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The primary pre-neoplastic lesion of the lower esophagus in the vicinity of the gastroesophageal junction (GEJ) is any Barrett's esophageal lesions (BE), and esophageal neoplasia has increased in the US population with predispositions (Caucasian males, truncal obesity, age, and GERD). The responses to BE are endoscopic and screening cytologic programs with endoscopic ablation of various forms. The former have not been proven to be cost-effective and there are mixed results for eradication. A fresh approach is sorely needed. We prospectively followed 2229 mostly male veterans at high risk for colorectal cancer in a 27-year longitudinal long-term study, collecting data on colorectal neoplasia development and other preneoplastic lesions, including BE and spontaneous regression (SR). Another cross-sectional BE study at a similar time period investigated antigenic changes at the GEJ in both BE glandular and squamous mucosa immunohistochemistry and the role of inflammation. Ten of the prospective cohort (21.7%) experienced SR out of a total of forty-six BE patients. Significant differences between SR and stable BE were younger age ( p < 0.007); lower platelet levels ( p < 0.02); rectal p87 elevation in SR ( p < 0.049); a reduced innate immune system (InImS) FEREFF ratio (ferritin: p87 colonic washings) ( p < 0.04). Ancillary testing showed a broad range of neoplasia biomarkers. InImS markers may be susceptible to intervention using commonplace and safe medical interventions and encourage SR.

Canines are an important model system for genetics and evolution. Recent advances in sequencing technologies have enabled the creation of large databases of genetic variation in canines, but analyses of allele sharing among canine groups have been limited. We applied GeoVar, an approach originally developed to study the sharing of single nucleotide polymorphisms across human populations, to assess the sharing of genetic variation among groups of wolves, village dogs, and breed dogs. Our analysis shows that wolves differ from each other at an average of approximately 2.3 million sites while dogs from the same breed differ at nearly 1 million sites. We found that 22% of the variants are common across wolves, village dogs, and breed dogs, that ~16% of variable sites are common across breed dogs, and that nearly half of the differences between two dogs of different breeds are due to sites that are common in all clades. These analyses represent a succinct summary of allele sharing across canines and illustrate the effects of canine history on the apportionment of genetic variation.

Purpose : Conceptual models provide frameworks to illustrate relationships among patient-, provider-, system-, and community-level factors that inform care delivery and research. Existing models of cancer survivorship care focus largely on pediatric or adult populations whose needs differ from adolescents and young adults (AYAs). We developed a patient-centered conceptual model of AYA survivorship care. Methods: We conducted a narrative literature review of current conceptual and theoretical models of care. We engaged AYA cancer survivors (n = 25) in semi-structured one-hour telephone interviews. Most participants were in their 20s and 30s, and the majority (84%) were women. Recruitment was stratified by age and time since cancer diagnosis. We conducted a thematic analysis of interview transcripts to identify themes that exemplified patient-centered care. Results : Most participants identified as white and female. Leukemia and breast cancer were the most common cancer types. Main themes included the need for (1) care coordination, (2) ongoing mental health support, (3) connection to AYA peer support, (4) support during fertility preservation efforts, (5) support with financial burden, (6) support for quality of life, (7) information about and support with side effects and late effects, and (8) attention to the unique needs of young adults. Conclusions: We present a patient-centered conceptual model of AYA survivorship care needs that can inform future cancer care delivery and research.

The field of cardio-oncology is an expanding frontier within cardiovascular medicine, and the need for evidence-based guidelines is apparent. One of the emerging focuses within cardio-oncology is the concomitant use of medications for cardioprotection in the setting of chemotherapy regimens that have known cardiovascular toxicity. While clinical trials focusing on cardioprotection during chemotherapy are sparse, an inaugural trial exploring the prophylactic potential of Sodium-Glucose Cotransporter-2 inhibitors (SGLT2is) for anthracycline (ANT)-induced cardiotoxicity has recently commenced. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, though less studied in this oncology demographic, have exhibited promise in preclinical studies for conferring cardiac protection during non-ischemic toxic insults. While primarily used to reduce low-density lipoprotein, PCSK9 inhibitors exhibit pleiotropic effects, including the attenuation of inflammation, reactive oxygen species, and endothelial dysfunction. In ANT-induced cardiotoxicity, these same processes are accelerated, resulting in premature termination of treatment, chronic cardiovascular sequelae, heart failure, and/or death. This review serves a dual purpose: firstly, to provide a concise overview of the mechanisms implicated in ANT-induced cardiotoxicity, and, finally, to summarize the existing preclinical data supporting the theoretical possibility of the cardioprotective effects of PCSK9 inhibition in ANT-induced cardiotoxicity., Competing Interests: Conflicts of Interest: The authors declare no relevant conflicts of interest.

The ability of bacteria to recycle exogenous amino acid-based peptides and amino sugars for peptidoglycan biosynthesis was extensively investigated using optical imaging. In particular, fluorescent AeK-NBD was effectively utilized to study the peptidoglycan recycling pathway in Gram-negative bacteria. Based on these promising results, we were inspired to develop the radioactive AeK conjugate [ 68 Ga]Ga-DOTA-AeK for the in vivo localization of bacterial infection using PET/CT. An easy-to-implement radiolabeling procedure for DOTA-AeK with [ 68 Ga]GaCI 3 followed by solid-phase purification was successfully established to obtain [ 68 Ga]Ga-DOTA-AeK with a radiochemical purity of ≥95%. [ 68 Ga]Ga-DOTA-AeK showed good stability over time with less protein binding under physiological conditions. The bacterial incorporation of [ 68 Ga]Ga-DOTA-AeK and its fluorescent Aek-NBD analog were investigated in live and heat-killed Escherichia coli ( E. coli ) and Staphylococcus aureus ( S. aureus ). Unfortunately, no conclusive in vitro intracellular uptake of [ 68 Ga]Ga-DOTA-AeK was observed for E. coli or S. aureus live and heat-killed bacterial strains ( p > 0.05). In contrast, AeK-NBD showed significantly higher intracellular incorporation in live bacteria compared to the heat-killed control ( p < 0.05). Preliminary biodistribution studies of [ 68 Ga]Ga-DOTA-AeK in a dual-model of chronic infection and inflammation revealed limited localization at the infection site with non-specific accumulation in response to inflammatory markers. Finally, our study demonstrates proof that the intracellular incorporation of AeK is necessary for successful bacteria-specific imaging using PET/CT. Therefore, Ga-68 was not a suitable radioisotope for tracing the bacterial uptake of AeK tripeptide, as it required chelation with a bulky metal chelator such as DOTA, which may have limited its active membrane transportation. An alternative for optimization is to explore diverse chemical structures of AeK that would allow for radiolabeling with 18 F or 11 C.

Background: Fragile X Syndrome (FXS) is the leading monogenetic cause of autism spectrum disorder (ASD) and is associated with seizures. We examined the impact of repeated seizures on the behavioral and molecular changes in male Fmr1 knockout (KO) mice and wild-type (WT) mice., Methods: Seizures were induced by administering three flurothyl seizures per day across postnatal days (PD) 7-11, for a total of 15 seizures. In adulthood, mice were tested in a battery of behavioral tasks to assess long-term behavioral deficits., Results: The two-hit impact of a Fmr1 knockout and seizures resulted in decreased anxiety-like behavior in the elevated plus maze test and a longer latency to their first nose poke (repetitive behavior). Seizures resulted in decreased activity, decreased repetitive behavior (grooming and rearings), and decreased social behavior, while they also increased habituation to auditory stimuli and increased freezing in delayed fear conditioning in both KO and control mice. KO mice displayed increased repetitive behavior in the open field task (clockwise revolutions) and repeated nose pokes, and decreased anxiety in the open field test. No differences in mTOR signaling were found., Conclusions: These findings further illuminate the long-term effects of synergistic impact of two hits on the developing brain.

