Citations

Importance Amblyopia is the leading cause of monocular decreased best-corrected vision in children. Early detection and intervention are key for optimal treatment outcomes; however, limited access to pediatric eye specialists may hinder timely care and affect visual outcomes. Given the shortage of specialty-trained eye care professionals in the US, there is need to support comprehensive eye care professionals who are willing to examine and treat children with amblyopia. Objective A panel from the Pediatric Eye Disease Investigator Group synthesized relevant literature and incorporated consensus opinion where direct evidence was lacking to create the Amblyopia Navigator Decision-Support Instrument, a free, web-based amblyopia decision support tool for eye care professionals. Evidence Review The decisions related to optimal diagnostic measures, pass/refer criteria, and management recommendations were informed by 147 publications. In areas where direct evidence was lacking, guidance was supplemented with clinical trial protocols or existing professional guidelines. When data were conflicting or unavailable, recommendations were established through committee consensus. A single reviewer independently performed standardized (though not systematic) literature reviews to avoid missing pertinent recent publications. Findings Presented are the process used, supporting evidence, and recommendations for testing methods, refractive correction, amblyopia treatment options, treatment adjustments, and monitoring schedules. Conclusions and Relevance Because amblyopia is common and typically responds well to treatment, decision support tools that optimize its management could increase access to pediatric eye care by facilitating earlier detection, enabling broader participation of primary eye care professionals, and ultimately improving visual outcomes. Through this work and the development of the forthcoming free, web-based application version, Amblyopia Navigator Decision-Support Instrument, the Pediatric Eye Disease Investigator Group has created decision support tools designed to assist optometrists and ophthalmologists in the care of children aged 3 to 17 years with amblyopia.

Objective Positive α‐synuclein seed amplification assay (SAA) is a biomarker found in most people with Parkinson's disease (PD). We explored if free‐water (FW) imaging detects microstructural differences in the brains of patients with early PD with SAA+ or SAA– status. Methods We studied patients with PD with baseline diffusion imaging and α‐synuclein SAA data from the Parkinson's Progression Markers Initiative (PPMI). We compared FW, FW corrected fractional anisotropy (FA T ), and clinical characteristics between SAA+ and SAA– groups. We also applied the Automated Imaging Differentiation for Parkinsonism (AIDP) at baseline to classify PD versus atypical parkinsonism, stratified by SAA status. Results Among 462 participants (41 SAA– and 421 SAA+), individuals with SAA+ had hyposmia and shorter motor symptom duration before baseline magnetic resonance imaging (MRI). AIDP identified PD in 92.4% (n = 427, 91.6% had SAA+) and classified 7.6% as atypical parkinsonism (n = 35, 85.7% had SAA+). At baseline, SAA+ individuals had lower FW in the superior cerebellar peduncle, compared to SAA– (pFDR < 0.05). No significant differences in FA T were found between groups. Interpretation Positive α‐synuclein SAA was associated with focal microstructural differences but did not distinguish broader diffusion MRI (dMRI) changes across FW and FA T metrics. These findings indicate that molecular confirmation of synuclein aggregation (via SAA) provides limited stratification of neurodegeneration detected by FW imaging in early PD. ANN NEUROL 2026;100:295–304

Abstract The genetic contributions of the X chromosome to Alzheimer’s disease (AD) remain poorly understood yet are expected to importantly shape sex differences in AD. We therefore performed large-scale X-chromosome-wide association studies (N=1,240,451), evaluating differential risk due to sex, APOE *4, and escape from X-chromosome inactivation, finding most X-linked loci appear relevant to female-biased AD etiology. In evaluating genetic pleiotropy with hormonal, lipid, and brain imaging traits, we discovered X-linked AD loci converged on white matter traits, particularly in the anterior corona radiata and splenium of the corpus callosum. Through brain-centric functional genomics analyses, we then nominated candidate causal genes, including 5 that appeared highly robust. Notably, we found the escape gene RBBP7 decreases AD risk in APOE *4 carriers likely through higher expression in excitatory neurons to counter tau-related neurodegeneration. Altogether, we provide an atlas of sex and APOE *4-informed candidate X-linked AD risk loci, genes, and mechanisms that will guide future studies.

Background: Considering the pathophysiological importance of the intestine-passing microbiota, we hypothesized that the mutational and microbial profiles of colorectal cancer might gradually change along detailed anatomical locations and that these trends might differ by the age of diagnosis and the microsatellite instability (MSI) status. Methods: We assessed somatic mutations and selected bacterial species in colorectal carcinomas along the cecum, ascending colon, transverse colon, descending colon, sigmoid colon, and rectum, utilizing targeted sequencing data ( N = 5685) from the Genetics and Epidemiology of Colorectal Cancer Consortium and tissue microbial data ( N = 1389) from the Health Professionals Follow-up Study and Nurses’ Health Study. Results: There were decreasing trends from the cecum to rectum in the prevalence of gene mutations in the IGF/PI3K, receptor tyrosine kinase (RTK)/RAS, TGFB, and WNT signaling pathways (all P trend < 0.0001), as well as high levels of Bacteroides fragilis ( P trend < 0.0001) and high levels of Fusobacterium nucleatum ( P trend = 0.0029) (but not enterotoxigenic Bacteroides fragilis or pks+ Escherichia coli ). Conversely, TP53 pathway mutations showed an increasing cecum-to-rectum trend ( P trend < 0.0001). Similar to later-onset cases diagnosed at ages 50 years and older, in early-onset cases diagnosed under the age of 50 years, we found generally decreasing cecum-to-rectum trends of IGF/PI3K, RTK/RAS, TGFB, and WNT pathway mutations and an increasing cecum-to-rectum trend in TP53 pathway mutations. By contrast, the cecum-to-rectum prevalence-changing trends in IGF/PI3K, RTK/RAS, TGFB, and TP53 pathway mutations were present in non–MSI-high tumors but not in MSI-high tumors (all P interaction < 0.0052). Conclusion: Non–MSI-high colorectal cancers exhibited decreasing cecum-to-rectum trends of IGF/PI3K, RTK/RAS, and TGFB pathway mutations (and an increasing trend of TP53 pathway mutations), in contrast to MSI-high tumors that demonstrated no such trends. Our study highlights the importance of detailed colorectal subsite information combined with tumor molecular and microbial characteristics in colorectal cancer research.

