Search

Weather is the most important driver of crop development. However, spatial variability in weather makes it hard to obtain reliable high resolution datasets across large areas. Most growers rely on data from a single station that can be up to 50km away to make decisions about irrigation, pest management and penology-associated cultural practices at the block level. In this regard, we hypothesize that kriging a large network of weather stations can improve thermal time data quality compared to using the closest station. This study aims to explore the spatial variability in California's Central Valley and what is the relationship between the density of weather stations used and the error in the measurement of temperature related metrics and derived models. For this purpose, we used temperature records from January 1st 2020 to March 1st 2021 collected by the California Irrigation Management Information System (CIMIS) and a system of 731 weather stations placed above the canopy of trees in commercial orchards (in-orchard). We observed large discrepancies (>300 GDDTb0) in thermal time accumulation between using an interpolation of all stations available and just using the closest CIMIS station. Our data suggests these differences are not systematic bias but true differences in mesoclimate. Similar results were observed for chill accumulation in areas especially prone to not meeting pistachio chill requirements where the discrepancies between using the site-specific in-orchard weather station network and not using them were up to 10 CP. The use of this high resolution network of weather stations revealed spatial patterns in grape, almond, pistachio and pests phenology not reported before. Whereas previous studies have been focused on predictions at the county or state or regional level, our data suggests that a finer resolution can result in major improvements in the quality of data crucial for crop decision making.

Abstract Background This prospective feasibility study explores Field-Cycling Imaging (FCI), a new MRI technology that measures the longitudinal relaxation time across a range of low magnetic field strengths, providing additional information about the molecular properties of tissues. This study aims to assess the performance of FCI and investigate new quantitative biomarkers at low fields within the context of breast cancer. Methods We conducted a study involving 9 people living with breast cancer (10 tumours in total, mean age, 54 ± 10 years). FCI images were obtained at four magnetic field strengths (2.3 mT to 200 mT). FCI images were processed to generate T1 maps and 1/T1 dispersion profiles from regions of tumour, normal adipose tissue, and glandular tissue. The dispersion profiles were subsequently fitted using a power law model. Statistical analysis focused on comparing potential FCI biomarkers using a Mann-Whitney U or Wilcoxon signed rank test. Results We show that low magnetic fields clearly differentiate tumours from adipose and glandular tissues without contrast agents, particularly at 22 mT (1/T1, median [IQR]: 6.8 [3.9–7.8] s−1 vs 9.1 [8.9–10.2] s−1 vs 8.1 [6.2–9.2] s−1, P

Summary: Decidualization denotes the differentiation of endometrial stromal cells into specialized decidual cells, essential for embryo implantation and pregnancy. The process requires coordination of progesterone and cAMP signaling, which converge on downstream transcription factors. PGE2 and relaxin, acting, respectively, through Gαs-coupled GPCRs EP2 and RXFP1, are putative candidates for generating cAMP in differentiating stromal cells. Here, we show that PGE2 is less efficacious than relaxin in elevating intracellular cAMP levels in primary stromal cells but more effective at driving the expression of decidual genes. PGE2-and relaxin-induced cAMP generation involves receptor internalization, but EP2 is endocytosed into very early endosomes (VEEs). Perturbation of VEE machinery through depletion of key trafficking proteins; APPL1 and GIPC, dysregulates PGE2-dependent cAMP profiles and disrupts key decidual signaling pathways, resulting in a disordered differentiation response. We demonstrate that regulation of EP2 via internalization is essential for coordinated activation of the downstream signaling cascades that govern decidualization.

Summary: Serotonin (5-HT) modulates early development during critical periods when experience drives heightened levels of plasticity in neurons. Here, we investigate the cellular mechanisms by which 5-HT modulates critical period plasticity (CPP) in the olfactory system of Drosophila. We first demonstrate that 5-HT is necessary for experience-dependent structural plasticity in response to chronic CO2 exposure and can re-open the critical period long after it normally closes. Knocking down 5-HT7 receptors in a subset of GABAergic local interneurons was sufficient to block CPP, as was knocking down GABA receptors expressed by CO2-sensing olfactory sensory neurons (OSNs). Furthermore, direct modulation of OSNs via 5-HT2B receptors in CO2-sensing OSNs and autoreceptor expression by serotonergic neurons was also required for CPP. Thus, 5-HT targets individual neuron types in the olfactory system via distinct receptors to enable sensory driven plasticity.

Abstract Mutations in LRBA, a BEACH domain protein, cause severe immune deficiency in humans. LRBA is expressed in many tissues and organs according to biochemical analysis, but little is known about its cellular and subcellular localization, and its deficiency phenotype outside the immune system. By LacZ histochemistry of Lrba gene-trap mice, we performed a comprehensive survey of LRBA expression in numerous tissues, detecting it in many if not all epithelia, in exocrine and endocrine cells, and in subpopulations of neurons. Immunofluorescence microscopy of the exocrine and endocrine pancreas, salivary glands, and intestinal segments, confirmed these patterns of cellular expression and provided information on the subcellular localizations of the LRBA protein. Immuno-electron microscopy demonstrated that in neurons and endocrine cells, which co-express LRBA and its closest relative, neurobeachin, both proteins display partial association with endomembranes in complementary, rather than overlapping, subcellular distributions. Prominent manifestations of human LRBA deficiency, such as inflammatory bowel disease or endocrinopathies, are believed to be primarily due to immune dysregulation. However, as essentially all affected tissues also express LRBA, it is possible that LRBA deficiency enhances their vulnerability and contributes to the pathogenesis.

Abstract SbtB is a PII-like protein that regulates the carbon-concentrating mechanism (CCM) in cyanobacteria. SbtB proteins can bind many adenyl nucleotides and possess a characteristic C-terminal redox sensitive loop (R-loop) that forms a disulfide bridge in response to the diurnal state of the cell. SbtBs also possess an ATPase/ADPase activity that is modulated by the redox-state of the R-loop. To investigate the R-loop in the cyanobacterium Synechocystis sp. PCC 6803, site-specific mutants, unable to form the hairpin and permanently in the reduced state, and a R-loop truncation mutant, were characterized under different inorganic carbon (Ci) and light regimes. Growth under diurnal rhythm showed a role of the R-loop as sensor for acclimation to changing light conditions. The redox-state of the R-loop was found to impact the binding of the adenyl-nucleotides to SbtB, its membrane association and thereby the CCM regulation, while these phenotypes disappeared after truncation of the R-loop. Collectively, our data imply that the redox-sensitive R-loop provides an additional regulatory layer to SbtB, linking the CO2-related signaling activity of SbtB with the redox state of cells, mainly reporting the actual light conditions. This regulation not only coordinates CCM activity in the diurnal rhythm but also affects the primary carbon metabolism.

