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Abstract Increasing water stress is emerging as a global phenomenon, and is anticipated to have a marked impact on forest function. The role of tree functional strategies is pivotal in regulating forest fitness and their ability to cope with water stress. However, how the functional strategies found at the tree or species level scale up to characterise forest communities and their variation across regions is not yet well-established. By combining eight water-stress-related functional traits with forest inventory data from the USA and Europe, we investigated the community-level trait coordination and the biogeographic patterns of trait associations for woody plants, and analysed the relationships between the trait associations and climate factors. We find that the trait associations at the community level are consistent with those found at the species level. Traits associated with acquisitive-conservative strategies forms one dimension of variation, while leaf turgor loss point, associated with stomatal water regulation strategy, loads along a second dimension. Surprisingly, spatial patterns of community-level trait association are better explained by temperature than by aridity, suggesting a temperature-driven adaptation. These findings provide a basis to build predictions of forest response under water stress, with particular potential to improve simulations of tree mortality and forest biomass accumulation in a changing climate.

Abstract The efficient release of magnetic energy in astrophysical plasmas, such as during solar flares, can in principle be achieved through magnetic diffusion, at a rate determined by the associated electric field. However, attempts at measuring electric fields in the solar atmosphere are scarce, and none exist for sites where the magnetic energy is presumably released. Here, we present observations of an energetic event using the National Science Foundation’s Daniel K. Inouye Solar Telescope, where we detect the polarization signature of electric fields associated with magnetic diffusion. We measure the linear and circular polarization across the hydrogen Hε Balmer line at 397 nm at the site of a brightening event in the solar chromosphere. Our spectro-polarimetric modeling demonstrates that the observed polarization signals can only be explained by the presence of electric fields, providing conclusive evidence of magnetic diffusion, and opening a new window for the quantitative study of this mechanism in space plasmas.

Abstract Background Depression is a leading cause of disability worldwide, and treatments could be more effective. Identifying methods to improve treatment success has the potential to reduce disease burden dramatically. Preparing or “priming” someone to respond more effectively to psychotherapy (e.g., cognitive behavioral therapy [CBT]) by preceding sessions with aerobic exercise, a powerful neurobiological activator, could enhance the success of the subsequently performed therapy. However, the success of this priming approach for increasing engagement of working mechanisms of psychotherapy (e.g., increased working alliance and behavioral activation) has yet to be formally tested. Methods The CBT + trial will be a parallel-arm randomized controlled trial that will recruit 40 adult participants with DSM-5 diagnosed depression (verified with clinical interview) via referrals, mass emails, local flyers, and social media posts. Participants will be randomized to an ActiveCBT or CalmCBT condition. The ActiveCBT group will receive an 8-week CBT intervention primed with 30 min of moderate-intensity aerobic exercise (cycling on a stationary bike at a 13 rating of perceived exertion). The CalmCBT group will receive the same 8-week CBT intervention while resting for 30 min before CBT (i.e., cycling vs no cycling is the only difference). The primary outcome measures will be mean working alliance (assessed with the client version of the Working Alliance Inventory—Short Revised) and mean behavioral activation (self-reported Behavioral Activation for Depression Scale) recorded at each of the 8 therapy sessions. Secondary outcomes include evaluation of state anhedonia and serum brain-derived neurotrophic factor before the active/calm conditions, between the condition and therapy, and after the therapy. Additional exploratory analyses will evaluate group differences in algorithm-generated ratings of therapist-participant interactions via the Lyssn platform. Discussion The novel approach of priming CBT with moderate-intensity aerobic exercise evaluated in a randomized controlled trial (CBT + trial) has the potential to demonstrate the usefulness of exercise as an augmentation strategy that improves working mechanisms of therapy and overall treatment outcomes for adults with depression. Trial registration ClinicalTrials.gov NCT06001346 . Registered on August 21, 2023.

Abstract Insulin resistance impairs the cellular insulin response, and often precedes metabolic disorders, like type 2 diabetes, impacting an increasing number of people globally. Understanding the molecular mechanisms in hepatic insulin resistance is essential for early preventive treatments. To elucidate changes in insulin signal transduction associated with hepatocellular resistance, we employed a multi-layered mass spectrometry-based proteomics approach focused on insulin receptor (IR) signaling at the interactome, phosphoproteome, and proteome levels in a long-term hyperinsulinemia-induced insulin-resistant HepG2 cell line with a knockout of the insulin-like growth factor 1 receptor (IGF1R KO). The analysis revealed insulin-stimulated recruitment of the PI3K complex in both insulin-sensitive and -resistant cells. Phosphoproteomics showed attenuated signaling via the metabolic PI3K-AKT pathway but sustained extracellular signal-regulated kinase (ERK) activity in insulin-resistant cells. At the proteome level, the ephrin type-A receptor 2 (EphA2) showed an insulin-induced increase in expression, which occurred through the ERK signaling pathway and was concordantly independent of insulin resistance. Induction of EphA2 by insulin was confirmed in additional cell lines and observed uniquely in cells with high IR-to-IGF1R ratio. The multi-layered proteomics dataset provided insights into insulin signaling, serving as a resource to generate and test hypotheses, leading to an improved understanding of insulin resistance.

Abstract Hepatoblastoma, the most prevalent pediatric liver cancer, almost always carries a WNT-activating CTNNB1 mutation, yet exhibits notable molecular heterogeneity. To characterize this heterogeneity and identify novel targeted therapies, we perform comprehensive analysis of hepatoblastomas and tumor-derived organoids using single-cell RNA-seq/ATAC-seq, spatial transcriptomics, and high-throughput drug profiling. We identify two distinct tumor epithelial signatures: hepatic ‘fetal’ and WNT-high ‘embryonal’, displaying divergent WNT signaling patterns. The fetal group is enriched for liver-specific WNT targets, while the embryonal group is enriched in canonical WNT target genes. Gene regulatory network analysis reveals enrichment of regulons related to hepatic functions such as bile acid, lipid and xenobiotic metabolism in the fetal subtype but not in the embryonal subtype. In addition, the dichotomous expression pattern of the transcription factors HNF4A and LEF1 allows for a clear distinction between the fetal and embryonal tumor cells. We also perform high-throughput drug screening using patient-derived tumor organoids and identify sensitivity to HDAC inhibitors. Intriguingly, embryonal and fetal tumor organoids are sensitive to FGFR and EGFR inhibitors, respectively, indicating a dependency on EGF/FGF signaling in hepatoblastoma tumorigenesis. In summary, our data uncover the molecular and drug sensitivity landscapes of hepatoblastoma and pave the way for the development of targeted therapies.

