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The speciation of Salmonella occurred by acquisition of genomic islands from other bacterial species and continued to diverge into subspecies and serovars with diferent range of host. S. enterica serovar Typhimurium (STM) is a generalist pathogen infecting hosts that include birds, mice, and humans, whilst S. enterica serovar Typhi (STY) is a restricted-host pathogen, infecting only humans. Despite their ranges of hosts, STM and STY possess 97–98% identity. Gain of genes by horizontal transference and loss of genes by mutations, are believed essential for differentiation of Salmonella. Salmonella pathogenicity island 3 (SPI-3) is an example combining these two processes. SPI-3 encodes misL and marT, among other genes. In STM, misL is required for gut colonization. Furthermore, protein MarT, positively regulates expression of misL by binding to misL-promoter. On the other hand, in SPI-3 of STY, marT and misL are pseudogenes. Interestingly, the gene t3766 (gene involved in resistance to H2O2) is present only in STY and is negatively regulated when marTSTM is heterologously expressed in STY. Based on the view that MarT might regulate genes implicated in virulence, this work searched for new genes regulated by MarT. In silico searches for possible MarT target genes were performed, and 4 genes were selected for further analysis as they contained at least 2 copies of the consensus MarT-binding sequence in their promoters. Mutating marT in STM or heterologously expressing marTSTM in STY confirmed that MarT negatively regulates ORF STY1408 or STM14_2003, its homologue in STM. STY1408 encodes for a putative protein with homology to methyl accepting chemotaxis proteins, which participate in chemotaxis and motility. Therefore, STY1408 was named mrmI (MarT-regulated motility gene I). Motility assays confirmed that the product of mrmI modulates motility. In addition, in vitro infection of cells with STM and STY mutants in mrmI reduces association with cells at 1, 3 and 24 h post-infection. Oral infection of mice showed that a mrmI null mutant was defective in producing systemic disease. Therefore, we conclude that MarT regulated mrmI, is involved in virulence of Salmonella. While pseudogenization of marT might modulate the fitness of narrow host range STY.

We characterized the on-board megavoltage imager (MVI) of a magnetic resonance-guided radiotherapy machine for beam output checks. Linearity and repeatability of its dose response were investigated. Alignment relative to the beam under clinical circumstances was evaluated for a year using daily measurements. Linearity and short-term repeatability were excellent. Long-term repeatability drifted 0.8 % per year, which can be overcome by monthly cross calibrations. Long-term alignment was stable. Thus, the MVI has suitable characteristics for beam output checks.

Background and purpose: This work reports on the results of a survey performed on the use of computed tomography (CT) imaging for motion management, surface guidance devices, and their quality assurance (QA). Additionally, it details the collected user insights regarding professional needs in CT for radiotherapy. The purpose of the survey is to understand current practice, professional needs and future directions in the field of fan-beam CT in radiation therapy (RT). Materials and methods: An online institutional survey was conducted between 1-Sep-2022 and 10-Oct-2022 among medical physics experts at Belgian and Dutch radiotherapy institutions, to assess the current status, challenges, and future directions of motion management and surface image-guided radiotherapy. The survey consisted of a maximum of 143 questions, with the exact number depending on participants’ responses. Results: The response rate was 66 % (31/47). Respiratory management was reported as standard practice in all but one institution; surface imaging during CT-simulation was reported in ten institutions. QA procedures are applied with varying frequencies and methodologies, primarily with commercial anatomy-like phantoms. Surface guidance users report employing commercial static and dynamic phantoms. Four main subjects are considered clinically important by the respondents: surface guidance, CT protocol optimisation, implementing gated imaging (4DCT, breath-hold), and a tattoo-less workflow. Conclusions: The survey highlights the scattered pattern of QA procedures for respiratory motion management, indicating the need for well-defined, unambiguous, and practicable guidelines. Surface guidance is considered one of the most important techniques that should be implemented in the clinical radiotherapy simulation workflow.

Background and purpose: To obtain an understanding of current practice, professional needs and future directions in the field of fan-beam CT in RT, a survey was conducted. This work presents the collected information regarding the use of CT imaging for dose calculation and structure delineation. Materials and methods: An online institutional survey was distributed to medical physics experts employed at Belgian and Dutch radiotherapy institutions to assess the status, challenges, and future directions of QA practices for fan-beam CT. A maximum of 143 questions covered topics such as CT scanner availability, CT scanner specifications, QA protocols, treatment simulation workflow, and radiotherapy dose calculation. Answer forms were collected between 1-Sep-2022 and 10-Oct-2022. Results: A 66 % response rate was achieved, yielding data on a total of 58 CT scanners. For MV photon therapy, all single-energy CT scans are reconstructed in Hounsfield Units for delineation or dose calculation, and a direct- or stoichiometric method was used to convert CT numbers for dose calculation. Limited use of dual-energy CT is reported for photon (N = 3) and proton dose calculations (N = 1). For brachytherapy, most institutions adopt water-based dose calculation, while approximately 26 % of the institutions take tissue heterogeneity into account. Commissioning and regular QA include eleven tasks, which are performed by two or more professions (29/31) with varying frequencies. Conclusions: Dual usage of a planning CT limits protocol optimization for both tissue characterization and delineation. DECT has been implemented only gradually. A variation of QA testing frequencies and tests are reported.

