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Abstract αβ T cell receptors (αβTCRs) co-recognise antigens when bound to Major Histocompatibility Complex (MHC) or MHC class I-like molecules. Additionally, some αβTCRs can bind non-MHC molecules, but how much intact antigen reactivities are achieved remains unknown. Here, we identify an αβ T cell clone that directly recognises the intact foreign protein, R-phycoerythrin (PE), a multimeric (αβ)6γ protein complex. This direct αβTCR–PE interaction occurs in an MHC-independent manner, yet triggers T cell activation and bound PE with an affinity comparable to αβTCR–peptide–MHC interactions. The crystal structure reveals how six αβTCR molecules simultaneously engage the PE hexamer, mediated by the complementarity-determining regions (CDRs) of the αβTCR. Here, the αβTCR mainly binds to two α-helices of the globin fold in the PE α-subunit, which is analogous to the antigen-binding platform of the MHC molecule. Using retrogenic mice expressing this TCR, we show that it supports intrathymic T cell development, maturation, and exit into the periphery as mature CD4/CD8 double negative (DN) T cells with TCR-mediated functional capacity. Accordingly, we show how an αβTCR can recognise an intact foreign protein in an antibody-like manner.

Abstract Unifying integration and segregation in the brain has been a fundamental puzzle in neuroscience ever since the conception of the “binding problem.” Here, we introduce a framework that places integration and segregation within a continuum based on a fundamental property of the brain–its structural connectivity graph Laplacian harmonics and a new feature we term the gap-spectrum. This framework organizes harmonics into three regimes–integrative, segregative, and degenerate–that together account for various group-level properties. Integrative and segregative harmonics occupy the ends of the continuum, and they share properties such as reproducibility across individuals, stability to perturbation, and involve “bottom-up” sensory networks. Degenerate harmonics are in the middle of the continuum, and they are subject-specific, flexible, and involve “top-down” networks. The proposed framework accommodates inter-subject variation, sensitivity to changes, and structure-function coupling in ways that offer promising avenues for studying cognition and consciousness in the brain.

Abstract Forest restoration is critical for meeting global objectives related to climate change mitigation, biodiversity conservation and sustainable livelihoods. Recently, new technologies such as unmanned aerial vehicles (hereafter drones) have been promoted to support activities across the planning, implementation, monitoring and maintenance stages of forest restoration. Yet, there is little empirical data on how the development and application of drones are perceived by restoration managers and stakeholders and how drones intersect with existing forest social–ecological systems (SESs). Here, we investigate how drone tree planting initiatives in Australia can support ecosystem restoration. Through interviews and focus groups with key actors, we examine the opportunities and challenges that have been experienced or are foreseen with drone use. Opportunities included the ability of drones to access degraded sites that are difficult or unsafe to access on foot, for example, following bushfires, floods or landslides. They were also perceived to ease the labour shortage of bush regenerators in Australia. Drones were considered particularly useful when operating at scales of around 20–100 ha. Challenges included restrictive flying regulations that prohibit use of artificial intelligence to plot courses through complex terrain, their unproven ability to control or eradicate weeds and the uncertain supply, germination and survival rates of seeds—upon which drone‐based restoration relies. Drone use may also reduce the emotional, spiritual and cultural connections of people to the land, as compared to hand‐planting seeds or seedlings. We conclude by conceptualising how drone‐assisted restoration can be embedded within a forest SESs management framework. Ultimately, we argue that drones offer a ‘boutique’ restoration approach that supports, rather than replaces, traditional forest restoration techniques. Read the free Plain Language Summary for this article on the Journal blog.

Abstract Quorum sensing (QS) is a mechanism that regulates group behavior in bacteria, and in Gram-positive bacteria, the communication molecules are often cyclic peptides, called autoinducing peptides (AIPs). We recently showed that pentameric thiolactone-containing AIPs from Listeria monocytogenes, and from other species, spontaneously undergo rapid rearrangement to homodetic cyclopeptides, which hampers our ability to study the activity of these short-lived compounds. Here, we developed chemically modified analogues that closely mimic the native AIPs while remaining structurally intact, by introducing N-methylation or thioester-to-thioether substitutions. The stabilized AIP analogues exhibit strong QS agonism in L. monocytogenes and allow structure–activity relationships to be studied. Our data provide evidence to suggest that the most potent AIP is in fact the very short-lived thiolactone-containing pentamer. Further, we find that the QS system in L. monocytogenes is more promiscuous with respect to the structural diversity allowed for agonistic AIPs than reported for the more extensively studied QS systems in Staphylococcus aureus and Staphylococcus epidermidis. The developed compounds will be important for uncovering the biology of L. monocytogenes, and the design principles should be broadly applicable to the study of AIPs in other species.

Abstract This study was designed to assess how different prompt engineering techniques, specifically direct prompts, Chain of Thought (CoT), and a modified CoT approach, influence the ability of GPT-3.5 to answer clinical and calculation-based medical questions, particularly those styled like the USMLE Step 1 exams. To achieve this, we analyzed the responses of GPT-3.5 to two distinct sets of questions: a batch of 1000 questions generated by GPT-4, and another set comprising 95 real USMLE Step 1 questions. These questions spanned a range of medical calculations and clinical scenarios across various fields and difficulty levels. Our analysis revealed that there were no significant differences in the accuracy of GPT-3.5's responses when using direct prompts, CoT, or modified CoT methods. For instance, in the USMLE sample, the success rates were 61.7% for direct prompts, 62.8% for CoT, and 57.4% for modified CoT, with a p-value of 0.734. Similar trends were observed in the responses to GPT-4 generated questions, both clinical and calculation-based, with p-values above 0.05 indicating no significant difference between the prompt types. The conclusion drawn from this study is that the use of CoT prompt engineering does not significantly alter GPT-3.5's effectiveness in handling medical calculations or clinical scenario questions styled like those in USMLE exams. This finding is crucial as it suggests that performance of ChatGPT remains consistent regardless of whether a CoT technique is used instead of direct prompts. This consistency could be instrumental in simplifying the integration of AI tools like ChatGPT into medical education, enabling healthcare professionals to utilize these tools with ease, without the necessity for complex prompt engineering.

Abstract Background The COVID-19 pandemic has highlighted the importance of evidence-informed priority setting and situational analysis in pandemic preparedness and response. Health Technology Assessment (HTA) has been identified as an essential tool for evidence-informed decision-making in healthcare. However, the potential role of HTA in pandemic preparedness and response in Africa has yet to be explored. The objective of this scoping review is to ascertain the current understanding of the possible role of HTA in Africa to support future pandemic preparedness and response. Methods We will conduct a scoping review of literature published between 2010 and 2024. Electronic databases like Embase, PubMed, Scopus, Web of Science, and Google Scholar will be utilized to perform the search. We will also search grey literature sources such as websites of relevant organizations and government agencies. The search will only include studies that were conducted in the English language. Two reviewers will evaluate the titles and abstracts of the publications independently to determine their eligibility using Covidence. Full-text articles will be reviewed for eligibility and data extraction. The data will be extracted using a standardized form. The extracted data will include information on the study design, objectives, methods, findings, and conclusions. The thematic analysis approach will guide the data analysis. Themes and sub-themes will be identified and reported. The review will be reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines. Discussion This scoping review will identify the existing knowledge on the potential role of HTA in Africa to support future pandemic preparedness and response. The findings will aid in identifying deficiencies in knowledge and provide valuable insights for future study. Additionally, they will inform policy-makers and other stakeholders about the potential contribution of the Health Technology Assessment (HTA) in enhancing Africa’s readiness and response to pandemics.