Background: It remains unknown whether there is a causal relationship between intraoperative hypotension and postoperative neurocognitive disorders. We tested the hypothesis that personalised—compared to routine—intraoperative blood pressure management reduces the incidence of postoperative neurocognitive disorders in patients having major noncardiac surgery. Methods: In this single-centre trial, 328 elective major noncardiac surgery patients were randomly allocated to receive personalised blood pressure management (i.e. maintaining intraoperative mean arterial pressure [MAP] above preoperative baseline MAP from automated 24-h blood pressure monitoring) or routine blood pressure management (i.e. maintaining MAP above 65 mm Hg). The primary outcome was the incidence of neurocognitive disorders (composite of delayed neurocognitive recovery and delirium) between postoperative days 3 and 7. Results: The primary outcome, neurocognitive disorders, occurred in 18 of 147 patients (12%) assigned to personalised and 21 of 148 patients (14%) assigned to routine blood pressure management (odds ratio [OR]=0.84, 95% confidence interval [CI]: 0.40–1.75, P=0.622). Delayed neurocognitive recovery occurred in 17 of 146 patients (12%) assigned to personalised and 17 of 145 patients (12%) assigned to routine blood pressure management (OR=0.99, 95% CI: 0.45–2.17, P=0.983). Delirium occurred in 2 of 157 patients (1%) assigned to personalised and 4 of 158 patients (3%) assigned to routine blood pressure management (OR=0.50, 95% CI: 0.04–3.53, P=0.684). Conclusions: Personalised intraoperative blood pressure management maintaining preoperative baseline MAP neither reduced the incidence of the composite primary outcome neurocognitive disorders between postoperative days 3 and 7 nor the incidences of the components of the composite primary outcome—delayed neurocognitive recovery and delirium—compared to routine blood pressure management in patients having major noncardiac surgery. Clinical trial registration: ClinicalTrials.gov (NCT03442907).

BackgroundTsetse flies (Glossina sp.) are vectors of Trypanosoma brucei subspecies that cause human African trypanosomiasis (HAT). Capturing and screening tsetse is critical for HAT surveillance. Classically, tsetse have been microscopically analysed to identify trypanosomes, but this is increasingly replaced with molecular xenomonitoring. Nonetheless, sensitive T. brucei-detection assays, such as TBR-PCR, are vulnerable to DNA cross-contamination. This may occur at capture, when often multiple live tsetse are retained temporarily in the cage of a trap. This study set out to determine whether infected tsetse can contaminate naïve tsetse with T. brucei DNA via faeces when co-housed.Methodology/principle findingsInsectary-reared teneral G. morsitans morsitans were fed an infectious T. b. brucei-spiked bloodmeal. At 19 days post-infection, infected and naïve tsetse were caged together in the following ratios: (T1) 9:3, (T2) 6:6 (T3) 1:11 and a control (C0) 0:12 in triplicate. Following 24-hour incubation, DNA was extracted from each fly and screened for parasite DNA presence using PCR and qPCR. All insectary-reared infected flies were positive for T. brucei DNA using TBR-qPCR. However, naïve tsetse also tested positive. Even at a ratio of 1 infected to 11 naïve flies, 91% of naïve tsetse gave positive TBR-qPCR results. Furthermore, the quantity of T. brucei DNA detected in naïve tsetse was significantly correlated with cage infection ratio. With evidence of cross-contamination, field-caught tsetse from Tanzania were then assessed using the same screening protocol. End-point TBR-PCR predicted a sample population prevalence of 24.8%. Using qPCR and Cq cut-offs optimised on insectary-reared flies, we estimated that prevalence was 0.5% (95% confidence interval [0.36, 0.73]).Conclusions/significanceOur results show that infected tsetse can contaminate naïve flies with T. brucei DNA when co-caged, and that the level of contamination can be extensive. Whilst simple PCR may overestimate infection prevalence, quantitative PCR offers a means of eliminating false positives.

Abstract 2D materials have received a lot of interest over the past decade. Especially van der Waals (vdW) 2D materials, such as transition metal dichalcogenides (TMDCs), and their heterostructures exhibit semiconducting properties that make them highly suitable for novel device applications. Controllable mixing and matching of the 2D materials with different properties and precise control of the in‐plane twist angle in these heterostructures are essential to achieve superior properties and need to be established through large‐scale device fabrication. To gain fundamental insight into the potential control of these twist angles, 2D heterostructures of tungsten disulfide (WS2) and graphene (Gr) grown by bottom‐up synthesis via metal‐organic chemical vapor deposition (MOCVD) are investigated using a scanning transmission electron microscope (STEM). Specifically, the combination of conventional high‐resolution imaging with scanning nanobeam diffraction (SNBD) using advanced 4D STEM techniques is used to analyze moiré structures. The latter technique is used to reveal the epitaxial alignment within the WS2/Gr heterostructure, showing a direct influence of the underlying Gr layers on the moiré structure in the subsequent WS2 layers. In particular, the importance of grain boundaries (GBs) within the underlying WS2 and Gr layers on the structure of moiré patterns with rotation angles below 2° is discussed.

Background Detailed visualization and precise measurements of aortic valve dimensions are critical for the success of transcatheter aortic valve implantation and for the prevention of complications. Currently, multislice computed tomography is the gold standard for assessment of the aortic annulus and surrounding structures to determine the prosthesis size. New technologies such as virtual reality (VR) not only enable 3‐dimensional (3D) visualization with the potential to improve understanding of anatomy and pathology but also allow measurements in 3D. This study aims to investigate the feasibility, accuracy, and reproducibility of VR for the visualization of the aortic valve, the surrounding structures, and its role in preprocedural sizing for transcatheter aortic valve implantation. Methods and Results Based on the preprocedural multislice computed tomography data, 3mensio measurements and 3D visualizations and measurements using VR software were performed retrospectively on 60 consecutive patients who underwent transcatheter aortic valve implantation at our heart center. There were no significant differences but strong correlations between the VR measurements compared with those performed with the 3mensio software. Furthermore, excellent or good intra‐ and interobserver reliability could be demonstrated for all values. In a structured questionnaire, users reported that VR simplified anatomical understanding, improved 3D comprehension of adjacent structures, and was associated with very good self‐perceived depth perception. Conclusions The use of VR for preprocedural transcatheter aortic valve implantation sizing is feasible and has precise and reproducible measurements. In addition, 3D visualization improves anatomical understanding and orientation. To evaluate the potential benefits of 3D visualization for planning further cardiovascular interventions, research in this field is needed.

Abstract The fixation index, FIS, has been a staple measure to detect selection, or departures from random mating in populations. However, current Next Generation Sequencing (NGS) cannot easily estimate FIS, in multi‐locus gene families that contain multiple loci having similar or identical arrays of variant sequences of ≥1 kilobase (kb), which differ at multiple positions. In these families, high‐quality short‐read NGS data typically identify variants, but not the genomic location, which is required to calculate FIS (based on locus‐specific observed and expected heterozygosity). Thus, to assess assortative mating, or selection on heterozygotes, from NGS of multi‐locus gene families, we need a method that does not require knowledge of which variants are alleles at which locus in the genome. We developed such a method. Like FIS, our novel measure, 1HIS, is based on the principle that positive assortative mating, or selection against heterozygotes, and some other processes reduce within‐individual variability relative to the population. We demonstrate high accuracy of 1HIS on a wide range of simulated scenarios and two datasets from natural populations of penguins and dolphins. 1HIS is important because multi‐locus gene families are often involved in assortative mating or selection on heterozygotes. 1HIS is particularly useful for multi‐locus gene families, such as toll‐like receptors, the major histocompatibility complex in animals, homeobox genes in fungi and self‐incompatibility genes in plants.

