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Abstract To determine the diagnostic yield of cone beam computed tomography (CBCT) compared with 3 T magnetic resonance imaging (MRI) for the evaluation of subchondral insufficiency fractures of the knee. Consecutive patients with subchondral insufficiency fractures of the knee examined by 3 T MRI and CBCT of the femoral condyles were reviewed. Two experienced raters graded the lesion severity on 3 T MRI and CBCT images: grade 1: no signs of a subchondral bone lesion; grade 2: subchondral trabecular fracture or cystic changes, but without infraction of the subchondral bone plate; grade 3: collapse of the subchondral bone plate. Ratings were repeated after six weeks to determine reliability. In addition, the bone lesion size was measured as elliptical area (mm2) and compared between CBCT and T1-weighted MRI sequences. Among 30 patients included (43.3% women; mean age: 60.9 ± 12.8 years; body mass index (BMI) 29.0 ± 12.8 kg/m2), the medial femoral condyle was affected in 21/30 patients (70%). The grading of subchondral lesions between MRI and CBCT did not match in 12 cases (40%). Based on MRI images, an underestimation (i.e., undergrading) compared with CBCT was observed in nine cases (30%), whereas overgrading occurred in three cases (10%). Compared to CBCT, routine T1-weighted 3 T sequences significantly overestimated osseus defect zones in sagittal (84.7 ± 68.9 mm2 vs. 35.9 ± 38.2 mm2, p

Abstract Background Renal outcomes in patients with type 2 diabetes following treatment with sodium–glucose co-transporter-2 inhibitors (SGLT2is) or glucagon-like peptide-1 receptor agonists (GLP1RAs) have not been directly compared. This study compared the impact of SGLT2i and GLP1RA therapy on renal function and metabolic parameters. Methods Patients with type 2 diabetes who initiated SGLT2i or GLP1RA therapy in a tertiary hospital between January 2009 and August 2023 were included to assess composite renal outcomes, such as a 40% decline in estimated glomerular filtration rate (eGFR), onset of end-stage renal disease, renal death, or new-onset macroalbuminuria. Alterations in blood pressure, glucose regulation parameters, lipid profile, and anthropometric parameters, including body fat and muscle masses, were examined over 4-years. Results A total of 2,112 patients were enrolled using a one-to-three propensity-score matching approach (528 patients for GLP1RAs, 1,584 patients for SGLT2i). SGLT2i treatment was favoured over GLP1RA treatment, though not significantly, for composite renal outcomes (hazard ratio [HR], 0.63; p = 0.097). SGLT2i therapy preserved renal function effectively than GLP1RAs (decrease in eGFR, ≥ 40%; HR, 0.46; p = 0.023), with improving albuminuria regression (HR, 1.72; p = 0.036). SGLT2i therapy decreased blood pressure and body weight to a greater extent. However, more patients attained HbA1c levels

Abstract Background Although mitral valve repair is the preferred surgical strategy in children with mitral valve disease, there are cases of irreparable severe dysplastic valves that require mitral valve replacement. The aim of this study is to analyze long-term outcomes following mitral valve replacement in children in a tertiary referral center. Methods A total of 41 consecutive patients underwent mitral valve replacement between February 2001 and February 2021. The study data was prospectively collected and retrospectively analyzed. Primary outcomes were in-hospital mortality, long-term survival, and long-term freedom from reoperation. Results Median age at operation was 23 months (IQR 5–93), median weight was 11.3 kg (IQR 4.8–19.4 kg). One (2.4%) patient died within the first 30 postoperative days. In-hospital mortality was 4.9%. Four (9.8%) patients required re-exploration for bleeding, and 2 (4.9%) patients needed extracorporeal life support. Median follow-up was 11 years (IQR 11 months − 16 years). Long-term freedom from re-operation after 1, 5, 10 and 15 years was 97.1%, 93.7%, 61.8% and 42.5%, respectively. Long-term survival after 1, 5, 10 and 15 years was 89.9%, 87%, 87% and 80.8%, respectively. Conclusion If MV repair is not feasible, MV replacement offers a good surgical alternative for pediatric patients with MV disease. It provides good early- and long-term outcomes.

Abstract Despite widespread engagement in contemplative religious practices, comparatively little research has been conducted on their potential effects on well-being. Furthermore, few studies have focused on how an explicitly religious framing may impact the outcomes of such practices. In this online randomized controlled trial (N = 702), we tested the well-being effects of a contemplative prayer practice called Centering Prayer on self-identifying Christians. We compared 1) presenting the practice with an explicitly religious framing (experimental condition), 2) presenting the practice without an explicitly religious framing (active control), and 3) presenting simple instructions to reflect on the day, without any instructions regarding a meditation-like practice (passive control). After randomization into one of these three conditions, participants were asked to complete their assigned practice daily for 28 days. We hypothesized that the religious framing version of the practice would increase well-being over the active and passive control conditions. Well-being was assessed at three follow-up time points: one day, one week, and one month after the practice period. We found no group differences between the conditions on our primary outcome measure of well-being at one-week post-intervention. Each group increased in well-being from baseline to follow-up. We found significant group differences on acute measures of spiritual experience, the Mystical Experience Questionnaire (MEQ-30) and Daily Spiritual Experience Questionnaire (DSES). These results suggest that a religious framing may not enhance well-being effects but may alter spiritual outcomes related to contemplative practices.

