Citations

Abstract Context Salivary cortisol and cortisone provide non-invasive measures of biologically active cortisol, but their performance during dynamic testing remains incompletely defined. The utility of salivary dexamethasone to confirm exposure during dexamethasone suppression testing (DST) is unknown. Objective To compare salivary cortisol, cortisone, and dexamethasone with serum measurements during dynamic adrenal testing and to derive salivary cortisol and cortisone thresholds corresponding to clinically relevant serum cortisol concentrations. Design and Setting Cross-sectional study at a tertiary referral center. Participants Adults undergoing DST (n = 473), cosyntropin stimulation testing (CST; n = 163), or overnight metyrapone testing (OMT; n = 11). Measurements Serum cortisol was measured by immunoassay. Serum and salivary dexamethasone, salivary cortisol and cortisone were quantified by liquid chromatography–tandem mass spectrometry. Results Among 640 participants, 815 paired serum and salivary samples were analyzed. Salivary cortisol and cortisone correlated well with serum cortisol across dynamic testing, with the greatest difference following 1-mg DST (r = 0.86 vs 0.53 for cortisone and cortisol, respectively; both P < 0.001). During CST, correlations ranged from r = 0.75–0.87 for both analytes (all P < 0.001). Salivary dexamethasone correlated with serum dexamethasone (r = 0.61, P < 0.001). Salivary cortisone thresholds corresponding to prespecified clinically relevant serum cortisol concentrations of 1.8, 5, 10, and 18 µg/dL (50, 138, 276, and 497 nmol/L) were 117, 329, 585, and 1262 ng/dL (3.25, 9.13, 16.23, and 35.01 nmol/L), respectively; corresponding salivary cortisol thresholds were 16.5, 38, 80, and 278 ng/dL (0.46, 1.05, 2.21, and 7.67 nmol/L). Conclusions These findings support saliva-based dynamic adrenal testing and identify clinically relevant salivary thresholds.

Abstract Background Immigrant women experience disproportionate psychosocial stress driven by acculturation, socioeconomic hardship, discrimination, and transnational responsibilities. Despite evidence supporting culturally tailored stress‑management interventions, limited formative research has examined program preferences across diverse immigrant communities. Methods Using a community‑based participatory research (CBPR) approach, we conducted three language‑concordant focus groups (Somali, Spanish, English; n = 18) and a mixed‑methods survey (n = 88) with immigrant women in southeast Minnesota. Qualitative data were analyzed using constant comparative methods; quantitative data were summarized descriptively. Results Participants described intersecting stressors including caregiving burdens, financial insecurity, immigration‑related fears, bicultural identity strain, and transnational obligations (e.g., “Every day you are being told of problems back at home”). Barriers to discussing stress included stigma, limited culturally concordant care, religious norms discouraging emotional disclosure, and structural constraints such as lack of insurance (e.g., “How are you gonna pay for a therapist if you don't have health insurance?”). Coping strategies varied culturally but consistently emphasized social support, spirituality, and practical stress‑reduction techniques. Survey findings indicated strong preference for education on stress, stigma reduction, culturally and linguistically aligned support groups, and flexible delivery formats (in‑person, hybrid). Conclusions Immigrant women experience multifaceted stress shaped by minority stress processes and structural inequities. Findings highlight the need for culturally responsive, community‑informed stress‑management interventions that integrate education, social support, and flexible delivery modalities. These results directly inform adaptation of a stress‑management program for Somali, Spanish‑, and English‑speaking immigrant women.