Abstract Purpose Patients with alpha-1 antitrypsin deficiency (AATD) often experience substantial delays from the onset of symptoms to a diagnosis. We explored the impact of delayed diagnosis of AATD on healthcare costs and utilization by assessing costs/utilization before and after diagnosis. Methods Retrospective claims data was used to conduct a longitudinal analysis of a cohort of patients with follow-up over four years in a commercial claims database was conducted. Patients with at least four years of claims experience between the years 2011 – 2017 were included in this study. Outcome measures were calculated for each year (Year 1 pre-index diagnosis, and Years 1, 2, and 3 post-index follow-up). Measures included healthcare costs (pharmacy and medical costs), medical costs, inpatient events, and emergency room visits. Unadjusted measures in the follow-up Year 1, Year 2, and Year 3 were compared to Year 1 pre-index. A separate multivariate analysis adjusting for age, sex, and comorbidities was conducted. Results Among 1258 patients, mean adjusted healthcare costs were significantly higher in Year 1 post-index compared to Year 1 pre-index ($51,785 vs $41,441, p =

Abstract This study contributes to understanding semi-automated ergonomic risk assessments in industrial manufacturing environments, proposing a practical tool for enhancing worker safety and operational efficiency. In the Industry 5.0 era, the human-centric approach in manufacturing is crucial, especially considering the aging workforce and the dynamic nature of the entire modern industrial sector, today integrating digital technology, automation, and sustainable practices to enhance productivity and environmental responsibility. This approach aims to adapt work conditions to individual capabilities, addressing the high incidence of work-related musculoskeletal disorders (MSDs). The traditional, subjective methods of ergonomic assessment are inadequate for dynamic settings, highlighting the need for affordable, automatic tools for continuous monitoring of workers’ postures to evaluate ergonomic risks effectively during tasks. To enable this perspective, 2D RGB Motion Capture (MoCap) systems based on computer vision currently seem the technologies of choice, given their low intrusiveness, cost, and implementation effort. However, the reliability and applicability of these systems in the dynamic and varied manufacturing environment remain uncertain. This research benchmarks various literature proposed MoCap tools and examines the viability of MoCap systems for ergonomic risk assessments in Industry 5.0 by exploiting one of the benchmarked semi-automated, low-cost and non-intrusive 2D RGB MoCap system, capable of continuously monitoring and analysing workers’ postures. By conducting experiments across varied manufacturing environments, this research evaluates the system’s effectiveness in assessing ergonomic risks and its adaptability to different production lines. Results reveal that the accuracy of risk assessments varies by specific environmental conditions and workstation setups. Although these systems are not yet optimized for expert-level risk certification, they offer significant potential for enhancing workplace safety and efficiency by providing continuous posture monitoring. Future improvements could explore advanced computational techniques like machine learning to refine ergonomic assessments further.

Abstract Percutaneous image-guided ablation techniques are a consolidated therapeutic alternative for patients with high preoperative surgical risk for the management of oncological diseases in multiple body districts. Each technique has both pros and cons according to the type of energy delivered, mechanism of action, and site of application. The present article reviews the most recent literature results on ablation techniques applied in the field of genitourinary diseases (kidney, adrenal glands, prostate, and uterus), describing the advantages of the use of each technique and their technical limitations and summarizing the major recommendations from an international consensus meeting. Critical relevant statement The article critically evaluates the efficacy and safety of ablation therapies for various genitourinary tract diseases, demonstrating their potential to improve patient outcomes and advance clinical radiology by offering minimally invasive, effective alternatives to traditional surgical treatments. Key Points Ablation therapies are effective alternatives to surgery for renal cell carcinoma. Ablation techniques offer effective treatment for intermediate-risk prostate cancer. Ablation is a promising tool for adrenal tumor management. Ablation reduces fibroid symptoms and volume, offering an alternative to surgery. Graphical Abstract

Abstract Coronary artery calcium (CAC) scans contain valuable information beyond the Agatston Score which is currently reported for predicting coronary heart disease (CHD) only. We examined whether new artificial intelligence (AI) applied to CAC scans can predict non-CHD events, including heart failure, atrial fibrillation, and stroke. We applied AI-enabled automated cardiac chambers volumetry and calcified plaque characterization to CAC scans (AI-CAC) of 5830 asymptomatic individuals (52.2% women, age 61.7 ± 10.2 years) in the multi-ethnic study of atherosclerosis during 15 years of follow-up, 1773 CVD events accrued. The AUC at 1-, 5-, 10-, and 15-year follow-up for AI-CAC vs. Agatston score was (0.784 vs. 0.701), (0.771 vs. 0.709), (0.789 vs. 0.712) and (0.816 vs. 0.729) (p

Abstract Gallbladder cancer (GBC) presents as an aggressive malignancy with poor patient outcome. Like other epithelial cancers, the mechanisms of GBC cancer progression remain vague and efforts in finding targeted therapies fall below expectations. This study combined proteomic analysis of formalin-fixed paraffin-embedded (FFPE) GBC samples, functional and molecular characterization of potential oncogenes and identification of potential therapeutic strategies for GBC. We identified Carcinoembryonic Antigen-related Cell Adhesion Molecule 6 (CEACAM6) as one of the significantly most upregulated proteins in GBC. CEACAM6 overexpression has been observed in other cancer entities but the molecular function remains unclear. Our functional analyses in vitro and in vivo mouse models revealed that CEACAM6 supported the initial steps of cancer progression and metastasis by decreasing cell adhesion and promoting migration and invasion of GBC cells. Conversely, CEACAM6 knockdown abolished GBC aggressiveness by increasing cell adhesion while reducing cell migration, cell proliferation, and colony formation. BirA-BioID followed by mass-spectrometry revealed Integrin Beta-1 (ITGB1) and Protein Kinase C Delta (PRKCD) as direct molecular and functional partners of CEACAM6 supporting GBC cell migration. ERK and AKT signaling and their downstream target genes were regulated by CEACAM6 and thus the treatment with AKT inhibitor capivasertib or ERK inhibitor ulixertinib mitigated the CEACAM6-induced migration. These findings demonstrate that CEACAM6 is crucially involved in gallbladder cancer progression by promoting migration and inhibiting cell adhesion through ERK and AKT signaling providing specific options for treatment of CEACAM6-positive cancers.

Abstract With the National Institutes of Health’s mandate to consider sex as a biological variable (SABV), there has been a significant increase of studies utilizing both sexes. Historically, we have known that biological sex and hormones influence immunological processes and now studies focusing on interactions between the immune, endocrine, and nervous systems are revealing sex differences that influence pain behavior and various molecular and biochemical processes. Neuroendocrine-immune interactions represent a key integrative discipline that will reveal critical processes in each field as it pertains to novel mechanisms in sex differences and necessary therapeutics. Here we appraise preclinical and clinical literature to discuss these interactions and key pathways that drive cell- and sex-specific differences in immunity, pain, and physiology.

Abstract Onsite production of gigawatt-scale wind- and solar-sourced hydrogen (H2) at industrial locations depends on the ability to store and deliver otherwise-curtailed H2 during times of power shortages. Thousands of tonnes of H2 will require storage in regions where subsurface storage is scarce, which may only be possible using liquid organic H2 carriers. We evaluate aboveground system with a focus on providing technical insights into toluene/methylcyclohexane (TOL/MCH) storage systems in locations suitable for gigawatt-scale wind- and solar-powered electrolyzer systems in the United States. Here we show that the levelized cost of storage, at a national median of US dollar $1.84/kg-H2 is spatially heterogeneous, causing minor impact on the cost of H2 supply in the Midwest, and significant impact in Central California and the Southeast. While TOL/MCH may be the cheapest aboveground bulk storage solution evaluated, upfront capital costs, modest energy efficiency, reliance on critical materials and pre-sulfided catalysts, and greenhouse gas emissions from heating are opportunities for further development.

