (CF) care warrant long-term analysis of the societal impact of the condition. This study aims to evaluate changes in key socioeconomic factors across three decades among people living with CF (pwCF), compared with both the general population and an early-onset chronic disease population. METHODS: This nationwide, registry-based, matched cohort study included all pwCF ≥ 18 years in Denmark in the years 1990, 2000, 2010, and 2018. Each person living with CF was matched to five individuals in the general population and five individuals living with type 1 diabetes or juvenile arthritis based on age, sex, and municipality. RESULTS: The Danish adult CF population increased nearly fourfold from 88 in 1990 to 331 in 2018, and mean age increased by ten years. The educational level of pwCF was similar to the two comparator cohorts, while pwCF were less often in employment and more often permanently outside the labor force. Personal and household income levels of the CF cohort were higher than those of the comparator cohorts. CONCLUSIONS: The disadvantage in employment for pwCF remained, but, over time, the societal profiles of the one-year CF cohorts increasingly converged with those of the comparator cohorts, indicative of improved clinical management, extended life expectancy, and the supportive role of the Danish welfare system in reducing health inequalities. Further research should be done to evaluate the effects of the newly introduced modulator therapies on employment, considering the broader societal impact and impact on quality of life.

Climatic forcing and individual heterogeneity in a resident mountain bird: legacy data reveal effects on reproductive strategies.

Optimization of clutch size and timing of reproduction have substantial effects on lifetime reproductive success in vertebrates, and both individual quality and environmental variation may impact life history strategies. We tested hypotheses related to maternal investment and timing of reproduction, using 17 years (1978-1994) of individual-based life history data on willow ptarmigan (Lagopus l. lagopus, n = 290 breeding females with n = 319 breeding attempts) in central Norway. We analysed whether climatic variation and individual state variables (age and body mass) affected the number of offspring and timing of reproduction, and individual repeatability in strategies. The results suggest that willow ptarmigan share a common optimal clutch size that is largely independent of measured individual states. While we found no clear direct weather effects on clutch size, higher spring temperatures advanced onset of breeding, and early breeding was followed by an increased number of offspring. Warmer springs were positively related to maternal mass, and mass interacted with clutch size in production of hatchlings. Finally, clutch size and timing of reproduction were highly repeatable within individuals, indicating that individual quality guided trade-offs in reproductive effort. Our results demonstrate how climatic forcing and individual heterogeneity in combination influenced life history traits in a resident montane keystone species.

Biodiscoveries within the Australian plant genus Eremophila based on international and interdisciplinary collaboration: results and perspectives on outstanding ethical dilemmas.

In a cross-continental research initiative, including researchers working in Australia and Denmark, and based on joint external funding by a 3-year grant from the Novo Nordisk Foundation, we have used DNA sequencing, extensive chemical profiling and molecular networking analyses across the entire Eremophila genus to provide new knowledge on the presence of natural products and their bioactivities using polypharmocological screens. Sesquiterpenoids, diterpenoids and dimers of branched-chain fatty acids with previously unknown chemical structures were identified. The collection of plant material from the Eremophila genus was carried out according to a 'bioprospecting agreement' with the Government of Western Australia. We recognize that several Eremophila species hold immense cultural significance to Australia's First Peoples. In spite of our best intentions to ensure that new knowledge gained about the genus Eremophila and any potential future benefits are shared in an equitable manner, in accordance with the Nagoya Protocol, we encounter serious dilemmas and potential conflicts in making benefit sharing with Australia's First Peoples a reality.

Exploitative Competition between Mountain Hare and Moose-Qualitative Effects on Hare Winter Forage?

Mountain hares (Lepus timidus) in Scandinavia are classified as Near Threatened in the Norwegian and Swedish Redlists. This is due to a possible population decline witnessed during the last decades in Scandinavia. Competition between large herbivores and mountain hares is one of several hypotheses that has been put forward to explain this decline. In a cafeteria trial we investigate the effects of previous moose (Alces alces) winter browsing on the food selection (i.e., biomass consumed, bites per minute and bitediameter) of downy birch (Betula pubescens) and goat willow (Salix caprea) by captive mountain hares. We find that mountain hares do not differentiate among previous browsing levels of downy birch, but have larger bite diameters of goat willow earlier browsed by moose, compared to non-browsed plants. Thus, effects of moose on mountain hare winter food quality seem to be limited. We highlight the need for studies focusing on (1) qualitative effects of moose browsing using wild mountain hares in a natural experimental design, and (2) quantitative effects of moose browsing on available mountain hare forage at a landscape scale during winter.