ABSTRACT Background Radiotherapy is a cornerstone of treatment for pediatric central nervous system (CNS) tumors, but dose selection remains uniform despite interpatient variability in tumor radiosensitivity. This is consequential in children, for whom toxicity can have lifelong effects. Genomic-adjusted radiation dose (GARD) integrates tumor genomics with delivered radiation dose to quantify the biological effect of radiotherapy and has been validated across adult malignancies. Its relevance in pediatric CNS tumors is unknown. Methods We performed a cohort study using gene expression and data from 246 pediatric patients with high-grade glioma, medulloblastoma, or ependymoma from the Children’s Brain Tumor Network. GARD was calculated using a sequencing-adapted radiosensitivity index integrated with radiation dose through the linear–quadratic model. Associations of GARD and physical radiation dose with event-free and overall survival were evaluated using Cox proportional hazards models stratified by tumor type and anatomic location. Patients who did not receive radiotherapy comprised a negative control cohort (sham-GARD). Results Among patients receiving radiotherapy, physical dose was uniform, whereas GARD showed substantial interpatient variability in biological effect. Higher GARD was associated with improved event-free survival (hazard ratio [HR] 0·90, 95% CI 0·83–0·97; p=0·004) and overall survival (HR 0·90, 95% CI 0·83–0·99; p=0·018). Physical dose was not associated with either endpoint. Among patients who did not receive radiotherapy, sham-GARD was not associated with outcomes, supporting GARD as a treatment-specific predictor rather than a prognostic biomarker. Conclusions In pediatric CNS tumors, the biological effect of radiotherapy quantified by GARD was associated with outcomes, whereas physical dose was not. These findings challenge uniform radiotherapy dosing and support genomically informed dose individualization. Prospective evaluation of GARD-guided radiotherapy is warranted to optimize tumor control while minimizing long-term toxicity in children.

Abstract Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two related neurodegenerative disorders that display overlapping features. The hexanucleotide repeat expansion GGGGCC (G 4 C 2 ) in the C9ORF72 gene is the most common cause of ALS and FTD, which results in the accumulation of dipeptide-repeat protein aggregates. Regulation of protein synthesis at the level of the initiation factor eIF2α has been suggested as a transversal event contributing to neurodegeneration in ALS and FTD. eIF2α phosphorylation blocks protein synthesis to alleviate protein misfolding overload, but conversely it can reduce the expression of synaptic proteins resulting in neuronal dysfunction. Dibenzoylmethane (DBM) is a small molecule that reverses the translational attenuation mediated by eIF2α phosphorylation which has been shown to alleviate neurodegeneration in prion-infected mice and Tau transgenic animals. Here we investigated the efficacy of the oral administration of DBM in protecting a mouse model of C9ORF72 pathogenesis. Treatment of mice with 0.5% of DBM mixture in powdered food ad libitum was sufficient to prevent cognitive impairment in C9ORF72 mice. Unexpectedly, DBM treatment did not modify the content of poly(GA) and poly(GR) protein inclusion in the hippocampus and brain cortex. Proteomic profiling of brain tissue indicated that DBM administration corrected nearly 70% of the changes in gene expression triggered by expanded G 4 C 2 , where the main pathways modified by DBM were related to cytoskeleton organization, ALS, and metabolic processes. Most proteins corrected by DBM in our C9ORF72 model were also altered in the brain of human FTD/ALS patients. Overall, our results reinforce the idea that targeting protein synthesis with small molecules in patients carrying C9ORF72 mutations may result in improved cognitive capacity.

Background: Noninvasive tests are well validated in metabolic dysfunction–associated steatotic liver disease, but evidence in metabolic dysfunction and alcohol-associated liver disease (MetALD) and alcohol-associated liver disease (ALD) is limited. We evaluated noninvasive test–based clinical care pathways for fibrosis risk stratification in MetALD and ALD. Methods: This is a multinational, multicenter, cross-sectional study across 35 centers in 16 countries (2013–2025), including adults with MetALD or ALD. Fibrosis was assessed by liver biopsy and/or vibration-controlled transient elastography (VCTE). In biopsy-proven participants, we analyzed the sequential pathway (Fibrosis-4 [FIB-4] first, followed by VCTE for indeterminate FIB-4) to identify advanced fibrosis (≥F3). Diagnostic accuracy was assessed using the AUC. Results: Among 893 participants (41.3% MetALD and 58.7% ALD), the median age was 52 [43.0–61.0] years, and 79.4% were male. The estimated prevalence of advanced fibrosis was 45% (32.2% in MetALD and 54.0% in ALD). Participants with MetALD had a more dysmetabolic profile but lower fibrosis stages than ALD. Among biopsy-proven participants, FIB-4 AUC was 0.720, and VCTE AUC was 0.833. FIB-4 performed better in MetALD than ALD (AUC 0.773 vs. 0.540), while VCTE accuracy was similar across groups. In the sequential pathways, the false-negative rate for advanced fibrosis (misclassified as low risk) was 6.8% (4.9% MetALD and 11.3% ALD). Conclusions: In biopsy-proven patients, FIB-4 performance was acceptable in MetALD but substantially weaker in ALD. The standard 2-step pathway performed adequately in MetALD but missed a clinically meaningful proportion of advanced fibrosis in ALD.