Abstract The intricate network of protein-chaperone interactions is crucial for maintaining cellular function. Recent discoveries have unveiled the existence of specialized chaperone assemblies, known as epichaperomes, which serve as scaffolding platforms that orchestrate the reconfiguration of protein-protein interaction networks, thereby enhancing cellular adaptability and proliferation. This study explores the structural and regulatory aspects of epichaperomes, with a particular focus on the role of post-translational modifications (PTMs) in their formation and function. A key finding is the identification of specific PTMs on HSP90, particularly at residues Ser226 and Ser255 within an intrinsically disordered region, as critical determinants of epichaperome assembly. Our data demonstrate that phosphorylation of these serine residues enhances HSP90’s interactions with other chaperones and co-chaperones, creating a microenvironment conducive to epichaperome formation. Moreover, we establish a direct link between epichaperome function and cellular physiology, particularly in contexts where robust proliferation and adaptive behavior are essential, such as in cancer and pluripotent stem cell maintenance. These findings not only provide mechanistic insights but also hold promise for the development of novel therapeutic strategies targeting chaperone assemblies in diseases characterized by epichaperome dysregulation, thereby bridging the gap between fundamental research and precision medicine.

Abstract Background Health-related stigma and its internalization among individuals with chronic health conditions contribute to impaired mental and physical health and quality of life. Research on health-related stigma has been siloed, with disease-specific measures that may not capture the experiences of individuals with multiple health conditions and that prevent comparisons across health conditions. The current study aimed to develop and test a transdiagnostic measure of internalized health-related stigma for use among adults with different physical health conditions. Methods An existing measure of internalized mental health stigma was adapted to assess stigma due to chronic physical health conditions following COSMIN procedures, with input from advisory boards of community members living with a range of stigmatized health conditions (obesity, type 1 and type 2 diabetes, skin diseases, HIV, chronic pain, and cancers) and of health professionals who specialized in these conditions. The new Internalized Health-Related Stigma (I-HEARTS) Scale was tested in an online sample of 300 adults with these health conditions, recruited from ResearchMatch. Additional psychosocial measures of mental health and quality of life were administered, and participants provided information about their health conditions and demographic characteristics. Exploratory factor analysis and tests of reliability and validity were conducted to determine the psychometric properties of the I-HEARTS Scale, and k-means clustering and receiver of characteristic curve analysis were used to determine a clinically meaningful cutoff score indicating high levels of internalized stigma. Results Factor analysis results yielded a 25-item scale with a 3-factor solution, with subscales of Perceived and Anticipated Stigma, Stereotype Application and Self-Devaluation, and Stigma Resistance. Psychometric properties for internal consistency, inter-item and item-total correlations, and test-retest reliability were strong. Certain demographics (e.g., younger age) and characteristics related to health conditions (e.g., greater symptom severity) were associated with higher levels of internalized stigma. I-HEARTS Scale scores correlated moderately to strongly with related but distinct psychosocial measures, and a cutoff score of 3.40 or higher on the 1–7 rating scale was determined to indicate clinically meaningful levels of internalized stigma. Conclusions The I-HEARTS Scale is a reliable and valid measure for the assessment of internalized health-related stigma among adults with varied stigmatized chronic health conditions. Study pre-registration https://osf.io/84c5d/?view_only=87238512f6d6475c87f8f64280a8a15f .

Abstract Hyperemia in response to neural activity is essential for brain health. A hyperemic response delivers O2 and nutrients, clears metabolic waste, and concomitantly exposes cerebrovascular endothelial cells to hemodynamic forces. While neurovascular research has primarily centered on the front end of hyperemia—neuronal activity-to-vascular response—the mechanical consequences of hyperemia have gone largely unexplored. Piezo1 is an endothelial mechanosensor that senses hyperemia-associated forces. Using genetic mouse models and pharmacologic approaches to manipulate endothelial Piezo1 function, we evaluated its role in blood flow control and whether it impacts cognition. We provide evidence of a built-in brake system that sculpts hyperemia, and specifically show that Piezo1 activation triggers a mechano-feedback system that promotes blood flow recovery to baseline. Further, genetic Piezo1 modification led to deficits in complementary memory tasks. Collectively, our findings establish a role for endothelial Piezo1 in cerebral blood flow regulation and a role in its behavioral sequelae.

Abstract Finalization of eukaryotic nuclear DNA replication relies on DNA ligase 1 (LIG1) to seal DNA nicks generated during Okazaki Fragment Maturation (OFM). Using a mutational reporter in Saccharomyces cerevisiae, we previously showed that mutation of the high-fidelity magnesium binding site of LIG1Cdc9 strongly increases the rate of single-base insertions. Here we show that this rate is increased across the nuclear genome, that it is synergistically increased by concomitant loss of DNA mismatch repair (MMR), and that the additions occur in highly specific sequence contexts. These discoveries are all consistent with incorporation of an extra base into the nascent lagging DNA strand that can be corrected by MMR following mutagenic ligation by the Cdc9-EEAA variant. There is a strong preference for insertion of either dGTP or dTTP into 3–5 base pair mononucleotide sequences with stringent flanking nucleotide requirements. The results reveal unique LIG1Cdc9-dependent mutational motifs where high fidelity DNA ligation of a subset of OFs is critical for preventing mutagenesis across the genome.

The study examines the impact of Point of Sale (POS) business on implementing the cashless policy in the Nigerian economy. The Technology Acceptance Model theory served as the theoretical foundation for this investigation. The work adopts quantitative and qualitative approaches to gather data that aligns with the study's objective. 100 questionnaires were distributed among Point of Sale (POS) operators and users of the services in the Federal Capital Territory, Abuja, Nigeria. 100 respondents (first-degree holders and university students, aged 18-55) were purposively selected to have the necessary knowledge about the subject matter. Questions asked: How do POS transactions impact Nigeria's economy? What are the challenges faced by point-of-sale businesses in Nigeria? The survey period is from 10th October 2023 to 10th May 2024. The study found that the point-of-sale business has significantly impacted the Nigerian economy. It has contributed to financial inclusion, employment generation and consequent economic growth. However, among the factors identified as challenges to POS business and cashless policy in Nigeria are exorbitant transaction charges, lack of adequate infrastructure required to run POS, irregular network connectivity, which erodes the users' trust, and security of network communications. The study provides some plausible recommendations, such as improving the infrastructure and reducing charges, among others.

Abstract Background 3D cell culture models have recently garnered increasing attention for replicating organ microarchitecture and eliciting in vivo-like responses, holding significant promise across various biological disciplines. Broadly, 3D cell culture encompasses organoids as well as single- and multicellular spheroids. While the latter have found successful applications in tumor research, there is a notable scarcity of standardized intestinal models for infection biology that mimic the microarchitecture of the intestine. Hence, this study aimed to develop structured multicellular intestinal spheroids (SMIS) specifically tailored for studying molecular basis of infection by intestinal pathogens. Results We have successfully engineered human SMIS comprising four relevant cell types, featuring a fibroblast core enveloped by an outer monolayer of enterocytes and goblet cells along with monocytic cells. These SMIS effectively emulate the in vivo architecture of the intestinal mucosal surface and manifest differentiated morphological characteristics, including the presence of microvilli, within a mere two days of culture. Through analysis of various differentiation factors, we have illustrated that these spheroids attain heightened levels of differentiation compared to 2D monolayers. Moreover, SMIS serve as an optimized intestinal infection model, surpassing the capabilities of traditional 2D cultures, and exhibit a regulatory pattern of immunological markers similar to in vivo infections after Campylobacter jejuni infection. Notably, our protocol extends beyond human spheroids, demonstrating adaptability to other species such as mice and pigs. Conclusion Based on the rapid attainment of enhanced differentiation states, coupled with the emergence of functional brush border features, increased cellular complexity, and replication of the intestinal mucosal microarchitecture, which allows for exposure studies via the medium, we are confident that our innovative SMIS model surpasses conventional cell culture methods as a superior model. Moreover, it offers advantages over stem cell-derived organoids due to scalability and standardization capabilities of the protocol. By showcasing differentiated morphological attributes, our model provides an optimal platform for diverse applications. Furthermore, the investigated differences of several immunological factors compared to monotypic monolayers after Campylobacter jejuni infection underline the refinement of our spheroid model, which closely mimics important features of in vivo infections.

