This is the first description of cutaneous mucormycosis in buffalo in the Brazilian Amazon biome. All buffalo showed apathy, inappetence, weight loss, reluctance to move, and prolonged sternal decubitus. Of the four affected animals, two died 15 and 30 days after the appearance of clinical signs. In the initial phase, the skin lesions were rounded areas with dry central regions, sensitive to palpation, with protruding edges and diameters ranging from 8 cm to 15 cm. These areas of necrosis were isolated or coalescing and present mainly on the limbs and sides. In an advanced stage of the disease, there was detachment of the skin from the necrotic areas with extensive wound formation, which sometimes exposed the subcutaneous tissue. The histopathology of the skin showed a multifocal inflammatory infiltrate composed of intact and degenerated eosinophils surrounded by epithelioid macrophages. At the center of these areas was a focally extensive area of epidermal ulceration characterized by intact and degenerated neutrophils, the necrosis of epithelial cells, and the accumulation of fibrin and erythrocytes. The mycological culture was positive for Rhizopus sp. The diagnosis of cutaneous dermatitis caused by Rhizopus sp. was based on clinical signs, macroscopic and histopathological findings, and the identification of the fungus by mycological and molecular techniques. Full article

Since 2016, the Ministry of Ecology and Environment and the Beijing Municipal Government have adjusted the minimum concentration limit for ambient air dustfall several times, indicating that they attach great importance to dustfall. To grasp the pollution characteristics and sources of dustfall, in this work, the filtration method was used to determine the insoluble dustfall and water-soluble dustfall in the urban area of Beijing. From our analysis, the influence of the meteorological parameters on dustfall was found, and the chemical components of dustfall were determined. The positive matrix factorization (PMF) model was also utilized to analyze the sources of dustfall. The results indicated that the average amount of dustfall in 2021–2022 was 4.4 t·(km²·30 d)⁻¹, and the proportion of insoluble dustfall deposition was 82.4%. Dustfall was positively correlated with the average wind speed and temperature and negatively correlated with the relative humidity and rain precipitation. The impact of the meteorological parameters on insoluble dustfall and water-soluble dustfall was the opposite. The average proportions of crustal material, ions, organic matter, element carbon, trace elements, and unknown components were 48%, 16%, 14%, 1.4%, 0.20%, and 20%, respectively. The proportions of the crustal material and ions were the highest in spring (57%) and summer (37%). The contribution rates of fugitive dust source, secondary inorganic source, mobile source, coal combustion source, snow melting agent source, and other sources were 42.4%, 19.3%, 8.3%, 3.0%, 2.7%, and 24.3%, respectively. This study supported dustfall pollution control by analysing the pollutant characteristics and sources of dustfall from the standpoint of total chemical components. In order to better control dustfall pollution, control measures and evaluation standards for fugitive dust pollution should be formulated. Full article

Domestic and international risk shocks have greatly increased the demand for systemic risk management in China. This paper estimates China’s multi-layer financial network based on multiple financial relationships among banks, assets, and firms, using China’s banking system data in 2021. An improved PageRank algorithm is proposed to identify systemically important banks and other economic sectors, and a stress test is conducted. This study finds that China’s multi-layer financial network is sparse, and the distribution of transactions across financial markets is uneven. Regulatory authorities should support economic recovery and adjust the money supply, while banks should differentiate competition and manage risks better. Based on the PageRank index, this paper assesses the systemic importance of large commercial banks from the perspective of network structure, emphasizing the role of banks’ transaction behavior and market participation. Different industries and asset classes are also assessed, suggesting that increased attention should be paid to industry risks and regulatory oversight of bank investments. Finally, stress tests confirm that the improved PageRank algorithm is applicable within the multi-layer financial network, reinforcing the need for prudential supervision of the banking system and revealing that the degree of transaction concentration will affect the systemic importance of financial institutions. Full article

