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Neuronal dysfunction and cognitive deterioration in Alzheimer's disease (AD) are likely caused by multiple pathophysiological factors. However, mechanistic evidence in humans remains scarce, requiring improved non-invasive techniques and integrative models. We introduce personalized AD computational models built on whole-brain Wilson-Cowan oscillators and incorporating resting-state functional MRI, amyloid-β (Aβ) and tau-PET from 132 individuals in the AD spectrum to evaluate the direct impact of toxic protein deposition on neuronal activity. This subject-specific approach uncovers key patho-mechanistic interactions, including synergistic Aβ and tau effects on cognitive impairment and neuronal excitability increases with disease progression. The data-derived neuronal excitability values strongly predict clinically relevant AD plasma biomarker concentrations (p-tau217, p-tau231, p-tau181, GFAP) and grey matter atrophy obtained through voxel-based morphometry. Furthermore, reconstructed EEG proxy quantities show the hallmark AD electrophysiological alterations (theta band activity enhancement and alpha reductions) which occur with Aβ-positivity and after limbic tau involvement. Microglial activation influences on neuronal activity are less definitive, potentially due to neuroimaging limitations in mapping neuroprotective vs detrimental activation phenotypes. Mechanistic brain activity models can further clarify intricate neurodegenerative processes and accelerate preventive/treatment interventions.

The molecular mechanisms underlying neuronal dysfunction in Alzheimer's disease (AD) remain uncharacterized. Here, we identify genes, molecular pathways and cellular components associated with whole-brain dysregulation caused by amyloid-beta (Aβ) and tau deposits in the living human brain. We obtained in-vivo resting-state functional MRI (rs-fMRI), Aβ- and tau-PET for 47 cognitively unimpaired and 16 AD participants from the Translational Biomarkers in Aging and Dementia cohort. Adverse neuronal activity impacts by Aβ and tau were quantified with personalized dynamical models by fitting pathology-mediated computational signals to the participant's real rs-fMRIs. Then, we detected robust brain-wide associations between the spatial profiles of Aβ-tau impacts and gene expression in the neurotypical transcriptome (Allen Human Brain Atlas). Within the obtained distinctive signature of in-vivo neuronal dysfunction, several genes have prominent roles in microglial activation and in interactions with Aβ and tau. Moreover, cellular vulnerability estimations revealed strong association of microglial expression patterns with Aβ and tau's synergistic impact on neuronal activity (q

Abstract Positron Emission Tomography (PET) ligands have advanced Alzheimer’s disease (AD) diagnosis and treatment. Using autoradiography and cryo-EM, we identify AD brain tissue with elevated tau burden, purify filaments, and determine the structure of second-generation high avidity PET ligand MK-6240 at 2.31 Å resolution, which bound at a 1:1 ratio within the cleft of tau paired-helical filament (PHF), engaging with glutamine 351, lysine 353, and isoleucine 360. This information elucidates the basis of MK-6240 PET in quantifying PHF deposits in AD and may facilitate the structure-based design of superior ligands against tau amyloids.

ImportanceNeuropsychiatric symptoms are commonly encountered and are highly debilitating in patients with Alzheimer disease. Understanding their underpinnings has implications for identifying biomarkers and treatment for these symptoms.ObjectiveTo evaluate whether glial markers are associated with neuropsychiatric symptoms in individuals across the Alzheimer disease continuum.Design, setting, and participantsThis cross-sectional study was conducted from January to June 2023, leveraging data from the Translational Biomarkers in Aging and Dementia cohort at McGill University, Canada. Recruitment was based on referrals of individuals from the community or from outpatient clinics. Exclusion criteria included active substance abuse, major surgery, recent head trauma, safety contraindications for positron emission tomography (PET) or magnetic resonance imaging, being currently enrolled in other studies, and having inadequately treated systemic conditions.Main outcomes and measuresAll individuals underwent assessment for neuropsychiatric symptoms (Neuropsychiatry Inventory Questionnaire [NPI-Q]), and imaging for microglial activation ([11C]PBR28 PET), amyloid-β ([18F]AZD4694 PET), and tau tangles ([18F]MK6240 PET).ResultsOf the 109 participants, 72 (66%) were women and 37 (34%) were men; the median age was 71.8 years (range, 38.0-86.5 years). Overall, 70 had no cognitive impairment and 39 had cognitive impairment (25 mild; 14 Alzheimer disease dementia). Amyloid-β PET positivity was present in 21 cognitively unimpaired individuals (30%) and in 31 cognitively impaired individuals (79%). The NPI-Q severity score was associated with microglial activation in the frontal, temporal, and parietal cortices (β = 7.37; 95% CI, 1.34-13.41; P = .01). A leave-one-out approach revealed that irritability was the NPI-Q domain most closely associated with the presence of brain microglial activation (β = 6.86; 95% CI, 1.77-11.95; P = .008). Furthermore, we found that microglia-associated irritability was associated with study partner burden measured by NPI-Q distress score (β = 5.72; 95% CI, 0.33-11.10; P = .03).Conclusions and relevanceIn this cross-sectional study of 109 individuals across the AD continuum, microglial activation was associated with and a potential biomarker of neuropsychiatric symptoms in Alzheimer disease. Moreover, our findings suggest that the combination of amyloid-β- and microglia-targeted therapies could have an impact on relieving these symptoms.