The speciation of Salmonella occurred by acquisition of genomic islands from other bacterial species and continued to diverge into subspecies and serovars with diferent range of host. S. enterica serovar Typhimurium (STM) is a generalist pathogen infecting hosts that include birds, mice, and humans, whilst S. enterica serovar Typhi (STY) is a restricted-host pathogen, infecting only humans. Despite their ranges of hosts, STM and STY possess 97-98% identity. Gain of genes by horizontal transference and loss of genes by mutations, are believed essential for differentiation of Salmonella. Salmonella pathogenicity island 3 (SPI-3) is an example combining these two processes. SPI-3 encodes misL and marT, among other genes. In STM, misL is required for gut colonization. Furthermore, protein MarT, positively regulates expression of misL by binding to misL-promoter. On the other hand, in SPI-3 of STY, marT and misL are pseudogenes. Interestingly, the gene t3766 (gene involved in resistance to H2O2) is present only in STY and is negatively regulated when marTSTM is heterologously expressed in STY. Based on the view that MarT might regulate genes implicated in virulence, this work searched for new genes regulated by MarT. In silico searches for possible MarT target genes were performed, and 4 genes were selected for further analysis as they contained at least 2 copies of the consensus MarT-binding sequence in their promoters. Mutating marT in STM or heterologously expressing marTSTM in STY confirmed that MarT negatively regulates ORF STY1408 or STM14_2003, its homologue in STM. STY1408 encodes for a putative protein with homology to methyl accepting chemotaxis proteins, which participate in chemotaxis and motility. Therefore, STY1408 was named mrmI (MarT-regulated motility gene I). Motility assays confirmed that the product of mrmI modulates motility. In addition, in vitro infection of cells with STM and STY mutants in mrmI reduces association with cells at 1, 3 and 24 h post-infection. Oral infection of mice showed that a mrmI null mutant was defective in producing systemic disease. Therefore, we conclude that MarT regulated mrmI, is involved in virulence of Salmonella. While pseudogenization of marT might modulate the fitness of narrow host range STY. [ABSTRACT FROM AUTHOR]

Navigation is an essential capability for autonomous robots. In particular, visual navigation has been a major research topic in robotics because cameras are lightweight, power-efficient sensors that provide rich information on the environment. However, the main challenge of visual navigation is that it requires substantial computational power and memory for visual processing and storage of the results. As of yet, this has precluded its use on small, extremely resource-constrained robots such as lightweight drones. Inspired by the parsimony of natural intelligence, we propose an insect-inspired approach toward visual navigation that is specifically aimed at extremely resource-restricted robots. It is a route-following approach in which a robot's outbound trajectory is stored as a collection of highly compressed panoramic images together with their spatial relationships as measured with odometry. During the inbound journey, the robot uses a combination of odometry and visual homing to return to the stored locations, with visual homing preventing the buildup of odometric drift. A main advancement of the proposed strategy is that the number of stored compressed images is minimized by spacing them apart as far as the accuracy of odometry allows. To demonstrate the suitability for small systems, we implemented the strategy on a tiny 56-gram drone. The drone could successfully follow routes up to 100 meters with a trajectory representation that consumed less than 20 bytes per meter. The presented method forms a substantial step toward the autonomous visual navigation of tiny robots, facilitating their more widespread application. Editor's summary: For navigation, robots often rely either on external infrastructure or on mapping-based navigation algorithms that are generally associated with high computational demands. van Dijk et al. have now developed an insect-inspired approach for visual navigation of resource-constrained miniature drones by exploiting both visual homing and odometry. The framework was tested on a 56-g drone, which was shown to be capable of following routes in indoor environments over long distances with minimal memory requirements. This approach could substantially improve the autonomous navigation of aerial robots with constraints in computational power, energy demands, and weight. —Amos Matsiko [ABSTRACT FROM AUTHOR]

This Review discusses the main results obtained in training end-to-end neural architectures for guidance and control of interplanetary transfers, planetary landings, and close-proximity operations, highlighting the successful learning of optimality principles by the underlying neural models. Spacecraft and drones aimed at exploring our solar system are designed to operate in conditions where the smart use of onboard resources is vital to the success or failure of the mission. Sensorimotor actions are thus often derived from high-level, quantifiable, optimality principles assigned to each task, using consolidated tools in optimal control theory. The planned actions are derived on the ground and transferred on board, where controllers have the task of tracking the uploaded guidance profile. Here, we review recent trends based on the use of end-to-end networks, called guidance and control networks (G&CNets), which allow spacecraft to depart from such an architecture and to embrace the onboard computation of optimal actions. In this way, the sensor information is transformed in real time into optimal plans, thus increasing mission autonomy and robustness. We then analyze drone racing as an ideal gym environment to test these architectures on real robotic platforms and thus increase confidence in their use in future space exploration missions. Drone racing not only shares with spacecraft missions both limited onboard computational capabilities and similar control structures induced from the optimality principle sought but also entails different levels of uncertainties and unmodeled effects and a very different dynamical timescale. [ABSTRACT FROM AUTHOR]