Transformer-based encoder-decoder networks for face super-resolution (FSR) have achieved promising success in delivering stunningly clear and detailed facial images by capturing local and global dependencies. However, these methods have certain limitations. Specifically, the deconvolution in upsampling layers neglects the relationship between adjacent pixels, which is crucial in facial structure reconstruction. Additionally, raw feature maps are fed to the transformer blocks directly without mining their potential feature information, resulting in suboptimal face images. To circumvent these problems, we propose an attention-guided transformer with pixel-related deconvolution network for FSR. Firstly, we devise a novel Attention-Guided Transformer Module (AGTM), which is composed of an Attention-Guiding Block (AGB) and a Channel-wise Multi-head Transformer Block (CMTB). AGTM at the top of the encoder-decoder network (AGTM-T) promotes both local facial details and global facial structures, while AGTM at the bottleneck side (AGTM-B) optimizes the encoded features. Secondly, a Pixel-Related Deconvolution (PRD) layer is specially designed to establish direct relationships among adjacent pixels in the upsampling process. Lastly, we develop a Multi-scale Feature Fusion Module (MFFM) to fuse multi-scale features for better network flexibility and reconstruction results. Quantitative and qualitative experimental results on various datasets demonstrate that the proposed method outperforms other state-of-the-art FSR methods. Full article

The vertical air pollutant concentrations and their relationships with synoptic- and local-scale air movement have been studied. This study measured the vertical profiles of PM_2.5 and O₃ using an unmanned aerial vehicle during summer in South Korea and analyzed the characteristics of the measured profiles. To understand the impact of synoptic air movements, we generated and categorized the 48 h air trajectories based on HYSPLIT, and we analyzed how the vertical profiles varied under different categories of long-range transport. We found that the vertical PM_2.5 concentration has a positive gradient with altitude when more polluted air was transported from China or North Korea and has negative gradient when cleaner air was transported from the East Sea. Unlike PM_2.5, the O₃ concentration did not depend significantly on the long-range transport scenario because of the short photochemical lifetime of O₃ during summer. For local-scale air movements, we found no significant impact of local wind on the measured profiles. Full article

With a view to maintaining the reputation of wine-producing regions among consumers, minimising economic losses caused by wine fraud, and achieving the purpose of data-driven terroir classification, the use of an absorbance–transmission and fluorescence excitation–emission matrix (A-TEEM) technique has shown great potential based on the molecular fingerprinting of a sample. The effects of changes in wine composition due to ageing and the stability of A-TEEM models over time had not been addressed, however, and the classification of wine blends required investigation. Thus, A-TEEM data were combined with an extreme gradient boosting discriminant analysis (XGBDA) algorithm to build classification models based on a range of Shiraz research wines (n = 217) from five Barossa Valley sub-regions over four vintages that had aged in bottle for several years. This spectral fingerprinting and machine learning approach revealed a 100% class prediction accuracy based on cross-validation (CV) model results for vintage year and 98.8% for unknown sample prediction accuracy when splitting the wine samples into training and test sets to obtain the classification models. The modelling and prediction of sub-regional production area showed a class CV prediction accuracy of 99.5% and an unknown sample prediction accuracy of 93.8% when modelling with the split dataset. Inputting a sub-set of the current A-TEEM data into the models generated previously for these Barossa sub-region wines yielded a 100% accurate prediction of vintage year for 2018–2020 wines, 92% accuracy for sub-region for 2018 wines, and 91% accuracy for sub-region using 2021 wine spectral data that were not included in the original modelling. Satisfactory results were also obtained from the modelling and prediction of blended samples for the vintages and sub-regions, which is of significance when considering the practice of wine blending. Full article