This retrospective study assesses the efficacy and tolerability of anti-calcitonin gene-related peptide (anti-CGRP) therapy in adolescents and young adults (ages 12-21) with migraine and chronic daily headaches unresponsive to standard treatments. Migraines in this demographic significantly impair school performance, self-esteem, psychological well-being, and cognitive health. These young patients are also particularly sensitive to the side effects of conventional medications, which are often prescribed off-label and come with high insurance denial rates. Medication overuse, including analgesics, triptans, and NSAIDs, is prevalent due to treatment failures. Elevated plasma CGRP levels observed during migraines suggest that anti-CGRP therapies, successful in adult populations, may also benefit this younger age group. Over a three-year period, patients at a specialized pediatric headache center were evaluated for the impact of anti-CGRP treatments, including monoclonal antibodies (erenumab, fremanezumab, and galcanezumab) and small-molecule CGRP receptor antagonists (ubrogepant, rimegepant, and atogepant), administered either alone or in combination with OnabotulinumtoxinA. Data were extracted from the hospital's electronic medical records, and patient progress was consistently documented using a structured template for each clinic visit. Additional patient satisfaction data were collected via telephone follow-ups and patient message reviews. The study included 23 patients, primarily treated for chronic migraine (CM) (78.3%), with a smaller subset addressing episodic migraine (EM), new daily persistent headaches (NDPHs), and post-traumatic headaches (PTHs). Comprehensive demographic and clinical data, including age, treatment duration, history of preventive treatment failures, and comorbidities like psychiatric conditions and sleep disorders, were collected. Anti-CGRP therapies, particularly when combined with traditional treatments or OnabotulinumtoxinA, resulted in significant improvements: 91.3% of patients experienced reduced migraine duration and intensity, 82.6% reported improvements in other bothersome symptoms, and 73.9% saw an improved response to rescue medications. Additionally, 78.3% of patients reported a reduction in their use of rescue medications per week by more than 50%, and emergency room visits were reduced for 56.5% of patients. Significant reductions in headache days were observed in 82.6% of patients after one month and 87% after three months, with nearly 40% experiencing more than a 50% reduction in both periods. The greatest benefits were observed in patients treated for more than six months. Adverse effects were minimal, with 95.7% of patients reporting no side effects, and patient satisfaction was high, with 69.6% opting to continue treatment. Overall, this study highlights the substantial potential of anti-CGRP therapy in improving outcomes for adolescents and young adults with CM and EM, offering a promising approach for a demographic that faces considerable challenges with conventional treatment options. However, further research is needed to confirm these findings and expand clinical applications in this age group.

Accurate and generalizable classification of brain states is essential for understanding their neural underpinnings and improving clinical diagnostics. Traditionally, functional connectivity patterns and graph-theoretic metrics have been utilized. However, cortical gradient features, which reflect global brain organization, offer a complementary approach. We hypothesized that a machine learning model integrating these three feature sets would effectively discriminate between baseline and atypical brain states across a wide spectrum of conditions, even though the underlying neural mechanisms vary. To test this, we extracted features from brain states associated with three meta-conditions including unconsciousness (NREM2 sleep, propofol deep sedation, and propofol general anesthesia), psychedelic states induced by hallucinogens (subanesthetic ketamine, lysergic acid diethylamide, and nitrous oxide), and neuropsychiatric disorders (attention-deficit hyperactivity disorder, bipolar disorder, and schizophrenia). We used support vector machine with nested cross-validation to construct our models. The soft voting ensemble model marked the average balanced accuracy (average of specificity and sensitivity) of 79% (62-98% across all conditions), outperforming individual base models (70-76%). Notably, our models exhibited varying degrees of transferability across different datasets, with performance being dependent on the specific brain states and feature sets used. Feature importance analysis across meta-conditions suggests that the underlying neural mechanisms vary significantly, necessitating tailored approaches for accurate classification of specific brain states. This finding underscores the value of our feature-integrated ensemble models, which leverage the strengths of multiple feature types to achieve robust performance across a broader range of brain states. While our approach offers valuable insights into the neural signatures of different brain states, future work is needed to develop and validate even more generalizable models that can accurately classify brain states across a wider array of conditions.

Metabolic dysfunction is commonly observed in schizophrenia spectrum disorders (SSDs). The causes of metabolic comorbidity in SSDs are complex and include intrinsic or biological factors linked to the disorder, which are compounded by antipsychotic (AP) medications. The exact mechanisms underlying SSD pathophysiology and AP-induced metabolic dysfunction are unknown, but dysregulated lipid metabolism may play a role. Lipidomics, which detects lipid metabolites in a biological sample, represents an analytical tool to examine lipid metabolism. This systematic review aims to determine peripheral lipid signatures that are dysregulated among individuals with SSDs (1) with minimal exposure to APs and (2) during AP treatment. To accomplish this goal, we searched MEDLINE, Embase, and PsychINFO databases in February 2024 to identify all full-text articles written in English where the authors conducted lipidomics in SSDs. Lipid signatures reported to significantly differ in SSDs compared to controls or in relation to AP treatment and the direction of dysregulation were extracted as outcomes. We identified 46 studies that met our inclusion criteria. Most of the lipid metabolites that significantly differed in minimally AP-treated patients vs. controls comprised glycerophospholipids, which were mostly downregulated. In the AP-treated group vs. controls, the significantly different metabolites were primarily fatty acyls, which were dysregulated in conflicting directions between studies. In the pre-to-post AP-treated patients, the most impacted metabolites were glycerophospholipids and fatty acyls, which were found to be primarily upregulated and conflicting, respectively. These lipid metabolites may contribute to SSD pathophysiology and metabolic dysfunction through various mechanisms, including the modulation of inflammation, cellular membrane permeability, and metabolic signaling pathways.

The incorporation of gold nanoparticles (GNPs) into retinal imaging signifies a notable advancement in ophthalmology, offering improved accuracy in diagnosis and patient outcomes. This review explores the synthesis and unique properties of GNPs, highlighting their adjustable surface plasmon resonance, biocompatibility, and excellent optical absorption and scattering abilities. These features make GNPs advantageous contrast agents, enhancing the precision and quality of various imaging modalities, including photoacoustic imaging, optical coherence tomography, and fluorescence imaging. This paper analyzes the unique properties and corresponding mechanisms based on the morphological features of GNPs, highlighting the potential of GNPs in retinal disease diagnosis and management. Given the limitations currently encountered in clinical applications of GNPs, the approaches and strategies to overcome these limitations are also discussed. These findings suggest that the properties and efficacy of GNPs have innovative applications in retinal disease imaging.

Pose estimation is crucial for ensuring passenger safety and better user experiences in semi- and fully autonomous vehicles. Traditional methods relying on pose estimation from regular color images face significant challenges due to a lack of three-dimensional (3D) information and the sensitivity to occlusion and lighting conditions. Depth images, which are invariant to lighting issues and provide 3D information about the scene, offer a promising alternative. However, there is a lack of strong work in 3D pose estimation from such images due to the time-consuming process of annotating depth images with 3D postures. In this paper, we present a novel approach to 3D human posture estimation using depth and infrared (IR) images. Our method leverages a three-stage fine-tuning process involving simulation data, approximated data, and a limited set of manually annotated samples. This approach allows us to effectively train a model capable of accurate 3D pose estimation with a median error of under 10 cm across all joints, using fewer than 100 manually annotated samples. To the best of our knowledge, this is the first work focusing on vehicle occupant posture detection utilizing only depth and IR data. Our results demonstrate the feasibility and efficacy of this approach, paving the way for enhanced passenger safety in autonomous vehicle systems.