Abstract The severity of bacterial pneumonia can be worsened by impaired innate immunity resulting in ineffective pathogen clearance. We describe a mitochondrial protein, aspartyl-tRNA synthetase (DARS2), which is released in circulation during bacterial pneumonia in humans and displays intrinsic innate immune properties and cellular repair properties. DARS2 interacts with a bacterial-induced ubiquitin E3 ligase subunit, FBXO24, which targets the synthetase for ubiquitylation and degradation, a process that is inhibited by DARS2 acetylation. During experimental pneumonia, Fbxo24 knockout mice exhibit elevated DARS2 levels with an increase in pulmonary cellular and cytokine levels. In silico modeling identified an FBXO24 inhibitory compound with immunostimulatory properties which extended DARS2 lifespan in cells. Here, we show a unique biological role for an extracellular, mitochondrially derived enzyme and its molecular control by the ubiquitin apparatus, which may serve as a mechanistic platform to enhance protective host immunity through small molecule discovery.

Abstract Background Nigeria commenced rollout of vaccination for coronavirus disease 2019 (COVID-19) in March 2021 as part of the national public health response to the pandemic. Findings from appropriately contextualized cost–effectiveness analyses (CEA) as part of a wider process involving health technology assessment (HTA) approaches have been important in informing decision-making in this area. In this paper we outline the processes that were followed to identify COVID-19 vaccine stakeholders involved in the selection, approval, funding, procurement and rollout of vaccines in Nigeria, and describe the process routes we identified to support uptake of HTA-related information for evidence-informed policy in Nigeria. Methods Our approach to engaging with policy-makers and other stakeholders as part of an HTA of COVID vaccination in Nigeria consisted of three steps, namely: (i) informal discussions with key stakeholders; (ii) stakeholder mapping, analysis and engagement; and (iii) communication and dissemination strategies for the HTA-relevant evidence produced. The analysis of the stakeholder mapping uses the power/interest grid framework. Results The informal discussion with key stakeholders generated six initial policy questions. Further discussions with policy-makers yielded three suitable policy questions for analysis: which COVID-19 vaccines should be bought; what is the optimal mode of delivery of these vaccines; and what are the cost and cost–effectiveness of vaccinating people highlighted in Nigeria’s phase 2 vaccine rollout prioritized by the government, especially the inclusion of those aged between 18 and 49 years. The stakeholder mapping exercise highlighted the range of organizations and groups within Nigeria that could use the information from this HTA to guide decision-making. These stakeholders included both public/government, private and international organizations The dissemination plan developed included disseminating the full HTA results to key stakeholders; production of policy briefs; and presentation at different national and international conferences and peer-reviewed publications. Conclusions HTA processes that involve stakeholder engagement will help ensure important policy questions are taken into account when designing any HTA including any underpinning evidence generation. Further guidance about stakeholder engagement throughout HTA is required, especially for those with low interest in vaccine procurement and use.

Abstract Background Neuroblastoma is the most common extra-cranial pediatric solid tumor. 131I-metaiodobenzylguanidine (MIBG) is a targeted radiopharmaceutical highly specific for neuroblastoma tumors, providing potent radiotherapy to widely metastatic disease. Aurora kinase A (AURKA) plays a role in mitosis and stabilization of the MYCN protein in neuroblastoma. We aimed to study the impact of AURKA inhibitors on DNA damage and tumor cell death in combination with 131I-MIBG therapy in a pre-clinical model of high-risk neuroblastoma. Results Using an in vivo model of high-risk neuroblastoma, we demonstrated a marked combinatorial effect of 131I-MIBG and alisertib on tumor growth. In MYCN amplified cell lines, the combination of radiation and an AURKA A inhibitor increased DNA damage and apoptosis and decreased MYCN protein levels. Conclusion The combination of AURKA inhibition with 131I-MIBG treatment is active in resistant neuroblastoma models.

Few studies describe workshops as a method for obtaining and integrating diverse participant perspectives for contextualisation. This article describes an online workshop as a transdisciplinary data collection method for contextualising theoretical elements of a framework for knowledge translation to improve wound care in South African nursing homes. Knowledge translation can be more effective when the theoretical components are contextualised and aligned with the specific needs in the context. The online workshop was conducted with 10 participants involved with wound care and change processes in nursing homes across South Africa. The participants consisted of healthcare professionals, family members of those in care and nursing home management staff. Participatory design principles were applied during the online workshop, which was hosted on BlackBoard CollaborateTM Ultra. In this qualitative study, live polls, facilitated discussion, virtual whiteboard posts, and breakaway activities were used to collect the data. The data were analysed and integrated using both deductive and inductive processes for a comprehensive understanding. The workshop enabled the researchers to ascertain integrated perspectives to contextualise the knowledge translation framework’s elements. Barriers to evidence-based wound care in nursing homes and nine values for dignified care for older persons were identified. Transdisciplinary contribution: This article shows how an online workshop was conducted with a group of participants from various healthcare disciplines, family members and institutional management to achieve a contextualised and pragmatic description of theoretical elements. Contextualisation aims to enhance the effectiveness of a knowledge translation framework for use in nursing homes.

Abstract Nest‐site fidelity is a common strategy in birds and is believed to be adaptive due to familiarity with local conditions. Returning to previously successful nest sites (i.e., the win‐stay lose‐switch strategy) may be beneficial when habitat quality is spatially variable and temporally predictable; however, changes in environmental conditions may constrain dispersal decisions despite previous reproductive success. We used long‐term (2000–2017) capture‐mark‐reencounter data and hierarchical models to examine fine‐scale nest‐site fidelity of emperor geese (Anser canagicus) on the Yukon–Kuskokwim Delta in Alaska. Our objectives were to quantify nest‐site dispersal distances, determine whether dispersal distance is affected by previous nest fate, spring timing, or major flooding events on the study area, and determine if nest‐site fidelity is adaptive in that it leads to higher nest survival. Consistent with the win‐stay lose‐switch strategy, expected dispersal distance for individuals that failed their nesting attempt in the previous year was greater (207.7 m, 95% HPDI: 151.1–272.7) than expected dispersal distance for individuals that nested successfully in the previous year (125.5 m, 95% HPDI: 107.1–144.9). Expected dispersal distance was slightly greater following years of major flooding events for individuals that nested successfully, although this pattern was not observed for individuals that failed their nesting attempt. We did not find evidence that expected dispersal distance was influenced by spring timing. Importantly, dispersal distance was positively related to daily survival probability of emperor goose nests for individuals that failed their previous nesting attempt, suggesting an adaptive benefit to the win‐stay lose‐switch strategy. Our results highlight the importance of previous experience and environmental variation for informing dispersal decisions of a long‐lived goose species. However, it is unclear if dispersal decisions based on previous experience will continue to be adaptive as variability in environmental conditions increases in northern breeding areas.

