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Lessons learnedThe combination of carotuximab with axitinib did not provide a benefit over axitinib monotherapy in patients with metastatic clear cell renal cell carcinoma who had previously progressed on one or more vascular endothelial growth factor (VEGF)-targeted therapies. Exploratory evaluation of pretreatment circulating biomarkers suggested the combination might benefit patients who have low baseline VEGF levels.BackgroundEndoglin is an angiogenic receptor expressed on proliferating tumor vessels and renal cell carcinoma (RCC) stem cells that is implicated as a mechanism of resistance to vascular endothelial growth factor receptor (VEGFR) inhibitors. This study evaluated an antiendoglin monoclonal antibody (carotuximab, TRC105) combined with axitinib in patients with advanced or metastatic clear cell renal cell carcinoma (mccRCC) who had progressed following one or more prior VEGF inhibitors.MethodsTRAXAR was a multicenter, international randomized 1:1 (stratified by ECOG, 0 vs. 1), phase II study of carotuximab combined with axitinib versus axitinib alone in mccRCC patients who had progressed following one or more prior VEGF inhibitors. The primary endpoint was progression-free survival (PFS) assessed by independent central review (ICR) per RECIST 1.1 RESULTS: A total of 150 patients were randomized. The combination therapy resulted in shorter median PFS by RECIST 1.1 than axitinib monotherapy (6.7 vs. 11.4 months). The combination was tolerated similarly to axitinib monotherapy, and there were no treatment related deaths. Exploratory evaluation of pretreatment circulating biomarkers suggested the combination might benefit patients who have low baseline VEGF levels.ConclusionThe combination of carotuximab with axitinib did not demonstrate additional efficacy over single agent axitinib in patients with mccRCC who progressed following one or more prior VEGF inhibitor treatment.

Abstract Background Essential oils are becoming increasingly popular in medicinal applications because of their antimicrobial effect. Thymus vulgaris L. (Lamiaceae) is a well-known and widely cultivated medicinal plant, which is used as a remedy for cold, cough and gastrointestinal symptoms. Essential oil content of thyme is responsible for its antimicrobial activity, however, it has been reported that the chemical composition of essential oils influences its biological activity. In order to explore flowering phenophases influence on the chemical composition of thyme essential oil and its antibacterial and anti-biofilm activity, plant materials were collected at the beginning of flowering, in full bloom and at the end of flowering periods in 2019. Methods Essential oils from fresh and dried plant materials were distilled and analyzed with gas chromatography-mass spectrometry (GC-MS) and gas chromatography-flame ionization detection (GC-FID). The antibacterial activity was performed by broth microdilution and thin layer chromatography-direct bioautography (TLC-DB) assays and the anti-biofilm effect by crystal violet assay, respectively. Scanning electron microscopy was applied to illustrate the cellular changes of bacterial cells after essential oil treatment. Results Thymol (52.33–62.46%) was the main component in the thyme essential oils. Thyme oil distilled from fresh plant material and collected at the beginning of flowering period exerted the highest antibacterial and anti-biofilm activity against Haemophilus influenzae, H. parainfluenzae and Pseudomonas aeruginosa. Conclusion The different flowering periods of Thymus vulgaris influence the antibacterial and anti-biofilm activity of its essential oils, therefore, the collection time has to be taken into consideration and not only the full bloom, but the beginning of flowering period may provide biological active thyme essential oil.