Porcine epidemic diarrhea virus (PEDV) is an acute enteric coronavirus, inducing watery diarrhea and high mortality in piglets, leading to huge economic losses in global pig industry. Ivermectin (IVM), an FDA-approved antiparasitic agent, is characterized by high efficacy and wide applicability. However, the poor bioavailability limits its application. Since the virus is parasitized inside the host cells, increasing the intracellular drug uptake can improve antiviral efficacy. Hence, we aimed to develop nanostructured lipid carriers (NLCs) to enhance the antiviral efficacy of IVM. The findings first revealed the capacity of IVM to inhibit the infectivity of PEDV by reducing viral replication with a certain direct inactivation effect. The as-prepared IVM-NLCs possessed hydrodynamic diameter of 153.5 nm with a zeta potential of −31.5 mV and high encapsulation efficiency (95.72%) and drug loading (11.17%). IVM interacted with lipids and was enveloped in lipid carriers with an amorphous state. Furthermore, its encapsulation in NLCs could enhance drug internalization. Meanwhile, IVM-NLCs inhibited PEDV proliferation by up to three orders of magnitude in terms of viral RNA copies, impeding the accumulation of reactive oxygen species and mitigating the mitochondrial dysfunction caused by PEDV infection. Moreover, IVM-NLCs markedly decreased the apoptosis rate of PEDV-induced Vero cells. Hence, IVM-NLCs showed superior inhibitory effect against PEDV compared to free IVM. Together, these results implied that NLCs is an efficient delivery system for IVM to improve its antiviral efficacy against PEDV via enhanced intracellular uptake. Full article

Tree-like structures, characterized by hierarchical relationships and power-law distributions, are prevalent in a multitude of real-world networks, ranging from social networks to citation networks and protein–protein interaction networks. Recently, there has been significant interest in utilizing hyperbolic space to model these structures, owing to its capability to represent them with diminished distortions compared to flat Euclidean space. However, real-world networks often display a blend of flat, tree-like, and circular substructures, resulting in heterophily. To address this diversity of substructures, this study aims to investigate the reconstruction of graph neural networks on the symmetric manifold, which offers a comprehensive geometric space for more effective modeling of tree-like heterophily. To achieve this objective, we propose a graph convolutional neural network operating on the symmetric positive-definite matrix manifold, leveraging Riemannian metrics to facilitate the scheme of information propagation. Extensive experiments conducted on semi-supervised node classification tasks validate the superiority of the proposed approach, demonstrating that it outperforms comparative models based on Euclidean and hyperbolic geometries. Full article

In the more than 70 years since Markowitz introduced mean-variance optimization for portfolio construction, academics and practitioners have documented numerous weaknesses in the approach. In this paper, we propose two easily understandable improvements to mean-variance optimization in the context of multi-asset class portfolios, each of which provides less extreme and more stable portfolio weights. The first method sacrifices a small amount of expected optimality for reduced weight concentration, while the second method randomly resamples the available assets. Additionally, we develop a process for testing the performance of portfolio construction approaches on simulated data assuming variable degrees of forecasting skill. Finally, we show that the improved methods achieve better out-of-sample risk-adjusted returns than standard mean-variance optimization for realistic investor skill levels. Full article

Background: This study aimed to examine the prevalence and associated factors of malnutrition in older community-dwellers and explore the interaction between associated factors. Methods: A total of 474,467 older community-dwellers aged 65 or above were selected in Guangzhou, China. We used a two-step methodology to detect the associated factors of malnutrition and constructed logistic regression models to explore the influencing factors and interactive effects on three patterns of malnutrition. Results: The prevalence of malnutrition was 22.28%. Older adults with both hypertension and diabetes (RERI = 0.13), both meat or fish diet and hypertension (RERI = 0.79), and both meat or fish diet and diabetes (RERI = 0.81) had positive additive interaction effects on the risk of obesity, whereas those on a vegetarian diet with hypertension (RERI = −0.25) or diabetes (RERI = −0.19) had negative additive interaction effects. Moreover, the interactions of physical activity with a meat or fish diet (RERI = −0.84) or dyslipidemia (RERI = −0.09) could lower the risk of obesity. Conclusions: Malnutrition was influenced by different health factors, and there were interactions between these influencing factors. Pertinent dietary instruction should be given according to different nutritional status indexes and the prevalence of metabolic diseases to avoid the occurrences of malnutrition among older adults. Full article