In this study, an eco-friendly and novel hydrogel based on a crosslinked polyvinyl alcohol (PVA), iota carrageenan (IC) and polyvinylpyrrolidone (PVP) scaffold, containing a large amount (10–50 wt%) of nanoscale palm fronds (NPF) as additives, for water purification was demonstrated. A life cycle assessment (LCA) findings on NPF as biomass waste incorporated into PVA_PVP_IC polymer matrix was presented, and the results highlight the necessity of focused actions to reduce environmental impact and support the palm waste utilization in a sustainable manner. The multicomponent nanocomposite hydrogels were examined as adsorbents in a system work in batches for methylene blue (MB) and paracetamol (PCT) removal. The results show that, the presence of NPF, which dispersed in the hydrogel PVA_PVP_IC scaffolds containing both covalent and non-covalent cross-linking bonds, greatly enhanced the MB and PCT adsorption efficiency. A response surface methodology (RSM) model was used to find the best operating parameters of contaminant adsorption, including time, adsorbent dose, and starting concentration of pollutants. By using this statistical model, it was found that the optimal conditions for the adsorption reaction to achieve the complete removal of MB are 66.7 h adsorption time duration, 98.5 mg L−1 starting concentration, and an adsorbent dose of 5.9 mg, while for the complete removal of PCT, it is 57.6 h adsorption time duration, 80 mg L−1 starting concentration, and an adsorbent dose of 6 mg. The reusability of the nanocomposite hydrogels were tested for 5 cycles, all showed high adsorption capacity, indicating the potential for practical application of this nanocomposite hydrogel system. This study indicates that the prepared nanocomposite hydrogel raises the standard used for treatment of wastewater and also gives a solution to protect the environment and mitigate global warming.

Introduction We previously reported global regional differences in smoking cessation outcomes, with smokers of US origin having lower quit rates than smokers from some other countries. This post-hoc analysis examined global regional differences in individual-level and country-level epidemiological, economic and tobacco regulatory factors that may affect cessation outcomes.Methods EAGLES (Evaluating Adverse Events in a Global Smoking Cessation Study) was a randomised controlled trial that evaluated first-line cessation medications and placebo in 8144 smokers with and without psychiatric disorders from 16 countries across seven regions. Generalised linear and stepwise logistic regression models that considered pharmacotherapy treatment, psychiatric diagnoses, traditional individual-level predictors (eg, demographic and smoking characteristics) and country-specific smoking prevalence rates, gross domestic product (GDP) per capita, relative cigarette cost and WHO-derived MPOWER scores were used to predict 7-day point prevalence abstinence at the end of treatment.Results In addition to several traditional predictors, three of four country-level variables predicted short-term abstinence: GDP (0.54 (95% CI 0.47, 0.63)), cigarette relative income price (0.62 (95% CI 0.53, 0.72)) and MPOWER score (1.03 (95% CI 1.01, 1.06)). Quit rates varied across regions (22.0% in Australasia to 55.9% in Mexico). With northern North America (USA and Canada) as the referent, the likelihood of achieving short-term abstinence was significantly higher in Western Europe (OR 1.4 (95% CI 1.14, 1.61)), but significantly lower in Eastern Europe (0.39 (95% CI 0.22, 0.69)) and South America (0.17 (95% CI 0.08, 0.35)).Conclusions Increased tobacco regulation was associated with enhanced quitting among participants in the EAGLES trial. Paradoxically, lower GDP, and more affordable cigarette pricing relative to a country’s GDP, were also associated with higher odds of quitting. Geographical region was also a significant independent predictor.Trial registration number ClinicalTrials.gov, NCT01456936.

Abstract Growing demands on ocean resources are placing increasing pressures on ocean ecosystems. To assess the current state of knowledge of future human pressures on the ocean, we conducted a literature review of recent and projected trends of 25 anthropogenic pressures, comprising most of the identified human pressures on the global oceans. To better understand gaps in the data, we developed a comprehensive framework of the activities contributing to each pressure. All pressures were allocated to five categories (biological disruption, disturbance and removal, altered ocean chemistry, pollution, and climate pressures). All pressures are expected to worsen in the future under business‐as‐usual scenarios (or similar) based on past trajectories and/or models of future scenarios. Eight of the pressures assessed have not been projected into the future (diseases and pathogens, introduced coastal wildlife predation, disruption to sediment dynamics, wildlife strikes, organic and inorganic chemical pollution, light and noise pollution), likely due to the limited availability of data describing current pressures, the challenges of modeling future pressures, and high levels of uncertainty. We thus recommend they receive priority attention to assess their likely future trajectories, given their potential magnitude of influence.

There are many potential approaches to marine carbon dioxide removal (mCDR), of which ocean iron fertilization (OIF) has the longest history of study. However, OIF studies to date were not primarily designed to quantify the durability of carbon (C) storage, nor how wise OIF might be as an mCDR approach. To quantify C sequestration, we introduce a metric called the “centennial tonne,” defined as 1,000 kg of C isolated from atmospheric contact for on average at least 100 years. We present the activities needed to assess OIF from a scientific and technological perspective, and additionally, how it might be responsibly studied and potentially deployed. The five activities include: field studies in the Northeast Pacific; improved modeling for field studies, data assimilation and predictions at larger scales; improvements in monitoring, reporting and verification (MRV) for C, and also MRV for tracking ecological and environmental impacts; and developing new iron sources and their delivery, to increase efficiencies and reduce costs. The fifth activity is to understand whether public and community support exists for OIF, and what governance structures might support further research and possible deployment of OIF. This article is written by a multidisciplinary experts group called Exploring Ocean Iron Solutions (ExOIS) that is organized around a responsible code of conduct. Of the mCDR approaches, OIF has the potential to be low cost, scalable, and rapidly deployable. Reducing CO2 emissions must lead the way, but there is also an urgency to decide under what conditions and whether OIF might be deployed or not.

Road networks and their associated vehicular traffic disturb many terrestrial systems, but inventories of roads used to assess these effects often focus on the ‘where’ (e.g., local road type and density) and neglect the ‘when’ (e.g., temporal disturbance) or ‘how much’ (e.g., traffic volume disturbance). We developed annual estimates of the ‘when’ (road age) and ‘how much’ (vehicular traffic volume) across 148,172 km of highways, arterials, collectors, local, and gravel/graded roads within the state of Wyoming for the years 1986 to 2020 to provide a comprehensive dataset for future ecological investigations. We leveraged a suite of ancillary data on surface disturbances (e.g., oil & gas drilling operations, wind turbines, and open pit mines) with known establishment dates and combined them using graph theory and centrality metrics to estimate the age of each road. We then predicted traffic volume obtained from the Wyoming Department of Transportation for each year across Wyoming using a machine learning method, XGBoost, and a separate set of spatial covariates hypothesized to explain traffic patterns across large regions. We found that 132,476 km of these roads likely existed before 1986, but that 16,693 km (10.7 %) of roads have been built since 1986. Overall, our estimates of road age were 89 % accurate when assessed on a subset of 1,330 roads with high-resolution aerial imagery. Mean absolute error for predicting traffic volume ranged from 35.2 to 77.9 annual average daily traffic (aadt) for trucks and 269.2 to 516.7 aadt for all-vehicles across the 35 years. We found that mean traffic volume across the state increased by 23 % for both truck-only traffic and all vehicular traffic from 1986 to 2020. However, changes in traffic volume have varied substantially across the state (e.g., 100 % increases in volume in some areas, while other areas experienced declines of up to 1,786 %). We also illustrate a novel application of these data by predicting rates of reported wildlife-vehicle collisions (WVCs) along a subset of roads. We found evidence of a non-linear relationship that supported a threshold hypothesis for WVCs, wherein increases in traffic volume equate to increases in WVCs up to a threshold, above which increases in traffic volume result in declines in WVCs. The data provided here will enable better-informed studies of road ecology to address how roads may affect wildlife populations and key ecosystems across Wyoming.