Background: The development of obesity-associated comorbidities such as type 2 diabetes (T2D) and hepatic steatosis has been linked to selected microRNAs in individual studies; however, an unbiased genome-wide approach to map T2D induced changes in the miRNAs landscape in human liver samples, and a subsequent robust identification and validation of target genes are still missing. Methods: Liver biopsies from age- and gender-matched obese individuals with (n=20) or without (n=20) T2D were used for microRNA microarray analysis. The candidate microRNA and target genes were validated in 85 human liver samples, and subsequently mechanistically characterized in hepatic cells as well as by dietary interventions and hepatic overexpression in mice. Results: Here, we present the human hepatic microRNA transcriptome of type 2 diabetes in liver biopsies and use a novel seed prediction tool to robustly identify microRNA target genes, which were then validated in a unique cohort of 85 human livers. Subsequent mouse studies identified a distinct signature of T2D-associated miRNAs, partly conserved in both species. Of those, human-murine miR-182–5 p was the most associated with whole-body glucose homeostasis and hepatic lipid metabolism. Its target gene LRP6 was consistently lower expressed in livers of obese T2D humans and mice as well as under conditions of miR-182–5 p overexpression. Weight loss in obese mice decreased hepatic miR-182–5 p and restored Lrp6 expression and other miR-182–5 p target genes. Hepatic overexpression of miR-182–5 p in mice rapidly decreased LRP6 protein levels and increased liver triglycerides and fasting insulin under obesogenic conditions after only seven days. Conclusions: By mapping the hepatic miRNA-transcriptome of type 2 diabetic obese subjects, validating conserved miRNAs in diet-induced mice, and establishing a novel miRNA prediction tool, we provide a robust and unique resource that will pave the way for future studies in the field. As proof of concept, we revealed that the repression of LRP6 by miR-182–5 p, which promotes lipogenesis and impairs glucose homeostasis, provides a novel mechanistic link between T2D and non-alcoholic fatty liver disease, and demonstrate in vivo that miR-182–5 p can serve as a future drug target for the treatment of obesity-driven hepatic steatosis. Funding: This work was supported by research funding from the Deutsche Forschungsgemeinschaft (KI 1887/2-1, KI 1887/2-2, KI 1887/3-1 and CRC-TR296), the European Research Council (ERC, CoG Yoyo LepReSens no. 101002247; PTP), the Helmholtz Association (Initiative and Networking Fund International Helmholtz Research School for Diabetes; MB) and the German Center for Diabetes Research (DZD Next Grant 82DZD09D1G).

Metal additive manufacturing technologies, such as Laser Powder-Bed Fusion, often rate as sustainable due to their high material efficiency. However, there are several drawbacks that reduce the overall sustainability and offer potential for improvement. One such drawback is waste emerging from the process. These smoulder particles form when the laser hits the powder-bed surface, are blown away from the part by the shielding gas stream and accumulate on the edge of the build chamber. Usually, smoulder does not contribute to the circular reuse of powder that was part of the powder-bed but was not integrated into a part. Instead, it marks an end-of-life state of powder. Significant amounts of smoulder accumulate depending on the irradiated area or the build volume in one job, respectively. This results in the waste of powder that was produced with low energy efficiency. This study investigates the question of whether smoulder can transform from waste to resource via common powder characterization methods and first build jobs using processed smoulder. The investigation of process-relevant powder properties like apparent density and flowability showed no significant difference between virgin powder and smoulder. Sample characterization indicated that neither porosity, surface quality nor mechanical properties deteriorate when samples contain about 50% smoulder. This allows for the reuse of smoulder in terms of powder characterization and part quality.

Abstract Metamaterials, especially lattice structures, are of great interest for many application areas such as aerospace, automotive and medicine due to their adjustable mechanical properties and their low weight. Due to their complex geometry, lattice structures are usually manufactured additively, which causes a large variance in the manufacturing-related mechanical properties. In order to establish metamaterials in industrial applications under cyclic loading, the fatigue behavior needs to be investigated to evaluate the load capacity of these structures. Here we analyze the fatigue behavior of AlSi10Mg truss structures fabricated with L-PBF using a load increase test in combination with acoustic emission measurements. The acoustic signals are evaluated in terms of time-dependent amplitude signal and frequency spectrum. Increasing load and increasing specimen damage resulted in changes of the acoustic spectrum and the amplitude of the time signal. Based on the results, a correlation of specimen properties with build platform position in the manufacturing process could be established. Acoustic emission measurement as an in situ characterization method during cyclic loading is promising for surveillance of lattice structures in safety related applications.

Abstract Background The global prevalence of vitamin D (VitD) deficiency associated with numerous acute and chronic diseases has led to strategies to improve the VitD status through dietary intake of VitD-fortified foods and VitD supplementation. In this context, the circulating form of VitD3 (cholecalciferol) in the human body, 25-hydroxy-VitD3 (calcifediol, 25OHVitD3), has a much higher efficacy in improving the VitD status, which has motivated researchers to develop methods for its effective and sustainable synthesis. Conventional monooxygenase-/peroxygenase-based biocatalytic platforms for the conversion of VitD3 to value-added 25OHVitD3 are generally limited by a low selectivity and yield, costly reliance on cyclodextrins and electron donor systems, or by the use of toxic co-substrates. Results In this study, we used a whole-cell approach for biocatalytic 25OHVitD3 synthesis, in which a molybdenum-dependent steroid C25 dehydrogenase was produced in the denitrifying bacterium Thauera aromatica under semi-aerobic conditions, where the activity of the enzyme remained stable. This enzyme uses water as a highly selective VitD3 hydroxylating agent and is independent of an electron donor system. High density suspensions of resting cells producing steroid C25 dehydrogenase catalysed the conversion of VitD3 to 25OHVitD3 using either O2 via the endogenous respiratory chain or externally added ferricyanide as low cost electron acceptor. The maximum 25OHVitD3 titer achieved was 1.85 g L–1 within 50 h with a yield of 99%, which is 2.2 times higher than the highest reported value obtained with previous biocatalytic systems. In addition, we developed a simple method for the recycling of the costly VitD3 solubiliser cyclodextrin, which could be reused for 10 reaction cycles without a significant loss of quality or quantity. Conclusions The established steroid C25 dehydrogenase-based whole-cell system for the value-adding conversion of VitD3 to 25OHVitD3 offers a number of advantages in comparison to conventional oxygenase-/peroxygenase-based systems including its high selectivity, independence from an electron donor system, and the higher product titer and yield. Together with the established cyclodextrin recycling procedure, the established system provides an attractive platform for large-scale 25OHVitD3 synthesis.

Zonisamide is used in dogs for the treatment of epileptic seizures. It is predominantly metabolised by CYP450 hepatic enzymes. When used concurrently with phenobarbital (PB), zonisamide clearance is increased and its elimination half-life decreases. However, the effect that zonisamide may have on serum PB concentrations in dogs has not been previously described. Eight dogs diagnosed with idiopathic epilepsy and two dogs with structural epilepsy commenced zonisamide at 8.0 mg/kg/12 h [7.4–10 mg/kg/12 h] following an increase in the frequency of epileptic seizures. Nine dogs were receiving PB every 12 h (4.2 mg/kg/12 h [3.8–6 mg/kg/12 h]), and one dog was receiving PB every 8 h (6 mg/kg/8 h). Following the addition of zonisamide and despite no increase in PB dosage, an increase in phenobarbital serum PB concentration was observed in 9 out of 10 dogs in subsequent measurements. In five dogs, phenobarbital serum concentrations were raised to concentrations higher than the reported hepatotoxic concentrations (trough>35 mg/L). This required a reduction in daily doses of PB. This case series suggests that zonisamide affects the metabolism of PB and causes an increase in PB serum concentrations over time.

