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The aberrant assembly of amyloid-ß (Aß) is implicated in Alzheimer's disease (AD). Recent clinical outcomes of Aß-targeted immunotherapy reinforce the notion that clearing Aß burden is a potential therapeutic approach for AD. Herein, to develop drug candidates for chemically driven clearance of Aß aggregates, we synthesized 51 novel polyfunctionalized furo[2,3-b:4,5-b']dipyridine-chalcone hybrid compounds. After conducting two types of cell-free anti-Aß functional assays, Aß aggregation prevention and Aß aggregate clearance, we selected YIAD-0336, (E)-8-((1H-pyrrol-2-yl)methylene)-10-(4-chlorophenyl)-2,4-dimethyl-7,8-dihydropyrido[3',2':4,5]furo[3,2-b]quinolin-9(6H)-one, for further in vivo investigations. As YIAD-0336 exhibited a low blood-brain barrier penetration profile, it was injected along with aggregated Aß directly into the intracerebroventricular region of ICR mice and ameliorated spatial memory in Y-maze tests. Next, YIAD-0336 was orally administered to 5XFAD transgenic mice with intravenous injections of mannitol, and YIAD-0336 significantly removed Aß plaques from the brains of 5XFAD mice. Collectively, YIAD-0336 dissociated toxic aggregates in the mouse brain and hence alleviated cognitive deterioration. Our findings indicate that chemically driven clearance of Aß aggregates is a promising therapeutic approach for AD.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Modelos Animales de Enfermedad , Ratones Transgénicos , Animales , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Ratones , Péptidos beta-Amiloides/metabolismo , Chalcona/química , Chalcona/farmacología , Chalcona/análogos & derivados , Chalconas/química , Chalconas/farmacología , Chalconas/administración & dosificación , Masculino , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Humanos , Memoria/efectos de los fármacos , Agregado de Proteínas/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/efectos de los fármacos , Aprendizaje por Laberinto/efectos de los fármacos , Piridinas/química , Piridinas/farmacología , Piridinas/administración & dosificaciónRESUMEN
BACKGROUND CONTEXT: Cross-modality image generation from magnetic resonance (MR) to positron emission tomography (PET) using the generative model can be expected to have complementary effects by addressing the limitations and maximizing the advantages inherent in each modality. PURPOSE: This study aims to generate synthetic PET/MR fusion images from MR images using a combination of generative adversarial networks (GANs) and conditional denoising diffusion probabilistic models (cDDPMs) based on simultaneous 18F-fluorodeoxyglucose (18F-FDG) PET/MR image data. STUDY DESIGN: Retrospective study with prospectively collected clinical and radiological data. PATIENT SAMPLE: This study included 94 patients (60 men and 34 women) with thoraco-lumbar pyogenic spondylodiscitis (PSD) from February 2017 to January 2020 in a single tertiary institution. OUTCOME MEASURES: Quantitative and qualitative image similarity were analyzed between the real and synthetic PET/ T2-weighted fat saturation MR (T2FS) fusion images on the test data set. METHODS: We used paired spinal sagittal T2FS and PET/T2FS fusion images of simultaneous 18F-FDG PET/MR imaging examination in patients with PSD, which were employed to generate synthetic PET/T2FS fusion images from T2FS images using a combination of Pix2Pix (U-Net generator + Least Squares GANs discriminator) and cDDPMs algorithms. In the analyses of image similarity between the real and synthetic PET/T2FS fusion images, we adopted the values of mean peak signal to noise ratio (PSNR), mean structural similarity measurement (SSIM), mean absolute error (MAE), and mean squared error (MSE) for quantitative analysis, while the discrimination accuracy by three spine surgeons was applied for qualitative analysis. RESULTS: Total of 2,082 pairs of T2FS and PET/T2FS fusion images were obtained from 172 examinations on 94 patients, which were randomly assigned to training, validation, and test data sets in 8:1:1 ratio (1664, 209, and 209 pairs). The quantitative analysis revealed PSNR of 30.634 ± 3.437, SSIM of 0.910 ± 0.067, MAE of 0.017 ± 0.008, and MSE of 0.001 ± 0.001, respectively. The values of PSNR, MAE, and MSE significantly decreased as FDG uptake increased in real PET/T2FS fusion image, with no significant correlation on SSIM. In the qualitative analysis, the overall discrimination accuracy between real and synthetic PET/T2FS fusion images was 47.4%. CONCLUSIONS: The combination of Pix2Pix and cDDPMs demonstrated the potential for cross-modal image generation from MR to PET images, with reliable quantitative and qualitative image similarities.
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Discitis , Fluorodesoxiglucosa F18 , Imagen por Resonancia Magnética , Tomografía de Emisión de Positrones , Humanos , Femenino , Masculino , Persona de Mediana Edad , Discitis/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Estudios Retrospectivos , Tomografía de Emisión de Positrones/métodos , Anciano , Adulto , Imagen Multimodal/métodos , Modelos Estadísticos , Radiofármacos , Procesamiento de Imagen Asistido por Computador/métodosRESUMEN
Case management is a widely utilized service in both youth and adult outpatient community mental health settings. Despite its widespread use, previous findings suggest that youth case management often lacks empirically tested models or frameworks. This article presents the results of a pilot study that involved adapting the Strengths Model, an adult case management model, for the child and adolescent outpatient community mental health population. The newly adapted model, known as the Strengths Model for Youth (SM-Y), was implemented in an urban community mental health center across five different youth case management teams. To assess changes over time in youth receiving SM-Y case management, marginal maximum likelihood multilevel modeling with adaptive Gaussian quadrature methods was applied. The study focused on three domains: socialization, education, and hospitalization. Utilizing the logit link function and Bernoulli conditional distribution due to the binary nature of the outcome data, three individual trajectories were drawn for socialization, education, and hospitalization. Positive findings indicated increases in socialization and educational performance among children and adolescents.