Abstract Meaning salience, or awareness of meaning in the present moment, is an emerging concept with potential implications for health and wellness. The purpose of this study was to understand the relationships between meaning salience and eight dimensions of wellness, and to see whether meaning salience moderated the relationship between presence of meaning and wellness. Participants (N = 1711) were recruited to complete a cross-sectional survey through Amazon’s Mechanical Turk. Meaning salience was related to better wellness in seven of the eight wellness domains (healthy eating and activity, financial stress, occupational wellness, sleep, perceived wellness, social wellness, and stress, excluding avoiding unhealthy foods). Meaning salience significantly moderated the relationships between presence of meaning and four of eight wellness dimensions, such that at high levels of meaning salience, both high and low presence of meaning had stronger relationships with wellness. Those with high meaning salience and high presence of meaning scored best on four wellness dimensions; however, those with high meaning salience and low presence of meaning scored the worst on four wellness dimensions. Future research should explore what factors drive the relationship between meaning salience and wellness.

Abstract Background Mobile device-based cognitive screening has the potential to overcome the limitations in diagnostic precision and efficiency that characterize conventional pen and paper cognitive screening. Several mobile device-based cognitive testing platforms have demonstrated usability, but the usability of take-home mobile device-based cognitive screening in typical adult primary care patients requires further investigation. Methods This study set out to test the usability of a prototype mobile device-based cognitive screening test in older adult primary care patients across a range of cognitive performance. Participants completed the St. Louis University Mental Status Examination (SLUMS) and then used a study-supplied mobile device application at home for 5 days. The application presented 7 modules lasting approximately 15 min. Participants completed the System Usability Scale (SUS) after using the application. Results A total of 51 individuals participated, with a median (IQR) age of 81 (74–85) years. Cognitive impairment (SLUMS score

Missing data and class imbalance hinder the accurate prediction of rare events such as dairy mastitis. Resampling and imputation are employed to handle these problems. These methods are often used arbitrarily, despite their profound impact on prediction due to changes caused to the data structure. We hypothesize that their use affects the performance of ML models fitted to automated milking systems (AMSs) data for mastitis prediction. We compare three imputations—simple imputer (SI), multiple imputer (MICE) and linear interpolation (LI)—and three resampling techniques: Synthetic Minority Oversampling Technique (SMOTE), Support Vector Machine SMOTE (SVMSMOTE) and SMOTE with Edited Nearest Neighbors (SMOTEEN). The classifiers were logistic regression (LR), multilayer perceptron (MLP), decision tree (DT) and random forest (RF). We evaluated them with various metrics and compared models with the kappa score. A complete case analysis fitted the RF (0.78) better than other models, for which SI performed best. The DT, RF, and MLP performed better with SVMSMOTE. The RF, DT and MLP had the overall best performance, contributed by imputation or resampling (SMOTE and SVMSMOTE). We recommend carefully selecting resampling and imputation techniques and comparing them with complete cases before deciding on the preprocessing approach used to test AMS data with ML models.

Abstract Background Recreational water activities at beaches are popular among Canadians. However, these activities can increase the risk of recreational water illnesses (RWI) among beachgoers. Few studies have been conducted in Canada to determine the risk of these illnesses. This protocol describes the methodology for a study to determine the risk and burden of RWI due to exposure to fecal pollution at beaches in Canada. Methods This study will use a mixed-methods approach, consisting of a prospective cohort study of beachgoers with embedded qualitative research. The cohort study involves recruiting and enrolling participants at public beaches across Canada, ascertaining their water and sand contact exposure status, then following-up after seven days to determine the incidence of acute RWI outcomes. We will test beach water samples each recruitment day for culture-based E. coli, enterococci using rapid molecular methods, and microbial source tracking biomarkers. The study started in 2023 and will continue to 2025 at beaches in British Columbia, Manitoba, Ontario, and Nova Scotia. The target enrollment is 5000 beachgoers. Multilevel logistic regression models will be fitted to examine the relationships between water and sand contact and RWI among beachgoers. We will also examine differences in risks by beachgoer age, gender, and beach location and the influence of fecal indicator bacteria and other water quality parameters on these relationships. Sensitivity analyses will be conducted to examine the impact of various alternative exposure and outcome definitions on these associations. The qualitative research phase will include focus groups with beachgoers and key informant interviews to provide additional contextual insights into the study findings. The study will use an integrated knowledge translation approach. Discussion Initial implementation of the study at two Toronto, Ontario, beaches in 2023 confirmed that recruitment is feasible and that a high completion rate (80%) can be achieved for the follow-up survey. While recall bias could be a concern for the self-reported RWI outcomes, we will examine the impact of this bias in a negative control analysis. Study findings will inform future recreational water quality guidelines, policies, and risk communication strategies in Canada.

Abstract Background Cisplatin (CDDP) remains a key agent in the treatment of muscle-infiltrating bladder carcinoma (MIBC). However, a proportion of MIBC patients do not respond to chemotherapy, which may be caused by the increased repair of CDDP-induced DNA damage. The purpose of this study was to explore the prognostic value of proteins involved in nucleotide excision repair (NER) and translesion DNA synthesis (TLS) in MIBC patients. Methods This is a retrospective analysis of 86 MIBC patients. The XPA, XPF, XPG, ERCC1, POLI, POLH and REV3L proteins were stained in primary bladder tumors and their levels were analyzed both in the total cohort and in a subgroup with metastatic urothelial carcinoma (mUC) that received gemcitabine and CDDP as a first-line therapy. Both cohorts were divided by percentage of cancer cells stained positive for each protein into subgroups with high and low expression. In the same manner, the combined expression of NER (XPA + ERCC1 + XPF + XPG) and TLS (POLI + POLH + REV3L), as the whole pathways, was analyzed. Results Mortality was 89.5% at the median follow-up of 120.2 months. In the total cohort, patients with tumors stained positive for XPA, XPG and POLI had significantly worse overall survival (OS) compared to those with negative staining [hazard ratio (HR) = 0.60, 0.62 and 0.53, respectively]. Both XPG and POLI were independent prognostic factors in multivariate analyses (MVA). In addition, an increase in NER and TLS pathway expression was significantly associated with worse OS in the total cohort (HR = 0.54 and 0.60, respectively). In the mUC subgroup, high POLI expression was associated with significant deterioration of OS (HR = 0.56) in univariate analyses, and its independent prognostic value was shown in MVA. Conclusions Our study showed significant correlations between the tumor expression of XPG and POLI, as well as NER and TLS as the whole pathways, and inferior OS. Hence, they could constitute prognostic biomarkers and potentially promising therapeutic targets in MIBC. However, a prospective trial is required for further validation, thereby overcoming the limitations of this study.

