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Pancreatic ductal adenocarcinoma (PDAC) has limited treatment options, emphasizing the urgent need for effective therapies. The predominant driver in PDAC is mutated KRAS proto‐oncogene, KRA, present in 90% of patients. The emergence of direct KRAS inhibitors presents a promising avenue for treatment, particularly those targeting the KRASG12C mutated allele, which show encouraging results in clinical trials. However, the development of resistance necessitates exploring potent combination therapies. Our objective was to identify effective KRASG12C‐inhibitor combination therapies through unbiased drug screening. Results revealed synergistic effects with son of sevenless homolog 1 (SOS1) inhibitors, tyrosine‐protein phosphatase non‐receptor type 11 (PTPN11)/Src homology region 2 domain‐containing phosphatase‐2 (SHP2) inhibitors, and broad‐spectrum multi‐kinase inhibitors. Validation in a novel and unique KRASG12C‐mutated patient‐derived organoid model confirmed the described hits from the screening experiment. Our findings propose strategies to enhance KRASG12C‐inhibitor efficacy, guiding clinical trial design and molecular tumor boards.

Objective: This study aimed to systematically review the relationship between secondary smoking and early childhood caries (ECC) among preschool children. Method: Two independent reviewers systematically searched English publications with keywords in PubMed, Web of Science, Medline, Scopus, and Embase to identify publications reporting on secondary smoking and ECC for children under 71 months. Observational studies, including cohort studies, case-control studies, and cross-sectional surveys, were included. The reviewers screened the titles and abstracts to remove duplicate records, reviews, and irrelevant studies. They performed meta-analyses to investigate the prevalence of ECC in children exposed to secondary smoking. Results: This study identified 1243 publications and included 16 publications. Twelve publications were cross-sectional studies. A meta-analysis of 11 of them revealed that children with secondary smoking exposure had an odds ratio of 1.77 in caries risk (P < .001), whereas one cross-sectional study found no increase in caries risk without data reporting. Two cohort studies with low and very low quality were combined into a meta-analysis, which found children from infancy with secondary smoking exposure had a relative risk of 1.45 in caries incidence (P < .001). Two case-control studies with moderate and low quality were combined into a meta-analysis, which found that children exposed to secondary smoking had an odds ratio of 4.46 in caries prevalence (P < .001). Conclusion: The literature has reported that preschool children with secondary smoking exposure have a higher risk of caries; however, the number and quality of these studies are limited.

Abstract Those with diabetes mellitus are at high-risk of developing psychiatric disorders, especially mood disorders, yet the link between hyperglycemia and altered motivation has not been thoroughly explored. Here, we characterized value-based decision-making behavior of a streptozocin-induced diabetic mouse model on Restaurant Row, a naturalistic neuroeconomic foraging paradigm capable of behaviorally capturing multiple decision systems known to depend on dissociable neural circuits. Mice made self-paced choices on a daily limited time-budget, accepting or rejecting reward offers based on cost (delays cued by tone pitch) and subjective value (flavors), in a closed-economy system tested across months. We found streptozocin-treated mice disproportionately undervalued less-preferred flavors and inverted their meal-consumption patterns shifted toward a more costly strategy overprioritizing high-value rewards. These foraging behaviors were driven by impairments in multiple decision-making processes, including the ability to deliberate when engaged in conflict and cache the value of the passage of time as sunk costs. Surprisingly, diabetes-induced changes in motivation depended not only on the type of choice being made, but also on the salience of reward-scarcity in the environment. These findings suggest that complex relationships between metabolic dysfunction and dissociable valuation algorithms underlying unique cognitive heuristics and sensitivity to opportunity costs can disrupt distinct computational processes leading to comorbid psychiatric vulnerabilities.

Marine conserved areas (MCAs) can provide a range of ecological and socio-economic benefits, including climate change mitigation from the protection and enhancement of natural carbon storage. Canada's MCA network is expanding to encompass 30% of its Exclusive Economic Zone by 2030. At present, the network aims to integrate climate change mitigation by protecting coastal vegetated blue carbon ecosystems (saltmarsh, seagrass, kelp). Here, we argue that incorporating unvegetated seabed sediments could bring similar benefits. Seabed sediments can store and/or accumulate high densities of organic carbon, and due to their large spatial extent, contain carbon stores orders of magnitude larger than coastal vegetated habitats. We estimate that currently designated MCAs encompass only 10.8% of Canada's seabed sediment organic carbon stocks on the continental margin, and only 13.4% of areas with high carbon densities. Proposed MCAs would cover an additional 8.8% and 6.1% of total stocks and high carbon areas, respectively. We identify an additional set of high-priority seabed areas for future research and potential protection, ranking their importance based on carbon stocks, proxies for lability, and ecological/biological significance. The incorporation of seabed sediments into MCA networks could support climate change mitigation by preventing future releases of stored carbon.

Abstract Climatic extremes have historically been seen as univariate; however, recent international reports have highlighted the potential for an increase in compound climate events (e.g., hot and dry events, recurrent flooding). Despite the projected increase in the frequency of compound climate events and the adoption of compound event terminology, few studies identify climate extremes as compound climate events and little evidence exists on the societal impacts of these compound climate events. This scoping review summarizes key findings and knowledge gaps in the current state of empirical studies that focus on the societal impacts of compound climate events. We identified 28 eligible studies published in four databases reporting on the societal impacts of compound climate events in four sectors: agriculture, public health, the built environment, and land use. Overall, we found the need for more research explicitly linking compound climate events to societal impacts, particularly across multiple compound climate events, rather than single case study events. We also noted several key findings, including changes in agricultural productivity, loss of habitat, increased fire risk, poor mental health outcomes, decreased health care access, and destruction of homes and infrastructure from these events. Additional research is needed both globally and locally to understand the implications of compound climate events across different geographic regions and populations to ensure responsive adaptation policies in a compound climate event framework.

Abstract The dynamic interactions between tumor endothelial cells (TECs) and the immune microenvironment play a critical role in the progression of non-small cell lung cancer (NSCLC). In general, endothelial cells exhibit diverse immunomodulatory properties, influencing immune cell recruitment, antigen presentation, and regulation of immune checkpoint expression. Understanding the multifaceted roles of TECs as well as assigning specific functional hallmarks to various TEC phenotypes offer new avenues for targeted development of therapeutic interventions, particularly in the context of advanced immunotherapy and anti-angiogenic treatments. This review provides insights into the complex interplay between TECs and the immune system in NSCLC including discussion of potential optimized therapeutic opportunities.

Abstract Conjugation plays a major role in dissemination of antimicrobial resistance genes. Following transfer of IncF-like plasmids, recipients become refractory to a second wave of conjugation with the same plasmid via entry (TraS) and surface (TraT) exclusion mechanisms. Here, we show that TraT from the pKpQIL and F plasmids (TraTpKpQIL and TraTF) exhibits plasmid surface exclusion specificity. The cryo-EM structures of TraTpKpQIL and TraTF reveal that they oligomerise into decameric champagne bottle cork-like structures, which are anchored to the outer membrane via a diacylglycerol and palmitic acid modified α-helical barrel domain. Unexpectedly, we identify chromosomal TraT homologues from multiple Gram-negative phyla which form numerous divergent lineages in a phylogenetic tree of TraT sequences. Plasmid-associated TraT sequences are found in multiple distinct lineages, including two separate clades incorporating TraT from Enterobacteriaceae IncF/F-like and Legionellaceae F-like plasmids. These findings suggest that different plasmid backbones have acquired and co-opted TraT on independent occasions.

