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INTRODUCTION: Down Syndrome Regression Disorder (DSRD) is a neuropsychiatric condition causing insomnia, catatonia, encephalopathy, and obsessive-compulsive behavior in otherwise healthy individuals with Down syndrome (DS). Smaller cohorts have identified heterogenous diagnostic abnormalities which have predicted immunotherapy responsiveness although pattern analysis in a large cohort has never been performed. METHODS: A multi-center, retrospective study of individuals with DSRD was performed. Individuals met international consensus criteria for DRSD and were aged 10-30 years. Clinical, demographic, and diagnostic data was extracted for all individuals. Serum studies were compared to a group of individuals with DS only. RESULTS: A total of 164 individuals with DSRD were identified. Individuals with DSRD were more likely to have a positive antinuclear antibody, low complement 3, abnormal cytokines, and elevated ferritin levels. In a minority of individuals, EEG (30%), MRI (33%) and cerebrospinal fluid (CSF) (21%) were abnormal. Individuals with CSF abnormalities demonstrated greater disease severity at diagnosis on the BFCRS and NPI-Q (p = 0.02 and p

White matter hyperintensities of presumed vascular origin (WMH) are associated with cognitive impairment and are a key imaging marker in evaluating brain health. However, WMH volume alone does not fully account for the extent of cognitive deficits and the mechanisms linking WMH to these deficits remain unclear. Lesion network mapping (LNM) enables us to infer if brain networks are connected to lesions and could be a promising technique for enhancing our understanding of the role of WMH in cognitive disorders. Our study employed LNM to test the following hypotheses: (i) LNM-informed markers surpass WMH volumes in predicting cognitive performance; and (ii) WMH contributing to cognitive impairment map to specific brain networks. We analysed cross-sectional data of 3485 patients from 10 memory clinic cohorts within the Meta VCI Map Consortium, using harmonized test results in four cognitive domains and WMH segmentations. WMH segmentations were registered to a standard space and mapped onto existing normative structural and functional brain connectome data. We employed LNM to quantify WMH connectivity to 480 atlas-based grey and white matter regions of interest (ROI), resulting in ROI-level structural and functional LNM scores. We compared the capacity of total and regional WMH volumes and LNM scores in predicting cognitive function using ridge regression models in a nested cross-validation. LNM scores predicted performance in three cognitive domains (attention/executive function, information processing speed, and verbal memory) significantly better than WMH volumes. LNM scores did not improve prediction for language functions. ROI-level analysis revealed that higher LNM scores, representing greater connectivity to WMH, in grey and white matter regions of the dorsal and ventral attention networks were associated with lower cognitive performance. Measures of WMH-related brain network connectivity significantly improve the prediction of current cognitive performance in memory clinic patients compared to WMH volume as a traditional imaging marker of cerebrovascular disease. This highlights the crucial role of network integrity, particularly in attention-related brain regions, improving our understanding of vascular contributions to cognitive impairment. Moving forward, refining WMH information with connectivity data could contribute to patient-tailored therapeutic interventions and facilitate the identification of subgroups at risk of cognitive disorders.

BackgroundIndividuals with Down syndrome (DS) are at high risk of early-onset Alzheimer's disease (AD); yet, some 20 percent do not develop any signs of dementia until after 65 years or in their lifetime. Mosaicism could contribute to this phenotypic variation, where some disomic cells could lead to lower levels of gene products from chromosome 21.MethodsWe examined longitudinal neuropsychological and biomarker data from two large studies of DS: the Alzheimer Biomarker Consortium-Down syndrome study (ABC-DS) (n = 357); and a legacy study (n = 468). We assessed mosaicism using karyotyping or GWAS data. Participants had data on plasma AD biomarkers (Aβ40, Aβ42, tau, and NfL) and longitudinal cognitive measures. A subset had cerebrospinal fluid biomarkers (Aβ40, Aβ42, tau, ptau181, and NfL) and amyloid and tau PET data.FindingsFor both cohorts, the prevalence of mosaicism was