Abstract Cognitive decline and spinal pain (back pain [BP] and neck pain [NP]) represent a major public health challenge, yet the potential relationship between them remains elusive. A retrospective analysis of the Longitudinal Study of Ageing Danish Twins was performed to determine any potential relationships between BP/NP and cognitive function adjusting for age, sex, educational and socioeconomic status. A total of 4731 adults (2788 females/1943 males) aged 78 ± 6 (SD) years were included in the analysis. We observed a 1‐month prevalence of 25% with BP, 21% with NP and 11% for combined BP/NP. While there were no differences in cognition scores for males and females reporting combined BP/NP, compared to those without combined BP/NP (34.38 points [95% confidence interval (CI) = 31.88, 36.88] vs. 35.72 points [95% CI = 35.19, 36.26]; P = 0.180; and 35.72 points [95% CI = 35.19, 36.26] vs. 35.85 points [95% CI = 35.39, 36.31]; P = 0.327; for male and females, respectively), an adjusted analysis revealed that males with combined BP/NP presented with lower cognitive scores compared to males without combined BP/NP (81.26 points [95% CI = 73.80, 88.72] vs. 79.48 points [95% CI = 70.31, 88.66]; P = 0.043). The findings of this hypothesis‐generating study may highlight a potential sex‐specific association between spinal pain and later‐life neurodegeneration.

Abstract Background Writing multiple choice questions (MCQs) for the purpose of medical exams is challenging. It requires extensive medical knowledge, time and effort from medical educators. This systematic review focuses on the application of large language models (LLMs) in generating medical MCQs. Methods The authors searched for studies published up to November 2023. Search terms focused on LLMs generated MCQs for medical examinations. Non-English, out of year range and studies not focusing on AI generated multiple-choice questions were excluded. MEDLINE was used as a search database. Risk of bias was evaluated using a tailored QUADAS-2 tool. Results Overall, eight studies published between April 2023 and October 2023 were included. Six studies used Chat-GPT 3.5, while two employed GPT 4. Five studies showed that LLMs can produce competent questions valid for medical exams. Three studies used LLMs to write medical questions but did not evaluate the validity of the questions. One study conducted a comparative analysis of different models. One other study compared LLM-generated questions with those written by humans. All studies presented faulty questions that were deemed inappropriate for medical exams. Some questions required additional modifications in order to qualify. Conclusions LLMs can be used to write MCQs for medical examinations. However, their limitations cannot be ignored. Further study in this field is essential and more conclusive evidence is needed. Until then, LLMs may serve as a supplementary tool for writing medical examinations. 2 studies were at high risk of bias. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

Abstract Recycling vanadium from alternative sources is essential due to its expanding demand, depletion in natural sources, and environmental issues with terrestrial mining. Here, we present a complexation-precipitation method to selectively recover pentavalent vanadium ions, V(V), from complex metal ion mixtures, using an acid-stable metal binding agent, the cyclic imidedioxime, naphthalimidedioxime (H2CIDIII). H2CIDIII showed high extraction capacity and fast binding towards V(V) with crystal structures showing a 1:1 M:L dimer, [V2(O)3(C12H6N3O2)2]2−, 1, and 1:2 M:L non-oxido, [V(C12H6N3O2)2] ̶ complex, 2. Complexation selectivity studies showed only 1 and 2 were anionic, allowing facile separation of the V(V) complexes by pH-controlled precipitation, removing the need for solid support. The tandem complexation-precipitation technique achieved high recovery selectivity for V(V) with a selectivity coefficient above 3 × 105 from synthetic mixed metal solutions and real oil sand tailings. Zebrafish toxicity assay confirmed the non-toxicity of 1 and 2, highlighting H2CIDIII’s potential for practical and large-scale V(V) recovery.

ABSTRACTObjectives To analyze contributions to microbial ecology of Reactive Electrophile Species (RES), including methylglyoxal, generated during glycolysis.Methods Genetic analyses were performed on the glyoxalase pathway in Streptococcus mutans (SM) and Streptococcus sanguinis (SS), followed by phenotypic assays and transcription analysis.Results Deleting glyoxalase I (lguL) reduced RES tolerance to a far greater extent in SM than in SS, decreasing the competitiveness of SM against SS. Although SM displays a greater RES tolerance than SS, lguL-null mutants of either species showed similar tolerance; a finding consistent with the ability of methylglyoxal to induce the expression of lguL in SM, but not in SS. A novel paralogue of lguL (named gloA2) was identified in most streptococci. SM mutant ∆gloA2SM showed little change in methylglyoxal tolerance yet a significant growth defect and increased autolysis on fructose, a phenotype reversed by the addition of glutathione, or by the deletion of a fructose: phosphotransferase system (PTS) that generates fructose-1-phosphate (F-1-P).Conclusions Fructose contributes to RES generation in a PTS-specific manner, and GloA2 may be required to degrade certain RES derived from F-1-P. This study reveals the critical roles of RES in fitness and interbacterial competition and the effects of PTS in modulating RES metabolism.

IntroductionCompanion animals offer a unique opportunity to investigate risk factors and exposures in our shared environment. Passive sampling techniques have proven effective in capturing environmental exposures in dogs and humans.MethodsIn a pilot study, we deployed silicone monitoring devices (tags) on the collars of a sample of 15 dogs from the Dog Aging Project Pack cohort for a period of 120 h (5 days). We extracted and analyzed the tags via gas chromatography–mass spectrometry for 119 chemical compounds in and around participants’ homes.ResultsAnalytes belonging to the following chemical classes were detected: brominated flame retardants (BFRs), organophosphate esters (OPEs), polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), pesticides, phthalates, and personal care products. The types and amounts of analytes detected varied substantially among participants.DiscussionData from this pilot study indicate that silicone dog tags are an effective means to detect and measure chemical exposure in and around pet dogs’ households. Having created a sound methodological infrastructure, we will deploy tags to a geographically diverse and larger sample size of Dog Aging Project participants with a goal of further assessing geographic variation in exposures.

IntroductionThis study evaluated changes in the white matter of the brain and psychological health variables, resulting from a neuroscience-based mindfulness intervention, the Training for Awareness, Resilience, and Action (TARA), in a population of healthy adolescents.MethodsA total of 100 healthy adolescents (57 female, age ranges 14–18 years) were randomized into the 12-week TARA intervention or a waitlist-control group. All participants were imaged with diffusion MRI to quantify white matter connectivity between brain regions. Imaging occurred at baseline/randomization and after 12 weeks of baseline (pre- and post-intervention in the TARA group). We hypothesized that structural connectivity in the striatum and interoceptive networks would increase following the TARA intervention, and that, this increased connectivity would relate to psychological health metrics from the Strengths and Difficulties Questionnaire (SDQ) and the Insomnia Severity Index (ISI). The TARA intervention and all assessments, except for the MRIs, were fully remotely delivered using secure telehealth platforms and online electronic data capture systems.ResultsThe TARA intervention showed high consistency, tolerability, safety, recruitment, fidelity, adherence, and retention. After 12 weeks, the TARA group, but not controls, also demonstrated significantly improved sleep quality (p = 0.02), and changes in the right putamen node strength were related to this improved sleep quality (r = −0.42, p = 0.006). Similarly, the TARA group, but not controls, had significantly increased right insula node strength related to improved emotional well-being (r = −0.31, p = 0.04). Finally, we used the network-based statistics to identify a white matter interoception network that strengthened following TARA (p = 0.009).DiscussionThese results suggest that the TARA mindfulness-based intervention in healthy adolescents is feasible and safe, and it may act to increase structural connectivity strength in interoceptive brain regions. Furthermore, these white matter changes are associated with improved adolescent sleep quality and emotional well-being. Our results suggest that TARA could be a promising fully remotely delivered intervention for improving psychological well-being in adolescents. As our findings suggest that TARA affects brain regions in healthy adolescents, which are also known to be altered during depression in adolescents, future studies will examine the effects of TARA on depressed adolescents.Clinical trial registrationhttps://clinicaltrials.gov/study/NCT04254796.