LOUPING-ILL VIRUS SEROSURVEY OF WILLOW PTARMIGAN (LAGOPUS LAGOPUS LAGOPUS) IN NORWAY.

In Norway, the Willow Ptarmigan (Lagopus lagopus lagopus) is experiencing population declines and is nationally Red Listed as Near Threatened. Although disease has not generally been regarded as an important factor behind population fluctuations for Willow Ptarmigan in Norway, disease occurrence has been poorly investigated. Both louping-ill virus (LIV) and the closely related tick-borne encephalitis virus are found along the southern part of the Norwegian coast. We assessed whether and where Norwegian Willow Ptarmigan populations have been infected with LIV. We expected to find infected individuals in populations in the southernmost part of the country. We did not expect to find infected individuals in populations further north and at higher altitudes because of the absence of the main vector, the sheep tick (Ixodes ricinus). We collected serum samples on Nobuto filter paper and used a hemagglutination inhibition assay for antibodies against LIV. We collected data at both local and country-wide levels. For local sampling, we collected and analyzed 87 hunter-collected samples from one of the southernmost Willow Ptarmigan populations in Norway. Of these birds, only three positives (3.4%) were found. For the country-wide sampling, we collected serum samples from 163 Willow Ptarmigan carcasses submitted from selected locations all over the country. Of these birds, 32% (53) were seropositive for LIV or a cross-reacting virus. Surprisingly, we found seropositive individuals from locations across the whole country, including outside the known distribution of the sheep tick. These results suggest that either LIV or a cross-reacting virus infects ptarmigan in large parts of Norway, including at high altitudes and latitudes.

Impacts of predator-mediated interactions along a climatic gradient on the population dynamics of an alpine bird.

According to classic theory, species' population dynamics and distributions are less influenced by species interactions under harsh climatic conditions compared to under more benign climatic conditions. In alpine and boreal ecosystems in Fennoscandia, the cyclic dynamics of rodents strongly affect many other species, including ground-nesting birds such as ptarmigan. According to the 'alternative prey hypothesis' (APH), the densities of ground-nesting birds and rodents are positively associated due to predator-prey dynamics and prey-switching. However, it remains unclear how the strength of these predator-mediated interactions change along a climatic harshness gradient in comparison with the effects of climatic variation. We built a hierarchical Bayesian model to estimate the sensitivity of ptarmigan populations to interannual variation in climate and rodent occurrence across Norway during 2007-2017. Ptarmigan abundance was positively linked with rodent occurrence, consistent with the APH. Moreover, we found that the link between ptarmigan abundance and rodent dynamics was strongest in colder regions. Our study highlights how species interactions play an important role in population dynamics of species at high latitudes and suggests that they can become even more important in the most climatically harsh regions.

Effect of tower base painting on willow ptarmigan collision rates with wind turbines.

Birds colliding with turbine rotor blades is a well-known negative consequence of wind-power plants. However, there has been far less attention to the risk of birds colliding with the turbine towers, and how to mitigate this risk.Based on data from the Smøla wind-power plant in Central Norway, it seems highly likely that willow ptarmigan (the only gallinaceous species found on the island) is prone to collide with turbine towers. By employing a BACI-approach, we tested if painting the lower parts of turbine towers black would reduce the collision risk.Overall, there was a 48% reduction in the number of recorded ptarmigan carcasses per search at painted turbines relative to neighboring control (unpainted) ones, with significant variation both within and between years.Using contrast painting to the turbine towers resulted in significantly reduced number of ptarmigan carcasses found, emphasizing the effectiveness of such a relatively simple mitigation measure.