Leptospirosis is a zoonosis of great importance for One Health. In this context, the Amazonian biome may harbor numerous hosts for Leptospira spp. that contribute to the maintenance of the pathogen in the environment. Some reptiles, such as chelonians, have been little studied in terms of their involvement with leptospires. The objective of this study was to detect Leptospira spp. DNA in Kinosternon scorpioides turtles kept in captivity in a region of the Brazilian Amazon. A total of 147 samples of blood (n = 40), cloacal fluid (n = 27), cloacal lavage (n = 40), and stomach (n = 40) were collected from 40 chelonians. After DNA extraction, the samples were subjected to amplification of a 331 base pair product of the 16S rRNA gene using the Lep1 and Lep2 primers. PCR products were Sanger sequenced, assembled, and subjected to online blast search and phylogenetic analysis. Of the animals tested, 40% (16/40, 95% confidence interval [CI]: 25–55) had at least one or two samples positive for Leptospira spp. Considering the total number of samples collected, 12.93% (19/147) were positive, being blood clots (27.5%; 11/40), followed by cloacal washings (10%; 4/40), cloacal fluid (11.11%; 3/27) and gastric washings (2.5%; 1/40). Of these, 11 samples were sequenced and showed 99% to 100% identity with Leptospira interrogans sequences, which was confirmed by phylogenetic analysis. This is the first study to detect pathogenic Leptospira DNA in chelonians in a region of the Brazilian Amazon. It has been concluded that K. scorpioides turtles in captivity have been exposed to pathogenic Leptospira. Full article

Placenta accreta spectrum (PAS) disorder is one of the leading causes of peripartum maternal morbidity and mortality; its early identification during pregnancy is of utmost importance to ensure the optimal clinical outcome. The aim of the present study is to investigate the possible association of the presence and type/location of placenta previa on MRI with PAS and maternal peripartum outcome. One hundred eighty-nine pregnant women (mean age: 35 years; mean gestational age: 32 weeks) at high risk for PAS underwent a dedicated placental MRI. All women underwent a C-section within 6 weeks from the MRI. All MRIs were evaluated by two experienced genitourinary radiologists for presence, type (complete/partial vs. marginal/low lying), and location (anterior vs. anterior-posterior vs. posterior) of placenta previa. Statistical analysis was performed for possible association of type/location of previa with placental invasiveness and peripartum outcomes. Intraoperative information was used as a reference standard. Complete/partial previa was detected in 143/189 (75.6%) and marginal/low lying previa in 33/189 (17.5%) women; in 88/189 (46.6%) women, the placenta had anterior–posterior, in 54/189 (28.6%) anterior and in 41/189 (21.7%) posterior. Complete/partial previa had an at least 3-fold probability of invasiveness and was more frequently associated with unfavorable peripartum events, including massive intraoperative blood loss or hysterectomy, compared to low-lying/marginal placenta. Posterior placental location was significantly associated with lower rates of PAS and better clinical outcomes. In conclusion, the type and location of placenta previa shown with MRI seems to be associated with severity of complications during delivery and should be carefully studied. Full article

An accurate and reliable sideslip angle is crucial for active safety control systems and advanced driver-assistance systems (ADAS). The direct measurement method of the sideslip angle suffers from challenges of high costs and environmental sensitivity, so sideslip angle estimation has always been a significant research issue. To improve the precision and robustness of sideslip angle estimation for distributed drive electric vehicles (DDEV) in extreme maneuvering scenarios, this paper presents a novel robust unscented particle filter (RUPF) algorithm based on low-cost onboard sensors. Firstly, a nonlinear dynamics model of DDEV is constructed, providing a theoretical foundation for the design of the RUPF algorithm. Then, the RUPF algorithm, which incorporates the unscented Kalman filter (UKF) to update importance density and utilizes systematic random resampling to mitigate particle degradation, is designed for estimation. Eventually, the availability of the proposed RUPF algorithm is validated on the co-simulation platform with non-Gaussian noises. Simulation results demonstrate that RUPF algorithm attains a higher precision and stronger robustness compared with the traditional PF and UKF algorithms. Full article