INTRODUCTION: Development of Alzheimers disease (AD) pathology in Downs syndrome (DS) occurs within a compressed timeline compared to sporadic or other genetic forms of AD. METHODS: Plasma glial fibrillary acidic protein (GFAP) and plasma pTau-217 levels were compared by AD pathophysiology (amyloid (A+) and tau (T+) positron emission tomography [PET]) in persons with DS (N = 348) and sibling controls (N = 42). Plasma GFAP, plasma pTau-217, amyloid-PET, and tau-PET levels were compared with regard to estimated years to onset of clinical symptoms (52.5 years old). We evaluated if plasma GFAP mediated the relationship between amyloid PET and plasma pTau-217 or tau PET. RESULTS: Plasma GFAP, a measure of astrogliosis, was elevated in A+/T- and A+/T+ individuals with DS. Plasma pTau-217 was elevated in A+/T+ individuals with DS. GFAP partially mediated the relationship between amyloid-PET and tau-PET (15.3%) and amyloid-PET and plasma pTau-217 (42.1%). DISCUSSION: Astrogliosis is a key component in the advancement of preclinical AD pathophysiology in DS. HIGHLIGHTS: Amyloid may be a necessary precursor for stimulating astrocytes. Astrogliosis may play a key role in modifications to tau phosphorylation. Targeting neuroinflammation may only aid amyloid positive individuals. Alzheimers disease timecourse is compressed in individuals with Downs syndrome.

By age 40 years, over 90% of adults with Down syndrome have Alzheimer's disease pathology and most progress to dementia. Despite having few systemic vascular risk factors, individuals with Down syndrome have elevated cerebrovascular disease markers that track with the clinical progression of Alzheimer's disease, suggesting a role of cerebrovascular disease that is hypothesized to be mediated by inflammatory factors. This study examined the pathways through which small vessel cerebrovascular disease contributes to Alzheimer's disease-related pathophysiology and neurodegeneration in adults with Down syndrome. One hundred eighty-five participants from the Alzheimer's Biomarkers Consortium-Down Syndrome [mean (SD) age = 45.2 (9.3) years] with available MRI and plasma biomarker data were included in this study. White matter hyperintensity (WMH) volumes were derived from T2-weighted fluid-attenuated inversion recovery MRI scans, and plasma biomarker concentrations of amyloid beta 42/40, phosphorylated tau 217, astrocytosis (glial fibrillary acidic protein) and neurodegeneration (neurofilament light chain) were measured with ultrasensitive immunoassays. We examined the bivariate relationships of WMH, amyloid beta 42/40, phosphorylated tau 217 and glial fibrillary acidic protein with age-residualized neurofilament light chain across Alzheimer's disease diagnostic groups. A series of mediation and path analyses examined statistical pathways linking WMH and Alzheimer's disease pathophysiology to promote neurodegeneration in the total sample and groups stratified by clinical diagnosis. There was a direct and indirect bidirectional effect through the glial fibrillary acidic protein of WMH on phosphorylated tau 217 concentration, which was associated with neurofilament light chain concentration in the entire sample. Amongst cognitively stable participants, WMH was directly and indirectly, through glial fibrillary acidic protein, associated with phosphorylated tau 217 concentration, and in those with mild cognitive impairment, there was a direct effect of WMH on phosphorylated tau 217 and neurofilament light chain concentrations. There were no associations of WMH with biomarker concentrations among those diagnosed with dementia. The findings from this cross-sectional study suggest that among individuals with Down syndrome, cerebrovascular disease promotes neurodegeneration by increasing astrocytosis and tau pathophysiology in the presymptomatic phases of Alzheimer's disease, but future studies will need to confirm these associations with longitudinal data. This work joins an emerging literature that implicates cerebrovascular disease and its interface with neuroinflammation as a core pathological feature of Alzheimer's disease in adults with Down syndrome.

Plasticity among cell lineages is a fundamental, but poorly understood, property of regenerative tissues. In the gut tube, the small intestine absorbs nutrients, whereas the colon absorbs electrolytes. In a striking display of inherent plasticity, adult colonic mucosa lacking the chromatin factor SATB2 is converted to small intestine. Using proteomics and CRISPR-Cas9 screening, we identify MTA2 as a crucial component of the molecular machinery that, together with SATB2, restrains colonic plasticity. MTA2 loss in the adult mouse colon activated lipid absorptive genes and functional lipid uptake. Mechanistically, MTA2 co-occupies DNA with HNF4A, an activating pan-intestinal transcription factor (TF), on colonic chromatin. MTA2 loss leads to HNF4A release from colonic chromatin, and accumulation on small intestinal chromatin. SATB2 similarly restrains colonic plasticity through an HNF4A-dependent mechanism. Our study provides a generalizable model of lineage plasticity in which broadly-expressed TFs are retained on tissue-specific enhancers to maintain cell identity and prevent activation of alternative lineages, and their release unleashes plasticity.