Objective. The Elekta unity MR-linac delivers step-and-shoot intensity modulated radiotherapy plans using a multileaf collimator (MLC) based on the Agility MLC used on conventional Elekta linacs. Currently, details of the physical Unity MLC and the computational model within its treatment planning system (TPS) Monaco are lacking in published literature. Recently, a novel approach to characterize the physical properties of MLCs was introduced using dynamic synchronous and asynchronous sweeping gap (aSG) tests. Our objective was to develop a step-and-shoot version of the dynamic aSG test to characterize the Unity MLC and the computational MLC models in the Monaco and RayStation TPSs. Approach. Dynamic aSG were discretized into a step-and-shoot aSG by investigating the number of segments/sweep and the minimal number of monitor units (MU) per segment. The step-and-shoot aSG tests were compared to the dynamic aSG tests on a conventional linac at a source-to-detector distance of 143.5 cm, mimicking the Unity configuration. the step-and-shoot aSG tests were used to characterize the Unity MLC through measurements and dose calculations in both TPSs. Main results. The step-and-shoot aSGs tests with 100 segments and 5 MU/segment gave results very similar to the dynamic aSG experiments. The effective tongue-and-groove width of the Unity gradually increased up to 1.4 cm from the leaf tip end. The MLC models in RayStation and Monaco agreed with experimental data within 2.0% and 10%, respectively. The largest discrepancies in Monaco were found for aSG tests with >10 mm leaf interdigitation, which are non-typical for clinical plans. Significance. The step-and-shoot aSG tests accurately characterize the MLC in step-and-shoot delivery mode. The MLC model in RayStation 2023B accurately describes the tongue-and-groove and leaf tip effects whereas Monaco overestimates the tongue-and-groove shadowing further away from the leaf tip end. [ABSTRACT FROM AUTHOR]

Viral mimicry of host cell structures has been postulated to curtail the B cell receptor (BCR) repertoire against persisting viruses through tolerance mechanisms. This concept awaits, however, experimental testing in a setting of natural virus--host relationship. We engineered mouse models expressing a monoclonal BCR specific for the envelope glycoprotein of lymphocytic choriomeningitis virus (LCMV), a naturally persisting mouse pathogen. When the heavy chain of the LCMV-neutralizing antibody KL25 was paired with its unmutated ancestor light chain, most B cells underwent receptor editing, a behavior reminiscent of autoreactive clones. In contrast, monoclonal B cells expressing the same heavy chain in conjunction with the hypermutated KL25 light chain did not undergo receptor editing but exhibited low levels of surface IgM, suggesting that light chain hypermutation had lessened KL25 autoreactivity. Upon viral challenge, these IgMlow cells were not anergic but up-regulated IgM, participated in germinal center reactions, produced antiviral antibodies, and underwent immunoglobulin class switch as well as further affinity maturation. These studies on a persisting virus in its natural host species suggest that central tolerance mechanisms prune the protective antiviral B cell repertoire. [ABSTRACT FROM AUTHOR]

Abstract Community-acquired pneumonia (CAP) is an acute infection of the lung parenchyma acquired outside the hospital or other healthcare settings, typically affecting previously healthy individuals. This intersociety consensus aims to provide evidence-based recommendations for the antibiotic treatment of mild to moderate CAP in previously healthy children in Italy. A systematic review was conducted to identify the most recent and relevant evidence. Embase, Scopus, PubMed, and Cochrane databases were systematically screened, with a date restriction from 2012 to April 2024, but without language limitations. The review included studies conducted in high-income countries on antibiotic therapy in children over 3 months of age diagnosed with mild-moderate CAP. The certainty of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methods. The final recommendations were obtained through a Delphi consensus of an expert panel. Amoxicillin is the first-line treatment if the child is at least immunized against Haemophilus influenzae type b (low/very low quality of evidence, strong recommendations), while amoxicillin-clavulanate or second- or third-generation cephalosporins should be prescribed for those unimmunized or with incomplete immunization coverage for both H. influenzae type b and Streptococcus pneumoniae (low/very low quality of evidence, strong recommendations). Macrolides should be considered in addition to amoxicillin in children over 5 years old, if symptoms persist and the clinical condition remains good after 48 h of therapy (low/very low quality of evidence, strong recommendations). The dosage of amoxicillin is 90 mg/kg/day divided in three doses, although two doses could be considered to improve compliance (moderate quality of evidence, weak recommendations). A five-day duration of therapy is recommended, with clinical monitoring and re-assessment approximately 72 h after the start of antibiotic treatment to evaluate symptom resolution (moderate quality of evidence, strong recommendations). To improve the management of CAP in pediatric patients, we have developed this consensus based on a thorough review of the best available evidence and extensive discussions with an expert panel. However, further efforts are needed. Future research should focus on enhancing diagnostic accuracy, optimizing antibiotic utilization, comparing the efficacy of different antibiotic regimens, and determining the optimal dosage and duration of treatment in different setting.

