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Abstract Protein copy numbers constrain systems-level properties of regulatory networks, but proportional proteomic data remain scarce compared to RNA-seq. We related mRNA to protein statistically using best-available data from quantitative proteomics and transcriptomics for 4366 genes in 369 cell lines. The approach starts with a protein’s median copy number and hierarchically appends mRNA–protein and mRNA–mRNA dependencies to define an optimal gene-specific model linking mRNAs to protein. For dozens of cell lines and primary samples, these protein inferences from mRNA outmatch stringent null models, a count-based protein-abundance repository, empirical mRNA-to-protein ratios, and a proteogenomic DREAM challenge winner. The optimal mRNA-to-protein relationships capture biological processes along with hundreds of known protein-protein complexes, suggesting mechanistic relationships. We use the method to identify a viral-receptor abundance threshold for coxsackievirus B3 susceptibility from 1489 systems-biology infection models parameterized by protein inference. When applied to 796 RNA-seq profiles of breast cancer, inferred copy-number estimates collectively re-classify 26–29% of luminal tumors. By adopting a gene-centered perspective of mRNA–protein covariation across different biological contexts, we achieve accuracies comparable to the technical reproducibility of contemporary proteomics.

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 < 0.0001 for all), respectively. AI-CAC plaque characteristics, including number, location, density, plus number of vessels, significantly improved CHD prediction in the CAC 1–100 cohort vs. Agatston Score. AI-CAC significantly improved the Agatston score for predicting all CVD events. [ABSTRACT FROM AUTHOR]

The gastrin-releasing peptide receptor (GRPr) has gained recognition as a promising target for both diagnostic and therapeutic applications in a variety of human cancers. This study aims to explore the primary tumor detection capabilities of [68Ga] Ga-GRPr PET imaging, specifically in newly diagnosed intra-prostatic prostate cancer lesions (PCa). Following PRISMA-DTA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses of Diagnostic Test Accuracy Studies) guidelines, a systematic literature search was conducted using the Medline, Embase, Scopus, and Web of Science databases. Data regarding patient characteristics and imaging procedure details—including the type of radiotracer used, administered activity, image acquisition time, scanner modality, criteria, and detection rate of index test—were extracted from the included studies. The pooled patient-and lesion-based detection rates, along with their corresponding 95% confidence intervals (CI), were calculated using a random effects model. The final analysis included 9 studies involving 291 patients and 350 intra-prostatic lesions with [68Ga] Ga-GRPr PET imaging in primary PCa. In per-patient-based analysis of [68Ga] Ga-GRPr PET imaging, the pooled detection rates of overall and patients with Gleason score ≥ 7 were 87.09% (95% CI 74.98–93.82) and 89.01% (95% CI 68.17–96.84), respectively. In per-lesion-based analysis, the pooled detection rate [68Ga] Ga-GRPr PET imaging was 78.54% (95% CI 69.8–85.29). The pooled detection rate mpMRI (multiparametric magnetic resonance imaging) in patient-based analysis was 91.85% (95% CI 80.12–96.92). The difference between the detection rates of the mpMRI and [68Ga] Ga-GRPr PET imaging was not statistically significant (OR 0.90, 95% CI 0.23–3.51). Our findings suggest that [68Ga] Ga-GRPr PET imaging has the potential as a diagnostic target for primary PCa. Future research is needed to determine the effectiveness of [68Ga] Ga-GRPr PET in delivering additional imaging data and guiding therapeutic decisions. [ABSTRACT FROM AUTHOR]

Background/Aim: The purpose of this review is to provide an overview of the contraindications, special warnings, and boxed warnings with the aim to establish a framework to create a prescription safety checklist for a class of drugs or disease indication. This study covers biologic disease modifying antirheumatic drugs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs). Methods: We identified contraindications, boxed warnings, and special warnings provided by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). The study included b/tsDMARDs approved for treating rheumatoid arthritis (RA), psoriatic arthritis (PsA), axial spondyloarthritis (SpA), and juvenile idiopathic arthritis (JIA) within the drug-classes anti-CD20, tumor necrosis factor inhibitors (TNFi), interleukin-1 inhibitors (IL-1i), cytotoxic T-lymphocyte-associated protein (CTLA) 4, interleukin-12/23 inhibitors (IL-12/23i), interleukin 6 receptor inhibitors (IL-6Ri), Janus kinase inhibitors (JAKi), phosphodiesterase 4 inhibitors (PDE4i), interleukin-17 inhibitors (IL-17i), and interleukin-23 inhibitors (IL-23i). Results: All drug classes, except PDE4i, had contraindications and/or warnings related to infections, including tuberculosis. A warning about herpes zoster was listed for anti-CD20, IL-1i, IL-6Ri, and JAKi, while a warning about hepatitis reactivation was listed for anti-CD20, TNFi, IL-1i, CTLA4-Ig, IL-6Ri, and JAKi. Malignancy risk was mentioned for all drug classes except PDE4i, IL-17i, and IL-23i. Other warnings included demyelinating disease (TNFi, CTLA4-Ig, and IL-6Ri), heart failure (anti-CD20 and TNFi), major adverse cardiac events (JAKi and IL-12/23) and venous thromboembolism (JAKi), hyperlipidemia (IL-6Ri and JAKi), liver impairment (TNFi, IL-1i, IL-6Ri, and JAKi), kidney impairment (IL-1i, JAKi, and PDE4i), inflammatory bowel disease (IL-17i), gastrointestinal perforation (IL-6Ri, JAKi), cytopenia (anti-CD20, TNFi, IL-1i, IL-6Ri, JAKi), and depression (PDE4i). Contraindications and warnings appeared to increase with the passage of time since the drug's approval. Conclusion: This review provides an overview to establish the framework to create an easily accessible and actionable prescription safety checklist from individual medical product prescription information provided by regulatory medical authorities. [ABSTRACT FROM AUTHOR]

Introduction: Benign prostatic obstruction (BPO) is one of the most common causes of male lower urinary tract symptoms. Some institutions routinely perform BPO surgeries in ambulatory setting, while others elect for overnight hospitalization. With the COVID-19 pandemic limiting resources and hospital space for elective surgery, we investigated the time trend of ambulatory BPO procedures performed around the COVID-19 outbreak. Methods: We identified BPO surgeries from the California State Inpatient and State Ambulatory Surgery Databases between 2018 and 2020. Our primary outcome was the proportion of procedures performed in ambulatory settings with a length of stay of zero days. Univariable and multivariable analyses were performed to analyze factors associated with ambulatory surgery around the COVID-19 outbreak. Spline regression with a knot at the pandemic outbreak was performed to compare time trends pre- and post-pandemic. Results: Among 37,148 patients who underwent BPO procedures, 30,067 (80.9%) were ambulatory. Before COVID-19, 80.1% BPO procedures were performed ambulatory, which increased to 83.4% after COVID-19 outbreak (p < 0.001). In multivariable model, BPO procedures performed after COVID-19 outbreak were 1.26 times more likely to be ambulatory (OR 1.26, 95% CI 1.14–1.40, p < 0.0001). Spline curve analysis indicated significantly different trend of change pre- and post-pandemic (p = 0.006). Conclusions: We observed a rising trend of BPO surgeries performed in ambulatory setting post-pandemic. It remains to be seen if the observed ambulatory transition remains as we continue to recover from the pandemic. [ABSTRACT FROM AUTHOR]