IntroductionAlthough dementia-related proteinopathy has a strong negative impact on public health, and is highly heritable, understanding of the related genetic architecture is incomplete.MethodsWe applied multidimensional generalized partial credit modeling (GPCM) to test genetic associations with dementia-related proteinopathies. Data were analyzed to identify candidate single nucleotide variants for the following proteinopathies: Aβ, tau, α-synuclein, and TDP-43.ResultsFinal included data comprised 966 participants with neuropathologic and WGS data. Three continuous latent outcomes were constructed, corresponding to TDP-43-, Aβ/Tau-, and α-synuclein-related neuropathology endophenotype scores. This approach helped validate known genotype/phenotype associations: for example, TMEM106B and GRN were risk alleles for TDP-43 pathology; and GBA for α-synuclein/Lewy bodies. Novel suggestive proteinopathy-linked alleles were also discovered, including several (SDHAF1, TMEM68, and ARHGEF28) with colocalization analyses and/or high degrees of biologic credibility.DiscussionA novel methodology using GPCM enabled insights into gene candidates for driving misfolded proteinopathies.HighlightsLatent factor scores for proteinopathies were estimated using a generalized partial credit model. The three latent continuous scores corresponded well with proteinopathy severity. Novel genes associated with proteinopathies were identified. Several genes had high degrees of biologic credibility for dementia risk factors.

Abstract Characterization of the vascular heterogeneity within the pancreas has previously been lacking. Here, we develop strategies to enrich islet-specific endothelial cells (ISECs) and acinar-specific endothelial cells (ASECs) from three human pancreases and corroborate these findings with three published pancreatic datasets. Single-cell RNA sequencing reveals the unique molecular signatures of ISECs, including structural genes COL13A1, ESM1, PLVAP, UNC5B, and LAMA4, angiocrine genes KDR, THBS1, BMPs and CXCR4, and metabolic genes ACE, PASK and F2RL3. ASECs display distinct signatures including GPIHBP1, CCL14, CD74, AQP1, KLF4, and KLF2, which may manage the inflammatory and metabolic needs of the exocrine pancreas. Ligand-receptor analysis suggests ISECs and ASECs interact with LUM+ fibroblasts and RGS5+ pericytes and smooth muscle cells via VEGF-A:VEGFR2, CXCL12:CXCR4, and LIF:LIFR pathways. Comparative expression and immunohistochemistry indicate disruption of endothelial-expressed CD74, ESM1, PLVAP, THBD, VWA1, and VEGF-A cross-talk among vascular and other cell types in diabetes. Thus, our data provide a single-cell vascular atlas of human pancreas, enabling deeper understanding of pancreatic pathophysiology in health and disease.

Abstract Background Older adults receiving home care often face significant safety risks related to medication management due to their chronic diseases and complex health needs. Despite the increasing reliance on home healthcare services, the specific factors contributing to medication safety risks in this demographic remain inadequately explored. Objective/Aim This study aims to explore the key factors involved in medication safety risks among older adults with chronic diseases receiving home healthcare in Iran. Methods Qualitative research employing conventional content analysis was conducted using Graneheim and Lundman’s approach. was conducted in three home care centers in Tehran (Iran) from August 2020 to July 2022. Data were collected through semi-structured interviews with 7 nurses, 2 supervisors, 2 nursing assistants (experts in non-nursing careers), 1 home care inspector (expert of the Deputy of Treatment), and 3 family caregivers in home settings, along with four participatory observations and visual methods (narrative photography) focusing on medication safety challenges. The trustworthiness of the research was evaluated using Lincoln and Guba’s four criteria for qualitative studies. Findings Factors associated with medication safety risks were found to rely on its major components Patients’ attribution, Families’ characteristics, Home care centers’ condition, Health caregivers’ characteristics, and the Homes’ situations, where these factors all account for various medication safety risks. Indeed, a medication safety risk can be attributed to more than one of the factors associated with medication safety risk by participants at home. Conclusion As a result, the analysis of factors associated with medication safety risks highlights a complex interplay among various elements, including patients, families, home care centers, health caregivers, and the home environment. These interconnected factors are crucial for identifying the diverse medication safety challenges faced by participants in home settings. A comprehensive understanding of these dynamics is essential for improving medication safety protocols and enhancing health outcomes for this vulnerable population.

In the past decade, open-air burning of rice husks has negatively impacted the environment and human health, particularly in developing and underdeveloped nations. Consequently, the present study established a sustainable and environmentally friendly method of manufacturing zinc oxide nanoparticles (ZnO NPs) from Oryza sativa rice husks using different concentrations of the precursor. The ZnO NPs obtained were analysed with an ultraviolet-visible (UV-Vis) spectrophotometer, which revealed a characteristic ZnO NPs band at 410 nm. Based on Debye-Scherrer’s equation, the ZnO NPs crystallites had a mean size of 20 nm. The Fourier-transform infrared (FTIR) spectra of the ZnO NPs were determined within the 400 to 4000 cm−1 range. The peak at 487 cm−1 indicated that a Zn-O bond was formed. A developed material further evaluated the antibacterial effectiveness of ZnO NPs against four harmful bacteria, demonstrating a moderate level of effectiveness. The findings indicated that all the tested bacteria exhibited heightened susceptibility to ZnO NPs at a higher concentration of 250 μg/mL.