Abstract One of the great diagnostic challenges for children with pulmonary arterial hypertension is the need for general anesthesia (GA) to enable successful right heart catheterization. Here, for the first time, we describe how echocardiographic estimates of right ventricular function and pulmonary pressures change in pediatric patients during GA.

Background: Acromioclavicular (AC) joint separations occur most often in young male patients, commonly in athletes. Initially described by Jones et al. in 2001, reconstruction with semitendinosus allograft via cerclage has been increasingly adopted in recent times, though this not been as well described in video journals. Indications: Operative management of AC joint separation is classically indicated in Rockwood grade IV or higher AC joint injuries and controversial for grade III separations. One such treatment is AC joint reconstruction with semitendinosus allograft as described in this 37-year-old male patient, with a grade IIIB AC joint separation. Technique Description: A 6-cm incision was created overlying the clavicle. No distal clavicle excision was performed, but coracoclavicular (CC) scar tissue was elevated with medial and lateral windows about the coracoid. A passing suture was placed around the coracoid, and holes were drilled in the clavicle at 17% and 31% of the total clavicle length, consistent with ratios described by Rios et al; 5-mm tunnels were created corresponding to the trapezial and conoid limbs of the CC ligaments and tapped to 5.5 mm. A semitendinosus allograft was passed and fixed with two 5.5 × 15 mm polyetheretherketone (PEEK) screws after primary fixation with a FiberTape cerclage looped around the coracoid and clavicle independently with use of a tensiometer for maximal tightening. A FiberTak was used to fix the additional graft limb at the acromion to stabilize the AC joint and reinforced on itself with 0 vicryl. The patient was placed in a sling and assigned physical therapy (PT) focusing on limiting shoulder abduction and forward flexion for the first 6 weeks. Results: At 6 months postoperation, the patient continues to progress from PT, with low pain and near full range of motion. Although PT protocols vary widely, a full recovery is expected by 6 months, with the patient able to return to work, lifting no greater than 50 pounds. Discussion/Conclusion: This study describes the treatment of an acute grade IV AC joint separation in a 37-year-old male patient. Further adoption of AC joint reconstruction utilizing a semitendinosus allograft via cerclage continues to be a viable option for patients requiring operative management. Patient Consent Disclosure Statement: The author(s) attests that consent has been obtained from any patient(s) appearing in this publication. If the individual may be identifiable, the author(s) has included a statement of release or other written form of approval from the patient(s) with this submission for publication.

Abstract The aim of this study was to identify risk factors for abdominal aortic aneurysm (AAA) from the largest Welsh screening cohort to date. Patients were recruited from 1993 (to 2015) as part of the South East Wales AAA screening programme through general practitioners. Demographic data and risk factors were collected by means of a self‐report questionnaire. Statistical tests were performed to determine whether associations could be observed between AAA and potential risk factors. Odds ratios (OR) were also calculated for each of the risk factors identified. A total of 6879 patients were included in the study. Two hundred and seventy‐five patients (4.0%) presented with AAA, of which 16% were female and 84% were male. Patients with AAA were older than the (no AAA) control group (p

Abstract Antarctic Bottom Water has been warming in recent decades throughout most of the oceans and freshening in regions close to its Indian and Pacific sector sources. We assess warming rates on isobars in the eastern Pacific sector of the Southern Ocean using CTD data collected from shipboard surveys from the early 1990s through the late 2010s together with CTD data collected from Deep Argo floats deployed in the region in January 2023. We show cooling and freshening in the temperature‐salinity relation for water colder than ∼0.4°C. We further find a recent acceleration in the regional bottom water warming rate vertically averaged for pressures exceeding 3,700 dbar, with the 2017/18 to 2023/24 trend of 7.5 (±0.9) m°C yr−1 nearly triple the 1992/95 to 2023/24 trend of 2.8 (±0.2) m°C yr−1. The 0.2°C isotherm descent rate for these same time periods nearly quadruples from 7.8 to 28 m yr−1.

Abstract 2D magnetic materials offer the opportunity to study and manipulate emergent collective excitations. Among these, spin–phonon coupling is one of the most important interactions correlating charge, spin and lattice vibrations. Understanding and controlling this coupling is important for spintronics applications, control of magnons and phonon by THz radiation, and for strain‐driven magnetoelastic applications. Here, a resonant mode‐selective spin–phonon coupling in several magnetic 2D metal thiophosphates (NiPS3, FePS3, CoPS3 and MnPS3) through multi‐excitation and temperature‐dependent Raman scattering measurements is uncovered. The phonon mode, which is a Raman‐active out‐of‐plane vibrational mode (∼250 cm−1 or 7.5 THz), exhibits an asymmetric Fano lineshape where its asymmetry is proportional to the spin–phonon coupling. The measurements reveal the coupling to be the highest in NiPS3, followed by FePS3 and CoPS3, and least in MnPS3. These differences are attributed to the metal–sulfur interatomic distances, which are the lowest in NiPS3, followed by CoPS3, FePS3 and MnPS3. Finally, the spin–phonon coupling is also observed in exfoliated materials, with a slight reduction between 20 and 30% in the thinnest flakes compared to the bulk crystals.

Aims: The aim of this study is to use generative artificial intelligence to perform bibliometric analysis on abstracts published at European Resuscitation Council (ERC) annual scientific congress and define trends in ERC guidelines topics over the last decade. Methods: In this bibliometric analysis, the WebHarvy software (SysNucleus, India) was used to download data from the Resuscitation journal's website through the technique of web scraping. Next, the Chat Generative Pre-trained Transformer 4 (ChatGPT-4) application programming interface (Open AI, USA) was used to implement the multinomial classification of abstract titles following the ERC 2021 guidelines topics. Results: From 2012 to 2022 a total of 2491 abstracts have been published at ERC congresses. Published abstracts ranged from 88 (in 2020) to 368 (in 2015). On average, the most common ERC guidelines topics were Adult basic life support (50.1%), followed by Adult advanced life support (41.5%), while Newborn resuscitation and support of transition of infants at birth (2.1%) was the least common topic. The findings also highlight that the Basic Life Support and Adult Advanced Life Support ERC guidelines topics have the strongest co-occurrence to all ERC guidelines topics, where the Newborn resuscitation and support of transition of infants at birth (2.1%; 52/2491) ERC guidelines topic has the weakest co-occurrence. Conclusion: This study demonstrates the capabilities of generative artificial intelligence in the bibliometric analysis of abstract titles using the example of resuscitation medicine research over the last decade at ERC conferences using large language models.

Low-cost production of nanocellulose from diverse lignocellulosic feedstocks has become an important topic for developing sustainable nanomaterials. The available feedstocks include both woody and non-woody plants, where the latter are relatively underutilized. Interestingly, the porous structure and low lignin content in most non-woody plants, such as agricultural residues and natural fibers, also makes them ideal sources for lower energy nanocellulose production using simpler methods than those required to process woody plants. To enhance the goal of circularity, this review first provides an overview of the nanocellulose conversion from cellulose and then comprehensively discusses the use of non-woody feedstocks for nanocellulose production. Specifically, the availability of suitable non-woody feedstocks and the use of low-cost processes for pulping and cellulose oxidation treatments, including alkaline, solvent pulping, and nitrogen-oxidation treatments, are discussed. The information in this review can lead to new opportunities to achieve greater sustainability in biobased economies. Additionally, demonstrations of nanocellulose-based water purification technologies using agricultural residues derived remediation materials are highlighted at the end of this review.