Our previous study discussed crystallin family induction in an experimental rat model of retinal detachment. Therefore, we attempted to evaluate the role of α-crystallin in photoreceptor survival in an experimental model of retinal detachment, as well as its association with the intrinsically neuroprotective protein Fas-apoptotic inhibitory molecule 2 (FAIM2). Separation of retina and RPE was induced in rat and mouse eyes by subretinal injection of hyaluronic acid. Retinas were subsequently analyzed for the presence αA-crystallin (HSPB4) and αB-crystallin (HSPB5) proteins using immunohistochemistry and immunoblotting. Photoreceptor death was analyzed using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) staining and cell counts. The 661W cells subjected to FasL were used as a cell model of photoreceptor degeneration to assess the mechanisms of the protective effect of αA-crystallin and its dependence on its phosphorylation on T148. We further evaluated the interaction between FAIM2 and αA-crystallin using a co-immunoprecipitation assay. Our results showed that α-crystallin protein levels were rapidly induced in response to retinal detachment, with αA-crystallin playing a particularly important role in protecting photoreceptors during retinal detachment. Our data also show that the photoreceptor intrinsically neuroprotective protein FAIM2 is induced and interacts with α-crystallins following retinal detachment. Mechanistically, our work also demonstrated that the phosphorylation of αA-crystallin is important for the interaction of αA-crystallin with FAIM2 and their neuroprotective effect. Thus, αA-crystallin is involved in the regulation of photoreceptor survival during retinal detachment, playing a key role in the stabilization of FAIM2, serving as an important modulator of photoreceptor cell survival under chronic stress conditions.

Background: Prior studies are inconclusive regarding the effect of obesity on mortality in persons with colorectal cancer (CRC). We sought to determine the association of pre-diagnosis body mass index (BMI) trajectories on mortality after CRC diagnosis., Methods: Utilizing the Multiethnic Cohort, we included adults aged 18-75 between 1 January 1993 and 1 January 2019 with a diagnosis of CRC and at least three available BMIs. The primary exposure, BMI, was subjected to group-based trajectory modeling (GBTM). We evaluated all-cause and CRC-specific mortality, using Cox proportional hazard (PH) models., Results: Of 924 persons, the median age was 60 years, and 54% were female. There was no statistically significant association between pre-cancer BMI trajectory and either all-cause or cancer-specific mortality. In competing risk analysis, the risk of CRC-specific mortality was higher for African Americans (HR = 1.56, 95% CI [1.00-2.43], p = 0.048) and smokers (HR = 1.59, 95% CI [1.10-2.32], p = 0.015). Risk of all-cause mortality was higher for Hawaiian persons (HR = 2.85, 95% CI [1.31-6.21], p = 0.009) and persons with diabetes (HR = 1.83, 95% CI [1.08-3.10], p = 0.026)., Conclusions: Pre-diagnosis BMI trajectories were not associated with mortality after CRC diagnosis, whereas race/ethnicity, diabetes, and smoking were associated with an increased risk of death. Our findings suggest the obesity paradox alone does not account for mortality after CRC diagnosis.

Since the introduction of the first immune checkpoint inhibitor (ICI), immunotherapy has changed the landscape of molecular therapeutics for cancers. However, ICIs do not work equally well on all cancers and for all patients. There has been a growing interest in using mathematical and computational models to optimize clinical responses. Ordinary differential equations (ODEs) have been widely used for mechanistic modeling in immuno-oncology and immunotherapy. They allow rapid simulations of temporal changes in the cellular and molecular populations involved. Nonetheless, ODEs cannot describe the spatial structure in the tumor microenvironment or quantify the influence of spatially-dependent characteristics of tumor-immune dynamics. For these reasons, agent-based models (ABMs) have gained popularity because they can model more detailed phenotypic and spatial heterogeneity that better reflect the complexity seen in vivo. In the context of anti-PD-1 ICIs, we compare treatment outcomes simulated from an ODE model and an ABM to show the importance of including spatial components in computational models of cancer immunotherapy. We consider tumor cells of high and low antigenicity and two distinct cytotoxic T lymphocyte (CTL) killing mechanisms. The preferred mechanism differs based on the antigenicity of tumor cells. Our ABM reveals varied phenotypic shifts within the tumor and spatial organization of tumor and CTLs despite similarities in key immune parameters, initial simulation conditions, and early temporal trajectories of the cell populations.

Autophagy, an evolutionarily conserved cellular mechanism essential for maintaining internal stability, plays a crucial function in female reproductive ability. In this review, we discuss the complex interplay between autophagy and several facets of female reproductive health, encompassing pregnancy, ovarian functions, gynecologic malignancies, endometriosis, and infertility. Existing research emphasizes the crucial significance of autophagy in embryo implantation, specifically in the endometrium, highlighting its necessity in ensuring proper fetal development. Although some knowledge has been gained, there is still a lack of research on the specific molecular impacts of autophagy on the quality of oocytes, the growth of follicles, and general reproductive health. Autophagy plays a role in the maturation, quality, and development of oocytes. It is also involved in reproductive aging, contributing to reductions in reproductive function that occur with age. This review explores the physiological functions of autophagy in the female reproductive system, its participation in reproductive toxicity, and its important connections with the endometrium and embryo. In addition, this study investigates the possibility of emerging treatment approaches that aim to modify autophagy, using both natural substances and synthetic molecules, to improve female fertility and reproductive outcomes. Additionally, this review intends to inspire future exploration into the intricate role of autophagy in female reproductive health by reviewing recent studies and pinpointing areas where current knowledge is lacking. Subsequent investigations should prioritize the conversion of these discoveries into practical uses in the medical field, which could potentially result in groundbreaking therapies for infertility and other difficulties related to reproduction. Therefore, gaining a comprehensive understanding of the many effects of autophagy on female fertility would not only further the field of reproductive biology but also open new possibilities for diagnostic and treatment methods.

Cyanobacterial blooms are increasingly common during winters, especially when they are mild. The goal of this study was to determine the summer and winter phytoplankton community structure, cyanotoxin presence, and toxigenicity in a eutrophic lake susceptible to cyanobacterial blooms throughout the year, using classical microscopy, an analysis of toxic cyanometabolites, and an analysis of genes involved in biosynthesis of cyanotoxins. We also assessed whether cyanobacterial diversity in the studied lake has changed compared to what was reported in previous reports conducted several years ago. Moreover, the bloom-forming cyanobacterial strains were isolated from the lake and screened for cyanotoxin presence and toxigenicity. Cyanobacteria were the main component of the phytoplankton community in both sampling times, and, in particular, Oscillatoriales were predominant in both summer ( Planktothrix / Limnothrix ) and winter ( Limnothrix ) sampling. Compared to the winter community, the summer community was denser; richer in species; and contained alien and invasive Nostocales, including Sphaerospermopsis aphanizomenoides , Raphidiopsis raciborskii , and Raphidiopsis mediterranea . In both sampling times, the blooms contained toxigenic species with genetic determinants for the production of cylindrospermopsin and microcystins. Toxicological screening revealed the presence of microcystins in the lake in summer but no cyanotoxins in the winter period of sampling. However, several cyanobacterial strains isolated from the lake during winter and summer produced anabaenopeptins and microcystins. This study indicates that summer and winter blooms of cyanobacteria in the temperate zone can differ in biomass, structure, and toxicity, and that the toxic hazards associated with cyanobacterial blooms may potentially exist during winter.

The young of toothed mammals must have teeth to reach feeding independence. How tooth eruption integrates with gestation, birth and weaning is examined in a life-history perspective for 71 species of placental mammals. Questions developed from high-quality primate data are then addressed in the total sample. Rather than correlation, comparisons focus on equivalence, sequence, the relation to absolutes (six months, one year), the distribution of error and adaptive extremes. These mammals differ widely at birth, from no teeth to all deciduous teeth emerging, but commonalities appear when infants transit to independent feeding. Weaning follows completion of the deciduous dentition, closest in time to emergence of the first permanent molars and well before second molars emerge. Another layer of meaning appears when developmental age is counted from conception because the total time to produce young feeding independently comes up against seasonal boundaries that are costly to cross for reproductive fitness. Mammals of a vast range of sizes and taxa, from squirrel monkey to moose, hold conception-to-first molars in just under one year. Integrating tooth emergence into life history gives insight into living mammals and builds a framework for interpreting the fossil record.

