Citations

Abstract Rare Mendelian disorders affect 300-400 million people globally. Although genetic testing has become widely adopted, gene-specific evidence for tailored variant interpretation remains scattered across resources. We present Gene Portals, a framework for gene-centered multimodal knowledge bases that co-localize expert-harmonized clinical data, functional assays, population variation, structural annotations and gene-specific ACMG/AMP specifications within a single resource. A modular interface integrates this unified evidence with VCEP-refined ACMG specifications to enable automated gene-specific variant classification, infer molecular mechanisms, and support cross-gene analyses. We demonstrate the framework’s utility across five Gene portals spanning eleven neurodevelopmental disorder-associated genes, integrating data from 4,423 individuals with 2,838 unique variants, 36,149 ClinVar submissions, and 1,044 expert-curated molecular readouts. By organizing evidence that is otherwise dispersed across multiple sources into a unified, queryable framework, the SCN, GRIN, CACNA1A, SATB2 and SLC6A1 Gene Portals became widely used community resources and provide an extensible template for standardized rare-disease variant interpretation and mechanism-aware discovery.

Evidence-Based Practice (EBP) has increased the availability of psychological treatments, yet many people do not benefit from therapy, some report deteriorations in symptoms, and dropout rates remain high. Precision Mental Health (PMH) is proposed as an extension of EBP by combining systematic measurement with predictive analytics to support the right intervention, at the right time, for the right person. Recent advances in Artificial Intelligence (AI) make PMH increasingly feasible in routine psychotherapy; however, the implementation of these approaches in routine care is still incipient. In this context, the present article has two main aims. First, we summarize key advances in PMH, particularly measurement-based care and data-informed decision making. Second, we introduce the NOVA project (Navigating Outcomes via Analytics), a multi-phase translational program designed to implement PMH in real-world psychological services. Guided by the Implementing Precision Methods framework, NOVA integrates (i) stakeholder-informed work on clinician acceptability and intention to use, (ii) pragmatic evaluation of decision support tools in routine care, (iii) development of robust and interpretable predictive models, and (iv) training and dissemination activities aligned with responsible innovation and professional competencies for AI-supported precision care. By detailing NOVA’s implementation pathway, we aim to provide a concrete roadmap for bridging AI innovation and psychological practice, accelerating the sustainable adoption of PMH in real-world settings.

Importance Sex and racial or ancestral disparities in Alzheimer disease remain incompletely understood; autopsy studies that examine amyloid, tau, and genetic factors are scarce. Objective To test whether neuritic plaque burden and cognitive outcomes differ by sex and whether sex modifies the effects of apolipoprotein E ε4 ( APOEε4 ), informant-reported race, and African ancestry. Design, Setting, and Participants This was a cross-sectional study using postmortem neuropathological data from the Biobank for Aging Studies, University of São Paulo, São Paulo, Brazil. A total of 2268 autopsies from a population-based, diverse clinicopathological sample were collected between April 2004 and March 2025. Exposures Sex, informant-reported race (Black, White), African ancestry proportion, and APOEε4 carrier status. Main Outcomes and Measures Neuritic plaque burden (Consortium to Establish a Registry for Alzheimer’s Disease [CERAD] score), and cognitive function (Clinical Dementia Rating–Sum of Boxes [CDR-SB]). Ordinal logistic regression examined association of sex with CERAD scores and 2- and 3-way interactions among sex, race, ancestry, and APOEε4 ; adjusting for age, education, vascular factors, and Braak stages. Linear models related pathology to CDR-SB, adding copathologies. Results The analysis included 2268 autopsies (median [IQR] age, 74.8 [63.8-83.3] years; 1152 [51% male] and 1116 [49%] female; 802 [35%] Black and 1466 [65%] White; other race groups not included owing to small numbers); female individuals were older than male individuals and more likely to exhibit cognitive impairment (CDR global score ≥0.5). Female individuals had higher plaque burden than male individuals (unadjusted odds ratio [OR], 1.97; 95% CI, 1.67-2.29; P < .001), and this association remained significant in adjusted models for sociodemographic and vascular factors and APOEε4 status (adjusted OR, 1.65; 95% CI, 1.33-2.20; P < .001). APOEε4 carriers of both sexes had an approximately 4-fold greater odds of plaques. Significant 2-way interactions were found between sex, APOEε4 status, race, and ancestry on CERAD scores. Black noncarriers (OR, 0.47; 95% CI, 0.34-0.67) and noncarriers of African ancestry (OR, 0.57; 95% CI, 0.43-0.76) were least likely to have high plaque burden, whereas this protection was weakened in ε4 carriers. No significant 3-way interaction was detected. Among individuals with a CERAD score of 2 or higher, female individuals were more likely than male individuals to reach Braak stage V-VI than male individuals (probability ratio, 1.25; 95% CI, 1.13-1.38; P = .002). Adding Braak stage to multivariable models attenuated the female-male difference in plaques and interaction of sex and plaque on CDR-SB was no longer significant. Conclusions and Relevance The findings indicate that female sex, APOEε4 , and both race and African ancestry were jointly associated with amyloid in this study population. Excess amyloid among women may partly explain their greater tau burden and steeper cognitive decline. These findings highlight the importance of incorporating sex, race, and ancestry into biomarker thresholds, risk stratification, and the design of preventive or disease-modifying trials for Alzheimer disease.