Artificial intelligence, specifically advanced language models such as ChatGPT, have the potential to revolutionize various aspects of healthcare, medical education, and research. In this review, we evaluate the myriad applications of artificial intelligence in diverse healthcare domains. We discuss its potential role in clinical decision-making, exploring how it can assist physicians by providing rapid, data-driven insights for diagnosis and treatment. We review the benefits of artificial intelligence such as ChatGPT in personalized patient care, particularly in geriatric care, medication management, weight loss and nutrition, and physical activity guidance. We further delve into its potential to enhance medical research, through the analysis of large datasets, and the development of novel methodologies. In the realm of medical education, we investigate the utility of artificial intelligence as an information retrieval tool and personalized learning resource for medical students and professionals.

Abstract Climate change is expected to impact vegetation in the western United States, leading to shifts in dominant Plant Functional Types and carbon storage. Here, we used a biogeographic model integrated with a biogeochemical model to predict changes in dominant Plant Functional Type by 2070−2100. Results show that under the Representative Concentration Pathway 4.5 scenario, 40% of the originally forested areas will transition to shrubland (7%) or grassland (32%), while under the Representative Concentration Pathway 8.5 scenario, 58% of forested areas shift to shrubland (18%) or grassland (40%). These shifts in Plant Functional Types result in a net overall loss in carbon storage equal to −60 gigagram of carbon and −82 gigagram of carbon under Representative Concentration Pathway 4.5 and 8.5, respectively. Our findings highlight the need for urgent action to mitigate the effects of climate change on vegetation and carbon storage in the region.

Abstract Inorganic pyrophosphate is a key molecule in many biological processes from DNA synthesis to cell metabolism. Here we introduce sp 3-functionalized (6,5) single-walled carbon nanotubes (SWNTs) with red-shifted defect emission as near-infrared luminescent probes for the optical detection and quantification of inorganic pyrophosphate. The sensing scheme is based on the immobilization of Cu2+ ions on the SWNT surface promoted by coordination to covalently attached aryl alkyne groups and a triazole complex. The presence of Cu2+ ions on the SWNT surface causes fluorescence quenching via photoinduced electron transfer, which is reversed by copper-complexing analytes such as pyrophosphate. The differences in the fluorescence response of sp 3-defect to pristine nanotube emission enables reproducible ratiometric measurements in a wide concentration window. Biocompatible, phospholipid-polyethylene glycol-coated SWNTs with such sp 3 defects are employed for the detection of pyrophosphate in cell lysate and for monitoring the progress of DNA synthesis in a polymerase chain reaction. This robust ratiometric and near-infrared luminescent probe for pyrophosphate may serve as a starting point for the rational design of nanotube-based biosensors.

Abstract The glycosylation of IgG plays a critical role during human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, activating immune cells and inducing cytokine production. However, the role of IgM N-glycosylation has not been studied during human acute viral infection. The analysis of IgM N-glycosylation from healthy controls and hospitalized coronavirus disease 2019 (COVID-19) patients reveals increased high-mannose and sialylation that correlates with COVID-19 severity. These trends are confirmed within SARS-CoV-2-specific immunoglobulin N-glycan profiles. Moreover, the degree of total IgM mannosylation and sialylation correlate significantly with markers of disease severity. We link the changes of IgM N-glycosylation with the expression of Golgi glycosyltransferases. Lastly, we observe antigen-specific IgM antibody-dependent complement deposition is elevated in severe COVID-19 patients and modulated by exoglycosidase digestion. Taken together, this work links the IgM N-glycosylation with COVID-19 severity and highlights the need to understand IgM glycosylation and downstream immune function during human disease.

Abstract Hypoxia has the potential to impair cognitive function; however, it is still uncertain which cognitive domains are adversely affected. We examined the effects of acute hypoxia (∼7 h) on central executive (Go/No‐Go) and non‐executive (memory) tasks and the extent to which impairment was potentially related to regional cerebral blood flow and oxygen delivery (CDO2). Twelve male participants performed cognitive tasks following 0, 2, 4 and 6 h of passive exposure to both normoxia and hypoxia (12% O2), in a randomized block cross‐over single‐blinded design. Middle cerebral artery (MCA) and posterior cerebral artery (PCA) blood velocities and corresponding CDO2 were determined using bilateral transcranial Doppler ultrasound. In hypoxia, MCA DO2 was reduced during the Go/No‐Go task (P = 0.010 vs. normoxia, main effect), and PCA DO2 was attenuated during memorization (P = 0.005 vs. normoxia) and recall components (P = 0.002 vs. normoxia) in the memory task. The accuracy of the memory task was also impaired in hypoxia (P = 0.049 vs. normoxia). In contrast, hypoxia failed to alter reaction time (P = 0.19 vs. normoxia) or accuracy (P = 0.20 vs. normoxia) during the Go/No‐Go task, indicating that selective attention and response inhibition were preserved. Hypoxia did not affect cerebral blood flow or corresponding CDO2 responses to cognitive activity (P > 0.05 vs. normoxia). Collectively, these findings highlight the differential sensitivity of cognitive domains, with memory being selectively vulnerable in hypoxia.

Abstract Target trial emulation is the process of mimicking target randomized trials using real-world data, where effective confounding control for unbiased treatment effect estimation remains a main challenge. Although various approaches have been proposed for this challenge, a systematic evaluation is still lacking. Here we emulated trials for thousands of medications from two large-scale real-world data warehouses, covering over 10 years of clinical records for over 170 million patients, aiming to identify new indications of approved drugs for Alzheimer’s disease. We assessed different propensity score models under the inverse probability of treatment weighting framework and suggested a model selection strategy for improved baseline covariate balancing. We also found that the deep learning-based propensity score model did not necessarily outperform logistic regression-based methods in covariate balancing. Finally, we highlighted five top-ranked drugs (pantoprazole, gabapentin, atorvastatin, fluticasone, and omeprazole) originally intended for other indications with potential benefits for Alzheimer’s patients.

Abstract We present a cost model for implementing a deployment scale effort for conducting ocean iron fertilization (OIF) for marine‐based carbon dioxide removal (CDR). The model incorporates basic oceanographic parameters critical for estimating the effective export of newly fixed CO2 into biomass that is stimulated by Fe addition to an Fe‐limited region of the Southern Ocean. Estimated costs can vary by nearly 100‐fold between best‐case and worst‐case scenarios, with best‐case values of $7/net tonne C captured versus worst‐case $1,500/net tonne C captured, without accounting for verification costs. Primary oceanographic factors that influence cost are the net primary productivity increases achieved via OIF, the amount of C exported into the deep ocean, and the amount of CO2 ventilated back to the atmosphere. The model compares ship‐based versus aerial delivery of Fe to the ocean, and estimates aerial delivery can be 30%–40% more cost effective; however, the specific requirements for aerial delivery require additional research and development. The model also estimates costs associated with verification and environmental monitoring of OIF. These costs increase $/net tonne C captured by 3–4‐fold. Best, intermediate, and worst cases for aerial delivery and ship delivery are $21, $83, $2,033, and $24, $94, $4,691, respectively, inclusive of verification costs. The primary goal of this model is to demonstrate the variability in cost of OIF as a CDR method, and to better understand where additional research is needed to determine the major factors that may make OIF a tractable, nature‐based CDR method.

Summary: Homeostatic regulation of synapses is vital for nervous system function and key to understanding a range of neurological conditions. Synaptic homeostasis is proposed to operate over hours to counteract the destabilizing influence of long-term potentiation (LTP) and long-term depression (LTD). The prevailing view holds that synaptic scaling is a slow first-order process that regulates postsynaptic glutamate receptors and fundamentally differs from LTP or LTD. Surprisingly, we find that the dynamics of scaling induced by neuronal inactivity are not exponential or monotonic, and the mechanism requires calcineurin and CaMKII, molecules dominant in LTD and LTP. Our quantitative model of these enzymes reconstructs the unexpected dynamics of homeostatic scaling and reveals how synapses can efficiently safeguard future capacity for synaptic plasticity. This mechanism of synaptic adaptation supports a broader set of homeostatic changes, including action potential autoregulation, and invites further inquiry into how such a mechanism varies in health and disease.