1,2,3,4,5-pentathiepines (PTEs) are naturally occurring polysulfides of increasing scientific interest based on their identified pharmacological activities. Artificial PTEs with N -heterocyclic backbones are efficiently synthesized via mediation by a molybdenum-oxo-bistetrasulfido complex. A common feature of all precursor alkynes successfully used to date in this reaction is the presence of a -CH(OEt) 2 group since the previously postulated mechanism requires the presence of one OEt - as the leaving group, and the second must become a transient ethoxonium moiety. This raised the question of whether there really is a need for two, maybe only one, or possibly even zero ethoxy substituents. This research problem was systematically addressed by respective variations in the precursor-alkyne derivatives and by employing one related allene species. It was found that the total absence of ethoxy substituents prevents the formation of PTEs entirely, while the presence of a single ethoxy group results in the possibility to distinctly functionalize the position on the resulting N -heterocyclic pyrrole five ring in the target compound. This position was previously exclusively occupied by an -OEt for all products of the molybdenum-mediated reaction. The allene was applied with similar success as precursor as with the related alkyne. The now-employable significant change in precursor composition gives access to a whole new PTE subfamily, allowing further modulation of (physico)-chemical properties such as solubility, and provides additional insight into the mechanism of PTE formation; it comprises a merely partial validation of the previous hypothesis. The new alkyne precursors and pentathiepines were characterized by a variety of instrumental analyses (NMR, mass spec, UV-vis) and in six cases (one alkyne precursor, one unexpected side product, and four PTEs) by single-crystal X-ray diffraction. Syntheses, isolation procedures, analytical data, and the impact of the findings on the previously proposed mechanism are described in detail herein.

Hepatocellular carcinoma (HCC) has emerged as a major contributor to the worldwide cancer burden. Improved methods are needed for early cancer detection and image-guided surgery. Peptides have small dimensions that can overcome delivery challenges to achieve high tumor concentrations and deep penetration. We used phage display methods to biopan against the extra-cellular domain of the purified EpCAM protein, and used IRDye800 as a near-infrared (NIR) fluorophore. The 12-mer sequence HPDMFTRTHSHN was identified, and specific binding to EpCAM was validated with HCC cells in vitro. A binding affinity of k d = 67 nM and onset of k = 0.136 min -1 (7.35 min) were determined. Serum stability was measured with a half-life of T 1/2 = 2.6 h. NIR fluorescence images showed peak uptake in vivo by human HCC patient-derived xenograft (PDX) tumors at 1.5 h post-injection. Also, the peptide was able to bind to foci of local and distant metastases in liver and lung. Peptide biodistribution showed high uptake in tumor versus other organs. No signs of acute toxicity were detected during animal necropsy. Immunofluorescence staining of human liver showed specific binding to HCC compared with cirrhosis, adenoma, and normal specimens.

In polymicrobial sepsis, the extracellular histones, mainly released from activated neutrophils, significantly contribute to cardiac dysfunction (septic cardiomyopathy), as demonstrated in our previous studies using Echo-Doppler measurements. This study aims to elucidate the roles of extracellular histones and their interactions with Toll-like receptors (TLRs) in cardiac dysfunction. Through ex vivo assessments of ECG, left ventricle (LV) function parameters, and in vivo Echo-Doppler studies in mice perfused with extracellular histones, we aim to provide comprehensive insights into the mechanisms underlying sepsis-induced cardiac dysfunction. Langendorff-perfused hearts from both wild-type and TLR2, TLR3, or TLR4 knockout (KO) mice were examined. Paced mouse hearts were perfused with histones to assess contractility and relaxation. Echo-Doppler studies evaluated cardiac dysfunction after intravenous histone injection. Histone perfusion caused defects in contractility and relaxation, with TLR2 and TLR3 KO mice being partially protected. Specifically, TLR2 KO mice exhibited the greatest reduction in Echo-Doppler abnormalities, while TLR4 KO exacerbated cardiac dysfunction. Among individual histones, H1 induced the most pronounced abnormalities in cardiac function, apoptosis of cardiomyocytes, and LDH release. Our data highlight significant interactions between histones and TLRs, providing insights into histones especially H1 as potential therapeutic targets for septic cardiomyopathy. Further studies are needed to explore specific histone-TLR interactions and their mechanisms.

This study investigated gelatin methacryloyl (GelMA) and polycaprolactone (PCL) blend scaffolds incorporating cerium oxide (CeO) nanoparticles at concentrations of 0%, 5%, and 10% w/w via electrospinning for periodontal tissue engineering. The impact of photocrosslinking on these scaffolds was evaluated by comparing crosslinked (C) and non-crosslinked (NC) versions. Methods included Fourier transform infrared spectroscopy (FTIR) for chemical analysis, scanning electron microscopy (SEM) for fiber morphology/diameters, and assessments of swelling capacity, degradation profile, and biomechanical properties. Biological evaluations with alveolar bone-derived mesenchymal stem cells (aBMSCs) and human gingival fibroblasts (HGFs) encompassed tests for cell viability, mineralized nodule deposition (MND), and collagen production (CP). Statistical analysis was performed using Kruskal-Wallis or ANOVA/post-hoc tests (α = 5%). Results indicate that C scaffolds had larger fiber diameters (~250 nm) compared with NC scaffolds (~150 nm). NC scaffolds exhibited higher swelling capacities than C scaffolds, while both types demonstrated significant mass loss (~50%) after 60 days ( p < 0.05). C scaffolds containing CeO showed increased Young's modulus and tensile strength than NC scaffolds. Cells cultured on C scaffolds with 10% CeO exhibited significantly higher metabolic activity (>400%, p < 0.05) after 7 days among all groups. Furthermore, CeO-containing scaffolds promoted enhanced MND by aBMSCs (>120%, p < 0.05) and increased CP in 5% CeO scaffolds for both variants (>180%, p < 0.05). These findings underscore the promising biomechanical properties, biodegradability, cytocompatibility, and enhanced tissue regenerative potential of CeO-loaded GelMA/PCL scaffolds for periodontal applications.

The use of family planning (FP) methods significantly contributes to improved outcomes for mothers and their offspring. However, the use of FP remains low, particularly in low- and middle-income countries. A cluster randomized controlled clinical trial was implemented in Ghana, comparing group antenatal care (ANC) with routine care. The group ANC intervention included eight meetings where the seventh group meeting incorporated information and discussion regarding methods of FP. Data collection occurred at five time points: baseline (T0), 34 weeks' gestation (T1), 6-12 weeks post birth (T2), 5-8 months post birth, and 11-14 months post birth (T4). At T1, there was a significantly greater increase in the knowledge of FP methods as well as the intention to use FP after the birth among the intervention group. The uptake of FP was significantly higher in the intervention group for all post-birth timepoints except for T4 where the control group had significantly higher rates. The reasons for the diminishing effect are unclear. An increasing uptake of FP methods requires a multifaceted approach that includes increasing accessibility, knowledge, and acceptability as well as addressing societal and cultural norms.

The microvasculature, which makes up the majority of the cardiovascular system, plays a crucial role in the process of thrombosis, with the pathological formation of blood clots inside blood vessels. Since blood microflow conditions significantly influence platelet activation and thrombosis, accurately mimicking the structure of bifurcating microvascular networks and emulating local physiological blood flow conditions are valuable for understanding blood clot formation. In this work, we present an in vitro model for blood clotting in microvessels, focusing on 3D bifurcations that align with Murray's law, which guides vascular networks by maintaining a constant wall shear rate throughout. Using these models, we demonstrate that microvascular bifurcations act as sites facilitating thrombus formation compared to straight models. Additionally, by culturing endothelial cells on the luminal surfaces of the models, we show the potential of using our in vitro platforms to recapitulate the initial clotting in diseases involving endothelial dysfunction, such as Thrombotic Thrombocytopenic Purpura.