ObjectiveThis study examined the prevalence of phubbing behavior among school and university students in Spain and analyzed the correlation of phubbing with other indicators of psychological well-being and mental health.MethodsThe study sample comprised a total of 1,351 school and university students, with ages ranging from 12 to 21 years. The study used the Phubbing Scale (PS), the Compulsive Internet Use Scale (CIUS), the Rosenberg Self-Esteem Scale (RSE), and the Interpersonal Emotion Regulation Questionnaire (IERQ) for data collection.ResultsThe results showed evidence of phubbing among approximately half of the students. Statistically significant differences were found based on gender and educational level in the Phone Obsession subscale and the PS total score, with male students and university students scoring higher in their respective parameters. In addition, phubbing was positively correlated with problematic internet use and negatively correlated with self-esteem.ConclusionPhubbing behavior is highly prevalent among adolescents aged 12–21 years and is positively correlated with low self-esteem and problematic internet use. Developing strategies for addressing this widespread issue at early ages, particularly within the educational context, such as schools, is crucial for implementing preventive measures. The inappropriate use of technological devices, including smartphones, in schools has the potential to negatively affect students’ well-being and ability to adapt to school.

The taxonomy of the family Paracortinidae Wang & Zhang, 1993 is revised based on literature, old and recently collected material. A new genus Crassipetalum Akkari & Stoev, gen. nov. is described, to accommodate a new species Crassipetalum magnum Akkari & Stoev, gen. nov. et sp. nov. and a recently described species Crassipetalum inflatum (Chen, Zheng & Jian, 2023), comb. nov. The genus Scotopetalum Shear, 2000 hitherto described for the Vietnamese species S. warreni Shear, 2000 and subsequently synonymised with the genus Paracortina Wang & Zhang, 1993 is here resurrected and supplemented with another species, S. chinensis (Stoev & Geoffroy, 2004), comb. nov., ex Paracortina chinensis Stoev & Geoffroy, 2004. The status of the fourth genus in the family, Angulifemur Zhang, 1997, is reconfirmed. Based on recently collected specimens from China, two new species of the genus Paracortina are described: P. asciformis Akkari & Stoev, sp. nov. (Sichuan Prov., Lixian County) and P. kabaki Akkari & Stoev, sp. nov. (Yunnan, Shangrila County). The Vietnamese species Paracortina multisegmentata Stoev & Geoffroy, 2004 and Paracortina kyrang Nguyen, Stoev, Nguyen & Vu, 2023 are considered of uncertain taxonomic position within Paracortinidae. Differential diagnoses for the proposed genera as well as for all the species are presented, and descriptions or descriptive notes for all the species are provided, using a standardised terminology, and when possible, accompanied by micrographs of the habitus and gonopod structures. An identification key based on gonopod structures is proposed for all the members of the family. A discussion on species affinities, secondary sexual characters, troglomorphic characters, geographical distribution, and habitat preferences are also provided together with a distribution map for all members of the family.

Background: The present study aims to analyze the prevalence of the problematic Internet use (PIU) among Spanish adolescents using the Compulsive Internet Use Scale (CIUS) and provide normative data. Method: The final sample consisted of a total of 1,977 (M age = 15.70, SD = 1.26, 53.7% female). Results: PIU were relatively common with many items seeing endorsement for between 6.5% and 33.1%. There were statistically significant differences both by gender. Females scored significantly more highly on four CIUS dimensions as well as total scores. With regards to age, we found statistically significant differences in preoccupation. No differences were found for the total score by age. Conclusions: Early detection strategies should be implemented in order to prevent PIU during adolescence, a critical developmental stage.

Assessing the embrittlement and hardening of reactor pressure vessel steels is critical for the extension of the service lifetime of nuclear power plants. This paper summarises the tensile test results on the irradiation behaviour of realistic VVER-1000 welds from the STRUMAT-LTO project. The welds were irradiated at the HFR (Petten, the Netherlands) to a fluence of up to 1.087 × 1020 n·cm−2, and their irradiation hardening was studied by means of tensile testing. The four grades, with different Mn and Ni contents, show different hardening behaviours. The highest degree of irradiation hardening is observed for the weld that has the highest combined Ni + Mn content. The results show that there is a synergetic effect of Mn and Ni on the irradiation hardening behaviour of the VVER-1000 welds. Besides irradiation hardening, the effectiveness of post-irradiation annealing treatments on the recovery of the tensile properties is studied in the present work. Post-irradiation annealing treatments conducted at 418 °C and at 475 °C proved to be effective for three of the four investigated welds. For the realistic weld with the highest combined Ni + Mn, only the annealing at 475 °C led to the complete recovery of the tensile properties.

Various pedagogical approaches have been proposed to attract more female students to STEM (science, technology, engineering, and mathematics), targeting student beliefs and perceptions that are linked to STEM study intentions. The current study, which took place in a secondary school in Cyprus and employed a quasi-experimental design, aims at contributing to this literature. Responses to pre- and post-questionnaires by 69 experimental and 27 control students show that students in the experimental group, who participated in an intervention in which they learned about the lives and accomplishments of STEM/STEAM role models via a game-based learning approach, improved their STEM ability perceptions compared to control group students, who reported similar pre-post survey levels of STEM ability perceptions. Female students benefited more compared to their male counterparts, and using a game-based learning approach contributed significantly to the effectiveness of students’ exposure to the role models. Taken together, study findings support the use of role models and learning games as tools to attract more female students to STEM.

Abstract Background Tissue environment is critical in determining tumour metabolic vulnerability. However, in vivo drug testing is slow and waiting for tumour growth delay may not be the most appropriate endpoint for metabolic treatments. An in vivo method for measuring energy stress would rapidly determine tumour targeting in a physiologically relevant environment. The sodium-iodide symporter (NIS) is an imaging reporter gene whose protein product co-transports sodium and iodide, and positron emission tomography (PET) radiolabelled anions into the cell. Here, we show that PET imaging of NIS-mediated radiotracer uptake can rapidly visualise tumour energy stress within minutes following in vivo treatment. Methods We modified HEK293T human embryonic kidney cells, and A549 and H358 lung cancer cells to express transgenic NIS. Next, we subjected these cells and implanted tumours to drugs known to induce metabolic stress to observe the impact on NIS activity and energy charge. We used [18F]tetrafluoroborate positron emission tomography (PET) imaging to non-invasively image NIS activity in vivo. Results NIS activity was ablated by treating HEK293T cells in vitro, with the Na+/K+ ATPase inhibitor digoxin, confirming that radiotracer uptake was dependent on the sodium–potassium concentration gradient. NIS-mediated radiotracer uptake was significantly reduced (− 58.2%) following disruptions to ATP re-synthesis by combined glycolysis and oxidative phosphorylation inhibition in HEK293T cells and by oxidative phosphorylation inhibition (− 16.6%) in A549 cells in vitro. PET signal was significantly decreased (− 56.5%) within 90 min from the onset of treatment with IACS-010759, an oxidative phosphorylation inhibitor, in subcutaneous transgenic A549 tumours in vivo, showing that NIS could rapidly and sensitively detect energy stress non-invasively, before more widespread changes to phosphorylated AMP-activated protein kinase, phosphorylated pyruvate dehydrogenase, and GLUT1 were detectable. Conclusions NIS acts as a rapid metabolic sensor for drugs that lead to ATP depletion. PET imaging of NIS could facilitate in vivo testing of treatments targeting energetic pathways, determine drug potency, and expedite metabolic drug development.