Abstract Passivating contactsin heterojunction (HJ) solar cells have shown great potential in reducing recombination losses, and thereby achieving high power conversion efficiencies in photovoltaic devices. In this direction, carbon nanomaterials have emerged as a promising option for carbon/silicon (C/Si) HJsolar cells due to their tunable band structure, wide spectral absorption, high carrier mobility, and properties such as multiple exciton generation. However, the current limitations in efficiency and active area have hindered the industrialization of these devices. In this review, they examine the progress made in overcoming these constraints and discuss the prospect of achieving high power conversion efficiency (PCE) C/Si HJ devices. A C/Si HJ solar cell is also designed by introducing an innovative interface passivation strategy to further boost the PCE and accelerate the large area preparationof C/Si devices. The physical principle, device design scheme, and performanceoptimization approaches of this passivated C/Si HJ cells are discussed. Additionally, they outline potential future pathways and directions for C/Si HJ devices, including a reduction in their cost to manufacture and their incorporation intotandem solar cells. As such, this review aims to facilitate a deeperunderstanding of C/Si HJ solar cells and provide guidance for their further development.

In a variety of neurons, action potentials (APs) initiate at the proximal axon, within a region called the axon initial segment (AIS), which has a high density of voltage-gated sodium channels (NaVs) on its membrane. In pyramidal neurons, the proximal AIS has been reported to exhibit a higher proportion of NaVs with gating properties that are "right-shifted" to more depolarized voltages, compared to the distal AIS. Further, recent experiments have revealed that as neurons develop, the spatial distribution of NaV subtypes along the AIS can change substantially, suggesting that neurons tune their excitability by modifying said distribution. When neurons are stimulated axonally, computational modelling has shown that this spatial separation of gating properties in the AIS enhances the backpropagation of APs into the dendrites. In contrast, in the more natural scenario of somatic stimulation, our simulations show that the same distribution can impede backpropagation, suggesting that the choice of orthodromic versus antidromic stimulation can bias or even invert experimental findings regarding the role of NaV subtypes in the AIS. We implemented a range of hypothetical NaV distributions in the AIS of three multicompartmental pyramidal cell models and investigated the precise kinetic mechanisms underlying such effects, as the spatial distribution of NaV subtypes is varied. With axonal stimulation, proximal NaV availability dominates, such that concentrating right-shifted NaVs in the proximal AIS promotes backpropagation. However, with somatic stimulation, the models are insensitive to availability kinetics. Instead, the higher activation threshold of right-shifted NaVs in the AIS impedes backpropagation. Therefore, recently observed developmental changes to the spatial separation and relative proportions of NaV1.2 and NaV1.6 in the AIS differentially impact activation and availability. The observed effects on backpropagation, and potentially learning via its putative role in synaptic plasticity (e.g. through spike-timing-dependent plasticity), are opposite for orthodromic versus antidromic stimulation, which should inform hypotheses about the impact of the developmentally regulated subcellular localization of these NaV subtypes.

BackgroundNeoantigens, mutated tumour-specific antigens, are key targets of anti-tumour immunity during checkpoint inhibitor (CPI) treatment. Their identification is fundamental to designing neoantigen-directed therapy. Non-canonical neoantigens arising from the untranslated regions (UTR) of the genome are an overlooked source of immunogenic neoantigens. Here, we describe the landscape of UTR-derived neoantigens and release a computational tool, PrimeCUTR, to predict UTR neoantigens generated by start-gain and stop-loss mutations.MethodsWe applied PrimeCUTR to a whole genome sequencing dataset of pre-treatment tumour samples from CPI-treated patients (n = 341). Cancer immunopeptidomic datasets were interrogated to identify MHC class I presentation of UTR neoantigens.ResultsStart-gain neoantigens were predicted in 72.7% of patients, while stop-loss mutations were found in 19.3% of patients. While UTR neoantigens only accounted 2.6% of total predicted neoantigen burden, they contributed 12.4% of neoantigens with high dissimilarity to self-proteome. More start-gain neoantigens were found in CPI responders, but this relationship was not significant when correcting for tumour mutational burden. While most UTR neoantigens are private, we identified two recurrent start-gain mutations in melanoma. Using immunopeptidomic datasets, we identify two distinct MHC class I-presented UTR neoantigens: one from a recurrent start-gain mutation in melanoma, and one private to Jurkat cells.ConclusionPrimeCUTR is a novel tool which complements existing neoantigen discovery approaches and has potential to increase the detection yield of neoantigens in personalised therapeutics, particularly for neoantigens with high dissimilarity to self. Further studies are warranted to confirm the expression and immunogenicity of UTR neoantigens.

ABSTRACT The complement system can be viewed as a “moderator” of innate immunity, “instructor” of humoral immunity, and “regulator” of adaptive immunity. While sex is known to affect humoral and cellular immune systems, its impact on complement in humans and rhesus macaques, a commonly used non-human primate model system, has not been well studied. To address this knowledge gap, we analyzed serum samples from 90 humans and 72 rhesus macaques for the abundance and activity of the complement system components. While sequences of cascade proteins were highly conserved, dramatically different levels were observed between species. Whereas the low levels detected in rhesus samples raised questions about the suitability of the test for use with macaque samples, differences in levels of complement proteins were observed in male and female humans. Levels of total and antibody-dependent deposition of C1q and C3b on a glycosylated antigen differed between humans and rhesus, suggesting differential recognition of glycans and balance between classical and alternative activation pathways. Functional differences in complement-mediated lysis of antibody-sensitized cells were observed in multiple assays and showed that human females frequently exhibited higher lytic activity than human males or rhesus macaques, which typically did not exhibit such sex-associated differences. Other differences between species and sexes were observed in more narrow contexts—for only certain antibodies, antigens, or assays. Collectively, these results expand knowledge of sex-associated differences in the complement system in humans, identifying differences absent from rhesus macaques.IMPORTANCEThe complement system is a critical part of host defense to many bacterial, fungal, and viral infections. In parallel, rich epidemiological, clinical, and biomedical research evidence demonstrates that sex is an important biological variable in immunity, and many sex-specific differences in immune system are intimately tied with disease outcomes. This study focuses on the intersection of these two factors to define the impact of sex on complement pathway components and activities. This work expands our knowledge of sex-associated differences in the complement system in humans and also identifies the differences that appear to be absent in rhesus macaques, a popular non-human primate model. Whereas differences between species suggest potential limitations in the ability of macaque model to recapitulate human biology, knowledge of sex-based differences in humans has the potential to inform clinical research and practice.

Background: During pulseless electrical activity (PEA) the cardiac mechanical and electrical functions are dissociated, a phenomenon occurring in 25–42% of in-hospital cardiac arrest (IHCA) cases. Accurate evaluation of the likelihood of a PEA patient transitioning to return of spontaneous circulation (ROSC) may be vital for the successful resuscitation. The aim: We sought to develop a model to automatically discriminate between PEA rhythms with favorable and unfavorable evolution to ROSC. Methods: A dataset of 190 patients, 120 with ROSC, were acquired with defibrillators from different vendors in three hospitals. The ECG and the transthoracic impedance (TTI) signal were processed to compute 16 waveform features. Logistic regression models where designed integrating both automated features and characteristics annotated in the QRS to identify PEAs with better prognosis leading to ROSC. Cross validation techniques were applied, both patient-specific and stratified, to evaluate the performance of the algorithm. Results: The best model consisted in a three feature algorithm that exhibited median (interquartile range) Area Under the Curve/Balanced accuracy/Sensitivity/Specificity of 80.3(9.9)/75.6(8.0)/ 77.4(15.2)/72.3(16.4) %, respectively. Conclusions: Information hidden in the waveforms of the ECG and TTI signals, along with QRS complex features, can predict the progression of PEA. Automated methods as the one proposed in this study, could contribute to assist in the targeted treatment of PEA in IHCA.