BACKGROUND: Plasma levels of vitamin D have been reported to be low in persons with Down syndrome (DS) and existing data is limited to small and homogenous cohorts. This is of particular importance in persons with DS given the high rates of autoimmune disease in this population and the known relationship between vitamin D and immune function. This study sought to investigate vitamin D status in a multi-center cohort of individuals with DS and compare them to individuals with autism spectrum disorder (ASD) and neurotypical (NT) controls. METHODS: A retrospective, multi-center review was performed. The three sites were located at latitudes of 42.361145, 37.44466, and 34.05349. Patients were identified by the International Classification of Diseases (ICD)-9 or ICD-10 codes for DS, ASD, or well-child check visits for NT individuals. The first vitamin D 25-OH level recorded in the electronic medical record (EMR) was used in this study as it was felt to be the most reflective of a natural and non-supplemented state. Vitamin D 25-OH levels below 30 ng/mL were considered deficient. RESULTS: In total, 1624 individuals with DS, 5208 with ASD, and 30,775 NT controls were identified. Individuals with DS had the lowest mean level of vitamin D 25-OH at 20.67 ng/mL, compared to those with ASD (23.48 ng/mL) and NT controls (29.20 ng/mL) (p < 0.001, 95% CI: -8.97 to -6.44). A total of 399 (24.6%) individuals with DS were considered vitamin D deficient compared to 1472 (28.3%) with ASD and 12,397 (40.3%) NT controls (p < 0.001, 95% CI: -5.43 to -2.36). Individuals with DS with higher body mass index (BMI) were found to be more likely to have lower levels of vitamin D (p < 0.001, 95% CI: -0.3849 to -0.1509). Additionally, having both DS and a neurologic diagnosis increased the likelihood of having lower vitamin D levels (p < 0.001, 95% CI: -5.02 to -1.28). Individuals with DS and autoimmune disease were much more likely to have lower vitamin D levels (p < 0.001, 95% CI: -6.22 to -1.55). Similarly, a history of autoimmunity in a first-degree relative also increased the likelihood of having lower levels of vitamin D in persons with DS (p = 0.01, 95% CI: -2.45 to -0.63). CONCLUSIONS: Individuals with DS were noted to have hypovitaminosis D in comparison to individuals with ASD and NT controls. Associations between vitamin D deficiency and high BMI, personal autoimmunity, and familial autoimmunity were present in individuals with DS.

Niche-derived growth factors support self-renewal of mouse spermatogonial stem and progenitor cells through ERK MAPK signaling and other pathways. At the same time, dysregulated growth factor-dependent signaling has been associated with loss of stem cell activity and aberrant differentiation. We hypothesized that growth factor signaling through the ERK MAPK pathway in spermatogonial stem cells is tightly regulated within a narrow range through distinct intracellular negative feedback regulators. Evaluation of candidate extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK)-responsive genes known to dampen downstream signaling revealed robust induction of specific negative feedback regulators, including Spry4, in cultured mouse spermatogonial stem cells in response to glial cell line-derived neurotrophic factor or fibroblast growth factor 2. Undifferentiated spermatogonia in vivo exhibited high levels of Spry4 mRNA. Quantitative single-cell analysis of ERK MAPK signaling in spermatogonial stem cell cultures revealed both dynamic signaling patterns in response to growth factors and disruption of such effects when Spry4 was ablated, due to dysregulation of ERK MAPK downstream of RAS. Whereas negative feedback regulator expression decreased during differentiation, loss of Spry4 shifted cell fate toward early differentiation with concomitant loss of stem cell activity. Finally, a mouse Spry4 reporter line revealed that the adult spermatogonial stem cell population in vivo is demarcated by strong Spry4 promoter activity. Collectively, our data suggest that negative feedback-dependent regulation of ERK MAPK is critical for preservation of spermatogonial stem cell fate within the mammalian testis.

