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This work introduces a novel family of boundary conditions for AdS3 General Relativity, constructed through a polynomial expansion in negative integer powers of the Brown-Henneaux central charge. The associated dynamics is governed by the Dym hierarchy of integrable equations. It is shown that the infinite set of Dym conserved charges generates an abelian asymptotic symmetry group. Additionally, these boundary conditions encompass black hole solutions, whose thermodynamic properties are examined. [ABSTRACT FROM AUTHOR]

Purpose: Spontaneous regression of Chiari malformation type 2 (CM2) is observed rarely, as CM2 is associated with meningomyelocele (MMC) that is surgically repaired either pre- or early postnatally. While the radiological regression of CM2 occurs frequently following prenatal repair of MMC, it has been reported in only a few studies after postnatal repair. Methods: From the consecutive series of children with postnatally repaired MMC, we reviewed the clinical and radiological data regarding CM2, particularly its regression either spontaneously or following CSF diversion. Results: Eighteen children underwent postnatal repair of MMC between February 2011 and April 2023. CM2 was present in 16 (89%), and hydrocephalus in 15 children (83%), requiring shunting in 14 of them. During the mean clinical observation time (from birth to April 2023) of 59 ± 51 months, three children with CM2 (19%) underwent 1–2 foramen magnum decompressions (FMD), five children (28%) 1–4 surgical untethering procedures and 13 children with shunted hydrocephalus (93%) 1–5 shunt revisions. Out of sixteen children with CM2, we observed regression of CM2 on MRI in only one case (6%) during the mean radiological follow-up (from birth to the last MRI taken) of 49 ± 51 months. Conclusion: In our experience, spontaneous regression of CM2 in children with postnatally repaired MMC occurs quite rarely. Pathophysiological mechanisms behind the development of CM2 in children with MMC remain unclear, but our observation supports the hypothesis of an association between the downward displacement of the hindbrain and the low intraspinal pressure secondary to CSF leakage in children born with MMC. [ABSTRACT FROM AUTHOR]

The goal of this paper is to study the number of sliding limit cycles of regularized piecewise linear visible–invisible twofolds using the notion of slow divergence integral. We focus on limit cycles produced by canard cycles located in the half-plane with an invisible fold point. We prove that the integral has at most 1 zero counting multiplicity (when it is not identically zero). This will imply that the canard cycles can produce at most 2 limit cycles. Moreover, we detect regions in the parameter space with 2 limit cycles. [ABSTRACT FROM AUTHOR]

This study investigates the relationship between international inventor teams and the technological variety of multinational enterprises. We frame this relationship conceptually by considering two possible attributes of diversity in international inventor teams: cultural differences and heterogeneous knowledge. We employ a dataset for 454 multinational enterprises with 71,126 subsidiaries across 185 countries that applied for 139,066 priority patents during the period 2007–2014. Fixed-effects panel estimations indicate that international inventor teams are positively associated with both related and unrelated technological variety at the level of the MNE. Such relationships display diminishing marginal returns, pointing to management and coordination costs reducing the benefits from international inventor teams. In addition, we find that MNEs with higher technological innovation capability deal with the additional complexity from managing and coordinating international inventor teams by consolidating technological variety. [ABSTRACT FROM AUTHOR]

About 1.5% of patients undergoing total hip (THA) or total knee arthroplasty (TKA) still develop postoperative venous thromboembolism (VTE), indicating that the current thromboprophylaxis strategy is not optimal. To evaluate the feasibility of therapeutic dosages of direct oral anticoagulants (DOACs) as thromboprophylaxis for high VTE risk patients, we determined the risks of major bleeding and VTE in patients who underwent THA/TKA and were treated with DOACs in therapeutic dosages for atrial fibrillation (AF). We conducted a registry-based cohort study from 2010 to 2018 in Denmark and included AF patients on therapeutic DOACs dose who underwent THA/TKA. AF patients were utilized as proxy since they have a life-long indication for therapeutic anticoagulant medication. The 49-days cumulative incidence (with death as competing risk) of major bleeding was assessed. The same was done for VTE at 49- and 90-days. 1,354 THA and TKA procedures were included. The 49-days cumulative incidence of major bleeding was 1.40% (95%Confidence Interval[CI] 0.88–2.14%). Most bleeding events occurred at the surgical site. The cumulative incidence of VTE at 49-days was 0.59% (95%CI 0.28–1.13%) and 0.74% (95%CI 0.38–1.32%) at 90-days. The incidence of major bleeding in THA/TKA patients on DOACs in therapeutic dosages was in line with previously reported incidences among THA/TKA patients on thromboprophylaxis dosages, while the incidence of VTE was relatively low. These data provide a solid basis for the design of randomized controlled trials to establish the safety and efficacy of therapeutic dosages of DOACs to prevent VTE in high-risk patients. Essentials: • Some arthroplasty patients still develop venous thromboembolism (VTE), despite thromboprophylaxis. • We assessed the feasibility of DOACs used in therapeutic dosage as thromboprophylaxis in high-risk THA/TKA patients. • Observed risks of major bleeding and VTE were 1.40% (49-days) and 0.74% (90-days), respectively. • A randomized clinical trial investigating the possible benefit of therapeutic dosages of DOACs as prophylactic strategy in high-risk arthroplasty patients seems a feasible next step. [ABSTRACT FROM AUTHOR]

Purpose: The CYP2D6 gene exhibits significant polymorphism, contributing to variability in responses to drugs metabolized by CYP2D6. While CYP2D6*2 and CYP2D6*35 are presently designated as alleles encoding normal metabolism, this classification is based on moderate level evidence. Additionally, the role of the formerly called "enhancer" single nucleotide polymorphism (SNP) rs5758550 is unclear. In this study, the impacts of CYP2D6*2, CYP2D6*35 and rs5758550 on CYP2D6 activity were investigated using risperidone clearance as CYP2D6 activity marker. Methods: A joint parent-metabolite population pharmacokinetic model was used to describe 1,565 serum concentration measurements of risperidone and 9-hydroxyrisperidone in 512 subjects. Risperidone population clearance was modeled as the sum of a CYP2D6-independent clearance term and the partial clearances contributed from each individually expressed CYP2D6 allele or haplotype. In addition to the well-characterized CYP2D6 alleles (*3-*6, *9, *10 and *41), *2, *35 and two haplotypes assigned as CYP2D6*2-rs5758550G and CYP2D6*2-rs5758550A were evaluated. Results: Each evaluated CYP2D6 allele was associated with significantly lower risperidone clearance than the reference normal function allele CYP2D6*1 (p < 0.001). Further, rs5758550 differentiated the effect of CYP2D6*2 (p = 0.005). The haplotype-specific clearances for CYP2D6*2-rs5758550A, CYP2D6*2-rs5758550G and CYP2D6*35 were estimated to 30%, 66% and 57%, respectively, relative to the clearance for CYP2D6*1. Notably, rs5758550 is in high linkage disequilibrium (R2 > 0.85) with at least 24 other SNPs and cannot be assigned as a functional SNP. Conclusion: CYP2D6*2 and CYP2D6*35 encode reduced risperidone clearance, and the extent of reduction for CYP2D6*2 is differentiated by rs5758550. Genotyping of these haplotypes might improve the precision of genotype-guided prediction of CYP2D6-mediated clearance. [ABSTRACT FROM AUTHOR]