Acute cholecystitis affects ∼200,000 individuals annually in the United States, with laparoscopic cholecystectomy as the gold standard treatment. However, in high-risk surgical candidates, alternative drainage methods are necessary. Percutaneous transhepatic gallbladder drainage (PT-GBD) has traditionally served as the primary alternative intervention, offering rapid decompression, but is limited by a negative impact on the patient’s quality of life, the risk of long-term or even permanent tube placement, adverse events, and high recurrence rates. Endoscopic approaches, such as endoscopic transpapillary gallbladder drainage (ET-GBD) and, more recently, endoscopic ultrasound-guided gallbladder drainage (EUS-GBD), have emerged as viable alternatives to PT-GBD. EUS-GBD, first introduced in 2007, offers technical and clinical outcomes comparable to PT-GBD with fewer adverse events, shorter hospital stays, and lower rates of recurrence. The introduction of lumen-apposing metal stents (LAMS) has revolutionized EUS-GBD, simplifying deployment and enabling subsequent internal gallbladder access, which allows additional interventions such as cholecystoscopy and stone removal. EUS-GBD is now supported by international guidelines, and 1 device has achieved FDA approval for the management of acute cholecystitis in nonsurgical candidates. Proper patient selection is essential, guided by multidisciplinary evaluation, with EUS-GBD contraindicated in specific scenarios such as gallbladder perforation, coagulopathy, and large-volume ascites. Technical considerations include choice of access site (transgastric versus transduodenal), stent type, and procedural route [direct (freehand) or wire-guided]. Postprocedural care and stent management remain variable and nonstandardized. Emerging data suggest that interval cholecystectomy can still be performed safely after EUS-GBD. As adoption of EUS-GBD with LAMS expands, structured training and standardization of practice are crucial to optimizing outcomes.

BACKGROUND Malignant peripheral nerve sheath tumors (MPNSTs) are malignant tumors that rarely demonstrate heterologous differentiation from angiosarcomatous components. These lesions can be hard to accurately diagnose. OBSERVATIONS A 25-year-old man with neurofibromatosis type 1 and a history of a left lumbar subcutaneous MPNST developed a lung metastasis of only the angiosarcoma component of the MPNST. Prior to H3K27me3 staining of the lung mass, there was no association of the angiosarcoma with the MPNST. Reinterpretation of the lumbar subcutaneous MPNST led to the identification of a previously unrecognized angiosarcomatous portion in that tumor as well. LESSONS This case highlights the importance of using H327me3 staining for accurate diagnosis of biopsies only capturing the heterologous components of MPNST. https://thejns.org/doi/10.3171/CASE251012

ABSTRACT Airway perforation is a potentially lethal complication from tracheal or mediastinal malignancies that require complex management. Advanced thyroid cancer is known to have high morbidity, and patients with tracheal metastatic lesions are vulnerable to injury. Therapeutic management typically comprises a combination of surgical and nonoperative treatment modalities, whose adverse effects can lead to significant airway injury. We present the case of a 67‐year‐old man with papillary thyroid carcinoma who developed a tracheocutaneous fistula following proton beam therapy and chemotherapy for metastatic disease. Airway repair and recanalization were successfully achieved through a combined surgical and bronchoscopic approach.