Abstract Background and introduction The place of last care carries importance for patients at the end of life. It is influenced by the realities of the social welfare and healthcare systems, cultural aspects, and symptom burden. This study aims to investigate the place of care trajectories of patients admitted to an acute palliative care unit. Materials and methods The medical records of all patients hospitalized on our acute palliative care unit in 2019 were assessed. Demographic, socio-economic and disease characteristics were recorded. Descriptive and inferential statistics were used to identify determinants for place of last care. Results A total of 377 patients were included in this study. Median age was 71 (IQR, 59–81) years. Of these patients, 56% (n = 210) were male. The majority of patients was Swiss (80%; n = 300); about 60% (n = 226) reported a Christian confession; and 77% had completed high school or tertiary education. Most patients (80%, n = 300) had a cancer diagnosis. The acute palliative care unit was the place of last care for 54% of patients. Gender, nationality, religion, health insurance, and highest level of completed education were no predictors for place of last care, yet previous outpatient palliative care involvement decreased the odds of dying in a hospital (OR, 0.301; 95% CI, 0.180–0.505; p-value

Abstract A meteorologically challenging situation that represents a demanding control task (rotational speed, pitch and yaw) for a wind turbine is presented and its implementation in a simulation is described. A high‐fidelity numerical process chain, consisting of the computational fluid dynamics (CFD) solver FLOWer, the multi‐body system (MBS) software SIMPACK and the Ffowcs Williams‐Hawkings code ACCO, is used. With it, the aerodynamic, servoelastic and aeroacoustic (

Abstract Background and Objective Human plasma is used for the generation of several life-saving drugs and contains valuable antibodies from the immunoglobulin classes IgG, IgM and IgA. Purified intravenous IgG solutions (IVIGs) form the majority of plasma-derived medicine to treat patients with various forms of immunodeficiencies. In conventional IVIG manufacturing processes, immunoglobulin classes IgM and IgA are often discarded as contaminants, but these antibody classes have been proven to be effective for the treatment of acute bacterial infections. Considering the increase in demand for human plasma-derived products and the ethical value of the raw material, a more resource-saving usage of human plasma is needed. Intensive research over the last decades showed that adverse reactions to IVIGs depend on the presence of thrombogenic factors, partially unfolded proteins, non-specific activation of the complement system, and blood group specific antibodies. Therefore, new IVIG preparations with reduced risks of adverse reactions are desirable. Method A new manufacturing process that yields two biologics was established and quality attributes of the new IVIG solution (Yimmugo®) obtained from this process are presented. Results Here, we provide a biochemical characterization of Yimmugo®, a new 10% IVIG preparation. It is derived from human blood plasma by a combined manufacturing process, where IgM and IgA are retained for the production of a new biologic (trimodulin, currently under investigation in phase III clinical trials). Several improvements have been implemented in the manufacturing of Yimmugo® to reduce the risk of adverse reactions. Gentle and efficient mixing by vibration (called “vibromixing”) during a process step where proteins are at risk to aggregate was implemented to potentially minimize protein damage. In addition, a dedicated process step for the removal of the complement system activator properdin was implemented, which resulted in very low anticomplementary activity levels. The absence of measurable thrombogenic activity in combination with a very high degree of functional monomeric antibodies predict excellent efficacy and tolerability. Conclusion Yimmugo® constitutes a new high quality IVIG preparation derived from a novel manufacturing process that takes advantage of the full therapeutic immunoglobulin potential of human plasma.

Introduction: Almost 25% of German adults have obesity and numbers are rising, making it an important health issue. Bariatric-metabolic surgery reduces body weight and complications for persons with obesity, but therapeutic success requires long-term post-operative care. Since, no German standards for follow-up by family physicians exist, follow-up is provided by surgical obesity centers, but they are reaching their limits. The ACHT study, funded by the German Innovation Fund, is designed to establish and evaluate the follow-up program, with local physicians following patients supported remotely by obesity centers. Methods: ACHT is a multicenter, prospective, non-randomized control-group study. The 18-month ACHT follow-up program is a digitally supported, structured, cross-sectoral, and close-to-home program to improve success after bariatric-metabolic surgery. Four groups are compared: intervention group 1 starts the program immediately (3 weeks) after Roux-en-Y gastric-bypass or sleeve-gastrectomy (months 1-18 postoperatively), intervention group 2 begins the program 18-months after surgery (months 19-36 postoperatively). Intervention groups are compared to corresponding control groups that had surgery 18 respectively 36 months previously. In total, 250 patients, enrolled in the intervention groups, are compared with 360 patients in the control groups, who only receive standard care. Results: The primary endpoint to compare intervention and control groups is the adapted King’s Score, a composite tool evaluating physical, psychological, socio-economic and functional health status. Secondary endpoints include changes in care structures and care processes for the intervention groups. Multivariate regression analyses adjusting for confounders (including the type of surgery) are used to compare intervention and control groups and to evaluate determinants in longitudinal analyses. The effect of the intervention on healthcare costs will be evaluated based on health insurance billing data of patients who had bariatric-metabolic surgery in the three years prior to the start of the study and of patients who undergo bariatric-metabolic surgery during the study period. Conclusions: ACHT will be the one of the first evaluated structured, close-to-home follow-up programs for bariatric surgery in Germany. It will evaluate the effectiveness of the implemented program regarding improvements in health status, mental health, quality of life and the feasibility of such a program outside of specialized obesity centers.

Abstract Objective Communication skills can deteriorate in neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal dementia (FTD); however, their clinical assessment and treatment in patient care can be challenging. In the present study, we aimed to quantify the distinctive communication resources and barriers reported by patients and their relatives in AD and FTD and associated these communicative characteristics with clinical parameters, such as the degree of cognitive impairment and atrophy in language‐associated brain areas. Methods We assessed self‐reported communication barriers and resources in 33 individuals with AD and FTD through an interview on daily‐life communication, using the Aachener KOMPASS questionnaire. We correlated reported communication barriers and resources with atrophy from high‐resolution 3T brain magnetic resonance imaging, neuropsychological assessment, and neurodegenerative markers from cerebrospinal fluid. Results Communicative impairment was higher in FTD compared to AD. Increased reported communication barriers in our whole sample were associated with the atrophy rate in the left middle temporal lobe, a critical site within the neuronal language network, and with depressive symptoms as well as the semantic word fluency from neuropsychological assessment. The best model for prediction of communicative impairment included the diagnosis (AD or FTD), semantic word fluency, and depressive symptoms. Conclusions Our study demonstrates that communication barriers and resources can be successfully assessed via a structured interview based on self‐report and report of patients’ relatives in practice and are reflected in neuroimaging specific for AD and FTD as well as in further clinical parameters specific for these neurodegenerative diseases. This can potentially open new treatment options for clinical practice and patient care.