Serrated Polyposis Syndrome (SPS) is characterized by multiple and/or large serrated polyps in the colon and an increased risk of colorectal cancer (CRC). The etiology is largely unknown, but in a subset of patients with SPS, monoallelic pathogenic variants in RNF43 are detected. To date, however, the penetrance and phenotypic spectrum of patients carrying pathogenic variants (PV) in RNF43 are poorly described. We present eight patients both with and without serrated polyps from four unrelated families with likely pathogenic variants (LPV) in RNF43 and compare the results to current literature. The patients were referred to genetic counseling due to suspicion of hereditary cancer. They underwent genetic testing with custom NGS gene panels including RNF43 as part of a routine genetic work-up. Three LPVs, one multi-exon deletion and two nonsense variants, were detected in four families. Family I had a history of CRC and serrated polyps, but in the three other families (II‒IV) there was no history of CRC or serrated polyps. Colonoscopies in the probands of these families did not reveal any serrated polyps and/or CRC despite some of them being relatively old. Our findings suggest that the penetrance of RNF43-related disease is much lower than previously thought, and raise questions about the connection between RNF43 and disease. The results highlight the complexity of genetic counseling in RNF43 positive families– particularly in families without polyposis. Further research is needed to elucidate the role of RNF43 in the risk of SPS and CRC. [ABSTRACT FROM AUTHOR]

Background: Several innovative treatments are expected for myasthenia gravis (MG) in the coming years. Healthcare payers usually require cost-effectiveness analyses before reimbursement. We aimed to investigate resource utilization and direct medical costs for patients with MG treated with intravenous immunoglobulin (IVIg) to inform such analyses. Methods: We identified patients with MG in the Norwegian Patient Registry based on at least two hospital encounters with an MG diagnosis (ICD-10 G70.0) from 1 Jan 2010 to 31 Dec 2021. IVIg treatment was identified by medical procedure and Anatomical Therapeutic Chemical (ATC) codes (RPGM05 and J06BA02). Using Diagnosis-Related Group (DRG) cost weights, we estimated direct medical costs for each year following the first MG diagnosis. Results: Over the study period, 1083 patients were diagnosed with MG in Norway, of whom 155 (14.3%) were treated with IVIg. No significant differences in age or sex were observed between IVIg and non-IVIg patients. Compared with non-IVIg patients, IVIg-patients had 2.3 times higher direct medical costs during the first year after MG diagnosis (EUR 35,714 vs. EUR 15,457) and 3.1 times higher costs during the second year (EUR 19,119 vs. EUR 6256). In the fifth year after diagnosis, IVIg-patients still had higher costs and resource utilization than non-IVIg patients (EUR 9953 vs. EUR 5634). Conclusion: IVIg treatment represents an important marker for high direct medical costs among patients with MG. The costs continue to be high during the first five years after MG diagnosis. [ABSTRACT FROM AUTHOR]

Purpose: Little is known about the effect of SARS-CoV-2 infection on glioblastoma (GBM) growth, metabolism, and prognosis. Immunological changes within GBM tissue are potentially symptomatic, underlining the urgent need for a better understanding of this phenomenon. To date, the complex underlying biology has not been fully elucidated. A decisive role of the tumor microenvironment (TME) and the components of the immune system acting within it is assumed. Methods: Immunohistochemical staining of SARS-CoV-2 spike protein and immune cell infiltration of TME was performed on the tumor tissue of one patient. This patient developed hemiparesis 14 days after symptomatic SARS-CoV-2 infection, leading to tumor diagnosis. Subsequently and after biopsy, there was an unexpectedly good response to chemotherapy only. In looking for further evidence of the potential of SARS-CoV-2 to influence the course of GBM, two additional adult patients that had transient MRI changes and neurological deterioration following SARS-CoV-2 infection were evaluated. Results: In the patient for whom neurological deterioration in the course of SARS-CoV-2 led to GBM diagnosis, immunohistochemistry revealed virus-specific protein accumulation in the tumor cells, microglial activation, and the formation of T-cell nodules. In the other two patients, the findings were compatible with symptomatic pseudoprogression that occurred in a temporal relationship with SARS-CoV-2 infection. Conclusion: The results indicate a possible association between clinically relevant changes in GBM biology and SARS-CoV-2 infection, with histological confirmation of SARS-CoV-2-associated changes within the tumor tissue. The exact pathomechanism and underlying inflammatory pathways require further investigation. [ABSTRACT FROM AUTHOR]

Purpose: This study seeks to contribute real-world data on the prevalence of BRCA1/2 and HRR gene mutations in prostate cancer. Methods: We compiled sequencing data of 197 cases of primary and metastatic prostate cancer, in which HRR mutation analysis was performed upon clinical request within the last 5 years. All cases were analyzed using a targeted NGS BRCAness multigene panel, including 8 HRR genes (ATM, BRCA1, BRCA2, CDK12, CHEK2, FANCA, HDAC2, PALB2). Results: Our findings reveal a prevalence of potentially targetable mutations based on FDA criteria of 20.8%, which is comparable to the literature. However, the frequency of targetable BRCA2 mutations within our cohort was lower than reported for mCRPC and ATM and CHEK2 mutations were more prevalent instead. Thus, while 20.8% (n = 38) of the cases meet the criteria for olaparib treatment per FDA approval, only 4.9% (n = 9) align with the eligibility criteria according to the EMA approval. Conclusion: This study offers valuable real-world insights into the landscape of BRCA1/2 and HRR gene mutations and the practical clinical management of HRR gene testing in prostate cancer, contributing to a better understanding of patient eligibility for PARPi treatment. [ABSTRACT FROM AUTHOR]

With climate change and anthropic influence on the coastal ecosystems, mangrove ecosystems are disappearing at an alarming rate. Accordingly, it becomes important to track, study, record and store the mangrove microbial community considering their ecological importance and potential for biotechnological applications. Here, we provide information on mangrove fungal community composition and diversity in mangrove ecosystems with different plant species and from various locations differing in relation to anthropic influences. We describe twelve newly assembled genomes, including four chromosomal-level genomes of fungal isolates from the mangrove ecosystems coupled with functional annotations. We envisage that these data will be of value for future studies including comparative genome analysis and large-scale temporal and/or spatial research to elucidate the potential mechanisms by which mangrove fungal communities assemble and evolve. We further anticipate that the genomes represent valuable resources for bioprospecting related to industrial or clinical uses. [ABSTRACT FROM AUTHOR]

Biocontrol by wild insects and other organisms is an important service provided to agriculture, but few studies have linked the role of this service to urban garden crop production. In 15 urban food gardens in Sydney, Australia, we assessed predation and parasitism of two sentinel prey species, recorded pest control activities undertaken by gardeners and the produce yielded by garden crops. We observed substantial removal of sentinel prey (mean removal 22% for Tenebrio molitor larvae and 59% for Helicoverpa armigera) but no parasitism. Vertebrate predators primarily consisted of urban adapted birds and mammals common throughout Australian cities. We measured a range of local and landscape scale environmental variables including plant richness and abundance, light, canopy cover, building density and distance to remnant vegetation. We found that gardeners undertook only basic pest control activities with little chemical use, yet high amounts of produce were harvested. Pest control services were poorly explained by environmental variables. Low active pest control activities, and high predation rates suggest pests are either well controlled or in low numbers in the surveyed urban food gardens. Given the vertebrate predators were generalist birds and mammals common to many parts of urban Australia, the provision of predation services to urban gardens by these taxa could be widespread across the continent. [ABSTRACT FROM AUTHOR]

Abstract Mutations in POLG disrupt mtDNA replication and cause devastating diseases often with neurological phenotypes. Defining disease mechanisms has been hampered by limited access to human tissues, particularly neurons. Using patient cells carrying POLG mutations, we generated iPSCs and then neural stem cells. These neural precursors manifested a phenotype that faithfully replicated the molecular and biochemical changes found in patient post‐mortem brain tissue. We confirmed the same loss of mtDNA and complex I in dopaminergic neurons generated from the same stem cells. POLG‐driven mitochondrial dysfunction led to neuronal ROS overproduction and increased cellular senescence. Loss of complex I was associated with disturbed NAD+ metabolism with increased UCP2 expression and reduced phosphorylated SirT1. In cells with compound heterozygous POLG mutations, we also found activated mitophagy via the BNIP3 pathway. Our studies are the first that show it is possible to recapitulate the neuronal molecular and biochemical defects associated with POLG mutation in a human stem cell model. Further, our data provide insight into how mitochondrial dysfunction and mtDNA alterations influence cellular fate determining processes.