Abstract Background The Mycobacterium avium complex (MAC) comprises the most frequent non-tuberculous mycobacteria (NTM) in Central Europe and currently includes twelve species. M. avium (MAV), M. intracellulare subsp. intracellulare (MINT), and M. intracellulare subsp. chimaera (MCH) are clinically most relevant. However, the population structure and genomic landscape of MAC linked with potential pathobiological differences remain little investigated. Methods Whole genome sequencing (WGS) was performed on a multi-national set of MAC isolates from Germany, France, and Switzerland. Phylogenetic analysis was conducted, as well as plasmids, resistance, and virulence genes predicted from WGS data. Data was set into a global context with publicly available sequences. Finally, detailed clinical characteristics were associated with genomic data in a subset of the cohort. Results Overall, 610 isolates from 465 patients were included. The majority could be assigned to MAV (n = 386), MCH (n = 111), and MINT (n = 77). We demonstrate clustering with less than 12 SNPs distance of isolates obtained from different patients in all major MAC species and the identification of trans-European or even trans-continental clusters when set into relation with 1307 public sequences. However, none of our MCH isolates clustered closely with the heater-cooler unit outbreak strain Zuerich-1. Known plasmids were detected in MAV (325/1076, 30.2%), MINT (62/327, 19.0%), and almost all MCH-isolates (457/463, 98.7%). Predicted resistance to aminoglycosides or macrolides was rare. Overall, there was no direct link between phylogenomic grouping and clinical manifestations, but MCH and MINT were rarely found in patients with extra-pulmonary disease (OR 0.12 95% CI 0.04–0.28, p

Abstract Non-tuberculous mycobacterial pulmonary disease (NTM-PD) is considered a growing health concern. The majority of NTM-PD cases in Europe are caused by slow-growing mycobacteria (SGM). However, distinct radiological features of different SGM remain largely uninvestigated. We applied a previously described radiological score to a patient cohort consisting of individuals with isolation of different SGM. Correlations between clinical data, species and computed tomography (CT) features were examined by logistic and linear regression analyses, as well as over the course of time. Overall, 135 pulmonary CT scans from 84 patients were included. The isolated NTM-species were mainly Mycobacterium avium complex (MAC, n = 49), as well as 35 patients with non-MAC-species. Patients with isolation of M. intracellulare had more extensive CT findings compared to all other SGM species (coefficient 3.53, 95% Cl − 0.37 to 7.52, p = 0.075) while patients meeting the ATS criteria and not undergoing therapy exhibited an increase in CT scores over time. This study provides insights into differential radiological features of slow-growing NTM. While M. intracellulare exhibited a tendency towards higher overall CT scores, the radiological features were similar across different SGM. The applied CT score might be a useful instrument for monitoring patients and could help to guide antimycobacterial therapy.

Abstract Background Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs). Method In this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed. Results Our analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer’s disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including IGH, PCMT1, CYP2A13, and SMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73 × 10–3) in PSP. Conclusions Through WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.

Abstract The development of the retina is under tight temporal and spatial control. To gain insights into the molecular basis of this process, we generate a single-nuclei dual-omic atlas of the human developing retina with approximately 220,000 nuclei from 14 human embryos and fetuses aged between 8 and 23-weeks post-conception with matched macular and peripheral tissues. This atlas captures all major cell classes in the retina, along with a large proportion of progenitors and cell-type-specific precursors. Cell trajectory analysis reveals a transition from continuous progression in early progenitors to a hierarchical development during the later stages of cell type specification. Both known and unrecorded candidate transcription factors, along with gene regulatory networks that drive the transitions of various cell fates, are identified. Comparisons between the macular and peripheral retinae indicate a largely consistent yet distinct developmental pattern. This atlas offers unparalleled resolution into the transcriptional and chromatin accessibility landscapes during development, providing an invaluable resource for deeper insights into retinal development and associated diseases.

Abstract Oxygen homeostasis is maintained in plants and animals by O2-sensing enzymes initiating adaptive responses to low O2 (hypoxia). Recently, the O2-sensitive enzyme ADO was shown to initiate degradation of target proteins RGS4/5 and IL32 via the Cysteine/Arginine N-degron pathway. ADO functions by catalysing oxidation of N-terminal cysteine residues, but despite multiple proteins in the human proteome having an N-terminal cysteine, other endogenous ADO substrates have not yet been identified. This could be because alternative modifications of N-terminal cysteine residues, including acetylation, prevent ADO-catalysed oxidation. Here we investigate the relationship between ADO-catalysed oxidation and NatA-catalysed acetylation of a broad range of protein sequences with N-terminal cysteines. We present evidence that human NatA catalyses N-terminal cysteine acetylation in vitro and in vivo. We then show that sequences downstream of the N-terminal cysteine dictate whether this residue is oxidised or acetylated, with ADO preferring basic and aromatic amino acids and NatA preferring acidic or polar residues. In vitro, the two modifications appear to be mutually exclusive, suggesting that distinct pools of N-terminal cysteine proteins may be acetylated or oxidised. These results reveal the sequence determinants that contribute to N-terminal cysteine protein modifications, with implications for O2-dependent protein stability and the hypoxic response.

Abstract Freshwater macroinvertebrates are a diverse group and play key ecological roles, including accelerating nutrient cycling, filtering water, controlling primary producers, and providing food for predators. Their differences in tolerances and short generation times manifest in rapid community responses to change. Macroinvertebrate community composition is an indicator of water quality. In Europe, efforts to improve water quality following environmental legislation, primarily starting in the 1980s, may have driven a recovery of macroinvertebrate communities. Towards understanding temporal and spatial variation of these organisms, we compiled the TREAM dataset (Time seRies of European freshwAter Macroinvertebrates), consisting of macroinvertebrate community time series from 1,816 river and stream sites (mean length of 19.2 years and 14.9 sampling years) of 22 European countries sampled between 1968 and 2020. In total, the data include >93 million sampled individuals of 2,648 taxa from 959 genera and 212 families. These data can be used to test questions ranging from identifying drivers of the population dynamics of specific taxa to assessing the success of legislative and management restoration efforts.

Abstract Background The clinical description of superior vena cava syndrome has been widely studied; however, there is limited information on bronchoscopic findings in clinical practice. Case presentation A 57-year-old man presented with facial and neck swelling and pedal edema of 6 months duration. Computed tomography showed mediastinal lesions in the right paratracheal stations with thrombosis of the right internal jugular vein and superior vena cava (SVC). Without establishing a diagnosis, he was started on oral steroids elsewhere and his symptoms progressed. He did not receive anticoagulation therapy. Bronchoscopy showed edematous supraglottic and glottic regions with hyperemia of the airway mucosa. Endobronchial Ultrasonography revealed a mediastinal mass of heterogeneous echotexture in the lower right paratracheal region, with mediastinal collateral blood vessels. He underwent EBUS-guided aspiration cytology and intranodal forceps biopsy, which confirmed the diagnosis of non-Hodgkin’s. Conclusion In cases with an unconfirmed diagnosis of lymphoma, it is prudent to refrain from administering glucocorticoids, as these medications can exhibit lympholytic properties and may hinder the diagnostic process. Due to extensive collateral formation in superior vena cava syndrome, utilizing Doppler during endobronchial ultrasound transbronchial needle aspiration (EBUS TBNA) can identify numerous mediastinal collateral vessels, thus minimizing the risk of bleeding.

