Preclinical cardiovascular research relies heavily on non-invasive in-vivo echocardiography in mice and rats to assess cardiac function and morphology, since the complex interaction of heart, circulation, and peripheral organs are challenging to mimic ex-vivo. While n-numbers of annually used laboratory animals worldwide approach 200 million, increasing efforts are made by basic scientists aiming to reduce animal numbers in cardiovascular research according to the 3R's principle. The chicken egg is well-established as a physiological correlate and model for angiogenesis research but has barely been used to assess cardiac (patho-) physiology. Here, we tested whether the established in-ovo system of incubated chicken eggs interfaced with commercially available small animal echocardiography would be a suitable alternative test system in experimental cardiology. To this end, we defined a workflow to assess cardiac function in 8-13-day-old chicken embryos using a commercially available high resolution ultrasound system for small animals (Vevo 3100, Fujifilm Visualsonics Inc.) equipped with a high frequency probe (MX700; centre transmit: 50 MHz). We provide detailed standard operating procedures for sample preparation, image acquisition, data analysis, reference values for left and right ventricular function and dimensions, and inter-observer variabilities. Finally, we challenged incubated chicken eggs with two interventions well-known to affect cardiac physiology-metoprolol treatment and hypoxic exposure-to demonstrate the sensitivity of in-ovo echocardiography. In conclusion, in-ovo echocardiography is a feasible alternative tool for basic cardiovascular research, which can easily be implemented into the small animal research environment using existing infrastructure to replace mice and rat experiments, and thus, reduce use of laboratory animals according to the 3R principle.

Background COVID-19 is associated with a prothrombotic state. Current guidelines recommend prophylactic anticoagulation upon hospitalization.

Methods COVID-PREVENT, an open-label, multicenter, randomized, clinical trial enrolled patients (≥ 18 years) with moderate to severe COVID-19 and age-adjusted d-dimers > 1.5 upper limit of normal (ULN). The participants were randomly assigned (1:1) to receive either therapeutic anticoagulation with rivaroxaban 20 mg once daily or thromboprophylaxis with a heparin (SOC) for at least 7 days followed by prophylactic anticoagulation with rivaroxaban 10 mg once daily for 28 days or no thromboprophylaxis. The primary efficacy outcome was the d-dimer level and the co-primary efficacy outcome the 7-category ordinal COVID-19 scale by WHO at 7 days post randomization. The secondary outcome was time to the composite event of either venous or arterial thromboembolism, new myocardial infarction, non-hemorrhagic stroke, all-cause death or progression to intubation and invasive ventilation up to 35 days post randomization.

Results The primary efficacy outcome d-dimer at 7 days was not different between patients assigned to therapeutic (n = 55) or prophylactic anticoagulation (n = 56) (1.21 mg/L [0.79, 1.86] vs 1.27 mg/L [0.79, 2.04], p = 0.78). In the whole study population d-dimer was significantly lower at 7 days compared to baseline (1.05 mg/L [0.75, 1.48] vs 1.57 mg/L [1.13, 2.19], p < 0.0001). Therapy with rivaroxaban compared to SOC was not associated an improvement on the WHO 7-category ordinal scale at 7 days (p = 0.085). Rivaroxaban improved the clinical outcome measured by the score in patients with a higher baseline d-dimer  > 2.0 ULN (exploratory analysis; 0.632 [0.516, 0.748], p = 0.026). The secondary endpoint occurred in 6 patients (10.9%) in the rivaroxaban group and in 12 (21.4%) in the SOC group (time-to-first occurrence of the components of the secondary outcome: HR 0.5; 95% CI 0.15–1.67; p = 0.264). There was no difference in fatal or non-fatal major or clinically relevant non-major bleeding between the groups.

Conclusions Therapeutic anticoagulation with rivaroxaban compared to prophylactic anticoagulation with a heparin did not improve surrogates of clinical outcome in patients with moderate to severe COVID-19. Whether initial rivaroxaban at therapeutic doses might be superior to thromboprophylaxis in patients with COVID-19 and a high risk as defined by d-dimer  > 2 ULN needs confirmation in further studies.