Abstract The share of social media attention to political candidates was shown to be a good predictor of election outcomes in several studies. This attention to individual candidates fluctuates due to incoming daily news and sometimes reflects long-term trends. By analyzing Twitter data in the 2013 and 2022 election campaign we observe that, on short timescales, the dynamics can be effectively characterized by a mean-reverting diffusion process on a logarithmic scale. This implies that the response to news and the exchange of opinions on Twitter lead to attention fluctuations spanning orders of magnitudes. However, these fluctuations remain centered around certain average levels of popularity, which change slowly in contrast to the rapid daily and hourly variations driven by Twitter trends and news. In particular, on our 2013 data we are able to estimate the dominant timescale of fluctuations at around three hours. Finally, by considering the extreme data points in the tail of the attention variation distribution, we could identify critical events in the electoral campaign period and extract useful information from the flow of data.

Abstract Peripheral neurotoxicity is a dose-limiting adverse reaction of primary frontline chemotherapeutic agents, including vincristine. Neuropathy can be so disabling that patients drop out of potentially curative therapy, negatively impacting cancer prognosis. The hallmark of vincristine neurotoxicity is axonopathy, yet its underpinning mechanisms remain uncertain. We developed a comprehensive drug discovery platform to identify neuroprotective agents against vincristine-induced neurotoxicity. Among the hits identified, SIN-1—an active metabolite of molsidomine—prevents vincristine-induced axonopathy in both motor and sensory neurons without compromising vincristine anticancer efficacy. Mechanistically, we found that SIN-1’s neuroprotective effect is mediated by activating soluble guanylyl cyclase. We modeled vincristine-induced peripheral neurotoxicity in rats to determine molsidomine therapeutic potential in vivo. Vincristine administration induced severe nerve damage and mechanical hypersensitivity that were attenuated by concomitant treatment with molsidomine. This study provides evidence of the neuroprotective properties of molsidomine and warrants further investigations of this drug as a therapy for vincristine-induced peripheral neurotoxicity.

Considerable evidence links the “Big Five” personality traits (neuroticism, extroversion, conscientiousness, agreeableness, and openness) with depression. However, potential mediating and moderating factors are less well understood. We utilized data from a cross-sectional survey of 3065 German-speaking adults from the D-A-CH region to estimate multivariable-adjusted odds ratios and 95% confidence intervalsbetween personality traits and lifetime prevalence of depression (overall and stratified by sex and age). We further explored proportions mediated by psychosocial factors optimism, empathy, perspective-taking, work–life balance, and interpersonal trust. High levels of neuroticism were associated with more than two-fold higher odds of depression, whereas higher levels of conscientiousness were associated with approximately 30% lower odds of depression. The association with neuroticism persisted in all investigated subgroups; apparently, stronger associations for females and participants aged ≥60 years did not correspond to statistically significant interactions. Overall and across all strata, the association of neuroticism with depression appeared to be mediated in part by the considered psychosocial factors; optimism explained the largest proportion of the association. Our results provide empirical evidence for the dynamic predisposition model. Further investigations of these relationships are warranted in longitudinal data with more precise outcome assessments.

The Arctic region is undergoing significant changes in maritime accessibility. This study investigates observed ship trajectories from 2013 to 2020 to demonstrate the recent trends of Arctic traffic. A notable surge in maritime activities has been observed, particularly during summer months, driven by economic interests and the increasing popularity of existing routes. Unique patterns in the northern Barents Sea have been observed where ships favour different routes based on seasonal ice conditions. Another contribution from this work is the validation of the Arctic Traffic Accessibility Model (ATAM) using the observed ship traffic data. Results show that the ATAM model underestimates the accessibility and vessel travel speed. This is largely due to outdated model parameters. The predefined ice multipliers and calculation of ice numerals used in the ATAM may not accurately reflect real-world conditions.

Abstract We perform a multi-scale analysis of the geometric structure of the network of X (Twitter at the time of data collection) interactions surrounding the Italian snap general elections of September 25th 2022. We identify within it the communities related to the major Italian political parties and after it we analyse both the large-scale structure of interactions between different parties, showing that it resembles the coalitions formed in the run-up to the elections and the internal structure of each community. We observe that some parties have a very centralised communication with the major leaders clearly occupying the central role, while others have a more horizontal communication strategy, with many accounts playing an important role. We observe that this can be characterized by checking whether the network in the community has a strongly connected giant component or not.

Objectives. To analyze the budget impact of upadacitinib (UPA) 15 mg + methotrexate (MTX) for the treatment of moderate-to-severe rheumatoid arthritis (RA) in patients with an inadequate response to conventional disease-modifying antirheumatic drugs (cDMARD-IR) from the perspective of social security and the private health sector in Argentina. Materials and methods. A budget impact analysis model was developed for a hypothetical cohort of 100,000 adults with health insurance coverage who were diagnosed with RA over a 5-year time horizon. The model parameters were obtained through literature review and validated by local experts. The costs are expressed in 2024 US dollars (USD). Results. The introduction of UPA 15 mg + MTX for the treatment of moderate-to-severe RA and cDMARD-IR resulted in minimal increase, with a five-year total cumulative incremental cost of USD 1,855 for social security and USD 1,812 for the private health sector, representing 2% of the total budget. The acquisition cost of UPA was the most influential variable in the sensitivity analysis. Conclusions. The introduction of UPA 15 mg + MTX for the treatment of moderate-to-severe RA and cDMARD-IR can provide an effective treatment option with a minimal increase in costs for the healthcare system in Argentina, which is especially important in developing countries where health system budgets are more limited. Providing evidence-based estimates is a valuable tool for informing healthcare policies and can help policymakers make informed decisions about the allocation of healthcare resources to improve patient outcomes while also managing costs.

