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Campylobacter spp. are important causes of bacterial zoonosis, most often transmitted by contaminated poultry meat. From an epidemiological and risk assessment perspective, further knowledge should be obtained on Campylobacter prevalence and genotype distribution in primary production. Consequently, 15 Austrian broiler flocks were surveyed in summer for their thermophilic Campylobacter spp. contamination status. Chicken droppings, dust and drinking water samples were collected from each flock at three separate sampling periods. Isolates were confirmed by PCR and subtyped. We also compared three alternative methods (culture-based enrichment in Bolton broth, culture-independent real-time PCR and a lateral-flow test) for their applicability in chicken droppings. Twelve flocks were found to be positive for thermophilic Campylobacter spp. during the entire sampling period. Seven flocks (46.6%) were contaminated with both, C. jejuni and C. coli, five flocks harboured solely one species. We observed to a majority flock-specific C. jejuni and C. coli genotypes, which dominated the respective flock. Flocks within a distance <2 km shared the same C. jejuni genotypes indicating a cross-contamination event via the environment or personnel vectors. Multilocus sequence typing ( MLST) of C. jejuni revealed that the majority of isolates were assigned to globally distributed clonal complexes or had a strong link to the human interface ( CC ST-446 and ST4373). The combination of techniques poses an advantage over risk assessment studies based on cultures alone, as, in the case of Campylobacter, occurrence of a high variety of genotypes might be present among a broiler flock. We suggest applying the lateral-flow test under field conditions to identify 'high-shedding' broiler flocks at the farm level. Consequently, poultry farmers and veterinarians could improve hygiene measurements and direct sanitation activities, especially during the thinning period. Ultimately, real-time PCR could be applied to quantify Campylobacter spp. directly from chicken droppings and avoid non-interpretable results achieved by culture-dependent methods. [ABSTRACT FROM AUTHOR]

Over 11 000 L of kerosene was deposited on the surface of Rabots glaciär on the Kebnekaise Massif, northern Sweden, following the crash of a Royal Norwegian Air Force aircraft in March 2012. An environmental monitoring programme was subsequently commissioned, including a series of dye tracing experiments during the 2013 melt season, conducted to investigate the transport of pollutants through the glacier hydrological system. This experimental set-up provided a basis from which we could gain new insight into the internal hydrological system of Rabots glaciär. Results of dye tracing experiments reveal a degree of homogeneity in the topology of the drainage system throughout July and August, with an increase in efficiency as the season progresses, as reflected by decreasing temporary storage and dispersivity. Early onset of melting likely led to formation of an efficient, discrete drainage system early in the melt season, subject to decreasing sinuosity and braiding as the season progressed. Four distinct meltwater flow regimes are identified to summarize the temporal and spatial evolution of the system. Analysis of turbidity-discharge hysteresis further supports the formation of discrete, efficient drainage, with clockwise diurnal hysteresis suggesting easy mobilization of readily available sediments in channels. Dye injection immediately downstream of the pollution source zone reveals prolonged storage of dye followed by fast, efficient release. Twinned with a low dye recovery, and supported by sporadic detection of hydrocarbons in the proglacial river, we suggest that meltwater, and thus pollutants in solution, may be released periodically through an efficient, and likely pressurized, hydrological system within the upper reaches of the glacier. [ABSTRACT FROM AUTHOR]

Over 11 000 L of hydrocarbon pollution was deposited on the surface of Rabots glaciar on the Kebnekaise Massif, northern Sweden, following the crash of a Royal Norwegian Air Force aircraft in March 2012. An environmental monitoring programme was subsequently commissioned, including water, snow and ice sampling. The scientific programme further included a series of dye tracing experiments during the 2013 melt season, conducted to investigate flow pathways for pollutants through the glacier hydrological system, and to gain new insight to the internal hydrological system of Rabots glaciar. Results of dye tracing reveal a degree of homogeneity in the topology of the drainage system throughout July and August, with an increase in efficiency as the season progresses, as reflected by decreasing temporary storage and dispersivity. Early onset of melting likely led to formation of an efficient, discrete drainage system early in the melt season, subject to decreasing sinuosity and braiding as the season progressed. Analysis of turbidity-discharge hysteresis further supports the formation of discrete, efficient drainage, with clockwise diurnal hysteresis suggesting easy mobilisation of readily-available sediments in channels. Dye injection immediately downstream of the pollution source zone revealed prolonged storage of dye followed by fast, efficient release. Twinned with a low dye recovery, and supported by sporadic detection of hydrocarbons in the proglacial river, we suggest that meltwater, and thus pollutants in solution, may be released periodically from this zone of the glacier hydrological system. The here identified dynamics of dye storage, dispersion and breakthrough indicate that the ultimate fate and permanence of pollutants in the glacier system is likely to be governed by storage of pollutants in the firn layer and ice mass, or within the internal hydrological system, where it may refreeze. This shows that future studies on the fate of hydrocarbons in pristine, glaciated mountain environments should address the extent to which pollutants in solution act like water molecules or whether they are more susceptible to, for example, refreezing into the surrounding ice, becoming stuck in micro-fractures and pore spaces, or sorption onto subglacial sediments. [ABSTRACT FROM AUTHOR]