Investigators in neuroscience have turned to Big Data to address replication and reliability issues by increasing sample size. These efforts unveil new questions about how to integrate data across distinct sources and instruments. The goal of this study was to link scores across common auditory verbal learning tasks (AVLTs). This international secondary analysis aggregated multisite raw data for AVLTs across 53 studies totaling 10,505 individuals. Using the ComBat-GAM algorithm, we isolated and removed the component of memory scores associated with site effects while preserving instrumental effects. After adjustment, a continuous item response theory model used multiple memory items of varying difficulty to estimate each individual's latent verbal learning ability on a single scale. Equivalent raw scores across AVLTs were then found by linking individuals through the ability scale. Harmonization reduced total cross-site score variance by 37% while preserving meaningful memory effects. Age had the largest impact on scores overall (− 11.4%), while race/ethnicity variable was not significant (p > 0.05). The resulting tools were validated on dually administered tests. The conversion tool is available online so researchers and clinicians can convert memory scores across instruments. This work demonstrates that global harmonization initiatives can address reproducibility challenges across the behavioral sciences. [ABSTRACT FROM AUTHOR]

Objective: This Systematic review aims to assess the efficacy of trehalose and hyaluronic acid in enhancing ocular recovery post-cataract surgery, focusing on their impact on tear film stability, ocular surface integrity, and patient-reported outcomes. Methods: A comprehensive search was conducted across MEDLINE, PubMed, and Cochrane Library databases to identify randomized controlled trials investigating the efficacy of trehalose, hyaluronic acid, or their combination in post-cataract surgery care. The inclusion criteria focused on peer-reviewed studies in English, detailing outcomes relevant to ocular recovery such as tear film stability, ocular surface integrity, patient-reported discomfort, or visual acuity (VA). The quality of the included studies was assessed using the Cochrane Risk of Bias Tool and synthesized the data qualitatively. Results: Four qualitative investigations met the inclusion criteria. The studies collectively assessed the efficacy of a 3% trehalose and 0.15% hyaluronic acid eye drop solution in reducing postoperative eye symptoms compared to various control solutions. Parameters measured included tear break-up time (TBUT), Fluorescein staining, tear production (Schirmer test), and Ocular Surface Disease Index (OSDI) scores. The results indicated significant improvements in tear film stability and ocular surface health for the treatment groups compared to controls, with a notable decrease in patient-reported discomfort. The study showed an improvement of − 18 (± 14.6) in the treatment group compared to − 7 (± 8.0) in the control group for OSDI. For TBUT, the treatment group improved by 3 (± 1.2) s, whereas the control group improved by 0.3 (± 0.71) s. VA, measured on a scale of 0–100, increased to 17 (± 0.7) in the treatment group compared to 15 (± 1.1) in the control group. Conclusions: Trehalose and hyaluronic acid may be beneficial in the postoperative period by enhancing tear film stability and ocular surface health. While the results are promising, further research is needed to confirm these findings, understand the mechanisms of action, and explore broader applications. [ABSTRACT FROM AUTHOR]

The complexity of modern societies necessitates that children learn highly abstract material, such as mathematics, which often conflicts with behavioral goals that are innately motivating. For instance, children’s educational success is generally evaluated based on their individual achievements, while humans are motivated to learn by engaging in socially relevant behaviors. Additionally, science-related content typically requires higher-level abstract thinking to comprehend related concepts and perform the underlying cognitive processes, whereas humans evolved primarily to monitor and manipulate the physical environment by moving within it to execute foraging and hunting behaviors. Moreover, school systems inherently prescribe top-down strategies in which teachers transfer knowledge by providing instructions to guide students' knowledge acquisition. By contrast, humans evolved to learn through bottom-up processes motivated by the learner's internal drive to explore their physical and social environment. As a consequence, skeletal cognitive competencies that evolved throughout human history create a mismatch between why children are motivated to learn and how they are expected to learn. This review adopts an evolutionary perspective to examine how the interplay between students’ internal physiological and psychological adaptations and external instructional methods of modern educational systems impacts motivation and learning. Ultimately, the review offers suggestions on how to motivate the learning process by integrating self-determination theory principles into a dynamical systems framework. [ABSTRACT FROM AUTHOR]

Effective and efficient measures of functional impairment in youth are needed, as few validated measures exist. The youth-adapted Sheehan Disability Scale (Y-SDS) measures (1) child-reported impairment (Y-SDS-C), (2) parent reported child impairment (Y-SDS-PC), and (3) parent report of their own impairment due to the child's symptoms (Y-SDS-PP). The present study aimed to evaluate the psychometric properties of the Y-SDS, explore potential age-related differences, and examine sensitivity to change over 15 sessions of cognitive behavioral therapy. The sample included 583 parent-child dyads presenting to treatment at a specialty outpatient clinic. Youth and parents reported mild to moderate impairment across domains. Cronbach's α was acceptable for all three scales with some variation in child report by age. Inter-rater agreement was fair between parent and child report of child's functional impairment. Greater Y-SDS-C and Y-SDS-PC were significantly correlated with higher clinician-rated illness, anxiety, and depression severity at baseline. Significant reductions in functional impairment were found across treatment and improvements were correlated with improved severity on clinician and child reported measures. Overall, the Y-SDS is a reliable and valid measure of youth and parent functional impairment with utility as an outcome measure in treatment. [ABSTRACT FROM AUTHOR]

Introduction: The acute phase of the COVID-19 pandemic impacted the sexual function and mental health of healthcare workers worldwide. However, the extent to which sexual health, including its relational dimension, was affected among different healthcare services and the protective coping strategies employed at that time is currently unclear. The present study aimed to investigate these two issues, exploring for the first time the role of meaning-centered coping on sexual health. Method: The sample consisted of 109 healthcare workers divided into two groups: a high-exposure group (Intensive Care Unit service, 63 participants) and a low-exposure group (gynecology, obstetrics, and pediatrics services, 46 participants). One year after the onset of the COVID-19 pandemic, participants completed an online survey comprised of sociodemographic and COVID-19 exposure variables, the Depression Anxiety and Stress Scale, the New Sexual Satisfaction Scale-Short Form, and the Meaning-Centered Coping Scale. Results: (1) High-exposure participants reported more anxiety and depressive symptoms, (2) anxiety, depression and stress were associated with decreased sexual health after the pandemic, (3) High-exposure participants reported a higher decrease in their sexual health, (4) High-exposure workers reported higher levels of meaning-centered coping, and (5) higher levels of meaning-centered coping predicted higher sexual health in both groups. Policy Implications: Various healthcare services pose distinct risks regarding the detrimental effects of collective health crises on mental and sexual health, and therefore they should be differently treated. The promotion of meaning-centered coping is a sensible policy to improve preparedness in healthcare contexts, especially in vulnerable services and subpopulations. [ABSTRACT FROM AUTHOR]

Conjugate gradient minimization methods (CGM) and their accelerated variants are widely used. We focus on the use of cubic regularization to improve the CGM direction independent of the step length computation. In this paper, we propose the Hybrid Cubic Regularization of CGM, where regularized steps are used selectively. Using Shanno's reformulation of CGM as a memoryless BFGS method, we derive new formulas for the regularized step direction. We show that the regularized step direction uses the same order of computational burden per iteration as its non-regularized version. Moreover, the Hybrid Cubic Regularization of CGM exhibits global convergence with fewer assumptions. In numerical experiments, the new step directions are shown to require fewer iteration counts, improve runtime, and reduce the need to reset the step direction. Overall, the Hybrid Cubic Regularization of CGM exhibits the same memoryless and matrix-free properties, while outperforming CGM as a memoryless BFGS method in iterations and runtime. [ABSTRACT FROM AUTHOR]

Abstract Identifying cooperating modules of driver alterations can provide insights into cancer etiology and advance the development of effective personalized treatments. We present Cancer Rule Set Optimization (CRSO) for inferring the combinations of alterations that cooperate to drive tumor formation in individual patients. Application to 19 TCGA cancer types revealed a mean of 11 core driver combinations per cancer, comprising 2–6 alterations per combination and accounting for a mean of 70% of samples per cancer type. CRSO is distinct from methods based on statistical co‐occurrence, which we demonstrate is a suboptimal criterion for investigating driver cooperation. CRSO identified well‐studied driver combinations that were not detected by other approaches and nominated novel combinations that correlate with clinical outcomes in multiple cancer types. Novel synergies were identified in NRAS‐mutant melanomas that may be therapeutically relevant. Core driver combinations involving NFE2L2 mutations were identified in four cancer types, supporting the therapeutic potential of NRF2 pathway inhibition. CRSO is available at https://github.com/mikekleinsgit/CRSO/ .