Whilst policymaking will always remain a highly political process, especially amidst crises, evidence-based pandemic management can benefit from adopting a socioecological perspective that integrates multi- and trans-disciplinary insights: from biology, biomedicine, mathematics, statistics, social and behavioural sciences, as well as the perspectives and experiences of non-scientific stakeholders. We make a case for an “integrated inter- and transdisciplinarity” that overcomes the typical additive nature of current interdisciplinary work and better captures the inherent complexity of public health and other public policy problems. We propose systems science and systems thinking approaches as a useful meta-theoretical, self-reflecting approach for such integration to take place. Enabled by systems thinking, the praxis of “integrated inter- and transdisciplinarity” allows for an understanding of public health crises in a human-centred socio-ecological perspective. This grounds more holistic policy responses, which by mobilising the whole of government and whole of society, put individuals, groups, governments and society at large in critical dialogue to co-produce and co-design interventions that address crises in all their physical, social, psychological, economic and political dimensions.

This paper compares the ancient Mediterranean and Mesopotamian civilizations’ concept of borders and their relation with the spaces they transformed through a comparative approach of selected ancient civilizations, putting these cosmogonies into a chronological evolutionary line. The distinct motifs, symbols, and theological frameworks are examined through secondary sources. While each of these civilizations counts with individual studies, few serious attempts have been made to address these four civilizations together. The discussion aims to set the premises of the importance of borders in contemporary urban and territorial studies when religion often has a secondary role. While they were critical elements in the definition of territorial limits in the past, their inheritance is still present in our contemporary concept of borders as producers of fears.

Summary: Nowadays cardiorespiratory fitness (CRF) is assessed using summary indexes of cardiopulmonary exercise tests (CPETs). Yet, raw time-series CPET recordings may hold additional information with clinical relevance. Therefore, we investigated whether analysis of raw CPET data using dynamic time warping combined with k-medoids could identify distinct CRF phenogroups and improve cardiovascular (CV) risk stratification. CPET recordings from 1,399 participants (mean age, 56.4 years; 37.7% women) were separated into 5 groups with distinct patterns. Cluster 5 was associated with the worst CV profile with higher use of antihypertensive medication and a history of CV disease, while cluster 1 represented the most favorable CV profile. Clusters 4 (hazard ratio: 1.30; p = 0.033) and 5 (hazard ratio: 1.36; p = 0.0088) had a significantly higher risk of incident adverse events compared to clusters 1 and 2. The model evaluation in the external validation cohort revealed similar patterns. Therefore, an integrative CRF profiling might facilitate CV risk stratification and management.

ABSTRACTHurricane Ian in 2022 was a destructive category 4 Atlantic hurricane striking the state of Florida, which caused hundreds of deaths and injuries, catastrophic property damage, and an economic loss of more than $112 billion. Before the landfall of Ian in Florida, the state government issued evacuation orders in high-risk zones to reduce casualties and injuries. However, there is limited data available to monitor the actual evacuation patterns and compliance with the evacuation orders at a large geographic scale. This study utilizes human mobility data (i.e. SafeGraph Weekly Pattern) to analyse the spatial patterns of evacuation during Hurricane Ian in 2022. The objectives of the study include three key aspects: 1) proposing an analytical workflow that utilizes human mobility data to detect mobility patterns in disasters and other emergency events; 2) identifying significant evacuation patterns, and 3) revealing the spatial variations in the compliance with evacuation orders in the affected areas. Using data science and spatial analysis techniques, this study detected notable changes in population movements, both within Florida and nationwide, which are potentially linked to the hurricane-induced population evacuation. The distance decay pattern of population flows from Florida demonstrates a propensity for individuals to relocate to nearby areas during the hurricane. Furthermore, the increase in population outflows from the impacted areas suggests the effectiveness of mandatory evacuation orders. A more pronounced increase in outflows from designated mandatory evacuation areas points to the public awareness of the evacuation zone designation. This study provides large-scale, fine-resolution analysis of evacuation behaviours in natural disasters which cannot be easily detected in traditional data sources. The analytical workflows provide actionable tools for government agencies and policymakers to evaluate the effectiveness of evacuation orders and improve evacuation plans in future disasters.