PTP1B-Inhibiting Branched-Chain Fatty Acid Dimers from Eremophila oppositifolia subsp. angustifolia Identified by High-Resolution PTP1B Inhibition Profiling and HPLC-PDA-HRMS-SPE-NMR Analysis.

Ten new branched-chain fatty acid (BCFA) dimers with a substituted cyclohexene structure, five new monomers, and two known monomers, (2E,4Z,6E)-5-(acetoxymethyl)tetradeca-2,4,6-trienoic acid and its 5-hydroxymethyl analogue, were identified in the leaf extract of Eremophila oppositifolia subsp. angustifolia using a combination of HPLC-PDA-HRMS-SPE-NMR analysis and semipreparative-scale HPLC. The dimers could be classified as three types of Diels-Alder reaction products formed between monomers at two different sites of unsaturation of the dienophile. Two of the monomers represent potential biosynthetic intermediates of branched-chain fatty acids. Several compounds were found by high-resolution bioactivity profiling to inhibit PTP1B and were purified subsequently by semipreparative-scale HPLC. The dimers were generally more potent than the monomers with IC50 values ranging from 2 to 66 µM, compared to 38-484 µM for the monomers. The ten fatty acid dimers represent both a novel class of compounds and a novel class of PTP1B inhibitors.

Quantifying suitable late summer brood habitats for willow ptarmigan in Norway.

BACKGROUND: Habitat models provide information about which habitat management should target to avoid species extinctions or range contractions. The willow ptarmigan inhabits alpine- and arctic tundra habitats in the northern hemisphere and is listed as near threatened (NT) in the Norwegian red list due to declining population size. Habitat alteration is one of several factors affecting willow ptarmigan populations, but there is a lack of studies quantifying and describing habitat selection in willow ptarmigan. We used data from an extensive line transect survey program from 2014 to 2017 to develop resource selection functions (RSF) for willow ptarmigan in Norway. The selection coefficients for the RSF were estimated using a mixed-effects logistic regression model fitted with random intercepts for each area. We predicted relative probability of selection across Norway and quantile-binned the predictions in 10 RSF bins ranging from low-(1) to high-(10) relative probability of selection. RESULTS: Random cross-validation suggest that our models were highly predictive, but validation based spatial blocking revealed that the predictability was better in southern parts of Norway compared to the northernmost region. Willow ptarmigan selected for herb-rich meadows and avoided lichen rich heathlands. There was generally stronger selection for vegetation types with dense field layer and for rich bogs and avoidance of vegetation types with sparse field layer cover and for lowland forest. Further, willow ptarmigan selected for areas around the timberline and for intermediate slopes. Mapping of the RSF showed that 60% of Norway is in the lowest ranked RSF bin and only 2% in the highest ranked RSF bin. CONCLUSIONS: Willow ptarmigan selected for vegetation types with dense field layer and bogs at intermediate slopes around the timberline. Selection coincides with previous habitat selection studies on willow ptarmigan. This is the first attempt to assess and quantify habitat selection for willow ptarmigan at a large scale using data from line transect distance sampling surveys. Spatial variation in predictability suggests that habitat selection in late summer might vary from north to south. The resource selection map can be a useful tool when planning harvest quotas and habitat interventions in alpine areas.

Atmospheric Oxidation of a Thiocarbamate Herbicide Used in Winter Cereals.

The gas-phase atmospheric degradation of prosulfocarb (a widely used thiocarbamate herbicide in winter cereals) at different NOx concentrations was investigated at the large outdoor European PHOtoREactor (EUPHORE) in Valencia, Spain. Photolysis under sunlight conditions and reaction with ozone were shown as unimportant. The rate constant for the reaction of prosulfocarb with OH radicals was determined as k = (2.9 ± 0.5) × 10-11 cm3 molecule-1 s-1 at 288 ± 10 K and atmospheric pressure by a conventional relative rate method. Significant ozone and aerosol formation was observed following the reaction of prosulfocarb with OH radicals, and the main detected carbon-containing gas-phase products were benzaldehyde, S-benzyl formyl(propyl)carbamothioate, and S-benzyl propanoyl(propyl)carbamothioate.