Sex differences and age-related changes in the human heart at the tissue, cell, and molecular level have been well-documented and many may be relevant for cardiovascular disease. However, how molecular programs within individual cell types vary across individuals by age and sex remains poorly characterized. To better understand this variation, we performed single-nucleus combinatorial indexing (sci) ATAC- and RNA-Seq in human heart samples from nine donors. We identify hundreds of differentially expressed genes by age and sex and find epigenetic signatures of variation in ATAC-Seq data in this discovery cohort. We then scale up our single-cell RNA-Seq analysis by combining our data with five recently published single nucleus RNA-Seq datasets of healthy adult hearts. We find variation such as metabolic alterations by sex and immune changes by age in differential expression tests, as well as alterations in abundance of cardiomyocytes by sex and neurons with age. In addition, we compare our adult-derived ATAC-Seq profiles to analogous fetal cell types to identify putative developmental-stage-specific regulatory factors. Finally, we train predictive models of cell-type-specific RNA expression levels utilizing ATAC-Seq profiles to link distal regulatory sequences to promoters, quantifying the predictive value of a simple TF-to-expression regulatory grammar and identifying cell-type-specific TFs. Our analysis represents the largest single-cell analysis of cardiac variation by age and sex to date and provides a resource for further study of healthy cardiac variation and transcriptional regulation at single-cell resolution. Analysis of single-nucleus RNA- and ATAC-Seq from healthy human heart revealed age- and sex-specific alterations, defines candidate developmental stage-specific regulatory patterns, and identifies cell type-specific regulatory signatures. [ABSTRACT FROM AUTHOR]

A fundamental challenge for ecologists is to evaluate the effects of anthropogenic disturbance on ecosystem processes and functions. Tropical rainforests in Borneo are biologically diverse and provide an array of ecosystem functions and services. However, these forests are being logged and converted to agricultural plantations at a rapid pace. While there are numerous studies on the impacts of these land-use changes on biodiversity, there are far fewer that investigate the consequences of forest disturbance for ecosystem functioning. We investigated the impacts of land-use change in Bornean tropical rainforests on invertebrate-mediated functions using a suite of six easily measurable processes that are linked to nutrient cycling and plant regeneration, and which can be used as indicators of the degree of disturbance and the health of the forest. We explored whether the conversion of primary forest to logged, fragmented forest or agricultural plantations altered the ecosystem processes of dung removal, predation of insect herbivores, functional activity of soil invertebrates, bioturbation, seed removal, and decomposition. Overall, ecosystem processes remained resistant to habitat change except for seed removal, which was lower in heavily logged forests and plantations than in primary forests. This suggests that, despite the loss of many species when forests are logged and converted to agriculture, ecosystem processes provided by invertebrates can remain robust across land-use gradients. [ABSTRACT FROM AUTHOR]

Objective: To assess the role of net water uptake (NWU) in predicting outcomes in acute ischemic stroke (AIS) patients. Methods: A systematic review and meta-analysis were performed, adhering to established guidelines. The search covered PubMed, Scopus, Web of Science, and Embase databases until July 1, 2023. Eligible studies reporting quantitative ischemic lesion NWU in admission CT scans of AIS patients, stratified based on outcomes, were included. Data analysis was performed using R software version 4.2.1. Results: Incorporating 17 original studies with 2217 AIS patients, NWU was significantly higher in patients with poor outcomes compared to those with good outcomes (difference of medians: 5.06, 95% CI: 3.00–7.13, p < 0.001). Despite excluding one outlier study, considerable heterogeneity persisted among the included studies (I2 = 90.8%). The meta-regression and subgroup meta-analyses demonstrated significantly higher NWU in patients with poor functional outcome, as assessed by modified Rankin Scale (difference of medians: 3.83, 95% CI: 1.98–5.68, p < 0.001, I2 = 72.9%), malignant edema/infarct (difference of medians: 8.30, 95% CI: 4.01–12.58, p < 0.001, I2 = 95.6%), and intracranial hemorrhage (difference of medians: 5.43, 95% CI: 0.44–10.43, p = 0.03, I2 = 91.1%). Conclusion: NWU on admission CT scans shows promise as a predictive marker for outcomes in AIS patients. Prospective, multicenter trials with standardized, automated NWU measurement are crucial for robustly predicting diverse clinical outcomes. Clinical relevance statement: The potential of net water uptake as a biomarker for predicting outcomes in acute ischemic stroke patients holds significant promise. Further validation through additional research could lead to its integration into clinical practice, potentially improving the accuracy of clinical decision-making and allowing for the development of more precise patient care strategies. Key Points: • Net water uptake, a CT-based biomarker, quantifies early brain edema after acute ischemic stroke. • Net water uptake is significantly higher in poor outcome acute ischemic stroke patients. • Net water uptake on CT scans holds promise in predicting diverse acute ischemic stroke outcomes. [ABSTRACT FROM AUTHOR]

This study investigated how different learning tasks influence students' collaborative interactions in immersive Virtual Reality (iVR). A set of chemistry learning activities was designed with iVR, and 35 pairs of undergraduate students went through the activities. Videos of students' interactions were analysed to identify patterns in students' physical, conceptual, and social interactions. When students were manipulating conceptually familiar virtual objects (several water molecules), they perceived the tasks as a simple extension of prior knowledge and did not attempt to explore the 3D visualisation much. They did not move around to take different perspectives, and conceptual discussions were brief. Their prior power relations (leader–follower) carried over in iVR environments. In contrast, when conceptually unfamiliar chemical structures (protein enzyme) were displayed, students perceived the tasks as complex, demanding a new mode of learning. They spontaneously moved around to explore and appreciate the 3D visualisation of iVR. Walking to different positions to observe the virtual objects from multiple angles, students engaged in more collaborative, exploratory conceptual discussions. As the perceived complexity of learning tasks or virtual objects triggers different collaborative interactions amongst students, careful considerations need to be placed on the design of iVR tasks to encourage productive collaborative learning. [ABSTRACT FROM AUTHOR]

The roles of Asgard archaea in eukaryogenesis and marine biogeochemical cycles are well studied, yet their contributions in soil ecosystems remain unknown. Of particular interest are Asgard archaeal contributions to methane cycling in wetland soils. To investigate this, we reconstructed two complete genomes for soil-associated Atabeyarchaeia, a new Asgard lineage, and a complete genome of Freyarchaeia, and predicted their metabolism in situ. Metatranscriptomics reveals expression of genes for [NiFe]-hydrogenases, pyruvate oxidation and carbon fixation via the Wood-Ljungdahl pathway. Also expressed are genes encoding enzymes for amino acid metabolism, anaerobic aldehyde oxidation, hydrogen peroxide detoxification and carbohydrate breakdown to acetate and formate. Overall, soil-associated Asgard archaea are predicted to include non-methanogenic acetogens, highlighting their potential role in carbon cycling in terrestrial environments. The roles of Asgard archaea in soil ecosystems are unclear. In this study, the authors report complete genomes and metatranscriptomic data of Asgard archaea that indicate a role in production and consumption of carbon compounds known to serve as substrates for methane production in wetland soils. [ABSTRACT FROM AUTHOR]