Mechanisms of resilience against tau pathology in individuals across the Alzheimer's disease spectrum are insufficiently understood. Longitudinal data are necessary to reveal which factors relate to preserved cognition (i.e. cognitive resilience) and brain structure (i.e. brain resilience) despite abundant tau pathology, and to clarify whether these associations are cross-sectional or longitudinal. We used a longitudinal study design to investigate the role of several demographic, biological and brain structural factors in yielding cognitive and brain resilience to tau pathology as measured with PET. In this multicentre study, we included 366 amyloid-β-positive individuals with mild cognitive impairment or Alzheimer's disease dementia with baseline 18F-flortaucipir-PET and longitudinal cognitive assessments. A subset (n = 200) additionally underwent longitudinal structural MRI. We used linear mixed-effects models with global cognition and cortical thickness as dependent variables to investigate determinants of cognitive resilience and brain resilience, respectively. Models assessed whether age, sex, years of education, APOE-ε4 status, intracranial volume (and cortical thickness for cognitive resilience models) modified the association of tau pathology with cognitive decline or cortical thinning. We found that the association between higher baseline tau-PET levels (quantified in a temporal meta-region of interest) and rate of cognitive decline (measured with repeated Mini-Mental State Examination) was adversely modified by older age (Stβinteraction = -0.062, P = 0.032), higher education level (Stβinteraction = -0.072, P = 0.011) and higher intracranial volume (Stβinteraction = -0.07, P = 0.016). Younger age, higher education and greater cortical thickness were associated with better cognitive performance at baseline. Greater cortical thickness was furthermore associated with slower cognitive decline independent of tau burden. Higher education also modified the negative impact of tau-PET on cortical thinning, while older age was associated with higher baseline cortical thickness and slower rate of cortical thinning independent of tau. Our analyses revealed no (cross-sectional or longitudinal) associations for sex and APOE-ε4 status on cognition and cortical thickness. In this longitudinal study of clinically impaired individuals with underlying Alzheimer's disease neuropathological changes, we identified education as the most robust determinant of both cognitive and brain resilience against tau pathology. The observed interaction with tau burden on cognitive decline suggests that education may be protective against cognitive decline and brain atrophy at lower levels of tau pathology, with a potential depletion of resilience resources with advancing pathology. Finally, we did not find major contributions of sex to brain nor cognitive resilience, suggesting that previous links between sex and resilience might be mainly driven by cross-sectional differences.

Purpose: This study explores the influence of religiosity and service satisfaction on customer decisions, focusing on the dynamics of these variables within the Islamic banking sector in Indonesia, one of the largest markets for Sharia-compliant financial services globally. Method: A quantitative research approach was used to collect data from 100 respondents via structured questionnaires. The data were analyzed using Partial Least Squares Structural Equation Modeling (PLS-SEM) to rigorously test the hypothesized relationships and evaluate the strength and direction of the proposed variables. Result: The findings indicate that religiosity has a statistically insignificant effect on customer decisions. While religious alignment may influence preferences, it does not substantially drive decision-making. In contrast, service satisfaction is a significant and dominant factor influencing customer decisions. Together, these variables account for 50.7% of the variance in customer decisions, highlighting the critical role of service quality in shaping customer behavior within the Islamic banking sector. Practical Implications for Economic Growth and Development: The study suggests that enhancing service satisfaction in the Islamic banking sector can significantly drive customer decisions, thereby contributing to economic growth and development by strengthening consumer trust and increasing market participation.

Political education for a number of indigenous peoples in Indonesia is one of the important measures in carrying out the democratic party. The political rights of the Orang Rimba have received less attention by election organizers, political parties and the government, one of which is marked by the absence of an identity card as a prerequisite for being able to exercise their voting rights. This research aims to explore the guarantee of the political rights of the Orang Rimba through political education. The method used is qualitative research and enriched by library studies by utilizing relevant literature sources to deepen the political education that has been received by the Orang Rimba. The results obtained show that political education has been carried out by the local government, and election organizing agencies, and the Indonesian Conservation Community WARSI. Limited knowledge in political education for Orang Rimba is an obstacle to political education to the fullest. Facing the General Election, Regional Head Election, and Legislative Election, the Provincial KPU has facilitated and educated the election for the Orang Rimba. This is a recognition of the political rights of the Orang Rimba, namely participation in the democratic process and providing access to political information for indigenous peoples.