Background: The role of biceps tenodesis (BT) during open reduction internal fixation (ORIF) of proximal humerus fractures (PHFs) remains unclear. A subset of patients undergoing ORIF have persistent pain with unclear etiology. The purpose of our study was to compare outcomes of ORIF of PHFs with and without concomitant BT. We hypothesize patients undergoing BT at the time of ORIF will have improved patient-reported outcome scores with fewer secondary procedures related to treatment of the biceps. Methods: In this retrospective cohort study, all patients undergoing ORIF for a PHF at a single level one trauma center from January 2019 to June 2022 were reviewed. Patients under the age of 18 were excluded. Primary outcomes were patient-reported outcomes measurement information system physical function, depression, and pain interference scores at 5 time points up to final follow-up. Secondary outcomes included total operative time, complications, subsequent procedures, steroid injections, and range of motion. Chi-square tests were performed for categorical values and paired t-tests for continuous variables. Results: 71 patients met inclusion criteria: 41 undergoing ORIF without BT and 30 undergoing ORIF with BT. Average follow-up was 11 months. There were no statistically significant differences in patient demographics between groups. There were no differences in patient-reported outcomes measurement information system scores at any time point postoperatively. At final follow-up patients in the ORIF with BT group had higher forward flexion than those who did not undergo BT (142 vs. 123 degrees, respectively, P

The study aimed at exploring the teachers’ self-efficacy belief for teaching critical thinking skills and practices of strategies in reading classroom. It also pursued if there is any significant relationship between the two variables. A descriptive survey study used sequential explanatory mixed-methods approach to collect data. The study involved 40 EFL teachers. The survey contained 19 items using five-point Likert scale. Qualitative data were collected via classroom observations. The results of quantitative data showed(m=3.3) that the participants implemented the strategies moderately. The findings of qualitative data revealed that most of critical thinking strategies were practiced rarely while participants were instructing reading lessons. However, the responsive strategy of teachers to their students’ responses was implemented better than others. Statistical analysis also disclosed a positive high significant correlation between the teachers’ self-efficacy belief for teaching CT and its implementation strategies during teaching reading lessons (r=0.99, p

Background: Human African trypanosomiasis is the third disease with most mortalities among the neglected tropical diseases. The absence of vaccines and the development of parasite resistance have necessitated the quest for new affordable and safe treatment options for the disease. This study aims to assess the potential of Uvaria ovata as an alternative new and safer antitrypanosomal therapeutics. Methods: Antitrypanosomal efficacies of extracts and fractions of U. ovata were determined by the Alamar Blue cell viability assay against Trypanosoma brucei brucei GUTat 3.1. Molecular docking was used to suggest the mechanism of action of the extracts and fractions by docking the curated compounds present in the plant against farnesyl diphosphate synthase (FPPS) and ornithine decarboxylase (ODC) enzymes. Results: Antitrypanosomal activities (IC50, μg/mL) obtained were within the range of 0.12–4.40, exceeding that of the standard suramin (4.96). A total of 17 known compounds from U. ovata that did not violate Lipinski’s rule of five with negligible toxicity produced molecular docking results against FPPS and ODC enzymes. Within the FPPS interaction landscape, mannosamine emerged as the most promising lead, with a binding energy of −6.4 kcal/mol and a predicted Ki value of 20.12 μM. With respect to ODC, 15 compounds exhibited binding affinities ranging from −4.6 to −6.3 kcal/mol, exceeding that of the known inhibitor allicin (−4.5 kcal/mol). Conclusion: This is the first report of the antitrypanosomal activity and mode of action suggestion of U. ovata. The study sets the foundation for further exploration and validation of the therapeutic prospect of U. ovata in the fight against trypanosomiasis.

Introduction: Optimizing the performance of emergency department (ED) teams impacts patient care, but the utility of current, team-based performance assessment tools to comprehensively measure this impact is underexplored. In this study we aimed to 1) evaluate ED team performance using current team-based assessment tools during an interprofessional in situ simulation and 2) identify characteristics of effective ED teams. Methods: This mixed-methods study employed case study methodology based on a constructivist paradigm. Sixty-three eligible nurses, technicians, pharmacists, and postgraduate year 2–4 emergency medicine residents at a tertiary academic ED participated in a 10-minute in situ simulation of a critically ill patient. Participants self-rated performance using the Team Performance Observation Tool (TPOT) 2.0 and completed a brief demographic form. Two raters independently reviewed simulation videos and rated performance using the TPOT 2.0, Team Emergency Assessment Measure (TEAM), and Ottawa Crisis Resource Management Global Rating Scale (Ottawa GRS). Following simulations, we conducted semi-structured interviews and focus groups with in situ participants. Transcripts were analyzed using thematic analysis. Results: Eighteen team-based simulations took place between January–April 2021. Raters’ scores were on the upper end of the tools for the TPOT 2.0 (R1 4.90, SD 0.17; R2 4.53, SD 0.27, IRR [inter-rater reliability] 0.47), TEAM (R1 3.89, SD 0.19; R2 3.58, SD 0.39, IRR 0.73), and Ottawa GRS (R1 6.6, SD 0.56; R2 6.2, SD 0.54, IRR 0.68). We identified six themes from our interview data: team member entrustment; interdependent energy; leadership tone; optimal communication; strategic staffing; and simulation empowering team performance. Conclusion: Current team performance assessment tools insufficiently discriminate among high performing teams in the ED. Emergency department-specific assessments that capture features of entrustability, interdependent energy, and leadership tone may offer a more comprehensive way to assess an individual’s contribution to a team’s performance.

Abstract The complexity and diversity of polymer topologies, or chain architectures, present substantial challenges in predicting and engineering polymer properties. Although machine learning is increasingly used in polymer science, applications to address architecturally complex polymers are nascent. Here, we use a generative machine learning model based on variational autoencoders and data generated from molecular dynamics simulations to design polymer topologies that exhibit target properties. Following the construction of a dataset featuring 1342 polymers with linear, cyclic, branch, comb, star, or dendritic structures, we employ a multi-task learning framework that effectively reconstructs and classifies polymer topologies while predicting their dilute-solution radii of gyration. This framework enables the generation of polymer topologies with target size, which is subsequently validated through molecular simulation. These capabilities are then exploited to contrast rheological properties of topologically distinct polymers with otherwise similar dilute-solution behavior. This research opens avenues for engineering polymers with more intricate and tailored properties with machine learning.

