CONTEXT: Several reports from small clinical trials have suggested that estrogen replacement therapy may be useful for the treatment of Alzheimer disease (AD) in women. OBJECTIVE: To determine whether estrogen replacement therapy affects global, cognitive, or functional decline in women with mild to moderate AD. DESIGN: The Alzheimer's Disease Cooperative Study, a randomized, double-blind, placebo-controlled clinical trial conducted between October 1995 and January 1999. SETTING: Thirty-two study sites in the United States. PARTICIPANTS: A total of 120 women with mild to moderate AD and a Mini-Mental State Examination score between 12 and 28 who had had a hysterectomy. INTERVENTIONS: Participants were randomized to estrogen, 0.625 mg/d (n = 42), or 1.25 mg/d (n = 39), or to identically appearing placebo (n = 39). One subject withdrew after randomization but before receiving medication; 97 subjects completed the trial. MAIN OUTCOME MEASURES: The primary outcome measure was change on the Clinical Global Impression of Change (CGIC) 7-point scale, analyzed by intent to treat; secondary outcome measures included other global measures as well as measures of mood, specific cognitive domains (memory, attention, and language), motor function, and activities of daily living; compared by the combined estrogen groups vs the placebo group at 2, 6, 12, and 15 months of follow-up. RESULTS: The CGIC score for estrogen vs placebo was 5.1 vs 5.0 (P = .43); 80% of participants taking estrogen vs 74% of participants taking placebo worsened (P = .48). Secondary outcome measures also showed no significant differences, with the exception of the Clinical Dementia Rating Scale, which suggested worsening among patients taking estrogen (mean posttreatment change in score for estrogen, 0.5 vs 0.2 for placebo; P = .01). CONCLUSIONS: Estrogen replacement therapy for 1 year did not slow disease progression nor did it improve global, cognitive, or functional outcomes in women with mild to moderate AD. The study does not support the role of estrogen for the treatment of this disease. The potential role of estrogen in the prevention of AD, however, requires further research.
Objective: To demonstrate the capabilities of Large Language Models (LLMs) as autonomous agents to reproduce findings of published research studies using the same or similar dataset. Materials and Methods: We used the "Quick Access" dataset of the National Alzheimer's Coordinating Center (NACC). We identified highly cited published research manuscripts using NACC data and selected five studies that appeared reproducible using this dataset alone. Using GPT-4o, we created a simulated research team of LLM-based autonomous agents tasked with writing and executing code to dynamically reproduce the findings of each study, given only study Abstracts, Methods sections, and data dictionary descriptions of the dataset. Results: We extracted 35 key findings described in the Abstracts across 5 Alzheimer's studies. On average, LLM agents approximately reproduced 53.2% of findings per study. Numeric values and range-based findings often differed between studies and agents. The agents also applied statistical methods or parameters that varied from the originals, though overall trends and significance were sometimes similar. Discussion: In some cases, LLM-based agents replicated research technique
Sharing clinical research data is essential for advancing research in Alzheimer's disease (AD) and other therapeutic areas. However, challenges in data accessibility, standardization, documentation, usability, and reproducibility continue to impede this goal. In this article, we highlight the advantages of using R packages to overcome these challenges using two examples. The A4LEARN R package includes data from a randomized trial (the Anti-Amyloid Treatment in Asymptomatic Alzheimer's [A4] study) and its companion observational study of biomarker negative individuals (the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration [LEARN] study). The ADNIMERGE2 R package includes data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), a longitudinal observational biomarker and imaging study. These packages collect data, documentation, and reproducible analysis vignettes into a portable bundle that can be installed and browsed within commonly used R programming environments. We also introduce the alzverse package which leverages a common data standard to combine study-specific data packages to facilitate meta-analyses. By promoting collaboration, transparency, and reprod
In the past two years, large language model (LLM)-based chatbots, such as ChatGPT, have revolutionized various domains by enabling diverse task completion and question-answering capabilities. However, their application in scientific research remains constrained by challenges such as hallucinations, limited domain-specific knowledge, and lack of explainability or traceability for the response. Graph-based Retrieval-Augmented Generation (GraphRAG) has emerged as a promising approach to improving chatbot reliability by integrating domain-specific contextual information before response generation, addressing some limitations of standard LLMs. Despite its potential, there are only limited studies that evaluate GraphRAG on specific domains that require intensive knowledge, like Alzheimer's disease or other biomedical domains. In this paper, we assess the quality and traceability of two popular GraphRAG systems. We compile a database of 50 papers and 70 expert questions related to Alzheimer's disease, construct a GraphRAG knowledge base, and employ GPT-4o as the LLM for answering queries. We then compare the quality of responses generated by GraphRAG with those from a standard GPT-4o mode