Abstract Background Precise delineation of non-contrast-enhancing tumor (nCET) in glioblastoma (GB) is critical for maximal safe resection, yet routine imaging cannot reliably separate infiltrative tumor from vasogenic edema. The aim of this study was to develop and validate an automated method to identify peritumoral subregions compatible with nCET and assess its prognostic value. Methods Pre-operative T2-weighted and FLAIR MRI from 940 patients with newly diagnosed GB in four multicenter cohorts were analyzed. A deep-learning model segmented enhancing tumor, edema and necrosis; a non-local, spatially varying finite mixture model was applied to identify edema subregions characterized by relatively lower FLAIR hyperintensity, hypothesized to reflect nCET-related tissue. The ratio of these subregions to total edema volume defined the T2/FLAIR Heterogeneity Index (TFHI). Associations between TFHI and overall survival (OS) were examined with Kaplan–Meier curves and multivariable Cox regression. Results Higher TFHI values stratified patients with shorter OS. In the NCT03439332, TFHI above the optimal threshold was associated with a twofold increased hazard of death (hazard ratio [HR] 2.07, 95 % confidence interval 1.33-3.21; P = .0013) and a reduction in median survival of 98 days. Significant, though smaller, prognostic effects were confirmed in GLIOCAT & BraTS (HR= 1.37; P = .047), OUS (HR = 1.37; P = .0032) and pooled analysis (HR= 1.26; P = .0008). TFHI remained an independent predictor after adjustment for age, extent of resection and MGMT methylation. Conclusions We present a reproducible, server-hosted tool for automated identification of imaging-defined, putative nCET-related peritumoral subregions and TFHI biomarker extraction that enables independent prognostic stratification. This approach provides a quantitative framework for studying peritumoral heterogeneity in GB.

Abstract Aims We sought to determine whether doxorubicin affected echocardiographic parameters of right ventricular (RV) size and function when compared with guideline defined values in patients with lymphoma. Methods and results We enrolled 356 patients with lymphoma from 2013 to 2020. Patients received a mean (SD) of 5.12 (1.48) chemotherapy cycles and a cumulative, body surface area–adjusted doxorubicin dosage of 243.6 (79.6) mg/m2. Echocardiographic assessments occurred at 3 time points: T0, baseline; T1, 3 to 6 months after starting doxorubicin (mean [SD], 5.1 [1.2] months); and T2, 6 to 18 months (mean [SD], 12.98 [2.6] months) after treatment. End-diastolic area remained unchanged (P = 0.12). End-systolic area increased from 10.55 cm2 at T0 to 11.41 cm2 at T1 and 11.32 cm2 at T2 (P < 0.001). Fractional area change decreased from 46.67% at T0 to 44.35% at T1 and 44.40% at T2 (P = 0.003). Tricuspid annular plane systolic excursion decreased from 23.17 (4.14) mm to 22.39 (4.10) mm at T1, and 22.13 (3.88) mm at T2 (P = 0.006). S′ declined from 0.14 m/s at T0 to 0.13 m/s at T1 and T2 (P < 0.001). Tricuspid regurgitant velocity (P = 0.58) and RV systolic pressure (P = 0.75) showed nonsignificant changes. RV free wall strain worsened from −26.29% at T0 to −25.37% at T2 (P = 0.001). All parameters remained within guideline defined values (P < 0.001). No significant differences were noted across dosage groups: <200, 200–300, and >300 mg/m2. Conclusion Echocardiography derived parameters of right ventricular size and function remained within normal guideline-defined values throughout a follow-up of up to 12.98 ± 2.6 months.

Abstract Clinical interventions and neuroimaging in the subcortex require anatomical definitions that exceed the resolution and anatomical detail of currently available deformable brain atlases. Here, we introduce a high-resolution human brain atlas comprising 95 manually segmented grey and white matter structures as well as 82 white matter tracts compiled from a multitude of resources including ex-vivo MRI, histology, fibre dissections, and neuroanatomy textbooks. The atlas is defined at an isotropic resolution of 100 μm and can be precisely deformed to individual subject brain anatomy. By providing precise definitions of both grey and white matter structures within and around the basal ganglia, thalamus, subthalamus, midbrain and cerebellum, the atlas provides a foundational resource for stereotactic surgery and subcortical brain imaging research, as well as for development of next-generation neuromodulation strategies.