Abstract Baryon number is an accidental symmetry of the Standard Model (SM) Lagrangian that so far has been measured to be exactly preserved, although it is expected to be violated at higher energies. In this work we compute order-of-magnitude estimates for the matching contributions of generic ultraviolet models to effective operators that generate nucleon decay processes. This is done in a systematic and automated way using operators constructed from SM fields up to dimension nine and working in a framework that has proved useful in the study of lepton-number violation. For each of the operators we derive estimates for the rates of different nucleon-decay channels. These allow us to establish model-independent lower bounds on the underlying new-physics scale and identify potential correlations between the various decay modes. The results are most relevant for families of models that generate the considered operator. This analysis is especially timely given the expected future sensitivities in numerous experiments such as Hyper-K, DUNE, JUNO and THEIA.

Abstract In the present study road safety impact analysis for certain advanced driver assistance systems (ADAS) was conducted. Based on a literature review, expert interviews and current adaptations in legislation, the most promising nine ADAS were selected. The impact was analysed based on statistical crash data from Austria. Factors such as infrastructure and weather conditions, market penetration, expected functionality of sensors, user acceptance and risk homeostasis were considered. A software tool was developed to calculate the crash reduction potential of the selected ADAS for the scenarios 2025, 2030 and 2040. The results show that the ADAS related to warning/braking have the greatest future reduction potential and could lead to a reduction of up to 8,700 crashes and 70 fatalities in Austria in 2040. In addition, the Intelligent Speed Assistance system would lead to an overall crash reduction of 8% compared to current crash numbers in Austria in 2040. The Turning Assistant for heavy goods vehicles shows the lowest reduction in crashes and casualties, but due to the highest severity per crash (93 fatalities per 1,000 crashes), it nevertheless provides an important contribution to the reduction of fatalities in road traffic. However, to benefit from the ADAS safety potential, it is highly relevant that these systems are used in a correct manner. In the future, it will be necessary to provide users with more information on the correct use, benefits and limitations of the respective ADAS and to integrate the use of these systems into driver education procedures and tests.

Abstract Non-alcoholic steatohepatitis (NASH) is characterized from its early stages by a profound remodeling of the liver microenvironment, encompassing changes in the composition and activities of multiple cell types and associated gene expression patterns. Hyperpolarized (HP) 13C MRI provides a unique view of the metabolic microenvironment, with potential relevance for early diagnosis of liver disease. Previous studies have detected changes in HP 13C pyruvate to lactate conversion, catalyzed by lactate dehydrogenase (LDH), with experimental liver injury. HP $$\propto $$ ∝ -ketobutyrate ( $$\propto $$ ∝ KB) is a close molecular analog of pyruvate with modified specificity for LDH isoforms, specifically attenuated activity with their LDHA-expressed subunits that dominate liver parenchyma. Building on recent results with pyruvate, we investigated HP $$\propto $$ ∝ KB in methionine-choline deficient (MCD) diet as a model of early-stage NASH. Similarity of results between this new agent and pyruvate (~ 50% drop in cytoplasmic reducing capacity), interpreted together with gene expression data from the model, suggests that changes are mediated through broad effects on intermediary metabolism. Plausible mechanisms are depletion of the lactate pool by upregulation of gluconeogenesis (GNG) and pentose phosphate pathway (PPP) flux, and a possible shift toward increased lactate oxidation. These changes may reflect high levels of oxidative stress and/or shifting macrophage populations in NASH.

Our previous work demonstrated the presence of lead (Pb) and cadmium (Cd) contamination in cow milk (CM) and soy beverages (SBs) in Portugal. These metals share carcinogenic mechanisms, suggesting at least additive effects. Our goals were to assess carcinogenic risks from Pb and Cd intake detected in various CM and SB brands on the Portuguese market and to determine the relative contributions of Pb and Cd. Furthermore, we modeled different consumption scenarios for various age/body weight groups to estimate cumulative Excess Lifetime Carcinogenic Risk (ELCR). ELCR was computed by multiplying chronic daily intake by a cancer slope factor for each metal, with an ELCR > 1 × 10−4 indicating carcinogenic risk. Five CM and three SB brands posed cancer risks in children, with the highest values at 1.75 × 10−4 and 9.12 × 10−5, respectively; Pb had mean relative contributions of 87.8 ± 3.1% in CM and 54.9 ± 12.1% in SB. Carcinogenic risks were observed for children, adolescents, and adults in several CM or SB consumption scenarios, albeit at levels above typical Portuguese intakes. Strict monitoring of metal levels, such as Pb and Cd, is advised because CM is a component of many foods, including baby food.

Abstract A newly discovered coronavirus called COVID-19 poses the greatest threat to mankind in the twenty-first century. Mortality has dramatically increased in all cities and countries due to the virus's current rate of spread. A speedy and precise diagnosis is also necessary in order to treat the illness. This study identified three groups for chest X-ray images: Covid, normal, and pneumonia. This study's objective is to present a framework for categorizing chest X-ray images into three groups of pneumonia, normal, and Covid scenarios. To do this, chest X-ray images from the Kaggle database which have been utilized in previous studies were obtained. It is suggested to use an Efficientnet_b0 model to identify characteristics in raw data hierarchically. An unedited X-ray image of the chest is enhanced for more reasonable assumptions in order to apply the proposed method in real-world situations. With an overall accuracy of 93.75%, the proposed network correctly identified the chest X-ray images to the classes of Covid, viral pneumonia, and normal on the test set. 90% accuracy rate for the test dataset was attained for the viral pneumonitis group. On the test dataset, the Normal class accuracy was 94.7%, while the Covid class accuracy was 96%. The findings indicate that the network is robust. In addition, when compared to the most advanced techniques of identifying pneumonia, the concluded findings from the suggested model are highly encouraging. Since the recommended network is successful at doing so utilizing chest X-ray imaging, radiologists can diagnose COVID-19 and other lung infectious infections promptly and correctly.