Introduction. Treatment planning systems (TPS) are an essential component for simulating and optimizing a radiation therapy treatment before administering it to the patient. It ensures that the tumor is well covered and the dose to the healthy tissues is minimized. However, the TPS provided by commercial companies often come with a large panel of tools, each implemented in the form of a black-box making it difficult for researchers to use them for implementing and testing new ideas. To address this issue, we have developed an open-source TPS. Approach. We have developed an open-source software platform, OpenTPS (opentps.org), to generate treatment plans for external beam radiation therapy, and in particular for proton therapy. It is designed to be a flexible and user-friendly platform (coded with the freely usable Python language) that can be used by medical physicists, radiation oncologists, and other members of the radiation therapy community to create customized treatment plans for educational and research purposes. Result. OpenTPS includes a range of tools and features that can be used to analyze patient anatomy, simulate the delivery of the radiation beam, and optimize the tre
Alzheimer's disease (AD) persists as a paramount challenge in neurological research, characterized by the pathological hallmarks of amyloid-beta (Abeta) plaques and neurofibrillary tangles composed of hyperphosphorylated tau. This review synthesizes the evolving understanding of AD pathogenesis, moving beyond the linear amyloid cascade hypothesis to conceptualize the disease as a cross-talk of intricately interacting pathologies, encompassing Abeta, tau, and neuroinflammation. This evolving pathophysiological understanding parallels a transformation in diagnostic paradigms, where biomarker-based strategies -- such as the AT(N) framework -- enable early disease detection during preclinical or prodromal stages. Within this new landscape, while anti-Abeta monoclonal antibodies (e.g., lecanemab, donanemab) represent a breakthrough as the first disease-modifying therapies, their modest efficacy underscores the limitation of single-target approaches. Therefore, this review explores the compelling rationale for combination therapies that simultaneously target Abeta pathology, aberrant tau, and neuroinflammation. Looking forward, we emphasize emerging technological platforms -- such as gen
This paper presents a scientometric analysis of research output from the University of Lagos, focusing on the two decades spanning 2004 to 2023. Using bibliometric data retrieved from the Web of Science, we examine trends in publication volume, collaboration patterns, citation impact, and the most prolific authors, departments, and research domains at the university. The study reveals a consistent increase in research productivity, with the highest publication output recorded in 2023. Health Sciences, Engineering, and Social Sciences are identified as dominant fields, reflecting the university's interdisciplinary research strengths. Collaborative efforts, both locally and internationally, show a positive correlation with higher citation impact, with the United States and the United Kingdom being the leading international collaborators. Notably, open-access publications account for a significant portion of the university's research output, enhancing visibility and citation rates. The findings offer valuable insights into the university's research performance over the past two decades, providing a foundation for strategic planning and policy formulation to foster research excellence
Demographic data collection is essential in education research, as demographic data allows researchers to better describe the participant population they study and to contextualize findings. However, current research practices for neurodiversity demographics often rely on prescriptive methods (e.g., requiring participants to report official diagnoses) rather than allowing participants to self-identify. This approach can: a) not allow participants to express their intersecting identities in ways that are authentic; and b) limit trustworthiness and reliability of the data and interpretation. In addition, inconsistent dissemination and representation of demographic data across studies hinder the accessibility and usability of this work. Through a literature review of neurodivergent student experiences with learning and performing STEM, we identified widespread discrepancies in how demographic information is collected and reported. This paper explores how neurodivergent identities can be more accurately and inclusively represented in education research. We present findings of a thematic analysis on the ways neurodivergent demographic data collection is done in the literature using data
This scientometric study analyzes Avian Influenza research from 2014 to 2023 using bibliographic data from the Web of Science database. We examined publication trends, sources, authorship, collaborative networks, document types, and geographical distribution to gain insights into the global research landscape. Results reveal a steady increase in publications, with high contributions from Chinese and American institutions. Journals such as PLoS One and the Journal of Virology published the highest number of studies, indicating their influence in this field. The most prolific institutions include the Chinese Academy of Sciences and the University of Hong Kong, while the College of Veterinary Medicine at South China Agricultural University emerged as the most productive department. China and the USA lead in publication volume, though developed nations like the United Kingdom and Germany exhibit a higher rate of international collaboration. "Articles" are the most common document type, constituting 84.6% of the total, while "Reviews" account for 7.6%. This study provides a comprehensive view of global trends in Avian Influenza research, emphasizing the need for collaborative efforts ac