BackgroundUnderstanding complex cardiac anatomy is essential for percutaneous left atrial appendage (LAA) closure. Conventional multi-slice computed tomography (MSCT) and transesophageal echocardiography (TEE) are now supported by advanced 3D printing and virtual reality (VR) techniques for three-dimensional visualization of volumetric data sets. This study aimed to investigate their added value for LAA closure procedures.MethodsTen patients scheduled for interventional LAA closure were evaluated with MSCT and TEE. Patient-specific 3D printings and VR models were fabricated based on MSCT data. Ten cardiologists then comparatively assessed LAA anatomy and its procedure relevant surrounding structures with all four imaging modalities and rated their procedural utility on a 5-point Likert scale questionnaire (from 1 = strongly agree to 5 = strongly disagree).ResultsDevice sizing was rated highest in MSCT (MSCT: 1.9 ± 0.8; TEE: 2.6 ± 0.9; 3D printing: 2.5 ± 1.0; VR: 2.5 ± 1.1; p

Background: Insufficient remnant liver volume (RLV) after the resection of hepatic malignancy could lead to liver failure and mortality. Portal vein ligation (PVL) prior to hepatectomy is subsequently introduced to increase the remnant liver volume and improve the outcome of hepatic malignancy. IL-22 has previously been reported to promote liver regeneration, while facilitating tumor development in the liver via Steap4 upregulation. Here we performed PVL in mouse models to study the role of IL-22 in liver regeneration post-PVL. Methods: Liver weight and volume was measured via magnetic resonance imaging (MRI). Immunohistochemistry for Ki67 and hepatocyte growth factor (HGF) was performed. IL-22 was analyzed by flow cytometry and quantitative polymerase chain reaction (qPCR) was used for acquisition of Il-33, Steap4, Fga, Fgb and Cebpd. To analyze signaling pathways, mice with deletion of STAT3 and a neutralizing antibody for IL-22 were used. Results: The remnant liver weight and volume increased over time after PVL. Additionally, we found that liver regenerative molecules, including Ki67 and HGF, were significantly increased in remnant liver at day 3 post-PVL, as well as IL-22. Administration of IL-22 neutralizing antibody could reduce Ki67 expression after PVL. The upregulation of IL-22 after PVL was mainly derived from innate cells. IL-22 blockade resulted in lower levels of IL-33 and Steap4 in the remnant liver, which was also the case in mice with deletion of STAT3, the main downstream signaling molecule of IL-22, in hepatocytes. Conclusion: IL-22 promotes liver regeneration after PVL. Thus, a combination of IL-22 supplementation and Steap4 blockade could potentially be applied as a novel therapeutic approach to boost liver regeneration without facilitating tumor progression after PVL.

Summary: To investigate underlying mechanisms for cancer metastasis and promising therapies in animal models, spontaneous metastasis models can be used to recreate metastasis development. Here, we present three mouse models of spontaneous lung and/or liver metastasis induction. We describe steps for cancer cell preparation, mouse analgesia, and three injection techniques (subcutaneous, intracecal, and intramucosal). We then detail procedures for evaluating metastasis. Most of these models generate metastasis in a time span of 4 weeks in the majority of injected mice.For complete details on the use and execution of this protocol, please refer to Giannou et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Optimised implantation depth (OID) is crucial to obtain the best haemodynamic and clinical outcome during transcatheter heart valve (THV) deployment. OID ensures a better haemodynamic profile and is associated with a potential reduction in permanent pacemaker implantations, both of which are important during transcatheter aortic valve replacement (TAVR). Apart from patient-related anatomic conditions, many factors, such as THV and wire selection, as well as implantation strategies, can be controlled by the operator and facilitate the implantation process. However, there are only limited data dealing with predictors for OID. Therefore, the aim of this review was to outline factors and tools that might influence the final implantation depth during TAVR procedures, potentially influencing the outcome.

Ailanthus altissima is among the most invasive woody species worldwide, outcompeting native trees. The fungus Verticillium nonalfalfae (VN) is promising for A. altissima biocontrol, and its effects on the host have been studied via visual assessment in a range of host species. However, little research was performed to address fungal effects on the physiological processes of non-target woody plants. We investigated the occurrence of visual and non-visually recognisable perturbations of VN infection on potted vines to evaluate the potential risks of the biocontrol pathogen on viticulture. Eighteen four-years-old Vitis vinifera (cultivar Grüner Veltliner grafted on Kober 5BB) potted plants were inoculated with VN conidial suspension of the fungus (F), while nine plants were treated with sterile water (C, control). Disease symptoms and physiological parameters were monitored throughout the experiment (seven evaluation dates), while leaf water potential, leaf mass per area (LMA) and biomass were measured at the end of the study when plant tissue was sampled for re-isolation of the fungus. In our trial, inoculations with VN induced characteristic wilting symptoms only in Ailanthus (used as side control of the inoculum), while vines remained asymptomatic, thus indicating a high degree of host specificity of VN. Limited or no impact was detected on the physiology of the non-target V. vinifera. Furthermore, the LMA and biomass measured in the two experimental groups were not different. Although fungal colonisation induced vascular discolouration in both species, the fungus could only be re-isolated from dying Ailanthus but not from vine tissue. Results suggest that V. vinifera cv Grüner Veltliner is resistant to the applied VN isolate. However, the susceptibility and physiology of additional grapevine cultivars, as well as other native woody species to VN, should be studied before promoting large-scale use of the biocontrol agent.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which is responsible for eliciting Coronavirus disease 2019 (COVID-19) still challenges healthcare services worldwide. While many patients only suffer from mild symptoms, patients with some pre-existing medical conditions are at a higher risk for a detrimental course of disease. However, the underlying mechanisms determining disease course are only partially understood. One key factor influencing disease severity is described to be immune-mediated. In this report, we describe a post-mortem analysis of 45 individuals who died from SARS-CoV-2 infection. We could show that although sociodemographic factors and premedical conditions such as obesity and diabetes mellitus reduced survival time in our cohort, they were not associated with changes in the expression of immune-related signature genes at the RNA level in the blood, the gut, or the liver between these different groups. Our data indicate that obesity and diabetes mellitus influence SARS-CoV-2-related mortality, without influencing the extrapulmonary gene expression of immunity-related signature genes at the RNA level.

Next to white and brown adipocytes present in white and brown adipose tissue (WAT, BAT), vascular endothelial cells, tissue-resident macrophages and other immune cells have important roles in maintaining adipose tissue homeostasis but also contribute to the etiology of obesity-associated chronic inflammatory metabolic diseases. In addition to hormonal signals such as insulin and norepinephrine, extracellular adenine nucleotides modulate lipid storage, fatty acid release and thermogenic responses in adipose tissues. The complex regulation of extracellular adenine nucleotides involves a network of ectoenzymes that convert ATP via ADP and AMP to adenosine. However, in WAT and BAT the processing of extracellular adenine nucleotides and its relevance for intercellular communications are still largely unknown. Based on our observations that in adipose tissues the adenosine-generating enzyme CD73 is mainly expressed by vascular endothelial cells, we studied glucose and lipid handling, energy expenditure and adaptive thermogenesis in mice lacking endothelial CD73 housed at different ambient temperatures. Under conditions of thermogenic activation, CD73 expressed by endothelial cells is dispensable for the expression of thermogenic genes as well as energy expenditure. Notably, thermoneutral housing leading to a state of low energy expenditure and lipid accumulation in adipose tissues resulted in enhanced glucose uptake into WAT of endothelial CD73-deficient mice. This effect was associated with elevated expression levels of de novo lipogenesis genes. Mechanistic studies provide evidence that extracellular adenosine is imported into adipocytes and converted to AMP by adenosine kinase. Subsequently, activation of the AMP kinase lowers the expression of de novo lipogenesis genes, most likely via inactivation of the transcription factor carbohydrate response element binding protein (ChREBP). In conclusion, this study demonstrates that endothelial-derived extracellular adenosine generated via the ectoenzyme CD73 is a paracrine factor shaping lipid metabolism in WAT.