Purpose With the onset of the COVID pandemic in Germany in March 2020, far-reaching restrictions were imposed that limited medical access for patients. Screening examinations such as colonoscopies were greatly reduced in number. As rapid surgical triage after diagnosis is prognostic, our hypothesis was that pandemic-related delays would increase the proportion of advanced colon cancers with an overall sicker patient population.

Methods A total of 204 patients with initial diagnosis of colon cancer were analyzed in this retrospective single-center study between 03/01/2018 and 03/01/2022. Control group (111 patients, pre-COVID-19) and the study group (93 patients, during COVID-19) were compared in terms of tumor stages, surgical therapy, complications, and delays in the clinical setting. The data were presented either as absolute numbers or as median for constant data.

Results A trend towards more advanced tumor stages (T4a p = 0.067) and a significant increase of emergency surgeries (p = 0.016) with higher rates of ileus and perforation (p = 0.004) as well as discontinuity resections (p = 0.049) during the pandemic could be observed. Delays in surgical triage after endoscopic diagnosis were seen during the 2nd lockdown (02/11/20–26/12/20; p = 0.031).

Conclusion In summary, the results suggest delayed treatment during the COVID-19 pandemic, with the infection pattern of COVID appearing to have a major impact on the time between endoscopic diagnosis and surgical triage/surgery. Adequate care of colon cancer patients is possible even during a pandemic, but it is important to focus on structured screening and tight diagnosis to treatment schedules in order to prevent secondary pandemic victims.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) coined by inflammation and neurodegeneration. The actual cause of the neurodegenerative component of the disease is however unclear. We investigated here the direct and differential effects of inflammatory mediators on human neurons. We used embryonic stem cell-derived (H9) human neuronal stem cells (hNSC) to generate neuronal cultures. Neurons were subsequently treated with tumour necrosis factor alpha (TNF alpha), interferon gamma (IFN gamma), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin 17A (IL-17A) and interleukin 10 (IL-10) separately or in combination. Immunofluorescence staining and quantitative polymerase chain reaction (qPCR) were used to assess cytokine receptor expression, cell integrity and transcriptomic changes upon treatment. H9-hNSC-derived neurons expressed cytokine receptors for IFN gamma, TNF alpha, IL-10 and IL-17A. Neuronal exposure to these cytokines resulted in differential effects on neurite integrity parameters with a clear decrease for TNF alpha- and GM-CSF-treated neurons. The combinatorial treatment with IL-17A/IFN gamma or IL-17A/TNF alpha induced a more pronounced effect on neurite integrity. Furthermore, combinatorial treatments with two cytokines induced several key signalling pathways, i.e. NF kappa B-, hedgehog and oxidative stress signalling, stronger than any of the cytokines alone. This work supports the idea of immune-neuronal crosstalk and the need to focus on the potential role of inflammatory cytokines on neuronal cytoarchitecture and function.

It is demonstrated that the longitudes of the planetary exaltations mentioned in numerous Greco-Roman and Late Antique astrological sources derive from Babylonian Normal-Star longitudes. This is achieved through a comparison between both sets of longitudes. Supporting evidence is found in the Late Babylonian astral compendium BM 36609+. The Babylonian longitudes were transferred to exaltations without significant changes, but their association with stars was discarded. The sun’s exaltation constitutes an exception, since it does not correspond to a Normal Star, but appears to have been defined in relation to the longitude of the Pleiades, which became the moon’s exaltation.

Learning faithful representations of quantum states is crucial to fully characterizing the variety of many-body states created on quantum processors. While various tomographic methods, such as classical shadow and matrix product state (MPS) tomography have shown promise in characterizing a wide class of quantum states, they face unique limitations in detecting topologically ordered two-dimensional states. To address this problem, we implement and study a heuristic tomographic method that combines variational optimization on tensor networks with randomized measurement techniques. Using this approach, we demonstrate its ability to learn the ground state of the surface-code Hamiltonian as well as an experimentally realizable quantum spin liquid state. In particular, we perform numerical experiments using MPS ansätze and systematically investigate the sample complexity required to achieve high fidelities for systems with sizes of up to 48 qubits. In addition, we provide theoretical insights into the scaling of our learning algorithm by analyzing the statistical properties of maximum-likelihood estimation. Notably, our method is sample-efficient and experimentally friendly, only requiring snapshots of the quantum state measured randomly in the 𝑋 or 𝑍 bases. Using this subset of measurements, our approach can effectively learn any real pure states represented by tensor networks, and we rigorously prove that random-𝑋⁢𝑍 measurements are tomographically complete for such states.