Abstract Bacteremia, a leading cause of death, generally arises after bacteria establish infection in a particular tissue and transit to secondary sites. Studying dissemination from primary sites by solely measuring bacterial burdens does not capture the movement of individual clones. By barcoding Klebsiella pneumoniae, a leading cause of bacteremia, we track pathogen dissemination following pneumonia. Variability in organ bacterial burdens is attributable to two distinct dissemination patterns distinguished by the degree of similarity between the lung and systemic sites. In metastatic dissemination, lung bacterial clones undergo heterogeneous expansion and the dominant clones spread to secondary organs, leading to greater similarity between sites. In direct dissemination, bacterial clones exit the lungs without clonal expansion, leading to lower burdens in systemic sites and more dissimilarity from the lung. We uncover bacterial and host factors that influence the dynamics of clonal sharing and expansion. Here, our data reveal unexpected heterogeneity in Klebsiella bacteremia dynamics and define a framework for understanding within-host bacterial dissemination.

Multiparametric magnetic resonance imaging (mpMRI) is strongly recommended by current clinical guidelines for improved detection of clinically significant prostate cancer (csPCa). However, the major limitations are the need for intravenous (IV) contrast and dependence on reader expertise. Efforts to address these issues include use of biparametric magnetic resonance imaging (bpMRI) and advanced, quantitative magnetic resonance imaging (MRI) techniques. One such advanced technique is the Restriction Spectrum Imaging restriction score (RSIrs), an imaging biomarker that has been shown to improve quantitative accuracy of patient-level csPCa detection. Advanced Restriction imaging and reconstruction Technology for Prostate MRI (ART-Pro) is a multisite, multinational trial that aims to evaluate whether IV contrast can be avoided in the setting of standardized, state-of-the-art image acquisition, with or without addition of RSIrs. Additionally, RSIrs will be evaluated as a stand-alone, quantitative, objective biomarker. ART-Pro will be conducted in two stages and will include a total of 500 patients referred for multiparametric prostate MRI with a clinical suspicion of prostate cancer at the participating sites. ART-Pro-1 will evaluate bpMRI, mpMRI, and RSIrs on the accuracy of expert radiologists’ detection of csPCa and will evaluate RSIrs as a stand-alone, quantitative, objective biomarker. ART-Pro-2 will evaluate the same MRI techniques on the accuracy of nonexpert radiologists’ detection of csPCa, and findings will be evaluated against the expertly created dataset from ART-Pro-1. The primary endpoint is to evaluate whether bpMRI is noninferior to mpMRI among expert (ART-Pro-1) and nonexpert (ART-Pro-2) radiologists for the detection of grade group ≥2 csPCa. This trial is registered in the US National Library of Medicine Trial Registry (NCT number: NCT06579417) at ClinicalTrials.gov. Patient accrual at the first site (UC San Diego) began in December 2023. Initial results are anticipated by the end of 2026.

Slavneft-YANOS was one of the first in Russia to obtain the ISO 14001 compliance certificate for the Environmental Management System (EMS). This quality standard has the highest requirements for environmental management, environmental protection, and environmental safety. The paper presents the industry-specific features of the introduction of a risk-oriented approach to the EMS of oil refineries. It also uses fuzzy logic to describe analysis mechanisms and methods for assessing the risks of failure to meet the performance indicators of the EMS. The main advantage of fuzzy control in EMS is that it provides an effective means of mapping uncertainties and inaccuracies because the fuzzy logic on which control is based is identical to human thinking as opposed to traditional logical systems. Fuzzy control proves most useful as part of EMS performance analysis when processes become difficult to evaluate using common quantitative methods or when available information sources are interpreted inaccurately and uncertainly.

Abstract Embracing local knowledge is vital to conserve and manage biodiversity, yet frameworks to do so are lacking. We need to understand which, and how many knowledge holders are needed to ensure that management recommendations arising from local knowledge are not skewed towards the most vocal individuals. Here, we apply a Wisdom of Crowds framework to a data-poor recreational catch-and-release fishery, where individuals interact with natural resources in different ways. We aimed to test whether estimates of fishing quality from diverse groups (multiple ages and years of experience), were better than estimates provided by homogenous groups and whether thresholds exist for the number of individuals needed to capture estimates. We found that diversity matters; by using random subsampling combined with saturation principles, we determine that targeting 31% of the survey sample size captured 75% of unique responses. Estimates from small diverse subsets of this size outperformed most estimates from homogenous groups; sufficiently diverse small crowds are just as effective as large crowds in estimating ecological state. We advocate for more diverse knowledge holders in local knowledge research and application.

Abstract Hyperspectral imaging (HSI) systems acquire images with spectral information over a wide range of wavelengths but are often affected by chromatic and other optical aberrations that degrade image quality. Deconvolution algorithms can improve the spatial resolution of HSI systems, yet retrieving the point spread function (PSF) is a crucial and challenging step. To address this challenge, we have developed a method for PSF estimation in HSI systems based on computed wavefronts. The proposed technique optimizes an image quality metric by modifying the shape of a computed wavefront using Zernike polynomials and subsequently calculating the corresponding PSFs for input into a deconvolution algorithm. This enables noise-free PSF estimation for the deconvolution of HSI data, leading to significantly improved spatial resolution and spatial co-registration of spectral channels over the entire wavelength range.

Abstract Cytomegalovirus (CMV) infection or reactivation in immune-compromised individuals can lead to a wide range of severe complications including hepatitis. However, its relation with immune checkpoint inhibitors (ICIs) induced hepatitis (ICI-hepatitis) and tumor responses in advanced melanoma patients remains unclear. Hundred and ninety metastatic cutaneous melanoma patients (mCM) who received ICI treatment, with CMV IgG or IgM information available at baseline, were included in the study (Cohort 1). Clinical characteristics and immune cell count in the blood were retrieved from medical records. In addition, anti-CMV IgG and IgM were measured in pre and on-treatment serum samples from 49 advanced skin cancer patients using ELISA (Cohort 2). In the event of a positive anti-CMV IgM, further analysis with PCR was performed. Univariate and multivariate analysis was used to assess the relationship between CMV IgG or IgM and ICI-hepatitis tumor outcomes. Twenty-one patients (11%) developed hepatitis during ICI treatment (Cohort 1). ICI-hepatitis was significantly associated with disease control rate (DCR; p = 0.017) and longer progression-free survival (PFS; p = 0.008) in mCM patients. Detection of CMV IgG or IgM antibodies were not associated with ICI-hepatitis (p > 0.05). However, increased CMV IgG values at baseline correlated with disease progression (p = 0.047) and shorter PFS (p = 0.081). In addition, increased CMV IgG values were associated with reduced levels of monocytes (p = 0.005), eosinophils (p = 0.062), and neutrophils (p = 0.065) in the blood. In summary, anti-CMV IgG or IgM in the blood may not be associated with ICI-hepatitis, but high anti-CMV IgG at baseline indicates poor outcomes in ICI-treated mCM patients.

Abstract The plastic waste crisis is among humanity’s most urgent challenges. However, widespread adoption of sustainable plastics is hindered by their often inadequate processing characteristics and performance. Here, we introduce a bio-inspired strategy for the modification of a representative high molar mass, biodegradable aliphatic polyester that helps overcome these limitations and remains effective at molar masses far greater than the entanglement molar mass. We use co-assembly of oligopeptide-based polymer end groups and a low molar mass additive to create a hierarchical structure characterized by regularly spaced nanofibrils interconnected by entangled polymer segments. The modified materials show a rubbery plateau at temperatures above their melting point, associated with strongly increased melt strength, extraordinary melt extensibility, improved dimensional stability, and accelerated crystallization. These thermomechanical property changes open up otherwise inaccessible processing routes and offer considerable scope for improving solid-state properties, thereby addressing typical shortcomings of sustainable alternatives to conventional plastics.

