Citations

Background: Several breast cancer (BC) risk prediction models have been developed to provide personal risk assessments. Though individually validated, their performance has not been systematically evaluated across a wide range of populations or ages. Methods: We harmonized individual-level baseline questionnaire data and incident BC diagnoses from 21 cohorts from North America, Europe, and Australia participating in the Breast Cancer Risk Prediction Project. Five-year absolute risk of invasive BC was estimated for five established risk prediction models using classical risk factors only. Discrimination was evaluated by area under the curve (AUC). Calibration was assessed using average and risk-decile specific expected to observed (E/O) ratios. Performance metrics were meta-analyzed across cohorts and models. Metaregression tested associations between cohort characteristics and performance metrics. Results: This analysis included 1,595,977 women aged 20-75 years, enrolled in studies between 1976-2015, with 19,062 (1.2%) invasive BC cases ascertained within 5 years from exposure assessment. Age-adjusted AUCs were similar across models and cohorts (pooled AUCs by model: 0.57-0.58), while E/O ratios varied substantially (pooled E/O ratios by model: 0.83-1.25). Overestimation was common among predicted high-risk individuals (>3%). No appreciable differences in model performance by cohort age, birth year, race, and variable missingness emerged. Calibration improved after assigning race-specific incidence rates. Conclusion: Existing BC risk prediction models provided similar risk discrimination across multiple cohorts, although there was overestimation of risk for high-risk individuals. Performance variation across cohorts was not driven by specific characteristics, which supports development of a unified risk model for diverse populations that leverages appropriate incidence rates.

Abstract The Tau Global Conference 2025, hosted by the Alzheimer's Association, CurePSP, and the Rainwater Charitable Foundation, convened international experts from academia, industry, government, and philanthropy to explore advances and challenges in tauopathy research. The meeting highlighted progress across tau biology, including emerging models of tau regulation, degradation, and propagation; advances in biomarker development for the diagnosis and staging of tauopathies; and evolving therapeutic strategies targeting diverse aspects of tau pathophysiology. Discussions also emphasized the importance of cross‐sector collaboration, and global initiatives to address disparities in tau research. This report synthesizes key insights from the conference and underscores the critical role of interdisciplinary, biomarker‐driven, and globally inclusive approaches in accelerating the translation of tau research into effective clinical applications.

Background: There is growing support for high-efficacy disease-modifying therapy (DMT) in multiple sclerosis (MS), but escalation (ESC) approaches remain common. Objective: To describe decision-making in a pragmatic trial of early high-efficacy treatment (EHT) versus ESC. Methods: DELIVER-MS is a multi-center, pragmatic, randomized controlled trial (RCT) with a parallel observational study (OBS), which enrolled treatment-naïve people with RRMS in 31 UK/US sites. Primary outcome was as follows: 36-month brain volume loss according to initial treatment approach (EHT vs. ESC). Stepwise multivariable logistic regression was used to predict participation in RCT versus OBS and choice of EHT versus ESC within the OBS cohort. Results: In total, 816 people with MS were enrolled. Participants declined randomization due to preference for a particular DMT (85%), efficacy concerns (20%), and safety concerns (9%). RCT versus OBS participation was associated with lower relapse rate ( p = 0.043) and greater brain parenchymal fraction ( p = 0.002). Among 374 in the OBS cohort, 125 (33%) chose ESC and 249 (67%) chose EHT. People commencing EHT had higher education attainment ( p < 0.001) and relapse rate ( p = 0.025). Conclusion: Baseline DELIVER-MS data demonstrate that participants with milder disease are more likely to participate in RCT. The choice of EHT versus ESC was associated with demographic factors and disease activity. Clinical trial registration: NCT03535298

Purpose: The study compares refractive outcomes of secondary intraocular lens (SIOL) surgery performed by vitreoretinal, anterior segment, and both surgeons. Methods: Eyes included in this study underwent SIOL surgery from 2012 to 2024 and had a final postoperative visual acuity of 20/50 or better. Regression analysis compared refractive outcomes, and chi-squared analysis compared complications between subspecialty of SIOL surgeons. Results: A total of 94, 104, and 80 eyes were included in the retina surgeon, anterior segment surgeon, and combo surgeon cohorts, respectively. There was no significant difference in error between target and final postoperative spherical equivalence between retina and combo ( P = 0.079), retina and anterior segment ( P = 0.135), or anterior segment and combo cohorts ( P = 0.567). There was no significant difference in number of eyes with final spherical equivalence within 1 diopter of target spherical equivalence between retina and combo ( P = 0.136), retina and anterior segment ( P = 0.061), or anterior segment and combo cohorts ( P = 0.783). The retina cohort had higher postoperative corneal edema than the combo ( P = 0.017) and the anterior segment cohorts ( P = 0.035). The combo cohort had more postoperative retinal detachment than the anterior segment cohort ( P = 0.046). Conclusion: In eyes with good final vision, retina and anterior segment surgeons have similar refractive outcomes after SIOL surgery.

