Citations

Background: Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterized by recurrent sinopulmonary infections due to motile cilia defects. The disease is genetically heterogeneous, with abnormalities in structural ciliary proteins. Zinc finger MYND-type containing 10 (ZMYND10) is essential for the assembly of outer dynein arms (ODA), with chaperones like Glucose-regulated protein 78 (GRP78) facilitating protein folding. This study investigates ZMYND10 and Dynein axonemal heavy chain 5 (DNAH5) mutations in individuals with PCD. Methods: Eight individuals aged 14–22 with clinical PCD symptoms and confirmed DNAH5 mutations were included. We analyzed the correlation between DNAH5 abnormalities and preassembly/chaperone proteins using immunofluorescence labeling. Nasal swabs were double-labeled (DNAH5–β-tubulin, β-tubulin–ZMYND10, β-tubulin–GRP78) and examined via fluorescence microscopy. Serum metabolomics and proteomics were also assessed. Results: The corrected total cell fluorescence (CTCF) levels of DNAH5, ZMYND10, and GRP78 were significantly different between PCD individuals and controls. Metabolomic analysis showed reduced valine, leucine, and isoleucine biosynthesis, with increased malate and triacylglycerol biosynthesis, malate-aspartate and glycerol phosphate shuttles, and arginine/proline metabolism, suggesting mitochondrial and ER stress. Conclusions: The altered expression of DNAH5, ZMYND10, and GRP78, along with metabolic shifts, points to a complex link between ciliary dysfunction and cellular stress in PCD. Further studies are needed to clarify the underlying mechanisms.

Abstract Background: Classic metaphyseal lesions (CMLs) are considered specific for child abuse, but the reliability of radiologists in distinguishing CMLs from metaphyseal variations is unclear. Objective: To evaluate whether radiologists can differentiate between CMLs and metaphyseal variations in the knees. Materials and Methods: We performed a retrospective review of distal femur and proximal tibia radiographs in children under two years of age who underwent skeletal surveys for suspected child abuse. The CML group included children diagnosed with abuse and reported CMLs. The metaphyseal variation group included children not diagnosed with abuse, with reported metaphyseal variations and either no fractures or an isolated skull fracture. Radiographs were trimmed to exclude other injuries. Four pediatric and four general radiologists reviewed anonymized studies and categorized each case as CML, metaphyseal variation, normal, or indeterminate, with confidence levels (high, moderate, low). We analyzed diagnoses with moderate or high confidence. Interobserver agreement was assessed using kappa statistics. Results: There were 48 children with CMLs (40 initial, 38 follow-up) and 27 with metaphyseal variations (20 initial, 12 follow-up). Metaphyseal fragmentation was the most common variation, identified in 259 of 356 femurs (72.8%) and 69 of 83 tibias (83.1%). Fragmentations were most frequently located in the posterior or medial metaphysis, or both, in 257 of 259 femurs (99.2%) (257/259) and 68 of 69 tibias (98.6%). In the CML group, 34 of 115 initial CML diagnoses (29.4%) were read on follow-up as either metaphyseal variation (n=17) or normal (n=17). In contrast, in the metaphyseal variation group, only one follow-up case was diagnosed as a CML; the remainder were diagnosed as metaphyseal variation (n=22) or normal (n=2). Diagnostic performance for CML demonstrated high specificity (90.7%) and positive predictive value (94.9%), with moderate accuracy (76.1%), sensitivity (70.2%), and negative predictive value (55.2%). Interobserver agreement was substantial, with a mean kappa of 0.61. Conclusion: Radiologists demonstrated substantial agreement and high specificity in distinguishing CMLs from metaphyseal variations. Metaphyseal fragmentation was the most common variation and was uncommonly diagnosed as CML on follow-up.