Abstract Climate change is an emerging global health crisis, disproportionately affecting low- and middle-income countries (LMICs) where health outcomes are increasingly compromised by environmental stressors such as pollution, natural disasters, and human migration. With a focus on promoting health equity, Global Surgery advocates for expanding access to surgical care and enhancing health outcomes, particularly in resource-limited and disaster-affected areas like LMICs. The healthcare industry—and more specifically, surgical care—significantly contributes to the global carbon footprint, primarily through resource-intensive settings, i.e. operating rooms that generate greenhouse gases and substantial medical waste. Therefore, Global Surgery efforts aimed at improving surgical access through an increase in surgical volumes may inadvertently exacerbate health challenges for vulnerable populations by further contributing to environmental degradation. This predicament is particularly pronounced in LMICs, who already suffer from a disproportionate share of the global burden of disease, and where the demand for surgery is rising without corresponding resilient infrastructure. LMICs face a double jeopardy of health inequity coupled with climate vulnerability. As a movement positioned to improve health around the world, Global Surgery has an increasingly significant role in envisioning and ensuring a sustainable future. Global Surgery initiatives must prioritise sustainable infrastructure in both high-income countries (HICs) and LMICs, all while accounting for the unequal polluting contributions between HICs and LMICs and, consequently, moral responsibilities moving forward. Moreover, through targeting upstream causes of poor health at urban and perioperative levels, Global Surgery’s interventions may help to reduce the global burden of disease—avoiding preventable surgeries and their carbon footprints from the outset. Altogether, Global Surgery and climate change are two matters of social justice whose solutions must synergistically centralise the health of both the planet and its most vulnerable people.

Abstract Arctic permafrost is undergoing rapid changes due to climate warming in high latitudes. Retrogressive thaw slumps (RTS) are one of the most abrupt and impactful thermal-denudation events that change Arctic landscapes and accelerate carbon feedbacks. Their spatial distribution remains poorly characterised due to time-intensive conventional mapping methods. While numerous RTS studies have published standalone digitisation datasets, the lack of a centralised, unified database has limited their utilisation, affecting the scale of RTS studies and the generalisation ability of deep learning models. To address this, we established the Arctic Retrogressive Thaw Slumps (ARTS) dataset containing 23,529 RTS-present and 20,434 RTS-absent digitisations from 20 standalone datasets. We also proposed a Data Curation Framework as a working standard for RTS digitisations. This dataset is designed to be comprehensive, accessible, contributable, and adaptable for various RTS-related studies. This dataset and its accompanying curation framework establish a foundation for enhanced collaboration in RTS research, facilitating standardised data sharing and comprehensive analyses across the Arctic permafrost research community.

Abstract Background The ongoing opioid epidemic in the United States has reinforced the need to provide multimodal and non-opioid pain management interventions. The PAMI-ED ALT program employed a multifaceted approach in the Emergency Department (ED) developing electronic health record (EHR) pain management order panels and discharge panels, as well as educating patients, clinicians, and ED staff on opioid alternatives, including non-pharmacologic interventions. The primary objective of this analysis was to compare changes in opioid and non-opioid analgesic administrations and prescribing in ED patients with select pain conditions (renal colic, headache, low back, and non-low back musculoskeletal pain) before and after implementation of PAMI ED-ALT. Secondary outcomes included characterizing changes in 30-day ED all-cause recidivism and hospital all-cause admissions within these pain populations. Methods Demographics, opioid and opioid alternative utilization, hospital admission, 30-day ED returns and change in pain intensity score were collected from January 2019-March 2020 (pre-program implementation) and January 2021-March 2023 (post-program implementation) for both the ED aggregate and program target pain populations. Results Pain management order panel utilization increased throughout the post-implementation period. When comparing pre to post program data, there was a reduction in opioid administrations and prescriptions for most of the target pain conditions, as well as within the ED aggregate population. Opioid alternative administrations and prescriptions increased for all pain conditions except renal colic. Hospital admissions decreased significantly amongst those with low back pain and headache/migraine and 30-day ED returns significantly declined in those with musculoskeletal pain. Conclusion Our findings demonstrate an opioid-alternatives program implemented within a safety-net hospital system serving a predominantly socially disadvantaged patient population can lead to changes in ED pain management and potentially reduce 30-day ED recidivism and hospitalizations.

Abstract Reaching net zero emissions and limiting global warming to 2 °C requires the widespread introduction of technology-based solutions to draw down existing atmospheric levels and future emissions of CO2. One such approach is direct air CO2 capture and storage (DACCS), a readily available, yet energy-intensive process. The combination of DACCS and ocean thermal energy conversion (OTEC) allows for independently powered carbon capture plants to inject concentrated carbon into deep marine sediments where storage is generally safe and permanent. OTEC is a form of electricity production that exploits the temperature difference between deep and shallow ocean waters, and can power DACCS on floating platforms at a price competitive with coal-generated electricity. Here we highlight the scale of the challenge facing society. We show that a safe and sustainable level of OTEC-generated electricity powering DACCS for 70 years could result in up to a 35% decrease in the relative global mean temperature warming compared to a business-as-usual emissions scenario.

Abstract Background Approximately one in six children has a disability, and effective, evidence-based rehabilitation can ameliorate the impact of these conditions over the lifespan. However, implementing interventions in real-world settings remains a challenge. This scoping review aimed to summarize the characteristics, implementation strategies, and outcomes of implementation studies in pediatric rehabilitation. Methods A comprehensive search was conducted in PubMed/MEDLINE, EMBASE, CINAHL, SCOPUS, and Web of Science from the database inception to December 2, 2022. Studies testing implementation strategies in pediatric rehabilitation interventions were included. Data extracted included study characteristics (e.g., country, intervention type, field of rehabilitation), implementation strategies characterized using the Expert Recommendations for Implementing Change taxonomy, and outcomes based on the Implementation Outcomes Framework. Results Of the 11,740 studies identified, 44 met the inclusion criteria. Most studies were conducted in the United States (n = 15, 34%) or Canada (n = 10, 23%) and used a mixed-methods design (n = 13, 30%). Interventions primarily targeted motor skills (n = 19, 43%) and were conducted in outpatient settings (n = 14, 32%) or homes (n = 11, 23%). The most commonly used implementation strategies were “train and educate key informant” (n = 21, 48%) and “use evaluative/iterative strategies” (n = 19, 43%). Feasibility (n = 19, 43%) and acceptability (n = 16, 36%) were the most frequently targeted implementation outcomes. Conclusions Reporting implementation strategies and outcomes in pediatric rehabilitation studies is limited and highly variable. Most strategies focused on developing and sharing educational materials, while administrative and systems-level interventions were largely absent. Standardized documentation of implementation strategies and outcomes could advance the field’s understanding of the effective development of interventions designed for implementation, encouraging faster uptake of effective interventions.

Abstract Antibiotics can trigger antimicrobial resistance and microbiome alterations. Reducing pathogen exposure and undernutrition can reduce infections and antibiotic use. We assess effects of water, sanitation, handwashing (WSH) and nutrition interventions on caregiver-reported antibiotic use in Bangladesh and Kenya, longitudinally measured at three timepoints among birth cohorts (ages 3–28 months) in a cluster-randomized trial. Over 50% of children used antibiotics at least once in the 90 days preceding data collection. In Bangladesh, the prevalence of antibiotic use was 10–14% lower in groups receiving WSH (prevalence ratio [PR] = 0.90 (0.82–0.99)), nutrition (PR = 0.86 (0.78–0.94)), and nutrition+WSH (PR = 0.86 (0.79–0.93)) interventions. The prevalence of using antibiotics multiple times was 26–35% lower in intervention arms. Reductions were largest when the birth cohort was younger. In Kenya, interventions did not affect antibiotic use. In this work, we show that improving WSH and nutrition can reduce antibiotic use. Studies should assess whether such reductions translate to reduced antimicrobial resistance.