Healthcare fraud, waste and abuse are costly problems that have huge impact on society. Traditional approaches to identify non-compliant claims rely on auditing strategies requiring trained professionals, or on machine learning methods requiring labelled data and possibly lacking interpretability. We present Clais, a collaborative artificial intelligence system for claims analysis. Clais automatically extracts human-interpretable rules from healthcare policy documents (0.72 F1-score), and it enables professionals to edit and validate the extracted rules through an intuitive user interface. Clais executes the rules on claim records to identify non-compliance: on this task Clais significantly outperforms two baseline machine learning models, and its median F1-score is 1.0 (IQR = 0.83 to 1.0) when executing the extracted rules, and 1.0 (IQR = 1.0 to 1.0) when executing the same rules after human curation. Professionals confirm through a user study the usefulness of Clais in making their workflow simpler and more effective. [ABSTRACT FROM AUTHOR]

Hematopoietic stem cell (HSC) mutations can result in clonal hematopoiesis (CH) with heterogeneous clinical outcomes. Here, we investigate how the cell state preceding Tet2 mutation impacts the pre-malignant phenotype. Using an inducible system for clonal analysis of myeloid progenitors, we find that the epigenetic features of clones at similar differentiation status are highly heterogeneous and functionally respond differently to Tet2 mutation. Cell differentiation stage also influences Tet2 mutation response indicating that the cell of origin's epigenome modulates clone-specific behaviors in CH. Molecular features associated with higher risk outcomes include Sox4 that sensitizes cells to Tet2 inactivation, inducing dedifferentiation, altered metabolism and increasing the in vivo clonal output of mutant cells, as confirmed in primary GMP and HSC models. Our findings validate the hypothesis that epigenetic features can predispose specific clones for dominance, explaining why identical genetic mutations can result in different phenotypes. HSC mutations lead to diverse clonal hematopoiesis outcomes. This study shows how epigenetic traits can predispose clones for dominance. Sox4 increases sensitivity to Tet2 KO, offering insights into variable phenotypes despite identical mutations. [ABSTRACT FROM AUTHOR]

Detailed knowledge regarding the associations between intake of different types of seafood and meat and the risk of type 2 diabetes (T2D), and insight into possible mechanisms are warranted. In this study we aimed to evaluate the associations between intake of different types of seafood and meat and the subsequent risk of T2D using the Norwegian Mother, Father, and Child Cohort Study (MoBa), and furthermore, by using a mouse model to gain further insight into possible molecular mechanisms contributing to the associated metabolic changes. Women in MoBa who were free of pharmacologically treated diabetes at baseline (n = 60,777) were prospectively evaluated for incident T2D, identified on the basis of medication usages > 90 days after delivery, ascertained by the Norwegian Prescription Database. Dietary intake was obtained with a validated 255-item food frequency questionnaire which assessed habitual diet during the first 4–5 months of pregnancy. Metabolic phenotypes and plasma metabolome were investigated in female mice fed isocaloric diets with different types of seafood and meat mimicking the dietary intake in the human cohort. During maximum 10-year and mean (SD) 7.2 (1.6) years follow-up time, 681 (1.1%) women developed pharmacologically treated T2D. All statistical models identified a higher risk of T2D with increased shellfish intake, whereas no associations were observed for total seafood, fatty fish, total meat and red meat in the adjusted models. In mice, the shellfish-based western diet induced reduced glucose tolerance and insulin secretion compared to the diet based on lean fish, and we identified a number of metabolites elevated in plasma from shellfish-fed mice that correlated with glucose intolerance. Mice fed a western diet based on meat also exhibited reduced glucose tolerance in comparison to lean fish fed mice, whereas mice fed fatty fish, total seafood or red meat did not differ from lean fish fed mice. We observed a diet-specific metabolic signature in plasma demonstrating five distinct metabolite profiles in mice fed shellfish, fatty fish, total seafood/lean fish, a mixed diet and meat. In conclusion, these findings demonstrate that different types of seafood have different outcome on T2D risk. In women, intake of shellfish was associated with higher risk of T2D. In female mice, a shellfish enriched diet reduced glucose tolerance and altered the abundance of several distinct plasma metabolites correlating with glucose tolerance. [ABSTRACT FROM AUTHOR]

The oral cavity harbors complex communities comprising bacteria, archaea, fungi, protozoa, and viruses. The oral microbiota is establish at birth and develops further during childhood, with early life factors such as birth mode, feeding practices, and oral hygiene, reported to influence this development and the susceptibility to caries. We here analyzed the oral bacterial composition in saliva of 260 Swedish children at two, three and five years of age using 16S rRNA gene profiling to examine its relation to environmental factors and caries development at five years of age. We were able to assign the salivary bacterial community in each child at each time point to one of seven distinct clusters. We observed an individual dynamic in the development of the oral microbiota related to early life factors, such as being first born, born by C-section, maternal perinatal antibiotics use, with a distinct transition between three and five years of age. Different bacterial signatures depending on age were related to increased caries risk, while Peptococcus consistently linked to reduced risk of caries development. [ABSTRACT FROM AUTHOR]

High-definition approaches are currently revolutionizing our understanding of the archaeology of urban archives. Multi-proxy studies at a high spatial resolution offer especially an opportunity to capture their high data potential. Here we present a study of complex floor layers from an occupation phase dating to c. AD 790–830 uncovered in the Viking-age emporium Ribe, Denmark (c. AD 700–900). In order to better understand stratigraphy and the use of indoor space, mapping for soil geochemistry (portable X-ray fluorescence analysis, pXRF) on a high-resolution grid (0.25 × 0.25 m, n = 1059), was combined with targeted sampling for soil micromorphology and artefact distributions. The results show that the studied occupation phase was composed of several short-lived floor phases belonging to two consecutive houses that had been sampled in conjunction, and which exhibited a complex stratigraphy. The older house phase had a primarily domestic function, where ten functional areas could be defined, and are interpreted as designated spaces for food preparation, storage, sitting or sleeping, and weaving. A younger house phase contained a metal workshop in addition to domestic functions. Methodologically, a number of new, potentially anthropogenic, elements of archaeological interest, such as arsenic, manganese and sulfur, were identified that may contribute to interpretations, while the multi-proxy approach elucidates the refined scale at which we can understand a complex stratigraphic sequence and the integrity of its units. This study shows how the various aspects of Viking-age urban life (craft production, domestic life) were integrated, and sheds light on the dynamics of urban occupation. [ABSTRACT FROM AUTHOR]