Two anelastic relaxation effects were found and studied ultrasonically in commercial alkali halide crystals. They are caused by (H2O)- and (OH)- impurities substituting for the halogen ions and orienting themselves along the six <100> directions. This degeneracy is lifted by elastic waves producing unequal strains along the cube axes. The resulting relaxation of the water ions is thermally activated with activation energies of E0 = 1.6 × 10-15 erg in NaCl and E0 = 3.7 × 10-15 erg in KCl. The high-temperature limits of the relaxation times are τ∞ = 2.5 × 10-11 and τ∞ = 2.2 × 10-11 sec, respectively. The relaxation of the hydroxyl ions does not depend on an activation energy. Relaxation times of the order of 10-8 sec are found in KCl crystals, in agreement with results from dielectric measurements. A simple model exhibiting all experimental features is presented. [ABSTRACT FROM AUTHOR]

Third-order elastic coefficients can be determined from the velocity of small-amplitude sound waves in statically stressed media. For this purpose, exact expressions are derived for the sound velocity, for the natural velocity (natural unstressed length divided by the transit time), and for their stress derivatives, evaluated at zero stress, in terms of second- and third-order coefficients. Attention is given to the proper variation of propagation direction with static stress in order to maintain propagation normal to a given crystal face as in ultrasonic experiments, and to the proper identification of isothermal and isentropic coefficients. The most convenient form of the results employs the natural velocity, which is computed directly from experimental data with no need to correct the path length for the effect of stress. The formulas apply to arbitrary crystal symmetry and to arbitrary homogeneous stress systems depending on a single scalar variable. Special formulas for hydrostatic and uniaxial stress are given for several crystal classes and for isotropic materials. [ABSTRACT FROM AUTHOR]

Two siblings showed increased galactose and galactose-related metabolites in neonatal screening. Diagnostic workup did not reveal abnormalities in any of the known disease-causing enzymes involved in galactose metabolism. Using whole-exome sequencing, we identified a homozygous missense variant in PPA1 encoding the cytosolic pyrophosphatase 1 (PPA1), c.557C>T (p.Thr186Ile). The enzyme activity of PPA1 was determined using a colorimetric assay, and the protein content was visualized via western blotting in skin fibroblasts from one of the affected individuals. The galactolytic activity of the affected fibroblasts was determined by measuring extracellular acidification with a Seahorse XFe96 analyzer. PPA1 activity decreased to 22% of that of controls in the cytosolic fraction of homogenates from patient fibroblasts. PPA1 protein content decreased by 50% according to western blot analysis, indicating a reduced stability of the variant protein. The extracellular acidification rate was reduced in patient fibroblasts when galactose was used as a substrate. Untargeted metabolomics of blood samples revealed an elevation of other metabolites related to pyrophosphate metabolism. Besides hyperbilirubinemia in the neonatal period in one child, both children were clinically unremarkable at the ages of 3 and 14 years, respectively. We hypothesize that the observed metabolic derangement is a possible mild manifestation of PPA1 deficiency. Unresolved abnormalities in galactosemia screening might result in the identification of more individuals with PPA1 deficiency, a newly discovered inborn metabolic disorder (IMD).

Tick-borne encephalitis (TBE) is a viral disease endemic in Eurasia. The virus is mainly transmitted to humans via ticks and occasionally via the consumption of unpasteurized milk products. The European Centre for Disease Prevention and Control reported an increase in TBE incidence over the past years in Europe as well as the emergence of the disease in new areas. To better understand this phenomenon, we investigated the drivers of TBE emergence and increase in incidence in humans through an expert knowledge elicitation. We listed 59 possible drivers grouped in eight domains and elicited forty European experts to: (i) allocate a score per driver, (ii) weight this score within each domain, and (iii) weight the different domains and attribute an uncertainty level per domain. An overall weighted score per driver was calculated, and drivers with comparable scores were grouped into three terminal nodes using a regression tree analysis. The drivers with the highest scores were: (i) changes in human behavior/activities; (ii) changes in eating habits or consumer demand; (iii) changes in the landscape; (iv) influence of humidity on the survival and transmission of the pathogen; (v) difficulty to control reservoir(s) and/or vector(s); (vi) influence of temperature on virus survival and transmission; (vii) number of wildlife compartments/groups acting as reservoirs or amplifying hosts; (viii) increase of autochthonous wild mammals; and (ix) number of tick species vectors and their distribution. Our results support researchers in prioritizing studies targeting the most relevant drivers of emergence and increasing TBE incidence.

Digital maps, particularly displayed on virtual globes, will represent the most important source of geographical knowledge in the future. The best known of these virtual globes is Google Earth, whose use in teaching at schools and universities is now common practice. As the first result of a series of forthcoming digital tick maps, the worldwide distribution of the marsh tick Dermacentor reticulatus is shown on Google Earth. For this purpose, various distribution maps of D. reticulatus were compiled, including digitized expert maps and a map of suitable habitats compiled with a species distribution model (SDM). A random forest model that estimates suitable habitats by combining information from tick observations, bioclimatic variables, altitude, and land cover was chosen for the latter. In the Google Earth application, the following maps can be selected: a historical expert map, a current expert map, a SDM predicted habitat suitability map, a combined expert-habitat suitability map (considered to be the best representation of the current distribution of D. reticulatus), and a map of rasterized tick locations. Users can overlay these maps according to their own requirements or combine it with other Google Earth content. For example, a comparison of the historical with the current expert map shows the spread of D. reticulatus over the past few decades. Additionally, high-resolution city maps of Bilbao (Spain), Grenoble (France), Berlin (Germany), Wrocław (Poland), Budapest (Hungary), Bucharest (Romania), and Tomsk (Russia) demonstrate the urban distribution of D. reticulatus in public parks, fallow land, and recreational areas. The Google Earth application, developed using the Keyhole Markup Language (KML), also contains fact sheets on biology, ecology, seasonal activity, and vector competence of D. reticulatus. This information has been prepared in a compact and easily understandable way for the target group, i.e. scientists from various disciplines, students, and lay people interested in the geographical distribution of ticks., Competing Interests: Declaration of Competing Interest Authors declare that they have no conflict of interest., (Copyright © 2022 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Companion animals have recently been proposed as ideal translational models of human aging due to their shared susceptibility for certain diseases, similar environments, and sophisticated veterinary medicine diagnostics, all of which are not possible in rodent laboratory models. Here, we introduce and propose the study of companion animals in China as a largely untapped resource in academic and veterinary aging research. Pet ownership rates along with economic gains in the pet industry have skyrocketed over the last decade in China. Yet, the majority of research institutions still focus on agricultural animal research, not companion animals. In this perspective, we compare available pet ownership rates between the USA, the European Union, and China before focusing on the potential of companion animal aging research in China. In addition, we highlight some ethical considerations that must be addressed before large-scale companion animal aging research can be completed., (© 2021. The Author(s).)