Objectives: To investigate whether a history of traumatic brain injury (TBI) is associated with greater long-term grey-matter loss in patients with mild cognitive impairment (MCI). Methods: 85 patients with MCI were identified, including 26 with a previous history of traumatic brain injury (MCI[TBI-]) and 59 without (MCI[TBI+]). Cortical thickness was evaluated by segmenting T1-weighted MRI scans acquired longitudinally over a 2-year period. Bayesian multilevel modelling was used to evaluate group differences in baseline cortical thickness and longitudinal change, as well as group differences in neuropsychological measures of executive function. Results: At baseline, the MCI[TBI+] group had less grey matter within right entorhinal, left medial orbitofrontal and inferior temporal cortex areas bilaterally. Longitudinally, the MCI[TBI+] group also exhibited greater longitudinal declines in left rostral middle frontal, the left caudal middle frontal and left lateral orbitofrontal areas sover the span of 2 years (median = 1–2%, 90%HDI [−0.01%: −0.001%], probability of direction (PD) = 90–99%). The MCI[TBI+] group also displayed greater longitudinal declines in Trail-Making-Test (TMT)-derived ratio (median: 0.737%, 90%HDI: [0.229%: 1.31%], PD = 98.8%) and differences scores (median: 20.6%, 90%HDI: [−5.17%: 43.2%], PD = 91.7%). Conclusions: Our findings support the notion that patients with MCI and a history of TBI are at risk of accelerated neurodegeneration, displaying greatest evidence for cortical atrophy within the left middle frontal and lateral orbitofrontal frontal cortex. Importantly, these results suggest that long-term TBI-mediated atrophy is more pronounced in areas vulnerable to TBI-related mechanical injury, highlighting their potential relevance for diagnostic forms of intervention in TBI. [ABSTRACT FROM AUTHOR]

Background: Mechanical Thrombectomy (MT) has improved outcomes in acute ischemic stroke (AIS) due to Large Vessel Obstruction (LVO). However, there is limited data on the safety and outcomes of MT in AIS patients with thrombocytopenia. This study aims to assess the efficacy and safety of MT in this population. Methods: Following the PRISMA guidelines, a comprehensive systematic review was conducted using PubMed, Embase, Web of Science, and Scopus. Studies meeting inclusion criteria underwent rigorous risk of bias assessment using the ROBINS-I tool. We compared outcomes between patients with and without thrombocytopenia undergoing MT. Using the R software version 4.3.1, meta-analyses were conducted employing random-effect models. Results: This meta-analysis encompassed data from 5 studies. Thrombocytopenic AIS patients who underwent MT (n = 974) exhibited lower rates of functional independence (OR 0.83, 95% CI 0.71–0.98; p = 0.030) compared to patients with normal platelet counts (n = 2036). In addition, the thrombocytopenic group experienced higher mortality as compared to the group with normal platelet counts (OR 1.76, 95% CI 1.26–2.45; p < 0.001). Rates of sICH were found to be similar between groups (OR 1.20, 95% CI 0.74–1.93; p = 0.456), as were rates of successful recanalization (OR 0.94, 95% CI 0.47–1.87; p = 0.863). Lastly, no significant differences were observed in procedure times between thrombocytopenic and non-thrombocytopenic groups. Conclusion: As compared to patients without thrombocytopenia, thrombocytopenic AIS patients undergoing MT displayed lower functional independence and higher mortality rates, with no significant differences in sICH or successful recanalization. [ABSTRACT FROM AUTHOR]

Objectives: To assess gingival crevicular fluid (GCF) levels of inflammatory and bone remodelling related biomarkers following transplantation of a tissue-engineered biocomplex into intrabony defects at several time-points over 12-months. Materials and methods: Group-A (n = 9) received the Minimal Access Flap (MAF) surgical technique combined with a biocomplex of autologous clinical-grade alveolar bone-marrow mesenchymal stem cells in collagen scaffolds enriched with an autologous fibrin/platelet lysate (aFPL). Group-B (n = 10) received the MAF surgery, with collagen scaffolds enriched with aFPL and Group-C (n = 8) received the MAF surgery alone. GCF was collected from the osseous defects of subjects via paper strips/30 sec at baseline, 6-weeks, 3-, 6-, 9-, 12-months post-surgery. Levels of inflammatory and bone remodelling-related biomarkers in GCF were determined by ELISA. Results: Group-A demonstrated significantly higher GCF levels of BMP-7 at 6–9 months than baseline, with gradually decreasing levels of pro-inflammatory and pro-osteoclastogenic markers (TNF-α, RANKL) over the study-period; and an overall decrease in the RANKL/OPG ratio at 9–12 months than baseline (all p < 0.001). In comparison, only modest interim changes were observed in Groups-B and -C. Conclusions: At the protein level, the approach of MAF and biocomplex transplantation provided greater tissue regeneration potential as cell-based therapy appeared to modulate inflammation and bone remodelling in residual periodontal defects. Clinical relevance: Transplantation of a tissue engineered construct into periodontal intrabony defects demonstrated a biochemical pattern for inflammatory control and tissue regeneration over 12-months compared to the control treatments. Understanding the biological healing events of stem cell transplantation may facilitate the design of novel treatment strategies. Clinical database registration: ClinicalTrials.gov ID: NCT02449005. [ABSTRACT FROM AUTHOR]

We present 4k video and whole transcriptome data for seven deep-sea invertebrate animals collected in the Eastern Pacific Ocean during a research expedition onboard the Schmidt Ocean Institute's R/V Falkor in August of 2021. The animals include one jellyfish (Atolla sp.), three siphonophores (Apolemia sp., Praya sp., and Halistemma sp.), one larvacean (Bathochordaeus mcnutti), one tunicate (Pyrosomatidae sp.), and one ctenophore (Lampocteis sp.). Four of the animals were sequenced with long-read RNA sequencing technology, such that the reads themselves define a reference assembly for those animals. The larvacean tissues were successfully preserved in situ and has paired long-read reference data and short read quantitative transcriptomic data for within-specimen analyses of gene expression. Additionally, for three animals we provide quantitative image data, and a 3D model for one siphonophore. The paired image and transcriptomic data can be used for species identification, species description, and reference genetic data for these deep-sea animals. [ABSTRACT FROM AUTHOR]

Cultural and genetic inheritance combine to enable rapid changes in trait expression, but their relative importance in determining trait expression across generations is not clear. Birdsong is a socially learned cognitive trait that is subject to both cultural and genetic inheritance, as well as being affected by early developmental conditions. We sought to test whether early-life conditions in one generation can affect song acquisition in the next generation. We exposed one generation (F1) of nestlings to elevated corticosterone (CORT) levels, allowed them to breed freely as adults, and quantified their son's (F2) ability to copy the song of their social father. We also quantified the neurogenetic response to song playback through immediate early gene (IEG) expression in the auditory forebrain. F2 males with only one corticosterone-treated parent copied their social father's song less accurately than males with two control parents. Expression of ARC in caudomedial nidopallium (NCM) correlated with father-son song similarity, and patterns of expression levels of several IEGs in caudomedial mesopallium (CMM) in response to father song playback differed between control F2 sons and those with a CORT-treated father only. This is the first study to demonstrate that developmental conditions can affect social learning and neurogenetic responses in a subsequent generation. [ABSTRACT FROM AUTHOR]