This study focuses on anti-trauma mats designed for buffaloes’ comfort, using as raw materials rubber powder from end-of-life tyres (ELTs) and an isocyanate-based polyurethane resin binder. The first part of the study focused on mat formulation. Whilst it was possible to select a unique combination of raw materials and design features, it was necessary to investigate the relationship between three critical parameters affecting mat consistency and therefore buffalo comfort: binder quantity, mat thickness, and desired final mat density (bulk). In order to quantitatively assess the variation in hardness, various combinations were investigated within well-defined ranges based on the relevant literature. The results obtained from nine selected combinations indicate that increases in the three critical parameters do not induce a real phase transition in the final product consistency, although the hardness suggests an increasing trend. The mats consistently exhibited a moderately soft/hard consistency, offering environmental benefits in terms of increased rubber usage and potentially reduced chemical binder, depending on the desired thickness. The selected mixture showed excellent resistance to heavy chemical loads, suggesting reliability for frequent cleaning operations. The second part of the study involved field trials of the mats with calves. This involved monitoring their weight gain and appetite levels over a 90-day period. The results showed excellent growth performance compared to uncoated grids (i.e., weight gain was approximately 20% higher at the end of the observation period); this was similar to that achieved with the use of straw bedding. However, compared to straw bedding, the mats (i) exhibit long-term durability, with no signs of wear from washing or trampling over the months of the trial, (ii) allow for quick and efficient cleaning, and (iii) enable companies to save on labour, material (straw), and waste disposal costs, while maintaining (or even improving) the same welfare levels associated with the use of straw.

Abstract We define bipartite and monopartite relational networks of chemical elements and compounds using two different datasets of inorganic chemical and material compounds, as well as study their topology. We discover that the connectivity between elements and compounds is distributed exponentially for materials, and with a fat tail for chemicals. Compounds networks show similar distribution of degrees, and feature a highly-connected club due to oxygen . Chemical compounds networks appear more modular than material ones, while the communities detected reveal different dominant elements specific to the topology. We successfully reproduce the connectivity of the empirical chemicals and materials networks by using a family of fitness models, where the fitness values are derived from the abundances of the elements in the aggregate compound data. Our results pave the way towards a relational network-based understanding of the inherent complexity of the vast chemical knowledge atlas, and our methodology can be applied to other systems with the ingredient-composite structure.

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase mainly found in the focal adhesion regions of the plasma membrane and it has a crucial role in migration and the remodeling of cellular morphology. FAK is also linked to several aspects of cancer biology, from cytokine production to angiogenesis, drug resistance, invasion, and metastasis, as well as epithelial-to-mesenchymal transition. The gene locus of FAK is frequently amplified in several human tumors, thus causing FAK overexpression in several cancers. Furthermore, FAK can influence extracellular matrix production and exosome secretion through cancer-associated fibroblasts, thus it has an important role in tumor microenvironment regulation. Although the role of FAK in solid tumors is well known, its importance in onco-hematological diseases remains poorly explored. This review collects studies related to FAK significance in onco-hematological diseases and their microenvironments. Overall, the importance of FAK in blood tumors is increasingly evident, but further research is required to confirm it as a new therapeutic target in hematological contexts.

Abstract Reversible axonal swelling and brainstem auditory evoked potential (BAEP) changes were observed in standard chronic (9‐month) toxicology studies in dogs treated with ritlecitinib, an oral Janus kinase 3/tyrosine kinase expressed in hepatocellular carcinoma family kinase inhibitor, at exposures higher than the approved 50‐mg human dose. To evaluate the clinical relevance of the dog toxicity finding, this phase 2a, double‐blind study assessed BAEP changes and intraepidermal nerve fiber (IENF) histology in adults with alopecia areata treated with ritlecitinib. Patients were randomized to receive oral ritlecitinib 50 mg once daily (QD) with a 4‐week loading dose of 200 mg QD or placebo for 9 months (placebo‐controlled phase); they then entered the active‐therapy extension and received ritlecitinib 50 mg QD (with a 4‐week loading dose of 200 mg in patients switching from placebo). Among the 71 patients, no notable mean differences in change from baseline (CFB) in Waves I–V interwave latency (primary outcome) or Wave V amplitude on BAEP at a stimulus intensity of 80 dB nHL were observed in the ritlecitinib or placebo group at Month 9, with no notable differences in interwave latency or Wave V amplitude between groups. The CFB in mean or median IENF density and in percentage of IENFs with axonal swellings was minimal and similar between groups at Month 9. Ritlecitinib treatment was also not associated with an imbalanced incidence of neurological and audiological adverse events. These results provide evidence that the BAEP and axonal swelling finding in dogs are not clinically relevant in humans.

Background Half of patients with heart failure with preserved ejection fraction (HFpEF) remain undiagnosed by resting evaluation alone. Therefore, exercise testing is proposed. The diastolic stress test (DST), however, has limited sensitivity. We aimed to determine the clinical significance of adding the mean pulmonary artery pressure over cardiac output (mPAP/CO) slope to the DST in suspected HFpEF. Methods and Results In this prospective cohort study, consecutive patients (n=1936) with suspected HFpEF underwent exercise echocardiography with simultaneous respiratory gas analysis. These patients were stratified by exercise E over e′ (exE/e′) and mPAP/CO slope, and peak oxygen uptake, natriuretic peptides (NT‐proBNP [N‐terminal pro‐B‐type natriuretic peptide]), and score‐based HFpEF likelihood were compared. Twenty‐two percent of patients (n=428) had exE/e′3 mm Hg/L per min, 24% (n=464) had a positive DST (exE/e′≥15), and 54% (n=1044) had a normal DST and slope. Percentage of predicted oxygen uptake was similar in the group with exE/e′3 mm Hg/L per min despite a negative DST. These patients had HFpEF characteristics and a peak oxygen uptake as low as patients with a positive DST. Therefore, an elevated mPAP/CO slope might indicate HFpEF irrespective of the DST result.