ABSTRACT Objective Automated insulin delivery (AID) has been established as an effective therapy for individuals with type 1 diabetes. This analysis evaluates the clinical and economic outcomes of AID compared with multiple daily injections plus continuous glucose monitoring (MDI/CGM) in adults with type 2 diabetes. Materials and Methods The IQVIA CORE Diabetes Model v10.0 was employed to simulate the impact of using the t:slim X2 insulin pump with Control‐IQ+ technology (Control‐IQ+) versus MDI/CGM over a 50‐year period using data from the 2IQP randomized controlled trial (NCT05785832). Trial data informed cohort demographics, intervention effects and resource utilization while literature sources provided health state utilities and costs. Scenario analyses examined the effect of Control‐IQ+ on reducing HbA1c based on alternative HbA1c progression estimates from the Swedish National Diabetes Registry and alternative resource use and treatment effects from real‐world evidence. Results The base case analysis indicated that direct medical costs per individual for type 2 diabetes management with Control‐IQ+ were $239 935 compared to $209 792 with MDI/CGM use. Control‐IQ+ resulted in 0.51 additional quality‐adjusted life years (QALYs: 10.36 vs. 9.85 for MDI/CGM), yielding an incremental cost‐effectiveness ratio (ICER) of $59 417 per QALY, 95% CI: ($55 836, $62 998). In probabilistic sensitivity analyses, 89% of simulations produced ICERs below $100 000/QALY. ICERs across all scenarios remained below $100 000 per QALY. Conclusions Control‐IQ+ is associated with increased life expectancy, higher QALYs and reduced complication rates. These findings suggest that Control‐IQ+ is cost‐effective relative to MDI/CGM for managing patients with type 2 diabetes in the United States.

Abstract Alzheimer’s disease (AD) is a multifactorial disease with mixed pathologies. Consequentially, drugs targeting multiple pathological processes may offer synergistic benefits. While histone deacetylase (HDAC) inhibitors have demonstrated efficacy in alleviating AD-related pathologies in animal models, the neuroprotective Wnt/β-catenin signaling pathway remains compromised in AD brain. CI-994 is a class I HDAC inhibitor containing N-(2-aminophenyl)-benzamide. Our recent studies indicate that CI-994 is also an activator of Wnt/β-catenin signaling by stabilizing Wnt co-receptor LRP6. We herein use CI-994 as a scaffold to develop novel potent dual modulators of class I HDACs and Wnt/β-catenin signaling for AD therapy. Our lead compound, W2A-28, selectively inhibits class I HDAC1, 2 and 3 with IC 50 values of 0.51 μM, 0.68 μM, and 0.22 μM, respectively, and shows no inhibitory activities on other HDACs. Furthermore, W2A-28 potently activates Wnt reporter activity with an EC 50 value of 1.61 μM in Wnt-3A-expressing HEK293 cells. As expected, activation of Wnt/β-catenin signaling by W2A-28 is associated with elevated LRP6 protein level. Importantly, W2A-28 displays excellent microsomal stability in both mouse and human liver microsomal stability assays, alongside high permeability and a lack of active efflux in MDR1-MDCKII models. Critically, W2A-28 treatment significantly enhances histone acetylation, activates Wnt/β-catenin signaling, and suppresses tau phosphorylation in AD patient-specific cerebral organoids carrying APOE ε4/ε4 or APOE ε3/ε4 with PSEN1 M146V mutation. Our findings position W2A-28 as a promising multi-target drug candidate for AD therapy.

Among patients with treatment-naive hepatocellular carcinoma, glass microsphere radiation segmentectomy before liver transplant achieved high rates of complete pathologic necrosis, which was positively associated with the number of optimized treatment parameter thresholds.

Abstract Expression quantitative trait locus (eQTL) mapping is used to identify the functional link between a genomic variant and a gene’s expression. A significant eQTL association does not mean a causal relationship or mechanism, and further investigation is needed to understand how a single-nucleotide polymorphism (SNP) impacts gene expression. One of the most plausible explanations for eQTL is that a genomic variant affects transcription factor (TF) binding and thus impacts its regulation on target genes (TGs). However, the current eQTL model does not provide information on the TF and how its regulation is mediated by the SNP’s genotypes. Here, we propose a new method called differential co-expression QTL (ceQTL) among different alleles using Chow statistics to specifically detect eQTLs that are bound by a particular TF. We start with building a trio of TF, its TG, and related SNP, and then test the significant coefficient difference among different genotypes of the SNP. We applied this ceQTL model to simulated data and the lung tissue datasets from the genotype-tissue expression project. The simulated data results showed that the model was robust to detect true ceQTLs at variable sample sizes and different minor allele frequencies as measured by area under the curve. Our tool also performed a TF binding affinity analysis to add another layer of evidence for functional interpretation. In summary, ceQTL analysis provides a more interpretable and biological insight into the mechanism of eQTL and transcriptomic regulation, which would help us better understand how genomic variants affect phenotypes and diseases.