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Importance Amyloid positron emission tomography (PET) is increasingly used in research and clinical settings to determine the etiology of cognitive decline and eligibility for amyloid-targeting therapies. To assist with amyloid PET evaluation and to guide clinical decision-making, images can be quantified in a standardized unit called Centiloid, the interpretation of which can vary according to the method and threshold used. Objective To collect Centiloid values from available studies and determine robust positivity cutoffs using data-driven methods and correspondence with visual reads. Data Sources PubMed search (October 2024) identified studies with Centiloid values. Corresponding authors were invited to share individual participant data. Additional data were obtained through access-controlled repositories and conference outreach (July 2024-July 2025). Study Selection Studies were included if they provided Centiloids, radiotracer, age, and sex. Data Extraction and Synthesis Each study was analyzed using a unified statistical pipeline; study estimates were pooled using random-effects meta-analysis. Main Outcomes and Measures Gaussian mixture models (GMMs) were fitted to Centiloid values for each study. In studies with a bimodal distribution (per integrated completed likelihood), single cutoffs for positivity were set as mean plus 2 SDs of the lower gaussian component. Using GMMs, a double-cutoff approach defined a lower certainty range using a 90% posterior probability cutoff for assignment to the low (amyloid-negative) vs high (amyloid-positive) component. An alternative Centiloid cutoff was derived from maximizing the correspondence (Cohen κ) with the binary visual reads when available. Results This meta-analysis included cross-sectional amyloid PET scans acquired with 5 radiotracers from 49 227 participants across 53 studies from 15 countries (mean age, 71 years; 54% female, 62% cognitively impaired). The data-driven GMM approach identified a bimodal distribution in 51 studies (n = 48 786), resulting in a single cutoff for positivity of 18 Centiloids (95% CI,16-19; I 2 = 97%). The double-cutoff approach revealed high confidence for interpreting scans as negative when Centiloid values were lower than 11 (95% CI, 9-13; I 2 = 95%) and interpreting scans as positive if Centiloid values were higher than 26 (95% CI, 24-28; I 2 = 95%). In analyses of correspondence with binary (positive or negative) visual reads of amyloid PET scans (n = 35 045; 36 studies), Centiloids were highly predictive of visual positivity (Cohen κ, 0.86; 95% CI, 0.83-0.89; I 2 = 96%) with a cutoff of 27 Centiloids (95% CI, 24-30; I 2 = 80%). Conclusions and Relevance In this individual participant data meta-analysis, positivity cutoffs converged around 18 Centiloids (data-driven) and 27 Centiloids (visual reads). Findings from a double-cutoff analysis suggest that scans in the 11 to 26 Centiloid range should be interpreted with caution depending on the context of use.

Abstract Background and Aims EUS-guided gastroenterostomy (EUS-GE) is an effective option to palliate symptoms of gastric outlet obstruction (GOO). While the jejunum is conventionally targeted (EUS-GJ), targeting the duodenum (EUS-GD) may offer clinical advantages. Outcomes were compared for EUS-GJ and EUS-GD. Methods Adult patients who underwent EUS-GE for GOO between 2020 and 2024 were included and categorized as an EUS-GD if the stent entered the transverse or ascending duodenum or an EUS-GJ if the stent entered more distally. The primary outcome was clinical success (soft diet tolerance at 7 days). Secondary outcomes included adverse events (AEs), stent misdeployment, and unplanned endoscopic reintervention. Baseline demographic variables and outcomes were compared with statistical significance at p < 0.05. Results Of the 139 included patients (median age 67 years (IQR 61–74); 41% female), 105 underwent EUS-GJ and 34 underwent EUS-GD. Clinical success was 98% for EUS-GJ and 94% for EUS-GD (p = 0.25). The misdeployment rate was 7% for EUS-GJ and 0% for EUS-GD (p = 0.19). The AE rate was 22% for EUS-GJ and 12% for EUS-GD (p = 0.23). There were no significant differences for stent obstruction (EUS-GJ 12% vs. EUS-GD 6%), bleeding (2% vs. 6%), perforation (4% vs. 0%), stent migration (1% vs. 0%), infection (3% vs. 0%), and unplanned reintervention (14% vs. 9%). Conclusion Both EUS-GJ and EUS-GD demonstrate high clinical success with no significant differences in adverse event rates. These data can support intraprocedural decision-making for endoscopists performing EUS-GE.