Virtual mono-energetic images (VMI) using dual-layer computed tomography (DLCT) enable substantial contrast medium (CM) reductions. However, the combined impact of patient size, tube voltage, and heart rate (HR) on VMI of coronary CT angiography (CCTA) remains unknown. This phantom study aimed to assess VMI levels achieving comparable contrast-to-noise ratio (CNR) in CCTA at 50% CM dose across varying tube voltages, patient sizes, and HR, compared to the reference protocol (100% CM dose, conventional at 120 kVp). A 5 mm artificial coronary artery with 100% (400 HU) and 50% (200 HU) iodine CM-dose was positioned centrally in an anthropomorphic thorax phantom. Horizontal coronary movement was matched to HR (at 0, < 60, 60–75, > 75 bpm), with varying patient sizes simulated using phantom extension rings. Raw data was acquired using a clinical CCTA protocol at 120 and 140 kVp (five repetitions). VMI images (40–70 keV, 5 keV steps) were then reconstructed; non-overlapping 95% CNR confidence intervals indicated significant differences from the reference. Higher CM-dose, reduced VMI, slower HR, higher tube voltage, and smaller patient sizes demonstrated a trend of higher CNR. Regardless of HR, patient size, and tube voltage, no significant CNR differences were found compared to the reference, with 100% CM dose at 60 keV, or 50% CM dose at 40 keV. DLCT reconstructions at 40 keV from 120 to 140 kVp acquisitions facilitate 50% CM dose reduction for various patient sizes and HR with equivalent CNR to conventional CCTA at 100% CM dose, although clinical validation is needed. [ABSTRACT FROM AUTHOR]

Background: Reliable RT-qPCR results are dependent on appropriate normalisation. Oocyte maturation studies can be challenging in this respect, as the stage of development can distinctively affect reference gene transcript abundance. The aim of this study was to validate the use of reference genes in oocyte in vitro maturation RT-qPCR studies, and thereafter, examine the abundance of transcripts supporting histone modification during oocyte and early embryo development in oocytes of contrasting quality. Methods and results: Total RNA from oocytes from prepubertal gilts and sows was extracted either directly succeeding follicle aspiration or after 44 h in vitro maturation, followed by RT-qPCR. The stability of YWHAG, HPRT1, ACTB, GAPDH, HMBS and PFKP, was analysed by NormFinder and further cross-validated by assessing results generated following application of different combinations of potential reference genes for normalisation of the RT-qPCR data. Combining ACTB and PFKP generated high stability according to NormFinder and concordant results. Applying this normalisation, gilt derived oocytes displayed significantly higher abundance than oocytes from sows of almost all the epigenetic-related transcripts studied (HDAC2, SIRT1, SALL4, KDM1A, KDM1B, KDM5A), both before and after maturation. Conclusions: This study identified the combined use of ACTB and PFKP as the optimal normalisation for porcine oocyte RT-qPCR data. In oocytes collected from prepubertal gilts, transcription did not appear to be silenced at the time of aspiration, and accumulation of transcripts supporting histone modification facilitating proper fertilization and further embryo development seemed delayed. The results imply the epigenetic-related transcripts may have potential as markers of oocyte quality. [ABSTRACT FROM AUTHOR]

The clinical development of an effective Chlamydia vaccine requires in-depth understanding of how well protective pre-clinical immune signatures translate to humans. Here, we report a comparative immunological characterization of CTH522/CAF®01 in female mice and humans. We find a range of immune signatures that translate from mouse to human, including a Th1/Th17 cytokine profile and antibody functionality. We identify vaccine-induced T cell epitopes, conserved among Chlamydia serovars, and previously found in infected individuals. Using the mouse model, we show that the common immune signature protected against ascending infection in mice, and vaccine induced antibodies could delay bacterial ascension to the oviduct, as well as development of pathology, in a T cell depleted mouse model. Finally, we demonstrate long-lasting immunity and protection of mice one year after vaccination. Based on the results obtained in the present study, we propose to further investigate CTH522/CAF®01 in a phase IIb study. Authors present a comparative immunological characterisation of Chlamydia vaccine, CTH522/CAF®01, in mice and humans. Findings suggest the mouse to be a good predictor of human immunity to the Chlamydia vaccine CTH522/CAF®01, and long-lasting protection in the mouse further supports the development of this promising vaccine candidate. [ABSTRACT FROM AUTHOR]

The neutrophil-to-lymphocyte ratio(NLR) is increased in chronic inflammation and myeloproliferative neoplasms (MPN). We hypothesize that NLR is associated with all-cause mortality and mortality by comorbidity burden in the general population and individuals with MPN. We included 835,430 individuals from The Danish General Suburban Population Study, general practitioners, and outpatient clinics. We investigated NLR on mortality stratified by prevalent and incident MPN, essential thrombocythemia (ET), polycythemia vera (PV), myelofibrosis (MF), comorbidity burden (CCI-score), and the Triple-A risk score using hazard ratio (HR) and 95% confidence interval (95%CI). NLR 1–1.9 was the reference level. During a median follow-up of 11.2 years, 197,802 deaths were recorded. All-cause mortality increased for a stepwise increasing NLR with a HR (95%CI) for NLR ≥ 6 of 2.06(2.03–2.09) for the whole population and 2.93(2.44–3.50) in prevalent MPN. ET, PV, and MF had a HR (95%CI) for NLR ≥ 2 of 2.14(1.71–2.69), 2.19(1.89–2.54), and 2.31(1.91–2.80). Results were similar for incident MPN. Mortality was higher for stepwise increasing NLR and CCI-score(pinteraction < 2×10–16), with a HR for NLR ≥ 6 of 2.23(2.17–2.29), 4.10(4.01–4.20), and 7.69(7.50–7.89), for CCI-score 0, 1–2, or ≥3. The Triple-A risk score demonstrated alignment with NLR. Increasing NLR and comorbidity burden were associated with lower survival in individuals without MPN but were even worse in prevalent and incident MPN, ET, PV, and MF. [ABSTRACT FROM AUTHOR]

In this paper, we provide a geometric analysis of a new hysteresis model that is based upon singular perturbations. Here hysteresis refers to a type of regularization of piecewise smooth differential equations where the past of a trajectory, in a small neighborhood of the discontinuity set, determines the vector-field at present. In fact, in the limit where the neighborhood of the discontinuity vanishes, hysteresis converges in an appropriate sense to Filippov’s sliding vector-field. Recently (2022), however, Bonet and Seara showed that hysteresis, in contrast to regularization through smoothing, leads to chaos in the regularization of grazing bifurcations, even in two dimensions. The hysteresis model we analyze in the present paper—which was developed by Bonet et al in a paper from 2017 as an attempt to unify different regularizations of piecewise smooth systems—involves two singular perturbation parameters and includes a combination of slow–fast and nonsmooth effects. The description of this model is therefore—from the perspective of singular perturbation theory—challenging, even in two dimensions. Using blowup as our main technical tool, we prove existence of an invariant cylinder carrying fast dynamics in the azimuthal direction and a slow drift in the axial direction. We find that the slow drift is given by Filippov’s sliding vector-field to leading order. Moreover, in the case of grazing, we identify two important parameter regimes that relate the model to smoothing (through a saddle-node bifurcation of limit cycles) and hysteresis (through chaotic dynamics, due to a folded saddle and a novel return mechanism). [ABSTRACT FROM AUTHOR]