Background: Previous studies suggest that internalized HIV stigma (IHS) results in HIV viral nonsuppression via directly increasing depression, which then reduces adherence leading to nonsuppression; however, the dynamics between IHS and mental health are likely more complex. We sought to better understand IHS-mental health dynamics using data from a longitudinal clinical cohort of people with HIV (PWH) receiving healthcare across 10 US primary care clinics. Methods: Among 8,506 PWH who had ≥2 timepoints in which IHS, depression, and anxiety were measured, we examined changes over time in both two-state (i.e., impact of IHS on depression or anxiety and vice versa) and four-state combinations of depression-IHS (i.e., no depression or IHS, depression/no IHS, no depression/IHS, both depression/IHS) and anxiety-IHS. Transition probabilities between states and factors influencing transitions were identified using multistate Markov models. Results: The impact of IHS on the transition rates of mental health measures (i.e., depression, anxiety) and vice versa were almost the same, suggesting that each influences the other. Over 50% of PWH remained in the same IHS-depression or IHS-anxiety state. PWH with IHS had almost twice the rate of transitioning from no depression/anxiety to having depression/anxiety compared to PWH without IHS; with similar results for the depression or anxiety with no IHS to reporting IHS transition. Conclusions: We demonstrate that IHS and mental health dynamics are more complex than previously suspected and that the associations are bidirectional, which has implications for both future analyses and optimal management of these conditions among PWH.

Abstract Cryo-electron microscopy (cryoEM) is a powerful tool for atomic- and molecular-resolution structure determination, while molecular dynamics (MD) simulations are similarly powerful tools for predicting molecular trajectories. Given the challenges in estimating biomolecule dynamics with cryoEM alone, MD simulations are employed to forecast molecular motions and to interpret cryoEM reconstructions. Few methods, however, can evaluate MD predictions directly. Here, we use multislice wave propagation to project sampled snapshots of MD trajectories, either coarse-grained (CG) or all-atom (AA), into simulated cryoEM 3D reconstructions. We compared simulated and experimental images of low- and high-curvature membranes to show that MD simulations qualitatively reflect the fluidity and thus the contrast of biological membranes observed by cryoEM. MD simulations also correctly predicted bilayer dimensions for single component flat bilayers observed in cryoEM images. However, Martini3 CG-MD simulations failed to predict changes in membrane thickness induced by high curvature and with heterogeneous lipid compositions. We pinpointed the misbehavior of polyunsaturated lipid tails and cholesterol in Martini3 simulations as the main error sources contributing to inaccurate bilayer thicknesses. Our comparisons also explain membrane structure discrepancies between cryoEM and small angle X-ray scattering (SAXS). Further testing of MD predictions by direct comparisons between simulated and experimental cryoEM images should lead to the development of more accurate MD force fields. Statement of Significance Molecular dynamics (MD) simulations are frequently employed to predict the dynamics of biological macromolecules and assemblies, but these predictions remain difficult to validate experimentally. Cryo-electron microscopy (cryoEM) can be used to directly image the conformational ensemble of macromolecules, but images of Coulombic potential cannot be easily compared to snapshots of atoms from MD simulations. Here, we show that a physics-based multislice image projection algorithm accurately converts MD trajectories to simulated cryoEM 2D images and 3D reconstructions. Using this approach, we identify consistencies and discrepancies between MD simulations and cryoEM experiments. Notably, coarse-grained MD performs poorly compared to all-atom MD when simulating membranes composed of mixtures of lipids that include cholesterol and polyunsaturated lipids, providing observables for MD force field improvement.

Abstract As Alzheimer's disease (AD) research advances, tau has emerged as both a critical biomarker and a promising therapeutic target, central to understanding disease mechanisms, tracking progression, and guiding treatment development. The Fall 2024 Alzheimer's Association Research Roundtable convened experts from academia, industry, National Institutes of Health (NIH), and the United States Food and Drug Administration (FDA) to explore current progress and future directions in tau‐centered diagnostics and therapeutics. Discussions addressed the integration of tau biomarkers into the 2024 Revised Diagnostic Criteria for AD, updates to amyloid and tau positron emission tomography (PET) imaging, and modeling of biomarker trajectories. Presenters highlighted tau‐targeting therapeutics including antisense oligonucleotides, monoclonal antibodies, and small molecules, alongside innovations in drug delivery. The interplay between anti‐amyloid and anti‐tau therapies and strategic design of combination trials were key themes. Regulatory insights facilitated discussions on drug approval pathways. The meeting highlighted the rapid evolution of tau research and emphasized opportunities to improve diagnostics, trial design, and treatment strategies in AD. Highlights The Alzheimer's Association Research Roundtable (AARR) convened leaders from industry, academia, and government, to explore current progress and future directions in tau‐centered diagnostics and therapeutics. Tau has emerged as both a critical biomarker and a promising therapeutic target, central to understanding disease mechanisms, tracking progression, and guiding treatment development. Discussions addressed the integration of tau biomarkers into the 2024 revised diagnostic criteria for AD, updates to amyloid and tau PET imaging, modeling of biomarker trajectories, tau‐targeting therapeutics, and interplay between anti‐amyloid and anti‐tau therapies and strategic design of combination trials.