Abstract Background Neuroblastoma is a common pediatric cancer, where preclinical studies suggest that a mesenchymal-like gene expression program contributes to chemotherapy resistance. However, clinical outcomes remain poor, implying we need a better understanding of the relationship between patient tumor heterogeneity and preclinical models. Results Here, we generate single-cell RNA-seq maps of neuroblastoma cell lines, patient-derived xenograft models (PDX), and a genetically engineered mouse model (GEMM). We develop an unsupervised machine learning approach (“automatic consensus nonnegative matrix factorization” (acNMF)) to compare the gene expression programs found in preclinical models to a large cohort of patient tumors. We confirm a weakly expressed, mesenchymal-like program in otherwise adrenergic cancer cells in some pre-treated high-risk patient tumors, but this appears distinct from the presumptive drug-resistance mesenchymal programs evident in cell lines. Surprisingly, however, this weak-mesenchymal-like program is maintained in PDX and could be chemotherapy-induced in our GEMM after only 24 h, suggesting an uncharacterized therapy-escape mechanism. Conclusions Collectively, our findings improve the understanding of how neuroblastoma patient tumor heterogeneity is reflected in preclinical models, provides a comprehensive integrated resource, and a generalizable set of computational methodologies for the joint analysis of clinical and pre-clinical single-cell RNA-seq datasets.

Abstract A major challenge in protein design is to augment existing functional proteins with multiple property enhancements. Altering several properties likely necessitates numerous primary sequence changes, and novel methods are needed to accurately predict combinations of mutations that maintain or enhance function. Models of sequence co-variation (e.g., EVcouplings), which leverage extensive information about various protein properties and activities from homologous protein sequences, have proven effective for many applications including structure determination and mutation effect prediction. We apply EVcouplings to computationally design variants of the model protein TEM-1 β-lactamase. Nearly all the 14 experimentally characterized designs were functional, including one with 84 mutations from the nearest natural homolog. The designs also had large increases in thermostability, increased activity on multiple substrates, and nearly identical structure to the wild type enzyme. This study highlights the efficacy of evolutionary models in guiding large sequence alterations to generate functional diversity for protein design applications.

Environmentally sensitive areas such as lands demarcated for urban green infrastructure and regional forest reserves by urban and regional plans are crucial to be protected due to the environmental, economic, social, and cultural services they provide. However, such environmentally sensitive areas are being threatened by various human activities, including urban dynamics. The current study, therefore, aimed to deploy existing scenario alternatives to predict and evaluate the environmental impacts of the possible future urban dynamics in environmentally sensitive areas to support the core of the Strategic Environmental Assessment process for sustainable urban and regional development planning and policy. The study deployed Geographic Information Systems, existing land cover maps, land use plans, calibrated and validated land use/land cover model, and scenario alternatives to predict the possible future urban and regional land dynamics using the Markov model. The matrix method of environmental impact magnitude and environmental sensitivity was used to define environmental impact significance. In so doing, the environmental impact magnitude in the environmentally sensitive area is categorised into very low (> 0% = 5% < 10%), medium (>= 10% < 15%), high (>= 15% < 20%), and very high (>= 20%). Key findings showed a significant and non-significant environmental impact of the possible future urban dynamics in environmentally sensitive areas associated with the Business As Usual scenario and alternative scenarios, respectively. The information from the current study is useful to support decision-makers in addressing problems associated with the core of the Strategic Environmental Assessment process and its application to land use planning in Sub-Saharan Africa in particular and other parts of the Global South in general.

Abstract This study focuses on the comprehensive reservoir characterization of the ‘Kukih’ Field within the onshore northeastern Niger Delta region, Nigeria. The absence of its detailed description with delineated reservoir properties, lateral continuity, and their use to identify potential reservoir quality and heterogeneity necessitated this study. Integrating well log and 3D seismic data, the investigation aims to elucidate reservoir properties, lithofacies, and depositional environments to unravel hydrocarbon potential. The geological setting, encompassing the Agbada Formation of Early and Middle Miocene age, is scrutinized through detailed geologic analysis. Petrophysical evaluation of four well logs (Kukih-1, Kukih-2, Kukih-3, and Kukih-4) facilitated the determination of key parameters such as shale volume, effective porosity, and water saturation. Seismic interpretation further enriched the structural characterization of the field. Results showcase three predominant reservoir sands (A, B, and C) with distinct lithofacies and thickness variations. Effective porosity ranges from Fair to Excellent, with permeability exhibiting high values for hydrocarbon reservoir potential. Water saturation trends, lithofacies distributions, and structural features were illuminated through iso-parametric maps and seismic analyses. Depositional environments were inferred through facies analysis, revealing the presence of funnel-, cylinder-, and bell-shaped successions that hint at intricate marine sedimentary processes. Challenges owing to limited core data were acknowledged, and the integration of methodologies emerged as a pivotal strategy for enhanced reservoir understanding. This study underscores the ‘Kukih’ Field's hydrocarbon potential, accentuating the significance of multidisciplinary approaches in deciphering complex reservoir systems. In light of the petrophysical analysis derived from the well logs and the identification of structural highs through the structural maps, this study recommends the drilling of unexplored zones exhibiting promising structural characteristics.