Background

Coxiella burnetii, the causative agent of Q fever, is a globally distributed pathogen with significant zoonotic and economic impacts, particularly in regions where humans and livestock interact closely. Although endemic in many countries, including Kenya, comprehensive epidemiological data on the pathogen are limited. To address this gap, we conducted a linked human and livestock populations study in Garbatulla, Isiolo County to assess seroprevalence and identify potential predictors of C. burnetii exposure.

Methods

We used a cross-sectional design with multistage sampling. Blood and serum samples were collected from 2,157 livestock and 683 humans that were recruited from 242 households. Additional data on herd/household and subject characteristics were collected using a structured questionnaire. Indirect enzyme-linked immunosorbent assay (ELISA) was used to test the serum samples for antibodies against C. burnetii. Univariable and multivariable analyses identified potential predictors of exposure in both livestock and humans.

Results

The overall seroprevalence of C. burnetii was 47.9% (95% CI: 45.7%-50.1%) in livestock and 44.7% (95% CI: 40.9%-48.5%) in humans. In livestock, significant variation in seroprevalence was found by species (p < 0.001). Goats were found to have significantly higher odds of being exposed to C. burnetii compared to cattle, sheep and camels. Both weaners and young animals had significantly lower odds of exposure compared to adults. In humans, the odds of C. burnetii exposure were lower among females compared to males. Herds seropositivity was also an important predictor of humans exposure to C. burnetii.

Conclusions

This study provides evidence of high seroprevalence of C. burnetii in both livestock and humans, highlighting the need for active surveillance programs targeting both populations. These programs should focus on identifying active shedding and implementing targeted control measures to mitigate the public health risks associated with C. burnetii.

This study aimed to improve the drug-like properties of benzimidazole-based Pt(II)-N-heterocyclic carbene (NHC) complexes, particularly by enhancing their water solubility and delivery to cancer cells. Accordingly, four new Pt(II) complexes of the benzimidazol-2-ylidene type, featuring monodentate carboxylato ligands, were prepared and their structures confirmed through a combination of spectroscopic and crystallographic techniques. Their stability in aqueous solution and cell culture medium was investigated by 1H NMR spectroscopy and HPLC-MS analysis. Cytotoxicity was assessed using the MTT assay in ovarian cancer cell lines (A2780wt (cisplatin sensitive) and A2780cis (cisplatin resistant)) and a noncancerous bone marrow stromal cell line (HS-5). Most complexes exhibited cytotoxicity comparable to or exceeding that of carboplatin, with preferential activity toward cancer cells. Loading of all four Pt(II) complexes into bacterial ghost cells (BGs) derived from two different nonpathogenic bacterial strains, Escherichia coli (E. coli) Nissle 1917 and E. coli NM522 notably enhanced the intracellular accumulation and cytotoxicity. Furthermore, mechanistic studies demonstrated that all tested compounds, regardless of formulation, induced apoptosis. Their potential to trigger immunogenic cell death was also evaluated, though only a modest effect was observed on selected hallmarks. Collectively, these findings highlight the potential of dicarboxylatoplatinum(II)-NHC complexes, particularly loaded into BG-based formulations, as promising anticancer drug candidates.