Summary: Background: Individuals with Down syndrome (DS) are at high risk of early-onset Alzheimer's disease (AD); yet, some 20 percent do not develop any signs of dementia until after 65 years or in their lifetime. Mosaicism could contribute to this phenotypic variation, where some disomic cells could lead to lower levels of gene products from chromosome 21. Methods: We examined longitudinal neuropsychological and biomarker data from two large studies of DS: the Alzheimer Biomarker Consortium–Down syndrome study (ABC-DS) (n = 357); and a legacy study (n = 468). We assessed mosaicism using karyotyping or GWAS data. Participants had data on plasma AD biomarkers (Aβ40, Aβ42, tau, and NfL) and longitudinal cognitive measures. A subset had cerebrospinal fluid biomarkers (Aβ40, Aβ42, tau, ptau181, and NfL) and amyloid and tau PET data. Findings: For both cohorts, the prevalence of mosaicism was

Pasar karbon di China merupakan langkah baru dalam mengurangi emisi CO2 dan mencegah perubahan iklim. China menerapkan pasar karbon melalui Emission Trading System (ETS) sebagai mekanisme pengurangan emisi dengan biaya rendah. Dalam pembangunan skema pasar karbon di China ini bekerja sama dengan Uni Eropa sebagai partner utama untuk kemudian memaksimalkan pasar karbon serta untuk memperluas pasar karbon diantara keduanya. Penelitian ini menganalisis implementasi kerja sama China-Uni Eropa melalui China-EU ETS Project tahun 2014-2021. Metode penelitian yang digunakan adalah kualitatif deskriptif dengan fokus pada kerja sama internasional dan konsep pasar karbon. Penelitian ini berangkat dari pemikiran bahwa China memerlukan kerja sama dengan Uni Eropa dalam mengurangi emisi karbon. Kemudian, dilanjutkan dengan bentuk kerja sama melalui China-EU ETS Project periode 2014-2021sehingga mencapai hasil kerja sama melalui China-EU ETS Project periode 2014-2021. Hasil penelitian menunjukkan bahwa kerja sama China-Uni Eropa tekait China-EU ETS dilakukan melalui 2 fase, dengan fase pertama yang tidak mencapai hasil yang maksimal. Kemudian dilanjutkan kerja sama fase kedua mencakup mempercepat keseluruhan perencanaan pasar karbon nasional. Dalam kerja sama ini, Uni Eropa memberikan bantuan kepada China dalam bentuk program dan kebijakan melalui lembaga-lembaga independen Uni Eropa yang bekerja sama dengan pemerintah China. Kemudian kerja sama dihadapkan oleh sejumlah tantangan yang berdampak pada relevansi sistem perdagangan emisi (ETS) yang sedang dibangun, meliputi perbedaan politik dan budaya, perubahan preferensi CCD di NDRC dari (Training of Trainers) ke pelatihan langsung, peralihan tanggung jawab pemerintah China dalam isu perubahan iklim (termasuk ETS) dipindahkan dari NDRC ke MEE, serta pandemi COVID-19 yang berdampak besar pada proyek China-EU ETS. Meskipun terdapat tantangan, kerja sama ini berhasil dalam mengembangkan pasar karbon di China secara nasional dan memperkuat komitmen kedua pihak dalam mitigasi perubahan iklim. Kerja sama ini membuktikan kesuksesan dalam mengurangi emisi karbon untuk industrinya, namun untuk emisi karbon secara keseluruhan di China masih cukup tinggi.

INTRODUCTION: The Alzheimers disease (AD) continuum begins with a long asymptomatic or preclinical stage, during which amyloid beta (Aβ) is accumulating for more than a decade prior to widespread cortical tauopathy, neurodegeneration, and manifestation of clinical symptoms. The AHEAD 3-45 Study (BAN2401-G000-303) is testing whether intervention with lecanemab (BAN2401), a humanized immunoglobulin 1 (IgG1) monoclonal antibody that preferentially targets soluble aggregated Aβ, initiated during this asymptomatic stage can slow biomarker changes and/or cognitive decline. The AHEAD 3-45 Study is conducted as a Public-Private Partnership of the Alzheimers Clinical Trial Consortium (ACTC), funded by the National Institute on Aging, National Institutes of Health (NIH), and Eisai Inc. METHODS: The AHEAD 3-45 Study was launched on July 14, 2020, and consists of two sister trials (A3 and A45) in cognitively unimpaired (CU) individuals ages 55 to 80 with specific dosing regimens tailored to baseline brain amyloid levels on screening positron emission tomography (PET) scans: intermediate amyloid (≈20 to 40 Centiloids) for A3 and elevated amyloid (>40 Centiloids) for A45. Both trials are being conducted under a single protocol, with a shared screening process and common schedule of assessments. A3 is a Phase 2 trial with PET-imaging end points, whereas A45 is a Phase 3 trial with a cognitive composite primary end point. The treatment period is 4 years. The study utilizes innovative approaches to enriching the sample with individuals who have elevated brain amyloid. These include recruiting from the Trial-Ready Cohort for Preclinical and Prodromal Alzheimers disease (TRC-PAD), the Australian Dementia Network (ADNeT) Registry, and the Japanese Trial Ready Cohort (J-TRC), as well as incorporation of plasma screening with the C2N mass spectrometry platform to quantitate the Aβ 42/40 ratio (Aβ 42/40), which has been shown previously to reliably identify cognitively normal participants not likely to have elevated brain amyloid levels. A blood sample collected at a brief first visit is utilized to screen out individuals who are less likely to have elevated brain amyloid, and to determine the participants eligibility to proceed to PET imaging. Eligibility to randomize into the A3 Trial or A45 Trial is based on the screening PET imaging results. RESULT: The focus of this article is on the innovative design of the study. DISCUSSION: The AHEAD 3-45 Study will test whether with lecanemab (BAN2401) can slow the accumulation of tau and prevent the cognitive decline associated with AD during its preclinical stage. It is specifically targeting both the preclinical and the early preclinical (intermediate amyloid) stages of AD and is the first secondary prevention trial to employ plasma-based biomarkers to accelerate the screening process and potentially substantially reduce the number of screening PET scans.