Objective The resurgence of virtual reality (VR) technologies has led to their increased use in contemporary healthcare education. One promising application is simulating the experiences of individuals with mental health conditions (MHCs) to reduce stigma among future healthcare professionals. This study set out to explore what those impacted by, or involved in, the education of healthcare students think about using VR in this way. Methods One individual interview and five focus groups were conducted with healthcare students ( n = 7), healthcare educators ( n = 6), and lived experience experts ( n = 5). Before sharing their perspectives, participants familiarised themselves with VR equipment and immersive materials simulating MHCs. The constant comparative method and thematic analysis were used to analyse the data. Results Participants recognised the acceptability and utility of VR for addressing mental health stigma in healthcare students, emphasising the immersive nature of this technology. However, some participants raised concerns about the limited insight VR could provide into the experiences of patients with the same MHCs and its potential emotional impact on users. Participants recommended the incorporation of interactive, realistic environments with a person-centred focus into future VR-based stigma reduction interventions while stressing the importance of providing healthcare students with opportunities for reflection and support. Conclusions Healthcare students, healthcare educators, and lived experience experts highlighted both advantages and barriers associated with using VR to understand the experience of patients with MHCs. Furthermore, the recommendations put forward can inform the design, content, and delivery of VR-based stigma reduction interventions in healthcare education.

Species of the gobiid genus Schindleria are among the smallest and fastest reproducing vertebrates of the oceans. We describe a new species, Schindleria qizma, from the Red Sea, Saudi Arabia. It is an extreme example of progenesis, within the already paedomorphic genus, with morphological traits clearly differentiating it from its congeners. Schindleria qizma has a unique, unflexed notochord with a straight urostyle of which the tip is inserted into the hypural cartilage, rather than the typical flexed notochord with an upturned urostyle of the other species of Schindleria. Schindleria qizma belongs to the short dorsal-fin type of Schindleria. It is further characterized by an elongated but relatively deep body; a short dorsal fin originating just slightly anterior to the anal fin (predorsal-fin length 59.4% of SL vs. preanal-fin length 60.2% of SL); a head continuously increasing in depth posteriorly with a straight dorsal profile; a short snout (18.6% of head length); large eyes (34.4% of head length); a short pectoral-radial plate (6.3% of SL); 13 dorsal-fin rays; 11 anal-fin rays; 0–2 procurrent rays (where the last procurrent ray is short, if present); an anal fin with the first anal-fin ray situated opposite the second dorsal-fin ray; toothless oral jaws; females with few (10–11, total) but very large (4.6% of SL) eggs and with a conspicuous urogenital papilla characterized by a wide urogenital opening flanked by two long, bilobed projections; a dorsally pigmented swim-bladder; blackish, iridescent eyes, capped by a silvery layer with irregular rows of black dots or blotches; and no additional external pigmentation on its body, at least in preserved specimens.

Research has been conducted investigating the neuronal pathways responsible for the generation of chronic neuropathic pain, including the components of it in conditions such as chronic post-surgical pain, phantom limb pain, and cluster headaches. Forming part of the management of such conditions, capsaicin as a molecule has proven effective. This review has investigated the central nervous system modifications exhibited in such conditions and the pharmacological mechanisms of capsaicin relevant to this. The current paradigm for explaining topical capsaicin-induced analgesia is that TRPV1-mediated calcium ion influx induces calpain, in turn causing axonal ablation and functional defunctionalisation in the PNS (Peripheral Nervous System). Demonstrated through the analysis of existing data, this review demonstrates the changes seen in the CNS (Central Nervous System) in chronic neuropathic pain, as well as some of the evidence for capsaicin modulation on the CNS. Further supporting this, the specific molecular mechanisms of capsaicin-induced analgesia will also be explored, including the action of TRPV1, as well as discussing the further need for clinical research into this area of uncertainty due to the limited specific data with suitable parameters. Further research this review identified as potentially useful in this field included fMRI (functional Magnetic Resonance Imaging) studies, though more specific observational studies of patients who have already been administered capsaicin as a current treatment may prove helpful in studying the modification of the CNS in the long term.

Background: Respiratory syncytial virus (RSV) is an important cause of childhood hospitalizations. The aim of the study was to estimate the rates of RSV-related hospitalizations in children aged less than 5 years in Poland. Methods: This retrospective observational cohort study was based on data obtained from the National Health Fund in Poland regarding all acute respiratory tract infections and RSV-coded admissions of children (age < 5 years) to public hospitals between July 2015 and June 2023. Patients were stratified based on the following age groups: 0–1 month, 2–3 months, 4–6 months, 7–12 months, 13–24 months, and 25–60 months. Results: The number of RSV-related hospitalizations increased every season, both before and through the ending phase of the coronavirus disease 2019 (COVID-19) pandemic. The COVID-19 pandemic was associated with a shift in the seasonality pattern of RSV infection. Hospitalization rates per 1000 inhabitants were the highest for children aged 0–12 months, reaching 47.3 in the 2022/23 season. Within this group, the highest hospitalization rate was observed for children aged 2–3 months—94.9 in the 2022/23 season. During the ending phase of the COVID-19 pandemic, the observed increase in admission rates was 2-, 4-, and 5-fold the pre-COVID rate for children aged

Summary: The transplantation model provides the opportunity to assess the relevance of a molecule of interest for tumor cell extravasation by using a respective genetically modified donor animal. Here, we present a protocol for orthotopic single-lung transplantation in mice as a tool for lung metastasis studies. We describe steps for animal preparation, lung transplantation, and tumor cell injection. We then detail procedures for the direct comparison of tumor cell spreading between the genetically modified left lung and the naive right lung parenchyma.For complete details on the use and execution of this protocol, please refer to Giannou et al. (2023).1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Background: The Quality Outcomes Framework (QOF) is a pay incentive scheme in England designed to improve and standardise general practice. QOF attainment has been used as a proxy for primary care quality in previous research. Aim: To investigate whether there is a relationship between socioeconomic deprivation and QOF attainment in primary care in England. Design & setting: Retrospective longitudinal study of primary care providers in England. Method: QOF scores were obtained for individual general practices in England from between 2007–2019 and linked to practice-level Indices of Multiple Deprivation (IMD) scores derived from census data. Beta regression analyses were used to analyse the relationship with either percentage of total QOF attainment or of domain-specific attainment with multivariate analyses, adjusting for additional practice-level demographics. QOF attainment in the most affluent quintile was used as the reference group. Results: General practices in less deprived areas have consistently outperformed those in more deprived areas in terms of QOF achievement. Initially, the gap between least and most deprived practices decreased, however since 2015 there has been relatively little change in comparative performance. The magnitude of inequality was reduced after adjusting for demographic factors. Of the independent variables analysed, the proportion of patients aged >65 years (‘over 65s’) had the strongest relationship with QOF attainment. Conclusion: There remains an inequality in primary care quality by socioeconomic deprivation in England, even after accounting for demographic differences.