Key summary points: Aim: Examine preadmission diagnoses, medication use, and preadmission healthcare utilization among older adults prior to a first potentially avoidable hospitalization. Findings: Our analysis revealed that preadmission morbidity, medication use, and a high and accelerating number of healthcare contacts are associated with potentially avoidable hospitalizations. Message: Preadmission morbidity and a high number of contacts with general practitioners are associated with potentially avoidable hospitalizations, which highlights the need for tailored clinical initiatives for older adults. Purpose: Examine preadmission diagnoses, medication use, and preadmission healthcare utilization among older adults prior to first potentially avoidable hospitalizations. Methods: A nationwide population-based case–control study using Danish healthcare data. All Danish adults aged ≥ 65 years who had a first potentially avoidable hospitalization from January 1995 through March 2019 (n = 725,939) were defined as cases, and 1:1 age- and sex-matched general population controls (n = 725,939). Preadmission morbidity and healthcare utilization were assessed based on a complete hospital diagnosis history within 10 years prior, and all medication use and healthcare contacts 1 year prior. Using log-binomial regression, we calculated adjusted prevalence ratios (PR) with 95% confidence intervals (CI). Results: Included cases and controls had a median age of 78 years and 59% were female. The burden of preadmission morbidity was higher among cases than controls. The strongest associations were observed for preadmission chronic lung disease (PR 3.8, CI 3.7–3.8), alcohol-related disease (PR 3.1, CI 3.0–3.2), chronic kidney disease (PR 2.4, CI 2.4–2.5), psychiatric disease (PR 2.2, CI 2.2–2.3), heart failure (PR 2.2, CI 2.2–2.3), and previous hospital contacts with infections (PR 2.2, CI 2.2–2.3). A high and accelerating number of healthcare contacts was observed during the months preceding the potentially avoidable hospitalization (having over 5 GP contacts 1 month prior, PR 3.0, CI 3.0–3.0). Conclusion: A high number of healthcare contacts and preadmission morbidity and medication use, especially chronic lung, heart, and kidney disease, alcohol-related or psychiatric disease including dementia, and previous infections are strongly associated with potentially avoidable hospitalizations. [ABSTRACT FROM AUTHOR]

Purpose: Investigation of Microtubuli-associated Protein 2 (MAP2) expression and its clinical relevance in prostate cancer. Material and Methods: MAP2 expression was immunohistochemically analysed on radical prostatectomy specimens using whole block sections (n = 107) and tissue microarrays (TMA; n = 310). The staining intensity was evaluated for carcinoma, benign tissue and prostatic intraepithelial neoplasia. Expression data were correlated with clinicopathological parameters and biochemical recurrence-free survival. Additionally, MAP2 protein expression was quantitatively analysed in the serum of histologically confirmed prostate carcinoma patients and the control group using a commercial enzyme-linked immunosorbent assay. Results: MAP2 staining was significantly stronger in neoplastic tissue than in non-neoplastic prostatic glands, both in whole block sections (p < 0.01) and in TMA sections (p < 0.05). TMA data revealed significantly stronger MAP2 staining in high-grade tumors. Survival analysis showed a significant correlation between strong MAP2 staining in carcinoma and shortened biochemical recurrence-free survival after prostatectomy (p < 0.001). Multivariate Cox regression analysis confirmed MAP2 as an independent predictor for an unfavourable course. Mean MAP2 serum levels for non-PCA vs. PCA patients differed significantly (non-PCA = 164.7 pg/ml vs. PCA = 242.5 pg/ml, p < 0.001). Conclusion: The present data support MAP2 as a novel biomarker in PCA specimens. MAP2 is correlated with tumor grade and MAP2 high-expressing PCA is associated with an increased risk of biochemical recurrence after radical prostatectomy. Future studies are necessary to evaluate MAP2 as a valuable immunohistochemical biomarker in preoperative PCA diagnostic procedures, in particular with regard to treatment modalities. [ABSTRACT FROM AUTHOR]

Climate change impact studies need climate projections for different scenarios and at scales relevant to planning and management, preferably for a variety of models and realizations to capture the uncertainty in these models. To address current gaps, we statistically downscaled (SD) 3–7 CMIP6 models for five key indicators of marine habitat conditions: temperature, salinity, pH, oxygen, and chlorophyll across European waters for three climate scenarios SSP1-2.6, SSP2-4.5, and SSP5-8.5. Results provide ensemble averages and uncertainty estimates that can serve as input data for projecting the potential success of a range of Nature-based Solutions, including the restoration of habitat-forming species such as seagrass in the Mediterranean and kelp in coastal areas of Portugal and Norway. Evaluation of the ensemble with observations from four European regions (North Sea, Baltic Sea, Bay of Biscay, and Mediterranean Sea) indicates that the SD projections realistically capture the climatological conditions of the historical period 1993–2020. Model skill (Liu-mean efficiency, Pearson correlation) clearly improves for both surface temperature and oxygen across all regions with respect to the original ESMs demonstrating a higher skill for temperature compared to oxygen. Warming is evident across all areas and large differences among scenarios fully emerge from the background uncertainties related to internal variability and model differences in the second half of the century. Scenario-specific differences in acidification significantly emerge from model uncertainty and internal variability leading to distinct trajectories in surface pH starting before mid-century (in some cases starting from present day). Deoxygenation is also present across all domains, but the climate signal was significantly weaker compared to the other two indicators when compared to model uncertainty and internal variability, and the impact of different greenhouse gas trajectories is less distinct. The substantial regional and local heterogeneity in these three abiotic indicators underscores the need for highly spatially resolved physical and biogeochemical projections to understand how climate change may impact marine ecosystems. [ABSTRACT FROM AUTHOR]

Changes in pharmacokinetics and endogenous metabolites may underlie additive biological effects of concomitant use of antipsychotics and opioids. In this study, we employed untargeted metabolomics analysis and targeted analysis to examine the changes in drug metabolites and endogenous metabolites in the prefrontal cortex (PFC), midbrain, and blood of rats following acute co-administration of quetiapine and methadone. Rats were divided into four groups and received cumulative increasing doses of quetiapine (QTP), methadone (MTD), quetiapine + methadone (QTP + MTD), or vehicle (control). All samples were analyzed using liquid chromatography-mass spectrometry (LC–MS). Our findings revealed increased levels of the quetiapine metabolites: Norquetiapine, O-dealkylquetiapine, 7-hydroxyquetiapine, and quetiapine sulfoxide, in the blood and brain when methadone was present. Our study also demonstrated a decrease in methadone and its metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) in the rat brain when quetiapine was present. Despite these findings, there were only small differences in the levels of 225–296 measured endogenous metabolites due to co-administration compared to single administrations. For example, N-methylglutamic acid, glutaric acid, p-hydroxyphenyllactic acid, and corticosterone levels were significantly decreased in the brain of rats treated with both compounds. Accumulation of serotonin in the midbrain was additionally observed in the MTD group, but not in the QTP + MTD group. In conclusion, this study in rats suggests a few but important additive metabolic effects when quetiapine and methadone are co-administered. [ABSTRACT FROM AUTHOR]

Background: One of the most popular time-efficient training methods when training for muscle hypertrophy is drop sets, which is performed by taking sets to concentric muscle failure at a given load, then making a drop by reducing the load and immediately taking the next set to concentric or voluntary muscle failure. The purpose of this systematic review and meta-analysis was to compare the effects of drop sets over traditional sets on skeletal muscle hypertrophy. Methods: This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The SPORTDiscus and MEDLINE/PubMed databases were searched on April 9, 2022, for all studies investigating the effects of the drop set training method on muscle hypertrophy that meets the predefined inclusion criteria. Comprehensive Meta-Analysis Version 3 (Biostat Inc., Englewood Cliffs, NJ, USA) was used to run the statistical analysis. Publication bias was assessed through visual inspection of the funnel plots for asymmetry and statistically by Egger's regression test with an alpha level of 0.10. Results: Six studies met the predefined inclusion criteria. The number of participants in the studies was 142 (28 women and 114 men) with an age range of 19.2–27 years. The average sample size was 23.6 ± 10.9 (range 9–41). Five studies were included in the quantitative synthesis. Meta-analysis showed that both the drop set and traditional training groups increased significantly from pre- to post-test regarding muscle hypertrophy (drop set standardized mean difference: 0.555, 95% CI 0.357–0.921, p < 0.0001; traditional set standardized mean difference: 0.437, 95% CI 0.266–0.608, p < 0.0001). No significant between-group difference was found (standardized mean difference: 0.155, 95% CI − 0.199 to − 0.509, p = 0.392). Conclusions: The results of this systematic review and meta-analysis indicate that drop sets present an efficient strategy for maximizing hypertrophy in those with limited time for training. There was no significant difference in hypertrophy measurements between the drop set and traditional training groups, but some of the drop set modalities took half to one-third of the time compared with traditional training. [ABSTRACT FROM AUTHOR]