Abstract ChatGPT has garnered attention as a multifaceted AI chatbot with potential applications in medicine. Despite intriguing preliminary findings in areas such as clinical management and patient education, there remains a substantial knowledge gap in comprehensively understanding the chances and limitations of ChatGPT’s capabilities, especially in medical test-taking and education. A total of n = 2,729 USMLE Step 1 practice questions were extracted from the Amboss question bank. After excluding 352 image-based questions, a total of 2,377 text-based questions were further categorized and entered manually into ChatGPT, and its responses were recorded. ChatGPT’s overall performance was analyzed based on question difficulty, category, and content with regards to specific signal words and phrases. ChatGPT achieved an overall accuracy rate of 55.8% in a total number of n = 2,377 USMLE Step 1 preparation questions obtained from the Amboss online question bank. It demonstrated a significant inverse correlation between question difficulty and performance with rs = -0.306; p

Abstract Background Mutations in the X-linked gene cyclin-dependent kinase-like 5 (CDKL5) cause a severe neurological disorder characterised by early-onset epileptic seizures, autism and intellectual disability (ID). Impaired hippocampal function has been implicated in other models of monogenic forms of autism spectrum disorders and ID and is often linked to epilepsy and behavioural abnormalities. Many individuals with CDKL5 deficiency disorder (CDD) have null mutations and complete loss of CDKL5 protein, therefore in the current study we used a Cdkl5 −/y rat model to elucidate the impact of CDKL5 loss on cellular excitability and synaptic function of CA1 pyramidal cells (PCs). We hypothesised abnormal pre and/or post synaptic function and plasticity would be observed in the hippocampus of Cdkl5 −/y rats. Methods To allow cross-species comparisons of phenotypes associated with the loss of CDKL5, we generated a loss of function mutation in exon 8 of the rat Cdkl5 gene and assessed the impact of the loss of CDLK5 using a combination of extracellular and whole-cell electrophysiological recordings, biochemistry, and histology. Results Our results indicate that CA1 hippocampal long-term potentiation (LTP) is enhanced in slices prepared from juvenile, but not adult, Cdkl5 −/y rats. Enhanced LTP does not result from changes in NMDA receptor function or subunit expression as these remain unaltered throughout development. Furthermore, Ca2+ permeable AMPA receptor mediated currents are unchanged in Cdkl5 −/y rats. We observe reduced mEPSC frequency accompanied by increased spine density in basal dendrites of CA1 PCs, however we find no evidence supporting an increase in silent synapses when assessed using a minimal stimulation protocol in slices. Additionally, we found no change in paired-pulse ratio, consistent with normal release probability at Schaffer collateral to CA1 PC synapses. Conclusions Our data indicate a role for CDKL5 in hippocampal synaptic function and raise the possibility that altered intracellular signalling rather than synaptic deficits contribute to the altered plasticity. Limitations This study has focussed on the electrophysiological and anatomical properties of hippocampal CA1 PCs across early postnatal development. Studies involving other brain regions, older animals and behavioural phenotypes associated with the loss of CDKL5 are needed to understand the pathophysiology of CDD.

Abstract Spaceflight induces an immune response in astronauts. To better characterize this effect, we generated single-cell, multi-ome, cell-free RNA (cfRNA), biochemical, and hematology data for the SpaceX Inspiration4 (I4) mission crew. We found that 18 cytokines/chemokines related to inflammation, aging, and muscle homeostasis changed after spaceflight. In I4 single-cell multi-omics data, we identified a “spaceflight signature” of gene expression characterized by enrichment in oxidative phosphorylation, UV response, immune function, and TCF21 pathways. We confirmed the presence of this signature in independent datasets, including the NASA Twins Study, the I4 skin spatial transcriptomics, and 817 NASA GeneLab mouse transcriptomes. Finally, we observed that (1) T cells showed an up-regulation of FOXP3, (2) MHC class I genes exhibited long-term suppression, and (3) infection-related immune pathways were associated with microbiome shifts. In summary, this study reveals conserved and distinct immune disruptions occurring and details a roadmap for potential countermeasures to preserve astronaut health.

Abstract The SpaceX Inspiration4 mission provided a unique opportunity to study the impact of spaceflight on the human body. Biospecimen samples were collected from four crew members longitudinally before (Launch: L-92, L-44, L-3 days), during (Flight Day: FD1, FD2, FD3), and after (Return: R + 1, R + 45, R + 82, R + 194 days) spaceflight, spanning a total of 289 days across 2021-2022. The collection process included venous whole blood, capillary dried blood spot cards, saliva, urine, stool, body swabs, capsule swabs, SpaceX Dragon capsule HEPA filter, and skin biopsies. Venous whole blood was further processed to obtain aliquots of serum, plasma, extracellular vesicles and particles, and peripheral blood mononuclear cells. In total, 2,911 sample aliquots were shipped to our central lab at Weill Cornell Medicine for downstream assays and biobanking. This paper provides an overview of the extensive biospecimen collection and highlights their processing procedures and long-term biobanking techniques, facilitating future molecular tests and evaluations.As such, this study details a robust framework for obtaining and preserving high-quality human, microbial, and environmental samples for aerospace medicine in the Space Omics and Medical Atlas (SOMA) initiative, which can aid future human spaceflight and space biology experiments.