5064 Background: FoundationOneCDx (F1CDx) supports two FDA-approved biomarkers to guide treatment decisions for ICI for patients with mCRPC: MSI status and TMB. MSI-H and TMB-H (10+ mut/MB) have strongly overlapping prevalence. We sought to better characterize ICI outcome associations of TMB-H / non-MSI-H population and relative effectiveness of taxanes & ICI among patients who received these agents in sequence. Methods: Following a prespecified analysis plan, this study used the nationwide (US-based) de-identified Flatiron Health-Foundation Medicine mCRPC clinico-genomic database (FH-FMI CGDB), with data originating from ~280 US cancer clinics (~800 sites of care). Inclusion criteria included patients with mCRPC treated with single-agent anti-PD(L)1 therapy in the FH network between 1/1/2011 - 3/30/2024. This study used the MSI and TMB algorithms from the tissue based F1CDx. Time to next treatment (TTNT) and OS were assessed with Kaplan-Meier plots and in multivariable Cox models adjusted for ECOG performance score, socioeconomic status, prior treatment history, and baseline PSA. Among patients who received taxanes in a prior line of therapy, the effectiveness (TTNT1 vs. TTNT2) of taxane and ICI were compared. Results: Among 2995 prostate cancer tissue specimens in the database, 95 (3.1%) were MSI-H and 142 (4.7%) were TMB-H. 94 (3.1%) were MSI-H & TMB-H, 1 was MSI-H & TMB-L, and 48 (1.6%) were TMB-H & not MSI-H. Among these, 84 patients with mCRPC were treated with ICI and met inclusion criteria, including MSI-H & TMB-H (n = 30), non-MSI-H & TMB-H (n = 8), and non-MSI-H and TMB-L (n = 46). The respective median TTNT on ICI was 8.0 vs. 9.6 vs. 3 months. The respective median OS from initiation of ICI was 10.9 vs. not reached vs. 4.4 months. In multivariable models evaluating ICI only, compared to non-MSI-H & TMB-L, the MSI-H & TMB-H group had more favorable TTNT (HR: 0.20, 95%CI: 0.10 – 0.41, p < 0.001) and OS (HR: 0.33, 95%CI: 0.16 – 0.70, p = 0.004), and the non-MSI-H & TMB-H group also had more favorable TTNT (HR: 0.13, 95%CI: 0.04 – 0.45, p = 0.002) and OS (HR: 0.20, 95%CI: 0.05 – 0.75, p = 0.017). 50 of the 84 (60%) patients treated with ICI had prior mCRPC taxane treatment. Better TTNT2 on subsequent ICI vs. prior taxane was observed for MSI-H (HR: 0.49, 95%CI: 0.23 – 1.01, p = 0.051) and TMB-H (0.54, 95%CI: 0.30 – 0.98, p = 0.044), but the opposite was true for non-MSI-H and TMB-L subgroups, with significant treatment interactions for each (p = 0.0018, p = 0.00052). Conclusions: TMB-H (4.7%) is more prevalent than MSI-H (3.1%) by F1CDx in mCRPC. Non-MSI-H / TMB-H (1.6%) in the routine practice cohort have similar outcome associations on ICI to MSI-H. Both MSI-H and TMB-H by F1CDx are predictive of differential benefit for ICI vs. taxanes in later mCRPC treatment lines.

e15581 Background: Sentinel lymph node (SLN) assessment is critical in colorectal cancer (CRC) for accurate staging and determining optimal treatment strategies. The one-step nucleic acid amplification (OSNA) assay, which measures cytokeratin 19 (CK19) mRNA expression, has shown potential as a molecular diagnostic tool for the intraoperative detection of SLN metastases. This study aims to evaluate the diagnostic accuracy of OSNA for SLN metastasis in CRC. Methods: A systematic search was conducted in PubMed, Cochrane Library, and Web of Science for studies published up to December 2024. Studies reporting diagnostic accuracy metrics for OSNA in detecting SLN metastases in CRC were included. R software (version 4.0.3) with the mada package was used to compute pooled sensitivity, specificity, false-positive rates, diagnostic odds ratios (DOR), and likelihood ratios (LR), all expressed within 95% confidence intervals (CI). Results: Six studies involving 3,016 patients, of whom 363 had SLNs, were included. The pooled sensitivity of OSNA was 91% (95% CI: 84.8–94.8%), while the specificity was 95.6% (95% CI: 91.7–97.8%). The diagnostic odds ratio (DOR) was 220.59 (95% CI: 74.02–657.43). The false-positive rate was 4.4% (95% CI: 2.2–8.3%). The positive likelihood ratio (LR+) was 20.8 (95% CI: 10.5–41.2), and the negative likelihood ratio (LR−) was 0.09 (95% CI: 0.05–0.16). These findings demonstrate that in diagnostic accuracy, OSNA outperforms traditional histopathological methods, such as hematoxylin and eosin (H&E) staining. Conclusions: OSNA demonstrates superior diagnostic accuracy for detecting SLN metastases in colorectal cancer, supporting its integration into clinical workflows. Its high diagnostic accuracy and rapid intraoperative turnaround time make it an invaluable resource for improving surgical decision-making. However, variability in CK19 expression across tissues and the lack of standardized assay thresholds remain challenges that require further investigation. However, its adoption has the potential to enhance staging accuracy and improve surgical and oncological outcomes, warranting broader implementation in CRC management.