Abstract Background Parallel to the growth of the oral healthcare market, there is a constantly increasing demand for natural products as well. Many customers prefer products that contain fewer toxic agents, therefore providing an environmentally friendly solution with the benefit of smaller risk to the user. Medieval and early modern medicinal knowledge might be useful when looking for natural, herbal-based components to develop modern products. Along with these considerations we created, tested, and compared an entirely natural mouthwash, named Herba Dei. Methods The manufacturing procedure was standardized, and the created tincture was evaluated by GC/MS analysis for active compounds, experimentally tested in cell-based cytotoxicity, salivary protein integrity, cell-free antioxidant activity, anti-bacterial and anti-viral assays, and compared with three market-leading mouthwashes. Results Our tincture did not show significant damage in the cytotoxicity assays to keratinocyte and Vero E6 cells and did not disrupt the low molecular weight salivary proteins. Its radical scavenging capacity surpassed that of two tested, partly natural, and synthetic mouthwashes, while its antibacterial activity was comparable to the tested products, or higher in the bacterial aerobic respiratory assay. The active compounds responsible for the effects include naturally occurring phenylpropanoids, terpenes, and terpenoids. Our mouthwash proved to be effective in vitro in lowering the copy number of SARS-CoV-2 in circumstances mimicking the salivary environment. Conclusions The developed product might be a useful tool to impede the transmission and spread of SARS-CoV-2 in interpersonal contact and aerosol-generating conditions. Our mouthwash can help reduce the oral bacterial flora and has an antioxidant activity that facilitates wound healing and prevents adverse effects of smoke in the oral cavity.

Abstract Transorbital sonography (TOS) could be a swift and convenient method to detect the atrophy of the optic nerve, possibly providing a marker that might reflect other quantitative structural markers of multiple sclerosis (MS). Here we evaluate the utility of TOS as a complementary tool for assessing optic nerve atrophy, and investigate how TOS-derived measures correspond to volumetric brain markers in MS. We recruited 25 healthy controls (HC) and 45 patients with relapsing–remitting MS and performed B-mode ultrasonographic examination of the optic nerve. Patients additionally underwent MRI scans to obtain T1-weighted, FLAIR and STIR images. Optic nerve diameters (OND) were compared between HC, MS patients with and without history of optic neuritis (non-ON) using a mixed-effects ANOVA model. The relationship between within-subject-average OND and global and regional brain volumetric measures was investigated using FSL SIENAX, voxel-based morphometry and FSL FIRST. OND was significantly different between HC-MS (HC = 3.2 ± 0.4 mm, MS = 3 ± 0.4 mm; p

The irresponsible overuse of antibiotics has increased the occurrence of resistant bacterial strains, which represents one of the biggest patient safety risks today. Due to antibiotic resistance and biofilm formation in bacteria, it is becoming increasingly difficult to suppress the bacterial strains responsible for various chronic infections. Honey was proven to inhibit bacterial growth and biofilm development, offering an alternative solution in the treatment of resistant infections and chronic wounds. Our studies included chestnut honey, valued for its high antibacterial activity, and the bacteria Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus, and S. epidermidis, known to form multi-species biofilm communities. Minimum inhibitory concentrations (MIC) of chestnut honey were determined for each bacterial strain. Afterwards, the mixed bacterial biofilms were treated with chestnut honey at different stages of maturity (incubation times: 2, 4, 6, 12, 24 h). The extent of biofilm inhibition was measured with a crystal violet assay and demonstrated by scanning electron microscopy (SEM). As the incubation time increased and the biofilm became more mature, inhibition rates decreased gradually. The most sensitive biofilm was the combination MRSA-S. epidermidis, with a 93.5% inhibition rate after 2 h of incubation. Our results revealed that chestnut honey is suitable for suppressing the initial and moderately mature stages of mixed biofilms.

Organ-on-a-chip technologies show exponential growth driven by the need to reduce the number of experimental animals and develop physiologically relevant human models for testing drugs. In vitro, microfluidic devices should be carefully designed and fabricated to provide reliable tools for modeling physiological or pathological conditions and assessing, for example, drug delivery through biological barriers. The aim of the current study was to optimize the utilization of three existing skin-on-a-chip microfluidic diffusion chambers with various designs. For this, different perfusion flow rates were compared using cellulose acetate membrane, polyester membrane, excised rat skin, and acellular alginate scaffold in the chips. These diffusion platforms were integrated into a single-channel microfluidic diffusion chamber, a multi-channel chamber, and the LiveBox2 system. The experimental results revealed that the 40 µL/min flow rate resulted in the highest diffusion of the hydrophilic model formulation (2% caffeine cream) in each system. The single-channel setup was used for further analysis by computational fluid dynamics simulation. The visualization of shear stress and fluid velocity within the microchannel and the presentation of caffeine progression with the perfusion fluid were consistent with the measured data. These findings contribute to the development and effective application of microfluidic systems for penetration testing.