Abstract Background We quantified SARS-CoV-2 dynamics in different community settings and the direct and indirect effect of the BNT162b2 mRNA vaccine in Monaco for different variants of concern (VOC). Methods Between July 2021 and September 2022, we prospectively investigated 20,443 contacts from 6320 index cases using data from the Monaco COVID-19 Public Health Programme. We calculated secondary attack rates (SARs) in households (n = 13,877), schools (n = 2508) and occupational (n = 6499) settings. We used binomial regression with a complementary log–log link function to measure adjusted hazard ratios (aHR) and vaccine effectiveness (aVE) for index cases to infect contacts and contacts to be infected in households. Results In households, the SAR was 55% (95% CI 54–57) and 50% (48–51) among unvaccinated and vaccinated contacts, respectively. The SAR was 32% (28–36) and 12% (10–13) in workplaces, and 7% (6–9) and 6% (3–10) in schools, among unvaccinated and vaccinated contacts respectively. In household, the aHR was lower in contacts than in index cases (aHR 0.68 [0.55–0.83] and 0.93 [0.74–1.1] for delta; aHR 0.73 [0.66–0.81] and 0.89 [0.80–0.99] for omicron BA.1&2, respectively). Vaccination had no significant effect on either direct or indirect aVE for omicron BA.4&5. The direct aVE in contacts was 32% (17, 45) and 27% (19, 34), and for index cases the indirect aVE was 7% (− 17, 26) and 11% (1, 20) for delta and omicron BA.1&2, respectively. The greatest aVE was in contacts with a previous SARS-CoV-2 infection and a single vaccine dose during the omicron BA.1&2 period (45% [27, 59]), while the lowest were found in contacts with either three vaccine doses (aVE − 24% [− 63, 6]) or one single dose and a previous SARS-CoV-2 infection (aVE − 36% [− 198, 38]) during the omicron BA.4&5 period. Conclusions Protection conferred by the BNT162b2 mRNA vaccine against transmission and infection was low for delta and omicron BA.1&2, regardless of the number of vaccine doses and previous SARS-CoV-2 infection. There was no significant vaccine effect for omicron BA.4&5. Health authorities carrying out vaccination campaigns should bear in mind that the current generation of COVID-19 vaccines may not represent an effective tool in protecting individuals from either transmitting or acquiring SARS-CoV-2 infection.

Coronary-pulmonary artery fistulas (CPAFs) are rare entities that can cause significant left-to-right shunting and complicate routine coronary artery bypass grafting. There are no best practice guidelines and a scarcity of reports regarding concomitant treatment of CPAF with coronary artery disease. We present a case of bilateral CPAFs in a 60-year-old man with symptomatic coronary artery disease treated successfully with coronary artery bypass, epicardial ligation, and transpulmonary closure of CPAF with patch reconstruction. This case highlights the importance of optimal myocardial protection and complete closure of the fistula to prevent risk of coronary steal.

ABSTRACT To infer adaptation of plant material, restoration practitioners often consider only surrogate geographic or climatic information. However, empirical biomass data could assist in deciding what material to use where. To test this approach, we transplanted seven bluebunch wheatgrass (BBWG; Pseudoroegneria spicata) and five Snake River wheatgrass (SRWG; Elymus wawawaiensis) populations to three sites ranging from low to high precipitation (LPPT, MPPT, and HPPT). We measured establishment‐year (2011) biomass at all sites and 2012–16 biomass at MPPT and HPPT. When data were standardized by site, P‐7 and Anatone produced the most BBWG biomass across sites and Wahluke the least in both 2011 and 2012–16, while E‐58X produced the most SRWG biomass and Secar and E‐49X the least in 2011 and 2012–16, respectively. Among BBWG populations in 2011, relative performance of P‐7 (G6 generation) and Goldar increased and Whitmar decreased at wetter sites, while Columbia was stable (high) and Wahluke was stable (low) over sites. Among SRWG populations in 2011, Secar, Secar78, and E‐58X increased at drier sites and Discovery at wetter sites. However, once established, populations of both species were much more similar for trend. In 2012–16, trend somewhat increased for five BBWG populations from MPPT to HPPT, was stable for Wahluke, but declined for Columbia, while all five SRWG populations declined at HPPT. These results suggest that, once established, BBWG is mostly stable across sites, while SRWG is less adapted to wetter sites. In 2012–16, BBWG populations originating at drier (or wetter) sites mostly performed relatively better at MPPT (or HPPT), suggesting adaptation to site. However, in the establishment year (2011), this relationship did not hold, suggesting seedling vigor and immature growth rate play a stronger role than precipitation at the site of origin.

Introduction Inadequate treatment of enlarged lateral lymph nodes (LLNs) in rectal cancer patients is associated with an increased lateral local recurrence (LLR) risk, despite neoadjuvant treatment and total mesorectal excision (TME) surgery. There is a promising role for LLN dissection (LLND) to lower this risk, but this challenging procedure requires appropriate training. This study protocol describes a prospective evaluation of oncological outcomes after standardised treatment based on multidisciplinary training, thereby aiming for a 50% reduction in LLR rate.Methods and analysis A prospective registration study will be opened in hospitals in which the involved multidisciplinary team members (radiologists, radiation oncologists, surgeons and pathologists) have received dedicated training to enhance knowledge and awareness of LLNs and in which standardised treatment including LLND has been implemented. Patients with rectal cancer and at least one enlarged LLN (short-axis ≥7.0 mm), or intermediate LLN (short-axis 5.0–6.9 mm) with at least one malignant feature on primary MRI, evaluated by a trained radiologist, are eligible. Patients will undergo neoadjuvant treatment by trained radiation oncologists, followed by TME surgery in combination with a minimally invasive, nerve-sparing LLND performed by trained surgeons. LLND specimens are evaluated by trained pathologists or grossing assistants. The primary outcome is LLR rate 3 years postoperatively. Secondary outcomes are morbidity, disease-free survival, overall survival and quality of life. To demonstrate a significant reduction in LLR rate from 13% (based on historical control data) to 6% after optimised treatment, 200 patients with enlarged LLNs are required.Ethics and dissemination The medical ethics board of the Vrije Universiteit Medical Centre (VUMC), the Netherlands, approved the study on 23 November 2022 (reference: 2021.0524). Participating centres must obtain local approval and participants are required to provide written informed consent. Results obtained from this study will be communicated via peer-reviewed medical journals and presentations at conferences.Trail registration number NCT04486131, 24 July 2020, https://clinicaltrials.gov/ct2/show/NCT04486131.

Freshwater crayfish are amongst the largest macroinvertebrates and play a keystone role in the ecosystems they occupy. Understanding the global distribution of these animals is often hindered due to a paucity of distributional data. Additionally, non-native crayfish introductions are becoming more frequent, which can cause severe environmental and economic impacts. Management decisions related to crayfish and their habitats require accurate, up-to-date distribution data and mapping tools. Such data are currently patchily distributed with limited accessibility and are rarely up-to-date. To address these challenges, we developed a versatile e-portal to host distributional data of freshwater crayfish and their pathogens (using Aphanomyces astaci, the causative agent of the crayfish plague, as the most prominent example). Populated with expert data and operating in near real-time, World of Crayfish™ is a living, publicly available database providing worldwide distributional data sourced by experts in the field. The database offers open access to the data through specialized standard geospatial services (Web Map Service, Web Feature Service) enabling users to view, embed, and download customizable outputs for various applications. The platform is designed to support technical enhancements in the future, with the potential to eventually incorporate various additional features. This tool serves as a step forward towards a modern era of conservation planning and management of freshwater biodiversity.