Patients consistently rate cancer-related fatigue (CrF) as the most prevalent and debilitating symptom. CrF is an important but often neglected patient concern, partly due to barriers to implementing evidence-based interventions. This study explored what an ideal intervention for CrF would look like from the perspectives of different stakeholders and the barriers to its implementation. Three participant populations were recruited: healthcare providers (HCPs; n = 32), community support providers (CSPs; n = 14), and cancer patients ( n = 16). Data were collected via nine focus groups and four semi-structured interviews. Data were coded into themes using content analysis. Two main themes emerged around addressing CrF: "It takes a village" and "This will not be easy". Participants discussed an intervention for CrF could be anywhere, offered by anyone and everyone, and provided early and frequently throughout the cancer experience and could include peer support, psychoeducation, physical activity, mind-body interventions, and interdisciplinary care. Patients, HCPs, and CSPs described several potential barriers to implementation, including patient barriers (i.e., patient variability, accessibility, online literacy, and overload of information) and systems barriers (i.e., costs, lack of HCP knowledge, system insufficiency, and time). As CrF is a common post-treatment symptom, it is imperative to offer patients adequate support to manage CrF. This study lays the groundwork for the implementation of a patient-centered intervention for CrF in Canada and possibly elsewhere.

Cell secretion repairs tissue damage and restores homeostasis throughout adult life. The extracellular heat shock protein-90alpha (eHsp90α) has been reported as an exosome cargo and a potential driver of wound healing. However, neither the mechanism of secretion nor the genetic evidence for eHsp90α in wound healing has been substantiated. Herein, we show that tissue injury causes massive deposition of eHsp90α in tissues and secretion of eHsp90α by cells. Sequential centrifugations of conditioned medium from relevant cell lines revealed the relative distributions of eHsp90α in microvesicle, exosome and trypsin-sensitive supernatant fractions to be approximately <2%, <4% and >95%, respectively. Establishing the cell-number-to-interstitial-fluid-volume (CIF) ratio for the microenvironment of human tissues as 1 × 10 9 cells: 1 mL interstitial fluid enabled us to predict the corresponding tissue concentrations of eHsp90α in these fractions as 3.74 μg/mL, 5.61 μg/mL and 178 μg/mL. Remarkably, the 178 μg/mL eHsp90α matches the previously reported 100-300 μg/mL of recombinant eHsp90α whose topical application promotes maximum wound healing in animal models. More importantly, we demonstrate that two parallel secretory autophagy-regulating gene families, the autophagy-regulating (AR) genes and the Golgi reassembly-stacking protein (GRASP) genes work together to mediate the secretion of the physiological concentration of eHsp90α to promote wound healing. Thus, utilization of the CIF ratio-based extrapolation method may enable investigators to rapidly predict biomarker targets from cell-conditioned-medium data.

Adenovirus infections of immunocompromised patients can cause life-threatening disseminated disease. While there are presently no drugs specifically approved to treat these infections, there are several compounds that showed efficacy against adenovirus in preclinical studies. For any such compound, low toxicity is an essential requirement. As cumulative drug effects can accentuate pathology, especially in patients with other morbidities, it is important to limit antiviral exposure to what is absolutely necessary. This is achievable by monitoring the virus burden of the patients and administering antivirals to suppress virus replication to a non-pathogenic level. We modeled such a system using Syrian hamsters infected with a replication-competent adenovirus vector, in which luciferase expression is coupled to virus replication. We found that virus replication could be followed in vivo in the same animal by repeated measurement of luciferase expression. To test the utility of an interrupted treatment regimen, we used NPP-669 and valganciclovir, two antiviral compounds with high and moderate anti-adenoviral efficacy, respectively. We found that short-term treatment of adenovirus-infected hamsters at times of peak virus replication can prevent virus-associated pathology. Thus, we believe that this animal model can be used to model different treatment regimens for anti-adenoviral compounds.

The main component of human skin is a collagen-rich extracellular matrix (ECM), known as the matrisome. The matrisome is essential for maintaining the structural integrity and mechanical properties of the skin. Recently, we reported notable decreases in matrisome proteins in natural aging and photoaging human skin. This study aims to investigate the mRNA expression of the core matrisome proteins in human skin, comparing young versus aged and sun-protected versus sun-exposed skin by quantitative real-time PCR and immunostaining. Our findings reveal a notable decrease in core matrisome transcription in aged skin. The mRNA expression of the core matrisome, such as collagen 1A1 (COL1A1), decorin, and dermatopontin, is significantly reduced in aged skin compared to its young skin. Yet, the majority of collagen mRNA expression levels of aged sun-exposed skin are similar to those found in young sun-exposed skin. This discrepancy is primarily attributable to a substantial decrease in collagen transcription in young sun-exposed skin, suggesting early molecular changes in matrisome transcription due to sun exposure, which preceded the emergence of clinical signs of photoaging. These findings shed light on the mRNA transcript profile of major matrisome proteins and their alterations in naturally aged and photoaged human skin, offering valuable insights into skin matrisome biology.

Laser surface remelting of aluminum alloys has emerged as a promising technique to enhance mechanical properties through refined microstructures. This process involves rapid cooling rates ranging from 10 3 to 10 8 °C/s, which increase solid solubility within aluminum alloys, shifting their eutectic composition to a larger value of silicon content. Consequently, the resulting microstructure combines a strengthened aluminum matrix with silicon fibers. This study focuses on the laser scanning of Al-Si aluminum alloy to reduce the size of aluminum matrix spacings and transform fibrous silicon particles from micrometer to nanometer dimensions. Analysis revealed that the eutectic structure contained 17.55% silicon by weight, surpassing the equilibrium eutectic composition of 12.6% silicon. Microstructure dimensions within the molten zones, termed 'melt pools', were extensively examined using Scanning Electron Microscopy (SEM) at intervals of approximately 20 μm from the surface. A notable increase in hardness, exceeding 50% compared to the base plate, was observed in the melt pool regions. Thus, it is exemplified that laser surface remelting introduces a novel strengthening mechanism in the alloy. Moreover, this study develops an in situ method for predicting melt pool properties and dimensions. A predictive model is proposed, correlating energy density and spectral signals emitted during laser remelting with mechanical properties and melt pool dimensions. This method significantly reduces characterization time from days to seconds, offering a streamlined approach for future studies in additive manufacturing.

Lesbian, bisexual, queer, trans and other gender diverse persons assigned female at birth (heretofore referred to as "LBQT+ persons") in Western Kenya experience intersectional oppression and stigma. This stigma can manifest in acts of sexual and gender-based violence (SGBV) and sexual and gender minority (SGM)-based violence, as well as various forms of discrimination-all of which have been linked to disproportionately higher levels of negative health outcomes for this group. Despite these challenges, many LBQT+ persons have been able to gain personal and collective power and thrive in this oppressive environment. The Empowerment for Us by Us (E4UBU) project is a mixed methods feminist participatory research study focused on exploring how LBQT+ persons conceptualize and define empowerment for themselves, and to understand their perspectives on how feelings of power and powerlessness influence their physical and mental health. This paper focuses on data from the first phase of the study, in which qualitative in-depth interviews were conducted with 40 LBQT+ persons (ages 19 to 50) from Kisumu and Homa Bay in Western Kenya. A participatory interpretive phenomenological analysis was conducted to understand the lived experiences of LBQT+ persons as they navigate intersectional oppression and its influence on their experiences of empowerment and subsequent health outcomes. Findings from this analysis were presented to two different focus groups composed of participants who had participated in the in-depth interviews to gather their insights on the interpretations of the interviews as a form of member checking. Findings revealed that "empowerment" was not experienced and viewed by LBQT+ persons as a monolithic construct, but rather a process through which LBQT+ persons are able to transform negative forces of intersectional oppression and powerlessness into experiences of power and subsequent individual and collective action and impact-all leading to improved mental health and well-being. This process is facilitated at several junctures by participatory seeking and attainment of community-appropriate resources at multiple socio-ecological levels that, when accessed with sufficient intensity, frequency, and duration, enhance one's journey through the process of empowerment. These facilitation junctures are viewed as likely points of focus for public health intervention. Analysis also revealed that the process of empowerment is dependent on the context within which the process is occurring, the specific issues being faced, and the population of focus. Recommendations for how this model can be used for future research and practice to improve the lives of LBQT+ persons in Kenya are discussed.