Models can be applied to extrapolate consequences of climate change for complex ecological systems in the future. The acknowledged systems' behaviour at present is projected into the future considering climate projection data. Such an approach can be used to addresses the future activity and density of the castor bean tick Ixodes ricinus, the most widespread tick species in Europe. It is an important vector of pathogens causing Lyme borreliosis and tick-borne encephalitis. The population dynamics depend on several biotic and abiotic factors. Such complexity makes it difficult to predict the future dynamics and density of I. ricinus and associated health risk for humans. The objective of this study is to force ecological models with high-resolution climate projection data to extrapolate I. ricinus tick density and activity patterns into the future. We used climate projection data of temperature, precipitation, and relative humidity for the period 1971-2099 from 15 different climate models. Tick activity was investigated using a climate-driven cohort-based population model. We simulated the seasonal population dynamics using climate data between 1971 and 2099 and observed weather data since 1949 at a specific location in southern Germany. We evaluated derived quantities of local tick ecology, e.g. the maximum questing activity of the nymphal stage. Furthermore, we predicted spatial density changes by extrapolating a German-wide tick density model. We compared the tick density of the reference period (1971-2000) with the counter-factual densities under the near-term scenario (2012-2041), mid-term scenario (2050-2079) and long-term scenario (2070-2099). We found that the nymphal questing peak would shift towards early seasons of the year. Also, we found high spatial heterogeneity across Germany, with predicted hotspots of up to 2,000 nymphs per 100 m2 and coldspots with constant density. As our results suggest extreme changes in tick behaviour and density, we discuss why caution is needed when extrapolating climate data-driven models into the distant future when data on future climate drive the model projection., Competing Interests: The authors have declared that no competing interests exist.

Beside mosquitoes, ticks are well-known vectors of different human pathogens. In the Northern Hemisphere, Lyme borreliosis (Eurasia, LB) or Lyme disease (North America, LD) is the most commonly occurring vector-borne infectious disease caused by bacteria of the genus Borrelia which are transmitted by hard ticks of the genus Ixodes. The reported incidence of LB in Europe is about 22.6 cases per 100,000 inhabitants annually with a broad range depending on the geographical area analyzed. However, the epidemiological data are largely incomplete, because LB is not notifiable in all European countries. Furthermore, not only differ reporting procedures between countries, there is also variation in case definitions and diagnostic procedures. Lyme borreliosis is caused by several species of the Borrelia (B.) burgdorferi sensu lato (s.l.) complex which are maintained in complex networks including ixodid ticks and different reservoir hosts. Vector and host influence each other and are affected by multiple factors including climate that have a major impact on their habitats and ecology. To classify factors that influence the risk of transmission of B. burgdorferi s.l. to their different vertebrate hosts as well as to humans, we briefly summarize the current knowledge about the pathogens including their astonishing ability to overcome various host immune responses, regarding the main vector in Europe Ixodes ricinus, and the disease caused by borreliae. The research shows, that a higher standardization of case definition, diagnostic procedures, and standardized, long-term surveillance systems across Europe is necessary to improve clinical and epidemiological data., (© 2022. The Author(s).)

A first compilation of georeferenced tick locations in Austria and South Tyrol, Italy, is presented here. This allows the tick fauna to be examined in the various climatic regions of the European Alps. The dataset comprises 424 tick locations of Austria and 48 tick locations of South Tyrol, which were digitized from literature and visualized in the form of geographical maps. The tick fauna of Austria includes two species of Argasidae in the genera Argas and Carios and 15 species of Ixodidae in the genera Dermacentor, Haemaphysalis, and Ixodes, altogether 17 tick species. In addition, two species of Ixodidae in the genera Hyalomma (each spring imported by migratory birds) and Rhipicephalus (occasionally imported by dogs returning from abroad with their owners) are included in the tick atlas. Of these, the georeferenced locations of 18 tick species are depicted in maps. The occurrence of the one remaining tick species, Ixodes inopinatus, is given at the level of the federal states. The first Austrian distribution map of the long-legged bat tick Ixodes vespertilionis, which was reported from 21 caves, deserves special mention. The most common and widespread tick species is Ixodes ricinus, with records in all nine federal states of Austria, followed by Ixodes canisuga, Ixodes hexagonus, and I. vespertilionis in six federal states each. Haemaphysalis concinna and Dermacentor reticulatus are only endemic in the eastern plains, while Dermacentor marginatus only occurs in the west, in the Tyrolean Alpine valleys. Eight tick species were reported from South Tyrol, Italy. There, the most frequently flagged tick from the vegetation is also I. ricinus, while D. marginatus and Haemaphysalis punctata are often collected from sheep. The locations are shown together with those from North and East Tyrol on a separate Tyrol map. The tick atlas in Austria and South Tyrol as well as the underlying digital dataset in the supplement contribute to the closing of data gaps in global distribution maps of ticks and improve the data basis for new species distribution models., (© 2022. The Author(s).)