Vibrio (V.) species, such as V. parahaemolyticus and V. cholerae, are commonly associated with foodborne infections and are frequently detected in seafood worldwide. Unfavorable environmental conditions and process-related factors can induce a shift from culturable Vibrio cells into viable but nonculturable (VBNC) cells. Conventional culture-based detection methods (ISO 21872-1:2023-06) cannot detect bacteria in the VBNC state, even though these cells remain metabolically active and pathogenic due to the expression of toxin−encoding genes. This study aimed to develop a detection method using viable quantitative PCR (vqPCR) to identify viable cells, including those in VBNC state. In parallel, a relatively rapid protocol for inducing the VBNC state to generate VBNC cell controls was established. The established vqPCR assays included a preliminary step to inhibit dead bacterial cells using a proprietary DNA intercalating dye (Reagent D) in combination with the detection of long gene fragments of groEL (510 bp) for V. parahaemolyticus and ompW (588 bp) for V. cholerae using previously published primers. These assays demonstrated a high sensitivity, detecting as low as 20 fg DNA = 3.5 V. parahaemolyticus cells and 30 fg DNA = 6.9 V. cholerae cells. An induction of Vibrio VBNC cells of ≈ 6.5 Log10 cells/ml was successfully achieved within one hour from an initial 7.3 Log10 viable Vibrio cells/ml by treating the cells with a solution containing 0.5 or 1.0% Lutensol A03 and 0.2 M ammonium carbonate. The results showed that the established vqPCR methods were able to detect V. parahaemolyticus and V. cholerae in up to 50% (2.6 to 4.2 Log10 cells/g) and 56% (2.8 to 5.2 Log10 cells/g) of retail samples, respectively, that were initially false-negative in culture-based tests. The use of vqPCR assays along with culture-based tests can significantly enhance the seafood safety assessment by enabling the detection of VBNC cells of the most important foodborne Vibrio pathogens. In addition, the induction assay can be used for a rapid production of VBNC cells to standardize and validate such detection methods.

Alterations in energy metabolism are recognized as a hallmark of cancer. Experimental evidence shows that oncogenes play a key role in the reprogramming of metabolism. In neuroblastoma, the oncogene MYCN, a main risk factor of poor prognosis, has been demonstrated to lead to expression changes in numerous glycolytic enzymes. It is not clear whether all these targets are required and how they jointly shape metabolic responses. Here we use a computational modeling approach to dissect the effects of MYCN targets on the pathway individually and in combination. We develop the first mathematical model of the energy metabolism in neuroblastoma cells based on our published experimental data. The analysis shows that overall, MYCN overexpression leads to Warburg-like flux alterations. However, individual MYCN targets can have opposing and sometimes unexpected effects. Interestingly, not all of them contribute to notable flux alterations, at least with regard to glycolysis. Moreover, our model predicts a potential bistability of cellular metabolism with a low-flux state likely representing a non-proliferative state. Overall, our study emphasizes that perturbations such as expression changes should be analysed in the context of realistic pathway models, in which specific interactions and complex regulations are captured.

Relaxation rates are key characteristics of quantum processes, as they determine how quickly a quantum system thermalizes, equilibrates, decoheres, and dissipates. While they play a crucial role in theoretical analyses, relaxation rates are also often directly accessible through experimental measurements. Recently, it was shown that for quantum processes governed by Markovian semigroups, the relaxation rates satisfy a universal constraint: the maximal rate is upper-bounded by the sum of all rates divided by the dimension of the Hilbert space. This bound, initially conjectured a few years ago, was only recently proven using classical Lyapunov theory. In this work, we present a new, purely algebraic proof of this constraint. Remarkably, our approach is not only more direct but also allows for a natural generalization beyond completely positive semigroups. We show that complete positivity can be relaxed to two-positivity without affecting the validity of the constraint. This reveals that the bound is more subtle than previously understood: two-positivity is necessary, but even when further relaxed to Schwarz maps, a slightly weaker—yet still non-trivial—universal constraint still holds. Finally, we explore the connection between these bounds and the number of steady states in quantum processes, uncovering a deeper structure underlying their behavior.