The systemic, metabolic, lifestyle factors have established associations with Alzheimer's Disease (AD) through epidemiologic and AD-specific biomarker studies. Whether colored fundus photography (CFP) contains retinal structural signatures corresponding to these AD-related risk domains remains unclear. To determine whether deep learning (DL) models can predict 12 AD-related risk factors from CFP and to characterize the retinal structures underlying these predictions, thereby assessing whether CFP reflects pathways to AD vulnerability. Using 62,876 CFPs from 44,501 unique participants from the UK Biobank, DL models were trained to predict 12 factors linked to AD incidence: 6 categorical (sex, smoking, sleeplessness, economic status, alcohol use, depression) and 6 continuous (age, age at completing education, BMI, systolic, diastolic blood pressure, HbA1c). Model performance, model saliency, and saliency-derived scores (CAM-Score) were evaluated and compared to retinal morphometry. The scores were also compared between incident-AD cases (average 8.55 years before onset) and matched controls. Performance of DL ranged from AUROC= 0.5654-0.9480 for categorical and R2=-0.0291-0.7620 for
Identifying objective neuroimaging biomarkers to forecast Alzheimer's disease (AD) progression is crucial for timely intervention. However, this task remains challenging due to the complex dysfunctions in the spatio-temporal characteristics of underlying brain networks, which are often overlooked by existing methods. To address these limitations, we develop an interpretable spatio-temporal graph neural network framework to predict future AD progression, leveraging dual Stochastic Differential Equations (SDEs) to model the irregularly-sampled longitudinal functional magnetic resonance imaging (fMRI) data. We validate our approach on two independent cohorts, including the Open Access Series of Imaging Studies (OASIS-3) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). Our framework effectively learns sparse regional and connective importance probabilities, enabling the identification of key brain circuit abnormalities associated with disease progression. Notably, we detect the parahippocampal cortex, prefrontal cortex, and parietal lobule as salient regions, with significant disruptions in the ventral attention, dorsal attention, and default mode networks. These abnormaliti
Progressive cognitive decline spanning across decades is characteristic of Alzheimer's disease (AD). Various predictive models have been designed to realize its early onset and study the long-term trajectories of cognitive test scores across populations of interest. Research efforts have been geared towards superimposing patients' cognitive test scores with the long-term trajectory denoting gradual cognitive decline, while considering the heterogeneity of AD. Multiple trajectories representing cognitive assessment for the long-term have been developed based on various parameters, highlighting the importance of classifying several groups based on disease progression patterns. In this study, a novel method capable of self-organized prediction, classification, and the overlay of long-term cognitive trajectories based on short-term individual data was developed, based on statistical and differential equation modeling. We validated the predictive accuracy of the proposed method for the long-term trajectory of cognitive test score results on two cohorts: the Alzheimer's Disease Neuroimaging Initiative (ADNI) study and the Japanese ADNI study. We also presented two practical illustrations
Early detection of Alzheimer's Disease (AD) and its prodromal state, Mild Cognitive Impairment (MCI), is crucial for providing suitable treatment and preventing the disease from progressing. It can also aid researchers and clinicians to identify early biomarkers and minister new treatments that have been a subject of extensive research. The application of deep learning techniques on structural Magnetic Resonance Imaging (MRI) has shown promising results in diagnosing the disease. In this research, we intend to introduce a novel approach of using an ensemble of the self-attention-based Bottleneck Transformers with a sharpness aware minimizer for early detection of Alzheimer's Disease. The proposed approach has been tested on the widely accepted ADNI dataset and evaluated using accuracy, precision, recall, F1 score, and ROC-AUC score as the performance metrics.
Cancer registries collect multisource data and provide valuable information that can lead to unique research opportunities. In the Netherlands, a registry and model-based approach (MBA) are used for the selection of patients that are eligible for proton therapy. We collected baseline characteristics including demographic, clinical, tumour and treatment information. These data were transformed into a machine readable format using the FAIR (Findable, Accessible, Interoperable, Reusable) data principles and resulted in a knowledge graph with baseline characteristics of proton therapy patients. With this approach, we enable the possibility of linking external data sources and optimal flexibility to easily adapt the data structure of the existing knowledge graph to the needs of the clinic.