Abstract Background Females represent approximately 70% of the Alzheimer’s disease (AD) cases and the literature has proposed a connection between the decreased estrogen levels during menopause and an increased AD risk. Previous investigations have predominantly focused on assessing how hormone therapy (HT) affects the likelihood of AD development and cognitive deterioration. However, as the research framework has shifted toward a biomarker-defined AD and alterations in specific biomarkers could take place years before cognitive decline becomes discernible, it is crucial to examine how HT influences AD biomarkers. The main goal of this study was to evaluate the impact of HT on AD biomarker-informed pathophysiology in both cognitively unimpaired (CU) and cognitively impaired (CI) post-menopausal females across the aging and AD spectrum. Methods This cross-sectional study included post-menopausal females without HT history (HT-) and with HT (HT+) at the time of PET imaging assessment from two cohorts: the Translational Biomarkers in Aging and Dementia (TRIAD) cohort, and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Participants underwent magnetic resonance imaging (MRI), positron emission tomography (PET) and biofluid collection. Voxel-based t-tests were performed to assess the differences in amyloid-β (Aβ) and tau neurofibrillary tangles (NFTs) loads between HT- and HT + females. Linear regression models with interaction terms were also conducted to examine the interactive effects of HT and Aβ-PET on regional tau-PET. Results HT + females demonstrated significantly lower tau-PET standardized uptake value ratio (SUVR) in Braak I-II ROIs (P

Abstract Alzheimer’s disease (AD) is a brain network disorder where pathological proteins accumulate through networks and drive cognitive decline. Yet, the role of network connectivity in facilitating this accumulation remains unclear. Using in-vivo multimodal imaging, we show that the distribution of tau and reactive microglia in humans follows spatial patterns of connectivity variation, the so-called gradients of brain organization. Notably, less distinct connectivity patterns (“gradient contraction”) are associated with cognitive decline in regions with greater tau, suggesting an interaction between reduced network differentiation and tau on cognition. Furthermore, by modeling tau in subject-specific gradient space, we demonstrate that tau accumulation in the frontoparietal and temporo-occipital cortices is associated with greater baseline tau within their functionally and structurally connected hubs, respectively. Our work unveils a role for both functional and structural brain organization in pathology accumulation in AD, and supports subject-specific gradient space as a promising tool to map disease progression.

Due to the growing global demand for electricity energy, photovoltaic systems are becoming increasingly important as a continuous and environmentally friendly alternative. They ensure the continuity of electrical production in a healthy and sustainable manner. To ensure the efficiency and optimal performance of these systems, an effective diagnostic model is urgently needed to classify faulty and working solar cells. In recent years, deep learning methods have been used to analyse and process images, providing new insights and guidance in the field of fault diagnosis in PV systems. This research proposes a comparative study of the deep learning models ResNet50, VGG-19, and AlexNet to test their effectiveness in analysing and classifying defective solar cells from non-defective cells using EL images.

Background Postoperative computed tomography imaging surveillance is an essential component of care after acute type A aortic dissection (ATAAD) repair. Prognostic imaging factors after ATAAD repair have not been systematically reviewed. Methods and Results We performed a systematic review to summarize postoperative computed tomography measurements including aortic diameter, cross‐sectional area, volume, growth rate, and false lumen thrombosis in addition mid‐ to long‐term clinical outcomes after ATAAD repair. Searches were conducted in Medline, Embase, and CENTRAL in October 2022. Studies were included if they reported clinical outcomes such as mortality or aortic reintervention after 1 year and included aforementioned computed tomography findings. Studies of chronic aortic dissection and studies of exclusive patient populations such as those with connective tissue diseases were excluded. Risk of bias was assessed with the Newcastle‐Ottawa Scale. Searches retrieved 6999 articles. Sixty‐eight studies met inclusion criteria (7885 patients). Extended repairs were associated with improved false lumen thrombosis, decreased aortic growth rate, and decreased rates of reintervention but not improved survival. Growth rates of the aorta post‐ATAAD repair were highest in the descending thoracic aorta. The most frequent prognostic imaging factors reported were a patent/partially thrombosed false lumen and postoperative aortic diameter >40 to 45 mm. Conclusions Established measurements of positive aortic remodeling, including complete false lumen thrombosis and stabilization of postoperative aortic diameter and growth are the most studied prognostic indicators for improved clinical outcomes after ATAAD repair. Growth rate of the aorta remains significant after ATAAD repair. Future studies should prospectively evaluate and compare prognostic factors for improved surveillance and management.