Sudden leakage during tunnel construction poses a great threat to the safety of the tunnel. There are relatively few studies on the mechanism of structural collapse induced by tunnel leakage, so it is difficult to propose effective control measures. To solve this problem, a coupled fluid–solid strata analysis model and a nonlinear FEM tunnel model were established based on model test results to analyze the mechanism of tunnel collapse. The following conclusions were drawn: (1) A DEM-based coupled fluid–solid model combined with a nonlinear FEM tunnel model can effectively simulate the physical process of tunnel collapse. (2) The mechanism of tunnel leakage-induced strata response is the continuous destabilization and reappearance of the soil arching effect, which restricts the erosion of the soil and results in macroscopic soil caves, and finally leads to the impact load of the destabilized soil. (3) The process of the tunnel structure collapse is as follows: firstly, a large deformation of the tunnel structure is caused by the redistribution of external loads generated by the earth arching effect; then, due to the multiple impact loads from the destabilization of the soil, plastic hinges are generated at the tunnel joints, and the tunnel collapses. Full article

Real-world clinical experience of using anti-programmed death-ligand 1 (PD-L1) immune checkpoint inhibitors (ICIs) combined with chemotherapy in the first-line treatment of extensive-stage small-cell lung cancer (SCLC) patients has rarely been reported. In this study, we aimed to perform a retrospective multicenter clinical analysis of extensive-stage SCLC patients receiving first-line therapy with anti-PD-L1 ICIs combined with chemotherapy. Between November 2018 and March 2022, 72 extensive-stage SCLC patients receiving first-line atezolizumab or durvalumab in combination with chemotherapy, according to the cancer center databases of Linkou, Chiayi, and Kaohsiung Chang Gung Memorial Hospitals, were retrospectively included in the analysis. Twenty-one patients (29.2%) received atezolizumab and fifty-one (70.8%) received durvalumab. Objective response (OR) and disease control (DC) rates of 59.7% and 73.6%, respectively, were observed with first-line ICI plus chemotherapy. The median progression-free survival (PFS) was 6.63 months (95% confidence interval (CI), 5.25–8.02), and the median overall survival (OS) was 16.07 months (95% CI, 15.12–17.0) in all study patients. A high neutrophil-to-lymphocyte ratio (NLR; >4) and a high serum lactate dehydrogenase (LDH) concentration (>260 UL) were identified as independent unfavorable factors associated with shorter OS in the multivariate analysis. Regarding safety, neutropenia was the most common grade 3 treatment-related adverse event (AE), but no treatment-related deaths occurred in the study patients. First-line anti-PD-L1 ICIs combined with chemotherapy are effective and safe for male extensive-stage SCLC patients. Further therapeutic strategies may need to be developed for patients with unfavorable outcomes (e.g., baseline high NLR and serum LDH level). Full article

Workers in the construction industry must endure different weather conditions, long working hours, and engage in repetitive and strenuous jobs with unrealistic deadlines. Sick leaves, caused by accidents and by work-related diseases, are common in the construction industry. Hand–arm vibration from hand-held power tools is a cause of significant ill health (disorders of the blood vessels, nerves, and joints). Self-compacting concrete (SCC) is a fluid concrete and does not need to be vibrated. Despite the health advantages of SCC, its market share in Sweden is lower than in comparable countries. The aim of this article is to describe views, opinions, and knowledge concerning the work environment and health in concrete casting and to identify barriers and facilitators of SCC usage. Semi-structured interviews were conducted with 24 interviewees from the construction industry in Sweden. The answers were analysed from a human–technology–organisation (HTO) perspective in order to identify barriers and facilitators for a broader usage of SCC. The results indicate that knowledge about SCC is low within the Swedish construction industry, including educational institutions; when SCC is chosen, it is chosen exclusively due to its technical characteristics, and not because it eliminates vibrations. Barriers to a broader usage of SCC comprise an incomplete knowledge base, clients who never choose it, recipes that are said to be too demanding, and workplace traditions. Facilitators comprise large companies investing in knowledge development about SCC and engaged persons promoting it. This study used an HTO-based model (BTOH) to identify barriers and facilitators for a broader usage of SCC, thus contributing to a deeper understanding of reasons for the low usage of SCC and ways of increasing it. Full article