The interplay between immune cells and malignant cells represents an essential chapter in the eradication of breast cancer. This widely distributed and diverse form of cancer represents a major threat to women worldwide. The incidence of breast cancer is related to several risk factors, notably genetic predisposition and family antecedents. Despite progress in treatment modalities varying from surgery and chemotherapy to radiotherapy and targeted therapies, persistently high rates of recurrence, metastasis, and treatment resistance underscore the urgent need for new therapeutic approaches. Immunotherapy has gained considerable ground in the treatment of breast cancer, as it takes advantage of the complex interactions within the tumor microenvironment. This dynamic interplay between immune and tumor cells has become a key point of focus in immunological research. This study investigates the role of various cancer markers, such as neoantigens and immune regulatory genes, in the diagnosis and treatment of breast tumors. Moreover, it explores the future potential of immune checkpoint inhibitors as therapeutically effective agents, as well as the challenges that prevent their efficacy, in particular tumor-induced immunosuppression and the difficulty of achieving tumor specificity.

BackgroundImportant insights into the early pathogenesis of Alzheimer's disease can be provided by studies of autosomal dominant Alzheimer's disease and Down syndrome. However, it is unclear whether the timing and spatial distribution of amyloid accumulation differs between people with autosomal dominant Alzheimer's disease and those with Down syndrome. We aimed to directly compare amyloid changes between these two groups of people.MethodsIn this cross-sectional study, we included participants (aged ≥25 years) with Down syndrome and sibling controls who had MRI and amyloid PET scans in the first data release (January, 2020) of the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) study. We also included carriers of autosomal dominant Alzheimer's disease genetic mutations and non-carrier familial controls who were within a similar age range to ABC-DS participants (25-73 years) and had MRI and amyloid PET scans at the time of a data freeze (December, 2020) of the Dominantly Inherited Alzheimer Network (DIAN) study. Controls from the two studies were combined into a single group. All DIAN study participants had genetic testing to determine PSEN1, PSEN2, or APP mutation status. APOE genotype was determined from blood samples. CSF samples were collected in a subset of ABC-DS and DIAN participants and the ratio of amyloid β42 (Aβ42) to Aβ40 (Aβ42/40) was measured to evaluate its Spearman's correlation with amyloid PET. Global PET amyloid burden was compared with regards to cognitive status, APOE ɛ4 status, sex, age, and estimated years to symptom onset. We further analysed amyloid PET deposition by autosomal dominant mutation type. We also assessed regional patterns of amyloid accumulation by estimated number of years to symptom onset. Within a subset of participants the relationship between amyloid PET and CSF Aβ42/40 was evaluated.Findings192 individuals with Down syndrome and 33 sibling controls from the ABC-DS study and 265 carriers of autosomal dominant Alzheimer's disease mutations and 169 non-carrier familial controls from the DIAN study were included in our analyses. PET amyloid centiloid and CSF Aβ42/40 were negatively correlated in carriers of autosomal dominant Alzheimer's disease mutations (n=216; r=-0·565; p

The recent National Institute of Health (NIH) INCLUDE (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE) initiative has bolstered capacity for the current increase in clinical trials involving individuals with Down syndrome (DS). This new NIH funding mechanism offers new opportunities to expand and develop novel approaches in engaging and effectively enrolling a broader representation of clinical trials participants addressing current medical issues faced by individuals with DS. To address this opportunity, the NIH assembled leading clinicians, scientists, and representatives of advocacy groups to review existing methods and to identify those areas where new approaches are needed to engage and prepare DS populations for participation in clinical trial research. This paper summarizes the results of the Clinical Trial Readiness Working Group that was part of the INCLUDE Project Workshop: Planning a Virtual Down Syndrome Cohort Across the Lifespan Workshop held virtually September 23 and 24, 2019.