Purpose: Research suggests that performance on the Death-Implicit Association Test (D-IAT) converges with explicit indicators of suicide risk (e.g., suicidal ideation, suicidal behaviors). However, the utility of the D-IAT in acute care settings has been questioned given limited studies and inconsistent findings. Additionally, it remains unclear whether the D-IAT incrementally improves the assessment of suicide risk beyond explicit measures. Method: The present study evaluated the validity of the D-IAT in a large sample of psychiatric inpatients who attempted suicide within the past two years (N = 203; M age = 32.93 [SD = 12.61]; 50.7% female; 63.5% White; 22.7% Hispanic/Latino). The D-IAT was scored three ways: (1) conventional D scoring where positive scores indicate stronger implicit associations with death, (2) dichotomized D scores where participants were categorized based on positive or negative D score, and (3) DD scoring, which is a novel procedure that differentiates self-identification with death (Me-DD) from a lack of identification with life (Not Me-DD). Results: D and Not Me-DD were weakly associated with suicide cognitions, hopelessness, suicidal ideation, and wishes to live/die and there were corresponding mean differences based on dichotomized D scores. D and Not Me-DD were also weakly correlated with number of lifetime suicide attempts. Me-DD evidenced fewer significant associations than Not Me-DD suggesting that a lack of association with life may be the central component of D scores. Conclusions: Findings suggest that the D-IAT may not be a useful standalone measure of suicide risk in high-risk populations. [ABSTRACT FROM AUTHOR]

Personalized gamification aims to address shortcomings of the one-size-fits-all (OSFA) approach in improving students' motivations throughout the learning process. However, studies still focus on personalizing to a single user dimension, ignoring multiple individual and contextual factors that affect user motivation. Unlike prior research, we address this issue by exploring multidimensional personalization compared to OSFA based on a multi-institution sample. Thus, we conducted a controlled experiment in three institutions, comparing gamification designs (OSFA and Personalized to the learning task and users' gaming habits/preferences and demographics) in terms of 58 students' motivations to complete assessments for learning. Our results suggest no significant differences among OSFA and Personalized designs, despite suggesting user motivation depended on fewer user characteristics when using personalization. Additionally, exploratory analyses suggest personalization was positive for females and those holding a technical degree, but negative for those who prefer adventure games and those who prefer single-playing. Our contribution benefits designers, suggesting how personalization works; practitioners, demonstrating to whom the personalization strategy was more or less suitable; and researchers, providing future research directions. [ABSTRACT FROM AUTHOR]

Sea level rise (SLR) affects coastal flood regimes and poses serious challenges to flood risk management, particularly on ungauged coasts. To address the challenge of monitoring SLR at local scales, we propose a high tide flood (HTF) thresholding system that leverages machine learning (ML) techniques to estimate SLR and HTF thresholds at a relatively fine spatial resolution (10 km) along the United States' coastlines. The proposed system, complementing conventional linear- and point-based estimations of HTF thresholds and SLR rates, can estimate these values at ungauged stretches of the coast. Trained and validated against National Oceanic and Atmospheric Administration (NOAA) gauge data, our system demonstrates promising skills with an average Kling-Gupta Efficiency (KGE) of 0.77. The results can raise community awareness about SLR impacts by documenting the chronic signal of HTF and providing useful information for adaptation planning. The findings encourage further application of ML in achieving spatially distributed thresholds. Using machine learning algorithms, this study estimates sea level rise and high tide flooding thresholds every 10 km along the United States' coasts, complementing conventional linear-/point-based estimates and offering insights for ungauged areas. [ABSTRACT FROM AUTHOR]

Background: Internal hemorrhoids (IH) is a common medical condition that can result in morbidity secondary to bleeding and discomfort. Treatment for IH has traditionally consisted of dietary and conservative medical management, focal treatments including banding and sclerotherapy or hemorrhoidectomy. Recently, rectal artery embolization (RAE) has been studied as a potential treatment for bleeding predominant IH. We performed a common design and data element analysis of studies that report on RAE. Materials and methods: We conducted a qualitative systematic literature review for rectal artery embolization (RAE) for symptomatic hemorrhoidal disease. The screening process involved five online databases (PubMed, Embase, Google Scholar, DOAJ, and Scopus). Additionally, ClinicalTrials.gov was examined for active, unpublished completed studies. The initial search yielded 2000 studies, with 15 studies meeting the inclusion criteria after screening and assessment. The included studies comprised one RCT, one case series, one pilot study and 12 cohort studies. Results: The population analysis revealed a male predominance across all studies, with varying cohort sizes. The baseline Goligher hemorrhoid grade was utilized in 80% of studies. The majority (73.3%) employed a transfemoral approach, and coils were the primary embolic material in 60% of studies, 26.6% were combination of coils and particles, and 6.6% were particles only. Patient selection criteria highlighted RAE's applicability for high surgical risk patients and those with anemia, chronic hematochezia, or treatment-refractory cases. Exclusion criteria emphasized factors such as previous surgeries, colorectal cancer, rectal prolapse, acute hemorrhoidal complications, and contrast allergy. Study designs varied, with cohort studies being the most common (12/15; 80%). Procedural details included the use of metallic coils and detachable micro-coils, with a high technical success rate reported in most studies ranging from 72 to 100%. The follow-up ranged from 1 to 18 months. The majority of studies reported no major immediate or post-procedural complications. Conclusion: While all studies focused on RAE as a treatment for IH, there was a great degree of heterogeneity among included studies, particularly regarding inclusion criteria, exclusion criteria, outcomes measures and timeframe. Future literature should attempt to standardize these design elements to help facilitate secondary analyses and increase understanding of RAE as a treatment option. [ABSTRACT FROM AUTHOR]

Background: Endovascular therapy (EVT) has been proven beneficial for treating acute ischemic strokes (AIS) with large vessel occlusion (LVO). Recent trials of DAWN and DEFUSE-3 have extended the treatment window to 6–24 h, sparking investigations into EVT outcomes for patients not eligible for DAWN/DEFUSE-3 criteria. Purpose: To assess the outcomes of endovascular therapy (EVT) for late-window anterior circulation large vessel occlusion (LVO) in acute ischemic stroke patients, comparing DAWN/DEFUSE-3 eligible (DD) and ineligible (NDND) groups. Methods: This systematic review and meta-analysis examined EVT outcomes for patients with late-window anterior circulation LVO beyond 6 h. We categorized patients as DAWN/DEFUSE-3 eligible (DD) and ineligible (NDND). Our search covered PubMed, Embase, Web of Science, and Scopus. A total of 464 records were initially identified. After duplicate removal, 298 studies were screened. Nine studies were included and analyzed. Our analysis focused on study characteristics, baseline comparisons, risk of bias, and outcomes. Results: Baseline characteristics showed comparable age, gender, most comorbidities, NIHSS score, and ASPECTS between DAWN/DEFUSE-3 eligible (DD) and ineligible (NDND) patients. NDND patients' history showed a higher rate of atrial fibrillation and larger infarct volumes on baseline imaging. Successful reperfusion rates (TICI 2b-3) were similar between DD and NDND with 354 out of 469 in the DD group and 364 out of 459 in the NDND group (OR = 0.86; 95% CI 0.40, 1.84; p = 0.689), though with significant heterogeneity (I2 = 73%; P = 0.002). The proportion of patients with distal occlusions was significantly higher in the NDND group as compared to the DD group (137 (39.4%) of 347 patients versus 47 (11%) of 428 patients, respectively), with significant heterogeneity across studies (I2 = 85%, p = 0.023). Functional independence at 90 days (mRS 0–2) showed no significant difference between groups with 259 out of 802 in the DD group and 197 out of 668 in the NDND group (OR = 1.12; 95% CI 0.77, 1.63; p = 0.552) but also exhibited notable heterogeneity (I2 = 46%, p = 0.063). Symptomatic intracranial hemorrhage (sICH) rates were lower in DD with 14 out of 309 in the DD group and 47 out of 400 in NDND group (OR = 0.49; 95% CI 0.25, 0.93; p = 0.029) as compared to the NDND patients, showing no heterogeneity (I2 = 0%, p = 0.552). 90-day mortality was lower in DD with 43 out of 304 in the DD group and 107 out of 399 in the NDND group (OR = 0.55; 95% CI 0.37, 0.82; p = 0.004) as compared to NDND patients, with no significant heterogeneity (I2 = 0%, p = 0.536). Conclusion: This meta-analysis demonstrates equivalent rates of functional independence between DD and NDND patients. However, the high proportion of distal occlusions and higher rates of sICH and mortality in NDND patients suggest caution in offering mechanical thrombectomy to DAWN/DEFUSE-3 ineligible patients. A more flexible approach to EVT eligibility criteria could benefit select patients in real-world practice. Nonetheless, further research is needed to identify which patients would benefit from expanded EVT eligibility criteria. [ABSTRACT FROM AUTHOR]