In this study, the performance of four alternative selective chromogenic B. cereus agar was compared to the reference mannitol-yolk polymyxin (MYP) agar (ISO 7932) using inclusion and exclusion test strains ( n = 110) and by analyzing naturally contaminated milk and other food samples ( n = 64). Subsequently, the panC group affiliation and toxin gene profile of Bacillus cereus senso lato ( s.l. ) isolates were determined. Our results corroborate that the overall best performing media CHROMagar™ B. cereus (93.6% inclusivity; 82.7% exclusivity) and BACARA ® (98.2% inclusivity, 62.7% exclusivity) are more sensitive and specific compared to Brilliance™ B. cereus , MYP and ChromoSelect Bacillus Agar. Both media allow unequivocal detection of B. cereus with low risks of misidentification. Media containing ß-D-glucosidase for the detection of presumptive B. cereus may form atypical colony morphologies resulting in a false negative evaluation of the sample. Naturally contaminated samples presented high numbers of background flora, while numbers of presumptive B. cereus were below the detection limit (<10 CFU g -1 or mL -1 ). Recovery after freezing resulted in the highest detection of B. cereus s.l . on BACARA ® (57.8%), CHROMagar™ B. cereus (56.3%) and MYP agar (54.7%). The panC /toxin profile combination IV/A was the most abundant (33.0%), followed by III/F (21.7%) and VI/C (10.4%). More panC and toxin combinations were present in 15.6% of samples when reanalyzed after freezing. In order to improve detection and confirmation of B. cereus s.l. in food samples, we recommend the parallel use of two complementary selective media followed by molecular characterization (e.g., panC typing combined with toxin gene profiling). When determining psychrotolerant or thermophilic members of the B. cereus group, the selective agar media should additionally be incubated at appropriate temperatures (5 °C, ≥45 °C). If high-risk toxin genes (e.g., ces or cytK-1 ) are detected, the strain-specific ability to produce toxin should be examined to decisively assess risk.

Background: The tick Ixodes ricinus is an important vector of tick-borne diseases including Lyme borreliosis. In continental Europe, the nymphal stage of I. ricinus often has a bimodal phenology with a large spring peak and a smaller fall peak. There is consensus about the origin of the spring nymphal peak, but there are two alternative hypotheses for the fall nymphal peak. In the direct development hypothesis, larvae quest as nymphs in the fall of the same year that they obtained their larval blood meal. In the developmental diapause hypothesis, larvae overwinter in the engorged state and quest as nymphs one year after they obtained their larval blood meal. These two hypotheses make different predictions about the time lags that separate the larval blood meal and the density of questing nymphs (DON) in the spring and fall., Methods: Inter-annual variation in seed production (masting) by deciduous trees is a time-lagged index for the density of vertebrate hosts (e.g., rodents) which provide blood meals for larval ticks. We used a long-term data set on the masting of the European beech tree and a 15-year study on the DON at 4 different elevation sites in western Switzerland to differentiate between the two alternative hypotheses for the origin of the fall nymphal peak., Results: Questing I. ricinus nymphs had a bimodal phenology at the three lower elevation sites, but a unimodal phenology at the top elevation site. At the lower elevation sites, the DON in the fall was strongly correlated with the DON in the spring of the following year. The inter-annual variation in the densities of I. ricinus nymphs in the fall and spring was best explained by a 1-year versus a 2-year time lag with the beech tree masting index. Fall nymphs had higher fat content than spring nymphs indicating that they were younger. All these observations are consistent with the direct development hypothesis for the fall peak of I. ricinus nymphs at our study site. Our study provides new insight into the complex bimodal phenology of this important disease vector., Conclusions: Public health officials in Europe should be aware that following a strong mast year, the DON will increase 1 year later in the fall and 2 years later in the spring. Studies of I. ricinus populations with a bimodal phenology should consider that the spring and fall peak in the same calendar year represent different generations of ticks., (© 2021. The Author(s).)

Congenital disorders of glycosylation are a genetically and phenotypically heterogeneous family of diseases affecting the co- and posttranslational modification of proteins. Using exome sequencing, we detected biallelic variants in GFUS (NM&#95;003313.4) c.[632G>A];[659C>T] (p.[Gly211Glu];[Ser220Leu]) in a patient presenting with global developmental delay, mild coarse facial features and faltering growth. GFUS encodes GDP-L-fucose synthase, the terminal enzyme in de novo synthesis of GDP-L-fucose, required for fucosylation of N- and O-glycans. We found reduced GFUS protein and decreased GDP-L-fucose levels leading to a general hypofucosylation determined in patient's glycoproteins in serum, leukocytes, thrombocytes and fibroblasts. Complementation of patient fibroblasts with wild-type GFUS cDNA restored fucosylation. Making use of the GDP-L-fucose salvage pathway, oral fucose supplementation normalized fucosylation of proteins within 4 weeks as measured in serum and leukocytes. During the follow-up of 19 months, a moderate improvement of growth was seen, as well as a clear improvement of cognitive skills as measured by the Kaufmann ABC and the Nijmegen Pediatric CDG Rating Scale. In conclusion, GFUS-CDG is a new glycosylation disorder for which oral L-fucose supplementation is promising., (© 2021 The Authors. Published under the terms of the CC BY 4.0 license.)