ABSTRACTMetastasis is a cancer-related systemic disease and is responsible for the greatest mortality rate among cancer patients. Interestingly, the interaction between the immune system and cancer cells seems to play a key role in metastasis formation in the target organ. However, this complex network is only partially understood. We previously found that IL-22 produced by tissue resident iNKT17 cells promotes cancer cell extravasation, the early step of metastasis. Based on these data, we aimed here to decipher the role of IL-22 in the last step of metastasis formation. We found that IL-22 levels were increased in established metastatic sites in both human and mouse. We also found that Th22 cells were the key source of IL-22 in established metastasis sites, and that deletion of IL-22 in CD4+ T cells was protective in liver metastasis formation. Accordingly, the administration of a murine IL-22 neutralizing antibody in the establishment of metastasis formation significantly reduced the metastatic burden in a mouse model. Mechanistically, IL-22-producing Th22 cells promoted angiogenesis in established metastasis sites. In conclusion, our findings highlight that IL-22 is equally as important in contributing to metastasis formation at late metastatic stages, and thus, identify it as a novel therapeutic target in established metastasis.

Objective: Several supra-annular self-expanding transcatheter systems are commercially available for transcatheter aortic valve implantation (TAVI). Comparative data in large-scale multicenter studies are scant. Methods: This study included a total of 5175 patients with severe aortic stenosis undergoing TAVI with the ACURATE neo (n = 1095), Evolut R (n = 3365), or Evolut PRO (n = 715) by a transfemoral approach at five high-volume centers. Propensity score matching resulted in 654 triplets. Outcomes are reported according to the Valve Academic Research Consortium-3 (VARC-3) consensus. Results: Moderate or severe paravalvular regurgitation (PVR) occurred significantly more often in the ACURATE neo group (5.2%) than in the Evolut R (1.8%) and Evolut PRO (3.3%) groups (p = 0.003). The rates of major vascular-/access-related complications (4.6%, 3.8%, and 5.0%; p = 0.56), type 3 or 4 bleeding (3.2%, 2.1%, and 4.1%; p = 0.12), and 30-day mortality (2.4%, 2.6%, and 3.7%; p = 0.40) were comparable. The rate of new permanent pacemaker implantation (PPI) was significantly lower in the ACURATE neo group (9.5%, 17.6%, and 16.8%; p

Abstract Background Hematologic patients requiring abdominal emergency surgery are considered to be a high-risk population based on disease- and treatment-related immunosuppression. However, the optimal surgical therapy and perioperative management of patients with abdominal emergency surgery in patients with coexisting hematological malignancies remain unclear. Methods We here report a single-center retrospective analysis aimed to investigate the impact of abdominal emergency surgery due to clinically suspected gastrointestinal perforation (group A), intestinal obstruction (group B), or acute cholecystitis (group C) on mortality and morbidity of patients with coexisting hematological malignancies. All patients included in this retrospective single-center study were identified by screening for the ICD 10 diagnostic codes for gastrointestinal perforation, intestinal obstruction, and ischemia and acute cholecystitis. In addition, a keyword search was performed in the database of all pathology reports in the given time frame. Results A total of 56 patients were included in this study. Gastrointestinal perforation and intestinal obstruction occurred in 26 and 13 patients, respectively. Of those, 21 patients received a primary gastrointestinal anastomosis, and anastomotic leakage (AL) occurred in 33.3% and resulted in an AL-related 30-day mortality rate of 80%. The only factor associated with higher rates of AL was sepsis before surgery. In patients with suspected acute cholecystitis, postoperative bleeding events requiring abdominal packing occurred in three patients and lead to overall perioperative morbidity of 17.6% and surgery-related 30-day mortality of 5.9%. Conclusion In patients with known or suspected hematologic malignancies who require emergency abdominal surgery due to gastrointestinal perforation or intestinal obstruction, a temporary or permanent stoma might be preferred to a primary intestinal anastomosis.

Abstract Background Chemical pollution forms a severe threat for human and environmental health. While the risks for European lowland water bodies are well known, there is little knowledge on remote aquatic ecosystems and particularly mountain lakes, despite their importance for the provision of freshwater. Here, we critically review the current knowledge on the exposure and risk by chemical pollution for mountain lakes and present a tiered approach on how to advance effectively our understanding in the future. Results Generally, pollutant monitoring data are currently incomplete, with many regions and substances having been only poorly investigated. More reliable data exist only for persistent organic pollutants (POPs). However, there is increasing evidence that even remote mountain lakes are exposed to a wide range of organic pollutants. Among them potent pesticides currently used in agricultural and biocidal applications, such as diazinon and permethrin. The exposure of mountain lakes to pollutants follows a complex pattern. Pollutants are introduced into mountain lakes via the atmospheric deposition and run-off from the watershed, but also local sources, like tourism and pastoralism. Our risk assessment and recent biomonitoring studies suggest that there are widespread chronic toxic risks on crustacean in mountain ranges. If mountain ranges are exposed to tourism and pastoralism, even acute toxic effects on crustacean are possible. Thereby, the vulnerability of mountain lakes to toxic effects has to be expected to be particularly high due to the harsh environmental conditions at high altitudes, the organism’s traits, the insular position of mountain lakes and a lower species richness with increasing altitudes. Furthermore, there is little knowledge on the biological processes leading to the degradation of chemical pollutants under the environmental and ecological conditions of mountain ecosystems. Conclusion While the exposure and sensitivity of mountain aquatic ecosystems is currently poorly investigated, the existing data suggest that it is very likely that also water bodies as remote as mountain lakes do suffer from pollution-induced toxicity. To verify this suggestion and expand the existing knowledge, it is necessary that future studies combine a more holistic pollution monitoring with exposure modelling and links to biological effects. Only then will it be possible to obtain a more reliable understanding of the impact of chemical pollution on aquatic mountain ecosystems and to protect these fragile ecosystems.

Abstract Background Nonalcoholic fatty liver disease (NAFLD), especially nonalcoholic steatohepatitis (NASH) increases the risk for liver cirrhosis. Noninvasive tests for NAFLD/NASH exist, but they are unreliable and thus liver biopsy remains the standard for diagnosis and new noninvasive diagnostic approaches are of great interest. The aim of this study was to test whether the serum levels of fatty acid-binding protein-4 (FABP4) and matrix metalloproteinase-9 (MMP9) could be used as a diagnostic tool for NASH. Methods Patients who underwent bariatric surgery and simultaneous liver biopsy were identified. Biopsies were assigned a NAFLD activity score (NAS). MMP9- and FABP4- Enzyme-linked Immunosorbent Assays (ELISAs) on serum samples were performed. The serum levels of FABP4/MMP9 were compared and different models to predict NASH were developed. Results A total of 84 patients were included, 28 patients (33.3%) were diagnosed with NASH. Higher concentrations of MMP9 in NASH patients (p