Abstract Background Heterogeneity in national SARS-CoV-2 infection surveillance capabilities may compromise global enumeration and tracking of COVID-19 cases and deaths and bias analyses of the pandemic’s tolls. Taking account of heterogeneity in data completeness may thus help clarify analyses of the relationship between COVID-19 outcomes and standard preparedness measures. Methods We examined country-level associations of pandemic preparedness capacities inventories, from the Global Health Security (GHS) Index and Joint External Evaluation (JEE), on SARS-CoV-2 infection and COVID-19 death data completion rates adjusted for income. Analyses were stratified by 100, 100–300, 300–500, and 500–700 days after the first reported case in each country. We subsequently reevaluated the relationship of pandemic preparedness on SARS-CoV-2 infection and age-standardized COVID-19 death rates adjusted for cross-country differentials in data completeness during the pre-vaccine era. Results Every 10% increase in the GHS Index was associated with a 14.9% (95% confidence interval 8.34–21.8%) increase in SARS-CoV-2 infection completion rate and a 10.6% (5.91–15.4%) increase in the death completion rate during the entire observation period. Disease prevention (infections: β = 1.08 [1.05–1.10], deaths: β = 1.05 [1.04–1.07]), detection (infections: β = 1.04 [1.01–1.06], deaths: β = 1.03 [1.01–1.05]), response (infections: β = 1.06 [1.00–1.13], deaths: β = 1.05 [1.00–1.10]), health system (infections: β = 1.06 [1.03–1.10], deaths: β = 1.05 [1.03–1.07]), and risk environment (infections: β = 1.27 [1.15–1.41], deaths: β = 1.15 [1.08–1.23]) were associated with both data completeness outcomes. Effect sizes of GHS Index on infection completion (Low income: β = 1.18 [1.04–1.34], Lower Middle income: β = 1.41 [1.16–1.71]) and death completion rates (Low income: β = 1.19 [1.09–1.31], Lower Middle income: β = 1.25 [1.10–1.43]) were largest in LMICs. After adjustment for cross-country differences in data completeness, each 10% increase in the GHS Index was associated with a 13.5% (4.80–21.4%) decrease in SARS-CoV-2 infection rate at 100 days and a 9.10 (1.07–16.5%) decrease at 300 days. For age-standardized COVID-19 death rates, each 10% increase in the GHS Index was with a 15.7% (5.19–25.0%) decrease at 100 days and a 10.3% (− 0.00–19.5%) decrease at 300 days. Conclusions Results support the pre-pandemic hypothesis that countries with greater pandemic preparedness capacities have larger SARS-CoV-2 infection and mortality data completeness rates and lower COVID-19 disease burdens. More high-quality data of COVID-19 impact based on direct measurement are needed.

Abstract Background Racial and ethnic inequities in palliative care are well-established. The way researchers design and interpret studies investigating race- and ethnicity-based disparities has future implications on the interventions aimed to reduce these inequities. If racism is not discussed when contextualizing findings, it is less likely to be addressed and inequities will persist. Objective To summarize the characteristics of 12 years of academic literature that investigates race- or ethnicity-based disparities in palliative care access, outcomes and experiences, and determine the extent to which racism is discussed when interpreting findings. Methods Following Arksey & O’Malley’s methodology for scoping reviews, we searched bibliographic databases for primary, peer reviewed studies globally, in all languages, that collected race or ethnicity variables in a palliative care context (January 1, 2011 to October 17, 2023). We recorded study characteristics and categorized citations based on their research focus—whether race or ethnicity were examined as a major focus (analyzed as a primary independent variable or population of interest) or minor focus (analyzed as a secondary variable) of the research purpose, and the interpretation of findings—whether authors directly or indirectly discussed racism when contextualizing the study results. Results We identified 3000 citations and included 181 in our review. Of these, most were from the United States (88.95%) and examined race or ethnicity as a major focus (71.27%). When interpreting findings, authors directly named racism in 7.18% of publications. They were more likely to use words closely associated with racism (20.44%) or describe systemic or individual factors (41.44%). Racism was directly named in 33.33% of articles published since 2021 versus 3.92% in the 10 years prior, suggesting it is becoming more common. Conclusion While the focus on race and ethnicity in palliative care research is increasing, there is room for improvement when acknowledging systemic factors – including racism – during data analysis. Researchers must be purposeful when investigating race and ethnicity, and identify how racism shapes palliative care access, outcomes and experiences of racially and ethnically minoritized patients.

Abstract Background The aim of the study was to develop a technique for quantitative determination of rat urine metabolites by HPLC–MS/MS, which can be used to search for biomarkers of acute intoxication with organophosphates (OPs). Results The content of metabolites in the urine of rats exposed to a single dose of paraoxon (POX1x); interval, twice daily administration of paraoxon (POX2x); exposure to 2-(o-cresyl)-4H-1, 3, 2-benzodioxaphosphorin-2-oxide and paraoxon (CBPOX) was investigated. New data were obtained on the content in the urine of intact rats as well as rats in 3 models of OP poisoning: 3-methylhistidine, threonine, creatine, creatinine, lactic acid, acetylcarnitine, inosine, hypoxanthine, adenine, 3-hydroxymethyl-butyrate and 2-hydroxymethyl-butyrate. Conclusions The proposed assay procedure is a simple and reliable tool for urine metabolomic studies. Within 1–3 days after OP exposure in all three models of acute intoxication, the concentration of metabolites in rat urine, with the exception of adenine, changes similarly and symmetrically, regardless of the method of poisoning modeling, in all three models of acute intoxication. Further studies are needed to determine the specificity and reliability of using urinary metabolite concentration changes as potential biomarkers of acute organophosphate intoxication. Graphical Abstract