Abstract Genetic studies have significantly advanced our understanding of tauopathies, yet the genetic aetiology of Pick’s disease, a rare 3-Repeat tauopathy, remains unclear. The MAPT p.A152T variant has been identified as a risk factor for Alzheimer’s disease and progressive supranuclear palsy, but its role in Pick’s disease is unknown. In this study, we examined the prevalence of MAPT p.A152T in the largest series of neuropathologically confirmed Pick’s disease cases to date (n = 401). Through genotyping, we identified a single mutation carrier in the Pick’s disease cohort (minor allele frequency = 0.12%). We previously reported MAPT p.A152T at a 0.20% frequency in healthy controls (n = 2456), suggesting that it does not associate with 3-Repeat tauopathy risk. To further investigate the effect of the variant on MAPT transcript expression, we used bulk RNA sequencing in Alzheimer’s disease and progressive supranuclear palsy A152T mutation carriers. We did not detect significant differences in 4-Repeat tau levels, though preliminary trends may indicate more nuanced effects that need to be examined with long-read sequencing in a larger series. Overall, our study suggests that MAPT p.A152T does not increase Pick’s disease risk and may instead be linked to 4-Repeat or mixed tau pathologies, warranting further functional investigation.

PURPOSE Precision medicine has revolutionized oncology; however, tumor biomarkers are not reflective of the heterogeneous cancer population. We evaluated NRG Oncology prostate cancer (PCa) clinical trials for demographic differences among patients with optional biospecimen collection (BC) consent and biospecimen submission (BSub). METHODS Data from 19 NRG PCa clinical trials closed before 2015 were analyzed. Patients who consented to BC and completed BSub were evaluated by race, ethnicity, median income, area deprivation index (ADI; categorized as highest v lowest three quartiles), age at enrollment, site, and year of enrollment. T/chi-square tests were used for continuous/categorical variables, respectively, followed by logistic regression. RESULTS Of the 15,648 randomized patients eligible for BC, 11,796 (75%) had specimens submitted. In all, 4,598 (82.2%) of 5,597 eligible patients consented for optional BC in nine clinical trials with a separate BC consent process (consent rates by race/ethnicity: 74.1% Black, 72.8% Hispanic/Latino, 83.8% White). A smaller proportion of Black and Hispanic/Latino patients consented to optional BC compared with those who did not (12.1% v 19.5% Black, P < .0001; 3.5% v 5.8% Hispanic, P = .0006). In univariable logistic regression models, high ADI (more socioeconomic disadvantage) was associated with a decreased likelihood for optional BC consent (odds ratio [OR], 0.67 [95% CI, 0.55 to 0.82]; P = .02), but not a decreased likelihood for BSub (OR, 0.74 [95% CI, 0.53 to 1.04]; P = .08). Multivariable models demonstrated that Black/Hispanic/Latino patients were less likely to consent to optional BC, and Black patients were less likely to have BSub ( P < .05 for all). CONCLUSION White/non-Hispanic patients and those with less socioeconomic disadvantage were more likely to consent to optional BC, whereas Black patients were less likely to have BSub. Targeted solutions are needed to improve biorepository representation so that precision medicine approaches better reflect the cancer population.

Primary enlargement of the cerebrospinal fluid (CSF)–filled brain ventricles, known as congenital cerebral ventriculomegaly (CCV), is a hallmark of congenital hydrocephalus. CCV is also enigmatically but frequently associated with autism and other neurodevelopmental disorders. To gain insight into the developmental genetic regulation of the human CSF-ventricular system, we conducted an integrated, multiomic study of about 2700 trio-based exomes from patients with primary CCV. We found that about 25% of cases were associated with rare, damaging de novo variants in mutation-intolerant genes, many of which are linked to other dominant Mendelian disorders. Thirty-five exome-wide significant CCV genes and dozens of other high-confidence CCV genes converged on pathways involved in ATP-dependent Brahma-related gene 1/Brahma-associated factor chromatin remodeling, histone H3 lysine 4 methylation, and phosphoinositide 3-kinase signaling. Knockout of selected CCV genes in mouse models supported that de novo variants in CCV genes caused ventriculomegaly by impairing both CSF dynamics and cortical cytoarchitecture through dysregulation of neuroprogenitor cell growth and maturation in the ventricular and subventricular zones. These findings indicated that genetic and epigenetic programs coordinate the “hand-in-glove” development of the CSF-ventricular system with that of the cerebral cortex and establish a genetic connection between CCV and neurodevelopmental disorders, potentially explaining why some patients with hydrocephalus continue to exhibit CCV and neurodevelopmental disorders despite CSF shunting. We suggest that combined brain imaging and whole-exome sequencing could enable early detection of, and intervention for, autism and other neurodevelopmental disorders.

