Amyotrophic lateral sclerosis (ALS) has an interactive, multifactorial etiology that makes treatment success elusive. This study evaluates how regulatory dynamics impact disease progression and treatment. Computational models of wild-type (WT) and transgenic SOD1-G93A mouse physiology dynamics were built using the first-principles-based first-order feedback framework of dynamic meta-analysis with parameter optimization. Two in silico models were developed: a WT mouse model to simulate normal homeostasis and a SOD1-G93A ALS model to simulate ALS pathology dynamics and their response to in silico treatments. The model simulates functional molecular mechanisms for apoptosis, metal chelation, energetics, excitotoxicity, inflammation, oxidative stress, and proteomics using curated data from published SOD1-G93A mouse experiments. Temporal disease progression measures (rotarod, grip strength, body weight) were used for validation. Results illustrate that untreated SOD1-G93A ALS dynamics cannot maintain homeostasis due to a mathematical oscillating instability as determined by eigenvalue analysis. The onset and magnitude of homeostatic instability corresponded to disease onset and progression. Oscillations were associated with high feedback gain due to hypervigilant regulation. Multiple combination treatments stabilized the SOD1-G93A ALS mouse dynamics to near-normal WT homeostasis. However, treatment timing and effect size were critical to stabilization corresponding to therapeutic success. The dynamics-based approach redefines therapeutic strategies by emphasizing the restoration of homeostasis through precisely timed and stabilizing combination therapies, presenting a promising framework for application to other multifactorial neurodegenerative diseases.

This work introduces TrialSieve, a novel framework for biomedical information extraction that enhances clinical meta-analysis and drug repurposing. By extending traditional PICO (Patient, Intervention, Comparison, Outcome) methodologies, TrialSieve incorporates hierarchical, treatment group-based graphs, enabling more comprehensive and quantitative comparisons of clinical outcomes. TrialSieve was used to annotate 1609 PubMed abstracts, 170,557 annotations, and 52,638 final spans, incorporating 20 unique annotation categories that capture a diverse range of biomedical entities relevant to systematic reviews and meta-analyses. The performance (accuracy, precision, recall, F1-score) of four natural-language processing (NLP) models (BioLinkBERT, BioBERT, KRISSBERT, PubMedBERT) and the large language model (LLM), GPT-4o, was evaluated using the human-annotated TrialSieve dataset. BioLinkBERT had the best accuracy (0.875) and recall (0.679) for biomedical entity labeling, whereas PubMedBERT had the best precision (0.614) and F1-score (0.639). Error analysis showed that NLP models trained on noisy, human-annotated data can match or, in most cases, surpass human performance. This finding highlights the feasibility of fully automating biomedical information extraction, even when relying on imperfectly annotated datasets. An annotator user study (n = 39) revealed significant (p < 0.05) gains in efficiency and human annotation accuracy with the unique TrialSieve tree-based annotation approach. In summary, TrialSieve provides a foundation to improve automated biomedical information extraction for frontend clinical research.

Background: Demographic factors such as education, sex, and age can significantly influence cognitive test performance, yet their impact on the Montreal Cognitive Assessment (MoCA) and Rey Complex Figure (CF) test has not been fully characterized in large, cognitively normal samples. Understanding these effects is critical for refining normative standards and improving the clinical interpretation of neuropsychological assessments. Methods: Data from 926 cognitively healthy adults (MoCA ≥ 24) were analyzed using supervised machine learning classifiers and complementary statistical models to identify the most predictive MoCA and CF features associated with education, sex, and age, while including race as a covariate. Feature importance analyses were conducted to quantify the relative contributions of accuracy-based and time-based measures after adjusting for demographic confounding. Results: Distinct patterns emerged across demographic groups. Higher educational attainment was associated with longer encoding times and improved recall performance, suggesting more deliberate encoding strategies. Sex differences were most apparent in the recall of visuospatial details and language-related subtests, with women showing relative advantages in fine detail reproduction and verbal fluency. Age-related differences were primarily reflected in slower task completion and reduced spatial memory accuracy. Conclusions: Leveraging one of the largest reported samples of cognitively healthy adults, this study demonstrates that education, sex, and age systematically influence MoCA and CF performance. These findings highlight the importance of incorporating demographic factors into normative frameworks to enhance diagnostic precision and the interpretability of cognitive assessments.

Background: Mechanistic reporting from large-scale biomedical knowledge graphs remains challenging, particularly when integrating structured graph evidence with large language model (LLM)–based explanation in a reproducible and auditable manner. Existing approaches either rely on manual synthesis of graph-derived results or generate unconstrained narratives that lack traceability to underlying evidence. Methods: We present SemNet Explorer, an evidence-grounded knowledge graph–LLM unified framework for automated mechanistic reporting across biomedical domains using SemNet 2.0, a PubMed-scale heterogeneous knowledge graph. Given a set of target concepts and a selected semantic layer, the framework organizes graph-derived evidence into structured regions and generates two complementary report types: global reports for process-level mechanisms and anchor-centric reports for localized mediator-based explanations. A central methodological contribution is an ablation-derived adaptive grounding policy: we systematically compare alternative evidence-integration strategies across report types, semantic layers, and region structures, and use the resulting preferences to guide prompt selection in the deployed system. Results: SemNet Explorer produces stable region decompositions and interpretable report scaffolds across molecular (AAPP), disease-level (DSYN), and pharmacologic (PHSU) representations. For global reports, explicit evidence grounding improves expression quality more consistently than content accuracy, with benefits dependent on evidence density and semantic abstraction. In contrast, anchor-centric reports show consistent improvements in both content and expression under stronger, mediator-constrained prompting. These findings are supported by both pairwise ablation comparisons and absolute score analyses. Conclusions: SemNet Explorer establishes a generalizable unified framework and interactive platform for transforming knowledge graph evidence into reproducible mechanistic narratives across biomedical domains, including multimorbidity analysis, comparative pathophysiology, drug repurposing, and adverse event discovery. The results demonstrate that effective knowledge graph–LLM integration requires adaptive, context-dependent evidence grounding rather than fixed prompting strategies.

Clinical Cohort Studies (CCS), such as randomized clinical trials, are a great source of documented clinical research. Ideally, a clinical expert inspects these articles for exploratory analysis ranging from drug discovery for evaluating the efficacy of existing drugs in tackling emerging diseases to the first test of newly developed drugs. However, more than 100 articles are published daily on a single prevalent disease like COVID-19 in PubMed. As a result, it can take days for a physician to find articles and extract relevant information. Can we develop a system to sift through the long list of these articles faster and document the crucial takeaways from each of these articles? In this work, we propose CCS Explorer, an end-to-end system for relevance prediction of sentences, extractive summarization, and patient, outcome, and intervention entity detection from CCS. CCS Explorer is packaged in a web-based graphical user interface where the user can provide any disease name. CCS Explorer then extracts and aggregates all relevant information from articles on PubMed based on the results of an automatically generated query produced on the back-end. For each task, CCS Explorer fine-tunes pre-trained language representation models based on transformers with additional layers. The models are evaluated using two publicly available datasets. CCS Explorer obtains a recall of 80.2%, AUC-ROC of 0.843, and an accuracy of 88.3% on sentence relevance prediction using BioBERT and achieves an average Micro F1-Score of 77.8% on Patient, Intervention, Outcome detection (PIO) using PubMedBERT. Thus, CCS Explorer can reliably extract relevant information to summarize articles, saving time by $\sim \text{660}\times$.