SS-, RR-, SR- and RR/SS-configured 1,3-diethyl-4,5-diphenyl-4,5-dihydro-1H-imidazol-2-ylidenes were introduced as new imidazoline-based N-heterocyclic carbene (NHC) ligands for the design of antitumor-active (NHC)gold(I) complexes (halido(NHC)gold(I) complexes: chlorido (5a-d), bromido (6a-d), iodido (7a-d); SS,SS-, RR,RR-, SR,SR-, and RR,SS-configured [(NHC)2Au(I)]+ complexes: 8a-d). X-ray structures of the SS-configured complexes 5a-7a showed bis-equatorially arranged phenyl rings and disturbed columnar structures with increased Au–Au distances (>5.6 Å). The SR-configuration forced the phenyl ring in a synclinal position above the NHC plane allowing only the formation of separated dimers (5c-7c). In case of the [(NHC)2Au(I)]+ complex 8c, single molecules were observed in the crystals. The steric and dynamic conditions reduced ligand scrambling in solution and thus increased stability. The complexes showed higher growth inhibitory effects in ovarian (A2780wt (wild-type), A2780cis (Cisplatin-resistant)) than in breast cancer cells (MDA-MB-231, MCF-7) and circumvented the Cisplatin resistance in A2780 cells (effects in A2780wt = A2780cis). Chlorido- and bromido(NHC)gold(I) complexes caused comparable effects, because of a fast Br/Cl exchange (6a-d → 5a-d). The iodido(NHC)gold(I) complexes 7a-d were more active, due to a partial degradation to 8a-d. The latter were the most cytotoxic compounds of this study. The configuration of the NHC ligand did not influence the cytotoxicity of the complexes. Enantiomers and diastereomers showed the same antimetabolic effects. On the examples of 5a-d and 8a-d, the cellular uptake was studied. The maximum gold levels in A2780wt and MDA-MB-231 cells were achieved within 30 min of incubation. At concentrations corresponding to the half maximal inhibitory concentration (IC50) values of the antiproliferative effect (5a-d: 20 μM, 8a-d: 5 μM), 5b, 5c, and 5d induced almost the same gold content in A2780wt cells, which was 30–50 % lower than that of 5a. The trend of accumulation for [(NHC)2Au(I)]+ complexes was 8d < 8a < 8b < 8c. Furthermore, 5a-d inhibited the cyclooxygenase-1 (COX-1) and thioredoxin reductase (TrxR) and upregulated the Glutathione (GSH) level in A2780wt cells. Contrarily, 8a-d did not reduce COX-1 and TrxR activity, but led to moderate GSH down-regulation. The GSH level was not lowered in favour of Glutathione disulfide (GSSG), demonstrating that 8a-d influence the formation of GSH.

Both exposure to nature and physical exercise have been shown to have positive effects on mental well-being. We reviewed the combined effects of physical exercise in nature (i.e., ‘green exercise’) on mental well-being. A systematic review of the databases Ovid Medline, PubMed and PsycINFO resulted in a total of 57 included studies (of which 25were meta-analysed). All eligible studies compared a green exercise intervention with: (1) a no intervention control group, (2) indoor exercise, (3) urban exercise, or (4) other interventions to improve mental well-being. Studies without a comparison group were excluded. Our results show that green exercise interventions have a positive effects on mental well-being (0.478; p = 0.001; 95% CI = [0.191, 0.766]). Subgroup analyses revealed that green exercise interventions had more positive effects on mental well-being compared to no-intervention control groups (5 studies; 0.851, se = 0.248, p < 0.001) and other mental well-being interventions (8 studies; 0.540, se = 0.188, p = 0.05), but not compared to indoor (5 studies; 0.04, se = 0.203, p = 0.819), or urban exercises (10 studies; 0.415, se = 0.268, p = 0.124). While green exercise clearly outperforms no activity and non-physical interventions in enhancing mental well-being, its benefits over other forms of physical activity may be more nuanced, potentially moderated by factors such as duration, environmental quality, and measurement sensitivity. Future interventions should explore what types of green exercise are the most beneficial, and which populations may benefit the most from participation in green exercise (e.g., clinical, youth, migrant communities).

Introduction

Poor sleep quality is a persistent and debilitating symptom of major depressive disorder (MDD), with dysregulations in the biological stress system constituting a potential underlying physiological mechanism. Accordingly, a psychotherapeutic intervention may affect the interplay between sleep quality, MDD and the biological stress system.We examined how basal cortisol, and alpha-amylase levels correspond to perceived sleep quality during an internet-based intervention for MDD. Furthermore, we investigated how changes in sleep quality during the intervention relate to changes in these biological stress system markers. We hypothesized that: 1) short-term and long-term sleep quality would improve during the intervention, 2a) across assessment time points, poor sleep quality would be associated with higher cortisol and alpha-amylase concentrations, and 2b) pre-to-post intervention improvements in sleep quality (treatment response) would be associated with pre-to-post decreases in both biological markers, compared to non-response.