Immunoglobulin A (IgA) is acknowledged to play a role in the defence of the mucosal barrier by coating microorganisms. Surprisingly, IgA-deficient humans exhibit few infection-related complications, raising the question if the more specific IgG may help IgM in compensating for the lack of IgA. Here we employ a cohort of IgA-deficient humans, each paired with IgA-sufficient household members, to investigate multi-Ig bacterial coating. In IgA-deficient humans, IgM alone, and together with IgG, recapitulate coating of most bacterial families, despite an overall 3.6-fold lower Ig-coating. Bacterial IgG coating is dominated by IgG1 and IgG4. Single-IgG2 bacterial coating is sparse and linked to enhanced Escherichia coli load and TNF-α. Although single-IgG2 coating is 1.6-fold more prevalent in IgA deficiency than in healthy controls, it is 2-fold less prevalent than in inflammatory bowel disease. Altogether we demonstrate that IgG assists IgM in coating of most bacterial families in the absence of IgA and identify single-IgG2 bacterial coating as an inflammatory marker. IgA protects mucosal barriers by coating microorganisms, yet infection related complications are rare in human IgA deficiency. Authors here show that in humans lacking IgA, IgG assists IgM in coating of most bacterial families, thus contributing to gut mucosal defence. [ABSTRACT FROM AUTHOR]

Purpose: The results after anterior cruciate ligament reconstruction (ACLR) are evaluated by laxity measures, functional tests, and patients' perception by patient-reported outcome measures (PROMs). It is not known, if one of these evaluation instruments is representative or if outcome scores from all must be reported to obtain a full evaluation of the condition. The aim was to study the correlations between these three types of outcomes 1 year after primary ACLR. Method: All adult patients (range 18–45 years) who had an ACLR between 1.1.2019 and 31.12.2021 were offered 1-year follow-up by an independent observer. Preoperative information about knee laxity and peroperative information about the condition of menisci and cartilage were registered. At 1-year follow-up clinical and instrumented knee stability and function assessed by four different hop tests were registered. Patients completed four PROMs (the Subjective International Knee Documentation Committee (IKDC) score, the Knee Numeric-Entity Evaluation Score (KNEES-ACL), the Knee injury and Osteoarthritis Outcome Score (KOOS) and the Lysholm score) and Tegner activity scale and answered anchor questions regarding satisfaction and willingness to repeat the operation. Results: A total of 190 adults attended the 1-year follow-up and 151 had all assessments. There were only a few positive and weak correlations between performance tests and PROMS and between clinical measurements and PROMS (r = 0.00–0.38), and the majority were of negligible strength. Tegner score had in general the highest correlation (low to moderate). The highest correlation was 0.53 (moderate) between the anchor question about patient satisfaction and Lysholm/IKDC scores. There was no difference in the correlations depending on meniscal condition. Conclusions: In ACLR patients there was no clinically relevant correlation between scores obtained by PROMs, a battery of functional performance tests and instrumented laxity of the knee at 1-year follow-up. Therefore, one type of outcome cannot represent the others. This is an argument for always to include and report all three types of outcomes, and conclusions based on one type of outcome may not be sufficient. Level of evidence: II. [ABSTRACT FROM AUTHOR]

Standard toxicity tests expose springtails (Collembola) through soil, while dietary exposure tests with animals visible on a surface are less commonly applied. We refined a method for dietary chemical exposure for two widely distributed and abundant Collembola species: Folsomia quadrioculata and Hypogastrura viatica as existing methods were sub-optimal. Newly hatched Collembola were offered bark with a natural layer of Cyanobacteria that was either moistened with a solution of the neonicotinoid insecticide imidacloprid using a micropipette or soaked in the solution overnight. The first method was superior in producing a measured concentration close to the nominal (0.21 and 0.13 mg/kg dry bark, respectively), and resulting in sub-lethal effects as expected. The adult body size was reduced by 8% for both species, but egg production only in H. viatica. Contrastingly, soaked bark resulted in a measured concentration of 8 mg/kg dry bark, causing high mortality and no egg production in either species. Next, we identified the sub-lethal concentration-range by moistening the bark to expose H. viatica to 0, 0.01, 0.04, 0.13, 0.43 and 1.2 mg imidacloprid/kg dry bark. Only the highest concentration affected survival, causing a mortality of 77%. Imidacloprid reduced moulting rate and the body size at first reproduction. The age at first reproduction appeared delayed as some replicates did not reproduce within the experiment duration. The method of moistened bark for dietary exposure proved optimal to continuously study life history traits, such as growth and reproductive outcomes, which are important to understand effects on key events crucial for population viability and growth. [ABSTRACT FROM AUTHOR]

Systematic exercise training effectively improves exercise capacity in patients with coronary artery disease (CAD), but the magnitude of improvements is highly heterogeneous. We investigated whether this heterogeneity in exercise capacity gains is influenced by the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene. Patients with CAD (n = 169) were randomly assigned to 12 weeks of exercise training or standard care, and 142 patients completed the study. The ACE polymorphism was determined for 128 patients (82% males, 67 ± 9 years). Peak oxygen uptake was measured before and after the 12-week intervention. The ACE I/D polymorphism frequency was n = 48 for D/D homozygotes, n = 61 for I/D heterozygotes and n = 19 for I/I homozygotes. Baseline peak oxygen uptake was 23.3 ± 5.0 ml/kg/min in D/D homozygotes, 22.1 ± 5.3 ml/kg/min in I/D heterozygotes and 23.1 ± 6.0 ml/kg/min in I/I homozygotes, with no statistical differences between genotype groups (P = 0.50). The ACE I/D polymorphism frequency in the exercise group was n = 26 for D/D, n = 21 for I/D and n = 12 for I/I. After exercise training, peak oxygen uptake was increased (P < 0.001) in D/D homozygotes by 2.6 ± 1.7 ml/kg/min, in I/D heterozygotes by 2.7 ± 1.9 ml/kg/min, and in I/I homozygotes by 2.1 ± 1.3 ml/kg/min. However, the improvements were similar between genotype groups (time × genotype, P = 0.55). In conclusion, the ACE I/D polymorphism does not affect baseline exercise capacity or exercise capacity gains in response to 12 weeks of high-intensity exercise training in patients with stable CAD. Clinical trial registration: www.clinicaltrials.gov (NCT04268992). [ABSTRACT FROM AUTHOR]