Treatment options for secondary progressive MS (SPMS) are limited, especially considering that the new drugs recently approved are licensed for actively relapsing patients. We aimed to compare the disability progression in a real-world cohort of SPMS patients treated with natalizumab (NTZ) or interferon beta-1b (IFNb-1b). This multicenter retrospective enrolled patients with a diagnosis of SPMS according to 2014 Lublin criteria, who received NTZ or IFNb-1b for at least 48 months between the 1st June 2012 and the 15th May 2018 ​at 33 Italian MS centers contributing to the Italian MS Registry NTZ or IFNb-1b. Confirmed Expanded Disability Status Scale worsening (CEW) and progression independent of relapse (PIRA) were evaluated. In order to correct for non-randomization, a propensity score matching of the groups was performed. Out of 5206 MS patients identified at the time of data extraction, 421 SPMS patients treated with NTZ (224 [53.2%] females, mean age 45.3 ​± ​25.4 years) and 353 with IFNb-1b (133 [37.8%] females, mean age 48.5 ​± ​19.8 years) were enrolled. After applying the matching procedure, 102 patients were retained in the NTZ group and 98 in the IFNb-2b group. The proportion of patients who reached the 48-month 1-point CEW was significantly higher in IFNb-1b compared to NTZ group (58.2% versus 30.4%, p ​= ​0.01). The proportion of patients who developed PIRA at 48 months were significantly higher in IFNb-1b compared to NTZ (72.4% versus 40.2%, p ​= ​0.01). EDSS before treatment initiation and SPMS duration were risk factors for disability progression in terms of PIRA (HR 2.54, 25%CI 1.67–5.7; p ​= ​0.006 and HR 2.04, 25%CI 1.22–3.35; p ​= ​0.01, respectively). Patients treated with IFNb-1b were 1.64 times more to likely to develop PIRA (HR 1.64, 25%CI 1.04–4.87; p ​= ​0.001). Treatment with NTZ in SPMS patients showed more favorable disability outcomes compared to IFNb-1b with beneficial effects over 48 months.

The increasing international proliferation of wooden constructions is a recent phenomenon that originated and was nurtured in Alpine regions, thanks to a gradual process of technological innovation developed over the last two decades through experimental architecture using new, engineered components. The result of this upsurge has been an unprecedented positive development trajectory for this sector in constant growth thanks to strategies of decarbonisation and the spread of bio-based construction materials as key drivers for Net Zero Carbon Buildings (NZCB), Climate-Neutral Buildings. Today this change in the “status” of wooden constructions is most clearly represented outside of Alpine regions, in urban landscapes where wooden superstructures, like multifunctional walls for energy retrofitting, new schools, university residential halls, hotels, and commercial buildings abound. In recent years, this evolution has been accompanied by a debate on the available approaches and models, which are reflected in the numerous European competitions and awards dedicated to wooden architecture, with the aim of promoting an understanding of the strategies and practices implemented in public and private projects. The Wood Architecture Prize, the first Italian award in the industry, promoted by Fiera Bolzano, Politecnico di Torino and IUAV Venezia, is a prime example of this advance. Around 150 architectural projects were submitted for consideration, prevalently by the new generation of professionals who are increasingly aware of the environmental and local sensibilities of architectural methods.

Facial expressions are essential for communication and emotional expression across species. Despite the improvements brought by tools like the Horse Grimace Scale (HGS) in pain recognition in horses, their reliance on human identification of characteristic traits presents drawbacks such as subjectivity, training requirements, costs, and potential bias. Despite these challenges, the development of facial expression pain scales for animals has been making strides. To address these limitations, Automated Pain Recognition (APR) powered by Artificial Intelligence (AI) offers a promising advancement. Notably, computer vision and machine learning have revolutionized our approach to identifying and addressing pain in non-verbal patients, including animals, with profound implications for both veterinary medicine and animal welfare. By leveraging the capabilities of AI algorithms, we can construct sophisticated models capable of analyzing diverse data inputs, encompassing not only facial expressions but also body language, vocalizations, and physiological signals, to provide precise and objective evaluations of an animal's pain levels. While the advancement of APR holds great promise for improving animal welfare by enabling better pain management, it also brings forth the need to overcome data limitations, ensure ethical practices, and develop robust ground truth measures. This narrative review aimed to provide a comprehensive overview, tracing the journey from the initial application of facial expression recognition for the development of pain scales in animals to the recent application, evolution, and limitations of APR, thereby contributing to understanding this rapidly evolving field.