An updated and increased compilation of georeferenced tick locations in Germany is presented here. This data collection extends the dataset published some years ago by another 1448 new tick locations, 900 locations of which were digitized from literature and 548 locations are published here for the first time. This means that a total of 3492 georeferenced tick locations is now available for Germany. The tick fauna of Germany includes two species of Argasidae in the genera Argas and Carios and 19 species of Ixodidae in the genera Dermacentor, Haemaphysalis, and Ixodes, altogether 21 tick species. In addition, three species of Ixodidae in the genera Hyalomma (each spring imported by migratory birds) and Rhipicephalus (occasionally imported by dogs returning from abroad with their owners) are included in the tick atlas. Of these, the georeferenced locations of 23 tick species are depicted in maps. The occurrence of the one remaining tick species, the recently described Ixodes inopinatus, is given at the level of the federal states. The most common and widespread tick species is Ixodes ricinus, with records in all 16 federal states. With the exception of Hamburg, Dermacentor reticulatus was also found in all federal states. The occurrence of the ixodid ticks Ixodes canisuga, Ixodes frontalis, Ixodes hexagonus and I. inopinatus were documented in at least 11 federal states each. The two mentioned argasid tick species were also documented in numerous federal states, the pigeon tick Argas reflexus in 11 and the bat tick Carios vespertilionis in seven federal states. The atlas of ticks in Germany and the underlying digital dataset in the supplement can be used to improve global tick maps or to study the effects of climate change and habitat alteration on the distribution of tick species.

In spring 2019, forecasts of the incidence of tick-borne encephalitis (TBE) for the next 2 years, i.e. 2019 and 2020, were made for the first time. For this purpose, negative binomial regression models with 4-5 predictors were fitted to the time series of annual human TBE incidences from Austria, Germany, and Switzerland. The most important predictor for TBE incidences is the fructification index of the European beech (Fagus sylvatica) 2 years prior as a proxi for the intensity of the TBE virus transmission cycle. These forecasts were repeated in spring 2020 after the updated predictors and the confirmed TBE cases for 2019 became available. Forecasting TBE incidences for 2020 and 2021 results in 156 ± 19 and 131 ± 23 TBE cases for Austria, 663 ± 95 and 543 ± 112 TBE cases for Germany as well as 472 ± 56 and 350 ± 62 TBE cases for Switzerland. The newly implemented operational TBE forecasts will be verified every year with confirmed TBE cases. An initial verification for 2019 demonstrates the high reliability of the forecasts., (Copyright © 2020 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Purpose: Biallelic CAD variants underlie CAD deficiency (or early infantile epileptic encephalopathy-50, [EIEE-50]), an error of pyrimidine de novo biosynthesis amenable to treatment via the uridine salvage pathway. We further define the genotype and phenotype with a focus on treatment., Methods: Retrospective case series of 20 patients., Results: Our study confirms CAD deficiency as a progressive EIEE with recurrent status epilepticus, loss of skills, and dyserythropoietic anemia. We further refine the phenotype by reporting a movement disorder as a frequent feature, and add that milder courses with isolated developmental delay/intellectual disability can occur as well as onset with neonatal seizures. With no biomarker available, the diagnosis relies on genetic testing and functional validation in patient-derived fibroblasts. Underlying pathogenic variants are often rated as variants of unknown significance, which could lead to underrecognition of this treatable disorder. Supplementation with uridine, uridine monophosphate, or uridine triacetate in ten patients was safe and led to significant clinical improvement in most patients., Conclusion: We advise a trial with uridine (monophosphate) in all patients with developmental delay/intellectual disability, epilepsy, and anemia; all patients with status epilepticus; and all patients with neonatal seizures until (genetically) proven otherwise or proven unsuccessful after 6 months. CAD deficiency might represent a condition for genetic newborn screening.

The forecast of human tick-borne encephalitis (TBE) incidence for the next years has been on the research agenda of epidemiologists since the discovery of this tick-borne zoonosis. Based on models to explain the trend as well as the low- and high-frequency oscillations in the Austrian TBE incidence series, TBE forecasts for Austria, Germany and Switzerland are presented here. For this purpose, generalized linear models (GLMs) of type negative binomial regression were calibrated with the TBE incidences of the period 1991-2018 to forecast the TBE incidences 2019 and 2020. The GLMs require only 4-5 predictors, 2 of which are large-scale synchronized over Central Europe and used for all 3 countries. Predictors used include the demographic parameters total population and net migration rate, the Scandinavian index which describes the large-scale atmospheric circulation patterns, the fructification index of the European beech (Fagus sylvatica) 2 years prior as a proxy for the intensity of the TBE virus transmission cycle, and the national TBE vaccination coverage. Since an official time series of TBE vaccination coverage is only available for Austria, the missing TBE vaccination coverages of Germany and Switzerland were reconstructed and presented as the first results. Model verification results in explained variances of 76% for Austria, 84% for Germany, and 89% for Switzerland. Thus, the best model fit was determined for the Swiss GLM which is able to predict the TBE incidence with a root-mean-square error of RMSE = 25 cases (19% of the mean TBE incidence 1991-2018 or 7% of the TBE incidence of 2018). Forecasting TBE incidences for 2019 and 2020 results in 92 ± 12 and 142 ± 26 TBE cases for Austria, 417 ± 71 and 670 ± 168 TBE cases for Germany as well as 235 ± 30 and 465 ± 91 TBE cases for Switzerland., (Copyright © 2020 The Authors. Published by Elsevier GmbH.. All rights reserved.)