Methods

We analyzed forty-one participants (age: 35 ± 12y; females: 82.6 %) suffering from mild to moderate MDD. The cognitive behavioral internet-based intervention consisted of seven weekly writing-based modules with individualized feedback. Participants collected 12 saliva samples at home over two consecutive weekdays at pre-, mid-, and post-intervention. Outcome parameters of the cortisol and alpha-amylase diurnal profiles were the awakening responses, the total diurnal output, and the diurnal slopes. Self-reported sleep quality was retrospectively assessed for the night before (short-term) and for the two-week period preceding saliva collection (long-term). Treatment response was determined using the reliable change index of the pre-to-post, two-week sleep quality difference scores. Hypotheses 1 and 2a were tested using random intercept hierarchical linear models, Hypothesis 2b was tested using linear regressions with age, biological sex, BMI and medication use on the day of sampling as covariates.

Results

Long-term sleep quality increased significantly from pre-to post-intervention (d = 0.78; p < 0.001), partially confirming Hypothesis 1. Contrary to the expected effect of Hypothesis 2a, poor long-term sleep quality at pre-intervention was associated with a blunted cortisol awakening response (CAR; p < 0.05). Post-hoc analyses showed an association of pre-to-post CAR changes and pre-intervention sleep quality (p < 0.01) indicating that individuals with higher pre-intervention sleep problems, on average, exhibited a pre-to-post increase in the CAR. The responder analyses showed that individuals with a marked pre-to-post sleep quality increase (i.e., responders) showed a higher increase in the CAR, compared to non-responders (p < 0.05), which again ran contrary to the effect proposed in Hypothesis 2b.

Discussion

Prior to psychotherapeutic treatment MDD patients with poor sleep quality showed a blunted CAR, pointing to hypocortisolemia in these individuals. Furthermore, intervention-induced changes in sleep quality may lead to a normalization of the CAR.

India has experienced the introduction of numerous non-native fish species (NNF), some of which have caused ecological and economic impacts. This systematic review provides a currently lacking overview of NNF research in India, potential biases, available evidence, and knowledge gaps. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework, we identified a total of 332 records, documenting the presence of 58 NNF distributed across 17 basins, and 19 translocated species in India. The Ganga was the most studied basin (113 studies), followed by the West Flowing Rivers Tadri to Kanyakumari basin (37 studies), however, with 30 NNF reported from each of these basins. We demonstrate how these results can be due to saturated sampling in the Ganga and identify which basins might be currently understudied. We also illustrate how extreme floods precipitated an increase in NNF into rivers and lakes from confinement in the West Flowing Rivers Tadri to Kanyakumari basin. The common carp, Cyprinus carpio, was the most frequently reported NNF (160 times), while Mozambique tilapia, Oreochromis mossambicus, was the most widely distributed NNF (13 basins). We found there is a growing number of publications in the field, but that up to 40% of studies have appeared in potentially predatory journals. A minority of studies (44%) investigated NNF impacts, most of which used data from the literature (58%) and reported only qualitative impacts (69%). Most documented impacts were ecological (79%), while some were socio-economic (11%) or both (10%). Only 18% of the studies addressed NNF management. The knowledge synthesized and the gaps identified in this study might serve as a basis for future studies and be useful for efficiently allocating limited resources for investigating NNF in India.

Mode I fractures in rocks and other heterogeneous materials do not grow straight – their traces have interruptions and overlappings caused by the fracture avoiding tough zones (e.g., strong inclusions or the compressive zones of a random stress field). The interruptions and overlappings create bridges working as columns or beams connecting the opposite faces of the fracture. The bridges are distributed over the whole fracture and can constrict the fracture opening. We model the constriction by introducing a Winkler layer of the stiffness proportional to the average bridge stiffness and the number of bridges per unit area of the fracture. Constriction is characterised by the constriction length − the ratio of Young’s modulus of the rock and the Winkler layer stiffness. Two asymptotic limits exist: fractures much smaller than the constriction length (they are the conventional tensile fractures) and fractures much larger than the constriction length. Interpolation formulae are developed to account for intermediate fracture lengths. Breakage of bridges contributes to the microseismisity associated with the fracture growth. Three basic fracture geometries, disc-like fractures, 2D (KGD) fractures and elongated elliptical fractures are considered. For large fracture growth times power scalings exist for fracture size and width. For toughness-dominated fractures, depending on fracture geometry, the constriction either increases the time scaling exponent of the fracture size and width or leaves them unaffected. For volume-balance fractures the constriction does not affect scalings of the fracture size. Constriction strengthens the time scaling for the fracture width of disc-like and 2D fractures but does not change scaling for the elongated elliptical fracture. Constriction does not affect the time scaling for the PKN fractures. The knowledge of scaling of fracture size and width may add to the determination of the type (geometry and constriction) of the hydraulic fracture. Comparison of the theoretical results with field data shows the significance of bridges which can control the behaviour of hydraulic fractures.