Book Review

The present essay aims to assess the very possibility of tracing a comparative history of Slavic cultures, by highlighting those elements that are potentially common to all these literary traditions. Starting from the examination of Marcello Garzaniti’s recent monograph Storia delle letterature slave. Libri, scrittori e idee dall’Adriatico alla Siberia (secoli ix-xxi) [History of Slavic Literatures: Books, Writers, and Ideas from the Adriatic to Siberia (9th-21st Centuries), Rome 2023], the author evaluates two possible comparative perspectives: constructing a binary structure between two phenomena or groups of phenomena (for example, Slavia Orthodoxa and Slavia Latina), or interpreting the plurality of a class of phenomena in light of some central unifying element, around which the entire series can be arranged. Both these strategies have proved unsatisfactory, as the space of Slavic cultures is an evolutionary system in dynamic equilibrium, not a fixed totality of materials. Thus, it might be appropriate to abandon the very idea of an integral model referring to what is an inevitably open and infinitely plural class of phenomena.

Major depressive disorder (MDD) represents a major health issue in adolescents and young adults, leading to high levels of disability and profoundly impacting overall functioning. The clinical presentation of MDD in this vulnerable age group may slightly differ from what can be observed in adult populations, and psychopharmacological strategies do not always lead to optimal response. Resistance to antidepressant treatment has a prevalence estimated around 40% in youths suffering from MDD and is associated with higher comorbidity rates and suicidality. Several factors, encompassing biological, environmental, and clinical features, may contribute to the emergence of treatment-resistant depression (TRD) in adolescents and young adults. Furthermore, TRD may underpin the presence of an unrecognized bipolar diathesis, increasing the overall complexity of the clinical picture and posing major differential diagnosis challenges in the clinical practice. After summarizing current evidence on epidemiological and clinical correlates of TRD in adolescents and young adults, the present review also provides an overview of possible treatment strategies, including novel fast-acting antidepressants. Despite these pharmacological agents are promising in this population, their usage is expected to rely on risk-benefit ratio and to be considered in the context of integrated models of care.

Background: Women are at greater risk for heart failure with preserved ejection fraction (HFpEF). Objectives: The aim of the study was to compare sex differences in the pathophysiology of exertional breathlessness in patients with high vs low HFpEF likelihood. Methods: This cohort study evaluated consecutive patients (n = 1,936) with unexplained dyspnea using cardiopulmonary exercise testing and simultaneous echocardiography and quantified peak oxygen uptake (peak VO2) and its determinants. HFpEF was considered likely when the H2FPEF or HFA-PEFF score was ≥6 or ≥5, respectively. Sex differences were evaluated with the Student’s t-test or Mann-Whitney U test and determinants of exercise capacity with a multivariable linear regression. Results: The cohort included 1,963 patients (49% women and 28% [n = 555] with a high HFpEF likelihood). HFpEF likelihood did not impact the magnitude of sex differences in peak VO2 and its determinants. Overall, women had lower peak VO2 (mean difference −4.4 mL/kg/min [95% CI: −3.7 to −5.1 mL/kg/min]) secondary to a reduced O2 delivery (−0.5 L/min [95% CI: −0.4 to −0.6 L/min]) and less oxygen extraction (−2.9 mL/dL [95% CI: −2.5 to −3.2 mL/dL]). Reduced O2 delivery was due to lower hemoglobin (−1.2 g/dL [95% CI: −0.9 to −1.5 g/dL]) and smaller stroke volume (−15 mL [95% CI: −14 to −17 mL]). Women demonstrated increased mean pulmonary artery pressure/cardiac output slope (+0.5 mm Hg/L/min [95% CI: 0.3-0.7 mm Hg/L/min]) and left ventricular ejection fraction (+1% [95% CI: 1%-2%]), while they had smaller left ventricular end-diastolic volumes (−9 mL/m2 [95% CI: −8 to −11 mL/m2]) and mass (−12 g/m2 [95% CI: −9 to −14 g/m2]) and more often iron deficiency (55% vs 33%; P < 0.001). Conclusions: Women with unexplained dyspnea had significantly lower peak VO2, regardless of HFpEF likelihood, attributed to both lower peak exercise O2 delivery and extraction. This suggests that physiologic sex differences, and not HFpEF likelihood, are an important factor contributing to functional limitations in females with exertional breathlessness.

Cardiovascular medical devices undergo a large number of pre- and post-market tests before their approval for clinical practice use. Sophisticated cardiovascular simulators can significantly expedite the evaluation process by providing a safe and controlled environment and representing clinically relevant case scenarios. The complex nature of the cardiovascular system affected by severe pathologies and the inherently intricate patient–device interaction creates a need for high-fidelity test benches able to reproduce intra- and inter-patient variability of disease states. Therefore, we propose an innovative cardiovascular simulator that combines in silico and in vitro modeling techniques with a soft robotic left ventricle. The simulator leverages patient-specific and echogenic soft robotic phantoms used to recreate the intracardiac pressure and volume waveforms, combined with an in silico lumped parameter model of the remaining cardiovascular system. Three different patient-specific profiles were recreated, to assess the capability of the simulator to represent a variety of working conditions and mechanical properties of the left ventricle. The simulator is shown to provide a realistic physiological and anatomical representation thanks to the use of soft robotics combined with in silico modeling. This tool proves valuable for optimizing and validating medical devices and delineating specific indications and boundary conditions.