The Indo-Australian Archipelago (IAA) today exhibits the highest marine biodiversity, which has been evolving since the early Miocene. The existence of this high palaeobiodiversity is attested to by the presence of many fossil invertebrates; however, the region’s fossil fish record is sparse and understudied, which is also the case for cartilaginous fishes. Elasmobranch fossils are dominantly represented by shark and ray teeth in the geological record and can give a quick overview of the composition of the fauna. The first IAA elasmo fossils, shark teeth were described from Java (Indonesia) at the end of the 19th century, and until today, most of the publications are known from this island. In the early and middle of the 20th century, remarkable fossils were also reported from the islands of Madura (NE Java) and Sulawesi, some with detailed taxonomical descriptions. In addition, only sporadic reports on fossil occurrences exist elsewhere from the IAA, but these lack any detailed taxonomic accounts. In 2019 our research group reported a late Miocene elasmobranch fauna from Brunei (Borneo), which is now the most diverse known shallow water fossil assemblage from the entire IAA. This fauna was described from a single fossiliferous outcrop, called Ambug Hill. However, several new localities have been discovered and studied over the years, as a result the number of fossils increased, and their age range extended. Here we provide an overview of these new sites and their elasmobranch fossils, and describe remains from ten taxa among, of which eight are new to the IAA fossil record (Chiloscyllium sp., cf. Hemitriakis sp., Paragaleus sp., Carcharhinus borneensis, C. limbatus, Lamiopsis sp., Scoliodon sp., Rhinobatos sp.). The overall north Bornean elasmo assemblage is then compared with other IAA occurrences. An extended fauna list is given based on literature review and preliminary investigation of the Naturalis Biodiversity Centre collection in Leiden (The Netherlands) where most of the fossil fishes of the early explorations are stored. These assemblages are also briefly summarized, and attention is drawn to some of the unique and thus far unreported taxa (e.g., Dalatias licha).

The number of battery systems is also growing significantly along with the rise in electric and hybrid car sales. Different vehicles use different types and numbers of batteries. Furthermore, the layout and operation of the control and protection electronics units may also differ. The research aims to develop an approach that can autonomously detect and localize the weakest cells. The method was validated by testing the battery systems of three different VW e-Golf electric vehicles. A wide-range discharge test was performed to examine the condition assessment and select the appropriate state of charge (SoC) for all three vehicles. On the one hand, the analysis investigated the cell voltage deviations from the average; the tests cover deviations of 0 mV, 12 mV, 60 mV, 120 mV, and 240 mV. On the other hand, the mean value calculation was used to filter out possible erroneous values. Another important aspect was examining the relationship between the state of charges (SoC) and the deviations. Therefore, the 10% step changes were tested to see which SoC level exhibited more significant voltage deviations. Based on the results, it was observed that there are differences between the cases, and the critical range is not necessarily at the lowest SoC level. Furthermore, the load rate (current) and time of its occurrence play an important role in the search for a faulty cell. An additional advantage of this approach is that the process currently being tested on the VW e-Golf can be relatively simply transferred to other types of vehicles. It can also be a very useful addition for autonomous vehicles, as it can self-test the cells in the system at low power consumption.

Background: Exercise-induced modifications in ECG parameters among individuals with an early repolarization pattern (ERP) have not been evaluated in detail. We aimed to assess this phenomenon, with potential associations with arrhythmogenesis. Methods: Twenty-three young, healthy males with ERP (ERP+) participated in this study, alongside a control group, which consisted of nineteen healthy males without ERP (ERP−). ECGs at baseline, at peak exercise (Bruce protocol), and during the recovery phase were analyzed and compared between the two groups. Results: The treadmill test demonstrated strong cardiovascular fitness, with similar chronotropic and pressor responses in both groups. In the baseline ECGs, the QRS complex and the QT interval were shorter in the ERP+ group. During exercise, the P-wave duration was significantly longer and the QRS was narrower in the ERP+ group. In the recovery phase, there was a longer P wave and a narrower QRS in the ERP+ group. During the treadmill test, the J wave disappeared or did not meet the criteria required for ERP diagnosis. Conclusions: The slowed intra-atrial conduction found during exercise could be predictive of atrial arrhythmogenesis in the setting of ERP. The disappearing of J waves during exercise, due to increased sympathetic activity, has potential clinical significance.