Efficient dewatering is necessary to achieve an economically sustainable large-scale production of microfibrillated cellulose (MFC) because the low solids content of the final product (< 3 wt.%) results in high costs related to transportation and storage, and problems for products with water incompatibility. Mechanical dewatering is preferred to thermal drying due to its lower energy demand, but MFC has a very high filtration resistance, which implies that an excessive filter area is necessary. Thus, to improve the dewatering, electro-assisted filtration may be used. In this study a bench-scale dead-end filter press was modified and the electro-assisted filtration of MFC, with two degrees of fibrillation, was investigated. The impact of the degree of fibrillation was clear when either pressure or electric field were applied separately. It was more challenging to dewater MFC with a higher degree of fibrillation using conventional filtration due to a greater surface area being subjected to the liquid flow. The opposite was found when using an electric field alone: the more fibrillated material has a higher surface charge and thereby is impacted more by the electric field. A combination of pressure and electric field resulted in a greatly improved dewatering rate, but no significant difference could be observed between the two qualities. After dewatering, the water retention value was slightly decreased, but the material still showed a gel-like behaviour, although the network strength was slightly reduced, as seen by a reduction in yield stress, storage and loss moduli. This was plausibly due to a decrease in the surface area and/or deformed network. [ABSTRACT FROM AUTHOR]

Offshore wind power projects are currently booming around the North Sea. However, there are inherent correlation challenges between wind farms in this area, which has implications for the optimal composition of locations and the scale-up of installed capacities. This paper is aimed at addressing the correlation problem by minimizing the variance of total wind power accumulated around the North Sea. We show that this nonlinear convex optimization problem can be solved by applying the Augmented Lagrangian Algorithm (ALA). The premise of the study is that more interconnections between the EU countries will be prioritized in order to optimize and smooth out the wind power production patterns. A publicly available dataset with historical hour-by-hour data spanning over 20 years was used for the analysis. We explore two distinct scenarios for Norwegian offshore wind development. In the first scenario, we consider the ongoing activities on the European continental side of the North Sea and their implications for Norway. Here, we illustrate the advantages of focusing on expanding wind power capacity in the northern regions of Norway to enhance the overall value of the generated wind power. In contrast, the second reference scenario neglects these interconnections, resulting in a significantly greater concentration of offshore wind development in the southern parts of Norway, particularly in Sørlige Nordsjø II. Additionally, our work estimates the wind power correlation coefficient in the North Sea as a function of distance. Furthermore, we analyze deviations and intermittencies in North Sea wind power over various time intervals, emphasizing that the perceived integration challenges are highly dependent on the chosen time resolution in the analysis. [ABSTRACT FROM AUTHOR]

Inflammatory fibroid polyps (IFP) are rare and benign mesenchymal tumours of the gastrointestinal tract. They are submucosal spindle cell lesions with an eosinophilic-rich inflammatory infiltrate and mutations in the platelet-derived growth factor receptor alpha (PDGFRA) gene. In this report, we present the case of a 74-year-old female with a solid tumour of the kidney, which presented as a bland proliferation of spindle cells with thin-walled blood vessels and an inflammatory infiltrate with eosinophilic granulocytes. Immunohistochemistry revealed a positivity for vimentin and a weak staining for CD99 and CD34 in the spindle cells. Because of the morphological similarity to IFPs of the gastrointestinal tract, a molecular pathology analysis was performed. This identified an oncogenic mutation in exon 18 of the PDGFRA gene, which is characteristic for inflammatory fibroid polyps of the gastrointestinal tract. To the best of our knowledge, this is the first case of an IFP in the urogenital tract. [ABSTRACT FROM AUTHOR]

Abstract B‐cell receptor (BCR) signaling is essential for the development and function of B cells; however, the spectrum of proteins involved in BCR signaling is not fully known. Here we used quantitative mass spectrometry‐based proteomics to monitor the dynamics of BCR signaling complexes (signalosomes) and to investigate the dynamics of downstream phosphorylation and ubiquitylation signaling. We identify most of the previously known components of BCR signaling, as well as many proteins that have not yet been implicated in this system. BCR activation leads to rapid tyrosine phosphorylation and ubiquitylation of the receptor‐proximal signaling components, many of which are co‐regulated by both the modifications. We illustrate the power of multilayered proteomic analyses for discovering novel BCR signaling components by demonstrating that BCR‐induced phosphorylation of RAB7A at S72 prevents its association with effector proteins and with endo‐lysosomal compartments. In addition, we show that BCL10 is modified by LUBAC‐mediated linear ubiquitylation, and demonstrate an important function of LUBAC in BCR‐induced NF‐κB signaling. Our results offer a global and integrated view of BCR signaling, and the provided datasets can serve as a valuable resource for further understanding BCR signaling networks.

Objectives: To compare vascular attenuation (VA) of an experimental half iodine-load dual-layer spectral detector CT (SDCT) lower limb computed tomography angiography (CTA) with control (standard iodine-load conventional 120-kilovolt peak (kVp) CTA). Methods: Ethical approval and consent were obtained. In this parallel RCT, CTA examinations were randomized into experimental or control. Patients received 0.7 vs 1.4 mL/kg of iohexol 350 mgI/mL in the experimental- vs the control group. Two experimental virtual monoenergetic image (VMI) series at 40 and 50 kiloelectron volts (keV) were reconstructed. Primary outcome: VA. Secondary outcomes: image noise (noise), contrast- and signal-to-noise ratio (CNR and SNR), and subjective examination quality (SEQ). Results: A total of 106 vs 109 were randomized and 103 vs 108 were analyzed in the experimental vs, control groups, respectively. VA was higher on experimental 40 keV VMI than on control (p < 0.0001), but lower on 50 keV VMI (p < 0.022). Noise was higher on experimental 40 keV VMI than on control (p = 0.00022), but lower on 50 keV VMI (p = 0.0033). CNR and SNR were higher than the control on experimental 40 keV VMI (both p < 0.0001) and 50 keV (p = 0.0058 and p = 0.0023, respectively). SEQ was better on both VMIs in the experimental group than in the control (both p < 0.0001). Conclusions: Half iodine-load SDCT lower limb CTA at 40 keV achieved higher VA than the control. CNR, SNR, noise, and SEQ were higher at 40 keV, while 50 keV showed lower noise. Clinical relevance statement: Spectral detector CT with low-energy virtual monoenergetic imaging performed halved iodine contrast medium (CM) lower limb CT-angiography with sustained objective and subjective quality. This facilitates CM reduction, improvement of low CM-dosage examinations, and examination of patients with more severe kidney impairment. Trial registration: Retrospectively registered 5 August 2022 at clinicaltrials.gov NCT05488899. Key Points: • Contrast medium dosage may be halved in lower limb dual-energy CT angiography with virtual monoenergetic images at 40 keV, which may reduce contrast medium consumption in the face of a global shortage. • Experimental half-iodine-load dual-energy CT angiography at 40 keV showed higher vascular attenuation, contrast-to-noise ratio, signal-to-noise ratio, and subjective examination quality than standard iodine-load conventional. • Half-iodine dual-energy CT angiography protocols may allow us to reduce the risk of PC-AKI, examine patients with more severe kidney impairment, and provide higher quality examinations or salvage poor examinations when impaired kidney function limits the CM dose. [ABSTRACT FROM AUTHOR]

Online death events constitute integral parts of many competitive online multiplayer games. Nonetheless, research has identified death events as frequently involved in the proceedings of toxic behaviors (Märtens et al., 2015). While much existing research has been attentive towards providing a range of explanations for the emergence of toxic behaviors in online games (see for example Kordyaka et al. in Internet Research, 30(4), 1081–1102, 2020; Kou, 2020; Kowert in Frontiers in Psychology, 11, 2020), research exploring the micro sociological mechanisms involved is currently limited. By applying a micro sociological situational approach to a sample of screen-recorded video data from an observational study of online toxic behaviors in League of Legends, we find that patterns of interactional rituals and situational properties play an important role in whether a death event, in which one or more players are killed, escalates into a toxic encounter. These preliminary results suggest a micro-situational understanding to be explored and refined in future empirical research. From the preliminary findings, a range of potential interventions to mitigate toxic behavior and promote social inclusion in online gaming are suggested. Among these, two types of social-norm interventions, targeting social referents and weakening social norms, align well with the main findings. [ABSTRACT FROM AUTHOR]