Summary: Background: The inflammatory response in patients with traumatic brain injury (TBI) offers opportunities for stratification and intervention. Previous unselected approaches to immunomodulation in patients with TBI have not improved patient outcomes. Methods: Serum and plasma samples from two prospective, multi-centre observational studies of patients with TBI were used to discover (Collaborative European NeuroTrauma Effectiveness Research [CENTER-TBI], Europe) and validate (Transforming Research and Clinical Knowledge in Traumatic Brain Injury [TRACK-TBI] Pilot, USA) individual variations in the immune response using a multiplex panel of 30 inflammatory mediators. Mediators that were associated with unfavourable outcomes (Glasgow outcome score-extended [GOS-E] ≤ 4) were used for hierarchical clustering to identify patients with similar signatures. Findings: Two clusters were identified in both the discovery and validation cohorts, termed early-inflammatory and pauci-inflammatory. The early-inflammatory phenotype had higher concentrations of interleukin-6 (IL-6), IL-15, and monocyte chemoattractant protein 1 (MCP1). Patients with the early-inflammatory phenotype were older and more likely to have an unfavourable GOS-E at 6 months. There were no differences in the baseline injury severity scores between patients in each phenotype. A combined IL-15 and MCP1 signature identified patients with the early-inflammatory phenotype in both cohorts. Inflammatory processes mediated outcomes in older patients with moderate-severe TBI. Interpretation: Our findings offer a precision medicine approach for future clinical trials of immunomodulation in patients with TBI, by using inflammatory signatures to stratify patients. Funding: CENTER-TBI study was supported by the European Union 7th Framework Programme. TRACK-TBI is supported by the National Institute of Neurological Disorders and Stroke.

Abstract Background We compared ultra-high resolution (UHR), standard resolution (SR), and virtual non-calcium (VNCa) reconstruction for coronary artery stenosis evaluation using photon-counting computed tomography (PC-CT). Methods One vessel phantom (4-mm diameter) containing solid calcified lesions with 25% and 50% stenoses inside a thorax phantom with motion simulation underwent PC-CT using UHR (0.2-mm slice thickness) and SR (0.6-mm slice thickness) at heart rates of 60 beats per minute (bpm), 80 bpm, and 100 bpm. A paired t-test or Wilcoxon test with Bonferroni correction was used. Results For 50% stenosis, differences in percent mean diameter stenosis between UHR and SR at 60 bpm (51.0 vs 60.3), 80 bpm (51.7 vs 59.6), and 100 bpm (53.7 vs 59.0) (p ≤ 0.011), as well as between VNCa and SR at 60 bpm (50.6 vs 60.3), 80 bpm (51.5 vs 59.6), and 100 bpm (53.7 vs 59.0) were significant (p ≤ 0.011), while differences between UHR and VNCa at all heart rates (p ≥ 0.327) were not significant. For 25% stenosis, differences between UHR and SR at 60 bpm (28.0 vs 33.7), 80 bpm (28.4 vs 34.3), and VNCa vs SR at 60 bpm (29.1 vs 33.7) were significant (p ≤ 0.015), while differences for UHR vs SR at 100 bpm (29.9 vs 34.0), as well as for VNCa vs SR at 80 bpm (30.7 vs 34.3) and 100 bpm (33.1 vs 34.0) were not significant (p ≥ 0.028). Conclusion Stenosis quantification accuracy with PC-CT improved using either UHR acquisition or VNCa reconstruction. Relevance statement PC-CT offers to scan with UHR mode and the reconstruction of VNCa images both of them could provide improved coronary stenosis quantification at increased heart rates, allowing a more accurate stenosis grading at low and high heart rates compared to SR. Key Points Evaluation of coronary stenosis with conventional CT is challenging at high heart rates. PC-CT allows for scanning with ECG-gated UHR and SR modes. UHR and VNCa images were compared in a dynamic phantom. UHR improves stenosis quantification up to 100 bpm. VNCa reconstruction improves stenosis evaluation up to 80 bpm. Graphical Abstract

Abstract Background Osteoporosis is increasingly being recognized in children, mostly secondary to systemic underlying conditions or medication. However, no imaging modality currently provides a full evaluation of bone health in children. We compared DXA, a radiographic bone health index (BHI (BoneXpert) and cone-beam CT for the assessment of low bone mass in children with juvenile idiopathic arthritis (JIA). Methods Data used in the present study was drawn from a large multicentre study including 228 children aged 4–16 years, examined between 2015 and 2020. All had a radiograph of the left hand, a DXA scan and a cone-beam CT of the temporomandibular joints within four weeks of each other. For the present study, we included 120 subjects, selected based on DXA BMD and BoneXpert BHI to secure values across the whole range to be tested. Results One hundred and twenty children (60.0% females) were included, mean age 11.6 years (SD 3.1 years). There was a strong correlation between the absolute values of BHI and BMD for both total body less head (TBLH) (r = 0.75, p

Abstract Background Trauma can result in systemic inflammation that leads to organ dysfunction, but the impact on the brain, particularly following extracranial insults, has been largely overlooked. Methods Building upon our prior findings, we aimed to understand the impact of systemic inflammation on neuroinflammatory gene transcripts in eight brain regions in rats exposed to (1) blast overpressure exposure [BOP], (2) cutaneous thermal injury [BU], (3) complex extremity injury, 3 hours (h) of tourniquet-induced ischemia, and hind limb amputation [CEI+tI+HLA], (4) BOP+BU or (5) BOP+CEI and delayed HLA [BOP+CEI+dHLA] at 6, 24, and 168 h post-injury (hpi). Results Globally, the number and magnitude of differentially expressed genes (DEGs) correlated with injury severity, systemic inflammation markers, and end-organ damage, driven by several chemokines/cytokines (Csf3, Cxcr2, Il16, and Tgfb2), neurosteroids/prostaglandins (Cyp19a1, Ptger2, and Ptger3), and markers of neurodegeneration (Gfap, Grin2b, and Homer1). Regional neuroinflammatory activity was least impacted following BOP. Non-blast trauma (in the BU and CEI+tI+HLA groups) contributed to an earlier, robust and diverse neuroinflammatory response across brain regions (up to 2–50-fold greater than that in the BOP group), while combined trauma (in the BOP+CEI+dHLA group) significantly advanced neuroinflammation in all regions except for the cerebellum. In contrast, BOP+BU resulted in differential activity of several critical neuroinflammatory-neurodegenerative markers compared to BU. t-SNE plots of DEGs demonstrated that the onset, extent, and duration of the inflammatory response are brain region dependent. Regardless of injury type, the thalamus and hypothalamus, which are critical for maintaining homeostasis, had the most DEGs. Our results indicate that neuroinflammation in all groups progressively increased or remained at peak levels over the study duration, while markers of end-organ dysfunction decreased or otherwise resolved. Conclusions Collectively, these findings emphasize the brain's sensitivity to mediators of systemic inflammation and provide an example of immune-brain crosstalk. Follow-on molecular and behavioral investigations are warranted to understand the short- to long-term pathophysiological consequences on the brain, particularly the mechanism of blood–brain barrier breakdown, immune cell penetration–activation, and microglial activation.