The Adam algorithm is a widely used optimizer for neural network training due to efficient convergence speed. The algorithm is prone to unstable learning rate and performance degradation on some models. To solve these problems, in this paper, an improved algorithm named Linear Curvature Momentum Adam (LCMAdam) is proposed, which introduces curvature-controlled gradient and linear interpolation strategies. The curvature-controlled gradient can make the gradient update smoother, and the linear interpolation technique can adaptively adjust the size of the learning rate according to the characteristics of the curve during the training process so that it can find the exact value faster, which improves the efficiency and robustness of training. The experimental results show that the LCMAdam algorithm achieves 98.49% accuracy on the MNIST dataset, 75.20% on the CIFAR10 dataset, and 76.80% on the Stomach dataset, which is more difficult to recognize medical images. The LCMAdam optimizer achieves significant performance gains on a variety of neural network structures and tasks, proving its effectiveness and utility in the field of deep learning. Full article

Amid growing concerns about antibiotic resistance, innovative strategies are imperative in addressing bacterial infections in aquaculture. Quorum quenching (QQ), the enzymatic inhibition of quorum sensing (QS), has emerged as a promising solution. This study delves into the QQ capabilities of the probiotic strain Bacillus velezensis D-18 and its products, particularly in Vibrio anguillarum 507 communication and biofilm formation. Chromobacterium violaceum MK was used as a biomarker in this study, and the results confirmed that B. velezensis D-18 effectively inhibits QS. Further exploration into the QQ mechanism revealed the presence of lactonase activity by B. velezensis D-18 that degraded both long- and short-chain acyl homoserine lactones (AHLs). PCR analysis demonstrated the presence of a homologous lactonase-producing gene, ytnP, in the genome of B. velezensis D-18. The study evaluated the impact of B. velezensis D-18 on V. anguillarum 507 growth and biofilm formation. The probiotic not only controls the biofilm formation of V. anguillarum but also significantly restrains pathogen growth. Therefore, B. velezensis D-18 demonstrates substantial potential for preventing V. anguillarum diseases in aquaculture through its QQ capacity. The ability to disrupt bacterial communication and control biofilm formation positions B. velezensis D-18 as a promising eco-friendly alternative to conventional antibiotics in managing bacterial diseases in aquaculture. Full article

The objective of this study was to evaluate the occurrence of Clostridium perfringens in stool samples and swabs collected from wild mammals in the Amazon biome. Sixty-five faecal and swab samples were collected in situ and ex situ from 16 species and three genera of wild mammals, some of which were in good health and some of which had diarrhoea. After pre-enrichment, the samples were plated on selective agar for C. perfringens. Characteristic colonies were subjected to multiplex PCR for the detection of genes encoding the main C. perfringens toxins (alpha, beta, epsilon, and iota toxin and enterotoxin). Among the 65 samples, 40 (61.5%) were positive for the gene encoding the alpha toxin and were classified as type A, 36 of which were asymptomatic animals and four were diarrheal. No other toxinotypes were found. The findings of this study suggest that C. perfringens type A is commonly found in mammal species of the Amazon biome. This seems to be the first study to identify C. perfringens type A in species such as B. variegatus (common ground sloth), C. didactylus (two-toed sloth), P. flavus (Jupará), T. tetradactyla (anteater), S. collinsi (squirrel monkey), S. niger (black marmoset), and S. apella (Guyana capuchin) and in the genus Didelphis sp. (opossum). Full article