Purpose: Hirayama disease, a rare cervical myelopathy in children and young adults, leads to progressive upper limb weakness and muscle loss. Non-invasive external cervical orthosis has been shown to prevent further neurologic decline; however, this treatment modality has not been successful at restoring neurologic and motor function, especially in long standing cases with significant weakness. The pathophysiology remains not entirely understood, complicating standardized operative guidelines; however, some studies report favorable outcomes with internal fixation. We report a successful surgically treated case of pediatric Hirayama disease, supplemented by a systematic review and collation of reported cases in the literature. Methods: A review of the literature was performed by searching PubMed, Embase, and Web of Science. Full-length articles were included if they reported clinical data regarding the treatment of at least one patient with Hirayama disease and the neurologic outcome of that treatment. Articles were excluded if they did not provide information on treatment outcomes, were abstract-only publications, or were published in languages other than English. Results: Of the fifteen articles reviewed, 63 patients were described, with 59 undergoing surgery. This encompassed both anterior and posterior spinal procedures and 1 hand tendon transfer. Fifty-five patients, including one from our institution, showed improvement post-treatment. Eleven of these patients were under 18 years old. Conclusion: Hirayama disease is an infrequent yet impactful cervical myelopathy with limited high-quality evidence available for optimal treatment. The current literature supports surgical decompression and stabilization as promising interventions. However, comprehensive research is crucial for evolving diagnosis and treatment paradigms. [ABSTRACT FROM AUTHOR]

Severe influenza A virus (IAV) infections can result in hyper-inflammation, lung injury and acute respiratory distress syndrome1–5 (ARDS), for which there are no effective pharmacological therapies. Necroptosis is an attractive entry point for therapeutic intervention in ARDS and related inflammatory conditions because it drives pathogenic lung inflammation and lethality during severe IAV infection6–8 and can potentially be targeted by receptor interacting protein kinase 3 (RIPK3) inhibitors. Here we show that a newly developed RIPK3 inhibitor, UH15-38, potently and selectively blocked IAV-triggered necroptosis in alveolar epithelial cells in vivo. UH15-38 ameliorated lung inflammation and prevented mortality following infection with laboratory-adapted and pandemic strains of IAV, without compromising antiviral adaptive immune responses or impeding viral clearance. UH15-38 displayed robust therapeutic efficacy even when administered late in the course of infection, suggesting that RIPK3 blockade may provide clinical benefit in patients with IAV-driven ARDS and other hyper-inflammatory pathologies.A newly developed RIPK3 inhibitor blocks necroptosis of lung cells, reduces lung inflammation and prevents mortality in a mouse model of influenza A virus infection. [ABSTRACT FROM AUTHOR]

De novo drug design aims to generate molecules from scratch that possess specific chemical and pharmacological properties. We present a computational approach utilizing interactome-based deep learning for ligand- and structure-based generation of drug-like molecules. This method capitalizes on the unique strengths of both graph neural networks and chemical language models, offering an alternative to the need for application-specific reinforcement, transfer, or few-shot learning. It enables the "zero-shot" construction of compound libraries tailored to possess specific bioactivity, synthesizability, and structural novelty. In order to proactively evaluate the deep interactome learning framework for protein structure-based drug design, potential new ligands targeting the binding site of the human peroxisome proliferator-activated receptor (PPAR) subtype gamma are generated. The top-ranking designs are chemically synthesized and computationally, biophysically, and biochemically characterized. Potent PPAR partial agonists are identified, demonstrating favorable activity and the desired selectivity profiles for both nuclear receptors and off-target interactions. Crystal structure determination of the ligand-receptor complex confirms the anticipated binding mode. This successful outcome positively advocates interactome-based de novo design for application in bioorganic and medicinal chemistry, enabling the creation of innovative bioactive molecules. The use of data-driven generative models for drug design is challenging due to the scarcity of data. Here, the authors introduce a "zero-shot" generative deep model to enable the generation of molecules by both structure- and ligand-based drug design and apply it to design PPARγ agonists with desired properties. [ABSTRACT FROM AUTHOR]

Physical activity has long been shown to be associated with biological and physiological performance and risk of diseases. It is of great interest to assess whether the effect of an exposure or intervention on an outcome is mediated through physical activity measured by modern wearable devices such as actigraphy. However, existing methods for mediation analysis focus almost exclusively on mediation variable that is in the Euclidean space, which cannot be applied directly to physical activity measured by wearable devices. Such data is best summarized in the form of a random distribution. In this paper, we develop a structural equation model to the setting where a random distribution is treated as the mediator. We provide sufficient conditions for identifying the average causal effects of a distribution mediator and present methods for estimating the direct and mediating effects of a random distribution mediator on the outcome. We apply our method to analyze the iCOMPARE data set that compares flexible duty-hour policies and standard duty-hour policies on interns' sleep related outcomes and to investigate the mediation effect of physical activity on the causal path between flexible duty-hour policies and sleep related outcomes. [ABSTRACT FROM AUTHOR]

The proper formation of the vertebrate embryonic heart relies on various mechanical forces which determine its form and function. Measuring these forces at the microscale of the embryo is a challenge. We propose a new tool utilizing high-resolution optical elastography and stiffness measurements of surrounding tissues to non-invasively track the changes in the pressure exerted by the heart on the neighboring yolk, as well as changes in contractile patterns during early cardiac growth in-vivo, using the zebrafish embryo as a model system. Cardiac development was characterized every three hours from 24 hours post-fertilization (hpf) to 30 hpf and compared between wildtype fish and those treated with MS-222, a commonly used fish anesthetic that decreases cardiac contractility. Wildtype embryos from 24 to 30 hpf showed an average yolk indentation pressure of 0.32 mmHg to 0.41 mmHg, respectively. MS-222 treated embryos showed an average yolk indentation pressure of 0.22 mmHg to 0.29 mmHg. Yolk indentation pressure between control and treated embryos at 24 hpf and 30 hpf showed a significant difference (p < 0.05). Our method allowed for contractility and pressure evaluation at these early developmental stages, which have not been previously reported in published literature, regardless of sample or imaging modality. This research could lead to a better understanding of heart development and improved diagnostic tools for congenital heart disease. [ABSTRACT FROM AUTHOR]