Abstract Purpose To evaluate the long-term clinical outcomes in patients with combined pars plana vitrectomy (PPV) with anterior chamber intraocular lens (ACIOL) to intrascleral haptic fixation (ISHF) using the Agarwal technique with fibrin glue to secure the scleral flap of a posterior chamber intraocular lens. Methods Retrospective, consecutive, single-center, comparative case series. 83 eyes were studied. Patients with

Abstract Pain and inflammation contribute immeasurably to reduced quality of life, yet modern analgesic and anti-inflammatory therapeutics can cause dependence and side effects. Here, we screened 1444 plant extracts, prepared primarily from native species in California and the United States Virgin Islands, against two voltage-gated K+ channels - T-cell expressed Kv1.3 and nociceptive-neuron expressed Kv7.2/7.3. A subset of extracts both inhibits Kv1.3 and activates Kv7.2/7.3 at hyperpolarized potentials, effects predicted to be anti-inflammatory and analgesic, respectively. Among the top dual hits are witch hazel and fireweed; polymodal modulation of multiple K+ channel types by hydrolysable tannins contributes to their dual anti-inflammatory, analgesic actions. In silico docking and mutagenesis data suggest pore-proximal extracellular linker sequence divergence underlies opposite effects of hydrolysable tannins on different Kv1 isoforms. The findings provide molecular insights into the enduring, widespread medicinal use of witch hazel and fireweed and demonstrate a screening strategy for discovering dual anti-inflammatory, analgesic small molecules.

Abstract Background The Coronavirus disease-2019 (COVID-19) vaccines were rolled out in many countries; however, sub-optimal COVID-19 vaccine uptake remains a major public health concern globally. This study aimed at assessing the factors that affected the uptake, hesitancy, and resistance of the COVID-19 vaccine among university undergraduate students in Malawi, a least developed country in Africa. Methods A descriptive cross-sectional study design was conducted using an online semi-structured questionnaire. A total of 343 University undergraduate students in Blantyre participated in this study after obtaining ethical clearance. Data was exported from Survey Monkey to Microsoft Excel version-21 for cleaning and was analysed using SPSS version-29. Descriptive statistics, including percentages, were performed to define the sample characteristics. Pearson Chi-square and Fisher’s exact test were performed to identify significant relationships between vaccine uptake and demographics. A 95% confidence interval was set, and a p-value of

Abstract By connecting old and recent notions, different spatial scales, and research domains, we introduce a novel framework on the consequences of brain injury focusing on a key role of slow waves. We argue that the long-standing finding of EEG slow waves after brain injury reflects the intrusion of sleep-like cortical dynamics during wakefulness; we illustrate how these dynamics are generated and how they can lead to functional network disruption and behavioral impairment. Finally, we outline a scenario whereby post-injury slow waves can be modulated to reawaken parts of the brain that have fallen asleep to optimize rehabilitation strategies and promote recovery.

Abstract Background Emergency department (ED) crowding is a major patient safety concern and has a negative impact on healthcare systems and healthcare providers. We hypothesized that it would be feasible to control crowding by employing a multifaceted approach consisting of systematically fast-tracking patients who are mostly not in need of a hospital stay as assessed by an initial nurse and treated by decision competent physicians. Methods Data from 120,901 patients registered in a secondary care ED from the 4tth quarter of 2021 to the 1st quarter of 2024 was drawn from the electronic health record’s data warehouse using the SAP Web Intelligence tool and processed in the Python programming language. Crowding was compared before and after ED transformation from a uniform department into a high flow (α) and a low flow (β) section with patient placement in gurneys/chairs or beds, respectively. Patients putatively not in need of hospitalization were identified by nurse, placed in in the α setting and assessed and treated by decision competent physicians. Incidence of crowding, number of patients admitted per day and readmittances within 72 h following ED admission before and after changes were determined. Values are number of patients, mean ± SEM and mean differences with 95% CIs. Statistical significance was ascertained using Student’s two tailed t-test for unpaired values. Results Before and after ED changes crowding of 130% amounted to 123.8 h and 19.3 h in the latter. This is a difference of -104.6 ± 23.9 h with a 95% CI of -159.9 to -49.3, Δ% -84 (p = 0.002). There was the same amount of patients / day amounting to 135.8 and 133.5 patients / day Δ% = -1.7 patients 95% CI -6.3 to 1.6 (p = 0.21). There was no change in readmittances within 72 h before and after changes amounting to 9.0% versus 9.5%, Δ% = 0.5, 95%, CI -0.007 to 1.0 (p > 0.052). Conclusion It appears feasible to abate crowding with unchanged patient admission and without an increase in readmittances by fast-track assessment and treatment of patients who are not in need of hospitalization.

Abstract The ongoing efforts to optimize rechargeable Li-ion batteries led to the interest in intercalation of nanoscale layered compounds, including bilayer graphene. Its lithium intercalation has been demonstrated recently but the mechanisms underpinning the storage capacity remain poorly understood. Here, using magnetotransport measurements, we report in-operando intercalation dynamics of bilayer graphene. Unexpectedly, we find four distinct intercalation stages that correspond to well-defined Li-ion densities. Transitions between the stages occur rapidly (within 1 sec) over the entire device area. We refer to these stages as ‘in-plane’, with no in-plane analogues in bulk graphite. The fully intercalated bilayers represent a stoichiometric compound C14LiC14 with a Li density of ∼2.7·1014 cm−2, notably lower than fully intercalated graphite. Combining the experimental findings and DFT calculations, we show that the critical step in bilayer intercalation is a transition from AB to AA stacking which occurs at a density of ∼0.9·1014 cm−2. Our findings reveal the mechanism and limits for electrochemical intercalation of bilayer graphene and suggest possible avenues for increasing the Li storage capacity.

Abstract Preclinical studies suggest that simultaneous HER2/VEGF blockade may have cooperative effects in gastroesophageal adenocarcinomas. In a single-arm investigator initiated clinical trial for patients with untreated advanced HER2+ gastroesophageal adenocarcinoma, bevacizumab was added to standard of care capecitabine, oxaliplatin, and trastuzumab in 36 patients (NCT01191697). Primary endpoint was objective response rate and secondary endpoints included safety, duration of response, progression free survival, and overall survival. The study met its primary endpoint with an objective response rate of 81% (95% CI 65–92%). Median progression free and overall survival were 14.0 (95% CI, 11.3–36.4) and 23.2 months (95% CI, 16.6–36.4), respectively. The median duration of response was 14.9 months. The regimen was well tolerated without unexpected or severe toxicities. In post-hoc ctDNA analysis, baseline ctDNA features were prognostic: Higher tumor fraction and alternative MAPK drivers portended worse outcomes. ctDNA at resistance identified oncogenic mutations and these were detectable 2–8 cycles prior to radiographic progression. Capecitabine, oxaliplatin, trastuzumab and bevacizumab shows robust clinical activity in HER2+ gastroesophageal adenocarcinoma. Combination of VEGF inhibitors with chemoimmunotherapy and anti-PD1 regimens is warranted.