The two ixodid tick species Dermacentor reticulatus (Fabricius) and Dermacentor silvarum Olenev occur at the northern distribution limit of the genus Dermacentor in Eurasia, within the belt of [Formula: see text] latitude. Whilst the distribution area of D. reticulatus extends from the Atlantic coast of Portugal to Western Siberia, that of D. silvarum extends from Western Siberia to the Pacific coast. In Western Siberia, the distribution areas of the two Dermacentor species overlap. Although the two tick species are important vectors of disease, detailed information concerning the entire distribution area, climate adaptation, and proven vector competence is still missing. A dataset was compiled, resulting in 2188 georeferenced D. reticulatus and 522 D. silvarum locations. Up-to-date maps depicting the geographical distribution and climate adaptation of the two Dermacentor species are presented. To investigate the climate adaptation of the two tick species, the georeferenced locations were superimposed on a high-resolution map of the Köppen-Geiger climate classification. The frequency distribution of D. reticulatus under different climates shows two major peaks related to the following climates: warm temperate with precipitation all year round (57%) and boreal with precipitation all year round (40%). The frequency distribution of D. silvarum shows also two major peaks related to boreal climates with precipitation all year round (30%) and boreal winter dry climates (60%). Dermacentor silvarum seems to be rather flexible concerning summer temperatures, which can range from cool to hot. In climates with cool summers D. reticulatus does not occur, it prefers warm and to a lesser extent hot summers. Lists are given in this paper for cases of proven vector competence for various agents of both Dermacentor species. For the first time, the entire distribution areas of D. reticulatus and D. silvarum were mapped using georeferenced data. Their climate adaptations were quantified by Köppen profiles.

Each year, blood transfusions save millions of lives. However, under current blood-matching practices, sensitization to non-self-antigens is an unavoidable adverse side effect of transfusion. We describe a universal donor typing platform that could be adopted by blood services worldwide to facilitate a universal extended blood-matching policy and reduce sensitization rates. This DNA-based test is capable of simultaneously typing most clinically relevant red blood cell (RBC), human platelet (HPA), and human leukocyte (HLA) antigens. Validation was performed, using samples from 7927 European, 27 South Asian, 21 East Asian, and 9 African blood donors enrolled in 2 national biobanks. We illustrated the usefulness of the platform by analyzing antibody data from patients sensitized with multiple RBC alloantibodies. Genotyping results demonstrated concordance of 99.91%, 99.97%, and 99.03% with RBC, HPA, and HLA clinically validated typing results in 89 371, 3016, and 9289 comparisons, respectively. Genotyping increased the total number of antigen typing results available from 110 980 to >1 200 000. Dense donor typing allowed identification of 2 to 6 times more compatible donors to serve 3146 patients with multiple RBC alloantibodies, providing at least 1 match for 176 individuals for whom previously no blood could be found among the same donors. This genotyping technology is already being used to type thousands of donors taking part in national genotyping studies. Extraction of dense antigen-typing data from these cohorts provides blood supply organizations with the opportunity to implement a policy of genomics-based precision matching of blood.

Tick-borne encephalitis (TBE) is the most common viral tick-borne disease in Europe causing thousands of human infections every year. Available risk maps in Europe are solely based on human incidences, but often underestimate areas with TBE virus circulation as shown by several autochthonous cases detected outside known risk areas. A dataset of more than 1300 georeferenced TBE virus detections in ticks and mammals except for humans was compiled and used to estimate the probability of TBE virus presence in Europe. For this, a random forests model was implemented using temperature- and precipitation-dependent bioclimatic variables of the WorldClim dataset, altitude, as well as land cover of the ESA GlobCover dataset. The highest probabilities of TBE virus presence were identified in Central Europe, in the south of the Nordic countries, and in the Baltic countries. The model performance was evaluated by an out-of-bag error (OOB) of 0.174 and a high area under the curve value (AUC) of 0.905. The TBE virus presence maps may subsequently be used to estimate the risk of TBE virus infections in humans and can support decision-makers to identify TBE risk areas and to encourage people to take appropriate actions against tick bites and TBE virus infections.

The first long-term monitoring to document both activity and density of questing ixodid ticks in Vienna, Austria, is introduced. It was started in 2017 and is planned to run over decades. Such long-term monitorings are needed to quantify possible effects of climate change or to develop tick density forecast models. The monthly questing tick density at three sites has been observed by using a standardized sampling method by dragging an area of [Formula: see text] at each occasion. Popular recreational areas were chosen as study sites. These are the Prater public park, the wooded Kahlenberg, and a wildlife garden in Klosterneuburg. First results show a 3-year time series of nymphs and adults of the Ixodes ricinus species complex and Haemaphysalis concinna for the period 2017-2019. Whereas questing nymphs of the I. ricinus species complex were collected from February to November, H. concinna nymphs were only dragged from May to October. The peak of nymphal activity of the I. ricinus species complex was in May, that of H. concinna in August. In addition, a brief overview is given about ticks and tick-borne pathogens occurring in urban and suburban areas of Vienna.