By 2050, the global population is anticipated to reach 10 billion, marking a significant 34% increase and raising concerns regarding food availability. Challenges such as the recent pandemic, which led to workforce and input shortages in agriculture, have made it difficult for many countries to maintain adequate food self-sufficiency (SSL). It is crucial to explore various farming methods to ensure that food remains available and affordable, especially in urban areas where over 55% of the population resides. Traditional agriculture faces issues like poor soil and excessive fertilizer use, which harm the environment. These factors threaten sustainable agriculture and food security, particularly in urban environments. Adopting sustainable soilless technology can enhance urban agriculture by providing a controlled environment for producing healthy food and addressing these challenges post-pandemic. This review, utilizing the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework, a widely recognized and rigorous method for conducting systematic reviews, focused on urban agriculture, specifically soilless technologies, as emerging trends in crop cultivation. It examined conventional and cutting-edge urban production systems aimed at promoting sustainable agriculture and food security. The review examined soilless farming techniques such as aeroponics, hydroponics, and aquaponics, highlighting their environmental impact, resource efficiency, and water usage. It carefully considered the advantages and disadvantages of these technologies compared to conventional soil-based farming. Furthermore, the review showcased the successful cultivation of various fresh vegetables and fruits using soilless technologies, each with advantages supporting urban agriculture and overall food security. The findings suggest that these innovative strategies hold promise in fostering sustainable urban agriculture and ensuring food security during a pandemic. These results lay the groundwork for establishing a framework to assess the sustainability of urban agricultural strategies and their practical application in real-world scenarios.

Abstract Objective To determine the prevalence of neuroimaging abnormalities in individuals with Down syndrome regression disorder (DSRD) and evaluate if neuroimaging abnormalities were predictive of therapeutic responses. Methods A multicenter, retrospective, case–control study which reviewed neuroimaging studies of individuals with DSRD and compared them to a control cohort of individuals with Down syndrome (DS) alone was performed. Individuals aged 10–30 years and meeting international consensus criteria for DSRD were included. The presence of T1, T2/FLAIR, and SWI signal abnormalities was reviewed. Response rates to various therapies, including immunotherapy, were evaluated in the presence of neuroimaging abnormalities. Results In total, 74 individuals (35%) had either T2/FLAIR and/or SWI signal abnormality compared to 14 individuals (12%) without DSRD (p

The purpose of this research was to design a wisdom process model with an emphasis on narrative and Qur'anic teachings from Islamic sources. The method of this research was a qualitative type of Grounded Theory, and in order to check content validity, the descriptive contextualization method was used. With the formation of the semantic domain, the concepts corresponding to wisdom were identified in Islamic sources and analyzed in four stages of open, focused, central and selective coding. The result of this stage was the achievement of 1276 open codes, 344 focused codes, 84 central codes, 19 categories and 10 main micro components. These components are: knowledge, distinction, mental processing, control, strength in practice, perspicacity, acumen, insight, comprehend and sagacity. Then, the hypothetical relationships between these components and the process of achieving wisdom were investigated. The findings showed that the hypothetical relationships between these ten components are classified into two levels of "core categories" and "active domains". Based on this, wisdom in the core has the basic elements of "cognition", " control", "diagnosis", "processing", and " strength in practice ", which led to "perception of the best interest" in the intrapersonal domain and "insight", "perception of inner motivation and goals", "perception of concepts and objects", and "acuity" in the extra personal domain. The results were the design of a process model of wisdom, which was evaluated by 6 experts in Islamic sciences and psychology, and analyzed and evaluated using (CVI).

The process of identifying suitable genome-wide association (GWA) studies and formatting the data to calculate multiple polygenic risk scores on a single genome can be laborious. Here, we present a centralized polygenic risk score calculator currently containing over 250,000 genetic variant associations from the NHGRI-EBI GWAS Catalog for users to easily calculate sample-specific polygenic risk scores with comparable results to other available tools. Polygenic risk scores are calculated either online through the Polygenic Risk Score Knowledge Base (PRSKB; https://prs.byu.edu ) or via a command-line interface. We report study-specific polygenic risk scores across the UK Biobank, 1000 Genomes, and the Alzheimer's Disease Neuroimaging Initiative (ADNI), contextualize computed scores, and identify potentially confounding genetic risk factors in ADNI. We introduce a streamlined analysis tool and web interface to calculate and contextualize polygenic risk scores across various studies, which we anticipate will facilitate a wider adaptation of polygenic risk scores in future disease research.