Aluminum-steel joints are increasingly used in the automotive industry to meet the requirements for energy saving and emission reduction. Among various joining technologies, self-pierce riveting (SPR) and resistance spot welding (RSW) are two well-established technologies for fabricating dissimilar joints with stable and high mechanical performance. However, corrosion will occur in these joints inevitably due to different electrochemical properties, which can degrade the surface quality and the mechanical performance, such as strength. This paper presents a method of understanding the corrosion mechanisms in joining aluminum and steel. For this understanding, a hybrid method combining experimental observations, mechanical properties identification, and analytical approaches was used to assess the evolution of the impact of corrosion on the joining performance, such as traction separation curves. The study was conducted on common combinations used in the vehicles, e.g., a 1.2 mm thickness aluminum alloy (AA 6022) and 2.0 mm thickness hot deep galvanized steel (HDG HSLA 340) joined by SPR and RSW. After the fabrication of these joints, accelerated cyclic corrosion tests of up to 104 cycles were performed, which reproduced the environmental conditions to which a vehicle was exposed. By investigating the microstructural evolution within the joints, the corrosion mechanisms of SPR and RSW joints were revealed, including the initiation and propagation. Moreover, the intrinsic impact of the corrosion on the mechanical performance, including the strength, axial stiffness, and crashworthiness, was analyzed by performing a lap-shear test. It showed that as corrosion proceeds, the fracture modes and mechanical performance are affected significantly.

Microtubule (MT)-dependent transport is a critical means of intracellular movement of cellular cargo by kinesin and dynein motors. MT-dependent transport is tightly regulated by cellular MT-associated proteins (MAPs) that directly bind to MTs and either promote or impede motor protein function. Viruses have been widely shown to usurp MT-dependent transport to facilitate their virion movement to sites of replication and/or for exit from the cell. However, it is unclear if viruses also negatively regulate MT-dependent transport. Using single-molecule motility and cellular transport assays, we show that the vaccinia virus (VV)-encoded MAP, A51R, inhibits kinesin-1-dependent transport along MTs in vitro and in cells. This inhibition is selective as the function of kinesin-3 is largely unaffected by VV A51R. Interestingly, we show that A51R promotes the perinuclear accumulation of cellular cargo transported by kinesin-1 such as lysosomes and mitochondria during infection. Moreover, A51R also regulates the release of specialized VV virions that exit the cell using kinesin-1-dependent movement. Using a fluorescently tagged rigor mutant of kinesin-1, we show that these motors accumulate on A51R-stabilized MTs, suggesting these stabilized MTs may form a "kinesin-1 sink" to regulate MT-dependent transport in the cell. Collectively, our findings uncover a new mechanism by which viruses regulate host cytoskeletal processes.

Bipolar disorder (BP) is a recurring psychiatric condition characterized by alternating episodes of low energy (depressions) followed by manias (high energy). Cortical network activity produced by GABAergic interneurons may be critical in maintaining the balance in excitatory/inhibitory activity in the brain during development. Initially, GABAergic signaling is excitatory; with maturation, these cells undergo a functional switch that converts GABA A channels from depolarizing (excitatory) to hyperpolarizing (inhibitory), which is controlled by the intracellular concentration of two chloride transporters. The earliest, NKCC1, promotes chloride entry into the cell and depolarization, while the second (KCC2) stimulates movement of chloride from the neuron, hyperpolarizing it. Perturbations in the timing or expression of NKCC1/KCC2 may affect essential morphogenetic events including cell proliferation, migration, synaptogenesis and plasticity, and thereby the structure and function of the cortex. We derived induced pluripotent stem cells (iPSC) from BP patients and undiagnosed control (C) individuals, then modified a differentiation protocol to form GABAergic interneurons, harvesting cells at sequential stages of differentiation. qRT-PCR and RNA sequencing indicated that after six weeks of differentiation, controls transiently expressed high levels of NKCC1. Using multi-electrode array (MEA) analysis, we observed that BP neurons exhibit increased firing, network bursting and decreased synchrony compared to C. Understanding GABA signaling in differentiation may identify novel approaches and new targets for treatment of neuropsychiatric disorders such as BP.

Autophagy, an intrinsic catabolic mechanism that eliminates misfolded proteins, dysfunctional organelles, and lipid droplets, plays a vital function in energy balance and cytoplasmic quality control, in addition to maintaining cellular homeostasis. Liver cancer such as hepatocellular carcinoma (HCC) is one of the most common causes of cancer deaths globally and shows resistance to several anticancer drugs. Despite the rising incidence and poor prognosis of malignant HCC, the underlying molecular mechanisms driving this aggressive cancer remain unclear. Several natural compounds, such as phytochemicals of dietary and non-dietary origin, affect hepatocarcinogenesis signaling pathways in vitro and in vivo, which may help prevent and treat HCC cells. Current HCC cells treatments include chemotherapy, radiation, and surgery. However, these standard therapies have substantial side effects, and combination therapy enhances side effects for an acceptable therapeutic benefit. Therefore, there is a need to develop treatment strategies for HCC cells that are more efficacious and have fewer adverse effects. Multiple genetic and epigenetic factors are responsible for the HCC cells to become resistant to standard treatment. Autophagy contributes to maintain cellular homeostasis, which activates autophagy for biosynthesis and mitochondrial regulation and recycling. Therefore, modifying autophagic signaling would present a promising opportunity to identify novel therapies to treat HCC cells resistant to current standard treatments. This comprehensive review illustrates how natural compounds demonstrate their anti-hepatocellular carcinoma function through autophagy.

Women seeking care during the perinatal period often face delays or long waits at healthcare facilities due to lack of providers and/or resources, leading to sub-optimal outcomes. We implemented a program whereby patients with concerns could receive same-day care virtually from a midwife rather than presenting to the clinic or hospital for care. Implementation strategies included virtual training, a staged increase in patient volume, and frequent communication between the midwives via text, email, and monthly meetings. Virtual visits included a variety of complaints, the five most common being to establish care, first-trimester bleeding, nausea and vomiting, mental health concerns, and postnatal breast problems. There was a threefold increase in virtual visits during the first 6 months with 92% of patients not requiring urgent face-to-face follow-up. Midwives were able to provide high-quality telehealth care that met the patients' needs and decreased the demand on hospital-based services. With the growing ubiquity of mobile phones and internet access, this strategy may be effective in providing quality care while decreasing demands on physical infrastructure. More research is needed to assess acceptability in other contexts. Reproducibility in low-resource settings may be limited if women lack access to video conferencing on phones or laptops.

Background: Cognitive behavioral therapy (CBT) has been successfully utilized in improving mental health (MH) and quality of life (QoL) in the general population, regardless of age. Cancer, which is most frequently diagnosed in older adults, is a debilitating illness that has a detrimental and long-lasting effect on patients' MH and QoL. While numerous studies have demonstrated CBT's efficacy, little evidence exists for its role in older cancer patients. This study, using MH and QoL metrics, evaluates the effectiveness of CBT for older adult cancer patients., Methods: Focusing on MH and QoL and an average age of over 60 years old, a final analysis was performed on 17 clinical trials with a total of 124 effect sizes, including 3073 participants receiving CBT. "Metaphor" and "Robumeta" packages in R Statistical Software (version 4.2.2) were used for analysis, which included robust variance estimation (RVE) in intercept-only meta-regression, and univariate meta-regression for moderator analysis., Results: With 17 clinical trials and 124 effect sizes, our results show that CBT moderately improves MH and QoL in cancer patients d = 0.19, 95% CI 0.0166-0.364, p < 0.0399. The delivery format was shown to be a strong moderator of CBT effectiveness with interpersonal technological interventions combined with pre-programmed segments having a very strong treatment effect size (d = 1.7307, 95% CI 1.5244-1.937, p < 0.001)., Conclusions: The use of CBT in older adult cancer patients statistically improves MH and QoL, with delivery format and stages of treatment having important roles. Tech-only interpersonal interventions combined with pre-programmed CBT provide an avenue for targeting older adult cancer patients.