Abstract Background Micro- and macrovascular diseases are common in patients with type 2 diabetes mellitus (T2D) and may be partly caused by nocturnal hypoxemia. The study aimed to characterize the composition of nocturnal hypoxemic burden and to assess its association with micro- and macrovascular disease in patients with T2D. Methods This cross-sectional analysis includes overnight oximetry from 1247 patients with T2D enrolled in the DIACORE (DIAbetes COhoRtE) study. Night-time spent below a peripheral oxygen saturation of 90% (T90) as well as T90 associated with non-specific drifts in oxygen saturation (T90non − specific), T90 associated with acute oxygen desaturation (T90desaturation) and desaturation depths were assessed. Binary logistic regression analyses adjusted for known risk factors (age, sex, smoking status, waist-hip ratio, duration of T2D, HbA1c, pulse pressure, low-density lipoprotein, use of statins, and use of renin-angiotensin-aldosterone system inhibitors) were used to assess the associations of such parameters of hypoxemic burden with chronic kidney disease (CKD) as a manifestation of microvascular disease and a composite of cardiovascular diseases (CVD) reflecting macrovascular disease. Results Patients with long T90 were significantly more often affected by CKD and CVD than patients with a lower hypoxemic burden (CKD 38% vs. 28%, p

Abstract Magnetic materials with noncoplanar magnetic structures can show unusual physical properties driven by nontrivial topology. Topologically-active states are often multi-q structures, which are challenging to stabilize in models and to identify in materials. Here, we use inelastic neutron-scattering experiments to show that the insulating double perovskites Ba2YRuO6 and Ba2LuRuO6 host a noncoplanar 3-q structure on the face-centered cubic lattice. Quantitative analysis of our neutron-scattering data reveals that these 3-q states are stabilized by biquadratic interactions. Our study identifies double perovskites as a highly promising class of materials to realize topological magnetism, elucidates the stabilization mechanism of the 3-q state in these materials, and establishes neutron spectroscopy on powder samples as a valuable technique to distinguish multi-q from single-q states, facilitating the discovery of topologically-nontrivial magnetic materials.

Abstract Healthy ecosystems and species have some degree of resilience to changing conditions, however as the frequency and severity of environmental changes increase, resilience may be diminished or lost. In Sweden, one example of a species with reduced resilience is the Atlantic cod (Gadus morhua). This species has been subjected to overfishing, and with additional pressures such as habitat degradation and changing environmental conditions there has been little to no recovery, despite more than a decade of management actions. Given the historical ecological, economical, and cultural significance of cod, it is important to understand how Atlantic cod respond to global climate change to recover and sustainably manage this species in the future. A multi-stressor experiment was conducted to evaluate physiological responses of juvenile cod exposed to warming, ocean acidification, and freshening, changes expected to occur in their nursery habitat. The response to single drivers showed variable effects related to fish biometrics and increased levels of oxidative stress dependent parameters. Importantly, two separate responses were seen within a single treatment for the multi-stressor and freshening groups. These within-treatment differences were correlated to genotype, with the offshore ecotype having a heightened stress response compared to the coastal ecotype, which may be better adapted to tolerate future changes. These results demonstrate that, while Atlantic cod have some tolerance for future changes, ecotypes respond differently, and cumulative effects of multiple stressors may lead to deleterious effects for this important species.

Abstract Some of the most metabolically diverse species of bacteria (e.g., Actinobacteria) have higher GC content in their DNA, differ substantially in codon usage, and have distinct protein folding environments compared to tractable expression hosts like Escherichia coli. Consequentially, expressing biosynthetic gene clusters (BGCs) from these bacteria in E. coli often results in a myriad of unpredictable issues with regard to protein expression and folding, delaying the biochemical characterization of new natural products. Current strategies to achieve soluble, active expression of these enzymes in tractable hosts can be a lengthy trial-and-error process. Cell-free expression (CFE) has emerged as a valuable expression platform as a testbed for rapid prototyping expression parameters. Here, we use a type III polyketide synthase from Streptomyces griseus, RppA, which catalyzes the formation of the red pigment flaviolin, as a reporter to investigate BGC refactoring techniques. We applied a library of constructs with different combinations of promoters and rppA coding sequences to investigate the synergies between promoter and codon usage. Subsequently, we assess the utility of cell-free systems for prototyping these refactoring tactics prior to their implementation in cells. Overall, codon harmonization improves natural product synthesis more than traditional codon optimization across cell-free and cellular environments. More importantly, the choice of coding sequences and promoters impact protein expression synergistically, which should be considered for future efforts to use CFE for high-yield protein expression. The promoter strategy when applied to RppA was not completely correlated with that observed with GFP, indicating that different promoter strategies should be applied for different proteins. In vivo experiments suggest that there is correlation, but not complete alignment between expressing in cell free and in vivo. Refactoring promoters and/or coding sequences via CFE can be a valuable strategy to rapidly screen for catalytically functional production of enzymes from BCGs, which advances CFE as a tool for natural product research.

Abstract Objectives The new data provide an important genomic resource for the Critically Endangered Cuban crocodile (Crocodylus rhombifer). Cuban crocodiles are restricted to the Zapata Swamp in southern Matanzas Province, Cuba, and readily hybridize with the widespread American crocodile (Crocodylus acutus) in areas of sympatry. The reported de novo assembly will contribute to studies of crocodylian evolutionary history and provide a resource for informing Cuban crocodile conservation. Data description The final 2.2 Gb draft genome for C. rhombifer consists of 41,387 scaffolds (contigs: N50 = 104.67 Kb; scaffold: N50-518.55 Kb). Benchmarking Universal Single-Copy Orthologs (BUSCO) identified 92.3% of the 3,354 genes in the vertebrata_odb10 database. Approximately 42% of the genome (960Mbp) comprises repeat elements. We predicted 30,138 unique protein-coding sequences (17,737 unique genes) in the genome assembly. Functional annotation found the top Gene Ontology annotations for Biological Processes, Molecular Function, and Cellular Component were regulation, protein, and intracellular, respectively. This assembly will support future macroevolutionary, conservation, and molecular studies of the Cuban crocodile.