Glioblastoma (GBM) is a devastating cancer with a dismal prognosis. Current treatment includes temozolomide (TMZ), which is more effective in about 50% of GBMs that have O 6 - methylguanine DNA methyltransferase ( MGMT ) promoter methylation. MGMT is a DNA repair protein that reverses TMZ-induced DNA damage. EGFR is a prime oncogene in GBM. Here, we report that EGFR inhibition induced the down-regulation of MGMT in GBM cells, revealing a previously unidentified link between EGFR signaling and response to TMZ. EGFR inhibition led to activation of two transcription factors, activator protein-1 (AP-1), which repressed MGMT transcription, and nuclear factor κB (NF-κB), which up-regulated MGMT transcription. EGFR inhibition also induced AP-1–mediated transcription of miR-616. miR-616 inhibited both MGMT translation and NF-κB activation. Thus, the overall effect of EGFR inhibition was down-regulation of MGMT expression. In addition, we provided an explanation for the prior failure of clinical trials that used concomitant EGFR tyrosine kinase inhibitors (TKIs) and TMZ. TMZ up-regulated MGMT, and concomitant treatment with EGFR TKIs and TMZ failed to down-regulate MGMT. However, pretreatment with EGFR TKIs followed by TMZ efficiently down-regulated MGMT and enhanced TMZ sensitivity in experimental models. Posttreatment tumor tissues from two clinical trials were used to validate these findings. We demonstrated that EGFR inhibitors induced down-regulation of MGMT in posttreatment resected tumor tissues from patients with GBM and the failure of EGFR inhibition to down-regulate MGMT if TMZ was used concomitantly. These data support using EGFR TKIs before TMZ treatment as a therapeutic approach in MGMT unmethylated GBM.

SignificanceCurrent clinical care following ischemic stroke provides intermittent assessments, potentially missing early detection of neurological deterioration. Optical imaging offers the potential for a continuous, portable alternative to the current combination of physical exams and radiological imaging. However, optical imaging technology has lacked the crucial combination of portability, resolution, and coverage required to assess spatially distributed brain function.AimHere, we present a proof-of-principle study that applies recent advancements in portable high-density diffuse optical tomography (HD-DOT) instrumentation and a functional connectivity analysis strategy to assess spatially distributed brain connectivity. Point-of-care brain health assessments with these tools may inform clinical care and our understanding of brain injury throughout acute stages of stroke recovery.ApproachWe measured spatially distributed cortical oxygenation with HD-DOT within the intensive care unit in N=13 patients with ischemic stroke within the first 72-h since last known normal. To assess brain function integrity, we developed a Similarity metric of functional connectivity (FC) through comparisons to FC in a healthy young adult population. To assess the sensitivity of this FC Similarity metric to disruptions caused by stroke, we compared these data with FC Similarity assessed in an older healthy cohort. We administered the NIH Stroke Scale to stroke patients to evaluate the potential of the FC Similarity metric to inform the severity of functional disruptions.ResultsThe FC Similarity metric applied to HD-DOT data in both acute stroke patients and healthy older controls exhibited a significant sensitivity to the presence of a stroke (Cohen’s d=1.5, p=1.2×10−3) and a significant relationship with the degree of neurological disruption as measured by the NIH Stroke Scale (R2=0.69, p=4.7×10−4).ConclusionsWe present a proof-of-principle for HD-DOT and the FC Similarity metric for assessing brain function during the acute stage of ischemic stroke recovery at the point-of-care.

Importance Risk-reducing salpingo-oophorectomy (RRSO) is an effective option to prevent ovarian cancer in high-risk individuals, but adverse effects from premature menopause are a barrier to uptake. Interval salpingectomy with delayed oophorectomy (ISDO) may be an effective alternative. Objective To evaluate the association of ISDO vs RRSO and sexual function and menopausal symptoms. Design, Setting, and Participants This prospective, multicenter, nonrandomized (patient preference) clinical trial was performed among Women Choosing Surgical Prevention participants with a pathogenic or likely pathogenic germline variant conferring an increased risk for ovarian cancer. Patients from 9 US centers were enrolled from June 2, 2016, to October 28, 2020; chose ISDO or RRSO; and were followed up for 24 months. The analysis was performed on November 13, 2024. Interventions Participant-selected RRSO or ISDO. Main Outcomes and Measures Changes in sexual function and menopausal symptoms from baseline to 6, 12, and 24 months. Inverse probability weighting was applied to achieve covariate balance across groups. Results The analytic sample included 334 female participants (mean [95% CI] age at consent, 39.2 [38.7-.9.7] years) who underwent RRSO (n = 165) or ISDO (n = 169) and completed 6-month questionnaires. Significantly more participants experienced clinically meaningful worsening of sexual function at 6 months compared with baseline after RRSO vs ISDO (33.1% [39 of 118] vs 16.8% [17 of 101], respectively; odds ratio, 2.00 [95% CI, 1.20-3.35]) and at 12 months (39.2% [38 of 97] vs 18.3% [17 of 93], respectively; odds ratio, 1.69 [95% CI, 1.09-2.63]). This finding was no longer significant at 24 months. When restricted to the RRSO group who took hormone replacement therapy, there was no significant worsening of total sexual function scores or menopausal symptoms compared with baseline. No interval ovarian cancers were reported. Conclusions and Relevance This nonrandomized clinical trial comparing RRSO with ISDO found that ISDO was less likely to impair sexual function, which addresses an important barrier to surgical prevention in high-risk patients in premenopause. After RRSO, use of hormone replacement therapy mitigated menopausal symptoms and prevented decline in sexual function. More information is needed about the safety of ISDO. Trial Registration ClinicalTrials.gov Identifier: NCT02760849