Survival prediction post-cystectomy is essential for the follow-up care of bladder cancer patients. This study aimed to evaluate artificial intelligence (AI)-large language models (LLMs) for extracting clinical information and improving image analysis, with an initial application involving predicting five-year survival rates of patients after radical cystectomy for bladder cancer. Data were retrospectively collected from medical records and CT urograms (CTUs) of bladder cancer patients between 2001 and 2020. Of 781 patients, 163 underwent chemotherapy, had pre- and post-chemotherapy CTUs, underwent radical cystectomy, and had an available post-surgery five-year survival follow-up. Five AI-LLMs (Dolly-v2, Vicuna-13b, Llama-2.0-13b, GPT-3.5, and GPT-4.0) were used to extract clinical descriptors from each patient's medical records. As a reference standard, clinical descriptors were also extracted manually. Radiomics and deep learning descriptors were extracted from CTU images. The developed multi-modal predictive model, CRD, was based on the clinical (C), radiomics (R), and deep learning (D) descriptors. The LLM retrieval accuracy was assessed. The performances of the survival predictive models were evaluated using AUC and Kaplan-Meier analysis. For the 163 patients (mean age 64 ± 9 years; M:F 131:32), the LLMs achieved extraction accuracies of 74%~87% (Dolly), 76%~83% (Vicuna), 82%~93% (Llama), 85%~91% (GPT-3.5), and 94%~97% (GPT-4.0). For a test dataset of 64 patients, the CRD model achieved AUCs of 0.89 ± 0.04 (manually extracted information), 0.87 ± 0.05 (Dolly), 0.83 ± 0.06~0.84 ± 0.05 (Vicuna), 0.81 ± 0.06~0.86 ± 0.05 (Llama), 0.85 ± 0.05~0.88 ± 0.05 (GPT-3.5), and 0.87 ± 0.05~0.88 ± 0.05 (GPT-4.0). This study demonstrates the use of LLM model-extracted clinical information, in conjunction with imaging analysis, to improve the prediction of clinical outcomes, with bladder cancer as an initial example.

Although there has been a reduction in head and neck squamous cell carcinoma occurrence, it continues to be a serious global health concern. The lack of precise early diagnostic biomarkers and postponed diagnosis in the later stages are notable constraints that contribute to poor survival rates and emphasize the need for innovative diagnostic methods. In this study, we employed machine learning alongside weighted gene co-expression network analysis (WGCNA) and network biology to investigate the gene expression patterns of blood platelets, identifying transcriptomic markers for HNSCC diagnosis. Our comprehensive examination of publicly available gene expression datasets revealed nine genes with significantly elevated expression in samples from individuals diagnosed with HNSCC. These potential diagnostic markers were further assessed using TCGA and GTEx datasets, demonstrating high accuracy in distinguishing between HNSCC and non-cancerous samples. The findings indicate that these gene signatures could revolutionize early HNSCC identification. Additionally, the study highlights the significance of tumor-educated platelets (TEPs), which carry RNA signatures indicative of tumor-derived material, offering a non-invasive source for early-detection biomarkers. Despite using platelet and tumor samples from different individuals, our results suggest that TEPs reflect the transcriptomic and epigenetic landscape of tumors. Future research should aim to directly correlate tumor and platelet samples from the same patients to further elucidate this relationship. This study underscores the potential of these biomarkers in transforming early diagnosis and personalized treatment strategies for HNSCC, advocating for further research to validate their predictive and therapeutic potential.

Physical inactivity contributes to over 800,000 deaths annually. Numerous non-pharmacological interventions provide a route to address this behavioural risk factor linked to the growth of non-communicable diseases. Here, we consider a nature-based intervention, specifically group outdoor health walks (GOHW), as a non-pharmacological intervention to increase physical activity and contribute to health and quality of life amongst older adults. We used the theoretically grounded Capability, Opportunity, Motivation, and Behaviour (COM-B) model as a lens to examine interviews with participants in a GOHW with an activity tracker and signposted by health clinics in Scotland, UK. Analysis identified capabilities, opportunities, and motivations, their impact on behaviour, and perceived physical and mental health. The application of the COM-B model to intervention evaluation allowed us to examine two separate behaviours, that of (i) engaging with the intervention itself, and (ii) incorporating the behaviour into one's life that the intervention targets. Analysis identified emerging capabilities, opportunities, and motivations that supported additional health-promoting behaviours, including increased time outdoors in nature and leadership to self-organise continued group walks. We offer insight into the design of nature-based interventions to effectively engage older adults with chronic health conditions and foster personal behaviour change for health and well-being.

Background: Cancer-associated fibroblasts have become a new target for therapy. Fibroblasts present within malignancies express the fibroblast activation protein (FAP). Inhibitors to FAP (FAPI) are small molecules recently developed as a theranostic agents for imaging and radiotherapy. All currently used FAPI rely on a linker-chelator complex attached to the 'inhibitor'. We describe a new automated method of the direct attachment of the radioisotope to the inhibitor, resulting in a >50% MW reduction with the hope of an improved tumor-to-background ratio and tumor uptake., Methods: [ 18 F]FluroFAPI was developed from a Sn precursor. This allowed for subsequent automated radioflourination. We obtained the biodistribution of [ 18 F]FluroFAPI in rats, performed estimated human radiation dosimetry, and performed a 100× expected single dose toxicology analysis for eventual first-in-human experiments., Results: The synthesis of the Sn precursor for FluorFAPI and the automated synthesis of [ 18 F]FluroFAPI was demonstrated. [ 18 F]FluroFAPI had favorable estimated human radiation dosimetry, and demonstrated no adverse effects when injected at a dose of 100× that planned for [ 18 F]FluroFAPI., Conclusions: With the successful development of an automated synthesis of [ 18 F]FluroFAPI, first-in-human testing can be planned with the hope of an improved tumor-to-background performance compared to other FAPI agents.

This study presents a novel absorption cell with a circular geometry that can be integrated into microfluidic devices for optical spectroscopy applications. The absorption cell is made of PDMS/SU8 and offers an optical path length that is 8.5 times its diameter, resulting in a significant increase in the sensitivity of the measurements. Overall, this design provides a reliable and efficient solution for optical spectroscopy in microfluidic systems, enabling the precise detection and analysis of small quantities of analytes.

Rooted in dynamic systems theory, convergent cross mapping (CCM) has attracted increased attention recently due to its capability in detecting linear and nonlinear causal coupling in both random and deterministic settings. One limitation with CCM is that it uses both past and future values to predict the current value, which is inconsistent with the widely accepted definition of causality, where it is assumed that the future values of one process cannot influence the past of another. To overcome this obstacle, in our previous research, we introduced the concept of causalized convergent cross mapping (cCCM), where future values are no longer used to predict the current value. In this paper, we focus on the implementation of cCCM in causality analysis. More specifically, we demonstrate the effectiveness of cCCM in identifying both linear and nonlinear causal coupling in various settings through a large number of examples, including Gaussian random variables with additive noise, sinusoidal waveforms, autoregressive models, stochastic processes with a dominant spectral component embedded in noise, deterministic chaotic maps, and systems with memory, as well as experimental fMRI data. In particular, we analyze the impact of shadow manifold construction on the performance of cCCM and provide detailed guidelines on how to configure the key parameters of cCCM in different applications. Overall, our analysis indicates that cCCM is a promising and easy-to-implement tool for causality analysis in a wide spectrum of applications.