Purpose: Vulvar squamous cell carcinoma (VSCC) is a rare malignancy of the female genital tract with increasing incidence rates. Etiologically, HPV-dependent and HPV-independent VSCC are distinguished. Surgical treatment and/or radiotherapy represent the therapeutic mainstay for localized disease. For recurrent or metastatic VSCC, treatment options are limited. Research has identified trophoblast cell surface antigen 2 (TROP-2) to be broadly expressed across different tumor entities. The aim of the present study was to systematically investigate the expression of TROP-2 in VSCC. Methods: TROP-2 protein expression was investigated by immunohistochemistry in a cohort comprising n = 103 patients with primary VSCC. A four-tier scoring system (0: no staining, 1 + : low staining, 2 + : moderate staining, 3 + : high staining) was applied for quantification of protein expression. For further analyses, two groups (low TROP-2 expression: 0/1 + ; high TROP-2 expression: 2 + /3 +) were generated. The entire study cohort, as well as HPV-dependent and HPV-independent VSCC were considered separately. Results: In the entire VSCC study cohort, TROP-2 expression was present in 97.1% of all cases (n = 100) with 74.8% displaying high TROP-2 expression (2 + /3 +). Only 2.9% of tumors showed absent TROP-2 expression. Of note, all HPV-dependent VSCC (n = 18) demonstrated high TROP-2 expression (2 + /3 +). In the subgroup of HPV-independent VSCC (n = 70), high TROP-2 expression was associated with favorable clinical outcomes based on log rank test and univariate cox analysis. Conclusion: TROP-2 protein expression is of prognostic value in HPV-independent VSCC. The broad expression of TROP-2 in VSCC indicates the TROP-2 directed ADC Sacituzumab govitecan as a potential new therapeutic strategy for VSCC patients. [ABSTRACT FROM AUTHOR]

There is a mistake in an expression in Kristiansen (2020, Eq. 3.61). In this erratum, we present the correct expression and adjust the proof of Kristiansen (2020, Lemma 3.12) accordingly. [ABSTRACT FROM AUTHOR]

Introduction: Due to established teratogenicity of valproates, the EU risk minimisation measures (RMMs) with a pregnancy prevention programme (PPP) for valproate were updated in March 2018. Objectives: To investigate the effectiveness of the 2018 EU RMMs on valproate utilisation in five European countries/regions. Methods: A multi-database, times series study of females of childbearing potential (12–55 years) was conducted using electronic medical records from five countries/regions (01.01.2010–31.12.2020): Denmark, Tuscany (Italy), Spain, the Netherlands, and the UK. Clinical and demographic information from each database was transformed to the ConcePTION Common Data Model, quality checks were conducted and a distributed analysis was performed using common scripts. Incident and prevalent use of valproate, proportion of discontinuers and switchers to alternative medicine, frequency of contraception coverage during valproate use, and occurrence of pregnancies during valproate exposure were estimated per month. Interrupted time series analyses were conducted to estimate the level or trend change in the outcome measures. Results: We included 69,533 valproate users from 9,699,371 females of childbearing potential from the five participating centres. A significant decline in prevalent use of valproates was observed in Tuscany, Italy (mean difference post-intervention −7.7%), Spain (−11.3%), and UK (−5.9%) and a non-significant decline in the Netherlands (−3.3%), but no decline in incident use after the 2018 RMMs compared to the period before. The monthly proportion of compliant valproate prescriptions/dispensings with a contraceptive coverage was low (<25%), with an increase after the 2018 RMMs only in the Netherlands (mean difference post-intervention 12%). There was no significant increase in switching rates from valproates to alternative medicine after the 2018 intervention in any of the countries/regions. We observed a substantial number of concurrent pregnancies during valproate exposure, but with a declining rate after the 2018 RMMs in Tuscany, Italy (0.70 per 1000 valproate users pre- and 0.27 post-intervention), Spain (0.48 and 0.13), the Netherlands (0.34 and 0.00), and an increasing rate in UK (1.13 and 5.07). Conclusion: There was a small impact of the 2018 RMMs on valproate use in the studied European countries/regions. The substantial number of concurrent pregnancies with valproate exposure warrants a careful monitoring of implementation of the existing PPP for valproate in clinical practice in Europe, to see if there is any need for additional measures in the future. [ABSTRACT FROM AUTHOR]

Reference materials are critical in assay development for calibrating and assessing their suitability. The devasting nature of the COVID-19 pandemic and subsequent proliferation of vaccine platforms and technologies has meant that there is even a greater need for standards for immunoassay development, which are critical to assess and compare vaccines’ responses. Equally important are the standards needed to control the vaccine manufacturing processes. Standardized vaccine characterization assays throughout process development are essential for a successful Chemistry, Manufacturing and Controls (CMC) strategy. In this perspective paper, we advocate for reference material incorporation into assays and their calibration to International Standards from preclinical vaccine development through control testing and provide insight into why this is necessary. We also provide information on the availability of WHO international antibody standards for CEPI-priority pathogens. [ABSTRACT FROM AUTHOR]

Purpose: N6-methyladenosine (m6A) is the most frequent type of messenger RNA (mRNA) modification and is implicated in diverse physiological processes. The procedure of m6A RNA modification is regulated by a dynamic interaction of writers (METTL3, METTL4, METTL14, WTAP, KIAA1429), erasers (FTO, ALKBH5), and readers (HNRNPA2B1, HNRNPC, YTHDC1, YTHDC1, YTHDF1-3). In the oncological context, alterations in m6A were identified to be critically involved in tumorigenesis, proliferation, angiogenesis, and drug resistance across diverse cancer entities including endometrial cancer (EC). Methods: In this study, we comprehensively examined the protein expression of m6A writers, readers and erasers by immunohistochemical staining in a cohort of N = 65 EC patients. Protein expression data were analyzed with regard to clinical outcomes. Results: We identified enhanced protein expression levels of METTL3, METTL14, FTO, HNRNPA2B1, and HNRNPC, respectively to be of prognostic value and linked to a shortened overall survival in EC. Conclusion: Overall, our study points toward dysregulated m6A modification in EC and its possibility to serve as a promising prognostic biomarker. [ABSTRACT FROM AUTHOR]

Myoglobin (MB) is expressed in different cancer types and may act as a tumor suppressor in breast cancer. The mechanisms by which basal MB expression level impacts murine mammary tumorigenesis are unclear. We investigated how MB expression in breast cancer influences proliferation, metastasis, tumor hypoxia, and chemotherapy treatment in vivo. We crossed PyMT and WapCreTrp53flox mammary cancer mouse models that differed in tumor grade/type and onset of mammary carcinoma with MB knockout mice. The loss of MB in WapCre;Trp53flox mice did not affect tumor development and progression. On the other hand, loss of MB decreased tumor growth and increased tissue hypoxia as well as the number of lung metastases in PyMT mice. Furthermore, Doxorubicin therapy prevented the stronger metastatic propensity of MB-deficient tumors in PyMT mice. This suggests that, although MB expression predicts improved prognosis in breast cancer patients, MB-deficient tumors may still respond well to first-line therapies. We propose that determining the expression level of MB in malignant breast cancer biopsies will improve tumor stratification, outcome prediction, and personalized therapy in cancer patients. [ABSTRACT FROM AUTHOR]