Abstract Quantum control of a linear oscillator using a static dispersive coupling to a nonlinear ancilla underpins a wide variety of experiments in circuit QED. Extending this control to more than one oscillator while minimizing the required connectivity to the ancilla would enable hardware-efficient multi-mode entanglement and measurements. We show that the spectrum of an ancilla statically coupled to a single mode can be made to depend on the joint photon number in two modes by applying a strong parametric beamsplitter coupling between them. This ‘joint-photon number-splitting’ regime extends single-oscillator techniques to two-oscillator control, which we use to realize a hardware-efficient erasure check for a dual-rail qubit encoded in two superconducting cavities. This scheme leverages the high-fidelity beamsplitter coupling already required for single- and two-qubit gates while permitting minimal crosstalk between circuit elements. Furthermore, the flexibility to choose the pulse shape allows us to limit the susceptibility to different error channels. We use this scheme to detect leakage errors with a missed erasure fraction of (9.0 ± 0.5) × 10−4 while incurring an erasure rate of 2.92 ± 0.01% and a Pauli error rate of 0.31 ± 0.01%, both of which are dominated by cavity errors.

Abstract Form-function relationships often have tradeoffs: if a material is tough, it is often inflexible, and vice versa. This is particularly relevant for the elephant trunk, where the skin should be protective yet elastic. To investigate how this is achieved, we used classical histochemical staining and second harmonic generation microscopy to describe the morphology and composition of elephant trunk skin. We report structure at the macro and micro scales, from the thickness of the dermis to the interaction of 10 μm thick collagen fibers. We analyzed several sites along the length of the trunk to compare and contrast the dorsal-ventral and proximal-distal skin morphologies and compositions. We find the dorsal skin of the elephant trunk can have keratin armor layers over 2 mm thick, which is nearly 100 times the thickness of the equivalent layer in human skin. We also found that the structural support layer (the dermis) of the elephant trunk contains a distribution of collagen-I (COL1) fibers in both perpendicular and parallel arrangement. The bimodal distribution of collagen is seen across all portions of the trunk, and is dissimilar from that of human skin where one orientation dominates within a body site. We hypothesize that this distribution of COL1 in the elephant trunk allows both flexibility and load-bearing capabilities. Additionally, when viewing individual fiber interactions of 10 μm thick collagen, we find the fiber crossings per unit volume are five times more common than in human skin, suggesting that the fibers are entangled. We surmise that these intriguing structures permit both flexibility and strength in the elephant trunk. The complex nature of the elephant skin may inspire the design of materials that can combine strength and flexibility.

Abstract Background Animal systematic reviews are critical to inform translational research. Despite their growing popularity, there is a notable lack of information on their quality, scope, and geographical distribution over time. Addressing this gap is important to maintain their effectiveness in fostering medical advancements. Objective This study aimed to assess the quality and demographic trends of animal systematic reviews in neuroscience, including changes over time. Methods We performed an umbrella review of animal systematic reviews, searching Medline and Embase for reviews until January 27, 2023. A data mining method was developed and validated to automatically evaluate the quality of these reviews. Results From 18‘065 records identified, we included 1‘358 animal systematic reviews in our study. These reviews commonly focus on translational research but with notable topical gaps such as schizophrenia, other psychiatric disorders, and brain tumours. They originate from 64 countries, with the United States, China, the UK, Brazil, and Iran being the most prolific. The automated quality assessment indicated high reliability, with F1-scores over 80% for most criteria. Overall, the reviews were of high quality and the quality improved over time. However, many systematic reviews did not report a pre-registered study protocol. Reviews with a pre-registered protocol generally scored higher in quality. No significant differences in quality were observed between countries. Conclusion Animal systematic reviews in neuroscience are of overall of high quality. Our study highlights specific areas for enhancement such as the recommended pre-publication of study protocols. It also identifies under-represented topics that could benefit from further investigation to inform translational research. Such measures can contribute to the effective translation of animal research findings to clinical applications.

Abstract Accurate prognostication guides optimal clinical management in skin cancer. Merkel cell carcinoma (MCC) is the most aggressive form of skin cancer that often presents in advanced stages and is associated with poor survival rates. There are no personalized prognostic tools in use in MCC. We employed explainability analysis to reveal new insights into mortality risk factors for this highly aggressive cancer. We then combined deep learning feature selection with a modified XGBoost framework, to develop a web-based prognostic tool for MCC termed ‘DeepMerkel’. DeepMerkel can make accurate personalised, time-dependent survival predictions for MCC from readily available clinical information. It demonstrated generalizability through high predictive performance in an international clinical cohort, out-performing current population-based prognostic staging systems. MCC and DeepMerkel provide the exemplar model of personalised machine learning prognostic tools in aggressive skin cancers.

“Simulation-based inference” is often considered a pedagogical strategy for helping students develop inferential reasoning, for example, giving them a visual and concrete reference for deciding whether the observed statistic is unlikely to happen by chance alone when the null hypothesis is true. In this article, we highlight for teachers some implications of different simulation strategies when analyzing two variables. In particular, does it matter whether the simulation models random sampling or random assignment? We present examples from comparing two means and simple linear regression, highlighting the impact on the standard deviation of the null distribution. We also highlight some possible extensions that simulation-based inference easily allows. Supplementary materials for this article are available online.

Abstract Background Pterocarpus erinaceus Poir. is a plant widely used in traditional medicine in Benin, treating various diseases such as diabetes, ulcers, parasitic infections, hypertension, and infertility. This plant is under strong anthropogenic pressure due to its overexploitation, putting it in danger of extinction. The study aims to explore the antimicrobial and enzymatic activities of endophytes produced by Pterocarpus erinaceus. Methods Fresh leaves, stems, and roots of P. erinaceus, collected in two phytogeographical zones of Benin, Savalou and Abomey-Calavi of Benin, were sterilized to eliminate surface microorganisms prior to cultivation and isolation of endophytes. Isolated endophytes were tested for various enzymatic activities (catalase, cellulase, protease, lipase, and amylase), and their antimicrobial activities were evaluated by measuring inhibition diameters. The content of total polyphenols and flavonoids was determined by spectrophotometry. Results The results showed that bacterial endophytes have a higher colonization (80.55%) and isolation (69.44%) rates than fungal endophytes (44.44% and 50%, respectively). Bacterial endophytes expressed more enzymatic activities such as lecithinase and amylase, whereas fungal endophytes showed little. Only two fungal isolates (HT1a and HF2b) showed antibacterial activity, and one isolate (HF2b) showed antifungal action against Candida albicans, while no bacterial isolate demonstrated significant antimicrobial activity. Fungal isolates show significant variation in polyphenol content, while bacterial isolates show similar levels. As far as flavonoids are concerned, bacterial strains such as F3b and SR2C have high levels, unlike fungal endophytes which contain very few. Conclusion These results underscore the importance of conserving P. erinaceus while exploring its endophytes for potential therapeutic applications.

Abstract Energy-resolved fast-neutron radiography is a powerful non-destructive technique that can be used to remotely measure the quantity and distribution of elements and isotopes in a sample. This is done by comparing the energy-dependent neutron transmission of a sample with the known cross-sections of individual isotopes. The reconstruction of the composition is possible due to the unique features (e.g. resonances) in the cross-sections of individual isotopes. At short-pulsed ( $${\lesssim }$$ 1 ns) neutron sources, such information is accessible via time-of-flight neutron imaging in principle, but requires a detector with nanosecond temporal resolution. Conventional neutron detectors can meet this requirement only by heavily compromising spatial resolution or efficiency. Here, we present a unique approach on fast neutron resonance radiography using a scintillator-based event-mode imaging detector at a short-pulsed neutron source, including first results on spatially mapped resonance profiles using MeV neutrons. The event mode approach applied in the presented detector allows recording of individual neutron interactions with nanosecond precision in time and sub-mm resolution in space. As a result, the entire available neutron energy spectrum can be measured for each pulse. At the same time, the use of a thick scintillator screen and lenses to focus the produced light results in a highly flexible field of view and a high interaction probability in the sensitive volume of the detector.