Abstract Entanglement plays a vital role in quantum information processing. Owing to its unique material properties, silicon carbide recently emerged as a promising candidate for the scalable implementation of advanced quantum information processing capabilities. To date, however, only entanglement of nuclear spins has been reported in silicon carbide, while an entangled photon source, whether it is based on bulk or chip-scale technologies, has remained elusive. Here, we report the demonstration of an entangled photon source in an integrated silicon carbide platform for the first time. Specifically, strongly correlated photon pairs are efficiently generated at the telecom C-band wavelength through implementing spontaneous four-wave mixing in a compact microring resonator in the 4H-silicon-carbide-on-insulator platform. The maximum coincidence-to-accidental ratio exceeds 600 at a pump power of 0.17 mW, corresponding to a pair generation rate of (9 ± 1) × 103 pairs/s. Energy-time entanglement is created and verified for such signal-idler photon pairs, with the two-photon interference fringes exhibiting a visibility larger than 99%. The heralded single-photon properties are also measured, with the heralded g (2)(0) on the order of 10−3, demonstrating the SiC platform as a prospective fully integrated, complementary metal-oxide-semiconductor compatible single-photon source for quantum applications.

Abstract Neuronal dysfunction and cognitive deterioration in Alzheimer’s disease (AD) are likely caused by multiple pathophysiological factors. However, mechanistic evidence in humans remains scarce, requiring improved non-invasive techniques and integrative models. We introduce personalized AD computational models built on whole-brain Wilson-Cowan oscillators and incorporating resting-state functional MRI, amyloid-β (Aβ) and tau-PET from 132 individuals in the AD spectrum to evaluate the direct impact of toxic protein deposition on neuronal activity. This subject-specific approach uncovers key patho-mechanistic interactions, including synergistic Aβ and tau effects on cognitive impairment and neuronal excitability increases with disease progression. The data-derived neuronal excitability values strongly predict clinically relevant AD plasma biomarker concentrations (p-tau217, p-tau231, p-tau181, GFAP) and grey matter atrophy obtained through voxel-based morphometry. Furthermore, reconstructed EEG proxy quantities show the hallmark AD electrophysiological alterations (theta band activity enhancement and alpha reductions) which occur with Aβ-positivity and after limbic tau involvement. Microglial activation influences on neuronal activity are less definitive, potentially due to neuroimaging limitations in mapping neuroprotective vs detrimental activation phenotypes. Mechanistic brain activity models can further clarify intricate neurodegenerative processes and accelerate preventive/treatment interventions.

Abstract Blood-based biomarkers for screening may guide tau positrion emissition tomography (PET) scan referrals to optimize prognostic evaluation in Alzheimer’s disease. Plasma Aβ42/Aβ40, pTau181, pTau217, pTau231, NfL, and GFAP were measured along with tau-PET in memory clinic patients with subjective cognitive decline, mild cognitive impairment or dementia, in the Swedish BioFINDER-2 study (n = 548) and in the TRIAD study (n = 179). For each plasma biomarker, cutoffs were determined for 90%, 95%, or 97.5% sensitivity to detect tau-PET-positivity. We calculated the percentage of patients below the cutoffs (who would not undergo tau-PET; “saved scans”) and the tau-PET-positivity rate among participants above the cutoffs (who would undergo tau-PET; “positive predictive value”). Generally, plasma pTau217 performed best. At the 95% sensitivity cutoff in both cohorts, pTau217 resulted in avoiding nearly half tau-PET scans, with a tau-PET-positivity rate among those who would be referred for a scan around 70%. And although tau-PET was strongly associated with subsequent cognitive decline, in BioFINDER-2 it predicted cognitive decline only among individuals above the referral cutoff on plasma pTau217, supporting that this workflow could reduce prognostically uninformative tau-PET scans. In conclusion, plasma pTau217 may guide selection of patients for tau-PET, when accurate prognostic information is of clinical value.