Background: Why human tick-borne encephalitis (TBE) cases differ from year to year, in some years more 100%, has not been clarified, yet. The cause of the increasing or decreasing trends is also controversial. Austria is the only country in Europe where a 40-year TBE time series and an official vaccine coverage time series are available to investigate these open questions., Methods: A series of generalized linear models (GLMs) has been developed to identify demographic and environmental factors associated with the trend and the oscillations of the TBE time series. Both the observed and the predicted TBE time series were subjected to spectral analysis. The resulting power spectra indicate which predictors are responsible for the trend, the high-frequency and the low-frequency oscillations, and with which explained variance they contribute to the TBE oscillations., Results: The increasing trend can be associated with the demography of the increasing human population. The responsible GLM explains 12% of the variance of the TBE time series. The low-frequency oscillations (10 years) are associated with the decadal changes of the large-scale climate in Central Europe. These are well described by the so-called Scandinavian index. This 10-year oscillation cycle is reinforced by the socio-economic predictor net migration. Considering the net migration and the Scandinavian index increases the explained variance of the GLM to 44%. The high-frequency oscillations (2-3 years) are associated with fluctuations of the natural TBE transmission cycle between small mammals and ticks, which are driven by beech fructification. Considering also fructification 2 years prior explains 64% of the variance of the TBE time series. Additionally, annual sunshine duration as predictor for the human outdoor activity increases the explained variance to 70%., Conclusions: The GLMs presented here provide the basis for annual TBE forecasts, which were mainly determined by beech fructification. A total of 3 of the 5 years with full fructification, resulting in high TBE case numbers 2 years later, occurred after 2010. The effects of climate change are therefore not visible through a direct correlation of the TBE cases with rising temperatures, but indirectly via the increased frequency of mast seeding.

Background: Culicoides biting midges transmit viruses resulting in disease in ruminants and equids such as bluetongue, Schmallenberg disease and African horse sickness. In the past decades, these diseases have led to important economic losses for farmers in Europe. Vector abundance is a key factor in determining the risk of vector-borne disease spread and it is, therefore, important to predict the abundance of Culicoides species involved in the transmission of these pathogens. The objectives of this study were to model and map the monthly abundances of Culicoides in Europe., Methods: We obtained entomological data from 904 farms in nine European countries (Spain, France, Germany, Switzerland, Austria, Poland, Denmark, Sweden and Norway) from 2007 to 2013. Using environmental and climatic predictors from satellite imagery and the machine learning technique Random Forests, we predicted the monthly average abundance at a 1 km 2 resolution. We used independent test sets for validation and to assess model performance., Results: The predictive power of the resulting models varied according to month and the Culicoides species/ensembles predicted. Model performance was lower for winter months. Performance was higher for the Obsoletus ensemble, followed by the Pulicaris ensemble, while the model for Culicoides imicola showed a poor performance. Distribution and abundance patterns corresponded well with the known distributions in Europe. The Random Forests model approach was able to distinguish differences in abundance between countries but was not able to predict vector abundance at individual farm level., Conclusions: The models and maps presented here represent an initial attempt to capture large scale geographical and temporal variations in Culicoides abundance. The models are a first step towards producing abundance inputs for R 0 modelling of Culicoides-borne infections at a continental scale.

: The genus Listeria now comprises up to now 21 recognized species and six subspecies, with L. monocytogenes and L. innocua as the most prevalent sensu stricto associated species. Reports focusing on the challenges in Listeria detection and confirmation are available, especially from food-associated environmental samples. L. innocua is more prevalent in the food processing environment (FPE) than L. monocytogenes and has been shown to have a growth advantage in selective enrichment and agar media. Until now, the adaptive nature of L. innocua in FPEs has not been fully elucidated and potential persistence in the FPE has not been observed. Therefore, the aim of this study is to characterize L. innocua (n = 139) and L. monocytogenes (n = 81) isolated from FPEs and cheese products collected at five dairy processing facilities (A-E) at geno- and phenotypic levels. Biochemical profiling was conducted for all L. monocytogenes and the majority of L. innocua (n = 124) isolates and included a rhamnose positive reaction. L. monocytogenes isolates were most frequently confirmed as PCR-serogroups 1/2a, 3a (95%). Pulsed-field gel electrophoresis (PFGE)-typing, applying the restriction enzymes AscI, revealed 33 distinct Listeria PFGE profiles with a Simpson's Index of Diversity of 0.75. Multi-locus sequence typing (MLST) resulted in 27 STs with seven new L. innocua local STs (ST1595 to ST1601). L. innocua ST1597 and ST603 and L. monocytogenes ST121 and ST14 were the most abundant genotypes in dairy processing facilities A-E over time. Either SSI-1 (ST14) or SSI-2 (ST121, all L. innocua) were present in successfully FPE-adapted strains. We identified housekeeping genes common in Listeria isolates and L. monocytogenes genetic lineage III. Wherever there are long-term contamination events of L. monocytogenes and other Listeria species, subtyping methods are helpful tools to identify niches of high risk., Competing Interests: Author Contributions: B.S., M.W. conceived and designed the experiments. I.K.-R., A.M. and S.M.-K performed the experiments. I.K.-R, K.B. and B.S. analyzed the data. B.S. and I.K.-R. Drafted the manuscript. K.-H.W. reviewed the manuscript. All authors read and approved the final version of the manuscript.