Abstract Background Mushrooms, an integral component of human diets, range from esteemed delicacies to potentially lethal toxins. The risk of severe poisoning from misidentified species, poses a significant challenge. For clinicians, recognizing mushroom poisoning amidst nonspecific symptoms and determining the specific mushroom ingested are critical yet complex tasks. Additionally, climate change affects the distribution and proliferation of mushroom species, potentially heightening the risk of exposure to toxic varieties. The identification of mushroom intoxication is critical for appropriate treatment. Poisoning with highly toxic species, such as Amanita phalloides (death cap), can result in acute liver and kidney failure. Considering the limited therapeutic options currently available for acute liver failure, we investigated the application of plasmapheresis, a procedure involving the replacement of the patient's plasma with donor plasma, as a potential intervention to improve clinical outcomes in severe cases of mushroom poisoning. Methods This study aimed to assess the trends and treatment outcomes of mushroom poisoning cases from 2005 to 2022, with a particular focus on the number of incidents and the potential impacts of climate change. We undertook a retrospective monocentric cohort study, evaluating 43 patients with mushroom poisoning. The study focused on identifying the variety of mushrooms involved, including psychotropic, spoiled, inedible, or toxic species, and closely examined patients with elevated transaminases indicative for liver damage. To assess clinical outcomes, we evaluated several aspects, including hepatic encephalopathy and other symptoms. Additionally, we monitored blood analysis results through serial measurements, including transaminases, bilirubin, INR, and creatinine levels. Furthermore, we explored the impact of climate changes on the incidence of mushroom poisoning. Results While the incidence of mushroom poisonings remained relatively stable during the first eight years of the study period, it nearly doubled over the past nine years. Nine distinct mushroom types were documented. The study showed no change in season patterns of mushroom poisonings. In cases of severe liver damage accompanied by coagulopathy, plasmapheresis was utilized to replace deficient clotting factors and mitigate the inflammatory response. This intervention proved effective in stabilizing coagulation parameters, such as the international normalized ratio (INR) Plasmapheresis was performed until the INR reached stable levels, preventing the occurrence of severe bleeding complications. In instances where liver failure was deemed irreversible, plasmapheresis functioned as a bridging therapy to manage bleeding risks and to stabilize the patient while awaiting liver transplantation. Conclusion The findings underscore the need for heightened awareness among healthcare professionals regarding mushroom poisoning and emphasize the importance of considering climate change as a factor that may alter mushroom distribution and toxicity. Additionally, this study highlights the potential of plasmapheresis in managing severe cases.

Abstract Africa, with 18.3% of the world’s population, faces a significant research output gap, contributing only 2% of global research despite bearing a substantial disease burden. This discrepancy is partly due to inadequate research infrastructure, limited funding, and a shortage of physician-scientists. These challenges exacerbate the continent’s reliance on research findings from high-income countries, which often does not align with Africa’s unique health issues. Establishing student research hubs in medical schools is a promising strategy to addressing this issue. Such hubs can cultivate a research-oriented mindset and enhance problem-solving skills among future medical professionals. This paper examines the operational model of the College Research and Innovation Hub (CRIH) at the University of Ibadan, Nigeria. Founded in 2019, CRIH has been successful in promoting research among medical students through structured programs and mentorship. The paper provides insights into CRIH’s strategies and impact, offering a framework for replicating this model in Nigeria to improve research output and address local health challenges.

Abstract Background In academic medicine, the lack of gender equity hinders the career progression of women academics. This can often affect scientific productivity and widen the gender gap that exists in this field. As such, this study aimed to understand how full-time faculty members in academic medicine perceive the climate for women academics and identify target areas for interventions supporting gender equity. Methods This study adopted an embedded mixed-methods design. Data collection was done from November 2022 to January 2023, at the National University of Singapore (NUS) School of Medicine. The participants comprised academic clinicians and non-clinician faculty members who were either currently employed full-time at the NUS School of Medicine or had recently resigned. They completed an adapted version of the Culture Conducive to Women’s Academic Success (CCWAS) questionnaire, which assessed their perceptions of the faculty climate across four domains: equal access, work-life balance, freedom from gender bias, and supportive leadership. Quantitative findings were complemented by qualitative data gathered through open-ended survey questions. ANOVA and t-test were used to analyse the quantitative data, and content analysis was used to analyse the qualitative data. Results Compared to female participants (M = 140.0, SD = 57.9), male participants perceived greater gender equity (M = 158.7, SD = 62.9). Personal experiences of gender inequity were described by some female participants. Participants also raised various suggestions to improve work-life balance for both male and female faculty members, mitigate structural gender bias and increasing support for women faculty. Conclusions Female faculty members tend to have a less favourable view of the working climate for women in academic medicine, compared to their male counterparts. This might be attributed to differences in awareness of gender inequity and understanding of gender bias. Findings of this study provided further insight into the perceptions of faculty members regarding workplace gender equity and interventions that can be implemented to support them in their career. Trial registration Ethical approval was obtained from the National University of Singapore Institutional Review Board (NUS-IRB-2022-325).

Abstract Background In cohort studies with time-to-event outcomes, covariates of interest often have values that change over time. The classical Cox regression model can handle time-dependent covariates but assumes linear effects on the log hazard function, which can be limiting in practice. Furthermore, when multiple correlated covariates are studied, it is of great interest to model their joint effects by allowing a flexible functional form and to delineate their relative contributions to survival risk. Methods Motivated by the World Trade Center (WTC)-exposed Fire Department of New York cohort study, we proposed a partial-linear single-index Cox (PLSI-Cox) model to investigate the effects of repeatedly measured metabolic syndrome indicators on the risk of developing WTC lung injury associated with particulate matter exposure. The PLSI-Cox model reduces the dimensionality of covariates while providing interpretable estimates of their effects. The model’s flexible link function accommodates nonlinear effects on the log hazard function. We developed an iterative estimation algorithm using spline techniques to model the nonparametric single-index component for potential nonlinear effects, followed by maximum partial likelihood estimation of the parameters. Results Extensive simulations showed that the proposed PLSI-Cox model outperformed the classical time-dependent Cox regression model when the true relationship was nonlinear. When the relationship was linear, both the PLSI-Cox model and classical time-dependent Cox regression model performed similarly. In the data application, we found a possible nonlinear joint effect of metabolic syndrome indicators on survival risk. Among the different indicators, BMI had the largest positive effect on the risk of developing lung injury, followed by triglycerides. Conclusion The PLSI-Cox models allow for the evaluation of nonlinear effects of covariates and offer insights into their relative importance and direction. These methods provide a powerful set of tools for analyzing data with multiple time-dependent covariates and survival outcomes, potentially offering valuable insights for both current and future studies.