The basolateral vesicle sorting machinery and basolateral proteins are recruited to the site of enteropathogenic E. coli microcolony growth at the apical membrane.

Foodborne Enteropathogenic Escherichia coli (EPEC) infections of the small intestine cause diarrhea especially in children and are a major cause of childhood death in developing countries. EPEC infects the apical membrane of the epithelium of the small intestine by attaching, effacing the microvilli under the bacteria and then forming microcolonies on the cell surface. We first asked the question where on epithelial cells EPEC attaches and grows. Using models of polarized epithelial monolayers, we evaluated the sites of initial EPEC attachment to the apical membrane and found that EPEC preferentially attached over the cell-cell junctions and formed microcolonies preferentially where three cells come together at tricellular tight junctions. The ability of EPEC to adhere increased when host cell polarity was compromised yielding EPEC access to basolateral proteins. EPEC pedestals contain basolateral cytoskeletal proteins. Thus, we asked if attached EPEC causes reorganization the protein composition of the host cell plasma membrane at sites of microcolony formation. We found that EPEC microcolony growth at the apical membrane resulted in a local accumulation of basolateral plasma membrane proteins surrounding the microcolony. Basolateral marker protein aquaporin-3 localized to forming EPEC microcolonies. Components of the basolateral vesicle targeting machinery were re-routed. The Exocyst (Exo70) was recruited to individual EPEC as was the basolateral vesicle SNARE VAMP-3. Moreover, several Rab variants were also recruited to the infection site, and their dominant-negative equivalents were not. To quantitatively study the recruitment of basolateral proteins, we created a pulse of the temperature sensitive basolateral VSVG, VSVG3-SP-GFP, from the trans-Golgi Network. We found that after release from the TGN, significantly more VSVG3-SP-GFP accumulated at the site of microcolony growth than on equivalent membrane regions of uninfected cells. This suggests that trafficking of vesicles destined for the basolateral membrane are redirected to the apical site of microcolony growth. Thus, in addition to disrupting host cell fence function, local host cell plasma membrane protein composition is changed by altered protein trafficking and recruitment of basolateral proteins to the apical microcolony. This may aid EPEC attachment and subsequent microcolony growth.

Alterations of the Benzoxazinoid Profiles of Uninjured Maize Seedlings During Freezing, Storage, and Lyophilization.

Benzoxazinoids are highly studied compounds due to their biological activity and presence in several cereals. They include compound classes such as hydroxamic acids and lactams and usually occur as inactive glucosides in unstressed plants. Injury to the plant causes enzymatic hydrolysis of the inactive glucosides to the biologically active hydroxamic acid and lactam aglucones. The hydroxamic acids further undergo spontaneous hydrolysis to benzoxazolinones in aqueous solution. Extraction methods that do not cause immediate inactivation of enzymes result in accumulation of aglucones in samples. Using HPLC-MS to profile benzoxazinoids in maize seedlings subjected to several sample preparation techniques, we have found that hydroxamic acid aglucones and benzoxazolinones are present in uninjured maize seedlings, but that the benxozazinoid profile varies depending on sample treatment, potentially underrepresenting the glucoside content and overrepresenting the aglucone and benzoxazolinone content.

Benzoxazinoids in Prostate Cancer Patients after a Rye-Intensive Diet: Methods and Initial Results.

Rye bread contains high amounts of benzoxazinoids, and in vitro studies have shown suppressive effects of selected benzoxazinoids on prostate cancer cells. Thus, research into benzoxazinoids as possible suppressors of prostate cancer is demanded. A pilot study was performed in which ten prostate cancer patients received a rye-enriched diet 1 week prior to prostatectomy. Plasma and urine samples were collected pre- and postintervention. Ten prostate biopsies were obtained from each patient and histologically evaluated. The biopsies exhibited concentrations above the detection limit of seven benzoxazinoids ranging from 0.15 to 10.59 ng/g tissue. An OPLS-DA analysis on histological and plasma concentrations of benzoxazinoids classified the subjects into two clusters. A tendency of higher benzoxazinoid concentrations toward the benign group encourages further investigations. Benzoxazinoids were quantified by an optimized LC-MS/MS method, and matrix effects were evaluated. At low concentrations in biopsy and plasma matrices the matrix effect was concentration-dependent and nonlinear. For the urine samples the general matrix effects were small but patient-dependent.