Cigarette butts, often discarded as litter, are considered a common form of waste, containing a variety of pollutants within this hazardous residue. This study, which was designed to assess the environmental release of certain metals from cigarette butts, investigates a variety of scenarios under varying climatic conditions. Thus, in order to assess the level of metal contamination, samples of cigarette butts were collected in urban areas from seven popular brands in China, smoked artificially, and examined through graphite furnace atomic absorption (GF-AAS). The findings indicated mean concentrations of 1.77 for Cr, 2.88 for Ni, 12.93 for Cu, 24.25 for Zn, and 1.77 µg/g for Pb in the case of newly smoked butts. The emission of each of the metals increases to 8–10% when cigarette butts remain in the environment for an extended period of time. Furthermore, rainfall can accelerate metal leaching, reaching values of 18–20% compared to the controlled scenario. The worst-case scenario releases 2129.31 kg/year of metals into the environment, while the best-case scenario sees a lower release of 844.97 kg/year. The data reflect variations in metal emissions across different scenarios. There was also a strong correlation between cigarette butts in public spaces and cities. This research highlights the need to educate smokers and increase urban maintenance efficiency to reduce this litter and the metals it leaches into the environment. Full article

Background: Understanding the dynamics of conduction velocity (CV) and voltage amplitude (VA) is crucial in cardiac electrophysiology, particularly for substrate-based catheter ablations targeting slow conduction zones and low voltage areas. This study utilizes ultra-high-density mapping to investigate the impact of heart rate and pacing location on changes in the wavefront direction, CV, and VA of healthy pig hearts. Methods: We conducted in vivo electrophysiological studies on four healthy juvenile pigs, involving various pacing locations and heart rates. High-resolution electroanatomic mapping was performed during intrinsic normal sinus rhythm (NSR) and electrical pacing. The study encompassed detailed analyses at three levels: entire heart cavities, subregions, and localized 5-mm-diameter circular areas. Linear mixed-effects models were used to analyze the influence of heart rate and pacing location on CV and VA in different regions. Results: An increase in heart rate correlated with an increase in conduction velocity and a decrease in voltage amplitude. Pacing influenced conduction velocity and voltage amplitude. Pacing also influenced conduction velocity and voltage amplitude, with varying effects observed based on the pacing location within different heart cavities. Pacing from the right atrium (RA) decreased CV in all heart cavities. The overall CV and VA changes in the whole heart cavities were not uniformly reflected in all subregions and subregional CV and VA changes were not always reflected in the overall analysis. Overall, there was a notable variability in absolute CV and VA changes attributed to pacing. Conclusions: Heart rate and pacing location influence CV and VA within healthy juvenile pig hearts. Subregion analysis suggests that specific regions of the heart cavities are more susceptible to pacing. High-resolution mapping aids in detecting regional changes, emphasizing the substantial physiological variations in CV and VA. Full article

Introduction: Docetaxel, a taxane used in the treatment of solid tumours, exerts pharmacological activity when in its unbound form. We report a sensitive assay to quantify unbound docetaxel after oral administration of docetaxel plus encequidar (oDox+E). Unbound drug quantification is important due to its direct correlation with drug-related toxicity and therapeutic efficacy. We improve on the sensitivity of current assay methods and demonstrate the utility of the assay on a novel formulation of oral docetaxel. Methods: Ultrafiltration followed by high-performance liquid chromatography and tandem mass spectrometry (HPLC-MS/MS) was utilized. Long-term stability, precision, accuracy, and recovery experiments were conducted to validate the assay. Additionally, patient samples from a Phase I dose-escalation pharmacokinetic study were analyzed using the developed assay. Results: The assay method exhibited long-term stability with an observed change between 0.8 and 6.9% after 131 days of storage at −60 °C. Precision and accuracy quality controls met the FDA acceptance criteria. An average recovery of 88% was obtained. Patient sample analysis demonstrated successful implementation of the assay. Conclusion: A validated sensitive assay was developed with an LLOQ of 0.084 ng/mL using 485 µL of human plasma. The sensitivity of the assay allowed quantification of unbound docetaxel concentrations in an early-phase oDox+E clinical study to compare it against IV docetaxel using pharmacokinetic modelling. Successful development of oDox+E represents an opportunity to replace the current IV docetaxel regimen with an oral regimen with lower cost, decreased side effects, and improve patient quality of life and experience. Full article