INTRODUCTION: Alzheimer's disease (AD) is genetically complex, complicating robust classification from genomic data. METHODS: We developed a transformer-based ensemble model (TrUE-Net) using Monte Carlo Dropout for uncertainty estimation in AD classification from whole-genome sequencing (WGS). We combined a transformer that preserves single-nucleotide polymorphism (SNP) sequence structure with a concurrent random forest using flattened genotypes. An uncertainty threshold separated samples into an uncertain (high-variance) group and a more certain (low-variance) group. RESULTS: We analyzed 1050 individuals, holding out half for testing. Overall accuracy and area under the receiver operating characteristic (ROC) curve (AUC) were 0.6514 and 0.6636, respectively. Excluding the uncertain group improved accuracy from 0.6263 to 0.7287 (10.24% increase) and F1 from 0.5843 to 0.8205 (23.62% increase). DISCUSSION: Monte Carlo Dropout-driven uncertainty helps identify ambiguous cases that may require further clinical evaluation, thus improving reliability in AD genomic classification.
Despite the high prevalence and burden of mental health conditions, there is a global shortage of mental health providers. Artificial Intelligence (AI) methods have been proposed as a way to address this shortage, by supporting providers with less extensive training as they deliver care. To this end, we developed the AI-Assisted Provider Platform (A2P2), a text-based virtual therapy interface that includes a response suggestion feature, which supports providers in delivering protocolized therapies empathetically. We studied providers with and without expertise in mental health treatment delivering a therapy session using the platform with (intervention) and without (control) AI-assistance features. Upon evaluation, the AI-assisted system significantly decreased response times by 29.34% (p=0.002), tripled empathic response accuracy (p=0.0001), and increased goal recommendation accuracy by 66.67% (p=0.001) across both user groups compared to the control. Both groups rated the system as having excellent usability.
The production of knowledge has become increasingly a global endeavor. Yet, location related factors, such as local working environment and national policy designs, may continue to affect what kind of science is being pursued. Here we examine the geography of the production of creative science by country, through the lens of novelty and atypicality proposed in Uzzi et al. (2013). We quantify a country's representativeness in novel and atypical science, finding persistent differences in propensity to generate creative works, even among developed countries that are large producers in science. We further cluster countries based on how their tendency to publish novel science changes over time, identifying one group of emerging countries. Our analyses point out the recent emergence of China not only as a large producer in science but also as a leader that disproportionately produces more novel and atypical research. Discipline specific analysis indicates that China's over-production of atypical science is limited to a few disciplines, especially its most prolific ones like materials science and chemistry.
In most countries, basic research is supported by research councils that select, after peer review, the individuals or teams that are to receive funding. Unfortunately, the number of grants these research councils can allocate is not infinite and, in most cases, a minority of the researchers receive the majority of the funds. However, evidence as to whether this is an optimal way of distributing available funds is mixed. The purpose of this study is to measure the relation between the amount of funding provided to 12,720 researchers in Quebec over a fifteen year period (1998-2012) and their scientific output and impact from 2000 to 2013. Our results show that both in terms of the quantity of papers produced and of their scientific impact, the concentration of research funding in the hands of a so-called "elite" of researchers generally produces diminishing marginal returns. Also, we find that the most funded researchers do not stand out in terms of output and scientific impact.
A common expectation is that career productivity peaks rather early and then gradually declines with seniority. But whether this holds true is still an open question. Here we investigate the productivity trajectories of almost 8,500 scientists from over fifty disciplines using methods from time series analysis, dimensionality reduction, and network science, showing that there exist six universal productivity patterns in research. Based on clusters of productivity trajectories and network representations where researchers with similar productivity patterns are connected, we identify constant, u-shaped, decreasing, periodic-like, increasing, and canonical productivity patterns, with the latter two describing almost three-fourths of researchers. In fact, we find that canonical curves are the most prevalent, but contrary to expectations, productivity peaks occur much more frequently around mid-career rather than early. These results outline the boundaries of possible career paths in science and caution against the adoption of stereotypes in tenure and funding decisions.
This paper explores the adaptation and application of i-TED Compton imagers for real-time dosimetry in Boron Neutron Capture Therapy (BNCT). The i-TED array, previously utilized in nuclear astrophysics experiments at CERN, is being optimized for detecting and imaging 478 keV gamma-rays, critical for accurate BNCT dosimetry. Detailed Monte Carlo simulations were used to optimize the i-TED detector configuration and enhance its performance in the challenging radiation environment typical of BNCT. Additionally, advanced 3D image reconstruction algorithms, including a combination of back-projection and List-Mode Maximum Likelihood Expectation Maximization (LM-MLEM), are implemented and validated through simulations. Preliminary experimental tests at the Institut Laue-Langevin (ILL) demonstrate the potential of i-TED in a clinical setting, with ongoing experiments focusing on improving imaging capabilities in realistic BNCT conditions.