Recent developments in protein design rely on large neural networks with up to 100s of millions of parameters, yet it is unclear which residue dependencies are critical for determining protein function. Here, we show that amino acid preferences at individual residues—without accounting for mutation interactions—explain much and sometimes virtually all of the combinatorial mutation effects across 8 datasets (R2 ~ 78-98%). Hence, few observations (~100 times the number of mutated residues) enable accurate prediction of held-out variant effects (Pearson r > 0.80). We hypothesized that the local structural contexts around a residue could be sufficient to predict mutation preferences, and develop an unsupervised approach termed CoVES (Combinatorial Variant Effects from Structure). Our results suggest that CoVES outperforms not just model-free methods but also similarly to complex models for creating functional and diverse protein variants. CoVES offers an effective alternative to complicated models for identifying functional protein mutations.Recent protein design methods rely on large neural networks, yet it is unclear which dependencies are critical for determining function. Here, authors show that learning the per residue mutation preferences, without considering interactions, enables design of functional and diverse protein variants. [ABSTRACT FROM AUTHOR]

During bacterial and viral pathogen investigation of 30 specimens of bats captured in periurban forest areas in the city of Belém, Pará, Brazil, a case of cerebral filariasis was observed. In the course of histopathological examination, adult filariae were found in pseudocystic cavities brain of Molossus barnesi (Molossidae) and classified morphologically as Litomosoides by the shape of the spicules—left spicule with a handle longer than the blade; right spicule curved, with a sclerotized heel supporting a dorsal notch; the area rugosa constituted by a ventral band of small longitudinal crests; tail rounded in males; long esophagus with a slightly glandular distal portion; and a muscular bent vagina. All the specimens lack a stoma (buccal capsule). We compared our filarioids with the description of specimens of Molossinema wimsatti. Morphological characteristics of M. wimsatti resemble the genus Litomosoides. Thus, we believe that M. wimsatti is a synonym of L. molossi Esslinger, 1973, and filarioid specimens from material reported by Lichtenfels et al. (Trans Am Micros Soc 100:216–219, 1981) and from de Souto et al. (J. Helminthol 1195:e65, 2021) most probably correspond to Litomosoides. We suggest that the reduction of the buccal capsule may be attributable to the ectopic location. No evidence of tissue responses by the host was observed. This is the first record of Litomosoides infecting brain tissue of Molossus barnesi from Brazil, representing a record of a new host species. More specimens of bats should be examined in order to find filarioids in the brain and verify its taxonomic position using molecular techniques. [ABSTRACT FROM AUTHOR]

The association between depression and dementia, particularly Alzheimer's disease (AD) and cerebrovascular disease (CVD), remains an active area of research. This study aimed to investigate the relationship between a history of depression and biomarkers of AD and CVD in patients with dementia in a clinical setting. A total of 126 patients from the University Health Network (UHN) Memory Clinic with comprehensive clinical evaluations, including neuropsychological testing and medical examinations, were included. Lumbar puncture was performed to collect cerebrospinal fluid (CSF) for biomarker analysis, and brain magnetic resonance imaging (MRI) scans were obtained to assess white matter hyperintensity (WMH) burden. The presence of depression was determined through medical records. The study findings did not reveal significant differences between participants with and without a history of depression in terms of AD biomarkers, WMH burden, neurofilament light chain levels, cognitive scores, age of symptom onset, disease duration, or vascular risk scores. Logistic regression analysis did not indicate a meaningful predictive value of these variables for depression status. This clinical study contributes to our understanding regarding the association between depression and AD/CVD biomarkers in patients with cognitive impairment. Further research is needed to elucidate the complex relationship between depression and dementia and to explore the potential mechanisms linking depression, AD, and CVD. [ABSTRACT FROM AUTHOR]

The most famous equation in physics, E = mc2, is rarely introduced in middle school physics curricula. Recent research has shown that teaching Einsteinian concepts at the middle school level is feasible and beneficial. This paper analyses an Einsteinian energy teaching module for Year 8 students (13–14 years old), which encompasses the two fundamental energy formulas in modern physics, E = mc2 and E = hf. In the context of activity-based learning, the Einsteinian energy module relates to all the forms of energy in traditional school curricula. This study uses a design-based research approach within the Model of Educational Reconstruction framework. Modern experiments, historical events, and educational research helped us identify relevant Einsteinian energy concepts, activities, and assessments. The study included 22 students who participated in nine in-class Einsteinian energy lessons. Analysing results in the post-test showed a 31% mean increase from the pre-test, a clear and significant positive change in students' conceptual understanding. The results demonstrated students' ability to deal with very large and small constants of proportionality and physical concepts involved in the module. [ABSTRACT FROM AUTHOR]

Plasticity and homeostatic mechanisms allow neural networks to maintain proper function while responding to physiological challenges. Despite previous work investigating morphological and synaptic effects of brain-derived neurotrophic factor (BDNF), the most prevalent growth factor in the central nervous system, how exposure to BDNF manifests at the network level remains unknown. Here we report that BDNF treatment affects rodent hippocampal network dynamics during development and recovery from glutamate-induced excitotoxicity in culture. Importantly, these effects are not obvious when traditional activity metrics are used, so we delve more deeply into network organization, functional analyses, and in silico simulations. We demonstrate that BDNF partially restores homeostasis by promoting recovery of weak and medium connections after injury. Imaging and computational analyses suggest these effects are caused by changes to inhibitory neurons and connections. From our in silico simulations, we find that BDNF remodels the network by indirectly strengthening weak excitatory synapses after injury. Ultimately, our findings may explain the difficulties encountered in preclinical and clinical trials with BDNF and also offer information for future trials to consider. A study uses MEA analysis, computation, and simulations to demonstrate how BDNF treatment after excitotoxic injury remodels hippocampal networks by promoting inhibitory neuron survival while indirectly strengthening weak excitatory synapses. [ABSTRACT FROM AUTHOR]

Background: The impact of age of onset on the presentation of progressive supranuclear palsy phenotypes is not well studied. We hypothesized that there is difference in presentation and phenotype between young- and late-onset PSP. Objectives: Our aim was to compare phenotypes and rate of change in disability between young-onset PSP (YOPSP) and late-onset PSP (LOPSP). Methods: Retrospective data of patients seen in the Rossy PSP Centre from March 2014 to April 2022 with clinical diagnosis of PSP as per the MDS 2017 diagnostic criteria were examined. We used cut-off age of 65 years to categorize the patients into YOPSP and LOPSP. We compared the prevalence of phenotypes, presenting symptoms, and MDS core criteria between the two groups. The severity of disease between the two groups was measured using PSP-RS. Results: We found 107 patients with clinical diagnosis of PSP as per MDS criteria, a third were defined as YOPSP. PSP speech/language (SL) phenotype was more prevalent in YOPSP (18% vs 0%, p < 0.001). Aphasia was significantly higher in YOPSP (16% vs 1.4%, p = 0.03). The speech and language dysfunction (C1) core criteria were more prevalent in YOPSP (33.3% vs 12.2%, p = 0.05). Longitudinal analysis of PSP-RS showed worsening of bulbar total score at 6 months in YOPSP (t (38) = 2.87; p = 0.05). Conclusion: Our study revealed that YOPSP are more likely to present with a speech and language variant. Our results highlight that age of onset may predict PSP phenotypes, which holds both clinical and prognostic importance. [ABSTRACT FROM AUTHOR]