Abstract Cognitive functions, such as learning and memory processes, depend on effective communication between brain regions which is facilitated by white matter tracts (WMT). We investigated the microstructural properties and the contribution of WMT to extinction learning and memory in a predictive learning task. Forty-two healthy participants completed an extinction learning paradigm without a fear component. We examined differences in microstructural properties using diffusion tensor imaging to identify underlying neural connectivity and structural correlates of extinction learning and their potential implications for the renewal effect. Participants with good acquisition performance exhibited higher fractional anisotropy (FA) in WMT including the bilateral inferior longitudinal fasciculus (ILF) and the right temporal part of the cingulum (CNG). This indicates enhanced connectivity and communication between brain regions relevant to learning and memory resulting in better learning performance. Our results suggest that successful acquisition and extinction performance were linked to enhanced structural connectivity. Lower radial diffusivity (RD) in the right ILF and right temporal part of the CNG was observed for participants with good acquisition learning performance. This observation suggests that learning difficulties associated with increased RD may potentially be due to less myelinated axons in relevant WMT. Also, participants with good acquisition performance were more likely to show a renewal effect. The results point towards a potential role of structural integrity in extinction-relevant WMT for acquisition and extinction.

The development, use, and timely promotion of Open Education (OE) has been effective in addressing myriad educational concerns, including inclusivity, accessibility and learning achievement, among many others. However, limited information exists in the literature concerning how OE could enhance Generative Artificial Intelligence (GenAI), which is receiving extensive interest and criticism at this time. To address this research gap, this study relies on the Open Educational Practices (OEP) framework of Huang et al. (2020) to provide various OEP scenarios that could help to promote and facilitate the effective and safe adoption of GenAI in education. The findings of this study could provide guidelines on how relying on OEP when adopting GenAI could help in ensuring quality education which is the sustainable development goal (SDG 4) of the United Nations (UN).

The study of ‘technological readiness and online learning self-efficacy’ has been thoroughly examined across multiple fields in recent years. Most investigations on this topic have consistently shown a contradictory relationship between the two factors. Moreover, there is a dearth of studies undertaken in the field of Physical Education within higher education, particularly in the setting of the Philippines. This study aimed to investigate the correlation between Technological Readiness (TR) and Online Learning Self Efficacy (OLSE) among a sample of 305 Physical Education Teacher Education (PETE) students in a higher education institution in the Philippines. Correlational and predictive analyses, specifically Pearson-r and Multiple Regression, were employed to ascertain the association between the four aspects of TR (Optimism, Insecurity, Innovativeness, and Discomfort) and OLSE. The findings indicate a positive and direct correlation between TR and OLSE. Moreover, the four dimensions of TR, exhibit a positive correlation with OLSE. According to the results, PETE students’ inclination to utilise advanced tools through online learning platforms could greatly enhance their online learning self-efficacy. The following recommendations and prospective research initiatives are hereby provided.

Biases in medical artificial intelligence (AI) arise and compound throughout the AI lifecycle. These biases can have significant clinical consequences, especially in applications that involve clinical decision-making. Left unaddressed, biased medical AI can lead to substandard clinical decisions and the perpetuation and exacerbation of longstanding healthcare disparities. We discuss potential biases that can arise at different stages in the AI development pipeline and how they can affect AI algorithms and clinical decision-making. Bias can occur in data features and labels, model development and evaluation, deployment, and publication. Insufficient sample sizes for certain patient groups can result in suboptimal performance, algorithm underestimation, and clinically unmeaningful predictions. Missing patient findings can also produce biased model behavior, including capturable but nonrandomly missing data, such as diagnosis codes, and data that is not usually or not easily captured, such as social determinants of health. Expertly annotated labels used to train supervised learning models may reflect implicit cognitive biases or substandard care practices. Overreliance on performance metrics during model development may obscure bias and diminish a model's clinical utility. When applied to data outside the training cohort, model performance can deteriorate from previous validation and can do so differentially across subgroups. How end users interact with deployed solutions can introduce bias. Finally, where models are developed and published, and by whom, impacts the trajectories and priorities of future medical AI development. Solutions to mitigate bias must be implemented with care, which include the collection of large and diverse data sets, statistical debiasing methods, thorough model evaluation, emphasis on model interpretability, and standardized bias reporting and transparency requirements. Prior to real-world implementation in clinical settings, rigorous validation through clinical trials is critical to demonstrate unbiased application. Addressing biases across model development stages is crucial for ensuring all patients benefit equitably from the future of medical AI.

Sustainable Indigenous resource use reflects balance between animal populations and levels of human consumption, influenced by natural cycles of faunal abundance, community size and subsistence needs, procurement technologies, and the requirements of trade or commodity production. Sustainability is “epiphenomenal” when animal populations are preserved, and community needs met, without deliberate measures to prevent overharvesting. Alternatively, Indigenous conservation—cultural practices that moderate use of a resource to prevent its depletion—may play a determinative role. In this study from the Tlingit community of Yakutat, Alaska in the Northwest Coast cultural region, we interweave Indigenous and scientific perspectives to trace the use and conservation of harbor seals (Phoca vitulina) from before Western contact through the Russian and American colonial periods to the present. Harbor seals, which concentrate in large numbers at a summer ice floe rookery near Hubbard Glacier, are the community's most important subsistence food and a key to its culture and history. The Smithsonian Institution and Yakutat Tlingit Tribe undertook collaborative research in historical ecology and archaeology in 2011–2014 including oral interviews with elders and subsistence providers, excavations at sealing sites, archaeofaunal analysis, historical and archival research, and consideration of climate cycles and biological regime shifts that influence the harbor seal population in the Gulf of Alaska. We compare technologies and hunting practices before and after Western contact, estimate harvest levels in different periods, and evaluate the effectiveness of traditional conservation practices that included hunting quotas enforced by clan leaders and the seasonal delay of hunting with firearms to prevent abandonment of the rookery by the seal herd.