Abstract Background The Surprise Question (SQ) - Would you be surprised if this patient died within the next 6 months? - is a validated tool for mortality prediction. The Mount Sinai Cardiac Intensive Care Unit (CICU) incorporated the SQ into a novel EHR workflow to identify patients who would benefit from early initiation of Palliative Care (PC). Methods Implementation of the SQ proceeded in two steps. During the feasibility pilot (December 2021-March 2022), providers answered the SQ using an EXCEL spreadsheet for all CICU patients, without changing other workflows. In April 2022, the CICU launched a new workflow-column built into the Epic patient-list dashboard with the SQ as the backbone. For patients with SQ answers of “NO,” providers were prompted to facilitate and document a goals of care (GOC) conversation. We conducted a retrospective, observational, quasi-experimental study of all admissions to the CICU with SQ = NO between December 2021-September 2022. Clinical data was obtained via EHR query and chart review. We compared the frequency and timing of GOC conversations and the likelihood of redirected GOC (defined as code status change and/or hospice discharge) during the 3-month pilot versus the 6-month implementation period. Results 195 admissions were included: median [IQR] age 72.0 [61.0, 84.0] years; LOS > 5 days 43.6%; CICU mortality 17.9%. These clinical characteristics were comparable between the pilot (N = 57) and implementation (N = 138) periods. However, ICU interventions (i.e. mechanical ventilation, renal replacement therapy) were more common among the pilot cohort (52.6% vs. 33.3%, p = .015). For the primary outcomes, compared to the pilot period, there was a significantly higher frequency of GOC conversations (61.4% vs. 81.2%, p = .004) and GOC conversations

The contemporary cultural practices associated with animals give rise to a novel dual concept of corporeality and sensuality. The growth of consumerism in accordance with the feline model of consumption gives rise to the formation of a society where the characteristics associated with the feline species become the prevailing norm. In light of the above, it seems pertinent to examine the strategies of social felinization and to identify the symbolic repressive markers that maintain it, as evidenced in viral cat content. The examination of the most prevalent feline-themed materials on the post-Soviet Internet reveals that the digital representation of cats is primarily shaped by human characteristics, rather than those inherent to the animal itself. This gives the digital cats a subjectivity that is more akin to that of humans. The increasing anthropomorphisation of cats and the felinization of humans has resulted in the emergence of a dystopian world characterised by the “cat police”. In this context, the cat assumes a more prominent role than its human counterpart, thereby conferring upon it the authority to exercise control and impose punishment. However, the methods of control and punishment employed by the “koshchichkina” remain flexible and adaptable to changing corporeality and sensuality, expressed through ironic memes, short videos and clips. The findings of this research can be incorporated into an interdisciplinary study of the mechanisms of identity formation of the modern man and the formation of a new canon of his sensuality and corporeality.

Hurricane Helene triggered 1792 landslides across western North Carolina and has caused damage to 79 bridges to date. Helene hit western North Carolina days after a low-pressure system dropped up to 254 mm of rain in some locations of western North Carolina (e.g., Asheville Regional Airport). The already waterlogged region experienced devastation as significant additional rainfall occurred during Helene, where some areas, like Asheville, North Carolina received an additional 356 mm of rain (National Weather Service, 2024). In this study, machine learning (ML)-generated multi-hazard landslide susceptibility maps are compared to the documented landslides from Helene. The landslide models use the North Carolina landslide database, soil survey, rainfall, USGS digital elevation model (DEM), and distance to rivers to create the landslide variables. From the DEM, aspect factors and slope are computed. Because recent research in western North Carolina suggests fault movement is destabilizing slopes, distance to fault was also incorporated as a predictor variable. Finally, soil types were used as a wildfire predictor variable. In total, 4794 landslides were used for model training. Random Forest and logistic regression machine learning algorithms were used to develop the landslide susceptibility map. Furthermore, landslide susceptibility was also examined with and without consideration of wildfires. Ultimately, this study indicates heavy rainfall and debris-laden floodwaters were critical in triggering both landslides and scour, posing a dual threat to bridge stability. Field investigations from Hurricane Helene revealed that bridge damage was concentrated at bridge abutments, with scour and sediment deposition exacerbating structural vulnerability. We evaluated the assumed flooding potential (AFP) of damaged bridges in the study area, finding that bridges with lower AFP values were particularly vulnerable to scour and submersion during flood events. Differentiating between landslide-induced and scour-induced damage is essential for accurately assessing risks to infrastructure. The findings emphasize the importance of comprehensive hazard mapping to guide infrastructure resilience planning in mountainous regions.

This study aimed to assess the contribution of leadership to Total Quality Management (TQM) implementation in secondary education and to determine the extent of TQM practices, as perceived by teachers, within the Ioannina region, NW Greece. The study also explored how these perceptions relate to various variables. A quantitative approach was employed, involving 128 teachers from secondary education schools in the Ioannina region, NW Greece. The findings illuminate the profound influence of leadership on successful TQM implementation. Effective leaders foster a climate of collaboration, provide resources, and encourage teamwork, ultimately contributing to the enhancement of teaching and learning quality. Moreover, this research study underscores the compatibility of the TQM and EFQM principles in promoting quality enhancement within educational settings. The EFQM Leadership score was calculated by averaging the ratings of leadership behaviors like collaboration, communication, and decision making. The results reveal a strong commitment to TQM principles, with overall TQM and EFQM Leadership scores of 3.58 (±0.11) and 3.46 (±0.30), respectively. The EFQM Leadership dimensions demonstrated significant alignment, particularly in areas such as teacher participation and communication of quality standards. However, there is room for improvement in encouraging two-way communication and ensuring consistent leadership decision implementation. This study highlights the crucial role of effective leadership in fostering a culture of quality and excellence in secondary education, emphasizing the importance of collaboration, communication, and alignment with EFQM principles for successful TQM implementation.

The purpose of this review is to compile and discuss available evidence in humans on the efficacy of YHM supplementation on performance in different exercise modalities. Yohimbine (YHM) is a naturally occurring alkaloid that induces increases in sympathetic nervous system (SNS) activation effectively initiating “fight or flight” responses. In supplement form, YHM is commonly sold as an isolated product or combined into multi-ingredient exercise supplements and is widely consumed in fitness settings despite the lack of empirical support until recently. YHM primarily acts as an α2-adrenergic receptor antagonist effectively increasing norepinephrine release from sympathetic neurons. YHM has been implicated in improving or altering cardiovascular function, blood flow, lactate metabolism, and muscle function. Emerging evidence has suggested that YHM may have the potential to improve performance in a wide range of exercise modes including endurance, sprint, and resistance exercise. Performance enhancement with YHM is mediated by mechanistic underpinnings of physiological and psychological alterations to exercise responses including increased sympathetic activation, adaptive hemodynamic changes, increased alertness, and decreased fatigue. However, YHM use is not without risk as it has high interindividual variability in bioavailability, can be deceptively potent, lacks widely accepted dosing recommendations, and, when taken in large doses, has been empirically documented to result in serious side effects. Despite this, the evidence presented in this review suggests low doses of YHM are tolerable and may serve as an ideal exercise training aid due to acute enhancement of physical performance. However, safety concerns remain outstanding and temperance should be used when using YHM and similar sympathomimetics.

Abstract Accurate intra‐operative Remaining Surgery Duration (RSD) predictions allow for anaesthetists to more accurately decide when to administer anaesthetic agents and drugs, as well as to notify hospital staff to send in the next patient. Therefore, RSD plays an important role in improved patient care and minimising surgical theatre costs via efficient scheduling. In endoscopic pituitary surgery, it is uniquely challenging due to variable workflow sequences with a selection of optional steps contributing to high variability in surgery duration. This article presents PitRSDNet for predicting RSD during pituitary surgery, a spatio‐temporal neural network model that learns from historical data focusing on workflow sequences. PitRSDNet integrates workflow knowledge into RSD prediction in two forms: (1) multi‐task learning for concurrently predicting step and RSD; and (2) incorporating prior steps as context in temporal learning and inference. PitRSDNet is trained and evaluated on a new endoscopic pituitary surgery dataset with 88 videos to show competitive performance improvements over previous statistical and machine learning methods. The findings also highlight how PitRSDNet improves RSD precision on outlier cases utilising the knowledge of prior steps.