The present study investigated whether different grafting combinations (hypobiont-epibiont) of Vitis spp. influence root infection with phylloxera and thus vine biomass on potted 2-year-old plants. The study was conducted simultaneously at two locations in Slovenia (VEM) and Hungary (GF). The dormant canes of ‘Johanniter’ (JOH), ‘Riesling’ (RR) and Vitis berlandieri × Vitis riparia ‘Teleki 5C’ (5C) were hetero-grafted (each with each) and autografted (each with itself), so that nine plant combinations were used for the trial. The roots of the experimental plants at different ages (1–2 years) were infested with two phylloxera populations originating from two locations (VEM, GF). Plant growth was quantified 120 days after inoculation by measuring root and shoot biomass, while the extent of phylloxera infestation was assessed by the number of feeding sites (nodosities, tuberosities) and the number of larval stages of phylloxera. In most cases, the genotype of the hypobiont influenced the degree of phylloxera infestation on all roots of the two-year-old root system. At both locations, the highest number of nodosities and the highest increase in phylloxera population was observed on the autografted Teleki 5C (5C/5C). The phylloxera biotype derived from Vitis vinifera roots (GF) induced tuberosities, especially on roots of combinations where JOH and RR were used as hypobionts. No correlation was found between biomass and phylloxera infestation. The hypobiont genotype had no effect on cane biomass at the end of the growth cycle at either experimental site.

Additive manufacturing of soft magnetic materials is a promising technology for creating topologically optimized electrical machines. High-performance electrical machines can be made from high-silicon-content FeSi alloys. Fe-6.5wt%Si material has exceptional magnetic properties; however, manufacturing this steel with the classical cold rolling methodology is not possible due to the brittleness of this material. Laser powder bed fusion technology (L-PBF) offers a solution to this problem. Finding the optimal printing parameters is a challenging task. Nevertheless, it is crucial to resolve the brittleness of the created materials so they can be used in commercial applications. The temperature dependence of magnetic hysteresis properties of Fe-6.5wt%Si materials is presented in this paper. The magnetic hysteresis properties were examined from 20 °C to 120 °C. The hysteresis measurements were made by a precision current generator–based hysteresis measurement tool, which uses fast Fourier transformation–based filtering techniques to increase the accuracy of the measurements. The details of the applied scalar hysteresis sensor and the measurement uncertainties were discussed first in the paper; then, three characteristic points of the static hysteresis curve of the ten L-PBF-manufactured identical toroidal cores were investigated and compared at different temperatures. These measurements show that, despite the volumetric ratio of the porosities being below 0.5%, the mean crack length in the samples is not significant for the examined samples. These small defects can cause a significant 5% decrement in some characteristic values of the examined hysteresis curve.

The contributions in this issue, selected from the ones presented at the DFGN.R 2023, a two-day event hosted at the METU Design Factory in Ankara, Turkey, and organized by the Design Factory Global Network, represent a broad cross-section encompassing various fields such as phenomenology, social theory, psychology, philosophy, artificial intelligence, and art, resonating with the principles of 21st Century learning and the United Nations’ Sustainable Development Goals, supporting the changing expectations of academics in producing alternative research outcomes in collaborative, practice-based research. These contributions offer valuable insights into how designers and innovators navigate the ever-expanding landscape of challenges and opportunities in multiple fields, elevating pedagogy and enhancing the art and science of learning, thinking, and doing.