Effectively identifying and characterizing the various dynamics present in complex and chaotic systems is fundamental for chaos control, chaos classification, and behavior-transition forecasting, among others. It is a complicated task that becomes increasingly difficult as systems involve more dimensions and parameters. Here, we extend methods inspired in ordinal patterns to analyze 2D iterative maps to unveil underlying approximate symmetries of their dynamics. We distinguish different families of chaos within the systems, find similarities among chaotic maps, identify approximate temporal and dynamical symmetries, and anticipate sharp transitions in dynamics. We show how this methodology displays the evolution of the spatial correlations in a dynamical system as the control parameter varies. We prove the power of these techniques, which involve simple quantifiers as well as combinations of them, in extracting relevant information from the complex dynamics of 2D systems, where other techniques are less informative or more computationally demanding.

Abstract The United States Medical Licensing Examination (USMLE) has been a subject of performance study for artificial intelligence (AI) models. However, their performance on questions involving USMLE soft skills remains unexplored. This study aimed to evaluate ChatGPT and GPT-4 on USMLE questions involving communication skills, ethics, empathy, and professionalism. We used 80 USMLE-style questions involving soft skills, taken from the USMLE website and the AMBOSS question bank. A follow-up query was used to assess the models’ consistency. The performance of the AI models was compared to that of previous AMBOSS users. GPT-4 outperformed ChatGPT, correctly answering 90% compared to ChatGPT’s 62.5%. GPT-4 showed more confidence, not revising any responses, while ChatGPT modified its original answers 82.5% of the time. The performance of GPT-4 was higher than that of AMBOSS's past users. Both AI models, notably GPT-4, showed capacity for empathy, indicating AI's potential to meet the complex interpersonal, ethical, and professional demands intrinsic to the practice of medicine.

There are a wide range of benign and malignant pathologies that the radiologist may encounter in the adrenal glands and kidneys, often incidentally when imaging is performed for other indications. Many imaging modalities including CT, MR, and US are often used in an attempt to characterize these lesions. A definitive radiological diagnosis, however, is not always possible. This is at times due to atypical presentations of typical lesions which may be mistaken for more aggressive or concerning pathologic conditions. Adrenal lesions that do not demonstrate characteristic benign imaging features might require surgical excision. Similarly, cystic renal lesions that demonstrate nodular enhancement are concerning for Bosniak IV lesions and require surgical management. We report 3 cases in 3 different patients of incidentally discovered hematomas with peripheral enhancement, 2 involving the adrenal gland and 1 involving the kidney. All 3 of these histologically proven hematomas demonstrated similar radiological manifestations of peripheral nodular progressive enhancement, mimicking neoplastic conditions, and necessitating surgical removal.

Introduction: Euglycemic diabetic ketoacidosis (DKA) (glucose 18 years old, met criteria for DKA on initial laboratories (pH ≤7.30, serum bicarbonate ≤18 millimoles per liter [mmol/L], anion gap ≥10), and were managed via a standardized DKA order set. Patients were divided into euglycemic (18 mmol/L and first long-acting insulin were similar. Incidence of hypoglycemia (

Abstract Background Genetic testing can identify cancer risk early, enabling prevention and early detection. We describe use of risk management interventions following genetic testing in the Cancer Health Assessment Reaching Many (CHARM) study. CHARM assessed risk and provided genetic testing to low income, low literacy, and other underserved populations that historically face barriers to accessing cancer genetic services. Methods CHARM was implemented in Kaiser Permanente Northwest (KPNW) and Denver Health (DH) between 2018 and 2020. We identified post‐testing screening (mammography, breast MRI, colonoscopy) and surgical (mastectomy, oophorectomy) procedures using electronic health records. We examined utilization in participants who did and did not receive actionable risk management recommendations from study genetic counselors following national guidelines. Results CHARM participants were followed for an average of 15.4 months (range: 0.4–27.8 months) after results disclosure. Less than 2% (11/680) received actionable risk management recommendations (i.e., could be completed in the initial years following testing) based on their test result. Among those who received actionable recommendations, risk management utilization was moderate (54.5%, 6/11 completed any procedure) and varied by procedure (mammogram: 0/3; MRI: 2/4; colonoscopy: 4/5; mastectomy: 1/5; oophorectomy: 0/3). Cancer screening and surgery procedures were rare in participants without actionable recommendations. Conclusion Though the number of participants who received actionable risk management recommendations was small, our results suggest that implementing CHARM's risk assessment and testing model increased access to evidence‐based genetic services and provided opportunities for patients to engage in recommended preventive care, without encouraging risk management overuse.

Abstract Children with single ventricle heart disease (SVHD) experience morbidity due to inadequate pulmonary blood flow. Using proteomic screening, our group previously identified members of the matrix metalloproteinase (MMP), tissue inhibitor of metalloproteinase (TIMP), and fibroblast growth factor (FGF) families as potentially dysregulated in SVHD. No prior study has taken a targeted approach to mapping circulating levels of these protein families or their relationship to pulmonary vascular outcomes in SVHD. We performed a prospective cohort study of 70 SVHD infants pre-Stage 2 palliation and 24 healthy controls. We report targeted serum quantification of 39 proteins in the MMP, TIMP, and FGF families using the SomaScan platform. Clinical variables were extracted from the medical record. Twenty of 39 tested proteins (7/14 MMPs, 2/4 TIMPs, and 11/21 FGFs) differed between cases and controls. On single variable testing, 6 proteins and no clinical covariates were associated with both post-Stage 2 hypoxemia and length of stay. Multiple-protein modeling identified increased circulating MMP 7 and MMP 17, and decreased circulating MMP 8 and FGFR2 as most associated with post-Stage 2 hypoxemia; increased MMP 7 and TIMP 4 and decreased circulating MMP 1 and MMP 8 were most associated with post-operation length of stay. The MMP, TIMP, and FGF families are altered in SVHD. Pre-Stage 2 imbalance of extracellular matrix (ECM) proteins—increased MMP 7 and decreased MMP 8—was associated with multiple adverse post-operation outcomes. Maintenance of the ECM may be an important pathophysiologic driver of Stage 2 readiness in SVHD.

Minimal joint space width (mJSW) is a radiographic measurement used in the diagnosis of hip osteoarthritis. A large variance when measuring mJSW highlights the need for a supporting diagnostic tool. This study aimed to estimate the reliability of a deep learning algorithm designed to measure the mJSW in pelvic radiographs and to estimate agreement between the algorithm and orthopedic surgeons, radiologists, and a reporting radiographer. The algorithm was highly consistent when measuring mJSW with a mean difference at 0.00. Human readers, however, were subject to variance with a repeatability coefficient of up to 1.31. Statistically, although not clinically significant, differences were found between the algorithm’s and all readers’ measurements with mean measured differences ranging from −0.78 to −0.36 mm. In conclusion, the algorithm was highly reliable, and the mean measured difference between the human readers combined and the algorithm was low, i.e., −0.5 mm bilaterally. Given the consistency of the algorithm, it may be a useful tool for monitoring hip osteoarthritis.