Background: Deficiencies of iron-sulfur (Fe-S) clusters, metal complexes that control redox state and mitochondrial metabolism, have been linked to pulmonary hypertension (PH), a deadly vascular disease with poorly defined molecular origins. BOLA3 (BolA Family Member 3) regulates Fe-S biogenesis, and mutations in BOLA3 result in multiple mitochondrial dysfunction syndrome, a fatal disorder associated with PH. The mechanistic role of BOLA3 in PH remains undefined., Methods: In vitro assessment of BOLA3 regulation and gain- and loss-of-function assays were performed in human pulmonary artery endothelial cells using siRNA and lentiviral vectors expressing the mitochondrial isoform of BOLA3. Polymeric nanoparticle 7C1 was used for lung endothelium-specific delivery of BOLA3 siRNA oligonucleotides in mice. Overexpression of pulmonary vascular BOLA3 was performed by orotracheal transgene delivery of adeno-associated virus in mouse models of PH., Results: In cultured hypoxic pulmonary artery endothelial cells, lung from human patients with Group 1 and 3 PH, and multiple rodent models of PH, endothelial BOLA3 expression was downregulated, which involved hypoxia inducible factor-2α-dependent transcriptional repression via histone deacetylase 1-mediated histone deacetylation. In vitro gain- and loss-of-function studies demonstrated that BOLA3 regulated Fe-S integrity, thus modulating lipoate-containing 2-oxoacid dehydrogenases with consequent control over glycolysis and mitochondrial respiration. In contexts of siRNA knockdown and naturally occurring human genetic mutation, cellular BOLA3 deficiency downregulated the glycine cleavage system protein H, thus bolstering intracellular glycine content. In the setting of these alterations of oxidative metabolism and glycine levels, BOLA3 deficiency increased endothelial proliferation, survival, and vasoconstriction while decreasing angiogenic potential. In vivo, pharmacological knockdown of endothelial BOLA3 and targeted overexpression of BOLA3 in mice demonstrated that BOLA3 deficiency promotes histological and hemodynamic manifestations of PH. Notably, the therapeutic effects of BOLA3 expression were reversed by exogenous glycine supplementation., Conclusions: BOLA3 acts as a crucial lynchpin connecting Fe-S-dependent oxidative respiration and glycine homeostasis with endothelial metabolic reprogramming critical to PH pathogenesis. These results provide a molecular explanation for the clinical associations linking PH with hyperglycinemic syndromes and mitochondrial disorders. These findings also identify novel metabolic targets, including those involved in epigenetics, Fe-S biogenesis, and glycine biology, for diagnostic and therapeutic development.

Background: Biting midges of the genus Culicoides (Diptera: Ceratopogonidae) are small hematophagous insects responsible for the transmission of bluetongue virus, Schmallenberg virus and African horse sickness virus to wild and domestic ruminants and equids. Outbreaks of these viruses have caused economic damage within the European Union. The spatio-temporal distribution of biting midges is a key factor in identifying areas with the potential for disease spread. The aim of this study was to identify and map areas of neglectable adult activity for each month in an average year. Average monthly risk maps can be used as a tool when allocating resources for surveillance and control programs within Europe., Methods: We modelled the occurrence of C. imicola and the Obsoletus and Pulicaris ensembles using existing entomological surveillance data from Spain, France, Germany, Switzerland, Austria, Denmark, Sweden, Norway and Poland. The monthly probability of each vector species and ensembles being present in Europe based on climatic and environmental input variables was estimated with the machine learning technique Random Forest. Subsequently, the monthly probability was classified into three classes: Absence, Presence and Uncertain status. These three classes are useful for mapping areas of no risk, areas of high-risk targeted for animal movement restrictions, and areas with an uncertain status that need active entomological surveillance to determine whether or not vectors are present., Results: The distribution of Culicoides species ensembles were in agreement with their previously reported distribution in Europe. The Random Forest models were very accurate in predicting the probability of presence for C. imicola (mean AUC = 0.95), less accurate for the Obsoletus ensemble (mean AUC = 0.84), while the lowest accuracy was found for the Pulicaris ensemble (mean AUC = 0.71). The most important environmental variables in the models were related to temperature and precipitation for all three groups., Conclusions: The duration periods with low or null adult activity can be derived from the associated monthly distribution maps, and it was also possible to identify and map areas with uncertain predictions. In the absence of ongoing vector surveillance, these maps can be used by veterinary authorities to classify areas as likely vector-free or as likely risk areas from southern Spain to northern Sweden with acceptable precision. The maps can also focus costly entomological surveillance to seasons and areas where the predictions and vector-free status remain uncertain.

The Usutu virus (USUV) is a mosquito-borne flavivirus closely related to the better known West Nile virus, and it can cause mass mortalities of song birds. In the present paper, a dataset of georeferenced locations of USUV-positive birds was compiled and then used to map the geographical distribution of suitable USUV habitats in Central Europe. Six habitat models, comprising BIOCLIM, DOMAIN, maximum entropy model (MAXENT), generalized linear model (GLM), boosted regression trees model (BRT), and random forests model (RF), were selected and tested for their performance ability to predict cases of disease in unsampled areas. Suitability index maps, a diagram depicting model performance by the Area Under the Curve (AUC) vs. the True Skill Statistic (TSS), and a diagram ranking sensitivity vs. specificity as well as correct classification ratio (CCR) vs. misclassification ratio (MCR) were presented. Of the models tested GLM, BRT, RF, and MAXENT were shown suitable to predict USUV-positive dead birds in unsampled regions, with BRT the highest predictive accuracy (AUC = 0.75, TSS = 0.50). However, the four models classified major parts of the model domain as USUV-suitable, although USUV was never confirmed there so far (MCR=0.49 to 0.61). DOMAIN and especially BIOCLIM can only be recommended for interpolating point observations to raster files, i.e. for analyzing observed USUV distributions (MCR = 0.10). Habitat models can be a helpful tool for informing veterinary authorities about the possible distribution of a given mosquito-borne disease. Nevertheless, it should be taken in consideration, that the spatial and temporal scales, the selection of an appropriate model, the availability of significant predictive variables as well as the representativeness and completeness of collected species or disease cases may strongly influence the modeling results., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)