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Manejo de Caso , Humanos , Adolescente , Masculino , Femenino , Niño , Proyectos Piloto , Hospitalización/estadística & datos numéricos , Servicios Comunitarios de Salud Mental , Socialización , Trastornos Mentales/terapia , Trastornos Mentales/psicología , EscolaridadRESUMEN
BACKGROUND: Gaps exist in understanding how to create and conduct culturally responsive evaluations. This information is particularly critical when working with evidence-based programs and when involving populations that have and continue to experience oppression and trauma. OBJECTIVE: We share our story of developing and carrying out a culturally responsive evaluation of an EBP, Strengthening Families Program (SFP), with Indigenous families. PARTICIPANTS AND SETTING: A collective storytelling approach was used based on reflections from the evaluation team and key implementation staff. METHODS: We used a collective storytelling approach, organizing the content around six previously identified principles of Indigenous research (Tsosie et al., 2022). RESULTS: Emerging themes, supported by quotes throughout, illustrate the importance of organizing the integration of culture into the evaluation through the six principles of Indigenous research: respect, relationship, relevance, reciprocity, responsibility, and representation. CONCLUSION: Working toward a culturally responsive evaluation allowed for the creation of more meaningful connections with Indigenous community partners and families. It also acknowledged insights that partners and families bring to the work and encouraged multi-directional learning to occur between evaluators, partners, and families.
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Aprendizaje , Grupos de Población , HumanosRESUMEN
BACKGROUND: Child welfare agencies commonly seek to use evidence-based programs (EBPs) for their demonstrated results. Challenges remain in adapting programs to fit for Indigenous populations. We suggest that relationality holds promise as a guide in the implementation of EBPs with Indigenous families and children. OBJECTIVE: We provide the story of a culturally integrated implementation of the EBP, Strengthening Families Program (SFP), with Indigenous families. PARTICIPANTS AND SETTING: Insights from the staff who implemented SFP, project leadership and a community steering committee were brought together to create the collective implementation story. METHODS: A relational approach was used in thematic analysis with a focus on the three Rs - responsibility, respect, and reciprocity- that support Indigenous knowledge organization. RESULTS: Findings offer insight into cultural integrations in the implementation of SFP. The program centered Indigenous and community identities through meals, gifts, parenting practice examples and discussions tailored by each group of families and staff. Practices related to responsibility, respect and reciprocity each proved to be essential concepts in the relationship building among caregivers, children, SFP staff, project leadership, and community supporters that led to program success. CONCLUSION: Cultural integration created a space that reflected Indigenous knowledge relationality. It respected the uniqueness among groups of families who participated in the evidence-based SFP. Our story supports the importance of having Indigenous staff and group leaders to guide cultural integration in relationship with tribal communities.
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Servicios de Salud del Indígena , Grupos de Población , Niño , Humanos , Responsabilidad Parental , Pueblos IndígenasRESUMEN
A highly efficient Friedel-Crafts type hydroxyalkylation at the C3 position of indolizines with (hetero)arylglyoxals has been achieved by the action of hexafluoroisopropanol (HFIP) under mild reaction conditions, leading to direct access to a variety of polyfunctionalized indolizines in excellent yields. Installation of more diverse functional groups at the C3 site of indolizine scaffold was realized via further elaboration of the resulting α-hydroxyketone moiety, allowing for expansion of indolizine chemical space.
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Consumer credit score has been used as an indicator of financial strain that could potentially impact health. Subjective financial well-being, or one's feelings about one's expectations, preferences, and satisfaction with their financial situation, is related to financial strain. This study examined whether subjective financial well-being mediates the association between credit score and self-reported physical health in a national representative sample. Using structural equation modeling (SEM), we test whether a mediating association exists between self-rated credit score and self-rated physical health. Results suggest that, after controlling for sociodemographic variables, those who reported higher credit scores have better health (ß = 0.175, p < .001) and higher financial well-being (ß = 0.469, p < .001), and those who reported higher financial well-being have better health (ß = 0.265, p < .001). The mediation effect of financial well-being on the association between credit and physical health is also positive and statistically significant (ß = 0.299, p < .001). Thus, subjective feelings about one's financial situation would enhance the observed positive association between credit and health. Practice and policy implications are included.
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Estrés Financiero , Estado de Salud , Humanos , AutoinformeRESUMEN
Perivascular spaces (PVS) in the human brain are related to various brain diseases. However, it is difficult to quantify them due to their thin and blurry appearance. In this paper, we introduce a deep-learning-based method, which can enhance a magnetic resonance (MR) image to better visualize the PVS. To accurately predict the enhanced image, we propose a very deep 3D convolutional neural network that contains densely connected networks with skip connections. The proposed networks can utilize rich contextual information derived from low-level to high-level features and effectively alleviate the gradient vanishing problem caused by the deep layers. The proposed method is evaluated on 17 7T MR images by a twofold cross-validation. The experiments show that our proposed network is much more effective to enhance the PVS than the previous PVS enhancement methods.