BACKGROUND: Cerebrovascular disease is prevalent in older adults and is associated with cognitive impairment. Although the association between brain infarcts and cognition has been widely investigated, the contribution of vascular disease to cognitive impairment has been less studied, particularly in non-White populations. We investigated the epidemiological and clinical characteristics of vascular disease phenotypes and their association with cognitive abilities in a diverse population. METHODS: In a Brazilian population–based clinicopathological study (recruitment between 2004 and 2024), inclusion criteria were age at death ≥18 years and the availability of an informant. Clinical information and cognitive abilities were assessed through informant interviews. Hyaline arteriolosclerosis (HA) was evaluated in 13 brain areas and categorized as absent, mild, moderate, or severe. Moderate/severe HA defined microvascular disease (Micro[+]). Intracranial atherosclerosis in the circle of Willis was similarly classified, with moderate/severe cases defining macrovascular disease (Macro[+]). Four vascular profiles were compared: Micro[+]/Macro[+], Micro[−]/Macro[+], Micro[+]/Macro[−], and Micro[−]/Macro[−]. Linear regression models adjusted for sociodemographic, clinical, and cerebrovascular/neurodegenerative lesions evaluated the association of cognition with vascular profiles, and microvascular and macrovascular diseases separately. RESULTS: Of 2418 participants, 834 with missing data were excluded, yielding a final sample of 1584 individuals (mean age, 74.3±13.4 years; 776 [49%] women; 982 [62%] White). Microvascular disease was slightly more frequent (31%) than macrovascular (29%). Regarding vascular profiles, 788 (50%) participants were Micro[−]/Macro[−], 334 (21%) Micro[+]/Macro[−], 301 (19%) Micro[−]/Macro[+], and 161 (10%) Micro[+]/Macro[+]. Micro[+] participants were older and more frequently women, and had worse cognitive abilities. Vascular groups were similar regarding most clinical comorbidities. HA (β, 0.81 [95% CI, 0.25–1.36]; P =0.004) and Micro[+]/Macro[+] phenotype (β, 1.25 [95% CI, 0.38–2.12]; P =0.005) were associated with worse cognitive abilities compared with HA-negative and Micro[−]/Macro[−] participants, respectively. CONCLUSIONS: HA was as frequent as intracranial atherosclerosis. HA and the vascular phenotype with both microvascular and macrovascular diseases were associated with worse cognition.

Background: Preparation for radioiodine (RAI) therapy in differentiated thyroid cancer (DTC) often requires thyroid hormone withdrawal (THW) to achieve thyrotropin (TSH) stimulation. Current guidelines recommend TSH ≥30 mIU/L, a target that prolongs hypothyroidism and worsens quality of life, yet rests on limited evidence. Objective: To evaluate the association between pre-RAI TSH levels and oncologic outcomes in adults with DTC prepared by THW. Methods: We conducted a systematic review and meta-analysis of studies comparing outcomes across pre-RAI TSH thresholds (<30 vs. ≥30, <60 vs. ≥60, and <90 vs. ≥90 mIU/L) in adults with DTC prepared by THW. Primary outcomes included disease-specific mortality, recurrence, and response to therapy. Searches in MEDLINE, Embase, Cochrane, and Scopus (inception to March 2025) identified eligible studies. Risk of bias was assessed using the CLARITY tool and certainty of evidence using GRADE. Pooled relative risks (RRs) were calculated using random-effects models. This systematic review was registered in PROSPERO (CRD42020158354). Results: This meta-analysis included eight retrospective cohort studies comprising a total of 4651 DTC patients, predominantly women (68.5%) with a mean age of 46 years. All patients underwent THW before RAI. Across all TSH thresholds examined (<30, <60, and <90 mIU/L), higher pre-RAI TSH levels were not associated with better treatment response, lower recurrence, or reduced mortality. Specifically, patients with higher pre-RAI TSH levels (≥30 mIU/L) did not have better oncologic outcomes compared with those with lower levels (<30 mIU/L). At 2- and 3-year follow-up, no significant differences were observed in excellent (pooled RR = 0.87; confidence interval [CI] 0.68–1.11) or indeterminate (RR = 1.28; CI 0.72–2.27) response rates. Similarly, recurrence rates did not differ (RR = 1.45; CI 0.83–2.55), and no study demonstrated a difference in disease-specific mortality across follow-up periods extending up to 10 years. The certainty of evidence for all outcomes was rated very low due to risk of bias, heterogeneity, and imprecision. Conclusions: The current evidence base is insufficient to support or refute the routine use of a specific TSH threshold before RAI administration. These findings question the recommendation to achieve TSH ≥30 mIU/L before RAI and highlight the need for trials to define the minimal effective level of TSH stimulation.