It is documented that Hispanic/Latinx kidney stone formers have inferior health-related quality of life (HRQoL) compared to the general population. We hypothesized that socioeconomic factors drive HRQoL disparities. Specifically, we sought to determine if medical insurance type is associated with HRQoL disparities among Hispanic/Latinx stone formers. This was a prospective cohort observational study of patients with kidney stones across the University of San Diego Health Care System. Patients enrolled from June 2018 to August 2020 completed a validated Wisconsin Stone Quality of Life questionnaire (WISQoL). Patient characteristics and self-reported HRQoL were compared between Hispanic/Latinx and non-Hispanic/Latinx stone formers using MANCOVA and ordinal logistic regression. Matched group comparisons were performed based on age, gender, body mass index, stone symptoms, and insurance type using MACOVA. A total of 270 patients were enrolled (Hispanic/Latinx n = 88; non-Hispanic/Latinx n = 182). Hispanic/Latinx stone formers had higher rates of public insurance at baseline (p < 0.001) with significantly lower HRQoL [social impact (p = 0.007)]. However, a matched cohort comparison demonstrated no differences. On multivariate analysis, private insurance increased the likelihood of having higher HRQoL (OR 2.21, p = 0.021), while stone symptoms (OR = 0.06, p < 0.001) and emergency department visits (OR = 0.04, p = 0.008) decreased chances of higher HRQoL. Ethnicity was not a significant factor in HRQoL scores on multivariate analysis. Our analysis suggests that differences in HRQoL among Hispanic/Latinx stone formers may be primarily driven by socioeconomic factors as opposed to clinical or racial differences. Specifically, source of insurance appears to have significant effect on HRQoL in this ethnic group. [ABSTRACT FROM AUTHOR]

The article discusses the need for a broader conversation about human assisted reproductive technologies (ARTs) and genetics. It emphasizes the importance of recognizing and addressing the responsibilities of reproductive medicine specialists. The article also highlights the significance of understanding the balance between cooperation and conflict in human reproduction, as well as the impact of pregnancy complications and pregnancy loss. It further explores the challenges and advancements in the field of reproductive medicine, including the role of controlled ovarian stimulation and cryopreservation technologies. The goal of the article is to improve pregnancy chances for patients and promote trust and confidence in the field. [Extracted from the article]

Enhancing the properties of advanced drug candidates is aided by the direct incorporation of specific chemical groups, avoiding the need to construct the entire compound from the ground up. Nevertheless, their chemical intricacy often poses challenges in predicting reactivity for C-H activation reactions and planning their synthesis. We adopted a reaction screening approach that combines high-throughput experimentation (HTE) at a nanomolar scale with computational graph neural networks (GNNs). This approach aims to identify suitable substrates for late-stage C-H alkylation using Minisci-type chemistry. GNNs were trained using experimentally generated reactions derived from in-house HTE and literature data. These trained models were then used to predict, in a forward-looking manner, the coupling of 3180 advanced heterocyclic building blocks with a diverse set of sp3-rich carboxylic acids. This predictive approach aimed to explore the substrate landscape for Minisci-type alkylations. Promising candidates were chosen, their production was scaled up, and they were subsequently isolated and characterized. This process led to the creation of 30 novel, functionally modified molecules that hold potential for further refinement. These results positively advocate the application of HTE-based machine learning to virtual reaction screening. Late-stage functionalization of drug molecules can tune their properties without the need for entirely new syntheses, however, predicting reactivity and planning synthesis for late-stage C-H activation remains challenging. Here, the authors develop a reaction screening approach combining high-throughput experimentation with computational graph neural networks to identify suitable substrates that can be used for late-stage C-H alkylation via Minisci-type chemistry. [ABSTRACT FROM AUTHOR]

Background: The impact of vitrification on oocyte developmental competence as a function of donor age remains an important issue in assisted reproductive technologies (ARTs). Methods: Equine germinal vesicle (GV) or metaphase II (M(II) oocytes were vitrified using the Cryotop® method. Spindle organization and chromosome alignment were evaluated from confocal imaging data sets of in vivo (IVO) or in vitro (IVM) matured oocytes subjected to vitrification or not. Intracytoplasmic sperm injection (ICSI) from the same groups was used to assess developmental potential. Results: An increase in chromosome misalignment was observed in spindles from older mares when compared to those of younger mares (P < 0.05). When MII oocytes subjected to vitrification were examined following warming, there was no difference in the percentage of oocytes displaying chromosome misalignment. Next, GV oocytes, collected from the ovaries of younger and older mares, were compared between fresh IVM and IVM following vitrification and warming. For nonvitrified samples, an age difference was again noted for spindle organization and chromosome alignment, with a higher (P < 0.05) percentage of normal bipolar meiotic spindles with aligned chromosomes observed in nonvitrified oocytes from young versus older mares. Vitrification led to a reduction of spindle length (P < 0.05) for oocytes from old mares, whether vitrified at GV or MII stages, whereas this effect was not observed in oocytes from young mares except those vitrified at GV and subjected to IVM. Oocyte developmental potential after vitrification was evaluated after ICSI of vitrified and warmed MII or GV oocytes from young mares. From 25 MII oocytes, 18 oocytes were injected with sperm, and six blastocysts were produced, which, upon transfer to mares' uteri, resulted in four pregnancies. Immature (GV) oocytes collected from live mares were also vitrified, warmed, and matured in vitro before ICSI. In this group, nonvitrified, control, and vitrified oocytes did not differ (P > 0.05) with respect to the incidence of maturation to MII, cleavage after ICSI, or blastocyst development. Conclusion: These findings demonstrate an effect of maternal age in an equine model at the level of meiotic spindle integrity and chromosome positioning that is influenced by both the meiotic stage at which oocytes are vitrified and whether meiotic maturation occurred in vivo or in vitro. [ABSTRACT FROM AUTHOR]

Janus kinase inhibitors (JAKi) have enormous appeal as immune-modulating therapies across many chronic inflammatory diseases, but recently this promise has been overshadowed by questions regarding associated cardiovascular and cancer risk emerging from the ORAL Surveillance phase 3b/4 post-marketing requirement randomized controlled trial. In that study of patients with rheumatoid arthritis with existing cardiovascular risk, tofacitinib, the first JAKi registered for chronic inflammatory disease, failed to meet non-inferiority thresholds when compared with tumor necrosis factor inhibitors for both incident major adverse cardiovascular events and incident cancer. While this result was unexpected by many, subsequently published observational data have also supported this finding. Notably, however, such a risk has largely not yet been demonstrated in patients outside the specific clinical situation examined in the trial, even in the face of many studies examining this. Nevertheless, this signal has practically re-aligned approaches to both tofacitinib and other JAKi to varying extents, in other patient populations and contexts: within rheumatoid arthritis, but also in psoriatic arthritis, axial spondyloarthritis, inflammatory bowel disease, atopic dermatitis, and beyond. Application to individual patients can be more challenging but remains important to harness the substantive potential of JAKi to the maximum extent safely possible. This review not only explores the evolution of the regulatory response to the signal, its informing data, biological plausibility, and its impact on guidelines, but also the many factors that clinicians must consider in navigating cardiovascular and cancer risk for their patients considering JAKi as immune-modulating therapy. [ABSTRACT FROM AUTHOR]

This study examines the changes in strain rate dependence and the deformation behavior of near-eutectic Sn-Bi alloys as a function of Sb concentration using nanoindentation. Alloying near-eutectic Sn-Bi solder with Sb has been shown to increase the strain to failure under tensile and shear conditions in solder ball geometries, with Sb additions remaining in solid solution up to 0.5 wt.% Sb. In this study, the resulting hardness of the three Sb-containing Sn-Bi alloys (Bi-42Sn eutectic, Bi-42Sn-0.5Sb, Bi-42Sn-1.0Sb) exhibits little solid solution hardening at room temperature, and the alloys all exhibited similar strain rate sensitivity behavior, independent of composition for this microstructure. Using nanoindentation and post-indentation microscopy to analyze the deformation behavior of these alloys, the out-of-plane deformation and slip behavior does change with composition. Solute Sb increases the strain hardening behavior at low strains while decreasing planar slip and out-of-plane deformation. The observed changes in deformation modes in this nanoindentation study with the addition of Sb as a solid solution alloy (less slip planarity, more uniform deformation, and more strain hardening) could play a role in previously observed changes in tensile failure modes without the formation of SbSn intermetallic compounds. [ABSTRACT FROM AUTHOR]