Background: Headache is among the most common symptoms following concussion, yet headache after concussion (HAC) remains poorly characterized. This study describes headache characteristics over the first four weeks following pediatric sport-related concussion., Methods: This is a retrospective case series of 87 athletes (mean: 14.9 years; range: 8.4-18.8 years; 38% female) treated in a specialty sports concussion clinic within 28 days of injury. Primary outcomes of headache consistency, frequency, duration, and associated migrainous symptoms were assessed at immediate (0 to 48 h) and weekly time points over the first 28 days post-injury. Generalized mixed linear models compared headache characteristics across time points. Secondary analyses compared each outcome by as-needed analgesic use., Results: During the immediate post-injury period, headache was more often constant ( p = 0.002) and associated with migrainous symptoms ( p < 0.001). By the third week post-injury, episodic headache was more prevalent ( p < 0.001). Most patients (54%) transitioned from constant, migrainous headache to episodic, non-migrainous headache. This finding was uninfluenced by as-needed analgesic medication use., Conclusions: These findings document the trajectory of HAC. Future studies should assess relationships between initial headache characteristics and recovery.

Choroideremia is an X-linked chorioretinal dystrophy caused by mutations in CHM , encoding Rab escort protein 1 (REP-1), leading to under-prenylation of Rab GTPases (Rabs). Despite ubiquitous expression of CHM , the phenotype is limited to degeneration of the retina, retinal pigment epithelium (RPE), and choroid, with evidence for primary pathology in RPE cells. However, the spectrum of under-prenylated Rabs in RPE cells and how they contribute to RPE dysfunction remain unknown. A CRISPR/Cas-9-edited CHM -/- iPSC-RPE model was generated with isogenic control cells. Unprenylated Rabs were biotinylated in vitro and identified by tandem mass tag (TMT) spectrometry. Rab12 was one of the least prenylated and has an established role in suppressing mTORC1 signaling and promoting autophagy. CHM -/- iPSC-RPE cells demonstrated increased mTORC1 signaling and reduced autophagic flux, consistent with Rab12 dysfunction. Autophagic flux was rescued in CHM -/- cells by transduction with gene replacement (ShH10-CMV- CHM ) and was reduced in control cells by siRNA knockdown of Rab12. This study supports Rab12 under-prenylation as an important cause of RPE cell dysfunction in choroideremia and highlights increased mTORC1 and reduced autophagy as potential disease pathways for further investigation.

On 11 September 2001, attacks on the World Trade Center (WTC) killed nearly three thousand people and exposed hundreds of thousands of rescue and recovery workers, passersby, area workers, and residents to varying amounts of dust and smoke. Former New York City Mayor Rudy Giuliani ordered the emergency evacuation of Lower Manhattan below Canal Street, but not all residents evacuated. Previous studies showed that those who did not evacuate had a higher incidence of newly diagnosed asthma. Among the 71,424 who enrolled in the WTC Health Registry in 2003-2004, we evaluated the bivariate association of educational attainment, household income, and race or ethnicity with reported evacuation on or after 9/11/01. We used log binomial regression to assess the relative risks of not evacuating from their home following the 9/11 attacks, adjusting for age, gender, and marital status. Out of a total of 11,871 enrollee residents of Lower Manhattan, 7345 or 61.79% reported evacuating their home on or after 9/11. In a fully adjusted model, the estimated relative risk for not evacuating was elevated for those who identified as non-Hispanic Black, Asian/Pacific Islander, and Hispanic residents compared to non-Hispanic White residents. Residents with a high school diploma/GED had an elevated estimated risk compared to those with at least a bachelor's degree. Those with lower household incomes had an elevated estimated risk compared to those with the highest income category. These significant inequities will need to be prevented in future disasters.

While recent advancements have been made towards a better understanding of the involvement of the prefrontal cortex (PFC) in the context of cognitive control, the exact mechanism is still not fully understood. Successful behavior requires the correct detection of goal-relevant cues and resisting irrelevant distractions. Frontal parietal networks have been implicated as important for maintaining cognitive control in the face of distraction. The present study investigated the role of gamma-band power in distraction resistance and frontoparietal networks, as its increase is linked to cholinergic activity. We examined changes in gamma activity and their relationship to frontoparietal top-down modulation for distractor challenges and to bottom-up distractor processing. Healthy young adults were tested using a modified version of the distractor condition sustained attention task (dSAT) while wearing an EEG. The modified distractor was designed so that oscillatory activities could be entrained to it, and the strength of entrainment was used to assess the degree of distraction. Increased top-down control during the distractor challenge increased gamma power in the left parietal regions rather than the right prefrontal regions predicted from rodent studies. Specifically, left parietal gamma power increased in response to distraction where the amount of this increase was negatively correlated with the neural activity reflecting bottom-up distractor processing in the visual area. Variability in gamma power in right prefrontal regions was associated with increased response time variability during distraction. This may suggest that the right prefrontal region may contribute to the signaling needed for top-down control rather than its implementation.

Early diagnosis of lung cancer can significantly improve patient outcomes. We developed a Growth Predictive model based on the Wasserstein Generative Adversarial Network framework (GP-WGAN) to predict the nodule growth patterns in the follow-up LDCT scans. The GP-WGAN was trained with a training set (N = 776) containing 1121 pairs of nodule images with about 1-year intervals and deployed to an independent test set of 450 nodules on baseline LDCT scans to predict nodule images (GP-nodules) in their 1-year follow-up scans. The 450 GP-nodules were finally classified as malignant or benign by a lung cancer risk prediction (LCRP) model, achieving a test AUC of 0.827 ± 0.028, which was comparable to the AUC of 0.862 ± 0.028 achieved by the same LCRP model classifying real follow-up nodule images ( p = 0.071). The net reclassification index yielded consistent outcomes (NRI = 0.04; p = 0.62). Other baseline methods, including Lung-RADS and the Brock model, achieved significantly lower performance ( p < 0.05). The results demonstrated that the GP-nodules predicted by our GP-WGAN model achieved comparable performance with the nodules in the real follow-up scans for lung cancer diagnosis, indicating the potential to detect lung cancer earlier when coupled with accelerated clinical management versus the current approach of waiting until the next screening exam.

People seeking asylum are susceptible to head injury (HI) due to exposure to various forms of violence including war, torture, or interpersonal violence. Yet, the extents to which clinicians assess HI, and if so, what the associated characteristics are, are not well known. We analyzed 200 U.S.-based medico-legal affidavits using descriptive, multivariate regression, and thematic analysis. Head injury was documented in 38% of affidavits. Those who experienced physical violence were eight times likelier to experience HI than those who did not experience physical violence. Five themes emerged: (1) HI occurred commonly in the context of interpersonal violence (44%), followed by militarized violence (33%); (2) mechanisms of HI included direct blows to the head and asphyxiation, suggesting potential for both traumatic brain injury and brain injury from oxygen deprivation; (3) HI was often recurrent and concurrent with other physical injuries; (4) co-morbid psychiatric and post-concussive symptoms made it challenging to assess neurological and psychiatric etiologies; and (5) overall, there was a paucity of assessments and documentation of HI and sequelae. Among individuals assessed for asylum claims, HI is common, often recurrent, occurring in the context of interpersonal violence, and concurrent with psychological and other physical trauma. Physical violence is an important risk factor for HI, which should be assessed when physical violence is reported.

Background: Social and Environmental Determinants of Health (SEDH) provide us with a conceptual framework to gain insights into possible associations among different human behaviors and the corresponding health outcomes that take place often in and around complex built environments. Developing better built environments requires an understanding of those aspects of a community that are most likely to have a measurable impact on the target SEDH. Yet data on local characteristics at suitable spatial scales are often unavailable. We aim to address this issue by application of different data disaggregation methods., Methods: We applied different approaches to data disaggregation to obtain small area estimates of key behavioral risk factors, as well as geospatial measures of green space access and walkability for each zip code of Allegheny County in southwestern Pennsylvania., Results: Tables and maps of local characteristics revealed their overall spatial distribution along with disparities therein across the county. While the top ranked zip codes by behavioral estimates generally have higher than the county's median individual income, this does not lead them to have higher than its median green space access or walkability., Conclusion: We demonstrated the utility of data disaggregation for addressing complex questions involving community-specific behavioral attributes and built environments with precision and rigor, which is especially useful for a diverse population. Thus, different types of data, when comparable at a common local scale, can provide key integrative insights for researchers and policymakers.