Introduction: The increasing utilization of real-world data platforms in medical research necessitates a comprehensive understanding of their methodological strengths and limitations. TriNetX has emerged as a significant platform for exploring large healthcare datasets. This review aims to critically evaluate the methodological framework and limitations of TriNetX, assess the impact of electronic health record coding accuracy on data reliability, and analyze the platform's capacity for generating generalizable real-world evidence in clinical research. Methods: We conducted a comprehensive review examining TriNetX's data architecture, quality metrics, and research applications, focusing on data integrity, platform architecture, and the external validity of research findings. Results: The analysis reveals significant methodological considerations. TriNetX's reliance on retrospective data introduces biases such as selection bias and confounding variables. The coding accuracy of electronic health records, which have not been independently validated, is a critical determinant of data reliability. The demographic representation is limited, affecting the generalizability of results. Discussion: Despite its extensive use, TriNetX's effective utilization requires careful consideration of its inherent limitations. The platform's data, predominantly from insured populations in academic and acute care settings, may not fully represent broader demographic groups. Addressing these methodological constraints is crucial for enhancing the reliability and applicability of research findings derived from TriNetX. Conclusions: TriNetX is a valuable resource for healthcare research. However, its limitations must be acknowledged, and future research should focus on standardizing data collection and enhancing data validation processes to mitigate platform-specific biases and improve the quality and applicability of the findings.

Alzheimer's disease progression follows distinct pathways in cognitively normal individuals: direct conversion to dementia versus sequential decline through mild cognitive impairment (MCI). The metabolic determinants of pathway selection remain unclear, limiting personalized intervention strategies. We analyzed 1136 cognitively normal participants from the Alzheimer's Disease Neuroimaging Initiative with baseline fluorodeoxyglucose positron emission tomography (FDG-PET) and longitudinal outcomes over ten years. Competing risks regression modeled pathway-specific transitions, while multinomial logistic regression predicted pathway membership using brain glucose metabolism. Cross-validation assessed pathway classification accuracy across temporal splits. Four progression pathways were concluded from our analyses, cognitive stability (32.8 %), sequential MCI-only decline (34.9 %), accelerated MCI-to-dementia progression (15.8 %), and rapid direct conversion (16.5 %). Brain glucose hypometabolism determined pathway selection with significant effects: participants with severe hypometabolism (FDG z-score < -0.5) demonstrated 7.4-fold acceleration in direct conversion velocity compared to preserved metabolism (17.12 vs 2.31 per 100 person-years, P-value<0.001). Pathway prediction models achieved excellent discrimination for direct conversion (AUC = 0.994) and acceptable performance for sequential pathways (AUC = 0.680). Metabolic phenotyping demonstrated peculiar vulnerability profiles, cognitive stability maintained metabolic reserve (FDG +0.57 ± 0.58), while rapid converters demonstrated metabolic failure patterns (FDG -0.18 ± 0.88). Based on our modeling findings, we observed that brain glucose metabolism could serve as a pathway determinant rather than simply a decline predictor, which could play a promising role in precision medicine approaches to Alzheimer's disease prevention. FDG-PET biomarkers can stratify individuals for pathway-specific interventions, transforming reactive dementia care into proactive pathway-guided management.

Background Previous studies comparing a direct aspiration first pass technique (ADAPT) and stent retrievers have inconsistent methodologies and data reporting, limiting the ability to accurately assimilate data from different studies that would inform treatment of acute ischemic stroke (AIS) treatment. Objective To conduct a systematic review to discuss and compare the findings of all relevant meta-analysis studies comparing the efficacy of the ADAPT and stent retriever techniques. Methods The study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), where meta-analyses comparing the efficacy of the ADAPT technique and stent retrievers in the treatment of AIS were included. We extracted all relevant data from the included studies and assessed the quality of the included meta-analyses using the Assessment of Multiple Systematic Review (AMSTAR-2). Results Seven relevant studies met our inclusion criteria and were suitable for the qualitative synthesis. All included studies obtained data from randomized controlled trials (RCTs) and observational investigations (including levels II, III, and IV). At the same time, none of them used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) for quality assessment. In accordance with AMSTAR-2, two studies were rated ‘high’, while the other five were rated ‘moderate’. Conclusions Present evidence is insufficient to clarify the superiority of one modality over the other. Further RCTs on this comparison must be conducted prior to designing further meta-analyses or making conclusive interpretations. Procedure duration and cost should be taken into consideration for any future studies.

Introduction: Idiopathic intracranial hypertension (IIH) is a neurological disorder characterised by elevated intracranial pressure (ICP), predominantly affecting obese women of reproductive age. While GLP‐1 receptor agonists have shown promise in IIH management, the potential of dual GIP/GLP‐1 receptor activation through tirzepatide remains unexplored. This study aimed to evaluate tirzepatide's efficacy as an adjunctive therapy in IIH management.Methods: We conducted a retrospective cohort analysis using the TriNetX Global Health Research Network, analysing data through November 2024. Through propensity score matching, we compared 193 tirzepatide‐exposed IIH patients with 193 controls receiving standard care. Primary outcomes included papilledema severity, visual function, headache frequency, and treatment resistance, monitored at multiple follow‐up timepoints.Results: Our analysis revealed significant improvements across all measured outcomes in the tirzepatide group. At 24 months, we observed a 68% reduction in papilledema risk (RR 0.320, 95% CI 0.189–0.542, p < 0.001), a 73.9% reduction in visual disturbance and blindness risk (RR 0.261, 95% CI 0.143–0.477, p < 0.001), and a 19.7% reduction in headache risk (RR 0.803, 95% CI 0.668–0.966, p = 0.019). The tirzepatide group demonstrated significant body‐mass index reductions, reaching −1.147 kg/m² (95% CI [−1.415, −0.879], p < 0.001) at 24 months compared to controls.Conclusions: Our results demonstrate that tirzepatide, when used as an adjunctive therapy, provides significant therapeutic benefits in IIH management, particularly in improving papilledema and visual outcomes. Our findings suggest that dual GIP/GLP‐1 receptor activation may offer advantages over traditional single‐receptor therapies, potentially through enhanced metabolic regulation and direct effects on ICP dynamics.