Can use of adaptive statistical iterative reconstruction reduce radiation dose in unenhanced head CT? An analysis of qualitative and quantitative image quality.

BACKGROUND: Iterative reconstruction can reduce image noise and thereby facilitate dose reduction. PURPOSE: To evaluate qualitative and quantitative image quality for full dose and dose reduced head computed tomography (CT) protocols reconstructed using filtered back projection (FBP) and adaptive statistical iterative reconstruction (ASIR). MATERIAL AND METHODS: Fourteen patients undergoing follow-up head CT were included. All patients underwent full dose (FD) exam and subsequent 15% dose reduced (DR) exam, reconstructed using FBP and 30% ASIR. Qualitative image quality was assessed using visual grading characteristics. Quantitative image quality was assessed using ROI measurements in cerebrospinal fluid (CSF), white matter, peripheral and central gray matter. Additionally, quantitative image quality was measured in Catphan and vendor's water phantom. RESULTS: There was no significant difference in qualitative image quality between FD FBP and DR ASIR. Comparing same scan FBP versus ASIR, a noise reduction of 28.6% in CSF and between -3.7 and 3.5% in brain parenchyma was observed. Comparing FD FBP versus DR ASIR, a noise reduction of 25.7% in CSF, and -7.5 and 6.3% in brain parenchyma was observed. Image contrast increased in ASIR reconstructions. Contrast-to-noise ratio was improved in DR ASIR compared to FD FBP. In phantoms, noise reduction was in the range of 3 to 28% with image content. CONCLUSION: There was no significant difference in qualitative image quality between full dose FBP and dose reduced ASIR. CNR improved in DR ASIR compared to FD FBP mostly due to increased contrast, not reduced noise. Therefore, we recommend using caution if reducing dose and applying ASIR to maintain image quality.

Tir Is Essential for the Recruitment of Tks5 to Enteropathogenic Escherichia coli Pedestals.

Enteropathogenic Escherichia coli (EPEC) is a bacterial pathogen that infects the epithelial lining of the small intestine and causes diarrhea. Upon attachment to the intestinal epithelium, EPEC uses a Type III Secretion System to inject its own high affinity receptor Translocated intimin receptor (Tir) into the host cell. Tir facilitates tight adhesion and recruitment of actin-regulating proteins leading to formation of an actin pedestal beneath the infecting bacterium. The pedestal has several similarities with podosomes, which are basolateral actin-rich extensions found in some migrating animal cells. Formation of podosomes is dependent upon the early podosome-specific scavenger protein Tks5, which is involved in actin recruitment. Although Tks5 is expressed in epithelial cells, and podosomes and EPEC pedestals share many components in their structure and mechanism of formation, the potential role of Tks5 in EPEC infections has not been studied. The aim of this study was to determine the subcellular localization of Tks5 in epithelial cells and to investigate if Tks5 is recruited to the EPEC pedestal. In an epithelial MDCK cell line stably expressing Tks5-EGFP, Tks5 localized to actin bundles. Upon infection, EPEC recruited Tks5-EGFP. Tir, but not Tir phosphorylation was essential for the recruitment. Time-lapse microscopy revealed that Tks5-EGFP was recruited instantly upon EPEC attachment to host cells, simultaneously with actin and N-WASp. EPEC infection of cells expressing a ΔPX-Tks5 deletion version of Tks5 showed that EPEC was able to both infect and form pedestals when the PX domain was deleted from Tks5. Future investigations will clarify the role of Tks5 in EPEC infection and pedestal formation.

Effects of dexamethasone and cox inhibitors on intracranial pressure and cerebral perfusion in the lipopolysaccharide treated rats with hyperammonemia.