BackgroundTelehealth studies have highlighted the positive benefits of having the service in rural areas. However, there is evidence of limited adoption and utilization. Our objective was to evaluate this gap by exploring U.S. healthcare systems' experience in implementing telehealth services in rural hospital emergency departments (TeleED) and by analyzing factors influencing its implementation and sustainability.MethodsWe conducted semi-structured interviews with 18 key informants from six U.S. healthcare systems (hub sites) that provided TeleED services to 65 rural emergency departments (spoke sites). All used synchronous high-definition video to provide the service. We applied an inductive qualitative analysis approach to identify relevant quotes and themes related to TeleED service uptake facilitators and barriers.ResultsWe identified three stages of implementation: 1) the start-up stage; 2) the utilization stage; and 3) the sustainment stage. At each stage, we identified emerging factors that can facilitate or impede the process. We categorized these factors into eight domains: 1) strategies; 2) capability; 3) relationships; 4) financials; 5) protocols; 6) environment; 7) service characteristics; and 8) accountability.ConclusionsThe implementation of healthcare innovation can be influenced by multiple factors. Our study contributes to the field by highlighting key factors and domains that play roles in specific stages of telehealth operation in rural hospitals. By appreciating and responding to these domains, healthcare systems may achieve more predictable and favorable implementation outcomes. Moreover, we recommend strategies to motivate the diffusion of promising innovations such as telehealth.

In this investigation, novel cellulose fibers were acquired from the Bassia Indica plant to serve as a reinforcement source in composite materials. The morphological characteristics were studied using Scanning Electron Microscopy (SEM). The surface chemistry, crystallinity, and functional groups of Bassia Indica fibers were analyzed using X-ray Diffraction (XRD), Energy Dispersive X-ray (EDX) spectroscopy, and Attenuated Total Reflectance-Fourier Transform Infrared spectroscopy (ATR-FTIR), which assess the crystal structure, elemental composition, and surface functional groups, respectively. The thermal behavior of Bassia Indica fibers were assessed through Thermogravimetric Analysis (TGA). Anatomical techniques demonstrated the abundant presence of fibroblasts in the fibers. The presence of lignocellulosic fiber (lignin, cellulose and hemicellulose) was confirmed through ATR-FTIR analysis. The analysis of physical properties unveiled a fiber density of 1.065 ± 0.025 g/cm³ and a diameter of 145.58 ± 7.89 μm. The crystalline size of Bassia Indica fibers reached 2.23 nm, with a crystallinity index of 40.12 %, and an activation energy of 93.78 kJ/mol, TGA research revealed that Bassia Indica fibers are thermally stable up to 260.24 °C. Additionally, the fibers experienced maximum degradation at 321.23 °C. Weibull statistical analysis was performed using parameters 2 and 3 to calculate the observed dispersion in the experimental tensile results after analyzing the mechanical properties of the fibers possessing a tensile strength of 417.50 ± 7.08 MPa, Young's modulus of 17.46 ± 1.55 GPa, stress at failure of 1.17 ± 0.02 % and interfacial shear strength of 6.99 ± 1.10 MPa. The results were additionally compared to how they were stated in the relevant sources. Bassia Indica fibers can be considered a viable choice for reinforcing lightweight bio-composites.

Solar ovens are eco-friendly ovens that use solar energy, a clean, sustainable and above all free source of energy. In the context of the economic and environmental crises facing the world today, solar cookers are considered a good alternative to electric cookers or those based on wood combustion. Several types of solar cooker have been developed in recent years. However, the box type remains the most efficient and simplest. To this end, an experimental study of three types of box-type solar cookers (triangle, trapezoid and rectangle) was carried out in this work. For each type of solar cooker, the effect of the number of reflectors added to the Cookers system was examined. The experimental tests were carried out in August 2023 under the climatic conditions of Morocco's eastern region. The evaluation of the systems studied is based on the hourly evolution of air, absorber and load temperatures for each type of solar furnace in different cases. Thermal photos were also taken using a Dia-Cam thermal imaging camera to visualize temperature distribution and analyze the thermal behavior of the systems. The obtained results show that the thermal behavior of three solar furnaces and the evolution of the absorber temperature depend on the load used. In addition, a significant improvement in absorber temperature and water boiling time was observed with the addition of solar reflectors. For example, the absorber temperature was increased by up to 40 °C and the water boiling time was reduced by more than 120 min in the case of triangle-type furnaces.