Abstract Improved surgical skill is generally associated with improved patient outcomes, although assessment is subjective, labour intensive, and requires domain‐specific expertise. Automated data‐driven metrics can alleviate these difficulties, as demonstrated by existing machine learning instrument tracking models. However, these models are tested on limited datasets of laparoscopic surgery, with a focus on isolated tasks and robotic surgery. Here, a new public dataset is introduced: the nasal phase of simulated endoscopic pituitary surgery. Simulated surgery allows for a realistic yet repeatable environment, meaning the insights gained from automated assessment can be used by novice surgeons to hone their skills on the simulator before moving to real surgery. Pituitary Real‐time INstrument Tracking Network (PRINTNet) has been created as a baseline model for this automated assessment. Consisting of DeepLabV3 for classification and segmentation, StrongSORT for tracking, and the NVIDIA Holoscan for real‐time performance, PRINTNet achieved 71.9% multiple object tracking precision running at 22 frames per second. Using this tracking output, a multilayer perceptron achieved 87% accuracy in predicting surgical skill level (novice or expert), with the ‘ratio of total procedure time to instrument visible time’ correlated with higher surgical skill. The new publicly available dataset can be found at https://doi.org/10.5522/04/26511049.

The rock art of the Minusinsk Basin has a long academic history; however, it still brings about new fascinating discoveries. Some petroglyphs of the Tesin period show people sitting cross-legged on the floor in the so-called Oriental fashion. These images have not yet received special scientific attention. Such images are most often single; they are to be found on such petroglyph sites and mound stones of the Minusinsk Basin as Oglakhty, Kamenka, Togr-Tag, Abakan-Perevoz, Tepsei, etc. The present analysis of their legs made it possible to describe the variability of the sitting posture. Their arms are symmetrically arranged, the hands being devoid of any attributes but for one exception: the cross-legged sitter on a mound stone in Tepsei is holding a snake. Ancient Oriental art has no iconographic patterns for the Snake-Holder. In some cases, the Snake-Holder is depicted kneeling. The Early Iron Age art renders a certain analogy to the Snake-Holder from Tepsei, i.e., the horned deity from the Gundestrup cauldron. The earliest images of an anthropomorphic creature sitting cross-legged on the floor belong to the Neolithic Age (Crete) and Bronze Age (Harappan civilization). The archaeological and ethnographic analysis revealed the polyvariant character of the cross-legged sitter. The images from the Minusinsk petroglyphs demonstrate obvious similarities with the art of the Early Iron Age and the early Middle Ages. Multiple variants of the cross-legged sitter appeared in ancient art of different peoples across the world. However, the similarity hardly indicates borrowing: the universal conditions of human routine and religious practices rendered similar body postures captured in art.

Abstract Background With the global population aging rapidly, dementia has become a pressing public health challenge, affecting the cognitive functions and daily activities of older adults worldwide. Enhancing literacy about dementia is a proactive prevention strategy, yet the effectiveness of educational programs can vary based on the target population’s background. Thus, understanding dementia knowledge levels across different communities and countries is essential for successful educational interventions. Despite the large аmount of studies, there is no common framework for studying dementia knowledge, leading to significant variability in methods and poor data comparability. Methods A narrative review is conducted to examine the methodological variability in studies of dementia knowledge and to propose a unified framework for future investigations. We hypothesize that significant differences will be evident in the methodologies employed, particularly regarding knowledge domains, research designs, influencing factors, and assessments of attitudes toward dementia. Results A total of 59 research publications published after 2000 were selected, revealing significant variability in approaches to studying dementia knowledge and confirming our hypothesis. We identified eight dementia knowledge domains and various sociodemographic and experiential correlates, along with commonly used complementary assessments. These findings were organized into a unified global framework comprising two core components—dementia knowledge domains and correlates—supplemented by a component addressing affective dispositions towards dementia and an action list to guide future research. The framework aims to provide a foundational basis for enhancing inter-study comparisons and deepening our understanding of dementia knowledge and attitudes across diverse communities. Conclusion Aligning methodologies for surveying dementia knowledge through a common framework can empower stakeholders to implement effective educational programs, fostering an informed and supportive environment for individuals affected by dementia.

Abstract Background Burnout is among the greatest challenges facing healthcare today. Healthcare providers have been found to experience burnout at significant rates, with COVID-19 exacerbating the challenge. Burnout in the healthcare setting has been associated with decreases in job satisfaction, productivity, professionalism, quality of care, and patient satisfaction, as well as increases in career choice regret, intent to leave, and patient safety incidents. In this context, there is a growing need to reduce provider burnout through targeted interventions, yet little is known about what types of interventions may be most effective. The present study aims to contribute to and extend prior literature by using rigorous randomized controlled trial (RCT) methodology with a parallel group design to examine the effectiveness of different interventions in decreasing mental distress, increasing self-efficacy and attenuating inefficiencies and dissatisfiers in the work environment to achieve sustainable improvement.’ Methods The present study is an ongoing randomized controlled trial (RCT) that examines the effectiveness of three different types of interventions to reduce provider burnout: an intervention targeting emotional wellbeing and resilience, Electronic Health Record (EHR) skills training, and performance improvement training, relative to a no-treatment control group. This study aims to enroll a total of 400 healthcare providers in a large urban hospital system. Outcomes will be assessed at post-treatment and 6-month follow-up. Key outcomes include burnout, emotional health, intent to leave, EHR mastery, and confidence in performance improvement. Changes in outcome measurements from baseline to post-intervention across the intervention and control groups will be conducted using linear mixed-effects models (LMM). Discussion This study is novel in that it compares several interventions addressing both personal as well as system-level drivers of provider burnout that have been theorized to operate among healthcare providers. In addition, post-treatment and longer-term follow-up assessments will provide insight into the maintenance of effects. Another innovation is the inclusion of different types of patient-facing providers in the study population (doctors, nurses, and therapists). Trial registration This study was registered at ClinicalTrials.gov (NCT05780892) on March 10th, 2023.

Abstract Background and objectives There is a growing demand for dementia care to be funded by long-term care insurance (LTCI). However, evidence indicates that people with dementia are overlooked in China’s LTCI policy and empirical research on this issue is notably scarce. Among the first seven LTCI pilot cities that officially enrolled people with dementia, Guangzhou is unique for roll-back LTCI policies related to eligibility criteria and benefits. This study aims to explore why people with dementia are overlooked in China’s LTCI policy, using Guangzhou as a case study. Methods Semi-structured interviews were conducted with stakeholders involved in LTCI need assessment and care delivery in Guangzhou. Eight LTCI assessment specialists, 22 formal caregivers, and six informal caregivers were interviewed from December 2021 to October 2022. Data was analyzed using NVivo 11.0 software and the Gilbert welfare framework to identify themes. Results Interviewees reported that need assessment lacked a clear definition, were poorly supervised, and had high moral hazards. Challenges to care delivery included unprofessionalism of formal caregivers, shortage of resources, unprepared informal caregivers, a lack of a supportive environment and the negative impact of COVID-19. Discussion and implications People with dementia are overlooked in LTCI policy which may result from difficulties in implementing dementia-related assessment criteria, and hampered service delivery due to a shortage of skilled caregivers. These issues need to be carefully considered before scaling up the coverage of LTCI policy nationwide.

Background : Roux-en-Y gastric bypass (RYGB) is a standard treatment for severe obesity, but some patients do not achieve the expected success in weight loss. The aim of this study was to evaluate possible predictors of weight loss after RYGB. Methods : Sixty-three patients were included. Pre- and postoperative data were collected from medical records, including comorbidities, anthropometry, energy/macronutrient intake, and physical activity level (PAL). Variants in the brain-derived neurotrophic factor (BDNF; rs6265) and lysophospholipase like 1 (LYPLAL1; rs4846567) genes were investigated. Excess weight loss (EWL) >50% was considered to be successful weight loss (SWL). Logistic regression models were used to verify predictor variables. Results : Participants’ median preoperative body mass index (BMI) was 53 kg/m2 (interquartile range, 46 to 58). At 12 and 24 months after surgery, EWL was 63% and 67%, and the failure rate was 19% and 16%, respectively. The individuals with insufficient weight loss (IWL) after 12 months had higher preoperative weight, BMI, and overweight. At 24 months, lowest frequency of individuals with SWL in the first year was found in the IWL group. No significant differences were found between the groups in dietary intake and PAL. In the logistic regression, high initial BMI was a predictor of the worst response in both periods, and high initial total weight loss was a predictor of a better response at 24 months. The polymorphism analysis did not show differences between groups in either gene. Conclusion : Lower preoperative BMI and greater weight loss at 12 months were predictors of SWL after RYGB.