This paper examines the sustainability of railways. A comprehensive international literature review was conducted on railway vehicles, traction, and railway permanent way. The main goal was to find the factors and parameters that affect railway sustainability the most. CO2 emissions from transportation, mining, raw material production, manufacturing, use, operation and maintenance, and demolition and restoration must be significantly reduced. Naturally, the attention will be on the considerable energy and financial savings. This article's main topics are sustainability, affordable and clean energy, industry, innovation, infrastructure, sustainable cities and communities, responsible consumption and production, climate action, and life on land. Building materials come from quarries and gravel pits, but availability is decreasing. Future pavement construction and maintenance require recycling demolition and industrial waste. Engineers must choose materials and technology that extend track lifetimes to ensure reliability, availability, maintainability, safety, sustainability, and economy in permanent railroad ways. Life-cycle costs can be reduced, e.g., by Building Information Modeling. Electric machinery is preferred for construction equipment, materials, and management. Sustainability, like grassed tracks and recyclable plastics, has improved urban life. Sheet metal forming using recycled materials and sustainability shows how important environmental protection is in car and train design. Electric road and rail propulsion are driven by environmental concerns, while supercapacitors and batteries are studied. In conclusion, by preferring rail for freight and passenger transport, both for private and public transport, energy savings and CO2 emissions can be up to 2-10 times higher than for other modes of transport.

ABSTRACT The importance of finite element analysis (FEA) is growing in orthopedic research, especially in implant design. However, Young's modulus (E) values, one of the most fundamental parameters, can range across a wide scale. Therefore, our study aimed to identify factors influencing E values in human bone specimens. We report our systematic review and meta‐analysis based on the recommendation of the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) 2020 guideline. We conducted the analysis on November 21, 2021. We included studies investigating healthy human bone specimens and reported on E values regarding demographic data, specimen characteristics, and measurement specifics. In addition, we included study types reporting individual specimen measurements. From the acquired data, we created a cohort in which we performed an exploratory data analysis that included the explanatory variables selected by random forest and regression trees methods, and the comparison of groups using independent samples Welch's t test. A total of 756 entries were included from 48 articles. Eleven different bones of the human body were included in these articles. The range of E values is between 0.008 and 33.7 GPa. The E values were most heavily influenced by the cortical or cancellous type of bone tested. Measuring method (compression, tension, bending, and nanoindentation), the anatomical region within a bone, the position of the bone within the skeleton, and the bone specimen size had a decreasing impact on the E values. Bone anisotropy, specimen condition, patient age, and sex were selected as important variables considering the value of E. On the basis of our results, E values of a bone change with bone characteristics, measurement techniques, and demographic variables. Therefore, the evaluation of FEA should be performed after the standardization of in vitro measurement protocol. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

The transition to reactor-relevant materials for the plasma facing components (PFCs) is an important and necessary step to provide a proof of principle that the stellarator concept can meet the requirements of a future fusion reactor by demonstrating high performance steady-state operation. As a first step to gain experience with tungsten as plasma-facing material in the Wendelstein 7-X (W7-X) stellarator, graphite tiles coated with an approximately 10 µm MedC tungsten layer (NILPRP Bucharest) were installed to complete the ECRH beam dump area in two of the five plasma vessel modules over an area of approximately one square meter each. In addition, tungsten baffle tiles are installed (40 tiles in total) with either bulk tungsten as part of NBI shine-through target or with a tungsten heavy alloy (W95-Ni3.5-Cu1.5) to replace the graphite tiles that were previously thermally overloaded. Based on an advanced diffusive field line tracing method and EMC3-Eirene simulations, the overloaded baffle tiles were redesigned by making the tiles thinner (i.e. moving the plasma-facing surface (PFS) away from the hot plasma region) and by reducing the local angle of incidence through toroidal displacement of the watershed. Significant erosion of the tungsten tiles can only be expected if sputtering by impurity ions such as carbon or oxygen ions contributes. However, the resulting central concentration of tungsten and the corresponding radiation losses are expected to be marginal. The expected deposition of carbon on the tungsten surfaces in the baffle regions mitigates further the possible tungsten enrichment in the core plasma. In OP2.1, no adverse effects of the installed tungsten PFCs on the plasma performance were observed during normal plasma operation. With the design changes made in the baffle area, the predicted heat load reductions could be experimentally confirmed.