AbstractObjectiveEpilepsy is a debilitating disorder affecting more than 50 million people worldwide, and one third of patients continue to have seizures despite maximal medical management. If patients' seizures localize to a discrete brain region, termed a seizure onset zone, resection may be curative. Localization is often confirmed with stereotactic electroencephalography; however, this may require patients to stay in the hospital for weeks to capture spontaneous seizures. Automated localization of seizure onset zones could therefore improve presurgical evaluation and decrease morbidity.MethodsUsing more than 1 000 000 interictal stereotactic electroencephalography segments collected from 78 patients, we performed five‐fold cross‐validation and testing on a multichannel, multiscale, one‐dimensional convolutional neural network to classify seizure onset zones.ResultsAcross held‐out test sets, our models achieved a seizure onset zone classification sensitivity of .702 (95% confidence interval [CI] = .549–.805), specificity of .741 (95% CI = .652–.835), and accuracy of .738 (95% CI = .687–.795), which was significantly better than models trained on random labels. The models performed well across the entire brain, with top five region performance demonstrating accuracies between 70.0% and 88.4%. When split by outcomes, the models performed significantly better on patients with favorable Engel outcomes after resection or who were responsive neurostimulation responders. Finally, SHAP (Shapley Additive Explanation) value analysis on median‐normalized input data assigned consistently high feature importance to interictal spikes and large deflections, whereas similar analyses on histogram‐equalized data revealed differences in feature importance assignments to low‐amplitude segments.SignificanceThis work serves as evidence that deep learning on brief interictal intracranial data can classify seizure onset zones across the brain. Furthermore, our findings corroborate current understandings of interictal epileptiform discharges and may help uncover novel interictal morphologies. Clinical application of our models may reduce dependence on recorded seizures for localization and shorten presurgical evaluation time for drug‐resistant epilepsy patients, reducing patient morbidity and hospital costs.

Importance Nontraumatic subarachnoid hemorrhage (SAH) represents the third most common stroke type with unique etiologies, risk factors, diagnostics, and treatments. Nevertheless, epidemiological studies often cluster SAH with other stroke types leaving its distinct burden estimates obscure. Objective To estimate the worldwide burden of SAH. Design, Setting, and Participants Based on the repeated cross-sectional Global Burden of Disease (GBD) 2021 study, the global burden of SAH in 1990 to 2021 was estimated. Moreover, the SAH burden was compared with other diseases, and its associations with 14 individual risk factors were investigated with available data in the GBD 2021 study. The GBD study included the burden estimates of nontraumatic SAH among all ages in 204 countries and territories between 1990 and 2021. Exposures SAH and 14 modifiable risk factors. Main Outcomes and Measures Absolute numbers and age-standardized rates with 95% uncertainty intervals (UIs) of SAH incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) as well as risk factor–specific population attributable fractions (PAFs). Results In 2021, the global age-standardized SAH incidence was 8.3 (95% UI, 7.3-9.5), prevalence was 92.2 (95% UI, 84.1-100.6), mortality was 4.2 (95% UI, 3.7-4.8), and DALY rate was 125.2 (95% UI, 110.5-142.6) per 100 000 people. The highest burden estimates were found in Latin America, the Caribbean, Oceania, and high-income Asia Pacific. Although the absolute number of SAH cases increased, especially in regions with a low sociodemographic index, all age-standardized burden rates decreased between 1990 and 2021: the incidence by 28.8% (95% UI, 25.7%-31.6%), prevalence by 16.1% (95% UI, 14.8%-17.7%), mortality by 56.1% (95% UI, 40.7%-64.3%), and DALY rate by 54.6% (95% UI, 42.8%-61.9%). Of 300 diseases, SAH ranked as the 36th most common cause of death and 59th most common cause of DALY in the world. Of all worldwide SAH-related DALYs, 71.6% (95% UI, 63.8%-78.6%) were associated with the 14 modeled risk factors of which high systolic blood pressure (population attributable fraction [PAF] = 51.6%; 95% UI, 38.0%-62.6%) and smoking (PAF = 14.4%; 95% UI, 12.4%-16.5%) had the highest attribution. Conclusions and Relevance Although the global age-standardized burden rates of SAH more than halved over the last 3 decades, SAH remained one of the most common cardiovascular and neurological causes of death and disabilities in the world, with increasing absolute case numbers. These findings suggest evidence for the potential health benefits of proactive public health planning and resource allocation toward the prevention of SAH.