Abstract Evaluating the effectiveness of cancer treatments in relation to specific tumor mutations is essential for improving patient outcomes and advancing the field of precision medicine. Here we represent a comprehensive analysis of 78,287 U.S. cancer patients with detailed somatic mutation profiling integrated with treatment and outcomes data extracted from electronic health records. We systematically identified 776 genomic alterations associated with survival outcomes across 20 distinct cancer types treated with specific immunotherapies, chemotherapies, or targeted therapies. Additionally, we demonstrate how mutations in particular pathways correlate with treatment response. Leveraging the large number of identified predictive mutations, we developed a machine learning model to generate a risk score for response to immunotherapy in patients with advanced non-small cell lung cancer (aNSCLC). Through rigorous computational analysis of large-scale clinico-genomic real-world data, this research provides insights and lays the groundwork for further advancements in precision oncology.

Background. Dryudella sp. is a Holarctic genus, which includes 58 species. The majority of them, however, 29 species in particular, are common in Palearctic. On the territory of Ukraine the genus was represented by four species, collected in the Eastern, Southern and Central Ukraine. The biology of the genus has been insufficiently studied; its certain aspects having been studied only for a few representatives of the genus. Materials and Methods. A specimen of a wasp was captured with the help of an entomological net using the method of selective catching on the territory of the Hrabunske department of Nature Reserve “Rivnenskyi” (https://www.inaturalist.org/observations/250256988). The species of the wasp was identified using appropriate descriptions and keys. The biotope in which the wasp was captured was identified with the help of the National Catalogue of Biotopes of Ukraine. Results and Discussion. A new species of wasp of the genus Dryudella was registered in the territory of Ukraine – Dryudella lineata Mocsáry, 1879 of the family Crabronidae (Apoidea: Crabronidae: Astatinae). The specimen female D. lineata was captured in July 2024 in the territory of Nature Reserve “Rivnenskyi”, in a pine forest in a sandy area. D. lineata is a rare and scarce species of wasp. It has only been recorded in the territory of eight countries. Conclusions. First discovery of D. lineata in Ukraine, in particular in Nature Reserve “Rivnenskyi”. The sample was inventoried (E20 – 3375) and stored in the entomological collection of the Zoological Museum of the Ivan Franko National University of Lviv.

Abstract Sensitivity analyses are important components of physiologically based pharmacokinetic (PBPK) model development and are required by regulatory agencies for PBPK submissions. They assess the impact of parametric uncertainty and variability on model estimates, aid model optimization by identifying parameters requiring calibration, and enable the testing of assumptions within PBPK models. One‐at‐a‐time (OAT) sensitivity analyses quantify the impact on a model output in response to changes in a single parameter while holding others fixed. Global sensitivity analysis (GSA) methods provide more comprehensive assessments by accounting for changes in all uncertain or variable parameters, though at a higher computational cost. This tutorial article presents a software package for conducting both OAT and GSA of PBPK models built in the Open Systems Pharmacology (OSP) Suite. The tool is accessible through either an R script or a graphical user interface, and the outputs consist of sensitivity metrics of pharmacokinetic (PK) parameters, such as Cmax and AUC, evaluated with respect to model input parameters. Results are formatted according to regulatory standards. The OAT analysis methods comprise two‐way local sensitivity analyses and probabilistic uncertainty analyses, whereas the GSA methods include the Morris, Sobol, and EFAST methods. These analyses can be conducted on single PBPK models or pairs of models for the evaluation of the sensitivity of PK parameter ratios in drug–drug interaction studies. The practical application of the package is demonstrated through three illustrative case studies.

The article is devoted to the consideration of the images of I. Stalin and A. Hitler in historical memory. The construction of ideas about the past is based on the possibilities of media, which in the digital age are becoming limitless. With the help of media, images of the past are integrated into the agenda and actualized in the mass consciousness, and personalized figures of history are most in demand. The historical memory of modern society is largely formed on the basis of ideas about the events and heroes of the 20th century, which include the history of totalitarian regimes and the Second World War. The authors put two key figures of the last century with contradictory historical reputations at the center of their research. The article shows the importance of I. Stalin and A. Hitler for historical memory on the basis of available sociological research data. A corpus analysis of the tonality of news reports mentioning these historical figures allowed us to present the proportions of positive and negative use of their names in foreign media publications. Quantitative data made it possible to compare attitudes towards Stalin and Hitler in English-language information resources and explain certain trends in the dynamics of their representation by the nature of the news content. The study of Internet users’ search queries allowed us to supplement the idea of the directions of constructing images of the Soviet leader and the Nazi Fuhrer in historical memory. The data obtained demonstrate the high interest of the world community in ambiguous historical figures. Their images have become part of popular culture, they are used in political struggle and entertainment network discourse, which leaves an imprint on the formation of ideas about them in the media environment. The use of quantitative analysis data to study the images of I. Stalin and A. Hitler makes it possible to determine their place in the historical memory of the modern global community.

The article deals with the mechanics of broadcasting ideology through online user content, dedicated to domestic cats. The author believes that digital culture is changing the logic of the relationship between written and oral, long and short genres of objectification of ideology in mass consciousness. It ensures the presence of complex long ideological genres of Modernity in the media space, reinforcing it with a wide “protective belt” of microformats characteristic of entertainment content. The most typical type of the latter is cat content, which is understood as a form of social reflection that sets a cliched reaction to a media message through the image of a digital cat. The purpose of the article is to analyze the use of political ideologies in the context of Soviet nostalgia. The author examines the polar versions of the visualization of Soviet nostalgia in the context using the example of Vasya Lozhkin’s cats and the VK public “Cats for Communism”. The semantic multilayering of Vasya Lozhkin’s paintings is ensured by the fluidity and interchangeability of zoo- and anthropomorphic features of the characters and the ease of their ethical (de)evolution. The transition of cats to the red side is shown as a rather late phenomenon of digital culture, inscribed in the period of the last five years. Digital cats dearchaize communist ideology by associating it with digital fashion. In general, digital cats disassemble ideological narratives into micro-rhythms and creolize them, performing the function of a mediator forwarding the actualized old ideologies into the digital media space.

Escherichia coli harbors various virulence factors responsible for diarrhea and other diseases in neonatal calves. The antimicrobial resistance (AMR) among the diarrheagenic and non-diarrheagenic E. coli may impose a potential health hazard among the calves and make the antibacterial therapy ineffective. The virulence gene expression among AMR strains plays a crucial role in establishing diarrheal disease with therapeutic complications. This study investigates the diversity of E. coli isolates from neonatal calves. E. coli isolated from the fecal samples were subsequently subjected to pathotyping and virulotyping using the PCR technique. AMR profiling was done by phenotypic and genotypic methods. The ERIC pattern of E. coli pathotypes was compared and correlated with the pattern of AMR and virulence traits. 179 isolates were obtained from 158 fecal samples collected from neonatal calves. Forty-two isolates were pathotypable; predominated by shigatoxigenic E. coli. Seventy-four isolates were ESBL producers. Nineteen isolates were carbapenem resistant and 68 isolates exhibited quinolone resistance. blaAmpC, blaVIM and qnrS were the predominant genes detected among ESBL, carbapenem and quinolone resistance genes, respectively. The present study indicated diverse virulence profiles and the presence of significant ESBL, carbapenem and fluoroquinolone resistance among E. coli pathotypes from calves. The analysis of resistance profiling indicates the risks associated with the indiscriminate antibiotic use among farm animals, which may pose a potential health hazard to livestock owners.