Transdiagnostic group interventions address the limitations of youth mental health care services, including the disorder-specific nature of existing treatments and the limited capacity of individual psychotherapies. This review synthesizes the 1) characteristics, applications, parental involvement, patient and public involvement (PPI), and 2) data on efficacy, adherence, safety and treatment satisfaction evidence of transdiagnostic group interventions for children and adolescents. Following PRISMA guidelines, a preregistered systematic literature search identified 6845 publications on transdiagnostic in-person group-based interventions for children and adolescents (mean age ≤ 18 years). Two reviewers independently screened for inclusion, extracted data, and assessed risk of bias using the RoB-2 and ROBINS-I tool. The review examined 80 studies encompassing 4152 participants (Mage = 12.81 years), mostly conducted in high-income countries. Cognitive behavioural therapy was the most commonly used approach (κ = 59), with the core components mindfulness, emotion regulation, and cognitive restructuring. Interventions averaged 11 sessions and 52 % involved parents. 22 studies targeted anxiety and depression jointly with positive pre-post effects. Significant reductions in symptom severity were also reported for other disorders, though outcome measures highly varied and group comparisons with active control conditions or treatment-as-usual were often non-significant. Few studies examined disorder-unspecific outcomes like psychosocial functioning, quality of life, or reported remission rates, treatment satisfaction or applied a PPI framework. While a large number of different transdiagnostic group interventions for youth have been developed and evaluated, the lack of rigorous reporting and high risk of bias highlight the need for better-quality research to strengthen evidence and improve clinical implementation.

The rise of anthelmintic-resistant strains in livestock threatens both animal and human health. Understanding the factors influencing anthelmintic resistance is crucial to mitigate the threat posed by these parasites. Due to difficulties in studying parasitic worms in the laboratory, the non-parasitic nematode Caenorhabditis elegans is used as a model organism to investigate anthelmintic resistance evolution. However, the suitability of this free-living nematode as a model for parasitic worms is debatable due to its rare androdioecious reproductive system, raising questions about the generalizability of findings from evolutionary experiments in C. elegans to other species. In this study, we developed a polygenic, population genetic model combined with pharmacodynamic approaches to investigate the effects of reproductive strategy and other aspects, such as dominance, mutational effects, the number of loci and population size, on determining the dynamics and outcome of evolutionary processes. We found that androdioecious populations showed both rapid initial adaptation typical for hermaphrodites and tolerance to high drug concentrations observed in dioecious populations. They also exhibited the highest diversity and shortest time for the fixation of the beneficial allele. These results suggest that androdioecious populations can harness the advantages of both selfing and outcrossing, optimizing their reproductive strategy in response to drug selection.

In this work, we show that learning the output distributions of brickwork random quantum circuits is average-case hard in the statistical query model. This learning model is widely used as an abstract computational model for most generic learning algorithms. In particular, for brickwork random quantum circuits on n qubits of depth d, we show three main results: – At super logarithmic circuit depth d=ω(log(n)), any learning algorithm requires super polynomially many queries to achieve a constant probability of success over the randomly drawn instance. – There exists a d=O(n), such that any learning algorithm requires Ω(2n) queries to achieve a O(2−n) probability of success over the randomly drawn instance. – At infinite circuit depth d→∞, any learning algorithm requires 22Ω(n) many queries to achieve a 2−2Ω(n) probability of success over the randomly drawn instance. As an auxiliary result of independent interest, we show that the output distribution of a brickwork random quantum circuit is constantly far from any fixed distribution in total variation distance with probability 1−O(2−n), which confirms a variant of a conjecture by Aaronson and Chen.