INTRODUCTION: Systemic inflammation may affect the brain by aggravating the stage of encephalopathy and increasing intracranial pressure (ICP) especially if liver insufficiency with hyperammonemia is present. The aim of this study was to determine if the influence of concomitant hyperammonemia and lipopolysaccharide (LPS) on the brain can be prevented by dexamethasone and cyclooxygenase (COX) inhibitors. METHOD: Fifty-four male Wistar rats, 6 in each group, were divided into the following groups: Saline+ saline; LPS (2 mg/kg)+saline; LPS+indomethacin (10 mg/kg); LPS+diclofenac (10mg/kg); LPS+dexamethasone (2mg/kg) in experiment A. Experiment-B included the following groups: LPS+NH3 (140 µmol/kg/min)+saline; LPS+NH3+indomethacin; LPS+NH3+diclofenac and LPS+NH3+dexamethasone. ICP was monitored via a catheter placed in cisterna magna and changes in CBF were recorded by laser Doppler flowmetry. RESULTS: LPS with and without NH3 induced a similar increase in plasma 6-keto-prostaglandin-F1α (6-keto-PGF1α) concentration together with a concomitant rise in CBF and ICP. Indomethacin and diclofenac prevented the increase in ICP by LPS alone, and with the addition of NH3 the increase in both CBF and ICP, which was associated with a decrease in 6-keto-PGF1α. Dexamethasone only reduced the LPS induced increase in ICP but not CBF, and partly the 6-keto-PGF1α plasma concentration in the combined setup. CONCLUSION: These data indicate that activation of cycloooxygenases is of central importance for development of cerebral hyperemia and high ICP during concomitant systemic inflammation and hyperammonemia.

Improved catalyzed reporter deposition, iCARD.

Novel reporters have been synthesized with extended hydrophilic linkers that in combination with polymerizing cross-linkers result in very efficient reporter deposition. By utilizing antibodies to stain HER2 proteins in a cell line model it is demonstrated that the method is highly specific and sensitive with virtually no background. The detection of HER2 proteins in tissue was used to visualize individual antigens as small dots visible in a microscope. Image analysis-assisted counting of fluorescent or colored dots allowed assessment of relative protein levels in tissue. Taken together, we have developed novel reporters that improve the CARD method allowing highly sensitive in situ detection of proteins in tissue. Our findings suggest that in situ protein quantification in biological samples can be performed by object recognition and enumeration of dots, rather than intensity-based fluorescent or colorimetric assays.

Optimal protocol for PTEN immunostaining; role of analytical and preanalytical variables in PTEN staining in normal and neoplastic endometrial, breast, and prostatic tissues.

In some tumors, phosphatase and tensin homolog (PTEN) inactivation may have prognostic importance and predictive value for targeted therapies. Immunohistochemistry (IHC) may be an effective method to demonstrate PTEN loss. It was claimed that PTEN IHC showed poor reproducibility, lack of standardization, and variable effects of preanalytical factors. In this study, we developed an optimal protocol for PTEN IHC, with clone 6H2.1, by checking the relevance of analytical variables in normal tissue and tumors of endometrium, breast, and prostate. Pattern and intensity of cellular staining and background nonspecific staining were quantified and subjected to statistical analysis by linear mixed models. The proposed protocol showed a statistically best performance (P < .05) and included a high target retrieval solution, 1:100 primary antibody dilution (2.925 mg/L), FLEX diluent, and EnVisionFLEX+ detection method, with a sensitivity and specificity of 72.33% and 78.57%, respectively. Staining specificity was confirmed in cell lines and animal models. Endometrial carcinomas with PTEN genetic abnormalities showed statistically lower staining than tumors without alterations (mean histoscores, 34.66 and 119.28, respectively; P = .01). Controlled preanalytical factors (delayed fixation and overfixation) did not show any statistically significant effect on staining with optimal protocol (P > .001). However, there was a trend of significance for decreased staining and fixation under high temperature. Moreover, staining was better in endometrial aspirates than in matched hysterectomy specimens, subjected to less controlled preanalytical variables (mean histoscores, 80 and 40, respectively; P = .002). A scoring system combining intensity of staining and percentage of positive cells was statistically associated with PTEN alterations (P = .01).